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非小细胞肺癌治疗(PDQ®)

非小细胞肺癌（NSCLC）的基本信息

NSCLC是除小细胞肺癌（SCLC）之外的其余上皮性肺癌。 最常见的NSCLC为鳞状细胞癌、大细胞癌和腺癌，但也有其他发病率较低的类型，所有类型都可以发生少见的组织学变异。 虽然NSCLC与吸烟相关，但从不吸烟的人群也会发生腺癌。与SCLC相比，NSCLC对化疗和放疗的敏感性相对较低。可切除性肿瘤患者可以通过手术或手术加化疗治愈。很多不可切除性肿瘤患者可通过放疗达到局部控制效果，但只有少数患者能治愈。局部晚期不可切除性肿瘤患者可通过放疗联合化疗长期生存。晚期转移性肿瘤患者可通过化疗、靶向药物与其他支持性治疗延长生存期、缓解症状。

发病率与死亡率

据估计，2020年美国肺癌（NSCLC与SCLC）新发病例和死亡病例数分别为：

  • 新发病例：228,820。
  • 死亡病例：135,720。

    • 在美国，肺癌是癌症相关死亡的首要原因。

    从1995年到2001年，肺癌患者的5年相对生存率为15.7%。患者5年相对生存率与诊断分期有显著关联性，局部、区域和远端转移肿瘤的5年相对生存率分别为49%、16%与2%。

    据估计，2015年中国肺癌新发病例和死亡病例分别为：

  • 新发病例：78.7万。
  • 死亡病例：63.1万。

    • 在中国，肺癌是首位恶性肿瘤死亡原因。

    从2012年到2015年，中国肺癌患者年龄标化的5年生存率为19.7%。

    解剖

    NSCLC来源于中心支气管到终末肺泡的肺上皮细胞。 NSCLC的组织学类型与原发部位相关，反映了支气管到肺泡的呼吸道上皮变化。 鳞状细胞癌通常来源于中心支气管附近。腺癌和支气管肺泡癌通常来源于周围肺组织。

    呼吸系统的解剖。

    发病机制

    吸烟相关肺癌变是一个多步骤过程。鳞状细胞癌与腺癌有明确的癌前病变。在具有侵袭性之前，肺上皮可能经过下列形态变化：

  • 增生。
  • 化生。
  • 异型增生。
  • 原位癌。

    • 异型增生和原位癌是主要的癌前病变，因为它们更容易进展为浸润性癌，自行消退的可能性较小。

    此外，肺癌切除术后，每年患者有1%到2%几率再次罹患肺癌。

    病理学

    NSCLC具有多种不同的组织学类型。最常见的组织学类型包括：

  • 表皮样癌或鳞状细胞癌。
  • 腺癌。
  • 大细胞癌。

    • 由于诊断、分期、预后和治疗方法相似，这些组织学类型通常一同分类。

    危险因素

    年龄增长是大多数癌症发生的最重要危险因素。肺癌的其他危险因素包括:

  • 既往或当前吸烟史：香烟、烟斗烟和雪茄烟。
  • 暴露于二手烟中的致癌物质。
  • 职业性暴露于石棉、砷、铬、铍、镍等物质。
  • 下列任何一项的辐射暴露:
  • 乳房或胸部放疗。
  • 家庭或工作场所中的氡暴露。
  • 医学影像学检查，如计算机断层扫描（CT）。
  • 原子弹辐射。
  • 生活在空气污染的地区。
  • 肺癌家族史。
  • 人类免疫缺陷病毒感染。
  • 重度吸烟者的β-胡萝卜素补充剂。

    • 肺癌发生的一个最重要的危险因素是吸烟。吸烟者的肺癌风险平均为终生非吸烟者（终生吸烟<100支）的10倍。随着吸烟数量和吸烟时间增加、开始吸烟年龄减小，肺癌危险也增加。

    戒烟引起癌前病变减少，发生肺癌的风险也下降。既往吸烟者在戒烟后数年肺癌风险仍偏高。石棉暴露与吸烟对肺癌风险可能具有协同效应。

    预防

    许多吸烟相关肺癌治愈患者可能再次罹患恶性肿瘤。在美国肺癌研究组试验907例T1N0可切除性肿瘤患者中，每年非肺部第二癌症发生率为1.8%，每年新肺癌发生率为1.6%。

    其他研究曾报道过长期生存者第二肿瘤风险增高，其中第二肺癌发生率为10%，所有第二癌症总发生率为20%。

    由于有吸烟史的患者肺癌复发的风险持续较高，许多随机对照临床研究为此评估了多种化疗预防方案。但在目前的III期临床研究中，尚无关于β胡萝卜素、视黄醇、13-顺式维甲酸、α生育酚、N-乙酰半胱氨酸或乙酰水杨酸有阳性、可重复性的结果。

    [证据等级：1iiA]针对早期的肺癌患者，预防上呼吸消化道出现第二原发性肿瘤的化疗预防方案正在进行临床评估。

    （如需了解更多信息，请参见PDQ肺癌预防总结。）

    筛查

    在被认为是肺癌高危患者的人群中，早期发现的唯一筛查方法是低剂量螺旋CT扫描。

    胸部影像和痰细胞学筛查肺癌研究未能证明筛查能降低肺癌死亡率。

    （如需了解更多信息，请参见PDQ肺癌筛查总结中的低剂量螺旋计算机断层扫描筛查。）

    临床特征

    肺癌可能出现症状或在胸部影像学上偶然发现。 症状与体征的产生可能来自原发性局部侵犯或对邻近胸腔结构的压迫、远端转移或副肿瘤综合征。发病时最常见的症状为咳嗽加重或胸痛。其他症状包括：

  • 咯血。
  • 乏力。
  • 体重下降。
  • 呼吸困难。
  • 声音嘶哑。

    • 症状产生的原因可能是局部侵犯或对邻近胸腔结构的压迫，例如压迫食管引起吞咽困难，压迫喉神经引起声音嘶哑，压迫上腔静脉引起面部水肿、头颈部浅静脉扩张等。也可能出现远端转移症状，例如脑转移引起神经源性损害或人格变化，或骨转移引起骨痛。少数患者可能出现副肿瘤疾病症状与体征，例如肥大性骨关节病合并杵状指，或甲状旁腺激素相关蛋白引起高钙血症。体格检查可能发现锁骨上淋巴结肿大、胸腔积液或肺不张、迁延性肺炎、或慢性阻塞性肺病或肺纤维化等合并症相关体征。

    诊断

    对怀疑NSCLC的患者，检查的主要目的是确诊、判断病变受累范围。患者治疗方法的选择取决于组织学、分期、一般情况和合并症等。

    确定是否为癌症的方法包括：

  • 病史。
  • 体格检查。
  • 常规实验室检查。
  • 胸部X线检查。
  • 胸部增强CT。
  • 活检。

    • 在患者开始肺癌治疗之前，必须由一位经验丰富的肺癌病理科医师审阅病理材料。这一点十分关键，因为SCLC对化疗反应良好，通常不进行手术治疗，在显微镜检查中可能与NSCLC混淆。

    免疫组化与电镜对诊断与分类的作用有限，多数肺部肿瘤可以通过光镜标准分类。

    （关于分期检查与步骤的更多信息，请参见本总结的分期评估章节。）

    分子学特征

    肺癌基因突变的发现促进了分子靶向治疗的发展，以改善转移性癌症患者的生存期。

    尤其是腺癌，人们已经发现编码表皮生长因子受体（EGFR）和下游的丝裂原活化蛋白激酶（MAPK）与磷脂酰肌醇3激酶（PI3K）信号通路组成成分的基因发生特定突变。这些突变可能能够解释药物敏感性与对激酶抑制剂的原发性或获得性耐药机制。

    与治疗决策相关的其他遗传异常包括对间变性淋巴瘤激酶（ALK）抑制剂敏感的间变性淋巴瘤激酶（ALK）-酪氨酸激酶受体易位和编码肝细胞生长因子受体的MET（间质上皮转换因子）扩增。MET扩增导致对EGFR酪氨酸激酶抑制剂的继发性耐药。

    预后因素

    多项研究曾试图鉴别很多临床病理因素对预后的意义。

    与预后不良相关的因素包括：

  • 有肺部症状。
  • 肿瘤较大（>3cm）。
  • 非鳞状细胞组织学。
  • TNM分期中有多发淋巴结转移。
  • （如需了解更多信息，请参见本总结的纵隔淋巴结转移评估章节。）
  • 血管侵犯。

    • 对于手术不能治疗的肿瘤患者，一般情况较差和体重下降超过10%对预后有不良影响。在积极综合干预的临床试验中排除了这些患者。

    在对临床试验数据的多项回顾性分析中，未发现高龄影响治疗的反应或生存期。

    （如需了解预后的更多信息，请参见本总结中各分期NSCLC对应的治疗章节。）

    因为几乎所有NSCLC患者的治疗效果均不理想，可考虑将合适的患者纳入临床试验。关于正在进行的临床试验信息，请访问NCI网站。

    相关总结内容

    其他包含与肺癌相关信息的PDQ总结包括：

  • 肺癌的预防
  • 肺癌的筛查
  • 小细胞肺癌的治疗

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    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    General Information About Non-Small Cell Lung Cancer (NSCLC)

    NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

    Incidence and Mortality

    Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2020:

  • New cases: 228,820.
  • Deaths: 135,720.

    • Lung cancer is the leading cause of cancer-related mortality in the United States.

    The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate for patients with local-stage (49%), regional-stage (16%), and distant-stage (2%) disease varies markedly, depending on the stage at diagnosis.

    Anatomy

    NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.

    Anatomy of the respiratory system.

    Pathogenesis

    Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include the following:

  • Hyperplasia.
  • Metaplasia.
  • Dysplasia.
  • Carcinoma in situ.

    • Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

    In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.

    Pathology

    NSCLC is a heterogeneous aggregate of histologies. The most common histologies include the following:

  • Epidermoid or squamous cell carcinoma.
  • Adenocarcinoma.
  • Large cell carcinoma.

    • These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

    Risk Factors

    Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:

  • History of or current tobacco use: cigarettes, pipes, and cigars.
  • Exposure to cancer-causing substances in secondhand smoke.
  • Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.
  • Radiation exposure from any of the following:
  • Radiation therapy to the breast or chest.
  • Radon exposure in the home or workplace.
  • Medical imaging tests, such as computed tomography (CT) scans.
  • Atomic bomb radiation.
  • Living in an area with air pollution.
  • Family history of lung cancer.
  • Human immunodeficiency virus infection.
  • Beta carotene supplements in heavy smokers.

    • The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.

    Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.

    Prevention

    A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.

    Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.

    Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials using the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.

    [Level of evidence: 1iiA] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

    (Refer to the PDQ summary on Lung Cancer Prevention for more information.)

    Screening

    In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning.

    Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.

    (Refer to the Screening by low-dose helical computed tomography subsection in the PDQ summary on Lung Cancer Screening for more information.)

    Clinical Features

    Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain. Other presenting symptoms include the following:

  • Hemoptysis.
  • Malaise.
  • Weight loss.
  • Dyspnea.
  • Hoarseness.

    • Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein. Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.

    Diagnosis

    Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease. Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient.

    The procedures used to determine the presence of cancer include the following:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Biopsy.

    • Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.

    Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

    (Refer to the Staging Evaluation section of this summary for more information on tests and procedures used for staging.)

    Molecular Features

    The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.

    In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.

    Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

    Prognostic Factors

    Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors.

    Factors that have correlated with adverse prognosis include the following:

  • Presence of pulmonary symptoms.
  • Large tumor size (>3 cm).
  • Nonsquamous histology.
  • Metastases to multiple lymph nodes within a TNM-defined nodal station.
  • (Refer to the Evaluation of Mediastinal Lymph Node Metastasis section of this summary for more information.)
  • Vascular invasion.

    • For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.

    In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.

    (Refer to the separate treatment sections for each stage of NSCLC in this summary for more information about prognosis.)

    Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials. Information about ongoing clinical trials is available from the NCI website.

    Related Summaries

    Other PDQ summaries containing information related to lung cancer include the following:

  • Lung Cancer Prevention
  • Lung Cancer Screening
  • Small Cell Lung Cancer Treatment

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    • 非小细胞肺癌治疗(PDQ®)
    Non-Small Cell Lung Cancer Treatment (PDQ®)
    非小细胞肺癌治疗(PDQ®)

    NSCLC的分期信息

    背景

    在非小细胞肺癌（NSCLC）中，分期确定对治疗和预后具有重要意义。仔细进行初步诊断评估确定部位与原发及转移性肿瘤受累情况对患者的适当治疗至关重要。

    一般通过症状、体征、实验室检查或远端转移风险认知评估是否存在远端转移。如果初步评估提示转移或III期肿瘤患者考虑积极的局部或综合治疗，应进行其他检查，例如骨扫描和颅脑计算机断层扫描（CT）/磁共振成像（MRI）。

    分期对治疗选择至关重要。疾病分期是很多临床因素和病理因素的综合结果。

    在评估生存期结局报告时应注意临床分期与病理分期之间的区别。

    确定疾病分期所用的方法包括：

  • 病史。
  • 体格检查。
  • 常规实验室检查。
  • 胸部X线检查。
  • 胸部增强CT扫描
  • 氟F 18-脱氧葡萄糖正电子发射断层扫描（18F-FDG-PET）。

    • 用于获得组织标本的操作包括支气管镜、纵隔镜检查或前纵隔切开术。NSCLC的病理分期依据包括：

  • 肿瘤检查。
  • 手术切缘情况。
  • 淋巴结。

    • 预后与治疗决策基于以下一些因素：

  • 病理类型。
  • 肿瘤大小与部位。
  • 胸膜受累情况。
  • 手术切缘情况。
  • 各站淋巴结的状态与位置。
  • 肿瘤分级。
  • 淋巴管浸润。

    • 诊断时可根据疾病范围和治疗方法将NSCLC患者分为三组：

  • 可手术切除的肿瘤（通常为I期、II期和选定的III期肿瘤）。
  • 预后最佳，这取决于多种肿瘤和宿主因素。
  • 有临床手术禁忌症的可切除肿瘤患者适合进行根治性放疗。
  • 术后含顺铂联合化疗可延长已切除的II期或IIIA期NSCLC患者的生存期。
  • 局部（T3-T4）和/或区域（N2-N3）晚期病灶。
  • 有不同的自然病史。
  • 选定的局部晚期肿瘤患者可能会受益于联合治疗。
  • 不能切除或N2-N3疾病的患者接受放疗联合化疗。
  • 选定的T3或N2疾病患者可以通过手术切除以及术前或术后化疗或放化疗得到有效治疗。
  • 远端转移性病灶（包括在诊断时发现的远端转移灶[M1]）。
  • 可以用放疗或化疗缓解原发性肿瘤症状。
  • 患者一般状态良好、女性患者和单一部位远端转移的病人生存期比其他患者更长。
  • 含铂化疗可短期缓解症状并延长生存期。
  • 目前，未推荐使用常规单一化疗方案。
  • 既往接受过铂类药物联合化疗的患者在接受多西他赛、培美曲塞或表皮生长因子受体抑制剂治疗后可有效控制症状并延长生存期。

    • 分期评估

    纵隔淋巴结转移的评估

    手术评估

    如需准确评估淋巴结情况以确定治疗方法，手术纵隔淋巴结分期是评估标准。

    准确的纵隔淋巴结分期能够提供重要的预后信息。

    证据（淋巴结情况）：

  • 根据1990年至2000年的人群监测、流行病学和最终结果（SEER）数据库评估了明确接受手术切除的I期NSCLC患者的生存期与手术期间淋巴结检查次数之间的关系。
  • 共有16,800例患者入组本研究。
  • 对未接受放疗患者的总生存期进行分析，结果表明，与对照组（1-4个淋巴结）相比，术中检查5-8个淋巴结的患者的生存期适度延长且具有统计学显著性，比例风险比（HR）为0.90（95%置信区间[CI]，0.84-0.97）。对于检查9-12个淋巴结的患者，HR为0.86 （95%CI，0.79-0.95），对于检查有13-16 个淋巴结的患者，HR为0.78（95%CI，0.68-0.90）。对检查16个以上的淋巴结患者进行评估，发现未出现远期改善。肺癌特定死亡率和接受放疗患者的相应结果无显著差异。
  • 上述结果表明，NSCLC切除术后的患者生存期与术中评价的淋巴结数量相关。因为这很可能是分期减少错误的结果，即随着淋巴结取样数量的增加，缺失阳性淋巴结的可能性降低，这表明淋巴结状态的评估中应使用11-16个淋巴结。

    • CT成像

    CT扫描主要用于确定肿瘤大小。 CT扫描可以向下延伸，以便显现肝和肾上腺区域。胸部与上腹部MRI扫描并不优于CT扫描。

    证据（CT扫描）：

  • 系统回顾了关于CT扫描对肺癌患者纵隔无创分期准确性的医学文献。在1991年至2006年6月发表的35项研究中，5,111名可评估的患者得到了确认。几乎所有研究均规定在静脉给予造影剂后进行CT扫描，试验结果阳性是指存在一个或多个短轴直径测量值大于1cm的淋巴结。
  • 纵隔转移病灶的中位患病率为28%（18%-56%）。
  • 汇总了CT扫描识别纵隔淋巴结转移的灵敏度和特异性数据，灵敏度概率为51%（95%CI，47%-54%)），特异性概率为86%（95%CI，84%-88%）。提供了相应的阳性（3.4%）和阴性（0.6%）似然比。
  • 系统性综述的结果与一项大型荟萃分析的结果相似。据报告，CT扫描识别恶性纵隔淋巴结的中位灵敏度和特异性分别为61%和79%。
  • 一项早期荟萃分析报告平均灵敏度为64%，特异性为74%。

    • 18F-FDG PET扫描

    18F-FDG PET扫描逐渐普及，其应用于分期评估改变了纵隔淋巴结及远端转移的分期评估方法。

    一些随机试验评估了18F-FDG PET扫描在潜在可切除的NSCLC中的应用，就非治愈性开胸手术数量是否相对减少的结果不一。

    虽然当前证据存在冲突，18F-FDG PET扫描可能识别无法通过手术切除、术前分期检查不能发现的转移灶证据，从而改善早期肺癌患者的结局。

    证据（18F-FDG PET扫描）：

  • 2001年，临床与评价科学研究所对健康技术评估进行了扩展，对18F-FDG PET扫描在肺癌诊断和分期中的准确性和实用性进行了评估。
  • 通过对文献的系统检索，确定了12份证据总结报告和15项18F-FDG PET扫描诊断准确性的前瞻性研究。在NSCLC的纵隔分期方面，18F-FDG PET扫描可能优效于CT成像。在区别小至1 cm的良恶性病灶方面，18F-FDG PET扫描的灵敏度较高，特异性较合理。
  • 一项关于18F-FDG PET扫描对肺癌患者纵隔无创分期准确性的医学文献系统回顾发现，1994年至2006年间发表了44项研究，2,865名可评估患者。
  • 纵隔转移病灶的中位患病率为29%（5%-64%）。汇总了识别纵隔转移的灵敏度和特异性预估值数据，灵敏度概率为74%（95%CI，69%-79%)），特异性概率为85%（95%CI，82%-88%）。提供了18F-FDG PET扫描识别纵隔病灶分期的相应阳性（4.9%）和阴性（0.3%）似然比。这些结果证明，在识别肺癌患者的纵隔病灶分期方面，18F-FDG PET扫描比CT扫描更准确。

    • 18F-FDG PET扫描的成本效益

    决策分析发现18F-FDG PET扫描可能降低医疗总支出，因其能发现纵隔淋巴结或其他未检测到的转移灶CT扫描假阴性患者。

    一些研究认为假阳性率高得令人无法接受，故18F-FDG PET阳性纵隔病变因省略纵隔镜检查而节省支出并不合理。

    一项随机研究发现除常用分期之外增加18F-FDG PET扫描可显著减少开胸手术。

    另一项随机研究评估了18F-FDG PET扫描对临床治疗的影响，发现18F-FDG PET扫描可提供相应的分期相关信息，但并未显著减少开胸手术。

    CT成像联合18F-FDG PET扫描

    CT成像联合18F-FDG PET扫描的灵敏度与特异性均高于单行CT成像。

    证据（CT/18F-FDG PET扫描）：

  • 如果无证据证明CT扫描识别出远端转移病灶，18F-FDG PET扫描可补充CT扫描的纵隔分期。大量18F-FDG PET扫描的非随机研究评价了纵隔淋巴结，使用手术（即纵隔镜检查和/或开胸术加纵隔淋巴结清扫）作为比较的金标准。
  • 在一项评价18F-FDG PET扫描和CT扫描的条件性测试性能的荟萃分析中，报告了18F-FDG PET扫描的中位灵敏度和特异性概率，淋巴结肿大患者的灵敏度为100%，特异性为78%。
  • 当淋巴结肿大时，认为18F-FDG PET扫描在识别恶性淋巴结受累方面非常准确。然而，18F-FDG PET扫描将其他原因(通常是由于炎症或感染，约占1/4)而出现淋巴结肿大的患者中错误地识别为恶性肿瘤。
  • 18F-FDG PET扫描对正常大小纵隔淋巴结患者的中位灵敏度和特异性分别为82%和93%。
  • 这些数据表明，近20%淋巴结大小正常但恶性受累的患者的18F-FDG PET扫描结果为假阴性。

    • 对于临床上可切除的NSCLC患者，建议对胸部CT扫描或18F-FDG PET扫描结果阳性的最短径大于1 cm的纵隔淋巴结行活检。而影像学上增大的纵隔淋巴结即便18F-FDG PET扫描结果阴性，也不能完全排除活检可能。如果CT与18F-FDG PET结果不匹配，需要行纵隔镜检测纵隔淋巴结是否癌变。

    脑转移的评估

    有脑转移风险的患者可行CT或MRI扫描明确分期。一项研究将332例有切除可能且并无神经系统症状的NSCLC患者进行肺癌术前随机分组，分别接受脑CT或MRI成像以判断有无隐匿的脑转移情况。MRI的术前检出率高于CT扫描（P=0.069），从治疗前到术后12个月的总检出率约为7%。

    I期或II期患者的检出率为4%（即200例患者中检出8例），但III期患者的检出率为11.4%（即132例患者中检出15例）。MRI组脑转移的平均最大径显著小于CT组。目前尚不明确MRI的检出率较高能否改善预后。并非所有患者都能耐受MRI，对于不能耐受MRI的患者，可选择对比剂增强CT扫描作为替代检查。

    除脑转移之外的其他远端转移评估

    大量非随机、前瞻性或回顾性研究发现18F-FDG PET扫描与常用影像学检查相比，对远端转移灶行分期具有更多诊断学优势，但标准的18F-FDG PET扫描亦有其局限性。18F-FDG PET扫描范围无法延伸至盆腔以下，故可能无法检测到下肢长骨的骨转移。因脑和泌尿系可有18F-FDG PET的代谢示踪剂累积，18F-FDG PET扫描对检测这些部位的转移亦不可靠。

    新修订的国际肺癌分期方法

    2010年，美国癌症联合委员会(AJCC)和国际抗癌联盟采纳了修订后的国际肺癌分期方法，该方法基于5000多名患者的临床数据库信息。

    这些修订内容为不同患者群提供了更多的预后特异性信息，但分期与预后之间的相关性早在PET成像被广泛应用前已经建立。

    AJCC分期组以及TMN分期定义

    AJCC对NSCLC进行了TMN（肿瘤、结节、转移灶）分期定义。

    表1. TNM隐匿性癌的定义表2. TNM分期0期的定义表3. TNM IA1, IA2, IA3, IB 分期的定义表4. IIA, IIB 分期的定义表5. TNM IIIA, IIIB, IIIC 期的定义表6. TNM IV, IVA, IVB 分期的定义
    分期TNM描述
    分期 TNM描述
    分期TNM描述论证
    分期 TNM描述论证
    分期TNM描述论证
    分期 TNM描述论证
    隐匿性癌TX, N0, M0TX=原发性肿瘤无法评估，或痰液、支气管灌洗液中找到恶性细胞，但影像学和支气管镜未发现肿瘤。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    分期 TNM描述
    0Tis, N0, M0Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS：原位腺癌；单纯附壁型腺癌，最大径≤3cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期TNM描述论证
    IA1T1mi, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T1a, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IA2T1b, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IA3T1c, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IBT2a, N0, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期 TNM描述论证
    IIAT2b, N0, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IIBT1a, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1b, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1c, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2a, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2b, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T3, N0, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肿瘤。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期TNM描述论证
    IIIAT1a, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1b, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1c, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2a, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2b, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T3, N1, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肺肿瘤。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T4, N0, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T4, N1, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    IIIBT1a, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1b, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1c, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2a, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2b, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T3, N2, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T4, N2, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N2=转移至纵隔和/或隆突下淋巴结转移。
    M0 = 无远端转移。
    IIICT3, N3, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T4, N3, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    分期 TNM描述论证
    IVAny T, Any N, M1TX=原发性肿瘤无法评估，或痰液、支气管灌洗液中找到恶性细胞，但影像学和支气管镜未发现肿瘤。
    T0 = 无原发性肿瘤的证据。
    Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS=原位腺癌：附壁型为主，最大径≤3cm。
    T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    NX = 区域淋巴结无法评估。
    N0 = 无区域淋巴结转移。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M1 = 远端转移。
    IVAAny T, Any N, M1aAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立的肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    Any T, Any N, M1bAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    IVBAny T, Any N, M1cAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    –M1c =单个器官或多个器官中的多个胸外转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    表2. TNM分期0期的定义表3. TNM IA1, IA2, IA3, IB 分期的定义表4. IIA, IIB 分期的定义表5. TNM IIIA, IIIB, IIIC 期的定义表6. TNM IV, IVA, IVB 分期的定义
    分期 TNM描述
    分期TNM描述论证
    分期 TNM描述论证
    分期TNM描述论证
    分期 TNM描述论证
    0Tis, N0, M0Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS：原位腺癌；单纯附壁型腺癌，最大径≤3cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期TNM描述论证
    IA1T1mi, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T1a, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IA2T1b, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IA3T1c, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IBT2a, N0, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期 TNM描述论证
    IIAT2b, N0, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IIBT1a, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1b, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1c, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2a, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2b, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T3, N0, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肿瘤。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期TNM描述论证
    IIIAT1a, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1b, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1c, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2a, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2b, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T3, N1, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肺肿瘤。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T4, N0, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T4, N1, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    IIIBT1a, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1b, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1c, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2a, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2b, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T3, N2, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T4, N2, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N2=转移至纵隔和/或隆突下淋巴结转移。
    M0 = 无远端转移。
    IIICT3, N3, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T4, N3, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    分期 TNM描述论证
    IVAny T, Any N, M1TX=原发性肿瘤无法评估，或痰液、支气管灌洗液中找到恶性细胞，但影像学和支气管镜未发现肿瘤。
    T0 = 无原发性肿瘤的证据。
    Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS=原位腺癌：附壁型为主，最大径≤3cm。
    T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    NX = 区域淋巴结无法评估。
    N0 = 无区域淋巴结转移。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M1 = 远端转移。
    IVAAny T, Any N, M1aAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立的肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    Any T, Any N, M1bAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    IVBAny T, Any N, M1cAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    –M1c =单个器官或多个器官中的多个胸外转移。
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    表3. TNM IA1, IA2, IA3, IB 分期的定义表4. IIA, IIB 分期的定义表5. TNM IIIA, IIIB, IIIC 期的定义表6. TNM IV, IVA, IVB 分期的定义
    分期TNM描述论证
    分期 TNM描述论证
    分期TNM描述论证
    分期 TNM描述论证
    IA1T1mi, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T1a, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IA2T1b, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IA3T1c, N0, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IBT2a, N0, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期 TNM描述论证
    IIAT2b, N0, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IIBT1a, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1b, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1c, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2a, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2b, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T3, N0, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肿瘤。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期TNM描述论证
    IIIAT1a, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1b, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1c, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2a, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2b, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T3, N1, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肺肿瘤。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T4, N0, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T4, N1, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    IIIBT1a, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1b, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1c, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2a, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2b, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T3, N2, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T4, N2, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N2=转移至纵隔和/或隆突下淋巴结转移。
    M0 = 无远端转移。
    IIICT3, N3, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T4, N3, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    分期 TNM描述论证
    IVAny T, Any N, M1TX=原发性肿瘤无法评估，或痰液、支气管灌洗液中找到恶性细胞，但影像学和支气管镜未发现肿瘤。
    T0 = 无原发性肿瘤的证据。
    Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS=原位腺癌：附壁型为主，最大径≤3cm。
    T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    NX = 区域淋巴结无法评估。
    N0 = 无区域淋巴结转移。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M1 = 远端转移。
    IVAAny T, Any N, M1aAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立的肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    Any T, Any N, M1bAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    IVBAny T, Any N, M1cAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    –M1c =单个器官或多个器官中的多个胸外转移。
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    表4. IIA, IIB 分期的定义表5. TNM IIIA, IIIB, IIIC 期的定义表6. TNM IV, IVA, IVB 分期的定义
    分期 TNM描述论证
    分期TNM描述论证
    分期 TNM描述论证
    IIAT2b, N0, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    IIBT1a, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1b, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T1c, N1, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2a, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T2b, N1, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T3, N0, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肿瘤。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    分期TNM描述论证
    IIIAT1a, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1b, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1c, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2a, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2b, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T3, N1, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肺肿瘤。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T4, N0, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T4, N1, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    IIIBT1a, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1b, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1c, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2a, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2b, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T3, N2, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T4, N2, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N2=转移至纵隔和/或隆突下淋巴结转移。
    M0 = 无远端转移。
    IIICT3, N3, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T4, N3, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    分期 TNM描述论证
    IVAny T, Any N, M1TX=原发性肿瘤无法评估，或痰液、支气管灌洗液中找到恶性细胞，但影像学和支气管镜未发现肿瘤。
    T0 = 无原发性肿瘤的证据。
    Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS=原位腺癌：附壁型为主，最大径≤3cm。
    T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    NX = 区域淋巴结无法评估。
    N0 = 无区域淋巴结转移。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M1 = 远端转移。
    IVAAny T, Any N, M1aAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立的肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    Any T, Any N, M1bAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    IVBAny T, Any N, M1cAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    –M1c =单个器官或多个器官中的多个胸外转移。
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    表5. TNM IIIA, IIIB, IIIC 期的定义表6. TNM IV, IVA, IVB 分期的定义
    分期TNM描述论证
    分期 TNM描述论证
    IIIAT1a, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1b, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T1c, N2, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2a, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T2b, N2, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T3, N1, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内的独立肺肿瘤。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    T4, N0, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N0 = 无区域淋巴结转移。
    M0 = 无远端转移。
    T4, N1, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    M0 = 无远端转移。
    IIIBT1a, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1b, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T1c, N3, M0T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2a, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T2b, N3, M0T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T3, N2, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    M0 = 无远端转移。
    T4, N2, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N2=转移至纵隔和/或隆突下淋巴结转移。
    M0 = 无远端转移。
    IIICT3, N3, M0T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    T4, N3, M0T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M0 = 无远端转移。
    分期 TNM描述论证
    IVAny T, Any N, M1TX=原发性肿瘤无法评估，或痰液、支气管灌洗液中找到恶性细胞，但影像学和支气管镜未发现肿瘤。
    T0 = 无原发性肿瘤的证据。
    Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS=原位腺癌：附壁型为主，最大径≤3cm。
    T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    NX = 区域淋巴结无法评估。
    N0 = 无区域淋巴结转移。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M1 = 远端转移。
    IVAAny T, Any N, M1aAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立的肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    Any T, Any N, M1bAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    IVBAny T, Any N, M1cAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    –M1c =单个器官或多个器官中的多个胸外转移。
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.
    表6. TNM IV, IVA, IVB 分期的定义
    分期 TNM描述论证
    IVAny T, Any N, M1TX=原发性肿瘤无法评估，或痰液、支气管灌洗液中找到恶性细胞，但影像学和支气管镜未发现肿瘤。
    T0 = 无原发性肿瘤的证据。
    Tis = 原位癌；SCIS = 原位鳞状细胞癌；AIS=原位腺癌：附壁型为主，最大径≤3cm。
    T1 = 肿瘤最大径≤3cm，被肺或脏层胸膜包绕，支气管镜检查无侵及叶支气管近端的证据（未侵主支气管）。
    –T1mi =微浸润性腺癌：腺癌（最大径≤3 cm），附壁型为主，最大径≤5 mm。
    –T1a =肿瘤最大径≤1cm。如果任意大小的肿瘤出现少见的表浅扩散，侵犯局限于支气管壁，可能向近端延伸到主支气管，亦被分类为T1a。
    –T1b = 肿瘤最大径＞1cm但≤2cm。
    –T1c = 肿瘤最大径＞2 cm但≤3 cm。
    T2=肿瘤最大径＞3cm但≤5cm，或肿瘤具有下列特征：侵犯主支气管，但距隆突远端一定距离，侵犯脏层胸膜（PL1或PL2），或伴肺不张或阻塞性肺炎波及肺门区域，但未累及一侧全肺。对于具有这些特征的T2肿瘤，如果≤4cm或无法确定大小，则分类为T2a；如果> 4 cm但≤5cm，则分类为T2b。
    –T2a = 肿瘤最大径＞3 cm但≤4 cm。
    –T2b = 肿瘤最大径＞4 cm但≤5 cm。
    T3=肿瘤最大径>5 cm但≤7 cm，或直接侵及下列任一器官：壁层胸膜（PL3）、胸壁（含肺上沟瘤）、膈神经、壁层心包；或与原发肿瘤位于同一肺叶内独立的结节。
    T4=肿瘤径>7 cm或任何大小的肿瘤侵犯下列一个或多个结构：隔膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、或隆突；位于原发性肿瘤同侧的不同肺叶内独立的结节。
    NX = 区域淋巴结无法评估。
    N0 = 无区域淋巴结转移。
    N1=转移至同侧支气管旁和（或）同侧肺门淋巴结与肺内淋巴结，包括直接侵犯。
    N2=转移至同侧纵隔和/或隆突下淋巴结。
    N3=转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌淋巴结或锁骨上淋巴结。
    M1 = 远端转移。
    IVAAny T, Any N, M1aAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立的肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    Any T, Any N, M1bAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    IVBAny T, Any N, M1cAny T = 请参见上文Any T、Any N、M1中的T描述。
    Any N = 请参见上面Any T、Any N、M1中的N描述。
    M1 = 远端转移。
    -M1a=独立肿瘤结节位于对侧肺叶内；伴有胸膜或心包结节或出现恶性胸水或心包积液。多数肺癌患者的胸膜（心包）积液是肿瘤引起。但也有一些患者的胸膜（心包）积液的细胞病理学检查发现肿瘤细胞阴性，积液非血性、非渗出液。如果出现这些情况且临床评估认为积液与肿瘤无关，则积液不作为分期依据。
    -M1b =单个器官中的单个胸外转移（包括单个非区域性淋巴结受累）。
    –M1c =单个器官或多个器官中的多个胸外转移。
    T = 原发性肿瘤；N = 区域淋巴结；M = 远端转移。
    经AJCC授权使用：肺。参考：Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual.8th ed. New York, NY: Springer, 2017, pp 431-56.

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    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Stage Information for NSCLC

    Background

    In non-small cell lung cancer (NSCLC), the determination of stage has important therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

    In general, symptoms, physical signs, laboratory findings, or perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are under consideration for aggressive local and combined modality treatments.

    Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors.

    The distinction between clinical stage and pathological stage should be considered when evaluating reports of survival outcome.

    Procedures used to determine staging include the following:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) scanning.

    • Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy. Pathological staging of NSCLC requires the following:

  • Examination of the tumor.
  • Resection margins.
  • Lymph nodes.

    • Prognostic and treatment decisions are based on some of the following factors:

  • Knowledge of histologic type.
  • Tumor size and location.
  • Involvement of pleura.
  • Surgical margins.
  • Status and location of lymph nodes by station.
  • Tumor grade.
  • Lymphovascular invasion.

    • At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:

  • Surgically resectable disease (generally stage I, stage II, and selected stage III tumors).
  • Has the best prognosis, which depends on a variety of tumor and host factors.
  • Patients with resectable disease who have medical contraindications to surgery are candidates for curative radiation therapy.
  • Postoperative cisplatin-based combination chemotherapy may provide a survival advantage for patients with resected stage II or stage IIIA NSCLC.
  • Locally (T3–T4) and/or regionally (N2–N3) advanced disease.
  • Has a diverse natural history.
  • Selected patients with locally advanced tumors may benefit from combined modality treatments.
  • Patients with unresectable or N2–N3 disease are treated with radiation therapy in combination with chemotherapy.
  • Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy.
  • Distant metastatic disease (includes distant metastases [M1] that were found at the time of diagnosis).
  • May be treated with radiation therapy or chemotherapy for palliation of symptoms of the primary tumor.
  • Patients with good performance status, women, and patients with distant metastases confined to a single site live longer than others.
  • Platinum-based chemotherapy has been associated with short-term palliation of symptoms and with a survival advantage.
  • Currently, no single chemotherapy regimen can be recommended for routine use.
  • Patients previously treated with platinum combination chemotherapy may derive symptom control and survival benefit from docetaxel, pemetrexed, or epidermal growth factor receptor inhibitors.

    • Staging Evaluation

    Evaluation of mediastinal lymph node metastasis

    Surgical evaluation

    Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.

    Accurate staging of the mediastinal lymph nodes provides important prognostic information.

    Evidence (nodal status):

  • The association between survival and the number of examined lymph nodes during surgery for patients with stage I NSCLC treated with definitive surgical resection was assessed from the population-based Surveillance, Epidemiology, and End Results (SEER) database for the period from 1990 to 2000.
  • A total of 16,800 patients were included in the study.
  • The overall survival analysis for patients without radiation therapy demonstrated that in comparison with the reference group (one to four lymph nodes), patients with five to eight lymph nodes examined during surgery had a modest but statistically significant increase in survival, with a proportionate hazard ratio (HR) of 0.90 (95% confidence interval [CI], 0.84–0.97). For patients with 9 to 12 examined lymph nodes, the HR was 0.86 (95% CI, 0.79–0.95), and for patients with 13 to 16 examined lymph nodes, the HR was 0.78 (95% CI, 0.68–0.90). There appeared to be no incremental improvement after evaluating more than 16 lymph nodes. The corresponding results for lung cancer–specific mortality and for patients receiving radiation therapy were not substantially different.
  • These results indicate that patient survival following resection for NSCLC is associated with the number of lymph nodes evaluated during surgery. Because this is most likely the result of a reduction-of-staging error, namely, a decreased likelihood of missing positive lymph nodes with an increasing number of lymph nodes sampled, it suggests that an evaluation of nodal status should include 11 to 16 lymph nodes.

    • CT imaging

    CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.

    Evidence (CT scan):

  • A systematic review of the medical literature relating to the accuracy of CT scanning for noninvasive staging of the mediastinum in patients with lung cancer has been conducted. In the 35 studies published between 1991 and June 2006, 5,111 evaluable patients were identified. Almost all studies specified that CT scanning was performed following the administration of intravenous contrast material and that a positive test result was defined as the presence of one or more lymph nodes that measured larger than 1 cm on the short-axis diameter.
  • The median prevalence of mediastinal metastasis was 28% (range, 18%–56%).
  • The pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% CI, 47%–54%) for sensitivity and 86% (95% CI, 84%–88%) for specificity. Corresponding positive (3.4%) and negative (0.6%) likelihood ratios were provided.
  • The results from the systematic review are similar to those of a large meta-analysis that reported the median sensitivity and specificity of CT scanning for identifying malignant mediastinal nodes as 61% for sensitivity and 79% for specificity.
  • An earlier meta-analysis reported an average sensitivity rate of 64% and specificity rate of 74%.

    • 18F-FDG PET scanning

    The wider availability and use of 18F-FDG PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.

    Randomized trials evaluating the utility of 18F-FDG PET scanning in potentially resectable NSCLC report conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.

    Although the current evidence is conflicting, 18F-FDG PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.

    Evidence (18F-FDG PET scan):

  • A systematic review, an expansion of a health technology assessment conducted in 2001 by the Institute for Clinical and Evaluative Sciences, evaluated the accuracy and utility of 18F-FDG PET scanning in the diagnosis and staging of lung cancer.
  • Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of 18F-FDG PET scanning were identified. 18F-FDG PET scanning appears to be superior to CT imaging for mediastinal staging in NSCLC. 18F-FDG PET scanning also appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm.
  • A systematic review of the medical literature relating to the accuracy of 18F-FDG PET scanning for noninvasive staging of the mediastinum in patients with lung cancer identified 44 studies published between 1994 and 2006 with 2,865 evaluable patients.
  • The median prevalence of mediastinal metastases was 29% (range, 5%–64%). Pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69%–79%) for sensitivity and 85% (95% CI, 82%–88%) for specificity. Corresponding positive (4.9%) and negative (0.3%) likelihood ratios were provided for mediastinal staging with 18F-FDG PET scanning. These findings demonstrated that 18F-FDG PET scanning is more accurate than CT scanning for staging of the mediastinum in patients with lung cancer.

    • Cost effectiveness of 18F-FDG PET scanning

    Decision analyses demonstrate that 18F-FDG PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases.

    Studies concluded that the money saved by forgoing mediastinoscopy in 18F-FDG PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results.

    A randomized study found that the addition of 18F-FDG PET scanning to conventional staging was associated with significantly fewer thoracotomies.

    A second randomized trial evaluating the impact of 18F-FDG PET scanning on clinical management found that 18F-FDG PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.

    Combination of CT imaging and 18F-FDG PET scanning

    The combination of CT imaging and 18F-FDG PET scanning has greater sensitivity and specificity than CT imaging alone.

    Evidence (CT/18F-FDG PET scan):

  • If there is no evidence of distant metastatic disease on CT scan, 18F-FDG PET scanning complements CT scan staging of the mediastinum. Numerous nonrandomized studies of 18F-FDG PET scanning have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison.
  • In a meta-analysis evaluating the conditional test performance of 18F-FDG PET scanning and CT scanning, the median sensitivity and specificity of 18F-FDG PET scans were reported as 100% for sensitivity and 78% for specificity in patients with enlarged lymph nodes.
  • 18F-FDG PET scanning is considered very accurate in identifying malignant nodal involvement when lymph nodes are enlarged. However, 18F-FDG PET scanning will falsely identify a malignancy in approximately one-fourth of patients with lymph nodes that are enlarged for other reasons, usually as a result of inflammation or infection.
  • The median sensitivity and specificity of 18F-FDG PET scanning in patients with normal-sized mediastinal lymph nodes were 82% for sensitivity and 93% for specificity.
  • These data indicate that nearly 20% of patients with normal-sized lymph nodes but with malignant involvement had falsely negative 18F-FDG PET scan findings.

    • For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found to be larger than 1 cm in shortest transverse axis on chest CT scan or were found to be positive on 18F-FDG PET scan. Negative 18F-FDG PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and 18F-FDG PET scan do not corroborate each other.

    Evaluation of brain metastasis

    Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC and no neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend towards a higher preoperative detection rate than CT scan (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.

    Patients with stage I or stage II disease had a detection rate of 4% (i.e., eight detections out of 200 patients); however, individuals with stage III disease had a detection rate of 11.4% (i.e., 15 detections out of 132 patients). The mean maximal diameter of the brain metastases was significantly smaller in the MRI group. Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.

    Evaluation of distant metastasis other than the brain

    Numerous nonrandomized, prospective, and retrospective studies have demonstrated that 18F-FDG PET scanning seems to offer diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard 18F-FDG PET scans have limitations. 18F-FDG PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in 18F-FDG PET scanning accumulates in the brain and urinary tract, 18F-FDG PET scanning is not reliable for detection of metastases in these sites.

    The Revised International System for Staging Lung Cancer

    The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.

    These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

    AJCC Stage Groupings and TNM Definitions

    The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define NSCLC.

    Table 1. Definitions of TNM Occult CarcinomaTable 2. Definitions of TNM Stage 0Table 3. Definitions of TNM Stages IA1, IA2, IA3, and IBTable 4. Definitions of TNM Stages IIA and IIBTable 5. Definitions of TNM Stages IIIA, IIIB, and IIICTable 6. Definitions of TNM Stages IV, IVA, and IVB
    StageTNMDescription
    Stage TNMDescription
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    Occult carcinomaTX, N0, M0TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    Stage TNMDescription
    0Tis, N0, M0Tis = Carcinoma in situ; SCIS =Squamous cell carcinoma in situ; AIS: Adenocarcinoma in situ; Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    StageTNMDescriptionIllustration
    IA1T1mi, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T1a, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IA2T1b, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IA3T1c, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IBT2a, N0, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IIAT2b, N0, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IIBT1a, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1b, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1c, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2a, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2b, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T3, N0, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (Including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    StageTNMDescriptionIllustration
    IIIAT1a, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1b, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1c, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2a, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2b, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T3, N1, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T4, N0, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T4, N1, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    IIIBT1a, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1b, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1c, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2a, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2b, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T3, N2, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T4, N2, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    IIICT3, N3, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T4, N3, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IVAny T, Any N, M1TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
    T0 = No evidence of primary tumor.
    Tis = carcinoma in situ; SCIS = squamous cell carcinoma in situ; AIS = adenocarcinoma in situ: Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M1 = Distant metastasis.
    IVAAny T, Any N, M1aAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    Any T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    IVBAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    –M1c = Multiple extrathoracic metastases in a single organ or in multiple organs.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    Table 2. Definitions of TNM Stage 0Table 3. Definitions of TNM Stages IA1, IA2, IA3, and IBTable 4. Definitions of TNM Stages IIA and IIBTable 5. Definitions of TNM Stages IIIA, IIIB, and IIICTable 6. Definitions of TNM Stages IV, IVA, and IVB
    Stage TNMDescription
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    0Tis, N0, M0Tis = Carcinoma in situ; SCIS =Squamous cell carcinoma in situ; AIS: Adenocarcinoma in situ; Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    StageTNMDescriptionIllustration
    IA1T1mi, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T1a, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IA2T1b, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IA3T1c, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IBT2a, N0, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IIAT2b, N0, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IIBT1a, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1b, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1c, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2a, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2b, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T3, N0, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (Including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    StageTNMDescriptionIllustration
    IIIAT1a, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1b, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1c, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2a, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2b, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T3, N1, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T4, N0, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T4, N1, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    IIIBT1a, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1b, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1c, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2a, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2b, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T3, N2, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T4, N2, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    IIICT3, N3, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T4, N3, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IVAny T, Any N, M1TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
    T0 = No evidence of primary tumor.
    Tis = carcinoma in situ; SCIS = squamous cell carcinoma in situ; AIS = adenocarcinoma in situ: Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M1 = Distant metastasis.
    IVAAny T, Any N, M1aAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    Any T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    IVBAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    –M1c = Multiple extrathoracic metastases in a single organ or in multiple organs.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    Table 3. Definitions of TNM Stages IA1, IA2, IA3, and IBTable 4. Definitions of TNM Stages IIA and IIBTable 5. Definitions of TNM Stages IIIA, IIIB, and IIICTable 6. Definitions of TNM Stages IV, IVA, and IVB
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    IA1T1mi, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T1a, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IA2T1b, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IA3T1c, N0, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IBT2a, N0, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IIAT2b, N0, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IIBT1a, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1b, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1c, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2a, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2b, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T3, N0, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (Including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    StageTNMDescriptionIllustration
    IIIAT1a, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1b, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1c, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2a, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2b, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T3, N1, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T4, N0, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T4, N1, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    IIIBT1a, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1b, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1c, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2a, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2b, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T3, N2, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T4, N2, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    IIICT3, N3, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T4, N3, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IVAny T, Any N, M1TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
    T0 = No evidence of primary tumor.
    Tis = carcinoma in situ; SCIS = squamous cell carcinoma in situ; AIS = adenocarcinoma in situ: Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M1 = Distant metastasis.
    IVAAny T, Any N, M1aAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    Any T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    IVBAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    –M1c = Multiple extrathoracic metastases in a single organ or in multiple organs.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    Table 4. Definitions of TNM Stages IIA and IIBTable 5. Definitions of TNM Stages IIIA, IIIB, and IIICTable 6. Definitions of TNM Stages IV, IVA, and IVB
    Stage TNMDescriptionIllustration
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    IIAT2b, N0, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    IIBT1a, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1b, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T1c, N1, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2a, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T2b, N1, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T3, N0, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (Including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    StageTNMDescriptionIllustration
    IIIAT1a, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1b, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1c, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2a, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2b, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T3, N1, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T4, N0, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T4, N1, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    IIIBT1a, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1b, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1c, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2a, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2b, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T3, N2, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T4, N2, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    IIICT3, N3, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T4, N3, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IVAny T, Any N, M1TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
    T0 = No evidence of primary tumor.
    Tis = carcinoma in situ; SCIS = squamous cell carcinoma in situ; AIS = adenocarcinoma in situ: Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M1 = Distant metastasis.
    IVAAny T, Any N, M1aAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    Any T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    IVBAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    –M1c = Multiple extrathoracic metastases in a single organ or in multiple organs.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    Table 5. Definitions of TNM Stages IIIA, IIIB, and IIICTable 6. Definitions of TNM Stages IV, IVA, and IVB
    StageTNMDescriptionIllustration
    Stage TNMDescriptionIllustration
    IIIAT1a, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1b, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T1c, N2, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2a, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T2b, N2, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T3, N1, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    T4, N0, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis.
    T4, N1, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    M0 = No distant metastasis.
    IIIBT1a, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1b, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T1c, N3, M0T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2a, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T2b, N3, M0T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T3, N2, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    T4, N2, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    M0 = No distant metastasis.
    IIICT3, N3, M0T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    T4, N3, M0T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M0 = No distant metastasis.
    Stage TNMDescriptionIllustration
    IVAny T, Any N, M1TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
    T0 = No evidence of primary tumor.
    Tis = carcinoma in situ; SCIS = squamous cell carcinoma in situ; AIS = adenocarcinoma in situ: Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M1 = Distant metastasis.
    IVAAny T, Any N, M1aAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    Any T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    IVBAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    –M1c = Multiple extrathoracic metastases in a single organ or in multiple organs.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.
    Table 6. Definitions of TNM Stages IV, IVA, and IVB
    Stage TNMDescriptionIllustration
    IVAny T, Any N, M1TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
    T0 = No evidence of primary tumor.
    Tis = carcinoma in situ; SCIS = squamous cell carcinoma in situ; AIS = adenocarcinoma in situ: Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
    T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
    –T1mi = Minimally invasive adenocarcinoma: Adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
    –T1a = Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
    –T1b = Tumor >1 cm but ≤2 cm in greatest dimension.
    –T1c = Tumor >2 cm but ≤3 cm in greatest dimension.
    T2 = Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
    –T2a = Tumor >3 cm but ≤4 cm in greatest dimension.
    –T2b = Tumor >4 cm but ≤5 cm in greatest dimension.
    T3 = Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
    T4 = Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
    N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
    N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
    M1 = Distant metastasis.
    IVAAny T, Any N, M1aAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    Any T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    IVBAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1.
    Any N = See N descriptions above in Any T, Any N, M1.
    M1 = Distant metastasis.
    –M1a = Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
    –M1b = Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
    –M1c = Multiple extrathoracic metastases in a single organ or in multiple organs.
    T = primary tumor; N = regional lymph node; M = distant metastasis.
    aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 431–56.

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    • 非小细胞肺癌治疗(PDQ®)

    NSCLC的治疗选择概述

    在非小细胞肺癌(NSCLC)中，标准治疗结果只适用于大多数局限期癌症。 所有新诊断的NSCLC患者都可作为评估新治疗的研究候选参与者。

    手术可能是本病最有效的治疗方法。 NSCLC患者在肿瘤切除后行术后化疗可能增加获益。 少数患者可通过放疗联合化疗治愈，多数患者可通过放疗联合化疗缓解症状。 预防性颅脑照射（PCI）可能降低脑转移发生率，但目前无生存期获益证据，PCI对生活质量的影响亦不明确。

    对于晚期癌症患者，化疗或表皮生长因子受体（EGFR）激酶抑制剂可适度改善中位生存期，但总生存期仍较差。

    化疗能短期缓解晚期NSCLC患者的肿瘤相关症状。 一些临床研究尝试评估化疗对肿瘤相关症状与生活质量的影响。 这些研究提示，可通过化疗控制肿瘤相关症状，同时不影响总体生活质量；

    但化疗对生活质量的影响需更深入的研究。 通常身体状况较好的老年患者的治疗获益与年轻患者相同。

    肺癌中基因突变的发现促进了分子靶向治疗的研发，以提高肿瘤转移患者的生存期。

    尤其是在NSCLC患者中发现的EGFR、MAPK、PI3K信号通路基因异常可能揭露了药物敏感性或对激酶抑制剂的原发、获得性耐药的机制。EGFR突变充分预测了EGFR抑制剂有效率增加、无进展生存期延长。未选定的NSCLC中3%到7%出现ALK与EML4基因融合产生易位产物，介导了克唑替尼等药对ALK的药理抑制作用。MET致癌基因编码肝细胞生长因子受体。已发现该基因的扩增与继发性EGFR酪氨酸激酶受体耐药相关。

    NSCLC各期的标准治疗选择见表7.

    表7. NSCLC的标准治疗选择
    分期（TNM分期标准）标准治疗选择
    隐匿性NSCLC手术
    0期NSCLC
    IA与IB期NSCLC
    IIA与IIB期NSCLC
    IIIA期NSCLC已切除或可切除肿瘤
    不可切除的肿瘤
    上沟瘤
    侵及胸壁的肿瘤
    IIIB与IIIC期NSCLC
    新诊断的复发性IV期NSCLC
    一线化疗后的维持治疗（针对四个疗程铂类联合化疗后病情稳定或缓解的患者）
    ALK抑制剂（针对ALK易位的患者）
    ROS1抑制剂（针对ROS1重排的患者）
    BRAF V600E和MEK抑制剂（针对BRAF V600E突变的患者）
    进展的复发性IV期NSCLC
    ALK =间变性淋巴瘤激酶；BRAF = v-raf鼠肉瘤病毒癌基因同源物B1；EGFR =表皮生长因子受体；MEK = MAPK激酶1；NSCLC =非小细胞肺癌；PD-L1 =编程化死亡配体1；TKI =酪氨酸激酶抑制剂；TNM = T，肿瘤大小以及癌细胞向附近组织扩散；N，癌细胞扩散到附近的淋巴结；M，癌细胞转移或扩散到人体其他部位。

    除表7所列出的标准治疗选择之外，经过临床评估亦可选择下列治疗：

  • 联合局部治疗（手术）。
  • 区域治疗（放疗）。
  • 全身治疗（化疗、免疫治疗与靶向药物）。
  • 开发更有效的全身治疗。

    • 随访

    一些小规模病例分析发现化疗、放疗或放化疗后的氟F 18-脱氧葡萄糖正电子发射断层扫描（18F-FDG PET）上病灶摄取值降低与病理学完全缓解和良好预后相关。

    一些研究曾使用不同的评估时机、18F-FDG PET参数与阈值来定义18F-FDG PET缓解。最大标准摄取值（SUV）降低至少80%预测病理学完全缓解的灵敏度为90%，特异性为100%，准确率为96%。

    肿瘤SUV值小于4的患者行肿瘤切除术后的中位生存期延长（分别56个月与19个月）。

    据报道，放疗后有完全代谢反应的患者中位生存期为31个月，而其他患者为11个月。

    18F-FDG PET评估诱导治疗反应的灵敏度与特异性可能高于计算机断层扫描（CT）。最佳检查时机仍待研究；但一项研究发现如果放疗后30天再行18F-FDG PET检查，灵敏度与特异性更佳。

    常规治疗后PET-CT扫描无明确的作用。

    [证据等级：3iiA]

    证据（放化疗或不放化疗后的监测影像）：

  • 由美国放射影像学院（ACRIN）和放疗肿瘤学小组（RTOG）合作小组（ACRIN 6668/RTOG 0235 [NCT00083083]）牵引的一项前瞻性多中心试验研究了约14周（范围为12-16周）时PET-CT的作用，以预测173例III期肿瘤患者接受标准治疗联合化疗和放疗后的总生存期（OS）。
  • 采用主要终点确定预先规定的二元临界值为SUVpeak 3.5时SUVpeak与OS之间的关系。
  • 研究表明，与SUVpeak ＞3.5相比，SUVpeak ＜3.5与OS之间无相关性，2年OS估计值分别为51%和37%（P = 0.29）。
  • 探索性分析显示OS和SUVpeak（作为连续变量）之间的相关性，二元临界值为SUVpeak 5.0和7.0。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

    参考文献

  • Lester JF, MacBeth FR, Coles B: Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 63 (3): 690-4, 2005.
  • Pöttgen C, Eberhardt W, Grannass A, et al.: Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 25 (31): 4987-92, 2007.
  • Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000.
  • Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.
  • Spiro SG, Rudd RM, Souhami RL, et al.: Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 59 (10): 828-36, 2004.
  • Clegg A, Scott DA, Hewitson P, et al.: Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57 (1): 20-8, 2002.
  • Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011.
  • Curran WJ, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011.
  • Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
  • Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
  • Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
  • Cerfolio RJ, Bryant AS, Winokur TS, et al.: Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg 78 (6): 1903-9; discussion 1909, 2004.
  • Pöttgen C, Levegrün S, Theegarten D, et al.: Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 12 (1): 97-106, 2006.
  • Eschmann SM, Friedel G, Paulsen F, et al.: 18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34 (4): 463-71, 2007.
  • Hellwig D, Graeter TP, Ukena D, et al.: Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg 128 (6): 892-9, 2004.
  • Cerfolio RJ, Bryant AS: When is it best to repeat a 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan on patients with non-small cell lung cancer who have received neoadjuvant chemoradiotherapy? Ann Thorac Surg 84 (4): 1092-7, 2007.
  • Mac Manus MP, Hicks RJ, Matthews JP, et al.: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 21 (7): 1285-92, 2003.
  • Machtay M, Duan F, Siegel BA, et al.: Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol 31 (30): 3823-30, 2013.
    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Treatment Option Overview for NSCLC

    In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.

    Surgery is potentially the most curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of prophylactic cranial irradiation on quality of life is not known.

    In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, although overall survival is poor.

    Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;

    however, the impact of chemotherapy on quality of life requires more study. In general, medically fit elderly patients with good performance status obtain the same benefits from treatment as younger patients.

    The identification of gene mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.

    In particular, genetic abnormalities in EGFR, MAPK, and PI3K signaling pathways in subsets of NSCLC may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR mutations strongly predict the improved response rate and progression-free survival of inhibitors of EGFR. Fusions of ALK with EML4 and other genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. The MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

    The standard treatment options for each stage of NSCLC are presented in Table 7.

    Table 7. Standard Treatment Options for NSCLC
    Stage (TNM Definitions)Standard Treatment Options
    Occult NSCLCSurgery
    Stage 0 NSCLC
    Stages IA and IB NSCLC
    Stages IIA and IIB NSCLC
    Stage IIIA NSCLCResected or resectable disease
    Unresectable disease
    Superior sulcus tumors
    Tumors that invade the chest wall
    Stages IIIB and IIIC NSCLC
    Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC
    Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
    ALK inhibitors (for patients with ALK translocations)
    ROS1 inhibitors (for patients with ROS1 rearrangements)
    BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations)
    Progressive Stage IV, Relapsed, and Recurrent NSCLC
    ALK = anaplastic lymphoma kinase; BRAF = v-raf murine sarcoma viral oncogene homolog B1; EGFR = epidermal growth factor receptor; MEK = MAPK kinase 1; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; TKI = tyrosine kinase inhibitors; TNM = T, size of tumor and any spread of cancer into nearby tissue; N, spread of cancer to nearby lymph nodes; M, metastasis or spread of cancer to other parts of body.

    In addition to the standard treatment options presented in Table 7, treatment options under clinical evaluation include the following:

  • Combining local treatment (surgery).
  • Regional treatment (radiation therapy).
  • Systemic treatments (chemotherapy, immunotherapy, and targeted agents).
  • Developing more effective systemic therapy.

    • Follow-Up

    Several small series have reported that reduction in fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlates with pathological complete response and favorable prognosis.

    Studies have used different timing of assessments, 18F-FDG PET parameters, and cutpoints to define 18F-FDG PET response. Reduction in maximum standardized uptake value (SUV) of higher than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.

    Median survival after resection was longer for patients with tumor SUV values of lower than 4 (56 months vs. 19 months).

    Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.

    18F-FDG PET may be more sensitive and specific than computed tomography (CT) scan in assessing response to induction therapy. Optimal timing of imaging remains to be defined; however, one study suggested that greater sensitivity and specificity of 18F-FDG PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.

    There is no clear role for routine posttreatment PET-CT scans.

    [Level of evidence: 3iiA]

    Evidence (surveillance imaging after radiation therapy with or without chemotherapy):

  • A prospective multicenter trial led by the American College of Radiology Imaging Network (ACRIN) and the Radiation Therapy Oncology Group (RTOG) cooperative group (ACRIN 6668/RTOG 0235 [NCT00083083]) studied the role of posttreatment PET-CT at approximately 14 weeks (range, 12–16 weeks) to predict overall survival (OS) after standard-of-care concurrent chemotherapy and radiation therapy in 173 patients with stage III disease.
  • The primary endpoint was to determine the relationship between SUVpeak at a prespecified binary cutoff of SUVpeak 3.5 with OS.
  • The study demonstrated no association between OS and SUVpeak of 3.5 or lower compared with SUVpeak higher than 3.5 with 2-year OS estimates of 51% vs. 37% (P = 0.29).
  • Exploratory analyses showed associations between OS and SUVpeak as a continuous variable, and binary cutoffs of SUVpeak 5.0 and 7.0.

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

    ReferenceSection

  • Lester JF, MacBeth FR, Coles B: Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 63 (3): 690-4, 2005.
  • Pöttgen C, Eberhardt W, Grannass A, et al.: Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 25 (31): 4987-92, 2007.
  • Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000.
  • Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.
  • Spiro SG, Rudd RM, Souhami RL, et al.: Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 59 (10): 828-36, 2004.
  • Clegg A, Scott DA, Hewitson P, et al.: Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57 (1): 20-8, 2002.
  • Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011.
  • Curran WJ, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011.
  • Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
  • Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
  • Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
  • Cerfolio RJ, Bryant AS, Winokur TS, et al.: Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg 78 (6): 1903-9; discussion 1909, 2004.
  • Pöttgen C, Levegrün S, Theegarten D, et al.: Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 12 (1): 97-106, 2006.
  • Eschmann SM, Friedel G, Paulsen F, et al.: 18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34 (4): 463-71, 2007.
  • Hellwig D, Graeter TP, Ukena D, et al.: Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg 128 (6): 892-9, 2004.
  • Cerfolio RJ, Bryant AS: When is it best to repeat a 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan on patients with non-small cell lung cancer who have received neoadjuvant chemoradiotherapy? Ann Thorac Surg 84 (4): 1092-7, 2007.
  • Mac Manus MP, Hicks RJ, Matthews JP, et al.: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 21 (7): 1285-92, 2003.
  • Machtay M, Duan F, Siegel BA, et al.: Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol 31 (30): 3823-30, 2013.
    • 非小细胞肺癌治疗(PDQ®)

    隐匿性NSCLC治疗

    隐匿性肺癌的诊断评估通常包括胸部X光片，必要时选择性使用支气管镜与密切随访（例如计算机断层扫描），以明确原发性肿瘤的部位与性质，这种方式发现的肿瘤通常为早期，可通过手术治愈。

    发现原发性肿瘤后，治疗前先明确肿瘤分期。 治疗方式等同于分期相同的其他非小细胞肺癌（NSCLC）患者。

    隐匿性NSCLC的标准治疗选择包括以下：

    隐匿性NSCLC的标准治疗选择包括以下：

  • 手术。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

    Non-Small Cell Lung Cancer Treatment (PDQ®)

    Occult NSCLC Treatment

    In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.

    After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other non-small cell lung cancer (NSCLC) patients with similar-stage disease.

    Standard Treatment Options for Occult NSCLC

    Standard treatment options for occult NSCLC include the following:

  • Surgery.

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

    非小细胞肺癌治疗(PDQ®)

    0期NSCLC治疗

    0期非小细胞肺癌（NSCLC）常进展为侵袭性癌症。

    可对患者行支气管镜随访，如检测到病变，可选治愈性治疗方法。

    0期NSCLC的标准治疗选择

    0期NSCLC的标准治疗选择包括以下：

  • 手术。
  • 支气管镜治疗包括光动力治疗、电烧、冷冻治疗和掺钕钇铝石榴石（Nd-YAG）激光治疗。

    • 手术

    因0期NSCLC患者发生第二肺癌的风险较高，故可行肺段切除术或楔形切除术以保留最多的正常肺组织。根据0期肿瘤的定义，这些肿瘤为非侵袭性且无转移性，故应行手术切除肿瘤，但如果发现病变位于中心，可能需要行肺叶切除术。

    支气管镜治疗

    中央型病变患者可根据情况选择治愈性经支气管镜治疗。保留肺功能的支气管镜治疗包括光动力治疗、电烧、冷冻治疗与Nd-YAG激光治疗。

    证据（支气管镜治疗）：

  • 一些小规模病例分析发现选定患者的完全缓解率偏高，且生存期延长。
  • [证据等级：3iiiDiii]

    • 这些治疗方式对早期NSCLC患者的有效性仍有待确定性随机对照临床试验的证实。

    第二原发性肿瘤的发病率较高。

    当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

    参考文献

  • Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 59 (7): 453-66, 1984.
  • Venmans BJ, van Boxem TJ, Smit EF, et al.: Outcome of bronchial carcinoma in situ. Chest 117 (6): 1572-6, 2000.
  • Jeremy George P, Banerjee AK, Read CA, et al.: Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax 62 (1): 43-50, 2007.
  • Kennedy TC, McWilliams A, Edell E, et al.: Bronchial intraepithelial neoplasia/early central airways lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 221S-233S, 2007.
  • Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
  • Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001.
  • van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998.
  • van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001.
    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Stage 0 NSCLC Treatment

    Stage 0 non-small cell lung cancer (NSCLC) frequently progresses to invasive cancer.

    Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies.

    Standard Treatment Options for Stage 0 NSCLC

    Standard treatment options for stage 0 NSCLC include the following:

  • Surgery.
  • Endobronchial therapies, including photodynamic therapy, electrocautery, cryotherapy, and neodymium-doped yttrium aluminum garnet (Nd-YAG) laser therapy.

    • Surgery

    Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue because patients with stage 0 NSCLC are at a high risk for second lung cancers. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.

    Endobronchial therapies

    Patients with central lesions may be candidates for curative endobronchial therapy. Endobronchial therapies that preserve lung function include photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.

    Evidence (endobronchial therapies):

  • Small case series have reported high complete response rates and long-term survival in selected patients.
  • [Level of evidence: 3iiiDiii]

    • Efficacy of these treatment modalities in the management of patients with early NSCLC remains to be proven in definitive randomized controlled trials.

    There is a high incidence of second primary cancers developing.

    Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

    ReferenceSection

  • Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 59 (7): 453-66, 1984.
  • Venmans BJ, van Boxem TJ, Smit EF, et al.: Outcome of bronchial carcinoma in situ. Chest 117 (6): 1572-6, 2000.
  • Jeremy George P, Banerjee AK, Read CA, et al.: Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax 62 (1): 43-50, 2007.
  • Kennedy TC, McWilliams A, Edell E, et al.: Bronchial intraepithelial neoplasia/early central airways lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 221S-233S, 2007.
  • Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
  • Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001.
  • van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998.
  • van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001.
    • 非小细胞肺癌治疗(PDQ®)

    IA与IB期NSCLC治疗

    IA与IB期NSCLC的标准治疗选择

    IA期非小细胞肺癌（NSCLC）与IB期NSCLC的标准治疗选择如下所示:

  • 手术。
  • 放疗（针对无法进行手术或选择不进行手术的患者）。

    • 在已经完全切除的I期NSCLC中，化疗和放疗后并未改善结局。

    手术

    手术是I期NSCLC患者的首选治疗。可根据情况选择肺叶切除术或肺段切除术、楔形切除术或袖状切除术。肺功能受损的原发性肿瘤患者适合行肺段切除术或楔形切除术。术前应详细评估患者的整体病情，尤其是肺储备功能，这对于考量手术获益至关重要。术后即刻死亡率与年龄相关，肺叶切除术的死亡率约为3%-5%。

    证据（手术）：

  • 肺癌研究小组进行了一项随机研究（LCSG-821），比较了肺叶切除术和有限切除术对I期肺癌患者的有效性。研究结果如下显示：
  • 与经有限切除术治疗的患者相比，接受肺叶切除术的患者局部复发率降低。
  • 总生存期（OS）无明显差异。
  • 比较解剖性肺段切除术和肺叶切除术的非随机临床试验中已报道了相似的结果。
  • 肺叶切除术对肿瘤径大于3 cm的患者具有生存期优势，但对于肿瘤径小于3 cm的患者则无生存期优势。
  • 肺叶切除术后局部复发率均显著降低，不考虑原发性肿瘤径。
  • 一项针对I期患者的研究显示：
  • 采用楔形切除术或肺段切除术治疗的患者尽管接受了完全切除术，但局部复发率仍为50%（即，62例患者中有31例复发）。
  • Cochrane协作网审查了11项随机试验，其中共1910例接受早期（I–IIIA）肺癌手术干预的患者。
  • 3项试验的汇总分析报告了以下内容：
  • 与接受切除术和淋巴结采样的NSCLC患者相比，接受切除术和同侧纵隔淋巴结系统性清扫（CMLND）的可切除I、II或IIIA期NSCLC患者的4年生存期更优；风险比（HR）估计为0.78（95%置信区间[CI]，0.65-0.93，P =0.005）。
  • [证据等级：1iiA]
  • CMLND组的任何癌症复发率（局部或远端）均显著降低（相对危险[RR]，0.79；95%CI，0.66-0.95；P =0.01），主要原因是远端复发数量减少（RR， 0.78；95% CI， 0.61–1.00；P =0.05）。
  • 手术死亡率无差异。
  • 持续超过5天的漏气在CMLND组的患者中更常见（RR， 2.94； 95% CI， 1.01–8.54；P =0.05）。
  • 在一项大型随机III期试验（ACOSOG-Z0030 [NCT00003831]）中评价了CMLND与淋巴结取样。
  • 手术发病率和死亡率的初步分析显示该手术的发生率相当。
  • OS、无病生存期、局部复发和区域复发无差异。
  • [证据等级：1iiA]

    • 目前证据表明在I、II或IIIA期NSCLC患者中，与肺癌切除术联合纵隔淋巴结系统采样相比，肺癌切除术联合CMLND无法改善生存期。

    [证据等级：1iiA]

    证据局限性（手术）：

    局灶性与区域性NSCLC患者行手术的有效性结论受限于迄今参与人数较少和试验的潜在方法学缺陷。

    辅助治疗

    很多术后患者发生区域或远端转移。

    这些患者适合纳入评估术后化疗或放疗的临床试验。 目前尚未证实术后化疗或放疗可改善已完全切除肿瘤的I期NSCLC患者的预后。

    辅助放疗

    有研究评估了术后（辅助）放疗（PORT）的意义，发现并不能改善完全切除肿瘤的I期NSCLC患者的预后。

    证据（辅助放疗）：

  • 根据10项随机对照试验和2,232例患者的结果进行荟萃分析，报告如下：
  • 与单独手术相比，接受PORT治疗的患者死亡风险相对增加18%（HR， 1.18；P = 0.002）。这相当于2年时的绝对损害率为6%（95%CI，2-9），OS从58%降低至52%。探索性亚组分析表明，这种不利影响在I/II期N0-N1疾病患者中最明显，而对于III期N2疾病患者，无明确的不良反应证据。
  • 局部（HR，1.13；P =0.02）、远端（HR，1.14；P =0.02）和总体（HR，1.10；P =0.06）无复发生存期的结果同样显示PORT有害。
  • [证据等级：1iiA]

    • 需行进一步分析判断这些预后是否可能随着技术进步、目标病变体积更明确和放疗射野中心脏受累体积更小而变化。

    辅助近距离放射治疗

    已经在接受肺叶切除术的I期NSCLC患者中评价了术中应用缝合线（辅助）近距离放射治疗的意义，以改善局部控制；尚未发现可改善预后。

    证据（辅助近距离放射治疗）：

  • 一项III期试验中随机分配了222例患者，接受亚肺叶切除术联合或不联合缝合线近距离放射治疗，结果报告如下：
  • 局部复发主要终点无差异（5年估计值，14.0% vs. 16.7%；P = 0.59）。
  • OS无差异（5年估计值，61.4% vs. 55.6%；P = 0.38）。
  • [证据等级：1iiDiii] vs [证据等级：1iiA]

    • 辅助化疗

    根据一项荟萃分析的结果，除临床试验之外，不建议I期NSCLC患者在完全切除术后行化疗。

    [证据等级：1iiA]

    证据（对I期NSCLC的辅助化疗）：

  • 收集了1995年含顺铂化疗后在完全切除肿瘤的NSCLC患者中实施的5项大型临床试验（4584例患者）的个体患者预后数据，并汇总进行一项荟萃分析。
  • 中位随访时间为5.2年时，总体死亡HR为0.89 （95%CI，0.82-0.96；P = 0.005），相当于化疗后5年绝对获益率为5.4%。
  • 获益随分期有所变化（趋势检验，P = 0.04；IA期HR，1.40；95%CI，0.95-2.06；IB期HR，0.93；95%CI，0.78-1.10；II期HR，0.83；95%CI，0.73-0.95；III期HR，0.83；95%CI，0.72-0.94）。
  • 化疗的效果与相关药物无显著差异（相互作用检验，P = 0.11），包括长春瑞滨（HR，0.80；95%CI，0.70–0.91）、依托泊苷或长春花生物碱（HR，0.92；95%CI，0.80–1.07）或其他药物（HR，0.97；95%CI，0.84–1.13）。
  • 长春瑞滨治疗后观察到的获益明显更大，这应谨慎解释，因为长春瑞滨和顺铂联合治疗通常需要给予更高剂量的顺铂。身体状态较好的患者的化疗效果较高。
  • 化疗效果与以下任何一项之间均无相互作用：
  • 性别。
  • 年龄。
  • 组织学。
  • 手术类型。
  • 计划放疗。
  • 计划的顺铂总剂量。
  • 一些其他随机对照临床试验与荟萃分析评估了术后化疗对I、II、IIIA期NSCLC患者的作用。

    • 尽管有充分证据表明术后化疗对II期或IIIA期NSCLC患者有效，但对IB期NSCLC患者的疗效尚不明确。

    证据（对IB期NSCLC的辅助化疗）：

  • 癌症和白血病B组研究（CALGB-9633 [NCT00002852]）阐述了辅助卡铂和紫杉醇的治疗结果以及344例切除肿瘤的IB期（即，病理T2，N0）NSCLC患者的OS观察结果。切除肿瘤后4-8周内，将患者随机分配至术后化疗组或观察组。
  • 生存期无显著差异（HR， 0.83；CI，0.64-1.08；P = 0.12），中位随访期为74个月。
  • 3-4级中性粒细胞减少症是主要毒性反应；无治疗相关死亡。
  • 事后探索性分析显示，对于肿瘤径≥4 cm的患者，显著的生存期差异有利于术后化疗（HR，0.69；CI，0.48-0.99；P =0.043）。

    • 对于观察到的生存期差异程度，CALGB-9633的效力可能不足以检出轻度但有临床意义的生存期改善。此外，卡铂与顺铂联合治疗可能会影响结果。 目前，尚无可靠证据证实术后化疗可延长IB期NSCLC患者的生存期

    [证据等级：1iiA]

    放疗

    可手术切除但有手术禁忌或肺储备功能良好但无法行手术的I期患者可选择治愈性放疗。

    常规放疗

    既往常用的主要放疗方法为用兆伏级设备对已知肿瘤体积中平面行约60 Gy至70 Gy分割放疗（1.8–2.0 Gy/天）。

    预后：

    在多项大型回顾性常规放疗研究中，接受确定性放疗且不可手术病灶患者的5年生存率达10%-30%。

    多项研究证实了T1、N0肿瘤患者的预后更佳，并发现该亚组5年生存率达30%-60%。

    然而，在接受60 Gy-65 Gy剂量常规放疗的患者中，多达50%的患者仅局部治疗失败。

    证据（常规放疗）：

  • 一份有关70岁以上可切除病灶（＜4 cm）且无法手术或拒绝接受手术的患者报告如下：
  • 根治性放疗后患者的5年生存期与历史对照组接受根治性切除术的同一年龄段患者相当。
  • 一些使用匹配对照的小规模病例分析结果如下：
  • 与外照射放疗（EBRT）相比，增加支气管近距离放射治疗可改善局部病灶控制。
  • [证据等级：3iiiDiii]

    • 很多患者因存在增加围手术期风险的合并症而无法行标准切除术。此时这些患者可考虑观察与放疗。

    非随机观察研究对比了切除术、放疗与观察的治疗结果，发现观察组患者的生存时间偏短、死亡率偏高。

    放疗技术的改进包括解释肿瘤运动的计划技术、更适形的计划技术（如3-D适形放疗和调强放疗）和治疗期间的影像引导。提供EBRT的现代治疗方法包括大分割放疗和立体定向体部放疗。但是，由于对比性研究的可靠数据有限，无法确定产生最佳效果的放疗方法。

    大分割放疗

    与常规分割放疗相比，大分割放疗涉及在较短的时间内每天给予略高剂量的放疗（如2.4-4.0 Gy）。 多项前瞻性I/II期试验证明，3-4周的60 Gy-70 Gy剂量大分割放疗（每天2.4 Gy-4.0 Gy）后中至重度毒性反应发生率较低，2年OS为50%-60%，2年肿瘤局部控制率为80%-90%。

    [证据等级：3iiiA]

    立体定向体部放疗（SBRT）

    SBRT包括在1至2周内给予的极大分割疗程（例如，1至5次治疗）中给予高度适形、高剂量放疗。 常用的治疗方案包括18 Gy×3、12 Gy-12.5 Gy×4、10 Gy-12 Gy×5，其生物学有效剂量明显高于历史常规放疗方案。

    多项前瞻性I/II期试验和中心多项研究已证明，SBRT的肺毒性反应发生率较低（症状性放射性肺炎的风险< 10%），2年OS为50%-60%，2年肿瘤控制率为90%-95%。

    [证据等级：3iiiA]

    证据（SBRT）：

  • 来自印第安纳大学的早期I/II期试验确定了三分段SBRT治疗T1肿瘤的最大耐受剂量为18 Gy×3，该治疗方案的2年OS为55%，2年局部肿瘤控制率为95%。
  • 中央型肿瘤（定义为从气管至叶支气管水平距气管支气管树2 cm以内）患者中观察到5级毒性反应发生率较高（8.6%），这让人难以接受。
  • 随后一项多中心试验（RTOG-0236 [NCT00087438]）仅在55例外周T1至T2肿瘤患者中研究了18 Gy×3治疗方案的疗效，并证实3年OS为56%，3年原发性肿瘤控制率为98%。
  • 中至重度毒性反应发生率较低，24%的患者出现3级毒性反应，4%的患者出现4级毒性反应，无患者出现5级毒性反应，3级放射性肺炎发生率为4%。
  • 阿姆斯特丹VU大学医学中心报告的大规模病例分析发现，676例T1-T2肿瘤患者采用风险调整方法（基于肿瘤接近关键器官的定制分割治疗方案）接受了三、五和八分段SBRT治疗。
  • 中位随访为32.9个月时，中位OS为40.7个月，2年局部肿瘤控制率为95%。
  • 虽然基于印第安纳州II期研究的数据，中心型部位为三分段SBRT的禁忌部位，但随后对315例患者（563个中心型肿瘤）的已发表报告进行系统性审查，结果显示严重毒性反应发生率偏低，包括较长期SBRT治疗方案（例如，4至10个治疗分段）的5级事件风险为1%-5%。
  • 一项多中心I/II期试验（RTOG-0813 [NCT00750269]）正在进行中，目的是确定5分段SBRT方案治疗中心型肿瘤的最大耐受剂量。

    • 常规放疗vs.SBRT（NCT01014130）、大分割放疗vs.SBRT（LUSTRE [NCT01968941]）的随机试验正在进行中，目的是确定最佳放疗方案，但立体定向体部放疗已广泛用于临床无法手术的I期NSCLC患者。

    处于临床评估阶段的治疗选择

    处于临床评估阶段的治疗选择如下所示：

  • 术后化疗预防临床试验（例如，经美国东部肿瘤协作组（ECOG）（ECOG-5597 [NCT00008385]试验证实）。
  • 支气管镜治疗（包括光动力治疗），针对精心选择的T1、N0、M0肿瘤患者。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

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  • Timmerman R, Papiez L, McGarry R, et al.: Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124 (5): 1946-55, 2003.
  • Timmerman R, McGarry R, Yiannoutsos C, et al.: Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 24 (30): 4833-9, 2006.
  • Lagerwaard FJ, Haasbeek CJ, Smit EF, et al.: Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 70 (3): 685-92, 2008.
  • Baumann P, Nyman J, Hoyer M, et al.: Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 27 (20): 3290-6, 2009.
  • Fakiris AJ, McGarry RC, Yiannoutsos CT, et al.: Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 75 (3): 677-82, 2009.
  • Timmerman R, Paulus R, Galvin J, et al.: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303 (11): 1070-6, 2010.
  • Senthi S, Lagerwaard FJ, Haasbeek CJ, et al.: Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol 13 (8): 802-9, 2012.
  • Senthi S, Haasbeek CJ, Slotman BJ, et al.: Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 106 (3): 276-82, 2013.
    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Stages IA and IB NSCLC Treatment

    Standard Treatment Options for Stages IA and IB NSCLC

    Standard treatment options for stages IA non-small cell lung cancer (NSCLC) and IB NSCLC include the following:

  • Surgery.
  • Radiation therapy (for patients who cannot have surgery or choose not to have surgery).

    • Chemotherapy and radiation therapy have not been shown to improve outcomes in stage I NSCLC that has been completely resected.

    Surgery

    Surgery is the treatment of choice for patients with stage I NSCLC. A lobectomy or segmental, wedge, or sleeve resection may be performed as appropriate. Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age related, but a 3% to 5% mortality rate with lobectomy can be expected.

    Evidence (surgery):

  • The Lung Cancer Study Group conducted a randomized study (LCSG-821) that compared lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed the following:
  • A reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision.
  • No significant difference in overall survival (OS).
  • Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.
  • A survival advantage was noted with lobectomy for patients with tumors larger than 3 cm but not for those with tumors smaller than 3 cm.
  • The rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.
  • A study of stage I patients showed the following:
  • Those treated with wedge or segmental resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.
  • The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.
  • A pooled analysis of three trials reported the following:
  • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND), compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93, P = .005).
  • [Level of evidence: 1iiA]
  • There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly because of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).
  • There was no difference in operative mortality.
  • Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).
  • CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030 [NCT00003831]).
  • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.
  • There was no difference in OS, disease-free survival, local recurrence, and regional recurrence.
  • [Level of evidence: 1iiA]

    • Current evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.

    [Level of evidence: 1iiA]

    Limitations of evidence (surgery):

    Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials.

    Adjuvant therapy

    Many patients treated surgically subsequently develop regional or distant metastases.

    Such patients are candidates for entry into clinical trials evaluating postoperative treatment with chemotherapy or radiation therapy following surgery. At present, neither chemotherapy nor radiation therapy has been found to improve the outcome of patients with stage I NSCLC that has been completely resected.

    Adjuvant radiation therapy

    The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated and has not been found to improve the outcome of patients with completely resected stage I NSCLC.

    Evidence (adjuvant radiation therapy):

  • A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:
  • An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2–9), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0-N1 disease, whereas for patients with stage III, N2 disease, there was no clear evidence of an adverse effect.
  • Results for local (HR, 1.13; P = .02), distant (HR, 1.14; P = .02), and overall (HR, 1.10; P = .06) recurrence-free survival similarly showed a detriment of PORT.
  • [Level of evidence: 1iiA]

    • Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

    Adjuvant brachytherapy

    The value of intraoperative (adjuvant) brachytherapy applied to the suture line has been evaluated in patients undergoing sublobar resections for stage I NSCLC to improve local control; it has not been found to improve outcomes.

    Evidence (adjuvant brachytherapy):

  • A phase III trial that randomly assigned 222 patients to undergo sublobar resection with or without suture line brachytherapy reported the following:
  • No difference in the primary endpoint of local recurrence (5-year estimate, 14.0% vs. 16.7%; P = .59).
  • No difference in OS (5-year estimate, 61.4% vs. 55.6%; P = .38).
  • [Level of evidence: 1iiDiii] vs [Level of evidence: 1iiA]

    • Adjuvant chemotherapy

    Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.

    [Level of evidence: 1iiA]

    Evidence (adjuvant chemotherapy for stage I NSCLC):

  • Data on individual patient outcomes from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC were collected and pooled into a meta-analysis.
  • With a median follow-up of 5.2 years, the overall HRdeath was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
  • The benefit varied with stage (test for trend, P = .04; HR for stage IA, 1.40; 95% CI, 0.95–2.06; HR for stage IB, 0.93; 95% CI, 0.78–1.10; HR for stage II, 0.83; 95% CI, 0.73–0.95; and HR for stage III, 0.83; 95% CI, 0.72–0.94).
  • The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
  • The apparent greater benefit seen with vinorelbine should be interpreted cautiously as vinorelbine and cisplatin combinations generally required that a higher dose of cisplatin be given. Chemotherapy effect was higher in patients with a better performance status.
  • There was no interaction between chemotherapy effect and any of the following:
  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.
  • Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.

    • Although there is sufficient evidence that postoperative chemotherapy is effective in patients with stage II or stage IIIA NSCLC, its usefulness in patients with stage IB NSCLC is less clear.

    Evidence (adjuvant chemotherapy for stage IB NSCLC):

  • The Cancer and Leukemia Group B study (CALGB-9633 [NCT00002852]) addressed the results of adjuvant carboplatin and paclitaxel versus observation for OS in 344 patients with resected stage IB (i.e., pathological T2, N0) NSCLC. Within 4 to 8 weeks of resection, patients were randomly assigned to postoperative chemotherapy or observation.
  • Survival was not significantly different (HR, 0.83; CI, 0.64–1.08; P = .12) at a median follow-up of 74 months.
  • Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths.
  • A post-hoc exploratory analysis demonstrated a significant survival difference in favor of postoperative chemotherapy for patients who had tumors 4 cm or larger in diameter (HR, 0.69; CI, 0.48–0.99; P = .043).

    • Given the magnitude of observed survival differences, CALGB-9633 may have been underpowered to detect small but clinically meaningful improvements in survival. In addition, the use of a carboplatin versus a cisplatin combination might have affected the results. At present, there is no reliable evidence that postoperative chemotherapy improves survival of patients with stage IB NSCLC.

    [Level of evidence: 1iiA]

    Radiation therapy

    Patients with potentially resectable tumors with medical contraindications to surgery or those with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent.

    Conventional radiation therapy

    Historically, conventional primary radiation therapy consisted of approximately 60 Gy to 70 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation (1.8–2.0 Gy per day).

    Prognosis:

    In the largest retrospective conventional radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% to 30%.

    Several series demonstrated that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 30% to 60% were found in this subgroup.

    However, local-only failure occurs in as many as 50% of patients treated with conventional radiation therapy to doses in the range of 60 Gy to 65 Gy.

    Evidence (conventional radiation therapy):

  • A single report of patients older than 70 years who had resectable lesions smaller than 4 cm but who had medically inoperable disease or who refused surgery reported the following:
  • Survival at 5 years after radiation therapy with curative intent was comparable with a historical control group of patients of similar age who were resected with curative intent.
  • A small case series using matched controls reported the following:
  • The addition of endobronchial brachytherapy improved local disease control compared with external-beam radiation therapy (EBRT).
  • [Level of evidence: 3iiiDiii]

    • A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Observation and radiation therapy may be considered for these patients.

    Nonrandomized observational studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients treated with observation only.

    Improvements in radiation techniques include planning techniques to account for tumor motion, more conformal planning techniques (e.g., 3-D conformal radiation therapy and intensity-modulated radiation therapy), and image guidance during treatment. Modern approaches to delivery of EBRT include hypofractionated radiation therapy and stereotactic body radiation therapy (SBRT).However, there are limited reliable data from comparative trials to determine which approaches yield superior outcomes.

    Hypofractionated radiation therapy

    Hypofractionated radiation therapy involves the delivery of a slightly higher dose of radiation therapy per day (e.g., 2.4–4.0 Gy) over a shorter period of time compared with conventionally fractionated radiation therapy. Multiple prospective phase I/II trials have demonstrated that hypofractionated radiation therapy to a dose of 60 Gy to 70 Gy delivered over 3 to 4 weeks with 2.4 Gy to 4.0 Gy per day resulted in a low incidence of moderate to severe toxicity, 2-year OS of 50% to 60%, and 2-year tumor local control of 80% to 90%.

    [Level of evidence: 3iiiA]

    Stereotactic body radiation therapy (SBRT)

    SBRT involves the delivery of highly conformal, high-dose radiation therapy over an extremely hypofractionated course (e.g., one to five treatments) delivered over 1 to 2 weeks. Commonly used regimens include 18 Gy × 3, 12 Gy to 12.5 Gy × 4, and 10 Gy to 12 Gy × 5, and deliver a substantially higher biologically effective dose compared with historic conventional radiation therapy regimens.

    Multiple prospective phase I/II trials and institutional series have demonstrated that SBRT results in a low incidence of pulmonary toxicity (<10% risk of symptomatic radiation pneumonitis), 2-year OS of 50% to 60%, and 2-year tumor control of 90% to 95%.

    [Level of evidence: 3iiiA]

    Evidence (SBRT):

  • Early phase I/II trials from Indiana University identified the maximum tolerated dose of three-fraction SBRT at 18 Gy × 3 for T1 tumors, and this regimen resulted in 2-year OS of 55% and 2-year local tumor control of 95%.
  • An unacceptably high incidence (8.6%) of grade 5 toxicity was observed in patients with central tumors (defined as within 2 cm of the tracheobronchial tree from the trachea to the level of the lobar bronchi).
  • A subsequent multicenter trial (RTOG-0236 [NCT00087438]) studied the 18 Gy × 3 regimen in 55 patients with peripheral T1 to T2 tumors only and demonstrated 3-year OS of 56% and 3-year primary tumor control of 98%.
  • The incidence of moderate to severe toxicity was low, with grade 3 toxicity in 24% of patients, grade 4 toxicity in 4% of patients, and no grade 5 toxicity, with a 4% incidence of grade 3 radiation pneumonitis.
  • In the largest reported series from VU University Medical Center Amsterdam, 676 patients with T1 to T2 tumors were treated with three-, five-, and eight-fraction SBRT using a risk-adapted approach (a tailored fractionation regimen based on tumor proximity to critical organs).
  • With a median follow-up of 32.9 months, the median OS was 40.7 months, and 2-year local tumor control was 95%.
  • While central location is a contraindication to three-fraction SBRT based on data from the Indiana phase II study, a subsequent systematic review of published reports of 315 patients with 563 central tumors demonstrated a much lower incidence of severe toxicity, including a 1% to 5% risk of grade 5 events with more protracted SBRT regimens (e.g., four to ten fractions).
  • A multicenter phase I/II trial (RTOG-0813 [NCT00750269]) is ongoing to identify the maximum tolerated dose for a five-fraction SBRT regimen for central tumors.

    • Randomized trials of conventional radiation therapy versus SBRT (NCT01014130), and hypofractionated radiation therapy versus SBRT (LUSTRE [NCT01968941]) are ongoing to determine the optimal radiation therapy regimen, but stereotactic body radiation therapy has been widely adopted for patients with medically inoperable stage I NSCLC.

    Treatment Options Under Clinical Evaluation

    Treatment options under clinical evaluation include the following:

  • Clinical trials of postoperative chemoprevention (as evidenced in the Eastern Cooperative Oncology Group (ECOG) (ECOG-5597 [NCT00008385] trial, for example).
  • Endobronchial therapies, including photodynamic therapy, for highly selected patients with T1, N0, M0 tumors.

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

    ReferenceSection

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  • Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.
  • Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
  • Strauss GM, Herndon JE, Maddaus MA, et al.: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26 (31): 5043-51, 2008.
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  • Timmerman R, McGarry R, Yiannoutsos C, et al.: Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 24 (30): 4833-9, 2006.
  • Lagerwaard FJ, Haasbeek CJ, Smit EF, et al.: Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 70 (3): 685-92, 2008.
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  • Senthi S, Haasbeek CJ, Slotman BJ, et al.: Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 106 (3): 276-82, 2013.
    • 非小细胞肺癌治疗(PDQ®)

    IIA与IIB期NSCLC治疗

    IIA与IIB期NSCLC的标准治疗选择

    IIA期非小细胞肺癌（NSCLC）与IIB期NSCLC的标准治疗选择如下所示：

  • 手术。
  • 辅助化疗。
  • 新辅助化疗。
  • 放疗（针对无法进行手术的患者）。

    • 辅助放疗尚未显示出可改善II期NSCLC患者的预后。

    手术

    手术是II期NSCLC患者的首选治疗。可根据情况选择肺叶切除术、全肺切除术或肺段切除术、楔形切除术或袖状切除术。术前应详细评估患者的整体病情，尤其是肺储备功能，这对于考量手术获益至关重要。不考虑术后即刻死亡率和术后死亡率与年龄相关之外，全肺切除术的死亡率约为5%-8%，肺叶切除术的死亡率约为3%-5%。

    证据（手术）：

  • Cochrane协作网审查了11项随机试验，其中共1,910例接受早期（I–IIIA）肺癌手术干预的患者。
  • 3项试验的汇总分析报告了以下内容：
  • 与接受切除术和淋巴结采样的NSCLC患者相比，接受切除术和同侧纵隔淋巴结系统性清扫（CMLND）的可切除I、II或IIIA期NSCLC患者的4年生存期更优；风险比（HR）估计为0.78（95%置信区间[CI]，0.65-0.93；P =0.005）。
  • [证据等级：1iiA]
  • CMLND组的任何癌症复发率（局部或远端）均显著降低（相对危险[RR]，0.79；95%CI，0.66-0.95；P =0.01），主要原因是远端复发数量减少（RR， 0.78；95% CI， 0.61–1.00；P =0.05）。
  • 手术死亡率无差异。
  • 在分配至CMLND组的患者中，持续超过5天的漏气显著更常见（RR， 2.94； 95% CI， 1.01–8.54；P =0.05）。
  • 在一项大型随机III期试验（ACOSOG-Z0030 [NCT00003831]）中评价了CMLND与淋巴结取样。
  • 手术发病率和死亡率的初步分析显示该手术的发生率相当。
  • 总生存期（OS）、无病生存期（DFS）、局部复发和区域复发无差异。
  • [证据等级：1iiA]

    • 目前证据表明在I、II或IIIA期NSCLC患者中，与肺癌切除术联合纵隔淋巴结系统采样相比，肺癌切除术联合CMLND无法改善生存期。

    [证据等级：1iiA]

    证据局限性（手术）：

    局灶性与区域性NSCLC患者行手术的有效性结论受限于迄今参与人数较少和试验的潜在方法学缺陷。

    辅助化疗

    多数证据表明术后顺铂联合化疗显著改善切除肿瘤的II期NSCLC患者的生存期。 术前化疗也可改善生存期。手术与化疗之间的先后顺序及术后放疗对可切除NSCLC患者的获益风险特征仍待评估。

    术后许多患者发生区域性或远端转移病灶。

    一些随机对照临床试验与荟萃分析评估了术后化疗对I、II、IIIA期NSCLC患者的作用。

    证据（辅助放疗）：

  • 收集了1995年含顺铂化疗后在完全切除肿瘤的NSCLC患者中实施的5项大型临床试验（4584例患者）的个体患者预后数据，并汇总进行一项荟萃分析。
  • 中位随访时间为5.2年时，总体死亡HR为0.89 （95%CI，0.82-0.96；P = 0.005），相当于化疗后5年绝对获益率为5.4%。
  • 获益随分期有所变化（趋势检验，P = 0.04；IA期HR，1.40；95%CI，0.95-2.06；IB期HR，0.93；95%CI，0.78-1.10；II期HR，0.83；95%CI，0.73-0.95；III期HR，0.83；95%CI，0.72-0.94）。
  • 化疗的效果与相关药物无显著差异（相互作用检验，P = 0.11），包括长春瑞滨（HR，0.80；95%CI，0.70–0.91）、依托泊苷或长春花生物碱（HR，0.92；95%CI，0.80–1.07）或其他药物（HR，0.97；95%CI，0.84–1.13）。
  • 与其他治疗方案相比，顺铂加长春瑞滨双联合治疗后观察到对生存期的影响更大，这应谨慎解释，因为接受的顺铂总剂量显著高于接受长春瑞滨治疗的患者中使用的剂量。
  • 荟萃分析和单项研究 支持术后含顺铂化疗联合长春瑞滨的治疗方案。
  • 顺铂辅助治疗肺评估（LACE）汇总分析（汇总HR，0.83；95%CI，0.73-0.95）、长春瑞滨辅助治疗国际试验师协会（ANITA）试验（HR，0.71；95%CI，0.49-1.03）以及加拿大国家癌症研究所临床试验组JBR.10试验（HR，0.59；95%CI，0.42–0.85）报告，试验人群和II期肿瘤患者的OS更优。
  • 体能状态（PS）较好的患者的化疗效果较好。
  • 化疗效果与以下任何一项之间均无相互作用：
  • 性别。
  • 年龄。
  • 组织学。
  • 手术类型。
  • 计划放疗。
  • 计划的顺铂总剂量。
  • 对一项术后顺铂和长春瑞滨治疗的III期试验进行了回顾性分析，结果发现65岁以上患者可从治疗中获益。
  • 化疗显著延长了老年患者的OS（HR，0.61；95%CI，0.38-0.98；P = 0.04）。
  • 尽管老年患者接受的治疗较少，但各年龄组的毒性反应、住院或治疗相关死亡无显著差异。
  • 一些其他随机对照临床试验与荟萃分析评估了术后化疗对I、II、IIIA期NSCLC患者的作用。

    • 基于这些数据，完全切除肿瘤的II期肺癌患者可能从术后含顺铂化疗中获益。

    [证据等级：1iiA]

    新辅助化疗

    一些临床试验研究了术前化疗的作用。 术前化疗的潜在获益包括：

  • 减少肿瘤体积，利于手术切除。
  • 早期根治微转移灶。
  • 提高患者的耐受性。

    • 但术前化疗有可能延误治愈性手术。

    证据（新辅助化疗）：

  • Cochrane协作网报告了7项随机对照试验的系统审查和荟萃分析结果，其中该试验包括988例患者并评价了手术加术前化疗与单独手术的有效性。这些试验评价了I、II和IIIA期NSCLC患者。
  • 术前化疗后所有分期病灶的生存率绝对提高了6％，5年生存率从14%提高至20%（HR，0.82；95%CI，0.69-0.97；P =0.022）。
  • [证据等级：1iiA]
  • 该分析无法解决诸如特定类型的患者是否可能在术前化疗中获益更多或更少等问题。
  • 在迄今为止报告的大型试验中，将519例患者随机分配至两组，一组接受单独手术，另一组接受3个疗程的含铂化疗，随后进行手术。多数患者（61%）的临床分期为I期；31%为II期；7%为III期。
  • 未观察到生存期优势。
  • 组间术后并发症相似，未观察到生活质量受损。
  • 无证据表明在OS方面获益（HR，1.02；95%CI，0.80-1.31；P = 0.86）。
  • 通过增加目前的结果更新系统审查结果，表明增加新辅助（术前）化疗的相对生存期获益为12%（1507例患者；HR，0.88；95%CI，0.76–1.01；P = 0.07），相当于5年生存率绝对提高5%。

    • 辅助放疗

    已评价了术后（辅助）放疗（PORT）的意义。

    证据（辅助放疗）：

  • 根据10项随机对照试验和2,232例患者的结果进行荟萃分析，报告如下：
  • 与单独手术相比，接受PORT治疗的患者死亡风险相对增加18%（HR， 1.18；P = 0.002）。这相当于2年时的绝对损害率为6%（95%CI，2%–9%），OS从58%降低至52%。探索性亚组分析表明，这种不利影响在I/II期N0-N1疾病患者中最明显，而对于III期N2疾病患者，无明确的不良反应证据。
  • 局部（HR，1.13；P =0.02）、远端（HR，1.14；P =0.02）和总体（HR，1.10；P =0.06）无复发生存期的结果同样显示PORT有害。
  • [证据等级：1iiA]

    • 需行进一步分析判断这些预后是否可能随着技术进步、目标病变体积更明确和放疗射野中心脏受累体积更小而变化。

    放疗

    可手术切除但有手术禁忌或肺储备功能良好但无法行手术的II期患者可选择治愈性放疗。

    主要放疗方法为用兆伏级设备对已知肿瘤中平面行约60 Gy分割放疗。 原发性肿瘤锥形束野的加量照射常用于强化对肿瘤的局部控制。 为得到最佳治疗效果，需使用模拟器进行详细的治疗计划，准确了解目标体积，尽可能避开关键的正常结构。

    预后：

    PS较佳的患者中，如能完成治愈性放疗疗程，则预期3年生存率为20%。

    证据（放疗）：

  • 在迄今为止报告的大型回顾性研究中，152例无法手术的NSCLC患者接受确定性放疗。研究报告如下所示：
  • 5年OS率为10%。
  • 44例T1期肿瘤患者的DFS精算率为60%。
  • 此回顾性研究还表明，大于60 Gy剂量放疗后DFS得到改善。

    • 处于临床评估阶段的治疗选择

    处于临床评估阶段的治疗选择如下所示：

  • 根治性手术后放疗的临床试验。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

    参考文献

  • Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.
  • Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006.
  • Darling GE, Allen MS, Decker PA, et al.: Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 141 (3): 662-70, 2011.
  • Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.
  • Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005.
  • Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.
  • Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008.
  • Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.
  • Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.
  • Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.
  • Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
  • Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006.
  • Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007.
  • Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007.
  • Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007.
  • PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
  • Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.
  • Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992.
    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Stages IIA and IIB NSCLC Treatment

    Standard Treatment Options for Stages IIA and IIB NSCLC

    Standard treatment options for stages IIA non-small cell lung cancer (NSCLC) and IIB NSCLC include the following:

  • Surgery.
  • Adjuvant chemotherapy.
  • Neoadjuvant chemotherapy.
  • Radiation therapy (for patients who cannot have surgery).

    • Adjuvant radiation therapy has not been shown to improve outcomes in patients with stage II NSCLC.

    Surgery

    Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, or segmental resection, wedge resection, or sleeve resection may be performed as appropriate. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. Despite the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.

    Evidence (surgery):

  • The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.
  • A pooled analysis of three trials reported the following:
  • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND), compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93; P = .005).
  • [Level of evidence: 1iiA]
  • There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly as the result of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).
  • There was no difference in operative mortality.
  • Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).
  • CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030 [NCT00003831]).
  • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.
  • There was no difference in overall survival (OS), disease-free survival (DFS), local recurrence, and regional recurrence.
  • [Level of evidence: 1iiA]

    • Current evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.

    [Level of evidence: 1iiA]

    Limitations of evidence (surgery):

    Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and potential methodological weaknesses of the trials.

    Adjuvant chemotherapy

    The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC remain to be determined.

    After surgery, many patients develop regional or distant metastases.

    Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.

    Evidence (adjuvant chemotherapy):

  • Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.
  • With a median follow-up time of 5.2 years, the overall HRdeath was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
  • The benefit varied with stage (test for trend, P = .04; HR for stage IA, 1.40; 95% CI, 0.95–2.06; HR for stage IB, 0.93; 95% CI, 0.78–1.10; HR for stage II, 0.83; 95% CI, 0.73–0.95; and HR for stage III, 0.83; 95% CI, 0.72–0.94).
  • The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
  • The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted cautiously as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
  • The meta-analysis and the individual studies support the administration of postoperative cisplatin-based chemotherapy in combination with vinorelbine.
  • Superior OS for the trial population and patients with stage II disease was reported for the Lung Adjuvant Cisplatin Evaluation (LACE) pooled analysis (pooled HR, 0.83; 95% CI, 0.73–0.95); the Adjuvant Navelbine International Trialist Association (ANITA) trial (HR, 0.71; 95% CI, 0.49–1.03); and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial (HR, 0.59; 95% CI, 0.42–0.85).
  • Chemotherapy effect was higher in patients with better performance status (PS).
  • There was no interaction between chemotherapy effect and any of the following:
  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.
  • In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.
  • Chemotherapy significantly prolonged OS for elderly patients (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
  • There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elderly patients received less treatment.
  • Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.

    • Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.

    [Level of evidence: 1iiA]

    Neoadjuvant chemotherapy

    The role of chemotherapy before surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include the following:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

    • Preoperative chemotherapy may, however, delay potentially curative surgery.

    Evidence (neoadjuvant chemotherapy):

  • The Cochrane Collaboration reported a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone. These trials evaluated patients with stages I, II, and IIIA NSCLC.
  • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).
  • [Level of evidence: 1iiA]
  • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.
  • In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery. Most patients (61%) had clinical stage I disease; 31% had stage II disease; and 7% had stage III disease.
  • No survival advantage was seen.
  • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
  • There was no evidence of a benefit in terms of OS (HR, 1.02; 95% CI, 0.80–1.31; P = .86).
  • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant (preoperative) chemotherapy (1,507 patients; HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.

    • Adjuvant radiation therapy

    The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.

    Evidence (adjuvant radiation therapy):

  • A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:
  • An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2%–9%), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0–N1 disease, whereas for patients with stage III, N2 disease there was no clear evidence of an adverse effect.
  • Results for local (HR, 1.13; P = .02), distant (HR, 1.14; P = .02), and overall (HR, 1.10; P = .06) recurrence-free survival similarly showed a detriment of PORT.
  • [Level of evidence: 1iiA]

    • Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

    Radiation therapy

    Patients with potentially operable tumors with medical contraindications to surgery or those with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.

    Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of the known tumor using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures, to the extent possible, is needed for optimal results; this requires the use of a simulator.

    Prognosis:

    Among patients with excellent PS, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed.

    Evidence (radiation therapy):

  • In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC were treated with definitive radiation therapy. The study reported the following:
  • A 5-year OS rate of 10%.
  • Forty-four patients with T1 tumors achieved an actuarial DFS rate of 60%.
  • This retrospective study also suggested that improved DFS was obtained with radiation therapy doses greater than 60 Gy.

    • Treatment Options Under Clinical Evaluation

    Treatment options under clinical evaluation include the following:

  • Clinical trials of radiation therapy after curative surgery.

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

    ReferenceSection

  • Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.
  • Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006.
  • Darling GE, Allen MS, Decker PA, et al.: Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 141 (3): 662-70, 2011.
  • Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.
  • Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005.
  • Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.
  • Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008.
  • Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.
  • Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.
  • Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.
  • Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
  • Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006.
  • Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007.
  • Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007.
  • Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007.
  • PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
  • Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.
  • Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992.
    • 非小细胞肺癌治疗(PDQ®)

    IIIA期NSCLC治疗

    IIIA期非小细胞肺癌（NSCLC）患者群具有较大的异质性。 患者可能有同侧转移、纵膈淋巴结转移、可能切除的T3期肿瘤侵及胸壁、或纵膈受累、支气管周围或肺门淋巴结转移（N1）。 肿瘤表现从有镜下转移的可切除肿瘤到淋巴结转移到有多站淋巴结受累的不可切除的较大肿瘤病变。

    预后：

    临床IIIA N2期患者的5年总生存（OS）率为10%-15%，但存在较大纵膈受累（即胸片可见病变）的患者5年生存率为2%-5%。 III期NSCLC患者可选的主要治疗方式包括放疗、化疗、手术及联合治疗，具体选择取决于临床情况。

    根据肿瘤部位与是否可切除选择治疗方法。

    IIIA N2期NSCLC切除术后或可切除肿瘤的标准治疗选择

    尽管经过细致的术前分期，仍发现一些患者在开胸手术时有纵膈N2淋巴结转移。

    切除术后/可切除肿瘤的标准治疗选择包括：

  • 手术。
  • 新辅助治疗。
  • 新辅助化疗。
  • 新辅助放化疗。
  • 辅助治疗。
  • 辅助化疗。
  • 辅助放化疗。
  • 辅助放疗。

    • 多数证据表明术后顺铂联合化疗显著改善隐匿性N2期NSCLC切除术后患者的生存期。手术与化疗之间的先后顺序及术后放疗对可切除NSCLC患者的获益风险特征仍待评估。

    手术

    如果完全切除肿瘤与淋巴结具可行性，此类患者可获益于手术及术后化疗。目前证据表明I、II或IIIA期NSCLC患者中，与行肺癌切除术加纵隔淋巴结系统采样相比，行肺癌切除术联合同侧纵膈系统性淋巴结清扫术（CMLND）无法改善生存期。

    [证据等级：1iiA]

    在一项III期试验中，对IIIA期NSCLC患者在放化疗基础上行手术治疗并没有改善OS，但确实改善了无进展生存期(PFS)和局部控制。

    [证据等级：1iiDiii]

    证据（手术）：

  • Cochrane协作网审查了11项随机试验，其中共1,910例接受早期（I–IIIA）肺癌手术干预的患者。
  • 3项试验的汇总分析报告了以下内容：
  • 与接受切除术和淋巴结采样的NSCLC患者相比，接受切除术和CMLND的可切除I、II或IIIA期NSCLC患者的4年生存期更优；风险比（HR）估计为0.78（95%置信区间[CI]，0.65-0.93；P =0.005）。
  • [证据等级：1iiA]
  • 在一项大型随机III期试验（ACOSOG-Z0030）中评价了CMLND与淋巴结采样。手术发病率和死亡率的初步分析显示该手术的发生率相当。
  • OS、无病生存期（DFS）、局部复发和区域复发无差异。
  • [证据等级：1iiA]

    • 证据局限性（手术）：

    局灶性与区域性NSCLC患者行手术的有效性结论受限于迄今参与人数较少和试验的潜在方法学缺陷。

    新辅助治疗

    新辅助化疗

    一些临床试验研究了术前化疗对III N2期NSCLC患者的作用。术前（新辅助）化疗的潜在获益包括：

  • 减少肿瘤体积，利于手术切除。
  • 早期根治微转移灶。
  • 提高患者的耐受性。

    • 证据（新辅助化疗）：

  • Cochrane协作网报告了7项随机对照试验的系统审查和荟萃分析结果，其中该试验包括988例患者并评价了手术加术前化疗与单独手术的有效性。
  • 这些试验评价了I、II和IIIA期NSCLC患者。
  • 术前化疗后所有分期病灶的生存率绝对提高了6％，5年生存率从14%提高至20%（HR，0.82；95%CI，0.69-0.97；P =0.022）。
  • [证据等级：1iiA]
  • 该分析无法解决诸如特定类型的患者是否可能或多或少从术前化疗中获益等问题。
  • 在迄今为止报告的大型试验中，将519例患者随机分配至两组，一组接受单独手术，另一组接受3个疗程的含铂化疗，随后进行手术。
  • 多数患者（61%）的临床分期为I期，31%为II期，7%为III期。
  • 组间术后并发症相似，未观察到生活质量受损。
  • 无证据表明在OS方面获益（HR，1.02；95%CI，0.80-1.31；P = 0.86）。
  • 通过增加目前的结果更新系统审查结果，表明增加术前化疗的相对生存期获益为12%（1507例患者；HR，0.88；95%CI，0.76–1.01；P = 0.07），相当于5年生存率绝对提高5%。

    • 新辅助放化疗

    术前给予新辅助化疗联合放疗可强化治疗效果，增加肿瘤负荷降期的可能性。 已在II期试验中研究的常用治疗方案包括顺铂/依托泊苷（EP5050）和每周一次卡铂/紫杉醇。

    在新辅助放化疗和手术vs.单独同步放化疗的随机试验中，OS无差异，但手术治疗后改善了PFS和局部控制。

    [证据等级：1iiDiii]

    证据（新辅助放化疗）：

  • Intergroup-0139 [NCT00002550]试验比较了单独放化疗与新辅助放化疗继之以手术治疗在396例IIIa期NSCLC患者中的有效性。
  • 手术未改善OS（5年OS，27% vs. 20%；HR：0.87 [0.70–1.10]；P =0.24）。
  • 手术改善了PFS（5年PFS，22%vs. 11%；HR 0.77 [0.62-0.96]；P =0.017）并降低了局部复发风险（10%vs. 22%；P =0.002）。
  • 新辅助放化疗加手术治疗后死亡率增加（8% vs. 2%），尤其是在接受肺切除术的患者亚组中。

    • 迄今为止，尚未使用现代治疗方案对新辅助化疗与新辅助放化疗进行直接比较；最佳新辅助治疗方法仍不明确。

    辅助治疗

    辅助化疗

    完全切除肿瘤的IIIA期NSCLC患者可能从术后含顺铂化疗中获益。

    [证据等级：1iiA]

    证据（辅助放疗）：

    随机对照临床试验证据表明如手术中意外发现IIIA期NSCLC，完全切除术后行化疗可延长生存期。

    一些随机对照临床试验与荟萃分析评估了术后化疗对I、II、IIIA期NSCLC患者的作用。

  • 收集了1995年含顺铂化疗后在完全切除肿瘤的NSCLC患者中实施的5项大型临床试验（4,584例患者）的个体患者预后数据，并汇总进行一项荟萃分析。
  • 中位随访时间为5.2年时，总体死亡HR为0.89 （95%CI，0.82-0.96；P = 0.005），相当于化疗后5年绝对获益率为5.4%。
  • 化疗的效果与相关药物无显著差异（相互作用检验，P = 0.11），包括长春瑞滨（HR，0.80；95%CI，0.70–0.91）、依托泊苷或长春花生物碱（HR，0.92；95%CI，0.80–1.07）或其他药物（HR，0.97；95%CI，0.84–1.13）。
  • 获益随分期有所差异（IIIA期HR为0.83；95％CI为0.72-0.94）。
  • 与其他治疗方案相比，顺铂加长春瑞滨双联合治疗后观察到对生存期的影响更大，这一结论应当被谨慎解读，因为接受的顺铂总剂量显著高于接受长春瑞滨治疗的患者中使用的剂量。
  • 两项试验（FRE-IALT和长春瑞滨辅助治疗国际试验师协会[ANITA]试验）报告了与IIIA期疾病术后化疗相关的显著OS获益。
  • 对于ANITA试验中的IIIA期患者亚组（n = 325），HR为0.69（95%CI，0.53-0.90），FRE-IALT试验（n = 728）的结果为HR，0.79 （95%CI，0.66-0.95）。
  • 体能状态（PS）较好的患者的化疗效果较优。
  • 化疗效果与以下任何一项之间均无相互作用：
  • 性别。
  • 年龄。
  • 组织学。
  • 手术类型。
  • 计划放疗。
  • 计划的顺铂总剂量。
  • 对一项术后顺铂和长春瑞滨治疗的III期试验进行了回顾性分析，结果发现65岁以上患者可从治疗中获益。
  • 化疗显著延长了老年患者的OS（HR，0.61；95%CI，0.38-0.98；P = 0.04）。
  • 尽管老年患者接受的治疗较少，但各年龄组的毒性反应、住院或治疗相关死亡无显著差异。

    • 辅助放化疗

    术前或术后给予的联合化疗和放疗应视为试验性治疗，并需要在未来的临床试验中进行评价。

    证据（辅助放化疗）：

  • 5项随机临床试验评估了手术切除后的术后联合放化疗与放疗的意义。
  • [证据等级：1iiA]
  • 仅1项试验报告DFS改善，无试验报告OS改善。
  • 3项试验评价了含铂联合化疗继之以手术与含铂化疗继之以单独放疗（60-69.6 Gy）的有效性，以确定手术或放疗是否最有效。
  • 尽管研究规模较小，但入组了73（放疗肿瘤组[RTOG]）（RTOG 89-01）、107（德克萨斯大学M.D.安德森癌症中心）和333（欧洲癌症研究和治疗组织[EORTC-08941；NCT00002623]）IIIa N2期患者，无临床试验报告局部控制或生存期的差异。
  • [证据等级：1iiA]
  • 在多项大型研究（EORTC-08941）中，579例经组织学或细胞学证实的IIIa N2期NSCLC患者接受3个疗程的含铂诱导化疗。
  • 随后333例缓解患者随机接受手术切除或放疗。154例（92%）接受手术的患者中，50%接受了根治性切除术，42%病理学分期降低，5%出现病理学完全缓解；4%在术后死亡。手术组62例（40%）接受术后（辅助）放疗（PORT）。在154例（93%）接受放疗的患者中，对放疗处方的总体依从性为55%，4%和7%患者发生3-4级急性和晚期食管、肺毒性反应；1例死于放射性肺炎。
  • 分配至肿瘤切除术组的患者的中位OS为16.4个月，分配至放疗组的患者为17.5个月；分配至肿瘤切除术组的患者的5年OS为15.7%，分配至放疗组的患者为14%（HR，1.06；95%CI，0.84-1.35）。
  • 两组的PFS率也相似。鉴于其发病率和死亡率较低，即得出结论：放疗应视为这些患者的首选局部治疗。

    • 辅助放疗

    已评估了PORT的意义。

    虽然一些研究认为PORT可改善术后淋巴结阳性患者的局部控制，但PORT是否改善患者生存期目前仍有争议。胸部PORT的最佳剂量尚不明确。多数研究的剂量为30 Gy-60 Gy，通常分割为2Gy-2.5Gy。

    加拿大国家癌症研究所与组间研究JBR.10（NCT00002583）发现，符合下列任一条件，可以考虑在选定的患者中行PORT来降低局部复发的风险:

  • 多站淋巴结受累。
  • 包膜外肿瘤细胞扩散。
  • 邻近切缘或切缘镜下阳性。

    • 证据（辅助放疗）：

    来自一项大型荟萃分析、多项随机临床试验的子集分析和一项大型人群研究的证据表明PORT可能降低局部复发率。 这些研究中关于PORT对OS影响的结果并不一致。

  • 10项评价PORT与单独手术的随机试验的荟萃分析显示：
  • 整个PORT组或N2患者子集的OS无差异。
  • [证据等级：1iiA]
  • 对比接受或未接受PORT的N2患者中5年OS的ANITA试验进行了非随机亚组分析，结果如下所述：
  • 观察组（接受PORT的患者为21%，未接受PORT的患者为17%）和化疗组（接受PORT的患者为47%，未接受PORT的患者为34%）中接受放疗的患者的生存率更高；然而，未进行比较的统计学检验。
  • 监测、流行病学和结局（SEER）项目的结果如下所示：
  • 大型SEER回顾性研究（N = 7,465）发现，对N2期肿瘤放疗后生存率更优（HR，0.855；95%CI，0.762–0.959）

    • IIIA N2期患者可获益于PORT，但PORT对早期NSCLC的作用仍待III期临床试验阐明。 需行进一步分析判断是否可随着技术进步、目标病变体积更明确和放疗射野中心脏受累体积更小而变化。

    不可切除IIIA N2期NSCLC的标准治疗选择

    不可切除NSCLC患者的标准治疗选择包括以下：

  • 放疗。
  • 针对局部晚期不可切除的肿瘤治疗。
  • 针对需要姑息性治疗的患者。
  • 放化疗。

    • 放疗

    针对局部晚期不可切除的肿瘤治疗

    化疗后放疗与放疗联合化疗可能有益于局部晚期不可切除III期NSCLC患者。

    预后：

    传统剂量放疗与分割放疗（每日每次1.8-2.0Gy，6-7周总量60-70Gy）使得患者的长期生存期获益5%-10%，结果可复制，且明显缓解症状。

    证据（放疗治疗局部晚期不可切除肿瘤）：

  • 一项前瞻性随机临床研究表明：
  • 与每日一次放疗相比，连续（包括周末）每日3次（连续超分割加速放疗）放疗后OS改善。
  • [证据等级：1iiA]
  • 接受单独放疗的患者的失败模式包括局部和远处复发。

    • 虽然不可切除IIIA期肿瘤患者可能获益于放疗，但因存在局部与全身复发，故长期效果总体较差。

    针对需要姑息性治疗的患者

    放疗可缓解NSCLC患者的局部受累症状，例如：

  • 气管、食管或支气管压迫。
  • 疼痛。
  • 声带麻痹。
  • 咯血。
  • 上腔静脉综合征。

    • 有时可用经支气管镜激光治疗和/或近距离放射治疗缓解近端梗阻性病变。

    证据（放疗作为姑息性治疗）：

  • 一次系统审查识别出了单独进行高剂量率支气管近距离放射治疗（HDREB）或联合外照射放疗（EBRT）或激光治疗的6项随机临床试验。
  • 在既往未接受过单独EBRT治疗的患者中，需要更佳的总体症状缓解和更少的再次治疗。
  • [证据等级：1iiC]
  • 尽管EBRT常用于缓解症状，但对于何时应使用分割方案尚未达成共识。
  • 对于EBRT，不同多分割治疗方案缓解症状的程度相似；
  • 然而，NCIC临床试验组试验（NCT00003685）显示，与大分割或标准治疗方案相比，单独分割放疗缓解症状的效果不佳。
  • [证据等级：1iiC]
  • 有证据表明，PS较佳的患者行高剂量EBRT后生存期适度延长。
  • [证据等级：1iiA]
  • 若技术上可行，HDREB可缓解既往接受EBRT治疗的复发性支气管内阻塞症状患者。

    • 放化疗

    前瞻性随机临床试验与荟萃分析评估了序贯放化疗与同步放化疗的效果。 总体上，同步治疗的生存获益最大，但毒性反应发生率亦增高。

    含铂类同步放化疗可能改善局部晚期NSCLC患者的生存期。但当前数据不足以准确评估治疗潜在获益程度，以及最优化疗方案。

    证据（放化疗）：

  • 11项随机临床试验的患者数据荟萃分析显示：
  • 与单独放疗相比，含顺铂联合放疗后死亡风险降低了10%。
  • [证据等级：1iiA]
  • 13项试验（基于2,214例可评价患者）的荟萃分析显示：
  • 根治性放疗同步化疗后2年死亡风险降低（相对风险[RR]，0.93；95% CI，0.88–0.98；P =0.01）。
  • 在11项含铂化疗试验中，RR为0.93（95%CI，0.87-0.99；P = 0.02）。
  • 1,764例患者的个体数据荟萃分析是基于9项临床试验，如下所示：
  • 与单独放疗相比，接受放疗和化疗的患者的死亡HR为0.89（95%CI，0.81-0.98；P =0.02)，相当于化疗后2年绝对获益为4%。
  • 铂类与依托泊苷联合用药比铂类单药更有效。

    • 同步与序贯放化疗

    两项随机试验（包括RTOG-9410 [NCT01134861]）和一项荟萃分析结果表明同步放化疗的生存获益优于序贯放疗，尽管其毒性反应发生率也增加。

    [证据等级：1iiA]

    证据（同步与序贯放化疗）：

  • 在第一项临床试验中，比较了丝裂霉素C、长春地辛和顺铂联合每日分疗程放疗（56 Gy）与化疗继之以连续每日放疗（56 Gy）的有效性。
  • 在5年OS方面，同步治疗显优（27% vs. 9%）。
  • 联合治疗组患者的骨髓抑制更严重，但两组的治疗相关死亡率均低于1%。
  • 在第二项试验中，将610例患者随机分配，接受顺铂和长春碱序贯化疗，继之以63 Gy的放疗，使用相同方案的同步放化疗，或顺铂和依托泊苷同步化疗联合每日两次放疗。
  • 每日放疗同步化疗组的中位生存期和5年生存率更优，分别为17个月和16%，而序贯方案为14.6个月和10%（P =0.046）。
  • 两项小型研究也报告了OS结果，与序贯化疗和放疗相比，同步治疗更优效，但结果不具有统计学显著性。
  • [证据等级：1iiA]
  • 3项试验的荟萃分析评价了同步与序贯治疗的有效性（711例患者）。
  • 分析表明，与序贯治疗相比，同步治疗具有显著获益（RR，0.86；95%CI，0.78–0.95；P = 0.003）。所有研究均采用含顺铂治疗方案和每日一次的放疗。
  • 同步治疗组报告的死亡更多（OS率为3%），但不具有统计学显著性（RR，1.60；CI，0.75-3.44；P =0.2）。
  • 与序贯治疗（范围，0%-4%；RR，6.77；P = 0.001）相比，同步治疗后急性食管炎发生率（3级或更差）偏高（范围，17%-26%）。总体而言，两组中性粒细胞减少症（3级或以上）的发生率相似。

    • 同步放化疗时放疗剂量递增

    20世纪90年代随着放疗-给药技术的改进，包括肿瘤运动管理和成像引导，I/II期临床验证明了剂量递增至74 Gy放疗同步化疗的可行性。

    然而，一项比较常规剂量60 Gy与剂量递增至74 Gy联合每周一次卡铂/紫杉醇治疗的III期临床试验未显示局部控制或PFS得到改善，OS随剂量递增而更差（HR，1.38 [1.09–1.76]；P = 0.004）。随着剂量递增，5级事件增加不明显（10% vs. 2%），3级食管炎的发生率增加（21% vs. 7%；P =0.0003）。因此，对于III期NSCLC，剂量递增至60 Gy以上的放疗无明显获益。

    [证据等级：1iiA]

    选择全身治疗同步放化疗

    证据（全身治疗同步放化疗）：

  • 随机III期PROCLAIM研究[NCT00686959]入组了598例新诊断、不可切除、非鳞状IIIA/B期NSCLC患者。
  • 患者按1:1的比例被随机分为两组:
  • A组：培美曲塞（500 mg/m2）和顺铂（75 mg/m2）静脉注射，每3周一次，共3个疗程加同步胸部放疗（60-66 Gy），继之以培美曲塞巩固治疗，每3周一次，共4个疗程。
  • B组：依托泊苷（50 mg/m2）和顺铂（50 mg/m2）标准治疗，静脉注射，每4周一次，共2个疗程加同步胸部放疗（60-66 Gy），继之以2个疗程的巩固含铂双药化疗。

    • 主要目的是评价OS。本研究设计为优效性试验，检测到OS HR为0.74的把握度达80%，一类错误为0.05。本研究随机选取598例患者（A组，301；B组，297），收治患者555例（A组，283；B组，272）。

  • 由于无效，提前停止入组。
  • A组的OS并不优于B组（HR，0.98；95%CI，0.79-1.20；中位数，26.8 vs. 25.0 个月；P = 0.831）。
  • 在整个治疗期间，A组任何药物相关3-4级不良事件的发生率显著降低（64.0%vs. 76.8%；P =0.001），包括中性粒细胞减少症（24.4%vs. 44.5%；P <0.001）。

    • 同步化疗和放疗之前或之后的其他全身治疗

    在同步化疗和放疗前添加诱导化疗尚未显示可延长生存期。

    [证据等级：1iiA]

    巩固免疫治疗

    度伐利尤单抗

    度伐利尤单抗是一种选择性人IgG1单克隆抗体，可阻断程序性死亡配体1（PD-L1）与程序性死亡1（PD-1）和CD80结合，从而使T细胞识别并杀死肿瘤细胞。

    证据（度伐利尤单抗）：

  • III期PACIFIC试验（NCT02125461）入组了713例接受2个或2个以上疗程含铂放化疗后疾病无进展的III期NSCLC患者。患者以2:1比例随机分配至度伐利尤单抗（10 mg/kg，静脉注射）组或安慰剂（每2周一次，长达12个月）组。
  • 协同主要终点为盲态独立中心审查评估的PFS和OS（期中分析未计划）。
  • 期中分析时，达到了协同主要终点PFS。度伐利尤单抗组的中位PFS为16.8个月，安慰剂组为5.6个月（HR，0.52；95%CI，0.42–0.65；P <0.001）。
  • [证据等级：1iiDiii]度伐利尤单抗组的18个月PFS率为44.2％，而安慰剂为27％。
  • 在所有预先指定的亚组中均可观察到PFS获益，并且与放化疗或吸烟状态前的PD-L1表达无关。在6％的患者中观察到表皮生长因子受体（EGFR）突变（度伐利尤单抗治疗组29例，安慰剂组14例）。EGFR突变亚组的未分层HR为0.76（95％CI，0.35-1.64）。
  • 度伐利尤单抗治疗组3或4级不良事件发生率为29.9％，安慰剂治疗组发生率为26.1％。度伐利尤单抗治疗组最常见的3或4级肺炎不良事件发生率为4.4％，安慰剂治疗组发生率为3.8％。
  • 在期中分析中未评估OS。

    • 其他全身巩固治疗

    其他全身巩固治疗（包括多西他赛、

    吉非替尼、

    和tecemotide（MUC1抗原特异性免疫治疗））

    的随机试验尚未显示出OS改善。[证据等级：1iiA]

    上沟瘤（T3,N0或N1,M0）的标准治疗选择

    上沟瘤的标准治疗选择包括以下：

  • 单独放疗。
  • 手术。
  • 放化疗联合手术。

    • 上沟部位NSCLC常称为Pancoast瘤，患者发生率不足5%。

    上沟瘤通常起源于肺尖部，其治疗具挑战性，因其临近胸廓入口处器官。该部位的肿瘤可能侵及壁层胸膜、胸壁、臂丛、锁骨下静脉、星状神经节和邻近的椎体。但Pancoast瘤可能治愈，尤其是T3,N0期肿瘤。

    不良的预后因素包括有纵隔淋巴结转移（N2期）、脊柱或锁骨下静脉受累（T4期）与切除受限（R1或R2）。

    单独放疗

    尽管放疗是Pancoast瘤治疗方法的一部分，已发表的病例分析所用的放疗剂量、方法和分期差别较大，故很难判断其有效性。

    预后：

    对仅有临床分期的患者行放疗的小规模回顾性病例分析结果显示5年生存率为0%-40%，生存率与T分期、总放疗剂量和其他预后因素相关。诱导放疗与整块切除可能治愈该病。

    证据（放疗）：

  • 一般建议术前在5周内使用45 Gy剂量，而在使用确定性放疗作为主要治疗时，则需要大约61 Gy的剂量。

    • 手术

    证据（手术）：

  • 一些回顾性病例分析发现，仅64％的T3 N0肿瘤和39％的T4 N0肿瘤得到完全切除。

    • 放化疗联合手术

    证据（放化疗）：

  • 两项大型前瞻性多中心的II期临床试验评估了诱导放化疗继之以切除术的有效性。
  • 在第一项试验（NCT00002642）中，有110例符合条件的患者（上沟纵隔镜检查呈阴性，临床T3–4，N0–1上沟瘤）入组。
  • 诱导治疗为两个疗程的依托泊苷和顺铂同步45Gy放疗。
  • 诱导方案耐受性良好，仅5例受试者产生3级或更高的毒性反应。
  • 诱导放化疗可以对原发灶进行灭菌。104例患者（95％）完成了诱导治疗。在95例符合手术条件的患者中，88例（80％）接受了开胸手术，其中2例（1.8％）术后死亡，83例（76％）完全切除。
  • 在61个（56％）切除标本中观察到病理学完全缓解或最小的微观病灶。与存在任何残留病灶时相比，病理学完全缓解后生存率更佳（P =0.02）。
  • 所有患者的五年生存率为44％，完全切除后为54％，T3和T4肿瘤之间无差异。疾病进展主要发生在远端部位。
  • 在第二项试验中，75例患者入组，并接受了丝裂霉素C、长春地辛和顺铂联合45 Gy放射治疗的诱导治疗。
  • 57例患者（76％）接受了手术切除，其中51例患者（68％）实现了完全切除。
  • 有12例出现病理学完全缓解。
  • 在8例患者中观察到了主要的术后发病率，包括乳糜胸、脓胸、肺炎、成人呼吸窘迫综合征和出血。出现3例治疗相关死亡。
  • 3年时，DFS率为49％，OS率为61％；5年时，DFS率为45％，OS率为56％。
  • [证据等级：3iiiDi]

    • 同步放化疗时放疗剂量递增

    20世纪90年代随着放疗-给药技术的改进，包括肿瘤运动管理和成像引导，I/II期临床试验证明了剂量递增至74 Gy放疗同步化疗的可行性。

    然而，一项比较常规剂量60 Gy与剂量递增至74 Gy联合每周一次卡铂/紫杉醇治疗的III期临床试验未显示局部控制或PFS得到改善，OS随剂量递增而更差（HR，1.38 [1.09–1.76]；P = 0.004）。随着剂量递增，5级事件增加不明显（10% vs. 2%），3级食管炎的发生率增加（21% vs. 7%；P =0.0003）。因此，对于III期NSCLC，剂量递增至60 Gy以上的放疗无明显获益。

    [证据等级：1iiA]

    选择全身治疗同步放化疗

    证据（全身治疗同步放化疗）：

  • 随机III期PROCLAIM研究[NCT00686959]入组了598例新诊断、不可切除、非鳞状IIIA/B期NSCLC患者。
  • 患者按1:1的比例被随机分为两组:
  • A组：培美曲塞（500 mg/m2）和顺铂（75 mg/m2）静脉注射，每3周一次，共3个疗程加同步胸部放疗（60-66 Gy），继之以培美曲塞巩固治疗，每3周一次，共4个疗程。
  • B组：依托泊苷（50 mg/m2）和顺铂（50 mg/m2）标准治疗，静脉注射，每4周一次，共2个疗程加同步胸部放疗（60-66 Gy），继之以2个疗程含铂双药化疗的巩固治疗。

    • 主要目的是评价OS。本研究设计为优效性试验，检测到OS HR为0.74的把握度达80%，一类错误为0.05。本研究随机选取598例患者（A组，301；B组，297），收治患者555例（A组，283；B组，272）。

  • 由于无效，提前停止入组。
  • A组的OS并不优于B组（HR，0.98；95%CI，0.79-1.20；中位数，26.8 vs. 25.0 个月；P = 0.831）。
  • 在整个治疗期间，A组任何药物相关3-4级不良事件的发生率显著降低（64.0%vs. 76.8%；P =0.001），包括中性粒细胞减少症（24.4%vs. 44.5%；P <0.001）。

    • 同步放化疗之前或之后的其他全身治疗

    在同步放化疗前添加诱导化疗尚未显示可延长生存期。

    [证据等级：1iiA]

    同步放化疗后巩固全身治疗对不可切除NSCLC的作用尚不明确。 巩固全身治疗（包括多西他赛、 吉非替尼、 和tecemotide（MUC1抗原特异性免疫治疗）） 的随机试验尚未显示出OS改善。[证据等级：1iiA]

    侵及胸壁肿瘤（T3,N0或N1,M0）的标准治疗选择

    侵及胸壁肿瘤的标准治疗选择包括：

  • 手术。
  • 手术和放疗。
  • 单独放疗。
  • 化疗联合放疗和/或手术。

    • 一些直接侵及胸壁的大肿块原发性肿瘤患者行手术完全切除肿瘤后可长期生存。

    证据（根治性手术）：

  • 一些小规模的97例患者病例分析发现，完全切除T3,N0,M0肿瘤的患者的5年生存率为44.2％。对于完全切除的T3,N1,M0肿瘤患者，其5年生存率为40.0％。对于完全切除的T3,N2,M0肿瘤患者，其5年生存率为6.2%。
  • [证据等级：3iiiDi]
  • 一些小规模的104例患者病例分析发现，完全切除T3,N0,M0肿瘤的患者的5年生存率为67.3%。对于完全切除的T3,N1,M0肿瘤患者，其5年生存率为100.0%。对于完全切除的T3,N2,M0肿瘤患者，其5年生存率为17.9%。
  • [证据等级：3iiiDi]
  • 在3个研究中心接受治疗的309例患者的一些病例分析发现，相较于接受胸膜外切除术的患者，接受整体切除的患者在预后方面显优（60.3% vs. 39.1%；P = 0.03）。
  • [证据等级：3iiiDi]

    • 对于切缘不明的患者，推荐辅助化疗，必要时也可选放疗。不完全切除和纵隔淋巴结受累的患者生存率较低。已有研究评估了综合治疗的效果以提高完全切除机率。

    处于临床评估阶段的治疗选择

    处于临床评估阶段的治疗选择如下所示：

  • 联合治疗，包括化疗、放疗和各种组合形式的手术。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

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  • Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
  • Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006.
  • Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.
  • Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005.
  • Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005.
  • Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005.
  • Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006.
  • Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.
  • Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
  • Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999.
  • Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
  • Curran WJ, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011.
  • Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
  • Rosenman JG, Halle JS, Socinski MA, et al.: High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54 (2): 348-56, 2002.
  • Socinski MA, Blackstock AW, Bogart JA, et al.: Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 26 (15): 2457-63, 2008.
  • Bradley JD, Bae K, Graham MV, et al.: Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol 28 (14): 2475-80, 2010.
  • Bradley JD, Paulus R, Komaki R, et al.: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16 (2): 187-99, 2015.
  • Senan S, Brade A, Wang LH, et al.: PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 34 (9): 953-62, 2016.
  • Vokes EE, Herndon JE, Kelley MJ, et al.: Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 25 (13): 1698-704, 2007.
  • Antonia SJ, Villegas A, Daniel D, et al.: Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377 (20): 1919-1929, 2017.
  • Hanna N, Neubauer M, Yiannoutsos C, et al.: Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26 (35): 5755-60, 2008.
  • Kelly K, Chansky K, Gaspar LE, et al.: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26 (15): 2450-6, 2008.
  • Butts C, Socinski MA, Mitchell PL, et al.: Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 15 (1): 59-68, 2014.
  • Rusch VW: Management of Pancoast tumours. Lancet Oncol 7 (12): 997-1005, 2006.
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  • Rusch VW, Parekh KR, Leon L, et al.: Factors determining outcome after surgical resection of T3 and T4 lung cancers of the superior sulcus. J Thorac Cardiovasc Surg 119 (6): 1147-53, 2000.
  • Kunitoh H, Kato H, Tsuboi M, et al.: Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol 26 (4): 644-9, 2008.
  • Rusch VW, Giroux DJ, Kraut MJ, et al.: Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 25 (3): 313-8, 2007.
  • Matsuoka H, Nishio W, Okada M, et al.: Resection of chest wall invasion in patients with non-small cell lung cancer. Eur J Cardiothorac Surg 26 (6): 1200-4, 2004.
  • Facciolo F, Cardillo G, Lopergolo M, et al.: Chest wall invasion in non-small cell lung carcinoma: a rationale for en bloc resection. J Thorac Cardiovasc Surg 121 (4): 649-56, 2001.
  • Doddoli C, D'Journo B, Le Pimpec-Barthes F, et al.: Lung cancer invading the chest wall: a plea for en-bloc resection but the need for new treatment strategies. Ann Thorac Surg 80 (6): 2032-40, 2005.
    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Stage IIIA NSCLC Treatment

    Patients with stage IIIA non-small cell lung cancer (NSCLC) are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes, potentially resectable T3 tumors invading the chest wall, or mediastinal involvement with metastases to peribronchial or hilar lymph nodes (N1). Presentations of disease range from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal stations.

    Prognosis:

    Patients with clinical stage IIIA N2 disease have a 5-year overall survival (OS) rate of 10% to 15%; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.

    Treatment options vary according to the location of the tumor and whether it is resectable.

    Standard Treatment Options for Resected/Resectable Stage IIIA N2 NSCLC

    Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy.

    Standard treatment options for resected/resectable disease include the following:

  • Surgery.
  • Neoadjuvant therapy.
  • Neoadjuvant chemotherapy.
  • Neoadjuvant chemoradiation therapy.
  • Adjuvant therapy.
  • Adjuvant chemotherapy.
  • Adjuvant chemoradiation therapy.
  • Adjuvant radiation therapy.

    • The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC are yet to be determined.

    Surgery

    If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative chemotherapy. Current evidence suggests that lung cancer resection combined with complete ipsilateral mediastinal lymph node dissection (CMLND) is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.

    [Level of evidence: 1iiA]

    The addition of surgery to chemoradiation therapy for patients with stage IIIA NSCLC did not result in improved OS in a phase III trial but did improve progression-free survival (PFS) and local control.

    [Level of evidence: 1iiDiii]

    Evidence (surgery):

  • The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.
  • A pooled analysis of three trials reported the following:
  • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and CMLND, compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93; P = .005).
  • [Level of evidence: 1iiA]
  • CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.
  • There was no difference in OS, disease-free survival (DFS), local recurrence, and regional recurrence.
  • [Level of evidence: 1iiA]

    • Limitations of evidence (surgery):

    Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and by the potential methodological weaknesses of the trials.

    Neoadjuvant therapy

    Neoadjuvant chemotherapy

    The role of chemotherapy before surgery in patients with stage III N2 NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include the following:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

    • Evidence (neoadjuvant chemotherapy):

  • The Cochrane Collaboration provided a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone.
  • These trials evaluated patients with stages I, II, and IIIA NSCLC.
  • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).
  • [Level of evidence: 1iiA]
  • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.
  • In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery.
  • Most patients (61%) had clinical stage I disease, 31% had stage II disease, and 7% had stage III disease.
  • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
  • There was no evidence of a benefit in terms of OS (HR, 1.02; 95% CI, 0.80–1.31; P = .86).
  • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of preoperative chemotherapy (1,507 patients, HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.

    • Neoadjuvant chemoradiation therapy

    Administering concurrent neoadjuvant chemotherapy and radiation therapy before surgery may intensify treatment and increase the likelihood of downstaging the tumor burden. Commonly utilized regimens that have been tested in the phase II setting include cisplatin/etoposide (EP5050) and weekly carboplatin/paclitaxel.

    In a randomized trial of neoadjuvant chemoradiation therapy and surgery versus concurrent chemoradiation therapy alone, there was no difference in OS, but surgery improved PFS and local control.

    [Level of evidence: 1iiDiii]

    Evidence (neoadjuvant chemoradiation therapy):

  • The Intergroup-0139 [NCT00002550] trial compared chemoradiation therapy alone with neoadjuvant chemoradiation followed by surgery in 396 patients with stage IIIA NSCLC.
  • Surgery did not improve OS (5-year OS, 27% vs. 20%; HR: 0.87 [0.70–1.10]; P = .24).
  • Surgery improved PFS (5-year PFS, 22% vs. 11%; HR 0.77 [0.62–0.96]; P = .017) and decreased the risk of local recurrence (10% vs. 22%; P = .002).
  • There was increased treatment mortality with neoadjuvant chemoradiation with surgery (8% vs. 2%), particularly in the subset of patients who underwent pneumonectomy.

    • A direct comparison of neoadjuvant chemotherapy versus neoadjuvant chemoradiation therapy using modern treatment regimens has not been performed to date; the optimal neoadjuvant approach remains unclear.

    Adjuvant therapy

    Adjuvant chemotherapy

    Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy.

    [Level of evidence: 1iiA]

    Evidence (adjuvant chemotherapy):

    Evidence from randomized controlled clinical trials indicates that when stage IIIA NSCLC is encountered unexpectedly at surgery, chemotherapy given after complete resection improves survival.

    Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.

  • Data on individual patient outcomes from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC were collected and pooled into a meta-analysis.
  • With a median follow-up of 5.2 years, the overall HRdeath was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
  • The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
  • The benefit varied with stage (HR for stage IIIA, 0.83; 95% CI, 0.72–0.94).
  • The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
  • Two trials (FRE-IALT and the Adjuvant Navelbine International Trialist Association [ANITA] trial) reported significant OS benefits associated with postoperative chemotherapy in stage IIIA disease.
  • For the subgroup of stage IIIA patients in the ANITA trial (n = 325), the HR was 0.69 (95% CI, 0.53–0.90), and the result for the FRE-IALT trial (n = 728) was HR, 0.79 (95% CI, 0.66–0.95).
  • The chemotherapy effect was higher in patients with a better performance status (PS).
  • There was no interaction between the chemotherapy effect and any of the following:
  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.
  • In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.
  • Chemotherapy significantly prolonged OS for elderly patients (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
  • There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elderly patients received less treatment.

    • Adjuvant chemoradiation therapy

    Combination chemotherapy and radiation therapy administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.

    Evidence (adjuvant chemoradiation therapy):

  • Five randomized trials have assessed the value of postoperative combination chemoradiation therapy versus radiation therapy following surgical resection.
  • [Level of evidence: 1iiA]
  • Only one trial reported improved DFS and no trial reported improved OS.
  • Three trials have evaluated platinum-based combination chemotherapy followed by surgery versus platinum-based chemotherapy followed by radiation therapy (60–69.6 Gy) alone to determine whether surgery or radiation therapy was most efficacious.
  • Although the studies were small, enrolling 73 (Radiation Therapy Oncology Group [RTOG]) (RTOG 89-01), 107 (The University of Texas M.D. Anderson Cancer Center), and 333 (European Organization for Research and Treatment of Cancer [EORTC-08941; NCT00002623]) patients with stage IIIA N2 disease, no trial reported a difference in local control or survival.
  • [Level of evidence: 1iiA]
  • In the largest series (EORTC-08941), 579 patients with histologic- or cytologic-proven stage IIIA N2 NSCLC were given three cycles of platinum-based induction chemotherapy.
  • The 333 responding patients were subsequently randomly assigned to surgical resection or radiation therapy. Of the 154 patients (92%) who underwent surgery, 50% had a radical resection, 42% had a pathologic downstaging, and 5% had a pathologic complete response; 4% died after surgery. Postoperative (adjuvant) radiation therapy (PORT) was administered to 62 patients (40%) in the surgery arm. Among the 154 patients (93%) who received radiation therapy, overall compliance to the radiation therapy prescription was 55%, and grade 3 to 4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis.
  • Median OS was 16.4 months for patients assigned to resection versus 17.5 months for patients assigned to radiation therapy; 5-year OS was 15.7% for patients assigned to resection versus 14% for patients assigned to radiation therapy (HR, 1.06; 95% CI, 0.84–1.35).
  • Rates of PFS were also similar in both groups. In view of its low morbidity and mortality, it was concluded that radiation therapy should be considered the preferred locoregional treatment for these patients.

    • Adjuvant radiation therapy

    The value of PORT has been assessed.

    Although some studies suggest that PORT can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. The optimal dose of thoracic PORT is not known at this time. The majority of studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.

    As referred to in the National Cancer Institute of Canada (NCIC) Clinical Trials Group JBR.10 study (NCT00002583), PORT may be considered in selected patients to reduce the risk of local recurrence, if any of the following are present:

  • Involvement of multiple nodal stations.
  • Extracapsular tumor spread.
  • Close or microscopically positive resection margins.

    • Evidence (adjuvant radiation therapy):

    Evidence from one large meta-analysis, subset analyses of randomized trials, and one large population study suggest that PORT may reduce local recurrence. Results from these studies on the effect of PORT on OS are conflicting.

  • A meta-analysis of ten randomized trials that evaluated PORT versus surgery alone showed the following:
  • No difference in OS for the entire PORT group or for the subset of N2 patients.
  • [Level of evidence: 1iiA]
  • Results from a nonrandomized subanalysis of the ANITA trial, comparing 5-year OS in N2 patients who did or did not receive PORT, found the following:
  • Higher survival rates in patients who received radiation therapy in the observation arm (21% in patients who received PORT vs. 17% in patients who did not receive PORT) and in the chemotherapy arm (47% with PORT vs. 34% without PORT); however, statistical tests of comparison were not conducted.
  • Results from the Surveillance, Epidemiology, and End Results (SEER) program suggest the following:
  • The large SEER retrospective study (N = 7,465) found superior survival rates associated with radiation therapy in N2 disease (HR, 0.855; 95% CI, 0.762–0.959).

    • There is benefit of PORT in stage IIIA N2 disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

    Standard Treatment Options for Unresectable Stage IIIA N2 NSCLC

    Standard treatment options for patients with unresectable NSCLC include the following:

  • Radiation therapy.
  • For treatment of locally advanced unresectable tumor.
  • For patients requiring palliative treatment.
  • Chemoradiation therapy.

    • Radiation therapy

    For treatment of locally advanced unresectable tumor

    Radiation therapy alone, administered sequentially with chemotherapy and concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC.

    Prognosis:

    Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.

    Evidence (radiation therapy for locally advanced unresectable tumor):

  • One prospective randomized clinical study showed the following:
  • Radiation therapy given continuously (including weekends) as three daily fractions (continuous hyperfractionated accelerated radiation therapy) improved OS compared with radiation therapy given as one daily fraction.
  • [Level of evidence: 1iiA]
  • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

    • Although patients with unresectable stage IIIA disease may benefit from radiation therapy, long-term outcomes have generally been poor because of local and systemic relapse.

    For patients requiring palliative treatment

    Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

    • In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.

    Evidence (radiation therapy for palliative treatment):

  • A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.
  • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.
  • [Level of evidence: 1iiC]
  • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
  • For EBRT, different multifraction regimens appear to provide similar symptom relief;
  • however, single-fraction radiation therapy may be insufficient for symptom relief compared with hypofractionated or standard regimens, as seen in the NCIC Clinical Trials Group trial (NCT00003685).
  • [Level of evidence: 1iiC]
  • Evidence of a modest increase in survival in patients with better PS given high-dose EBRT is available.
  • [Level of evidence: 1iiA]
  • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

    • Chemoradiation therapy

    The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials and meta-analyses. Overall, concurrent treatment may provide the greatest benefit in survival with an increase in toxic effects.

    Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.

    Evidence (chemoradiation therapy):

  • A meta-analysis of patient data from 11 randomized clinical trials showed the following:
  • Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.
  • [Level of evidence: 1iiA]
  • A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:
  • The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% CI, 0.88–0.98; P = .01).
  • For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).
  • A meta-analysis of individual data from 1,764 patients was based on nine trials and showed the following:
  • The HRdeath among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02), corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
  • The combination of platinum with etoposide appeared to be more effective than platinum alone.

    • Concurrent versus sequential chemoradiation therapy

    The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.

    [Level of evidence: 1iiA]

    Evidence (concurrent vs. sequential chemoradiation therapy):

  • In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.
  • Five-year OS favored concurrent therapy (27% vs. 9%).
  • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.
  • In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 63 Gy of radiation therapy, concurrent chemoradiation therapy using the same regimen, or concurrent chemotherapy with cisplatin and etoposide with twice-daily radiation therapy.
  • Median and 5-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 months vs. 14.6 months and 16% vs. 10% for sequential regimen [P = .046]).
  • Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.
  • [Level of evidence: 1iiA]
  • A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).
  • The analysis indicated a significant benefit of concurrent over sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All studies used cisplatin-based regimens and once-daily radiation therapy.
  • More deaths (3% OS rate) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; CI, 0.75–3.44; P = .2).
  • There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range, 17%–26%) compared with sequential treatment (range, 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

    • Radiation therapy dose escalation for concurrent chemoradiation

    With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.

    However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P =.0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.

    [Level of evidence: 1iiA]

    Choice of systemic therapy for concurrent chemoradiation

    Evidence (systemic therapy for concurrent chemoradiation):

  • The randomized phase III PROCLAIM study [NCT00686959] enrolled 598 patients with newly diagnosed, stage IIIA/B, unresectable, nonsquamous NSCLC.
  • Patients were randomly assigned on a 1:1 ratio to either of two arms:
  • Arm A: Pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) intravenously every 3 weeks for three cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles.
  • Arm B: Standard therapy with etoposide (50 mg/m2) and cisplatin (50 mg/m2) intravenously every 4 weeks for two cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy.

    • The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS HR of 0.74 with a type 1 error of .05. This study randomly assigned 598 patients (arm A, 301; arm B, 297) and treated 555 patients (arm A, 283; arm B, 272).

  • Enrollment was stopped early because of futility.
  • OS in arm A was not superior to arm B (HR, 0.98; 95% CI, 0.79–1.20; median, 26.8 vs. 25.0 months; P = .831).
  • Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001), including neutropenia (24.4% vs. 44.5%; P < .001), during the overall treatment period.

    • Additional systemic therapy before or after concurrent chemotherapy and radiation therapy

    The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.

    [Level of evidence: 1iiA]

    Consolidation Immunotherapy

    Durvalumab

    Durvalumab is a selective human IgG1 monoclonal antibody that blocks programmed death ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.

    Evidence (durvalumab):

  • The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).
  • The coprimary endpoints were PFS assessed by blinded independent central review and OS (unplanned for the interim analysis).
  • At the interim analysis, the coprimary endpoint of PFS was met. The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR, 0.52; 95% CI, 0.42–0.65; P< .001).
  • [Level of evidence:1iiDiii] The 18-month PFS rate was 44.2% with durvalumab versus 27% with placebo.
  • PFS benefit was seen across all prespecified subgroups and was irrespective of PD-L1 expression before chemoradiation therapy or smoking status. Epidermal growth factor receptor (EGFR) mutations were observed in 6% of patients (29 treated with durvalumab vs. 14 treated with placebo). The unstratified HR for the EGFR-mutated subgroup was 0.76 (95% CI, 0.35–1.64).
  • Grade 3 or 4 adverse events occurred in 29.9% of patients treated with durvalumab and in 26.1% of patients treated with placebo. The most common adverse event of grade 3 or 4 was pneumonia in 4.4% of the patients receiving durvalumab and in 3.8% of the patients receiving placebo.
  • OS was not assessed at the interim analysis.

    • Other systemic consolidation therapies

    Randomized trials of other consolidation systemic therapies, including docetaxel,

    gefitinib,

    and tecemotide (MUC1 antigen-specific immunotherapy)

    have not shown an improvement in OS.[Level of evidence: 1iiA]

    Standard Treatment Options for Superior Sulcus Tumors (T3, N0 or N1, M0)

    Standard treatment options for superior sulcus tumors include the following:

  • Radiation therapy alone.
  • Surgery.
  • Chemoradiation therapy followed by surgery.

    • NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.

    Superior sulcus tumors usually arise from the apex of the lung and are challenging to treat because of their proximity to structures at the thoracic inlet. At this location, tumors may invade the parietal pleura, chest wall, brachial plexus, subclavian vessels, stellate ganglion, and adjacent vertebral bodies. However, Pancoast tumors are amenable to curative treatment, especially in patients with T3, N0 disease.

    Adverse prognostic factors include the presence of mediastinal nodal metastases (N2 disease), spine or subclavian-vessel involvement (T4 disease), and limited resection (R1 or R2).

    Radiation therapy alone

    While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that were used in various published series make it difficult to determine its effectiveness.

    Prognosis:

    Small, retrospective series of radiation therapy in patients who were only clinically staged have reported 5-year survival rates of 0% to 40%, depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en-bloc resection was shown to be potentially curative.

    Evidence (radiation therapy):

  • In the preoperative setting, a dose of 45 Gy over 5 weeks is generally recommended, while a dose of approximately 61 Gy is required when using definitive radiation therapy as the primary modality.

    • Surgery

    Evidence (surgery):

  • Retrospective case series have reported that complete resection was achieved in only 64% of T3, N0 tumors and 39% of T4, N0 tumors.

    • Chemoradiation therapy followed by surgery

    Evidence (chemoradiation therapy):

  • Two large, prospective, multicenter phase II trials have evaluated induction chemoradiation therapy followed by resection.
  • In the first trial (NCT00002642), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4, N0–1 tumors of the superior sulcus.
  • Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy.
  • The induction regimen was well tolerated, and only five participants had grade 3 or higher toxic effects.
  • Induction chemoradiation therapy could sterilize the primary lesion. Induction therapy was completed by 104 patients (95%). Of the 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resections.
  • Pathologic complete response or minimal microscopic disease was seen in 61 (56%) resection specimens. Pathologic complete response led to better survival than when any residual disease was present (P = .02).
  • Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Disease progression occurred mainly in distant sites.
  • In the second trial, 75 patients were enrolled and treated with induction therapy with mitomycin C, vindesine, and cisplatin combined with 45 Gy of radiation therapy.
  • Fifty-seven patients (76%) underwent surgical resection, and complete resection was achieved in 51 patients (68%).
  • There were 12 patients with pathologic complete response.
  • Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths.
  • At 3 years, the DFS rate was 49%, and the OS rate was 61%; at 5 years, the DFS rate was 45%, and the OS rate was 56%.
  • [Level of evidence: 3iiiDi]

    • Radiation therapy dose escalation for concurrent chemoradiation

    With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.

    However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.

    [Level of evidence: 1iiA]

    Choice of systemic therapy for concurrent chemoradiation

    Evidence (systemic therapy for concurrent chemoradiation):

  • The randomized phase III PROCLAIM study [NCT00686959] enrolled 598 patients with newly diagnosed stage IIIA/B unresectable nonsquamous NSCLC.
  • Patients were randomly assigned in a 1:1 ratio to either of two arms:
  • Arm A: Pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) intravenously every 3 weeks for three cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles.
  • Arm B: Standard therapy with etoposide (50 mg/m2) and cisplatin (50 mg/m2) intravenously every 4 weeks for two cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy.

    • The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS HR of 0.74 with a type 1 error of .05. This study randomly assigned 598 patients (arm A, 301; arm B, 297) and treated 555 patients (arm A, 283; arm B, 272).

  • Enrollment was stopped early because of futility.
  • OS in arm A was not superior to arm B (HR, 0.98; 95% CI, 0.79–1.20; median, 26.8 vs. 25.0 months; P = .831).
  • Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001), including neutropenia (24.4% vs. 44.5%; P < .001), during the overall treatment period.

    • Additional systemic therapy before or after concurrent chemotherapy and radiation therapy

    The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.

    [Level of evidence: 1iiA]

    The role of consolidation systemic therapy after concurrent chemotherapy and radiation therapy for unresectable NSCLC remains unclear. Randomized trials of consolidation systemic therapy including docetaxel, gefitinib, and tecemotide (MUC1 antigen-specific immunotherapy) have not shown an improvement in OS.[Level of evidence: 1iiA]

    Standard Treatment Options for Tumors That Invade the Chest Wall (T3, N0 or N1, M0)

    Standard treatment options for tumors that invade the chest wall include the following:

  • Surgery.
  • Surgery and radiation therapy.
  • Radiation therapy alone.
  • Chemotherapy combined with radiation therapy and/or surgery.

    • Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.

    Evidence (radical surgery):

  • In a small case series of 97 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 44.2%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 40.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 6.2%.
  • [Level of evidence: 3iiiDi]
  • In a small case series of 104 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 67.3%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 100.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 17.9%.
  • [Level of evidence: 3iiiDi]
  • In a case series of 309 patients treated at three centers, patients who underwent en bloc resection had superior outcomes compared with patients who underwent extrapleural resections (60.3% vs. 39.1%; P = .03).
  • [Level of evidence: 3iiiDi]

    • Adjuvant chemotherapy is recommended and radiation therapy is reserved for cases with unclear resection margins. Survival rates were lower in patients who underwent incomplete resection and had mediastinal lymph node involvement. Combined-modality approaches have been evaluated to improve ability to achieve complete resection.

    Treatment Options Under Clinical Evaluation

    Treatment options under clinical evaluation include the following:

  • Combined modality therapy, including chemotherapy, radiation therapy, and surgery in various combinations.

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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    • 非小细胞肺癌治疗(PDQ®)

    IIIB与IIIC期NSCLC治疗

    根据监测、流行病学和结局（SEER）数据库，IIIB期非小细胞肺癌（NSCLC）的发病率约为17.6%。

    临床分期为IIIB期NSCLC的多数患者5年生存率为3%-7%。

    一些小规模病例分析发现原发肺叶仅有卫星结节的T4,N0-1期患者的5年生存率为20%。

    [证据等级：3iiiA]

    IIIB与IIIC期NSCLC的标准治疗选择

    IIIB与IIIC期NSCLC的标准治疗选择包括以下：

  • 序贯或同步放化疗。
  • 同步放化疗时放疗剂量递增。
  • 同步化疗和放疗之前或之后的其他全身治疗。
  • 单独放疗。
  • 针对不适合化疗患者的局部晚期不可切除的肿瘤治疗。
  • 针对需要姑息性治疗的患者。

    • 通常IIIB期和IIIC期NSCLC患者单独手术获益不佳，最好选用初期化疗、化疗联合放疗或单独放疗，具体选择需考虑下列因素：

  • 肿瘤侵犯部位。
  • 患者体能状况（PS）。

    • 体能状况较佳的多数患者适合行联合化放疗，但下列患者除外：

  • 一些T4,N0患者可选用综合治疗与手术，类似于上沟瘤患者。

    • 序贯或同步放化疗

    针对不可切除III期NSCLC患者的多项随机研究显示，与单独放疗相比，术前或同步含顺铂化疗加胸部放疗可延长生存期。虽然不可切除IIIB期或III期患者可能受益于放疗，但长期预后总体较差，常出现局部和全身复发。一些前瞻性随机临床试验评估了序贯和同步放化疗的效果。

    证据（序贯或同步放化疗）：

  • 11项随机临床试验的患者数据荟萃分析显示：
  • 与单独放疗相比，以顺铂为基础的化疗联合放疗后死亡风险降低了10%。
  • [证据等级：1iiA]
  • 13项试验（基于2,214例可评价患者）的荟萃分析显示：
  • 根治性放疗同步化疗后2年死亡风险降低（相对风险[RR]，0.93；95%置信区间[CI]，0.88–0.98；P =0.01）。
  • 在11项含铂化疗试验中，RR为0.93（95%CI，0.87-0.99；P = 0.02）。
  • 1,764例患者个体数据的荟萃分析评估了9项临床试验。
  • 与单独放疗相比，接受放疗和化疗的患者的死亡风险比（HR）为0.89（95%CI，0.81-0.98；P =0.02)，相当于化疗后2年绝对获益为4%。
  • 铂类与依托泊苷联合用药比铂类单药更有效。 含铂类同步放化疗可能改善局部晚期NSCLC患者的生存期。但当前数据不足以准确评估治疗潜在获益程度，以及最优化疗方案。
  • 两项随机试验（包括RTOG-9410 [NCT01134861]）和一项荟萃分析结果表明同步放化疗的生存获益优于序贯放疗，尽管毒性反应发生率也增加。
  • [证据等级：1iiA]
  • 在第一项临床试验中，比较了丝裂霉素C、长春地辛和顺铂联合每日分疗程放疗（56 Gy）与化疗继之以连续每日放疗（56 Gy）的有效性。
  • 在5年总生存期（OS）方面，同步治疗显优（27% vs. 9%）。
  • 联合治疗组患者的骨髓抑制更严重，但两组的治疗相关死亡率均低于1%。
  • 在第二项试验中，将610例患者随机分配，接受顺铂和长春碱序贯化疗，继之以63 Gy的放疗，使用相同方案的同步放化疗，或顺铂和依托泊苷同步化疗联合每日两次放疗。
  • 每日放疗同步化疗组的中位生存期和5年生存率更优，分别为17个月和16%，而序贯方案为14.6个月和10%（P =0.046）。
  • 两项小型研究也报告了OS结果，与序贯化疗和放疗相比，同步治疗显优，但结果不具有统计学显著性。
  • [证据等级：1iiA]；
  • 3项试验的荟萃分析评价了同步与序贯治疗的有效性（711例患者）。
  • 分析表明，与序贯治疗相比，同步治疗具有显著获益（RR，0.86；95%CI，0.78–0.95；P = 0.003）。所有研究均采用含顺铂治疗方案和每日一次的放疗。
  • 同步治疗组报告的死亡数更多（总体达3%），但不具有统计学显著性（RR，1.60；CI，0.75-3.44；P =0.2）。
  • 与序贯治疗（范围，0%-4%；RR，6.77；P = 0.001）相比，同步治疗后急性食管炎发生率（3级或更差）偏高（范围，17%-26%）。总体而言，两组中性粒细胞减少症（3级或以上）的发生率相似。

    • 同步放化疗时放疗剂量递增

    20世纪90年代随着放疗-给药技术的改进，包括肿瘤运动管理和成像引导，I/II期临床试验证明了剂量递增至74 Gy放疗同步化疗的可行性。

    然而，一项比较常规剂量60 Gy与剂量递增至74 Gy联合每周一次卡铂/紫杉醇治疗的III期临床试验未显示局部控制或无进展生存期（PFS）得到改善，OS随剂量递增而更差（HR，1.38 [1.09–1.76]；P = 0.004）。随着剂量递增，5级事件增加不明显（10% vs. 2%），3级食管炎的发生率增加（21% vs. 7%；P =0.0003）。

    [证据等级：1iiA]

    同步放化疗之前或之后的其他全身治疗

    在同步放化疗前添加诱导化疗尚未显示可延长生存期。

    [证据等级：1iiA]

    巩固免疫治疗

    度伐利尤单抗

    度伐利尤单抗是一种选择性人IgG1单克隆抗体，可阻断程序性死亡配体1（PD-L1）与程序性死亡1（PD-1）和CD80结合，从而使T细胞识别并杀死肿瘤细胞。

    证据（度伐利尤单抗）：

  • III期PACIFIC试验（NCT02125461）入组了713例接受2个或2个以上疗程含铂放化疗后疾病无进展的III期NSCLC患者。患者以2:1比例随机分配至度伐利尤单抗（10 mg/kg，静脉注射）组或安慰剂（每2周一次，长达12个月）组。
  • 协同主要终点为盲态独立中心审查评估的PFS和OS（期中分析未计划）。
  • 期中分析时，达到了协同主要终点PFS。度伐利尤单抗组的中位PFS为16.8个月，安慰剂组为5.6个月（HR，0.52；95%CI，0.42–0.65；P <0.001）。
  • [证据等级：1iiDiii]度伐利尤单抗组的18个月PFS率为44.2％，而安慰剂为27％。
  • 在所有预先指定的亚组中均可观察到PFS获益，并且与放化疗或吸烟状态前的PD-L1表达无关。在6％的患者中观察到表皮生长因子受体（EGFR）突变（度伐利尤单抗治疗组29例，安慰剂组14例）。EGFR突变亚组的未分层HR为0.76（95％CI，0.35-1.64）。
  • 度伐利尤单抗治疗组3或4级不良事件发生率为29.9％，安慰剂治疗组发生率为26.1％。度伐利尤单抗治疗组最常见的3或4级肺炎不良事件发生率为4.4％，安慰剂治疗组发生率为3.8％。
  • 在期中分析中未评估OS。

    • 其他全身巩固治疗

    其他全身巩固治疗（包括多西他赛、 吉非替尼、 和tecemotide（MUC1抗原特异性免疫治疗）） 的随机试验尚未显示出OS改善。[证据等级：1iiA]

    同步化疗和放疗后巩固全身治疗对不可切除NSCLC的作用尚不明确。 巩固全身治疗（包括常规化疗（多西他赛）、 酪氨酸激酶抑制剂（吉非替尼）和免疫治疗（tecemotide：MUC1抗原特异性免疫治疗） 的III期试验尚未显示出OS改善。[证据等级：1iiA]

    单独放疗

    针对不适合化疗患者的局部晚期不可切除的肿瘤治疗

    化疗后放疗与同步放化疗可能有益于局部晚期不可切除III期NSCLC患者。虽然同步放化疗的生存获益最大，但毒性反应发生率亦增高。

    预后：

    传统剂量放疗与分割放疗（每日每次1.8-2.0Gy，6-7周总量60-70Gy）使得患者的长期生存期获益5%-10%，结果可复制，且明显缓解症状。

    证据（放疗治疗局部晚期不可切除肿瘤）：

  • 一项前瞻性随机临床研究表明：
  • 与每日一次放疗相比，每日3次放疗后OS改善。
  • [证据等级：1iiA]
  • 接受单独放疗的患者的失败模式包括局部和远端失败。

    • 针对需要姑息性治疗的患者

    放疗可缓解NSCLC患者的局部受累症状，例如：

  • 气管、食管或支气管压迫。
  • 疼痛。
  • 声带麻痹。
  • 咯血。
  • 上腔静脉综合征。

    • 有时可用经支气管镜激光治疗和/或近距离放射治疗缓解近端梗阻性病变。

    证据（放疗作为姑息性治疗）：

  • 一次系统审查识别出了单独进行高剂量率支气管近距离放射治疗（HDREB）或联合外照射放疗（EBRT）或激光治疗的6项随机临床试验。
  • 在以前未经治疗的仅使用EBRT的患者中，需要更好的整体症状缓解和更少的再治疗。
  • [证据等级：1iiC]
  • 若技术上可行，HDREB可缓解既往接受EBRT治疗的复发性支气管内阻塞症状患者。
  • 尽管EBRT常用于缓解症状，但对于何时应使用分割方案尚未达成共识。
  • 尽管不同多分割治疗方案缓解症状的程度相似，
  • 加拿大国家癌症研究所临床试验小组试验（NCT00003685）显示，与大分割或标准治疗方案相比，单独分割放疗缓解症状的效果不佳。
  • [证据等级：1iiC]
  • 有证据表明，PS较佳的患者行高剂量放疗后生存期适度延长。
  • [证据等级：1iiA]

    • PS较差的IIIB或IIIC期患者可选用胸部放疗，以缓解肺部症状（例如咳嗽、呼吸急促、咯血或疼痛）。

    [证据等级：3iiiC]（如需了解更多信息，请参见PDQ心肺综合征和癌痛总结。）

    处于临床评估阶段的治疗选择

    因IIIB期或IIIC期NSCLC患者的总体结果较差，故这些患者可参与临床试验，可能有助于改善疾病控制。

    处于临床评估阶段的治疗选择如下所示：

  • 新分割时间表。
  • 放射增敏剂（NCT02186847）。
  • 联合治疗方法。
  • 在EGFR突变或ALK易位肿瘤患者中将靶向药物纳入联合治疗中（RTOG-1306[NCT01822496]；11-464[NCT01553942]）。
  • 治疗期间使用基于正电子发射断层扫描的反应评估进行自适应放疗（RTOG-1106 / ACRIN-6697）。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

    参考文献

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  • Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
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  • Socinski MA, Blackstock AW, Bogart JA, et al.: Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 26 (15): 2457-63, 2008.
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  • Hanna N, Neubauer M, Yiannoutsos C, et al.: Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26 (35): 5755-60, 2008.
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    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Stages IIIB and IIIC NSCLC Treatment

    On the basis of the Surveillance, Epidemiology, and End Results (SEER) program registry, the estimated incidence of stage IIIB non-small cell lung cancer (NSCLC) is 17.6%.

    The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3% to 7%.

    In small case series, selected patients with T4, N0-1 disease, solely as the result of satellite tumor nodule(s) within the primary lobe, have been reported to have 5-year survival rates of 20%.

    [Level of evidence: 3iiiA]

    Standard Treatment Options for Stages IIIB and IIIC NSCLC

    Standard treatment options for stages IIIB NSCLC and IIIC NSCLC include the following:

  • Sequential or concurrent chemotherapy and radiation therapy.
  • Radiation therapy dose escalation for concurrent chemoradiation.
  • Additional systemic therapy before or after concurrent chemotherapy and radiation therapy.
  • Radiation therapy alone.
  • For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy.
  • For patients requiring palliative treatment.

    • In general, patients with stages IIIB and IIIC NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the following:

  • Sites of tumor involvement.
  • The patient's performance status (PS).

    • Most patients with excellent PS are candidates for combined-modality chemotherapy and radiation therapy with the following exceptions:

  • Selected patients with T4, N0 disease may be treated with combined-modality therapy and surgery similar to patients with superior sulcus tumors.

    • Sequential or concurrent chemotherapy and radiation therapy

    Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stages IIIB or IIIC disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.

    Evidence (sequential or concurrent chemotherapy and radiation therapy):

  • A meta-analysis of patient data from 11 randomized clinical trials showed the following:
  • Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.
  • [Level of evidence: 1iiA]
  • A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:
  • The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% confidence interval [CI], 0.88–0.98; P = .01).
  • For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).
  • A meta-analysis of individual data from 1,764 patients evaluated nine trials.
  • The hazard ratio (HR)death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
  • The combination of platinum with etoposide appeared to be more effective than platinum alone. Concomitant platinum-based chemotherapy and radiation therapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.
  • The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.
  • [Level of evidence: 1iiA]
  • In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.
  • Five-year overall survival (OS) favored concurrent therapy (27% vs. 9%).
  • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.
  • In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 63 Gy of radiation therapy, concurrent chemoradiation therapy using the same regimen, or concurrent chemotherapy with cisplatin and etoposide with twice-daily radiation therapy.
  • Median and 5-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 months vs. 14.6 months and 16% vs. 10% for sequential regimen [P = .046]).
  • Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.
  • [Level of evidence: 1iiA];
  • A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).
  • The analysis indicated a significant benefit of concurrent versus sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All used cisplatin-based regimens and once-daily radiation therapy.
  • More deaths (3% overall) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; CI, 0.75–3.44; P = .2).
  • There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range, 17%–26%) compared with sequential treatment (range, 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

    • Radiation therapy dose escalation for concurrent chemoradiation

    With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.

    However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or progression-free survival (PFS), and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003).

    [Level of evidence: 1iiA]

    Additional systemic therapy before or after concurrent chemotherapy and radiation therapy

    The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.

    [Level of evidence: 1iiA]

    Consolidation Immunotherapy

    Durvalumab

    Durvalumab is a selective human IgG1 monoclonal antibody that blocks programmed death ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.

    Evidence (durvalumab):

  • The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).
  • The coprimary endpoints were PFS assessed by blinded independent central review and OS (unplanned for the interim analysis).
  • At the interim analysis, the coprimary endpoint of PFS was met. The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR, 0.52; 95% CI, 0.42–0.65; P < .001).
  • [Level of evidence:1iiDiii] The 18-month PFS rate was 44.2% with durvalumab versus 27% with placebo.
  • PFS benefit was seen across all prespecified subgroups and was irrespective of PD-L1 expression before chemoradiation therapy or smoking status. Epidermal growth factor receptor (EGFR) mutations were observed in 6% of patients (29 treated with durvalumab vs. 14 treated with placebo). The unstratified HR for the EGFR-mutated subgroup was 0.76 (95% CI, 0.35–1.64).
  • Grade 3 or 4 adverse events occurred in 29.9% of patients treated with durvalumab and in 26.1% of patients treated with placebo. The most common adverse event of grade 3 or 4 was pneumonia in 4.4% of patients treated with durvalumab and in 3.8% of patients treated with placebo.
  • OS was not assessed at the interim analysis.

    • Other systemic consolidation therapies

    Randomized trials of other consolidation systemic therapies, including docetaxel, gefitinib, and tecemotide (MUC1 antigen-specific immunotherapy) have not shown an improvement in OS.[Level of evidence: 1iiA]

    The role of consolidation systemic therapy after concurrent chemotherapy and radiation therapy for unresectable NSCLC remains unclear. Phase III trials of consolidation systemic therapy including conventional chemotherapy (docetaxel), tyrosine kinase inhibitors (gefitinib), and immunotherapy (tecemotide: MUC1 antigen-specific immunotherapy) have not shown an improvement in OS.[Level of evidence: 1iiA]

    Radiation therapy alone

    For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy

    Radiation therapy alone, administered sequentially or concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC. However, combination chemoradiation therapy delivered concurrently provides the greatest benefit in survival with an increase in toxic effects.

    Prognosis:

    Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.

    Evidence (radiation therapy for locally advanced unresectable tumor):

  • One prospective randomized clinical study showed the following:
  • Radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.
  • [Level of evidence: 1iiA]
  • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

    • For patients requiring palliative treatment

    Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

    • In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.

    Evidence (radiation therapy for palliative treatment):

  • A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.
  • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.
  • [Level of evidence: 1iiC]
  • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.
  • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
  • Although different multifraction regimens appear to provide similar symptom relief,
  • single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as shown in the National Cancer Institute of Canada Clinical Trials Group trial (NCT00003685).
  • [Level of evidence: 1iiC]
  • Evidence of a modest increase in survival in patients with better PS given high-dose radiation therapy is available.
  • [Level of evidence: 1iiA]

    • Patients with stages IIIB or IIIC disease with poor PS are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).

    [Level of evidence: 3iiiC] (Refer to the PDQ summaries on Cardiopulmonary Syndromes and Cancer Pain for more information.)

    Treatment Options Under Clinical Evaluation

    Because of the poor overall results, patients with stages IIIB or IIIC NSCLC are candidates for clinical trials, which may lead to improvement in the control of disease.

    Treatment options under clinical evaluation include the following:

  • New fractionation schedules.
  • Radiosensitizers (NCT02186847).
  • Combined-modality approaches.
  • Incorporation of targeted agents into combined modality therapy in patients with EGFR-mutant or ALK-translocated tumors (RTOG-1306 [NCT01822496]; 11-464 [NCT01553942]).
  • Adaptive radiation therapy using positron emission tomography–based response assessment during treatment (RTOG-1106/ACRIN-6697).

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

    ReferenceSection

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    • 非小细胞肺癌治疗(PDQ®)

    新诊断的复发性IV期NSCLC治疗

    40%的新诊断非小细胞肺癌（NSCLC）患者为IV期肿瘤。治疗目的是延长生存期与控制疾病相关症状。 治疗选择包括细胞毒性药物化疗、靶向药物和免疫治疗。 影响治疗选择的因素包括合并症、体能状况评分（PS）、肿瘤的组织学和分子遗传学特征。因此，在开始治疗之前，评估肿瘤基因组变化和程序性死亡配体1（PD-L1）表达至关重要。放疗和手术常用于缓解某些患者的症状。

    治疗的决定因素

    在体能状况评分良好的IV期肿瘤患者中开展的随机对照临床试验显示含顺铂化疗可改善患者生存期并可缓解疾病相关症状。

    [证据等级：1iiA]紫杉醇与卡铂联合贝伐单抗可能有助于使组织学非鳞状细胞、身体状况评分良好、无咯血或其他出血性疾病病史且近期亦无心血管事件的患者获益。以EGFR酪氨酸激酶抑制剂（TKI）取代一线或二线化疗可能有助于使携带EGFR外显子19或21突变的肿瘤患者，尤其是东亚患者、从未吸烟者与腺癌患者获益。以ALK或ROS1抑制剂取代一线或二线化疗可能有助于使携带间变性淋巴瘤激酶（ALK）易位或ROS1重排的肿瘤患者获益。帕博利珠单抗治疗可延长表达PD-L1（免疫组织化学> 50％）的肿瘤患者的生存期。卡铂加培美曲塞化疗中添加帕博利珠单抗治疗非鳞状晚期肺癌后患者生存期延长，与PD-L1表达水平无关。

    [证据等级：1iiA] 纳武利尤单抗、多西他赛、培美曲塞或帕博利珠单抗二线全身治疗PD-L1阳性肿瘤后PS良好患者（在一线治疗中未接受相同或相似药物治疗）的生存期延长。

    [证据等级：1iiA]

    尚不确定全身治疗在东部肿瘤协作组PS低于2的患者中的作用。

    组织学

    腺癌患者可能从培美曲塞治疗中获益和贝伐珠单抗以及帕博利珠单抗联合化疗中获益。

    年龄与合并症

    有证据表明，即PS良好且合并症有限的老年患者可从联合化疗中获益。单纯年龄无法说明晚期NSCLC患者的治疗相关决策。与单独的支持治疗相比，接受化疗的PS良好老年患者的生存期更长，生活质量更佳。当将老年患者（70-79岁）的数据外推到80岁或80岁以上患者时，应谨慎行事，因为只有极少数80岁或80岁以上患者入组了临床试验，并且该组的获益仍有待证明。

    证据（年龄 vs.合并症）：

  • 与支持治疗或单药治疗相比，含铂联合化疗方案可提供临床获益。但是，由于许多器官的功能储备随年龄的增长而减少和/或伴有其他疾病，这种治疗在某些老年患者中可能禁用。约三分之二的NSCLC患者年龄在65岁或以上，约40％的年龄在70岁或以上。
  • 监测、流行病学和结局（SEER）数据显示，70岁以上患者所占百分比接近50％。
  • 对1994年至1999年SEER Medicare数据进行审查发现，总体人群的化疗使用率远低于预期。
  • 同样的数据表明，如果无禁忌症，老年患者可能具有更多合并症或功能受损率更高，这将使研究参与越发困难；缺乏临床试验数据可能会影响标准化疗治疗个体患者的决策。
  • 单药化疗和联合化疗显然至少使一些老年患者获益。 在意大利一项老年肺癌长春瑞滨的研究中，将154例70岁以上患者随机分配至长春瑞滨治疗组或支持治疗组。
  • 使用长春瑞滨治疗的患者的一年生存率为32％，相比之下，仅接受支持治疗的患者为14％。 化疗组的生活质量参数也得到显著改善，并且毒性反应可以接受。
  • 日本一项临床试验比较了多西他赛单药和长春瑞滨在180例PS良好的老年患者中的有效性。
  • 多西他赛治疗组的缓解率（22％vs. 10％）和无进展生存期（PFS）（5.4个月vs. 3.1个月）明显更佳，但中位生存期（14.3个月vs. 9.9个月）和1年生存率（59％ vs. 37％）无统计学显著性。
  • 分析并比较参加双药联合治疗的大型随机试验的年轻（＜70岁）患者与老年（≥70岁）患者的回顾性数据还显示，老年患者可能获得相同的生存期获益，但骨髓中出现毒性反应的风险较高。

    • 体能状态

    PS是NSCLC患者生存期最重要的预后因素之一。

    通过回顾性分析和前瞻性临床试验评估了该组患者治疗的获益。

    结果支持进一步评价化疗在转移性和局部晚期NSCLC中的作用；然而，由于确定了当前含铂化疗联合治疗的疗效，故不能将任何特定治疗方案视为标准疗法。在临床试验以外，仅PS良好且可评估肿瘤病变的患者可以接受化疗，在充分了解其预期风险和有限获益后才能进行此治疗。

    证据（PS）：

  • 癌症和白血病B组试验（CLB-9730 [NCT00003117]）比较了卡铂和紫杉醇与紫杉醇单药的有效性，纳入了99例PS为2的患者（占研究人群的18％）。
  • 与PS为0-1且中位生存期为8.8个月且1年生存率为38％的患者相比，PS为2的患者的相应中位生存期为3.0个月且1年生存率为14％；这表明PS较低可引起不良预后。 这些差异具有统计学显著性。
  • 对治疗组PS为2的患者分析发现，与紫杉醇单药治疗组患者相比，联合化疗组患者的缓解率（24％ vs.10％）显著更高、中位生存期更长（4.7个月 vs.2.4个月）且1年生存率更高（18％ vs.10％）。
  • 一项III期临床试验比较了培美曲塞单药联合卡铂和培美曲塞在205例既往未接受过化疗的PS为2的患者中的有效性。
  • [证据等级：1iiA]
  • 培美曲塞单药治疗组的中位总生存期（OS）为5.3个月，而卡铂和培美曲塞联合治疗组为9.3个月（风险比[HR]，0.62；95%置信区间[CI]，0.46-0.83；P = 0.012）。
  • 培美曲塞单药治疗组的中位PFS为2.8个月，卡铂和培美曲塞联合治疗组为5.8个月（P <.001）。
  • 培美曲塞单药治疗组的缓解率为10.3%，卡铂和培美曲塞联合治疗组为23.8%（P =0.032）。
  • 如预期，联合治疗组的副作用更为常见。

    • 这项研究在巴西的八个研究中心和美国的一个中心进行，报告的OS和PFS率高于大多数（尽管不是全部）其他已发表研究的历史记录。 这可能表明患者选择有所差异。

  • 数据显示该试验中对68例PS为2患者进行了亚组分析，其中该试验的1,200多例患者随机接受四种铂类药物治疗方案。
  • 尽管不良事件（包括五例死亡）的发生率偏高，但最终分析表明，PS为2的患者出现的总体毒性反应与PS为0-1的患者出现的总体毒性反应无显著差异。
  • 疗效分析表明，总缓解率为14％，中位生存时间为4.1个月，一年生存率为19％；均明显低于PS为0-1的患者。
  • 一项有关顺铂加吉西他滨和卡铂加紫杉醇减毒剂量的II期随机试验（E-1599 [NCT00006004]）包括102例PS为2的患者。
  • 顺铂加吉西他滨组的缓解率为25％，卡铂加紫杉醇组的缓解率为16％；顺铂加吉西他滨组的中位生存时间为6.8个月，卡铂加紫杉醇组的中位生存时间为6.1个月；顺铂加吉西他滨组的1年生存率为25％，卡铂加紫杉醇组的1年生存率19％。这些差异均无统计学显著性，但根据历史对照，生存期比预期延长。
  • 两项试验结果表明，PS为2的患者的症状可能得到改善。

    • 新诊断的复发性IV期NSCLC的标准治疗选择（一线治疗）

    新诊断为复发性IV期疾病患者的标准治疗选择包括：

  • 铂类（顺铂或卡铂）和紫杉醇、吉西他滨、多西他赛、长春瑞滨、伊立替康、蛋白结合型紫杉醇或培美曲塞细胞毒性药物联合化疗。
  • 联合化疗。
  • 药物和给药方案。
  • 化疗联合单抗。
  • 贝伐珠单抗。
  • 西妥昔单抗。
  • Necitumumab。
  • 一线化疗后维持治疗（针对四个疗程铂类联合化疗后病情稳定或缓解的患者）。
  • 一线化疗后维持治疗。
  • 一线含铂药物联合化疗继之以培美曲塞治疗。
  • 含铂双药化疗后厄洛替尼维持治疗。
  • 表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）（针对EGFR突变患者）。
  • 奥希替尼。
  • 吉非替尼。
  • 厄洛替尼。
  • 阿法替尼。
  • 间变性淋巴瘤激酶（ALK）抑制剂（针对ALK易位的患者）。
  • 阿来替尼。
  • 克唑替尼。
  • 塞瑞替尼。
  • 布加替尼。
  • Lorlatinib。
  • ROS1抑制剂（针对ROS1重排的患者）。
  • 克唑替尼。
  • BRAF V600E和MEK抑制剂（针对BRAF V600E突变的患者）。
  • 达拉非尼和曲美替尼。
  • 神经营养性酪氨酸激酶（NTRK）抑制剂（针对NTRK融合患者）。
  • Larotrectinib。
  • 与或不与化疗联用的免疫检查点抑制剂。
  • 帕博利珠单抗联合化疗。
  • 帕博利珠单抗单药治疗。
  • 局部治疗和特殊考虑。
  • 支气管激光治疗和/或近距放射治疗（用于阻塞病变）。
  • 外照射放疗（EBRT）（主要用于缓解局部症状性肿瘤生长）。
  • 第二大原发性肿瘤治疗。
  • 脑转移治疗。

    • 细胞毒性联合化疗

    联合化疗

    在随机对照试验和荟萃分析中已充分评估了用于治疗晚期NSCLC患者的化疗药物的类型和数量。

    多项随机试验评估了多种药物联合顺铂或卡铂在先前未接受治疗的晚期NSCLC患者中的有效性。 根据试验的荟萃分析，可以得出以下结论：

  • 添加靶向药物的某些三药联合治疗可能改善生存期。
  • EGFR抑制剂可能使某些携带EGFR突变的患者获益。
  • 4个疗程铂类联合化疗后行维持化疗可能延长PFS和OS。
  • 铂类联合长春瑞滨、紫杉醇、多西他赛、吉西他滨、伊立替康、蛋白结合型紫杉醇与培美曲塞联合化疗改善生存率的效果相似， 但毒性反应的类别和发生率各异，进行患者个体化治疗方案选择时需考虑这些因素。腺癌患者可能从培美曲塞治疗中获益。
  • 顺铂与卡铂改善预后的效果相似，但毒性反应不同。一些（而非所有）临床试验与荟萃分析发现顺铂可能更优，尽管顺铂的毒性反应如恶心、呕吐等的发生率也较高。
  • 非铂类药物联合化疗与含铂类药物化疗相比无更多优势，一些研究甚至认为其劣于后者。
  • 常见化疗药的三药联合化疗与两药联合化疗相比并没有进一步提高生存率，毒性却更大。

    • 证据（联合化疗）：

  • Cochrane协作网审查了1980年1月至2006年6月间发表的所有随机对照试验的数据，其中该试验比较了双药治疗方案与单药治疗方案或三药治疗方案与双药治疗方案在晚期NSCLC患者中的有效性。
  • 确定了65项试验（13,601例患者）。
  • 在比较双药治疗方案和单药治疗方案的试验中，观察到肿瘤缓解率（比值比[OR]，0.42；95％CI，0.37–0.47；P <0.001）和1年生存率（OR，0.80；95％CI，0.70-0.91；P <0.001）显著提高，双药治疗方案显优。绝对获益的1年生存率为5％，相当于1年生存率从单药治疗方案的30％提高到双药治疗方案的35％。与单药治疗后的发生率相比，双药治疗方案引起的3级和4级毒性反应的发生率增加具有统计学意义，OR范围为1.2-6.2。双药治疗方案的感染率未增加。
  • 三药治疗方案与双药治疗方案的一年生存率均未增加（OR，1.01；95％CI，0.85-1.21；P =0.88）。中位生存率为1.00（95％CI，0.94–1.06；P = 0.97）。
  • 多项荟萃分析评估了顺铂或卡铂治疗方案是否显优，结果却不尽相同。
  • 一项荟萃分析报告了9项随机试验中2968例患者的个体患者数据。
  • 接受顺铂治疗的患者的客观缓解率（ORR）高于接受卡铂治疗的患者，分别为30％和24％；（OR，1.37；95％CI，1.16-1.61；P <0.001）。
  • 相对于顺铂治疗，卡铂治疗与死亡危险增加相关但不具有统计学显著性（HR，1.07；95％CI，0.99-1.15；P =0.100）。
  • 对于非鳞状细胞瘤患者和接受第三代化疗的患者，含卡铂化疗与死亡率增加相关且具有统计学显著性（非鳞状细胞瘤患者的HR，1.12；95％CI，1.01-1.23；接受第三代化疗治疗的患者的HR，1.11；95％CI，1.01–1.21）。
  • 在荟萃分析中还评估了与治疗相关的毒性反应。卡铂治疗后血小板减少症发生率高于顺铂（12％ vs. 6％；OR，2.27；95％CI，1.71–3.01；P <0.001），但顺铂治疗后恶心和呕吐（8％vs. 18％；OR，0.42；95％CI，0.33-0.53；P <0.001）和肾毒性反应（0.5％vs. 1.5％；OR，0.37；95％CI，0.15-0.88；P =0.018）的发生率较高。
  • 作者得出结论，顺铂治疗与严重毒性反应的总体风险显著增加无关。这项全面的个体患者荟萃分析结论与基于基本相同的临床试验但仅使用已发表数据的其他荟萃分析保持一致。
  • 对比较铂类药物与非铂类药物联合治疗的试验进行了三项基于文献的荟萃分析。
  • 首项荟萃分析确定了37项可评估的试验，包括7,633例患者。
  • 含铂治疗后OR提高了62％（OR，1.62；95％CI，1.46-1.8；P <0.001）。含铂治疗后1年生存率提高了5％（34％ vs.29％；OR，1.21；95％CI，1.09–1.35；P = 0.003）。
  • 当将含铂治疗与第三代联合治疗方案进行比较时，发现1年生存率未提高且具有统计学显著性（OR，1.11；95％CI，0.96-1.28；P =0.17）。
  • 铂类药物治疗方案的毒性反应在血液学毒性反应、肾毒性反应、恶心和呕吐方面显著增高，但在神经系统毒性反应、发热性中性粒细胞减少症或毒性死亡率方面则不明显。这些结果与第二大基于文献的荟萃分析保持一致。
  • 第二项荟萃分析确定了17项试验，包括4,920例患者。
  • 含铂双药治疗方案使用后1年生存率略高（相对风险[RR]，1.08；95％CI，1.01％–1.16％； P =0.03），部分缓解更佳（RR，1.11；95％CI，1.02-1.21；P =0.02），贫血、恶心和神经系统毒性反应风险增加。
  • 在亚分析中，含顺铂双药治疗方案使用后1年生存率延长（RR，1.16％；95％CI，1.06-1.27；P =0.001），出现完全缓解（RR，2.29；95％CI，1.08–4.88；P =0.03）和部分缓解（RR，1.19；95％CI，1.07–1.32；P =0.002），贫血、中性粒细胞减少症、神经毒性反应和恶心风险增加。
  • 相反，含卡铂双药治疗方案使用后1年生存率并未提高（RR，0.95；95％CI，0.85-1.07；P = 0.43）。
  • III期临床试验中将含铂类药物与非铂类药物联合治疗作为一线化疗随机分配，第三项荟萃分析确定了14项临床试验。
  • 实验组包括吉西他滨和长春瑞滨（n = 4）、吉西他滨和紫杉烷（n = 7）、吉西他滨和表柔比星（n = 1）、紫杉醇和长春瑞滨（n = 1）、吉西他滨和异环磷酰胺（n = 1）。 仅对11项使用含铂双药治疗的III期临床研究的患者组（含铂类药物组2298例，非铂类药物组2304例）进行这项荟萃分析。
  • 接受含铂类药物治疗方案的患者1年死亡风险降低且具有统计学显著性（OR，0.88； 95％CI，0.78-0.99；P = 0.044），并且化疗难治的风险更低（OR，0.87；CI，0.73-0.99；P = 0.049）。
  • 据报道，含铂类药物治疗方案有44（1.9％）例毒性相关死亡，而非铂类药物治疗方案有29（1.3％）例毒性相关死亡（OR，1.53；CI，0.96-2.49；P = 0.08）。经统计学证明，接受含铂类药物化疗的患者发生3至4级胃肠道和血液学毒性反应的风险增加。发热性中性粒细胞减少症的风险未增加且具有统计学显著性（OR，1.23；CI，0.94-1.60；P =0.063）。

    • 药物和给药方案

    在活性药物联合治疗中，除了卡铂、培美曲塞和帕博利珠单抗之外。无法就药物剂量和给药方案对组织学非鳞状肿瘤患者提出明确的建议。

    证据（药物和给药方案）：

  • 一项包含2,867例患者的7项试验的荟萃分析评估了多西他赛相对于长春瑞滨的有效性。
  • 在三项试验中，多西他赛与含铂类药物联合治疗，在两项试验中与吉西他滨联合治疗，或在两项试验中作为单药治疗。在六项试验中长春花生物碱（六项试验中的长春瑞滨和一项试验中的长春地辛）与顺铂联合治疗，或在一项试验中单药治疗。
  • 汇总的OS预估值显示OS提高了11％，多西他赛显优（HR，0.89；95％CI，0.82-0.96；P = 0.004）。仅将长春瑞滨作为对照药或仅采用双药治疗方案的敏感性分析显示出类似的改善。
  • 与长春花生物碱为主的治疗方案（OR，0.68；95％CI，0.55-0.84；P <0.001）相比，多西他赛为主的治疗方案（OR，0.59；95％CI，0.38-0.89；P = 0.013）使用后3至4级中性粒细胞减少症和3至4级严重不良事件发生率较低。
  • 两项随机临床试验比较了每周一次与每3周一次紫杉醇和卡铂给药的有效性，其中每周一次给药的疗效和耐受性无显著差异。
  • 尽管随机对照临床试验的荟萃分析表明顺铂联合治疗可能优于卡铂或非铂联合治疗，但疗效差异的临床相关性必须与预期的耐受性、给药后勤和医务人员对治疗的熟悉程度相平衡，以便对个体患者做出治疗决策。
  • 一项大型、非劣效性、III期随机研究比较了1,725例化疗初治的IIIB / IV期NSCLC和PS 0-1的患者的OS。
  • 患者在第1天接受顺铂75 mg / m2和在第1天和第8天接受吉西他滨1,250 mg / m2（n = 863）或在第1天接受顺铂75 mg / m2和培美曲塞500 mg / m2（n = 862），每3周一次，最多6个疗程。
  • 在OS方面，顺铂和培美曲塞（中位生存期10.3个月）不劣效于顺铂和吉西他滨（中位生存期10.3个月；HR，0.94；95％CI，0.84％–1.05％）。
  • 在腺癌患者（n = 847）的OS方面，顺铂和培美曲塞（12.6个月）在统计学上优效于顺铂和吉西他滨（10.9个月）。在大细胞癌患者（n = 153）的OS方面，顺铂和培美曲塞（10.4个月）在统计学上优效于顺铂和吉西他滨（6.7个月）。
  • 相反，在鳞状细胞癌患者中（n = 473），与顺铂和培美曲塞（9.4个月）相比，顺铂和吉西他滨（10.8个月）的生存率有显著改善。对于顺铂和培美曲塞，3或4级中性粒细胞减少症、贫血和血小板减少症（P≤0.001）；发热性中性粒细胞减少症（P = 0.002）；和脱发（P <0.001）的发生率显著降低，而3级或4级恶心（P = 0.004）更常见。
  • 该研究结果表明，顺铂和培美曲塞双药治疗是晚期NSCLC一线化疗的另一种双药治疗方案，并提示根据组织学情况可能存在预后差异。

    • 化疗联合单抗

    贝伐珠单抗

    证据（贝伐珠单抗）：

  • 两项随机临床试验评估了标准一线联合化疗中添加贝伐珠单抗（一种靶向血管内皮生长因子的抗体）的有效性。
  • 在一项有关878例复发性或晚期IIIB / IV期NSCLC患者的随机临床研究中，444例患者接受了紫杉醇和卡铂单药治疗，434例患者接受了紫杉醇和卡铂+贝伐珠单抗联合治疗。
  • 每3周进行一次化疗，共6个疗程，每3周一次给予贝伐珠单抗，直至疾病进展明显或出现无法耐受的毒性反应。排除鳞状细胞癌、脑转移、临床上明显咯血或器官功能不全或PS（美国东部肿瘤协作组PS> 1）的患者。
  • 化疗联合贝伐珠单抗组的中位生存期为12.3个月，而单独化疗组的中位生存期为10.3个月（死亡HR，0.79；P = 0.003）。
  • 化疗联合贝伐珠单抗组的中位PFS为6.2个月（疾病进展的HR，0.66；P < 0.001），缓解率为35％（P <0.001），而单独化疗组为4.5个月（疾病进展的HR为0.66；P <0.001），缓解率为15％（P <0.001）。
  • 化疗联合贝伐珠单抗组的临床显著出血率为4.4％，单独化疗组为0.7％（P <0.001）。化疗联合贝伐珠单抗组出现15例治疗相关死亡，其中5例由肺出血引起。
  • 对于该亚组NSCLC患者，在紫杉醇和卡铂中添加贝伐珠单抗可能会延长生存期。
  • [证据等级：1iiA]
  • 另一项随机III期临床试验研究了顺铂-吉西他滨联合贝伐珠单抗的疗效和安全性。
  • 患者随机接受最多6个疗程的顺铂（80 mg / m2）和吉西他滨（1,250 mg / m2）联合低剂量贝伐珠单抗（7.5 mg / kg）、高剂量贝伐珠单抗（15 mg / kg）或安慰剂（每3周一次）治疗，直至出现疾病进展。在研究过程中，主要终点从OS更改为PFS。 共计1,043例患者（安慰剂组，n = 347；低剂量组，n = 345；高剂量组，n = 351）。
  • 添加贝伐珠单抗可显著延长PFS；与安慰剂组相比，低剂量组PFS的HR为0.75（中位PFS，6.7个月，安慰剂组为6.1个月；P = 0.03），高剂量组为0.82（中位PFS，6.5个月，安慰剂组为6.1个月；P = 0.03）。
  • [证据等级：1iiB]
  • 添加贝伐珠单抗后ORR提高，安慰剂为20.1％，低剂量贝伐珠单抗为34.1％，高剂量贝伐珠单抗联合顺铂/吉西他滨为30.4％。
  • 两组的3级或更高级别不良事件的发生率相近。
  • 尽管有9％患者接受了抗凝治疗，但所有组的3级或更高级别的肺出血发生率均为1.5％或更低。
  • 这些结果支持将贝伐珠单抗添加到含铂化疗中，但结果显示其疗效远远劣于卡铂-紫杉醇联合治疗。
  • 此外，如摘要报道，本研究未显示生存率有显著差异。
  • 总而言之，这些结果可能表明，添加贝伐珠单抗后，化疗的主作用可能至关重要。

    • 西妥昔单抗

    证据（西妥昔单抗）：

  • 两项临床试验评估了一线联合化疗中添加西妥昔单抗的有效性。
  • 在第一项临床试验中，676例化疗初治的IIIB期（胸腔积液）或IV期NSCLC患者，在不受组织学或EGFR表达限制的情况下，接受了西妥昔单抗联合紫杉烷（紫杉醇或多西他赛联合卡铂）治疗或联合化疗。
  • 添加西妥昔单抗后PFS、主要研究终点或OS未改善且具有统计学显著性。
  • 西妥昔单抗化疗组患者的中位PFS为4.40个月，而紫杉烷-卡铂组患者为4.24个月（HR，0.902；95％CI，0.761–1.069；P = 0.236）。
  • 西妥昔单抗化疗组患者的中位OS为9.69个月，而单独化疗组患者为8.38个月（HR，0.890；95％CI，0.754–1.051；P = 0.169）。
  • 治疗特定分析未发现EGFR表达、突变、拷贝数或KRAS突变与PFS、OS和缓解之间存在显著关联。
  • 第二项试验包括1,125例化疗初治的EGFR表达IIIB / IV期NSCLC患者，接受顺铂-长春瑞滨化疗联合西妥昔单抗治疗或单独化疗。
  • 接受西妥昔单抗和化疗治疗的患者的主要研究终点OS较长（中位11.3个月 vs. 10.1个月；死亡HR，0.871；95％CI，0.762-0.996；P = 0.044）。
  • 在所有组织学亚组中均观察到生存期获益；但是，在非白人或亚洲患者中未见生存期获益。仅治疗和种族之间的相互作用显著（P = 0.011）。
  • 与西妥昔单抗相关的主要不良事件为痤疮样皮疹（3级，10％）。
  • 目前尚不清楚这两项研究的结果差异是否是由研究人群、EGFR表达的肿瘤特征或化疗方案差异所致。

    • Necitumumab

    证据（Necitumumab）：

  • 两项III期临床试验评估了铂类药物双药化疗中添加第二代重组人免疫球蛋白G1 EGFR抗体necitumumab在晚期非鳞状细胞和鳞状细胞NSCLC患者一线治疗中的有效性。
  • SQUIRE（NCT00981058）试验随机分配了1,093例晚期鳞状NSCLC患者，接受一线化疗联合顺铂和吉西他滨或以相同方案添加necitumumab（每个疗程的第1天和第8天为800 mg）。
  • 添加necitumumab可延长中位OS（11.5个月 vs. 9.9个月；P = 0.01）。
  • 添加necitumumab也可延长PFS（5.7个月vs. 5.5个月）；但是，两组的ORR相似（31% vs. 28%）。
  • 含necitumumab治疗组的3级和4级不良事件发生率较高（72% vs. 62%）。
  • Necitumumab与更高的毒性和相对中等的获益有关。
  • INSPIRE（NCT00982111）试验随机分配了633例晚期非鳞状NSCLC患者接受一线化疗，包括顺铂和培美曲塞或顺铂和培美曲塞中添加necitumumab（每个疗程的第1天和第8天为800 mg）。
  • 该研究表明，在标准一线化疗中添加necitumumab对晚期非鳞状NSCLC无益。
  • 含necitumumab治疗组患者的OS为11.3个月（95％CI，9.5–13.4），而单独化疗组患者为11.5个月（95％CI，10.1–13.1）；P ＝ 0.96。同样，在ORR或PFS方面，各组之间也无差异。
  • 含necitumumab治疗组患者的严重不良事件和包括血栓栓塞事件在内的3级和4级不良事件的发生率更高；治疗相关的死亡发生率也更高（5% vs. 3%）。
  • 基于这些结果，对于晚期非鳞状NSCLC患者，不建议将necitumumab与标准一线化疗联合治疗。

    • 一线化疗后维持治疗（针对四个疗程铂类联合化疗后病情稳定或缓解的患者）

    一种经过广泛研究的NSCLC治疗策略是对化疗初次反应后的维持治疗。已研究的维持治疗选择包括：

  • 继续初始联合化疗方案。
  • 继续单药化疗。
  • 使用新药作为“维持治疗”。

    • 很多随机临床试验评估了继续沿用一线联合细胞毒性化疗药超过3-4疗程的效果。

    证据（一线化疗后的维持治疗）：

  • 继续细胞毒性联合治疗试验均未显示出明显的OS优势，且其持续时间超过四个疗程。对于非鳞状NSCLC患者，两项研究表明，通过换用或持续维持化疗（例如，初始顺铂和吉西他滨治疗后培美曲塞维持治疗，或初始顺铂和培美曲塞治疗后培美曲塞维持治疗）后，PFS和OS得以改善。
  • 三项临床试验显示，额外的化疗后PFS或进展时间显著延长。
  • 未报告生活质量持续改善。
  • 长期化疗后化疗相关毒性反应更大。

    • 这些数据表明，非鳞状NSCLC患者的PFS和OS可以通过继续四个疗程以上的有效化疗或立即开始替代化疗而得到改善。然而，PFS改善因不良事件的增加而受到抑制，这些不良事件包括额外的细胞毒性化疗以及未持续改善的生活质量。对于疾病稳定或对一线治疗有反应的患者，证据不支持在病情进展前继续联合细胞毒性化疗或在病情进展前开始不同的化疗。总之，这些试验表明，对于疾病治疗无反应的患者，应在疾病进展时或在四个疗程治疗后停止一线细胞毒性联合化疗；最多可以给予6个疗程治疗。

    对于在四至六个疗程的铂类药物联合化疗后有反应或疾病稳定的非鳞状NSCLC患者，应考虑使用培美曲塞维持化疗。

    证据（一线含铂药物联合化疗继之以培美曲塞治疗）：

  • 两项随机试验（NCT00102804和NCT00789373）的结果表明，在标准一线含铂药物联合化疗后添加培美曲塞可以改善预后。
  • 在第一项试验中，将663例接受四个疗程非培美曲塞含铂药物化疗后未出现疾病进展的IIIB / IV期疾病患者随机分配（按2:1比例），以接受培美曲塞或安慰剂治疗，直至疾病进展。
  • 添加培美曲塞维持治疗后，主要终点PFS和次要终点OS均延长且具有统计学显著性（中位PFS，4.3个月 vs. 2.6个月；HR，0.50；95％CI，0.42-0.61；P <0.0001；中位OS，13.4个月 vs. 10.6个月；HR，0.79；95％CI，0.65-0.95；P = 0.012）。
  • 组织学为鳞状细胞癌患者未见获益。
  • 培美曲塞组3级以上毒性反应和因药物相关毒性反应所致的治疗中止率高于安慰剂组。
  • 未发生培美曲塞相关的死亡。
  • 培美曲塞组接受停药后全身治疗的患者相对少于安慰剂组（227 [51％] vs. 149 [67％]； P = 0.0001）。
  • 培美曲塞维持治疗期间的生活质量与安慰剂相似，除了使用肺癌症状量表评估的食欲减退、疼痛和咯血明显延迟恶化。
  • 生活质量的结果需要谨慎评估，因为对生活质量主要终点进行了高度审查（> 50％），这是症状恶化的时间。
  • 试验未评估疾病进展时培美曲塞维持治疗与培美曲塞的有效性。
  • 在第二项试验中，将539例接受培美曲塞和顺铂治疗后无进展的非鳞状NSCLC患者随机分配，继续接受培美曲塞或安慰剂治疗。
  • 主要终点PFS（4.1个月 vs. 2.8个月，HR，0.62；95％CI，0.49–0.79）和次要终点OS（13.9个月 vs. 11个月，HR，0.78）有所延长且具有统计学显著性；95％CI，0.64–0.96）。
  • [证据等级：1iDiii]

    • 证据（含铂双药化疗后厄洛替尼维持治疗）：

  • 一项试验（NCT00556712）报告显示，疾病稳定患者在四个疗程的含铂药物双药化疗继之以厄洛替尼维持治疗后预后良好。
  • 在该试验中，将889例NSCLC且无疾病进展的患者随机分配，接受厄洛替尼（150 mg /天）或安慰剂治疗，直到出现疾病进展或不可耐受的毒性。
  • 厄洛替尼治疗的中位PFS显著长于安慰剂治疗：厄洛替尼组患者为12.3周，而安慰剂组患者为11.1周（HR，0.71；95％CI，0.62-0.82；P < 0.0001）。
  • 在总体人群中，厄洛替尼维持治疗后EGFR突变激活的肿瘤患者的PFS获益最大（n = 49；HR，0.10；P < 0.0001）。
  • 肿瘤为野生型EGFR的患者的PFS（HR，0.78）和OS（HR，0.77）也显著延长。
  • 在肿瘤未激活EGFR突变的疾病稳定患者亚组中（n = 217），厄洛替尼治疗后PFS（HR，0.72；95％CI，0.54-0.96；P = 0.0231）和OS（HR，0.65；95％CI，0.48–0.87；P = 0.0041）显著延长。
  • 对于肿瘤激活EGFR突变的患者（n = 30），厄洛替尼治疗后OS也延长（HR，0.48；95％CI，0.14–1.62），但在该分析中无统计学显著性。
  • EGFR免疫组化、EGFR荧光原位杂交（FISH）、KRAS突变和内含子1重复长度状态中的EGFR CA简单序列重复不能预估厄洛替尼的疗效。
  • KRAS突变状态是PFS重要的、阴性预后因素。
  • [证据等级：1iDiii]

    • EGFR酪氨酸激酶抑制剂

    某些患者可能获益于EGFR TKI单药治疗。在未行过化疗的携带EGFR突变的NSCLC患者中开展的随机对照临床试验显示EGFR抑制剂与联合化疗相比，提高PFS，但不提高OS，且毒性反应较轻。

    奥希替尼

    证据（奥希替尼）：

  • 一项III期、多中心、随机、双盲、对照试验（FLAURA [NCT02296125]）在既往未经治疗的EGFR突变阳性（外显子19缺失或L858R）晚期NSCLC患者中比较了奥希替尼与EGFR TKI（吉非替尼或厄洛替尼）标准治疗作为一线治疗的有效性，这得到美国食品药品监督管理局（FDA）批准的试验检测证实。
  • 将556例患者按1:1比例随机分配。
  • 研究者评估的PFS是主要终点，奥希替尼治疗后明显更长（18.9个月vs.10.2个月；HR，0.46；95％CI，0.37–0.57，P<0.0001）。
  • [证据等级：1iDiii]
  • 两组的客观缓解率相似（奥希替尼治疗组为80％，EGFR TKI标准治疗组为76％）。
  • 奥希替尼治疗组中位反应持续时间为17.2个月（95％CI，13.8–22.0），而EGFR TKI标准治疗组为8.5个月（95％CI，7.3–9.8）。
  • OS数据不成熟。
  • 与TKI标准治疗（45％）相比，奥希替尼治疗组3级或更高级别不良事件的发生率更低（34％）。

    • 奥希替尼已被FDA批准用于EGFR突变NSCLC（外显子19缺失或L858R）的一线治疗。

    吉非替尼

    证据（吉非替尼）：

  • 一项III期、多中心、随机试验比较了吉非替尼与卡铂联合紫杉醇作为一线治疗方案，在临床上选择的从未吸烟或曾轻度吸烟的东亚晚期肺腺癌患者中的有效性。
  • 该研究达到了主要目的，即证明了在PFS方面吉非替尼优于卡铂-紫杉醇联合治疗（进展或死亡的HR，0.74；95％CI，0.65-0.85；P < 0.001）。
  • 吉非替尼组的中位PFS为5.7个月，卡铂-紫杉醇组的中位PFS为5.8个月。
  • [证据等级：1iDiii]
  • 在中止化疗并继续接受吉非替尼治疗后，PFS曲线明显分离，提示吉非替尼显优。
  • 吉非替尼组的12个月PFS率为24.9％，卡铂-紫杉醇组为6.7％。
  • 在该试验中，超过90％的突变患者具有del19或21外显子 L858R突变，这已显示出对EGFR抑制剂敏感。在具有突变的患者亚组中，接受吉非替尼治疗的患者的PFS明显更长（HR，0.48；95％CI，0.36-0.64；P < 0.001）；然而，在突变阴性的患者亚组中，接受卡铂-紫杉醇联合治疗的患者的PFS明显更长（吉非替尼联合治疗的HR，2.85；95％CI，2.05-3.98；P < 0.001）。在PFS方面，治疗与EGFR突变之间存在显著的相互作用（P < 0.001）。
  • 接受吉非替尼和卡铂-紫杉醇治疗的患者的OS相似，总体治疗（HR，0.90；95％CI，0.79-1.02；P = 0.109）或EGFR突变阳性（HR，1.00；95％CI，0.76-1.33；P = 0.990）或EGFR突变阴性（HR，1.18；95％CI，0.86-1.63；P = 0.309；治疗与EGFR突变相互作用，P = 0.480）亚组无显著差异。随机分配至卡铂-紫杉醇治疗方案的EGFR突变阳性患者中，大多数（64.3％）接受了随后的EGFR TKI治疗。对于同时具有较高EGFR基因拷贝数和EGFR突变的患者，吉非替尼治疗后PFS显著更长（HR，0.48；95％CI，0.34–0.67），但是在较高EGFR基因拷贝数不伴有EGFR突变时，PFS显著缩短（HR，3.85；95％CI，2.09–7.09）。
  • 日本两项III期前瞻性临床试验证实，吉非替尼治疗时，NSCLC和EGFR突变的患者的PFS延长，但OS未延长。
  • 在第一项试验中，230例化疗初治的转移性NSCLC和EGFR突变患者随机接受吉非替尼或卡铂-紫杉醇治疗。
  • 计划的前200例患者数据期中分析发现，吉非替尼组的PFS明显长于标准化疗组（吉非替尼的死亡或疾病进展HR，0.36；P < 0.001），导致研究提前终止。
  • 吉非替尼组的中位PFS显著更长（10.8个月，化疗组为5.4个月；HR，0.30；95％CI，0.22-0.41；P < 0.001）。
  • [证据等级：1iiDiii]吉非替尼组的中位OS为30.5个月，标准化疗组为23.6个月（P = 0.31）。
  • 在第二项试验中，西日本肿瘤学小组对177例年龄在75岁或以下，并被确诊为IIIB / IV期NSCLC或术后复发且携带EGFR突变（外显子19缺失或L858R点突变）的化疗初治患者进行了III期临床研究（WJTOG3405）。
  • 患者随机接受吉非替尼或顺铂加多西他赛治疗（每21天给药一次，共3-6个疗程）。主要终点为PFS。
  • 吉非替尼组的PFS明显长于顺铂加多西他赛组，中位PFS分别为9.2个月（95％CI，8.0-13.9）和6.3个月（范围5.8-7.8个月；HR，0.489；95％CI，0.336–0.710，log-rank；P < 0.0001）。
  • [证据等级：1iiDiii]

    • 厄洛替尼

    证据（厄洛替尼）：

  • 在一项来自中国的开放性、随机、III期临床试验（NCT00874419）中，165例18岁以上组织学确诊为IIIB / IV期NSCLC并证实EGFR突变激活（即19外显子缺失或21外显子L858R点突变）患者口服厄洛替尼（150 mg /天），直至出现疾病进展或出现不可耐受的毒性反应，或者接受了四个疗程的吉西他滨联合卡铂治疗。
  • 厄洛替尼治疗组患者的中位PFS明显长于化疗组患者（13.1个月[95％CI，10.58-16.53]vs. 4.6个月[范围，4.21-5.42个月]；HR，0.16；95％CI，0.10–0.26；P < 0.0001）。
  • [证据等级：1iiDiii]
  • 在一项欧洲研究（EURTAC [NCT00446225]）中，筛选了1,227例EGFR突变的晚期NSCLC患者。 其中，174例EGFR突变患者随机接受厄洛替尼或含铂类药物化疗。
  • 主要终点为PFS。
  • 在前153例患者的期中分析中，化疗组的PFS为5.2个月（95％CI，4.5-5.8），而厄洛替尼组为9.7个月（95％CI，8.4-12.3）（HR，0.37；P < 0.0001）。化疗组患者的中位生存期为19.3个月，而厄洛替尼组患者为19.5个月（HR，0.80；P = 0.42）。
  • [证据等级：1iiDiii]

    • 阿法替尼

    证据（阿法替尼）：

  • 在一项开放性、随机、III期临床研究中（LUX-Lung 3 [NCT00949650]）中，对345例证实EGFR突变（即19外显子缺失，L858R或其他[345例患者中38例的其他突变较少见]）的亚洲人（72％）和白人（26％）IIIB / IV期NSCLC患者进行筛选，340例患者接受了至少一剂研究药物治疗，即口服40 mg阿法替尼（一种不可逆的EGFR /人表皮受体（HER）TKI），每日一次或接受最多六个疗程的顺铂和培美曲塞一线治疗。
  • 主要终点为PFS。在这项研究中，阿法替尼组的PFS明显长于顺铂加培美曲塞组，阿法替尼的中位PFS为11.1个月，化疗的中位PFS为6.9个月（HR，0.58；95％CI，0.43-0.78；P = 0.001）。
  • [证据等级：1iiDiii]
  • OS评估是次要终点，需要另行报告。
  • 根据EGFR突变类型和种族对OS进行分层，与PFS分析类似。
  • 中位随访时间为41个月时，两组患者中位OS为28.2个月（HR，0.88；95％CI，0.66-1.17；P = 0.39）。
  • 在携带常见EGFR突变（即19外显子缺失和L858R）的患者中，治疗组之间的生存期无显著差异（HR，0.78；95％CI，0.58–1.06；P = 0.11）。但是，预先规定的亚组分析显示，在携带EGFR del19突变的肿瘤患者中，阿法替尼比化疗具有生存优势（中位OS，33.3个月 vs. 21.1个月；HR，0.54；95％CI，0.36-0.79；P = 0.0015），但在携带L858R突变的肿瘤患者中治疗组之间无显著差异（中位OS，27.6个月vs. 40.3个月；HR，1.30；95％CI，0.80-2.11；P = 0.29）。
  • 在携带EGFR del19突变的NSCLC患者中，阿法替尼一线治疗与化疗相比具有显著的生存优势，但在EGFR L858R突变的患者或整个EGFR突变阳性患者人群中则无生存优势。
  • [证据等级：1iiA]
  • 在一项开放性、随机、III期研究中（LUX-Lung 6 [NCT01121393]），将364例IIIB / IV期NSCLC并确诊EGFR突变（即外显子19缺失，L858R或其他）的东亚患者随机分配（按2:1比例），每日一次口服40 mg阿法替尼或吉西他滨和顺铂，最多六个疗程，作为一线治疗。
  • 主要终点为PFS。阿法替尼组（11.0个月；95％CI，9.7–13.7）的PFS显著长于吉西他滨和顺铂组（5.6个月，[范围：5.1–6.7个月]；HR，0.28；95％CI，0.20 –0.39；P < 0.0001）。
  • [证据等级：1iiDiii]
  • OS评估是预先规定的次要终点，需要另行报告。
  • 根据EGFR突变类型和种族来源对OS进行分层，与PFS分析类似。
  • 中位随访时间为33个月时，阿法替尼组患者的中位OS为23.1个月，化疗组患者为23.5个月（HR，0.93；95% CI，0.72–1.22；P = 0.61）。
  • 在携带常见EGFR突变（即19外显子缺失和L858R）的患者中，治疗组之间的生存期无显著差异（HR，0.83；95％CI，0.62–1.09；P = 0.18）。但是，预先规定的亚组分析显示，在携带EGFR del19突变的肿瘤患者中，阿法替尼比化疗具有生存优势（中位OS，31.4个月 vs. 18.4个月；HR，0.64；95％CI，0.44-0.94；P = 0.023），但在携带L858R突变的肿瘤患者中治疗组之间无显著差异（中位OS，19.6个月vs. 24.3个月；HR，1.22；95％CI，0.81-1.83；P = 0.34）。
  • 在携带EGFR del19突变的NSCLC患者中，阿法替尼一线治疗与化疗相比具有显著的生存优势，但在EGFR L858R突变的患者或整个EGFR突变阳性患者人群中则无生存优势。
  • [证据等级：1iiA]

    • ALK抑制剂（针对ALK易位的患者）

    阿来替尼

    证据（阿来替尼）：

  • 在一项开放性、随机、III期研究（ALEX试验[NCT02075840]）中，303例既往未接受治疗的ALK重排晚期NSCLC患者接受了阿来替尼（600 mg bid）或克唑替尼（250 mg bid）。
  • 主要终点为研究者评估的PFS。
  • 阿来替尼组的PFS率明显高于克唑替尼组；阿来替尼组的12个月无事件生存率为68.4％（95％CI，40.4-56.9），而克唑替尼组为48.7％（95％CI，40.4-56.9）（HR，0.47；95％CI，0.34-0.65；P < 0.001）。阿来替尼治疗后未达到中位PFS。独立审查委员会评估的PFS结果保持一致。
  • [证据等级：1iiDiii]
  • 与克唑替尼组（45％）相比，阿来替尼组的中枢神经系统（CNS）进展事件发生率较低（12％）（HR，0.16；95％CI，0.10-0.28；P < 0.001）。
  • 两组的缓解率相似，阿来替尼组为82.9％，克唑替尼组为75.5％（P = 0.09）。
  • 与克唑替尼组（50％）相比，阿来替尼组3至5级不良事件的发生率更低（41％）。
  • 第二项开放性、随机、III期临床试验（J-ALEX）招募了207例ALK抑制剂初治且化疗初治或既往接受一种化疗方案治疗的ALK阳性NSCLC日本患者。患者按1:1比例随机接受阿来替尼（300 mg bid，这是日本批准的剂量，低于其他地方批准的600 mg剂量每日两次）以及克唑替尼（250 mg bid）治疗。
  • 主要终点为由独立审查委员会评估的PFS。
  • 在第二次主要中期分析的数据截止日期，独立数据监测委员会确定已达到主要终点（HR，0.34；99.7％CI，0.17-0.71；P < 0.0001），并建议立即发布数据。阿来替尼治疗组未达到中位PFS，但克唑替尼治疗组达到了，为10.2个月。
  • 与克唑替尼组（52%）相比，阿来替尼组3或4级不良事件的发生率更低（26%）。

    • 克唑替尼

    证据（克唑替尼）：

  • 在一项开放性、随机、III期研究中，343例携带ALK易位的IIIB / IV期NSCLC患者口服250 mg克唑替尼（每日两次），或接受培美曲塞与顺铂或卡铂联合治疗，最多六个疗程。
  • 在疾病进展时，化疗组的患者可以交叉使用克唑替尼；化疗组60％的患者随后接受了克唑替尼治疗。本研究的主要终点是PFS。
  • 该研究达到了其主要终点，并证明了克唑替尼在延长PFS方面优于化疗（中位值，10.9个月 vs.7.0个月；HR，0.454；95％CI，0.346-0.596；P < 0.0001）。
  • [证据等级：1iiDiii]

    • 塞瑞替尼

    证据（塞瑞替尼）：

  • 在一项开放性、随机、III期研究中，376例IIIB / IV期ALK重排非鳞状NSCLC患者接受口服750 mg塞瑞替尼（每日一次）或含铂类药物化疗（顺铂或卡铂和培美曲塞）（每3周一次），共四个疗程，继之以培美曲塞维持治疗。
  • 主要终点为PFS，并在记录有进展后允许化疗和塞瑞替尼交叉使用。
  • 塞瑞替尼组的中位PFS（通过盲态独立审查评估）为16.6个月，化疗组为8.1个月（HR，0.55；95％CI，0.42-0.73；P <0.00001）。
  • 塞瑞替尼组未达到中位OS，化疗组中位OS为26.2个月（HR，0.73；95%CI，0.50–1.08；P =0.056）。
  • [证据等级：1iiDiii]

    • 布加替尼

    证据（布加替尼）：

  • II期开放性试验（NCT02094573）入组了222例克唑替尼治疗后疾病进展的ALK易位的局部晚期或转移性NSCLC患者。患者随机接受90 mg qd（n = 112；109例接受治疗）或180 mg qd，以及7天90 mg qd导入（n = 110）治疗。
  • 研究者评估的主要终点是ORR。90 mg剂量组患者的ORR为45％（97.5％CI，34–56），180 mg剂量组患者为54％（97.5％CI，43–65）。
  • 90 mg剂量组患者的中位PFS为9.2个月（95％CI，7.4–15.6），180 mg剂量组患者为12.9个月（95% CI，11.1–未达到）。
  • 在数据截止日期，90 mg剂量组患者的中位缓解时间为13.8个月（95％CI，5.6–13.8），180 mg剂量组患者为11.1个月（95％CI，9.2–13.8）。
  • [证据等级：1iiDiv]
  • 90 mg qd剂量组患者中具有可测量CNS病灶的患者的CNS ORR为42％（n = 26），180 mg qd剂量组患者为67％（n = 18）。
  • 常见不良事件主要为1级或2级恶心、腹泻、头痛和咳嗽，高剂量组发生率为27％-38％。219例接受治疗的患者中有14例发生了一部分早期发作（发作中位值，第2天）的肺部不良事件（所有等级，6％；≥3，3％）；剂量递增至180 mg后未发生任何事件。这些事件包括呼吸困难、缺氧、咳嗽、肺炎或局限性肺炎。可通过中断剂量进行治疗。14例患者中有7例使用布加替尼成功治愈。
  • FDA批准的布加替尼剂量为90 mg qd，共7天；如果可以耐受，剂量应增加至180 mg qd。

    • Lorlatinib

    证据（Lorlatinib）。

  • 在一项正在进行的具有多个队列的II期开放性研究中，根据ALK状况和治疗史，转移性ALK重排的NSCLC患者入组6个ALK扩展（EXP）队列。
  • 患者连续接受lorlatinib 100 mg治疗，每日一次，每21天为一个疗程。主要终点为关键合并亚组中通过独立中心审查评估的客观肿瘤缓解和颅内肿瘤缓解。
  • [证据等级：3iiiDiv]
  • 每个队列或合并队列中接受治疗的患者数、ORR和颅内缓解率如下所示：
  • EXP1（n = 30，初治）。
  • RR = 90.0%；95% CI，73.5‒97.9。
  • 颅内（n = 3），RR = 66.7％；95％CI，9.4‒99.2。
  • EXP2（n = 27，既往仅接受克唑替尼治疗）和EXP3A（n = 32，既往接受过克唑替尼和化疗），RR = 69.5％；95％CI，56.1‒80.8。
  • 颅内（n = 23），RR = 87.0%；95％CI，66.4-97.2。
  • EXP3B（n = 28，既往接受过一种第二代ALK抑制剂，联合或不联合化疗），RR = 32.1％；95％CI，15.9-52.4。
  • 颅内（n = 9），RR = 55.6%；95％CI，21.2‒86.3。
  • EXP4（n = 65，既往接受过两种ALK抑制剂，联合或不联合化疗）和EXP5（n = 46，既往接受过3线ALK抑制剂，联合或不联合化疗），RR = 38.7％；95％CI，29.6-48.5。
  • 颅内（n = 49），RR = 53.1%；95％CI，38.3‒67.5。
  • 对于所有合并队列，均未达到中位缓解时间。
  • 最常见的不良事件是高胆固醇血症（16％，3-4级），有3％的患者因不良事件而中止治疗。

    • ROS1抑制剂（针对ROS1重排的患者）

    大约1％的NSCLC患者出现ROS1重排。

    克唑替尼

    克唑替尼已获批用于治疗肿瘤呈ROS1阳性的转移性NSCLC患者，不考虑既往全身治疗的次数。

    证据（克唑替尼）：

  • 在克唑替尼的I期研究的扩展队列中，50例ROS1重排呈阳性的晚期NSCLC患者口服250 mg克唑替尼治疗，每日两次。
  • 使用分离的FISH或逆转录酶-聚合酶链反应法确定为ROS1重排。7例患者（14％）既往未接受过任何晚期疾病治疗，21例患者（42％）既往接受过一种治疗，22例患者（44％）既往接受过一种以上治疗。主要终点为缓解率。
  • 总缓解率为72％（95％CI，58-84）。6％患者出现完全缓解，66％患者出现部分缓解，18％患者疾病稳定，这是最佳反应。
  • 中位PFS数19.2个月（95％CI，14.4-未达到）。估计的缓解持续时间为17.6个月（95％CI，14.5-未达到）。
  • [证据等级：3iiiDiv]
  • 在一项II期、开放性、单组试验中，127例ROS1阳性NSCLC的东亚患者接受250 mg克唑替尼治疗，每日两次。
  • 24例患者（18.9%）既往未接受过任何晚期疾病治疗，53例患者（41.7%）既往接受过一种治疗，50例患者（39%）既往接受过两种或3种治疗。主要终点为通过独立审查的客观缓解率。
  • 客观缓解率为71.7%（95％CI，63.0–79.3）。 缓解率相似，不考虑既往治疗次数。13.4％患者出现完全缓解，而58.3％患者出现部分缓解，16.5％患者疾病稳定，这是最佳反应。
  • [证据等级：3iiiDiv]
  • 中位PFS为15.9个月（95％CI，12.9–24）。缓解持续时间为19.7个月（95％CI，14.1-未达到）。
  • 中位OS为32.5个月（95％CI，32.5-未达到）。

    • BRAF V600E和MEK抑制剂（针对BRAF V600E突变的患者）

    BRAF V600E突变，见于1%到2%的肺腺癌。

    达拉非尼和曲美替尼

    证据（达拉非尼和曲美替尼）：

  • 在一项II期、多中心、非随机、开放性研究（NCT01336634）中，36例既往未接受治疗且BRAF V600E突变检测呈阳性的转移性NSCLC患者接受了150 mg bid达拉非尼（一种BRAF抑制剂）和2 mg qd曲美替尼（一种MEK抑制剂）治疗。
  • 通过Oncomine Dx目标检测（ThermoFisher Scientific）确定为BRAF V600E突变。主要终点为研究者评估的总缓解率。
  • 总缓解率为64%（95％CI，46-79）。6％患者出现完全缓解，58％患者出现部分缓解。
  • 研究者评估的中位PFS为10.9个月（95％CI，7.0–16.6个月）。估计的中位缓解持续时间为10.4个月（95％CI，8.3–17.9）。在数据截止日期，47％患者死亡，中位OS为24.6个月（95％CI，12.3-不可估计）。
  • 69％患者至少发生1例3或4级不良事件，其中最常见的是发热、丙氨酸转氨酶升高、高血压或呕吐。不良事件导致22％的患者永久停药，75％的患者给药中断或延迟以及39％的患者剂量减少。
  • [证据等级：3iiiDiv]

    • 达拉非尼和曲美替尼联合治疗已获批，可用于治疗通过FDA批准的试验检测出其肿瘤携带BRAF V600E突变的NSCLC患者。

    NTRK抑制剂（针对NTRK融合的患者）

    NTRK中的体细胞基因融合发生在许多实体瘤中，包括少于0.5％的NSCLC肿瘤。

    不吸烟的肺腺癌患者出现这些融合的概率更高。

    Larotrectinib

    证据（Larotrectinib）：

  • 存在三种Larotrectinib研究方案： 一项涉及成人的I期研究、一项涉及儿童的I / II期研究以及一项涉及青少年和成人的II期研究。
  • 使用FISH或下一代测序方法证实了肿瘤中融合。综合分析的主要终点是通过独立审查评估的客观缓解率，该分析在监管机构的意见下进行，目的是排除下限低于30％的缓解率。 共55例有17种不同NTRK融合阳性肿瘤类型的患者（中位年龄，45岁（范围，4个月-76岁））入组。所有患者均出现转移性病灶（82％）或局部晚期不可切除的病灶（18％）。入组患者既往接受过全身性治疗（中位值：2）。
  • 客观缓解率为75％（95％CI，61％‒75％），其中73％持续至少6个月。
  • [证据等级：3iiiDiv]
  • 对治疗的耐受性良好，93％的不良事件为1至2级。最常见的3至4级不良事件是贫血（11％患者）、转氨酶减少（7％）和中性粒细胞减少症（7％）。

    • Larotrectinib已获得FDA批准，用于治疗携带NTRK基因融合且无已知获得性耐药突变的局部晚期或转移性肿瘤患者，以及无令人满意的替代治疗或在治疗后癌症进展的患者。

    和或不和化疗联用的免疫检查点抑制剂

    帕博利珠单抗是一种人源化单克隆抗体，可抑制肿瘤细胞上表达的PD-1共抑制性免疫检查点与浸润免疫细胞及其配体PD-L1和程序性细胞死亡配体2（PD-L2）之间的相互作用。

    帕博利珠单抗联合化疗

    证据（帕博利珠单抗联合化疗）：

  • 一项III期双盲试验（KEYNOTE-189 [NCT02578680]）按2:1比例对符合下列条件的616例患者进行随机分配：出现转移性非鳞状NSCLC、对EGFR突变或ALK重排不敏感、既往未接受过转移性病灶治疗。患者接受培美曲塞和含铂类药物联合200 mg帕博利珠单抗或安慰剂治疗，每3周一次，共4个疗程，继之以帕博利珠单抗或安慰剂（共35个疗程）联合培美曲塞治疗。
  • 在含安慰剂的联合治疗组患者中证实进展后，允许交叉使用帕博利珠单抗单药治疗。主要终点为OS和PFS，由盲态独立中心委员会放射学审查进行评估。
  • 中位随访时间为10.5个月后，帕博利珠单抗联合治疗组12个月时估计的OS率为69.2％（95％CI，64.1–73.8），相比之下，安慰剂联合治疗组为49.4%（95% CI，42.1–56.2）（HR，0.49；95% CI，0.38–0.64；P < 0.001）。
  • [证据等级：1iA]
  • 在所有PD-L1类别中均观察到生存率提高。
  • 帕博利珠单抗联合治疗组的中位PFS为8.8个月，而安慰剂联合治疗组为4.9个月（HR，0.52；95% CI，0.43–0.64；P < 0.001）。
  • 在两个治疗组中，3级或更高级别不良事件的发生率相似（帕博利珠单抗联合治疗组为67.2％，安慰剂联合治疗组为65.8％）。

    • 帕博利珠单抗单药治疗

    证据（帕博利珠单抗单药治疗）：

  • 一项III期开放性研究（KEYNOTE-024）中，将305例既往未经治疗的≥50％肿瘤细胞上PD-L1表达且对EGFR突变或ALK易位不敏感的晚期NSCLC患者，随机分配至帕博利珠单抗静脉注射组（200 mg，每3周一次，最多35个疗程）或含铂类药物化疗组（4-6个疗程，由研究者选择；培美曲塞维持治疗可用于治疗非鳞状肿瘤）。
  • 主要终点为PFS。
  • 使用PD-L1免疫组化22C3 pharmDx分析法（Dako North America）集中评估PD-L1表达水平。在检查的1,653例患者样本中，有30.2％的PD-L1肿瘤表达水平达到50％或更高。
  • 帕博利珠单抗治疗后中位PFS显著改善（10.3个月vs. 6.0个月；HR，0.50；95％CI，0.37–0.68；P < 0.001）。帕博利珠单抗组总缓解率（44.8% vs. 27.8%）、中位缓解持续时间（未达到，[范围，1.9 + –14.5 +个月]vs.6.3个月[范围，2.1 + –12.6 +个月]）和6个月时估计的OS（80.2％vs. 72.4％；HR，0.60；95％CI，0.41-0.89；P = 0.005）均高于化疗组。
  • 本研究的进一步随访证实了帕博利珠单抗在OS方面的优势。接受帕博利珠单抗治疗的患者的中位OS为30个月（95％CI，18.3个月-未达到），而接受化疗的患者的中位OS为14.2个月，此后交叉使用免疫治疗的概率为75％，这表明交叉用药并不影响生存期。
  • 帕博利珠单抗治疗组不良事件（任何级别）发生率均低于化疗组（73.4％vs. 90.0％）。
  • 帕博利珠单抗治疗组3-5级不良事件发生率为26.6%，化疗组发生率为53.3%。
  • 帕博利珠单抗治疗组3或4级免疫相关事件发生率为9.7%，化疗组发生率为0.7%。
  • 与帕博利珠单抗相关的最常见3级或4级免疫相关事件为严重皮肤反应（3.9％）、肺炎（2.6％）和结肠炎（1.3％）。
  • 未发生5级免疫相关事件。
  • 与化疗组相比，帕博利珠单抗治疗组PFS、OS和缓解持续时间显著改善，不良事件发生率较低。
  • [证据等级：1iiDiii]

    • 帕博利珠单抗联合培美曲塞和卡铂已获得FDA批准，作为转移性非鳞状NSCLC患者的一线治疗，不考虑PD-L1表达水平。帕博利珠单抗也获批作为一线单药治疗，用于治疗肿瘤表达PD-L1（经FDA批准的试验确定染色≥50％）的NSCLC患者。在接受帕博利珠单抗之前，EGFR或ALK基因组肿瘤异常的患者应先行FDA批准的治疗确定疾病进展（参见FDA的帕博利珠单抗标签）。

    局部治疗和特殊考虑

    支气管激光治疗和/或近距放射治疗（用于阻塞病变）

    放疗可有效缓解NSCLC局部受累症状患者，例如：

  • 气管、食管或支气管压迫。
  • 疼痛。
  • 声带麻痹。
  • 咯血。
  • 上腔静脉综合征。

    • 有时可用经支气管镜激光治疗和/或近距离放射治疗缓解近端梗阻性病变。

    EBRT（主要用于缓解有局部症状的肿瘤生长）

    虽然EBRT常用于缓解症状，但对于何时应使用分割方案尚未达成共识。尽管不同多分割治疗方案缓解症状的程度相似，

    NCT00003685临床试验显示，与大分割或标准治疗方案相比，单独分割放疗缓解症状的效果不佳。

    [证据等级：1iiC]有证据表明，PS较佳的患者行高剂量放疗后生存期适度延长。

    [证据等级：1iiA]对于密切观察中的无症状患者，治疗通常应适当推迟到肿瘤进展产生症状或体征时再进行。

    证据（放疗）：

  • 一次系统审查识别出了单独进行高剂量率支气管近距离放射治疗（HDREB）或联合EBRT或激光治疗的6项随机临床试验。
  • 在既往未接受过单独EBRT治疗的患者中，需要更好的总体症状缓解和更少的再治疗。
  • [证据等级：1iiC]
  • 若技术上可行，HDREB可缓解既往接受EBRT治疗后复发性支气管内阻塞的症状。

    • 第二原发肿瘤治疗

    最初切除的支气管癌发生孤立性肺转移可能不常见。 肺是原发性肺癌患者中第二原发性恶性肿瘤的发病部位。 新病变是新的原发性癌还是转移灶可能很难确定。 研究表明，在大多数患者中，新病变是第二原发性肿瘤，在切除后，一些患者可以实现长期生存。因此，如果第一原发性肿瘤得到控制，应切除第二原发性肿瘤（如果可能）。

    脑转移治疗

    切除原发性NSCLC病灶后出现孤立性脑转移且无颅外肿瘤迹象的患者可通过手术切除脑转移瘤和术后全脑放疗来延长无病生存期。

    在这种情况下无法切除的脑转移瘤可采用立体定向放射外科手术进行治疗。

    约50％的患者接受切除术和术后放疗后肿瘤在大脑中复发。某些患者将适合进一步治疗。

    对于选择的PS良好且在脑外无转移的患者，治疗选择包括再次手术或立体定向放射手术。

    对于大多数患者，可以考虑其他放疗；但是，这种治疗的姑息治疗作用有限。

    [证据等级：3iiiDiii]

    处于临床评估阶段中新诊断的复发性IV期NSCLC治疗选择（一线治疗）

    处于临床评估阶段中新诊断的复发性IV期NSCLC治疗选择（一线治疗）包括

  • 临床试验可视为一线治疗。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

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    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC Treatment

    Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy, targeted agents, and immunotherapy. Factors influencing treatment selection include comorbidity, performance status (PS), histology, and molecular and immunologic features of the cancer. Therefore, assessment of tumor-genomic changes and programmed death-ligand 1 (PD-L1) expression is critical before initiating therapy. Radiation therapy and surgery are generally used in selective cases for symptom palliation.

    Determinants of treatment

    Randomized controlled trials of patients with stage IV disease and good PS have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.

    [Level of evidence: 1iiA] Patients with nonsquamous cell histology, good PS, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with tumors harboring sensitizing mutations in exons 19 or 21 of EGFR, particularly those from East Asia, never smokers, and those with adenocarcinoma may benefit from EGFR tyrosine kinase inhibitors (TKI) as an alternative to first- or second-line chemotherapy. Patients with tumors harboring anaplastic lymphoma kinase (ALK) translocations or ROS1 rearrangements may benefit from ALK or ROS1 inhibitors as an alternative to first- or second-line chemotherapy. Patients with tumors expressing PD-L1 (>50% by immunohistochemistry) have improved survival with pembrolizumab. The addition of pembrolizumab to carboplatin plus pemetrexed chemotherapy for nonsquamous advanced lung cancer improves survival irrespective of PD-L1 expression.

    [Level of evidence: 1iiA] Second-line systemic therapy with nivolumab, docetaxel, pemetrexed, or pembrolizumab for PD-L1-positive tumors also improves survival in patients with good PS (who have not received the same or a similar agent in the first-line setting).

    [Level of evidence: 1iiA]

    The role of systemic therapy in patients with an Eastern Cooperative Oncology Group PS below 2 is less certain.

    Histology

    Patients with adenocarcinoma may benefit from pemetrexed and bevacizumab as well as from combination chemotherapy with pembrolizumab.

    Age versus comorbidity

    Evidence supports the concept that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Elderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for elderly patients (aged 70–79 years) to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled on clinical trials, and the benefit in this group is uncertain.

    Evidence (age vs. comorbidity):

  • Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older, and approximately 40% are aged 70 years or older.
  • Surveillance, Epidemiology, and End Results (SEER) data suggest that the percentage of patients aged older than 70 years is closer to 50%.
  • A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.
  • The same data suggested that elderly patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated; lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.
  • Single-agent chemotherapy and combination chemotherapy clearly benefit at least some elderly patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.
  • Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.
  • A trial from Japan compared single-agent docetaxel with vinorelbine in 180 elderly patients with good PS.
  • Response rates (22% vs. 10%) and progression-free survival (PFS) rates (5.4 months vs. 3.1 months) were significantly better with docetaxel, but median survival rates (14.3 months vs. 9.9 months) and 1-year survival rates (59% vs. 37%) did not reach statistical significance.
  • Retrospective data analyzing and comparing younger (age <70 years) patients with older (age ≥70 years) patients who participated in large randomized trials of doublet combinations have also shown that elderly patients may derive the same survival benefit, but with a higher risk of toxic effects in the bone marrow.

    • Performance status

    PS is among the most important prognostic factors for survival of patients with NSCLC.

    The benefit of therapy for this group of patients has been evaluated through retrospective analyses and prospective clinical trials.

    The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire this treatment after being fully informed of its anticipated risks and limited benefits.

    Evidence (PS):

  • The Cancer and Leukemia Group B trial (CLB-9730 [NCT00003117]), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a PS of 2 (18% of the study's population).
  • When compared with patients with a PS of 0 to 1, who had a median survival of 8.8 months and a 1-year survival rate of 38%, the corresponding median survival figures for patients with a PS of 2 were 3.0 months and a 1-year survival rate of 14%; this demonstrates the poor prognosis conferred by a lower PS. These differences were statistically significant.
  • When patients with a PS of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 months vs. 2.4 months), and a superior 1-year survival rate (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.
  • A phase III trial compared single-agent pemetrexed with the combination of carboplatin and pemetrexed in 205 patients with a PS of 2 who had not had any previous chemotherapy.
  • [Level of evidence: 1iiA]
  • Median overall survival (OS) was 5.3 months for the pemetrexed-alone group and 9.3 months for the carboplatin-and-pemetrexed group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.46–0.83; P = .001).
  • Median PFS was 2.8 months for the pemetrexed-alone group and 5.8 months for the carboplatin-and-pemetrexed group (P < .001).
  • The response rates were 10.3% for the pemetrexed-alone group and 23.8% for the carboplatin-and-pemetrexed group (P = .032).
  • Side effects were more frequent in the combination arm, as expected.

    • This study, which was performed in eight centers in Brazil and one center in the United States, reported rates of OS and PFS that were higher than has historically been noted in most, although not all, other published studies. This may indicate differences in patient selection.

  • A subset analysis of 68 patients with a PS of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.
  • Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a PS of 2 was not significantly different from that experienced by patients with a PS of 0 to 1.
  • An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with PS of 0 to 1.
  • A phase II randomized trial (E-1599 [NCT00006004]) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a PS of 2.
  • Response rates were 25% in the cisplatin-plus-gemcitabine arm and 16% in the carboplatin-plus-paclitaxel arm; median survival times were 6.8 months in the cisplatin-plus-gemcitabine arm and 6.1 months in the carboplatin-plus-paclitaxel arm; 1-year survival rates were 25% in the cisplatin-plus-gemcitabine arm and 19% in the carboplatin-plus-paclitaxel arm. None of these differences was statistically significant, but the survival figures were longer than expected, based on historical controls.
  • Results from two trials suggest that patients with a PS of 2 may experience symptom improvement.

    • Standard Treatment Options for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-line Therapy)

    Standard treatment options for patients with newly diagnosed stage IV, relapsed, and recurrent disease include the following:

  • Cytotoxic combination chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, protein-bound paclitaxel, or pemetrexed.
  • Combination chemotherapy.
  • Drug and dose schedule.
  • Combination chemotherapy with monoclonal antibodies.
  • Bevacizumab.
  • Cetuximab.
  • Necitumumab.
  • Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy).
  • Maintenance therapy following first-line chemotherapy.
  • Pemetrexed following first-line platinum-based combination chemotherapy.
  • Maintenance erlotinib following platinum-based doublet chemotherapy.
  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) (for patients with EGFR mutations).
  • Osimertinib.
  • Gefitinib.
  • Erlotinib.
  • Afatinib.
  • Anaplastic lymphoma kinase (ALK) inhibitors (for patients with ALK translocations).
  • Alectinib.
  • Crizotinib.
  • Ceritinib.
  • Brigatinib.
  • Lorlatinib.
  • ROS1 inhibitors (for patients with ROS1 rearrangements).
  • Crizotinib.
  • BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations).
  • Dabrafenib and trametinib.
  • Neurotrophic tyrosine kinase (NTRK) inhibitors (for patients with NTRK fusions).
  • Larotrectinib.
  • Immune checkpoint inhibitors with or without chemotherapy.
  • Pembrolizumab plus chemotherapy.
  • Pembrolizumab alone.
  • Local therapies and special considerations.
  • Endobronchial laser therapy and/or brachytherapy (for obstructing lesions).
  • External-beam radiation therapy (EBRT) (primarily for palliation of local symptomatic tumor growth).
  • Treatment of second primary tumor.
  • Treatment of brain metastases.

    • Cytotoxic combination chemotherapy

    Combination chemotherapy

    The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.

    Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatin in previously untreated patients with advanced NSCLC. On the basis of meta-analyses of the trials, the following conclusions can be drawn:

  • Certain three-drug combinations that add so-called targeted agents may result in superior survival.
  • EGFR inhibitors may benefit selected patients with EGFR mutations.
  • Maintenance chemotherapy after four cycles of platinum combination chemotherapy may improve PFS and OS.
  • Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, protein-bound paclitaxel, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.
  • Cisplatin and carboplatin yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.
  • Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
  • Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

    • Evidence (combination chemotherapy):

  • The Cochrane Collaboration reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.
  • Sixty-five trials (13,601 patients) were identified.
  • In the trials that compared a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% CI, 0.37–0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates after single-agent therapy, with ORs ranging from 1.2 to 6.2. Infection rates did not increase in doublet regimens.
  • There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).
  • Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.
  • One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.
  • The objective response rate (ORR) was higher for patients treated with cisplatin (30%) than for patients treated with carboplatin (24%); (OR, 1.37; 95% CI, 1.16–1.61; P < .001).
  • Carboplatin treatment was associated with a nonstatistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR, 1.07; 95% CI, 0.99–1.15; P = .100).
  • In patients with nonsquamous cell tumors and in patients treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 in patients with nonsquamous cell tumors and HR, 1.11; 95% CI, 1.01–1.21 in patients treated with third-generation chemotherapy).
  • Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001), but cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018).
  • The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses that were based on essentially the same clinical trials but which used only published data.
  • Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.
  • The first meta-analysis identified 37 assessable trials that included 7,633 patients.
  • A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003).
  • No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96–1.28; P = .17).
  • The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.
  • The second meta-analysis identified 17 trials that included 4,920 patients.
  • The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%–1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurologic toxic effects.
  • In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06–1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08–4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07–1.32; P = .002), with an increased risk of anemia, neutropenia, neurologic toxic effects, and nausea.
  • Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43).
  • The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.
  • Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).
  • Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).
  • Forty-four (1.9%) toxic-related deaths were reported for platinum-based regimens and 29 (1.3%) toxic-related deaths were reported for nonplatinum regimens (OR, 1.53; CI, 0.96–2.49; P = 0.08). An increased risk of grade 3 to 4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in the risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063).

    • Drug and dose schedule

    Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of carboplatin, pemetrexed, and pembrolizumab for patients with nonsquamous tumor histology.

    Evidence (drug and dose schedule):

  • One meta-analysis of seven trials that included 2,867 patients assessed the benefit of docetaxel versus vinorelbine.
  • Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.
  • The pooled estimate for OS showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.
  • Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens (OR, 0.59; 95% CI, 0.38–0.89; P = .013) versus vinca alkaloid-based regimens (OR, 0.68; 95% CI, 0.55–0.84; P < .001).
  • Two randomized trials compared weekly versus every 3 weeks' dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.
  • Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff in making treatment decisions for individual patients.
  • A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naïve patients with stage IIIB/IV NSCLC and a PS of 0 to 1.
  • Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
  • OS for cisplatin and pemetrexed (median survival, 10.3 months) was noninferior to cisplatin and gemcitabine (median survival, 10.3 months; HR, 0.94; 95% CI, 0.84%–1.05%).
  • In patients with adenocarcinoma (n = 847), OS was statistically superior for cisplatin and pemetrexed (12.6 months) versus cisplatin and gemcitabine (10.9 months); in patients with large cell carcinoma (n = 153), OS was statistically superior for cisplatin and pemetrexed (10.4 months) versus cisplatin and gemcitabine (6.7 months).
  • In contrast, in patients with squamous cell histology (n = 473), there was a significant improvement in survival with cisplatin and gemcitabine (10.8 months) versus cisplatin and pemetrexed (9.4 months). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
  • The results of this study suggested that the cisplatin and pemetrexed doublet is another alternative doublet for first-line chemotherapy for advanced NSCLC and also suggested that there may be differences in outcome depending on histology.

    • Combination chemotherapy with monoclonal antibodies

    Bevacizumab

    Evidence (bevacizumab):

  • Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.
  • In a randomized study of 878 patients with recurrent or advanced stage IIIB/IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.
  • Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (Eastern Cooperative Oncology Group PS >1) were excluded.
  • Median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HRdeath, 0.79; P = .003).
  • Median PFS was 6.2 months in the group assigned to chemotherapy plus bevacizumab (HR for disease progression, 0.66; P < .001), with a 35% response rate (P < .001), and 4.5 months in the chemotherapy-alone group (HR for disease progression, 0.66; P < .001), with a 15% response rate (P < .001).
  • Rates of clinically significant bleeding were 4.4% in the group assigned to chemotherapy plus bevacizumab and 0.7% in the chemotherapy-alone group (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.
  • For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.
  • [Level of evidence: 1iiA]
  • Another randomized, phase III trial investigated the efficacy and safety of cisplatin-gemcitabine plus bevacizumab.
  • Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary endpoint was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).
  • PFS was significantly prolonged with the addition of bevacizumab; the HRs for PFS were 0.75 in the low-dose group (median PFS, 6.7 months vs. 6.1 months for placebo group; P = .03) and 0.82 in the high-dose group compared with the placebo group (median PFS, 6.5 months vs. 6.1 months for placebo group; P = .03).
  • [Level of evidence: 1iiB]
  • ORRs were also improved with the addition of bevacizumab, and they were 20.1% for placebo, 34.1% for low-dose bevacizumab, and 30.4% for high-dose bevacizumab plus cisplatin/gemcitabine.
  • Incidence of grade 3 or greater adverse events was similar across arms.
  • Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.
  • These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.
  • Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.
  • Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.

    • Cetuximab

    Evidence (cetuximab):

  • Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.
  • In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.
  • The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study endpoint, or OS.
  • Median PFS was 4.40 months for patients in the cetuximab-chemotherapy arm versus 4.24 months for patients in the taxane-carboplatin arm (HR, 0.902; 95% CI, 0.761–1.069; P = .236).
  • Median OS was 9.69 months for patients in the cetuximab-chemotherapy arm versus 8.38 months for patients in the chemotherapy-alone arm (HR, 0.890; 95% CI, 0.754–1.051; P = .169).
  • No significant associations were found between EGFR expression, EGFR mutation, EGFR copy number, or KRAS mutations and PFS, OS, and response in the treatment-specific analyses.
  • The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB/IV NSCLC treated with cisplatin-vinorelbine chemotherapy plus cetuximab or chemotherapy alone.
  • The primary study endpoint, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HRdeath, 0.871; 95% CI, 0.762–0.996; P = .044).
  • A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in nonwhite or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).
  • The main cetuximab-related adverse event was acne-like rash (grade 3, 10%).
  • It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.

    • Necitumumab

    Evidence (necitumumab):

  • Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.
  • The SQUIRE (NCT00981058) trial randomly assigned 1,093 patients with advanced squamous NSCLC to receive either first-line chemotherapy with cisplatin and gemcitabine or the same regimen with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).
  • Median OS was prolonged with the addition of necitumumab (11.5 months vs. 9.9 months; P = .01).
  • PFS was also prolonged with the addition of necitumumab (5.7 months vs. 5.5 months); however, ORR was similar in both groups (31% vs. 28%).
  • Grades 3 and 4 adverse events were higher in the necitumumab-containing arm (72% vs. 62%).
  • Necitumumab is associated with higher toxicity and relatively modest benefit.
  • The INSPIRE (NCT00982111) trial randomly assigned 633 patients with advanced nonsquamous NSCLC to receive either first-line chemotherapy with cisplatin and pemetrexed or to cisplatin and pemetrexed with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).
  • This study showed no benefit from the addition of necitumumab to standard first-line chemotherapy for advanced nonsquamous NSCLC.
  • OS was 11.3 months (95% CI, 9.5–13.4) for patients in the necitumumab-containing arm versus 11.5 months (95% CI, 10.1–13.1) for patients in the chemotherapy alone arm; P = .96. Similarly, there was no difference between the arms in terms of ORR or PFS.
  • Serious adverse events and rates of grades 3 and 4 adverse events, including thromboembolic events, were higher in patients in the necitumumab-containing arm; the incidence of treatment-related deaths was also higher (5% vs. 3%).
  • On the basis of these results, necitumumab is not recommended as combination therapy with standard first-line chemotherapy for patients with advanced nonsquamous NSCLC.

    • Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)

    One extensively investigated treatment strategy in NSCLC is maintenance therapy after initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:

  • Continuing the initial combination chemotherapy regimen.
  • Continuing only single-agent chemotherapy.
  • Introducing a new agent as maintenance.

    • Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

    Evidence (maintenance therapy following first-line chemotherapy):

  • None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles. For patients with nonsquamous NSCLC, two studies have demonstrated improved PFS and OS with either switch or continuous maintenance chemotherapy (e.g., maintenance pemetrexed after initial cisplatin and gemcitabine or maintenance pemetrexed after initial cisplatin and pemetrexed).
  • Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.
  • No consistent improvement in quality of life was reported.
  • Chemotherapy-related toxicities were greater with prolonged chemotherapy.

    • These data suggest that PFS and OS for patients with nonsquamous NSCLC may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events including additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of combination cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy before disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.

    For patients with nonsquamous NSCLC who have a response or stable disease after four to six cycles of platinum combination chemotherapy, maintenance chemotherapy with pemetrexed should be considered.

    Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

  • The findings of two randomized trials (NCT00102804 and NCT00789373) have shown improved outcomes with the addition of pemetrexed after standard first-line platinum-based combination chemotherapy.
  • In the first trial, 663 patients with stage IIIB/IV disease who had not progressed on four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.
  • Both the primary endpoint of PFS and the secondary endpoint of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).
  • Benefit was not seen in patients with squamous histology.
  • Higher than grade 3 toxicity and treatment discontinuations that resulted from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
  • No pemetrexed-related deaths occurred.
  • Relatively fewer patients in the pemetrexed group than in the placebo group received systemic postdiscontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
  • Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.
  • The quality-of-life results require cautious evaluation because there was a high degree of censoring (> 50%) with the primary quality-of-life endpoint, which was time to worsening of symptoms.
  • Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.
  • In the second trial, 539 patients with nonsquamous NSCLC with nonprogression after treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.
  • There was a statistically significant improvement in the primary endpoint of PFS (4.1 months vs. 2.8 months, HR, 0.62; 95% CI, 0.49–0.79) and in the secondary endpoint of OS (13.9 months vs. 11 months, HR, 0.78; 95% CI, 0.64–0.96).
  • [Level of evidence: 1iDiii]

    • Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):

  • One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.
  • In this trial, 889 patients with NSCLC but without progressive disease were randomly assigned to receive erlotinib (150 mg/day) or placebo until they experienced progressive disease or unacceptable toxicity.
  • Median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for patients in the placebo group (HR, 0.71; 95% CI, 0.62–0.82; P < .0001).
  • In the overall population, patients whose tumors had activating EGFR mutations derived the greatest PFS benefit from maintenance erlotinib treatment (n = 49; HR, 0.10; P < .0001).
  • Patients whose tumors were wild-type EGFR also obtained significant PFS (HR, 0.78) and OS (HR, 0.77) improvements.
  • In the subgroup of patients with stable disease whose tumors did not have activating EGFR mutations (n = 217), both PFS (HR, 0.72; 95% CI, 0.54–0.96; P = .0231) and OS (HR, 0.65; 95% CI, 0.48–0.87; P = .0041) were significantly prolonged with erlotinib.
  • In patients whose tumors had activating EGFR mutations (n = 30), OS was also improved with erlotinib (HR, 0.48; 95% CI, 0.14–1.62) but was not statistically significant in this analysis.
  • EGFR immunohistochemistry, EGFR fluorescence in situ hybridization (FISH), KRAS mutation, and EGFR CA-simple sequence repeat in intron 1 repeat length status were not predictive for erlotinib efficacy.
  • KRAS mutation status was a significant, negative prognostic factor for PFS.
  • [Level of evidence: 1iDiii]

    • EGFR tyrosine kinase inhibitors

    Selective patients may benefit from single-agent EGFR TKIs. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR mutations have shown that EGFR inhibitors improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy.

    Osimertinib

    Evidence (osimertinib):

  • A phase III, multicenter, randomized, double-blind, controlled trial (FLAURA [NCT02296125]) compared osimertinib with standard of care EGFR TKIs (gefitinib or erlotinib) as first-line treatment of patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R), advanced NSCLC, as detected by a U.S. Food and Drug Administration (FDA)-approved test.
  • The 556 patients were randomly assigned in a 1:1 ratio.
  • Investigator-assessed PFS, the primary endpoint, was significantly longer with osimertinib (18.9 months vs. 10.2 months; HR, 0.46; 95% CI, 0.37–0.57, P < .0001).
  • [Level of evidence: 1iDiii]
  • The objective response rate was similar for both groups (80% for the osimertinib group vs. 76% for the standard EGFR TKI group).
  • The median duration of response was 17.2 months (95% CI, 13.8–22.0) with osimertinib versus 8.5 months (95% CI, 7.3–9.8) with standard EGFR TKIs.
  • Data on OS are immature.
  • Adverse events of grade 3 or higher were less frequent with osimertinib (34%) than with standard TKIs (45%).

    • Osimertinib was approved by the FDA for first-line treatment of EGFR-mutant NSCLC (exon 19 deletion or L858R).

    Gefitinib

    Evidence (gefitinib):

  • A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.
  • The study met its primary objective of demonstrating the superiority of gefitinib compared with the carboplatin-paclitaxel combination for PFS (HR for progression or death, 0.74; 95% CI, 0.65–0.85; P < .001).
  • The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.
  • [Level of evidence: 1iDiii]
  • Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.
  • The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.
  • More than 90% of the patients in the trial with mutations had either del19 or exon 21 L858R mutations, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with a mutation, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36–0.64; P < .001); however, in the subgroup of patients who were negative for a mutation, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05–3.98; P < .001). There was a significant interaction between treatment and EGFR mutation with respect to PFS (P < .001).
  • OS was similar for patients who received gefitinib and carboplatin-paclitaxel, with no significant difference between treatments overall (HR, 0.90; 95% CI, 0.79–1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76–1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86–1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to the carboplatin-paclitaxel regimen received subsequent EGFR TKIs. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34–0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09–7.09).
  • Two phase III trials from Japan prospectively confirmed that patients with NSCLC and EGFR mutations have improved PFS but not OS when treated with gefitinib.
  • In the first trial, 230 chemotherapy-naïve patients with metastatic NSCLC and EGFR mutations were randomly assigned to receive gefitinib or carboplatin-paclitaxel.
  • In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (HRdeath or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.
  • The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22–0.41; P < .001).
  • [Level of evidence: 1iiDiii] The median OS was 30.5 months in the gefitinib group and 23.6 months in the standard chemotherapy group (P = .31).
  • In the second trial, the West Japanese Oncology Group conducted a phase III study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R-point mutation).
  • Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (administered every 21 days for three to six cycles). The primary endpoint was PFS.
  • The gefitinib group had significantly longer PFS than the cisplatin-plus-docetaxel group, with a median PFS of 9.2 months (95% CI, 8.0–13.9) versus 6.3 months (range, 5.8–7.8 months; HR, 0.489; 95% CI, 0.336–0.710, log-rank; P < .0001).
  • [Level of evidence: 1iiDiii]

    • Erlotinib

    Evidence (erlotinib):

  • In an open-label, randomized, phase III trial (NCT00874419) from China, 165 patients older than 18 years with histologically confirmed stage IIIB/IV NSCLC and a confirmed activating mutation of EGFR (i.e., exon 19 deletion or exon 21 L858R-point mutation) received either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.
  • Median PFS was significantly longer in erlotinib-treated patients than in patients treated with chemotherapy (13.1 months [95% CI, 10.58–16.53] vs. 4.6 months [range, 4.21–5.42 months]; HR, 0.16; 95% CI, 0.10–0.26; P < .0001).
  • [Level of evidence: 1iiDiii]
  • In a European study (EURTAC [NCT00446225]), 1,227 patients with advanced NSCLC were screened for EGFR mutations. Of these, 174 patients with EGFR mutations were randomly assigned to receive erlotinib or platinum-based chemotherapy.
  • The primary endpoint was PFS.
  • In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared with 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in patients in the chemotherapy arm and 19.5 months in patients in the erlotinib arm (HR, 0.80; P = .42).
  • [Level of evidence: 1iiDiii]

    • Afatinib

    Evidence (afatinib):

  • In an open-label, randomized, phase III study (LUX-Lung 3 [NCT00949650]), 345 Asian (72%) and white (26%) patients with stage IIIB/IV NSCLC and confirmed EGFR mutations (i.e., exon 19 deletion, L858R, or other [38 of 345 patients had other less-common mutations]) were screened, and 340 patients received at least one dose of study medication, which was either 40 mg of oral afatinib, an irreversible EGFR/human epidermal receptor (HER) TKI, daily or up to six cycles of cisplatin and pemetrexed for first-line treatment.
  • The primary endpoint was PFS. In this study, the afatinib group had significantly longer PFS than the cisplatin-plus-pemetrexed group, with a median PFS of 11.1 months for afatinib and 6.9 months for chemotherapy (HR, 0.58; 95% CI, 0.43–0.78; P = .001).
  • [Level of evidence: 1iiDiii]
  • Assessment of OS was a secondary endpoint and was reported separately.
  • Similar to the PFS analysis, OS was stratified based on EGFR-mutation type and ethnic origin.
  • With a median follow-up of 41 months, median OS was 28.2 months in patients in both arms (HR, 0.88; 95% CI, 0.66–1.17; P = .39).
  • In patients harboring common EGFR mutations (i.e., exon 19 deletion and L858R), survival did not differ significantly between treatment arms (HR, 0.78; 95% CI, 0.58–1.06; P = .11). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with tumors harboring the EGFR del19 mutation (median OS, 33.3 months vs. 21.1 months; HR, 0.54; 95% CI, 0.36–0.79; P = .0015) but no significant difference between treatment arms in patients with tumors harboring the L858R mutation (median OS, 27.6 months vs. 40.3 months; HR, 1.30; 95% CI, 0.80–2.11; P = .29).
  • First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC-harboring EGFR del19 mutations but not in patients with EGFR L858R mutations or in the overall EGFR–mutation-positive patient population.
  • [Level of evidence: 1iiA]
  • In an open-label, randomized, phase III study (LUX-Lung 6 [NCT01121393]), 364 East Asian patients with stage IIIB/IV NSCLC and confirmed EGFR mutations (i.e., exon 19 deletion, L858R, or other) were randomly assigned (2:1 ratio) to 40 mg of afatinib daily or gemcitabine and cisplatin for up to six cycles for first-line treatment.
  • The primary endpoint was PFS. Median PFS was significantly longer in the afatinib group (11.0 months; 95% CI, 9.7–13.7) than in the gemcitabine and cisplatin group (5.6 months, [range, 5.1–6.7 months]; HR, 0.28; 95% CI, 0.20–0.39; P < .0001).
  • [Level of evidence: 1iiDiii]
  • Assessment of OS was a prespecified secondary endpoint and was reported separately.
  • Similar to the PFS analysis, OS was stratified based on EGFR-mutation type and ethnic origin.
  • With a median follow-up of 33 months, median OS was 23.1 months in patients in the afatinib arm and 23.5 months in patients in the chemotherapy arm (HR, 0.93; 95% CI, 0.72–1.22; P = .61).
  • In patients harboring common EGFR mutations (i.e., exon 19 deletion and L858R), survival did not differ significantly between treatment arms (HR, 0.83; 95% CI, 0.62–1.09; P = .18). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with tumors harboring the EGFR del19 mutation (median OS, 31.4 months vs. 18.4 months; HR, 0.64; 95% CI, 0.44–0.94; P = .023), but no significant difference between treatment arms was seen in patients with tumors harboring the L858R mutation (median OS, 19.6 months vs. 24.3 months; HR, 1.22; 95% CI, 0.81–1.83; P = .34).
  • First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC-harboring EGFR del19 mutations but not in patients with EGFR L858R mutations or in the overall EGFR-mutation-positive patient population.
  • [Level of evidence: 1iiA]

    • ALK inhibitors (for patients with ALK translocations)

    Alectinib

    Evidence (alectinib):

  • In an open-label, randomized, phase III study (the ALEX trial [NCT02075840]), 303 patients with previously untreated, advanced ALK-rearranged NSCLC received either alectinib (600 mg bid) or crizotinib (250 mg bid).
  • The primary endpoint was investigator-assessed PFS.
  • The rate of PFS was significantly higher with alectinib than crizotinib; the 12-month event-free survival was 68.4% for the alectinib group (95% CI, 40.4–56.9) compared with 48.7% for the crizotinib group (95% CI, 40.4–56.9) (HR, 0.47; 95% CI, 0.34–0.65; P < .001). The median PFS was not reached with alectinib. The results of independent review committee-assessed PFS were consistent.
  • [Level of evidence: 1iiDiii]
  • Central nervous system (CNS) progression events were less frequent with alectinib (12%) than with crizotinib (45%) (HR, 0.16; 95% CI, 0.10–0.28; P <.001).
  • The response rate was similar for both groups, 82.9% for the alectinib group compared with 75.5% for the crizotinib group (P = .09).
  • Grade 3 to 5 adverse events were less frequent with alectinib (41%) than with crizotinib (50%).
  • A second, open-label, randomized, phase III trial (J-ALEX) recruited 207 ALK-inhibitor–naïve Japanese patients with ALK-positive NSCLC who were chemotherapy-naïve or had received one previous chemotherapy regimen. Patients were randomly assigned in a 1:1 ratio to receive alectinib (300 mg bid, which is the dose approved in Japan and is lower than the 600 mg twice daily dose approved elsewhere) versus crizotinib (250 mg bid).
  • The primary endpoint was PFS-assessed by an independent review committee.
  • At data cutoff for the second primary interim analysis, the independent data monitoring committee determined that the primary endpoint was met (HR, 0.34; 99.7% CI, 0.17–0.71; P <.0001) and recommended immediate release of the data. Median PFS had not been reached with alectinib but was reached at 10.2 months with crizotinib.
  • Grade 3 or 4 adverse events occurred less frequently with alectinib (26% occurrence rate) than with crizotinib (52% occurrence rate).

    • Crizotinib

    Evidence (crizotinib):

  • In an open-label, randomized, phase III study, 343 patients with stage IIIB/IV NSCLC harboring translocations in ALK received either 250 mg of crizotinib orally twice a day or the combination of pemetrexed and cisplatin or carboplatin for up to six cycles.
  • At the time of disease progression, patients on the chemotherapy arm were allowed to cross over to crizotinib; 60% of patients in the chemotherapy arm subsequently received crizotinib. The primary endpoint of this study was PFS.
  • The study met its primary endpoint and demonstrated that crizotinib is superior to chemotherapy in prolonging PFS (median, 10.9 months vs. 7.0 months; HR, 0.454; 95% CI, 0.346–0.596; P < .0001).
  • [Level of evidence: 1iiDiii]

    • Ceritinib

    Evidence (ceritinib):

  • In an open-label, randomized, phase III study, 376 patients with stage IIIB/IV ALK-rearranged nonsquamous NSCLC received either oral ceritinib 750 mg daily or platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) every 3 weeks for four cycles, followed by maintenance pemetrexed.
  • The primary endpoint was PFS and crossover from chemotherapy to ceritinib was allowed upon documented progression.
  • Median PFS, assessed by blinded independent review, was 16.6 months in the ceritinib group and 8.1 months in the chemotherapy group (HR, 0.55; 95% CI, 0.42–0.73; P < .00001).
  • The median OS was not reached with ceritinib, and it was 26.2 months with chemotherapy (HR, 0.73; 95% CI, 0.50–1.08; P = .056).
  • [Level of evidence: 1iiDiii]

    • Brigatinib

    Evidence (brigatinib):

  • A phase II, open-label trial (NCT02094573) enrolled 222 patients with ALK-translocated locally advanced or metastatic NSCLC who had disease progression after crizotinib treatment. Patients were randomly assigned to receive 90 mg qd (n = 112; 109 treated) or 180 mg qd with a 7-day lead-in at 90 mg qd (n = 110).
  • The primary endpoint assessed by the investigators was ORR. ORR was 45% (97.5% CI, 34–56) for patients who received the 90 mg dose and 54% (97.5% CI, 43–65) for patients who received the 180 mg dose.
  • Median PFS was 9.2 months (95% CI, 7.4–15.6) for patients who received the 90 mg dose and 12.9 months (95% CI, 11.1–not reached) for patients who received the 180 mg dose.
  • At data cutoff, the median duration of response was 13.8 months (95% CI, 5.6–13.8) for patients who received the 90 mg dose and 11.1 months (95% CI, 9.2–13.8) for patients who received the 180 mg dose.
  • [Level of evidence: 1iiDiv]
  • The CNS ORR in patients with measurable CNS lesions was 42% in patients receiving 90 mg qd (n = 26) and 67% in patients receiving 180 mg qd (n = 18).
  • Common adverse events, which were mainly grade 1 or 2 and occurred in 27% to 38% of patients at the higher dose, were nausea, diarrhea, headache, and cough. A subset of pulmonary adverse events with early onset (median onset, day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥3, 3%); none occurred after escalation to 180 mg. These events included dyspnea, hypoxia, cough, pneumonia, or pneumonitis. They were managed with dose interruption. Seven of the 14 patients were successfully retreated with brigatinib.
  • The FDA-approved dose of brigatinib is 90 mg qd for 7 days; if tolerated, the dose is increased to 180 mg qd.

    • Lorlatinib

    Evidence (lorlatinib):

  • In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts based on their ALK status and treatment history.
  • They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary endpoint was objective tumor response and intracranial tumor response by independent central review, as assessed in key pooled subgroups.
  • [Level of evidence: 3iiiDiv]
  • The number of patients treated, the ORRs, and the intracranial response rates in each cohort or pooled cohorts are as follows:
  • EXP1 (n = 30, treatment naïve).
  • RR = 90.0%; 95% CI, 73.5‒97.9.
  • Intracranial (n = 3), RR = 66.7%; 95% CI, 9.4‒99.2.
  • EXP2 (n = 27, previous crizotinib only) and EXP3A (n = 32, previous crizotinib and chemotherapy), RR = 69.5%; 95% CI, 56.1‒80.8.
  • Intracranial (n = 23), RR = 87.0%; 95% CI, 66.4‒97.2.
  • EXP3B (n = 28, one previous second-generation ALK inhibitor with or without chemotherapy), RR = 32.1%; 95% CI, 15.9‒52.4.
  • Intracranial (n = 9), RR = 55.6%; 95% CI, 21.2‒86.3.
  • EXP4 (n = 65, two previous ALK inhibitors with or without chemotherapy) and EXP5 (n = 46, three previous lines of ALK inhibitors, with or without chemotherapy), RR = 38.7%; 95% CI, 29.6‒48.5.
  • Intracranial (n = 49), RR = 53.1%; 95% CI, 38.3‒67.5.
  • The median duration of response has not been reached for any of the pooled cohorts.
  • The most common adverse event was hypercholesterolemia (16% grade 3-4), and 3% of patients discontinued treatment due to adverse events.

    • ROS1 inhibitors (for patients with ROS1 rearrangements)

    ROS1 rearrangements occur in approximately 1% of patients with NSCLC.

    Crizotinib

    Crizotinib was approved for patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.

    Evidence (crizotinib):

  • In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.
  • ROS1 rearrangements were identified using break-apart FISH or reverse-transcriptase-polymerase-chain-reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one prior treatment. The primary endpoint was response rate.
  • The overall response rate was 72% (95% CI, 58–84). Six percent of patients had a complete response, 66% had a partial response, and 18% had stable disease as their best response.
  • Median PFS was 19.2 months (95% CI, 14.4–not reached). The estimated duration of response was 17.6 months (95% CI, 14.5–not reached).
  • [Level of evidence: 3iiiDiv]
  • In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.
  • Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary endpoint was objective response rate by independent review.
  • The objective response rate was 71.7% (95% CI, 63.0–79.3). Response rates were similar, irrespective of the number of previous therapies. Complete responses occurred in 13.4% of patients, while 58.3% of patients had partial responses, and 16.5% of patients had stable disease as their best response.
  • [Level of evidence: 3iiiDiv]
  • Median PFS was 15.9 months (95% CI, 12.9–24). The duration of response was 19.7 months (95% CI, 14.1–not reached).
  • OS was 32.5 months (95% CI, 32.5–not reached).

    • BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations)

    BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas.

    Dabrafenib and trametinib

    Evidence (dabrafenib and trametinib):

  • In a phase II multicenter, nonrandomized, open-label study (NCT01336634), 36 patients with previously untreated metastatic NSCLC who tested positive for BRAF V600E mutations were treated with dabrafenib (a BRAF inhibitor) 150 mg bid and trametinib (a MEK inhibitor) 2 mg qd.
  • BRAF V600E mutations were identified by the Oncomine Dx Target Test (ThermoFisher Scientific). The primary endpoint was investigator-assessed overall response.
  • The overall response rate was 64% (95% CI, 46–79). Six percent of patients had a complete response, and 58% of patients had a partial response.
  • The median investigator-assessed PFS was 10.9 months (95% CI, 7.0–16.6 months). The estimated median duration of response was 10.4 months (95% CI, 8.3–17.9). At data cutoff, 47% of patients had died, and the median OS was 24.6 months (95% CI, 12.3–not estimable).
  • Sixty-nine percent of patients had at least one grade 3 or 4 adverse event, of which the most common were pyrexia, alanine aminotransferase increase, hypertension, or vomiting. Adverse events led to permanent discontinuation in 22% of patients, dose interruption or delay in 75% of patients, and dose reduction in 39% of patients.
  • [Level of evidence: 3iiiDiv]

    • The combination of dabrafenib and trametinib received approval in the treatment of patients with NSCLC whose tumors harbor BRAF V600E mutations as detected by an FDA-approved test.

    NTRK inhibitors (for patients with NTRK fusions)

    Somatic gene fusions in NTRK occur across a range of solid tumors including in fewer than 0.5% of NSCLC tumors.

    These fusions appear to occur more frequently in nonsmokers with lung adenocarcinoma.

    Larotrectinib

    Evidence (larotrectinib):

  • Larotrectinib was studied in three protocols: a phase I study involving adults, a phase I/II study involving children, and a phase II study involving adolescents and adults.
  • Fusions were confirmed in the tumors using either FISH or next-generation sequencing methods. The primary endpoint for the combined analysis was objective response rate by independent review and was conducted with input from regulators with the goal of excluding a lower bound of less than 30% for response rate. In total, 55 patients with a median age of 45 years (range, 4 months‒76 years) were enrolled across 17 different NTRK fusion positive tumor types. All patients had either metastatic disease (82%) or locally advanced unresectable disease (18%). Enrolled patients had received a median of two previous systemic therapies.
  • The objective response rate was 75% (95% CI, 61%‒75%) and 73% of these responses lasted at least 6 months.
  • [Level of evidence: 3iiiDiv]
  • Treatment was well tolerated with 93% of adverse events being grade 1 to 2; the most common grade 3 to 4 adverse events were anemia (11% of patients), transaminitis (7%), and neutropenia (7%).

    • The FDA has approved larotrectinib for the treatment of patients who have locally advanced or metastatic tumors that harbor an NTRK gene fusion without a known acquired resistance mutation, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.

    Immune checkpoint inhibitors with or without chemotherapy

    Pembrolizumab is a humanized monoclonal antibody that inhibits the interaction between the PD-1 coinhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells and its ligands, PD-L1 and programmed cell death-ligand 2 (PD-L2).

    Pembrolizumab plus chemotherapy

    Evidence (pembrolizumab plus chemotherapy):

  • A phase III double-blind trial (KEYNOTE-189 [NCT02578680]) randomly assigned, in a 2:1 ratio, 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR mutations or ALK rearrangements who had received no previous treatment for metastatic disease. Patients received pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance.
  • Crossover to pembrolizumab monotherapy was permitted after verified progression among patients in the placebo-containing combination group. The primary endpoints were OS and PFS as assessed by blinded independent central committee radiologic review.
  • After a median follow-up of 10.5 months, the estimated rate of OS at 12 months was 69.2% (95% CI, 64.1–73.8) in the pembrolizumab combination group compared with 49.4% (95% CI, 42.1–56.2) in the placebo combination group (HR, 0.49; 95% CI, 0.38–0.64; P < .001).
  • [Level of evidence: 1iA]
  • Improvement in survival was seen across all PD-L1 categories.
  • Median PFS was 8.8 months in the pembrolizumab combination group compared with 4.9 months in the placebo combination group (HR, 0.52; 95% CI, 0.43–0.64; P < .001).
  • Adverse events of grade 3 or higher occurred with similar frequency in both treatment groups (67.2% in the pembrolizumab combination group vs. 65.8% in the placebo combination group).

    • Pembrolizumab alone

    Evidence (pembrolizumab alone):

  • A phase III, open-label study (KEYNOTE-024) randomly assigned 305 patients with previously untreated, advanced NSCLC with PD-L1 expression on 50% or more tumor cells and no sensitizing EGFR mutations or ALK translocations to either intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or platinum-based chemotherapy (4–6 cycles, investigator’s choice; pemetrexed maintenance was allowed for nonsquamous tumors).
  • The primary endpoint was PFS.
  • PD-L1 expression was centrally assessed using the PD-L1 immunohistochemistry 22C3 pharmDx assay (Dako North America). PD-L1 tumor expression of 50% or more was found in 30.2% of 1,653 patient samples that were examined.
  • Pembrolizumab demonstrated significant improvement in median PFS (10.3 months vs. 6.0 months; HR, 0.50; 95% CI, 0.37–0.68; P < .001). The overall response rate (44.8% vs. 27.8%), the median duration of response (not reached, [range 1.9+–14.5+ months] vs. 6.3 months [range, 2.1+–12.6+ months]), and the estimated rate of OS at 6 months (80.2% vs. 72.4%; HR, 0.60; 95% CI, 0.41–0.89; P = .005) were all higher with pembrolizumab than with chemotherapy.
  • Further follow up of this study confirmed an OS advantage in favor of pembrolizumab; the median OS for patients who received pembrolizumab was 30 months (95% CI, 18.3 months–not reached) versus 14.2 months for patients who received chemotherapy, with a 75% crossover to immunotherapy afterwards, suggesting the crossover did not impact survival.
  • Adverse events (any grade) were less frequent with pembrolizumab than with chemotherapy (73.4% vs. 90.0%).
  • Grade 3–5 adverse events occurred in 26.6% of patients treated with pembrolizumab and 53.3% of patients treated with chemotherapy.
  • Grade 3 or 4 immune-related events occurred in 9.7% of patients treated with pembrolizumab and 0.7% of patients treated with chemotherapy.
  • The most common grade 3 or 4 immune-related events associated with pembrolizumab were severe skin reactions (3.9%), pneumonitis (2.6%), and colitis (1.3%).
  • There were no grade 5 immune-related events.
  • Pembrolizumab treatment demonstrated significant improvement in PFS, OS, and duration of response with less frequent adverse events compared with chemotherapy treatment.
  • [Level of evidence: 1iiDiii]

    • Pembrolizumab in combination with pemetrexed and carboplatin received FDA approval as first-line treatment of patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Pembrolizumab also received approval as a first-line monotherapy for patients with NSCLC whose tumors express PD-L1 (≥50% staining as determined by a test approved by the FDA). Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapies before receiving pembrolizumab (refer to the FDA label for pembrolizumab).

    Local therapies and special considerations

    Endobronchial laser therapy and/or brachytherapy (for obstruction lesions)

    Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

    • In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.

    EBRT (primarily for palliation of local symptomatic tumor growth)

    Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief,

    single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.

    [Level of evidence: 1iiC] Evidence of a modest increase in survival in patients with a better PS given high-dose radiation therapy is available.

    [Level of evidence: 1iiA] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

    Evidence (radiation therapy):

  • A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with EBRT or laser therapy.
  • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.
  • [Level of evidence: 1iiC]
  • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

    • Treatment of second primary tumor

    A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.

    Treatment of brain metastases

    Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy.

    Unresectable brain metastases in this setting may be treated with stereotactic radiosurgery.

    Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.

    In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.

    For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.

    [Level of evidence: 3iiiDiii]

    Treatment Options Under Clinical Evaluation for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-line Therapy)

    Treatment options under clinical evaluation for newly diagnosed stage IV, recurrent, and relapsed NSCLC (first-line therapy) include the following:

  • Clinical trials can be considered as first-line therapy.

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

    ReferenceSection

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    • 非小细胞肺癌治疗(PDQ®)

    进展的复发性IV期NSCLC治疗

    进展的复发性IV期NSCLC的标准治疗选择（二线治疗）

    进展的复发性IV期非小细胞肺癌（NSCLC）患者的标准治疗选择（二线治疗及以上）包括：

  • 化疗。
  • 多西他赛。
  • 多西他赛联合雷莫芦单抗。
  • 培美曲塞。
  • 表皮生长因子受体（EGFR）靶向治疗。
  • 一线化疗后EGFR靶向治疗。
  • 厄洛替尼。
  • 吉非替尼。
  • 阿法替尼。
  • 既往接受EGFR靶向治疗后进行EGFR靶向治疗（针对获得性EGFR T790M突变）。
  • 奥希替尼。
  • 靶向间变性淋巴瘤激酶（ALK）的酪氨酸激酶抑制剂（TKI）治疗。
  • 一线化疗后靶向ALK的TKI治疗。
  • 克唑替尼。
  • 既往ALK TKI治疗后靶向ALK的TKI治疗。
  • 塞瑞替尼。
  • 阿来替尼。
  • 布加替尼。
  • 靶向ROS1的治疗。
  • 克唑替尼。
  • BRAF V600E和MEK抑制剂（针对BRAF V600E突变的患者）。
  • 达拉非尼和曲美替尼。
  • 免疫治疗。
  • 纳武利尤单抗。
  • 帕博利珠单抗。
  • 阿替利珠单抗。

    • 化疗

    对于转移性病灶患者，化疗使用产生了客观缓解并且生存率略有提高。

    [证据等级：[1iiA]在检查对症反应的研究中显示，主观症状改善的发生率高于客观缓解。

    体能状态（PS）良好且有症状性复发的知情患者可采用含铂类药物化疗方案缓解症状。对于含铂类药物化疗后复发的患者，可以考虑二线治疗。

    多西他赛

    证据（多西他赛）：

  • 两项前瞻性随机研究显示，与长春瑞滨、异环磷酰胺或最佳支持治疗相比，多西他赛治疗后的生存率较高；
  • 但是，选择合适的患者进行二线治疗的标准尚不明确。
  • 据报告，865例患者的5项临床试验评估了多西他赛给药（每周一次或每3周一次）的疗效和安全性，并对其试验结果进行荟萃分析。
  • 分析结果如下所示：
  • 每3周一次接受治疗的患者中位生存期为27.4周，每周一次接受治疗的患者中位生存期为26.1周（P = 0.24，对数秩检验）。
  • 每周一次多西他赛治疗后严重中性粒细胞减少症和发热性中性粒细胞减少症明显较少（两者均P <0.001）；但是，在贫血、血小板减少症和非血液学毒性反应方面未观察到显著差异。

    • 多西他赛联合雷莫芦单抗

    证据（多西他赛联合雷莫芦单抗）：

  • 在一项双盲、安慰剂对照的III期研究中，美国东部肿瘤协作组(ECOG)1,253例 PS 0-1且一线化疗后疾病进展的患者被随机分配，接受多西他赛和安慰剂或多西他赛和雷莫芦单抗治疗。
  • [证据等级：1iiA] 雷莫芦单抗是一种人免疫球蛋白G1单克隆抗体，靶向作用于血管内皮生长因子受体2的细胞外结构域。研究的主要终点是总生存期（OS），次要终点是无进展生存期（PFS）和客观缓解率（ORR）。该研究招募了非鳞状或鳞状NSCLC患者。但是，排除了高血压控制不佳、胃肠道穿孔或瘘管、6个月内发生动脉血栓栓塞事件（随机分配之前）、2个月内出现大咯血或3个月内出现3至4级胃肠道出血的患者。此外，该试验不包括大血管受累或肿瘤内空化的肿瘤患者。
  • 与安慰剂联合多西他赛相比，雷莫芦单抗联合多西他赛治疗后中位OS延长（10.5个月vs.9.1个月；风险比[HR]，0.86；95％置信区间[CI]，0.75-0.98），ORR（23 ％vs. 14％）和PFS（4.5个月vs. 3个月）。在包括组织学鳞状和非鳞状肿瘤患者亚组中，添加雷莫芦单抗后OS延长。
  • 多西他赛和雷莫芦单抗治疗组3至4级治疗相关不良事件的发生率为79％，而多西他赛和安慰剂治疗组为71％。在多西他赛中添加雷莫芦单抗后，发热性中性粒细胞减少症、乏力和高血压毒性反应更常见。两组之间3至4级出血的发生率无显著差异。
  • 根据该研究，对于一线化疗后疾病进展但PS良好的晚期NSCLC患者，可以考虑在多西他赛化疗中添加雷莫芦单抗。

    • 培美曲塞

    证据（培美曲塞）：

  • 一项旨在证明培美曲塞非劣效于多西他赛的571例患者的III期随机临床试验显示，缓解率、PFS或OS均无差异。
  • [证据等级：[1iiA]值得注意的是，组织学鳞状肿瘤患者获益于多西他赛，而组织学非鳞状肿瘤患者可能获益于培美曲塞。

    • 靶向EGFR的治疗

    一线化疗后EGFR靶向治疗

    厄洛替尼

    证据（厄洛替尼）：

  • 一项随机、安慰剂对照试验表明，与安慰剂相比，厄洛替尼可延长一线或二线化疗后NSCLC患者的生存期及症状恶化的时间，
  • 但与标准二线化疗联合多西紫杉醇或培美曲塞相比，并不能延长生存期。
  • 比较厄洛替尼与最佳支持治疗两者有效性的临床试验包括731例患者；49％既往接受过两种化疗方案，而93％接受过含铂类药物化疗。
  • 既往接受过两种化疗方案后患者的OS为6.7个月，而接受含铂类药物化疗后患者的OS为4.7个月。HR为0.70（P <0.001），厄洛替尼治疗显优。
  • [证据等级：1iiA]
  • 在为了证实一线含铂类药物联合治疗后疾病进展后使用厄洛替尼优效于标准二线化疗的试验（NCT00556322）中，将424例患者随机分配。
  • 主要终点OS无差异（中位OS，5.3个月vs. 5.5个月；HR，0.96；95％CI，0.78-1.19）。
  • [证据等级：1iiA]

    • 吉非替尼

    证据（吉非替尼）：

  • 一项随机的III期临床试验中，评估了吉非替尼vs.安慰剂在1,692例既往接受过治疗的NSCLC患者中的疗效，结果表明：
  • 吉非替尼不能延长OS。
  • 在总体人群（吉非替尼组为5.6个月，安慰剂组为5.1个月；HR，0.89；95％CI，0.77–1.02；P = 0.087）或812例腺癌患者（6.3个月vs. 5.4个月；HR，0.84；CI，0.68–1.03；P = 0.089）中，两组之间的中位生存期无显著差异。
  • 预先计划的亚组分析显示，对于从未吸烟者（n = 375；95％CI，0.67 [0.49–0.92]；P = 0.012；中位生存期8.9个月vs. 6.1个月）和亚洲血统的患者（n = 342；95％CI，0.66 [0.48-0.91]；P = 0.01；中位生存期9.5个月vs. 5.5个月），吉非替尼组的生存期显著长于安慰剂组。
  • [证据等级：1iiA]
  • 一项大型的随机临床试验中，比较了吉非替尼与多西他赛在接受含铂类药物化疗预先治疗的局部晚期或转移性NSCLC患者中的有效性。
  • 主要目的是比较两组之间的OS，并进行辅助分析，以评估在总体人群中的非劣效性以及在意向治疗人群中EGFR基因拷贝数高的患者的优越性。1,466例患者随机接受吉非替尼（250 mg，每日一次，PO； n = 733）或多西他赛（75 mg / m2，每3周一次，IV；n = 733）。
  • 在OS方面，证实吉非替尼非劣效于多西他赛（HR，1.020；95％CI，0.905-1.150）。然而，尚未证明吉非替尼在高EGFR基因拷贝数患者中的优效性（85例患者vs 89例患者）（HR，1.09；95％CI，0.78–1.51；P = 0.62）。
  • 在吉非替尼组中，最常见的不良事件是皮疹或痤疮（49% vs. 10%）和腹泻（35% vs. 25%）。在多西他赛组中，中性粒细胞减少症（5％vs. 74％）、乏力（25％vs. 47％）和脱发（3％vs. 36％）最为常见。
  • 该试验显示，在患者生存期方面，吉非替尼非劣效于多西他赛，这表明吉非替尼是晚期NSCLC患者预先治疗的有效药物。

    • 厄洛替尼和吉非替尼治疗后从未吸烟的东亚女性患者以及腺癌和支气管肺泡癌患者的ORR较高。

    缓解可能与EGFR酪氨酸激酶结构域中的致敏突变有关，

    但与KRAS突变无关。

    [证据等级：3iiiDiii]对于通过免疫组化检测EGFR蛋白表达水平或通过荧光原位杂交研究获得的EGFR基因拷贝数增加的患者，其生存期获益可能更大，

    但是通过免疫组化进行EGFR检测的临床实用性受到质疑。

    阿法替尼

    证据（阿法替尼）：

  • 比较了阿法替尼（一种不可逆的受体ErbB家族抑制剂）与厄洛替尼作为二线治疗在晚期鳞状细胞癌患者中的有效性。在一项随机、对照的III期临床试验（LUX-Lung 8 [NCT01523587]）中，将一线含铂类药物化疗后疾病进展的IIIB / IV期鳞状细胞NSCLC患者按1:1比例随机分配，接受阿法替尼（398例患者，40 mg PO qd）或厄洛替尼（397例患者，150 mg PO qd）。
  • [证据等级：1iiDiii]主要终点为PFS。次要终点包括OS和缓解率。
  • 中位随访时间为6.7个月时，PFS为2.4个月与1.9个月（HR，0.82；95％CI，0.68–1.00）。
  • 中位随访时间为18.4个月后，阿法替尼组的中位OS明显更长（7.9个月vs.6.8个月；HR，0.81；95％CI，0.69-0.95；P = 0.007）。接受阿法替尼治疗的患者中6个月（63.6％vs. 54.6％；P = 0.009）、12个月（36.4％vs. 28.2％；P = 0.015）和18个月（22％vs. 14.4％；P = 0.013）生存率均明显提高。
  • 两组之间的缓解率无显著差异（6% vs. 3%；P = 0.551）。
  • 两组之间的不良事件发生率相似，其中3级或更高级别不良事件的发生率为57％。阿法替尼组3级治疗有关的腹泻和口腔炎发生率较高。但是，接受厄洛替尼治疗的患者中3级皮疹或痤疮更为常见。
  • 与厄洛替尼相比，阿法替尼是IV期鳞状细胞NSCLC患者二线治疗的另一种选择。

    • 既往接受EGFR靶向治疗后进行EGFR靶向治疗（针对获得性EGFR T790M突变）

    奥希替尼

    证据（奥希替尼）：

  • 一项开放性III期试验（AURA 3 [NCT02151981]）研究了奥希替尼在EGFR致敏突变的NSCLC患者中的有效性，这些患者一线EGFR抑制剂治疗后疾病发生进展，且出现T790M EGFR耐药突变（通过Cobas®EGFR突变试验确定）。
  • 该试验随机分配419例患者（按2:1比例），接受奥希替尼80 mg PO qd或培美曲塞加卡铂或顺铂IV给药，每3周一次，最多六个疗程；化疗组允许使用培美曲塞维持治疗。主要终点为PFS。
  • 在延长中位PFS方面，奥希替尼优效于化疗（10.1个月vs. 4.4个月；HR，0.30；95% CI，0.23–0.41；P < 0.001）。
  • 奥希替尼治疗组的ORR为71％，铂类药物治疗组为31％（客观缓解的比值比为5.39；95％CI，3.47-8.48；P < 0.001）。
  • 在144例中枢神经系统（CNS）转移患者中，奥希替尼治疗组的中位PFS持续时间为8.5个月，铂类药物治疗组为4.2个月（HR，0.32；95％CI，0.21-0.49）。
  • 奥希替尼治疗组3级或更高级别的不良事件的发生率为23％，铂类药物治疗组为47％。
  • [证据等级：1iiDiii]

    • 靶向ALK的酪氨酸激酶抑制剂（TKI）治疗

    一线化疗后靶向ALK的TKI治疗

    克唑替尼

    证据（克唑替尼）：

  • 一项研究（NCT00585195）对1,500例ALK重排的NSCLC患者进行了筛选，确定了82例入组一项临床试验的晚期ALK阳性疾病患者：一项在I期剂量递增（推荐剂量为克唑替尼双药和ALK抑制剂250 mg bid，每28天为一个疗程）确定后进行的扩展队列研究。
  • 大多数患者既往接受过治疗。
  • 平均治疗时间为6.4个月，总缓解率为57％（82例患者中的47例，其中46例确认部分缓解，1例确认完全缓解）。27例患者（33％）疾病稳定。
  • [证据等级：3iiiD]
  • 6个月PFS的估计概率为72％。
  • 1年OS为74％（95％CI，63-82），2年OS为54％（40-66）。
  • 在二线或三线治疗中接受克唑替尼治疗的30例ALK阳性患者的生存期显著长于不同队列中接受二线治疗的23例ALK阳性对照患者的生存期（中位OS尚未达到[95％ CI，14个月-未达到] vs.6个月[95％CI，4–17]，1年OS，70％[95％CI，50-83]vs.44％[95％CI，23-64]，2年OS，55％[33-72]vs.12％[2-30]；HR，0.36；95％CI，0.17-0.75；P = 0.004）。
  • [证据等级：3iiiD]
  • 常见毒性为1级或2级（轻度）胃肠道副作用。
  • ALK重排的患者往往比未重排的患者年轻。大多数患者很少吸烟或不吸烟；且患者为腺癌。
  • 在一项开放性、随机、III期研究中，既往接受过一种含铂类药物化疗方案的347例ALK易位IIIB / IV期NSCLC患者接受了克唑替尼（250 mg PO，每日两次）或化疗（如果培美曲塞初治则培美曲塞500 mg / m2，或多西他赛75 mg / m2）。
  • 主要终点为PFS。中位PFS明显更长，克唑替尼显优（7.7个月vs. 3.0个月，P < 0.001）。
  • [证据等级：1iiDiii]
  • OS（次要终点）无显著差异，设计中存在明显交叉。

    • 既往ALK TKI治疗后靶向ALK的TKI治疗

    塞瑞替尼

    证据（塞瑞替尼）：

  • 一项单组开放性试验入组了163例ALK易位IIIB / IV期NSCLC患者，其中该患者在接受克唑替尼治疗期间出现疾病进展或对该药物不耐受。
  • 根据实体瘤缓解评估标准（RECIST，版本1.0），主要终点为ORR，次要终点为缓解持续时间（DOR）。盲态独立审查委员会评估的ORR为43.6％（95％CI，36-52），中位DOR为7.1个月（范围为5.6-不可估计）。
  • [证据等级：3iiiDiv]
  • 值得注意的是，由于胃肠道毒性反应，38％患者需要调整剂量。丙氨酸转氨酶升高至正常值上限五倍以上的发生率为27％。

    • 阿来替尼

    证据（阿来替尼）：

  • 一项II期开放性试验（NCT01871805）入组了87例克唑替尼治疗后疾病进展的ALK易位IIIB/IV期NSCLC患者。
  • 主要终点是根据RECIST（1.1版）标准确定的客观缓解。在这项正在进行的研究的主要终点分析时，通过盲态独立复查确定48％患者（95％CI，36-60）已确认部分缓解，32％患者疾病稳定。中位DOR为13.5个月（95％CI，6.7-无法估计）。估计的中位PFS为8.1个月（95％CI，6.2–12.6）。
  • [证据等级：3iiiDiv]
  • 16例患者在基线时出现可测量的CNS病灶，其中11例既往接受过放疗。CNS ORR为75％（95％CI，48-93），其中25％患者达到完全缓解，50％患者达到部分缓解。
  • 最常见副作用的严重程度为1级或2级；便秘、疲乏、肌痛和外周水肿是最常见的不良事件，发生率为23％-36％。36％的患者需要中断剂量，而16％的患者需要降低剂量。
  • 第二项II期开放性试验入组了138例克唑替尼治疗后疾病进展的ALK阳性IIIB/IV期NSCLC患者。
  • 主要终点为由独立中心审查确定的ORR。ORR为50％（95％CI，41-59）。中位DOR为11.2个月（95％CI，9.6-未达到）。中位PFS为8.9个月（95％CI，5.6–11.3）。
  • [证据等级：3iiiDiv]
  • 35例可测量的CNS病灶患者中的CNS ORR为57％（95％CI，39-74）。
  • 常见的不良事件为便秘、乏力和外周水肿，主要为1级或2级，发生率为25％-33％。

    • 布加替尼

    证据（布加替尼）：

  • II期开放性试验（NCT02094573）入组了222例克唑替尼治疗后疾病进展的ALK易位的局部晚期或转移性NSCLC患者。患者随机接受90 mg qd（n = 112；109例接受治疗）或180 mg qd，以及7天90 mg qd导入（n = 110）治疗。
  • 研究者评估的主要终点是ORR。90 mg剂量组患者的ORR为45％（97.5％CI，34–56），180 mg剂量组患者为54％（97.5％CI，43–65）。
  • 90 mg剂量组患者的中位PFS为9.2个月（95％CI，7.4–15.6），180 mg剂量组患者为12.9个月（95% CI，11.1–未达到）。
  • 在数据截止日期，90 mg剂量组患者的中位DOR为13.8个月（95％CI，5.6–13.8），180 mg剂量组患者为11.1个月（95％CI，9.2–13.8）。
  • [证据等级：1iiDiv]
  • 90 mg qd剂量组患者中具有可测量CNS病灶的患者的CNS ORR为42％（n = 26），180 mg qd剂量组患者为67％（n = 18）。
  • 常见不良事件主要为1级或2级恶心、腹泻、头痛和咳嗽，高剂量组发生率为27％-38％。219例接受治疗的患者中有14例发生了一部分早期发作（发作中位值，第2天）的肺部不良事件（所有等级，6％；≥3，3％）；剂量递增至180 mg后未发生任何事件。这些事件包括呼吸困难、缺氧、咳嗽、肺炎或局限性肺炎。可通过中断剂量进行治疗。14例患者中有7例使用布加替尼成功治愈。
  • 美国食品药品监督管理局（FDA）批准的布加替尼剂量为90 mg qd，共7天；如果可以耐受，剂量应增加至180 mg qd。

    • 靶向ROS1的治疗

    大约1％的NSCLC患者出现ROS1重排。

    克唑替尼

    克唑替尼已获批用于治疗肿瘤呈ROS1阳性的转移性NSCLC患者，不考虑既往全身治疗的次数。

    证据（克唑替尼）：

  • 在克唑替尼的I期研究扩展队列中，50例ROS1重排呈阳性的晚期NSCLC患者口服250 mg克唑替尼治疗，每日两次。
  • 使用分离的荧光原位杂交或逆转录酶-聚合酶链反应法确定为ROS1重排。7例患者（14％）既往未接受过任何晚期疾病治疗，21例患者（42％）既往接受过一种治疗，22例患者（44％）既往接受过一种以上治疗。主要终点为缓解率。
  • 总缓解率为72％（95％CI，58-84）。6％患者出现完全缓解，66％患者出现部分缓解，18％患者疾病稳定。
  • 中位PFS数19.2个月（95％CI，14.4-未达到）。估计的DOR为17.6个月（95％CI，14.5-未达到）。
  • [证据等级：3iiiDiv]
  • 在一项II期、开放性、单组试验中，127例ROS1阳性NSCLC的东亚患者接受250 mg克唑替尼治疗，每日两次。
  • 24例患者（18.9%）既往未接受过任何晚期疾病治疗，53例患者（41.7%）既往接受过一种治疗，50例患者（39%）既往接受过两种或3种治疗。主要终点为通过独立审查的客观缓解率。
  • 客观缓解率为71.7%（95％CI，63.0–79.3）。 不考虑既往治疗次数，缓解率相似。13.4％患者出现完全缓解，而58.3％患者出现部分缓解，16.5％患者疾病稳定。
  • [证据等级：3iiiDiv]
  • 中位PFS为15.9个月（95％CI，12.9–24）。缓解持续时间为19.7个月（95％CI，14.1-未达到）。
  • 中位OS为32.5个月（95％CI，32.5-未达到）。

    • BRAF V600E和MEK抑制剂（针对BRAF V600E突变的患者）

    BRAF V600E突变，见于1%到2%的肺腺癌。

    达拉非尼和曲美替尼

    证据（达拉非尼和曲美替尼）：

  • 在一项II期、多中心、非随机、开放性研究（NCT01336634）中，57例既往至少接受1-3种含铂治疗方案治疗非转移性NSCLC后疾病进展且BRAF V600E突变检测呈阳性的患者接受了150 mg bid达拉非尼（一种BRAF抑制剂）和2 mg qd曲美替尼（一种MEK抑制剂）治疗。
  • 通过局部检测确定了BRAF V600E突变。主要终点为研究者评估的总缓解率。
  • 由研究者和独立审查委员会评估独立确定的总缓解率为63.2％（95％CI，49.3-75.6）。经研究者评估有36例中有2例完全缓解；独立审查委员会认为均为部分缓解。
  • 研究者评估的中位PFS为9.7个月（95％CI，6.9-19.6个月）。估计的中位DOR为9.0个月（95％CI，6.9-18.3）。OS数据不成熟。
  • 49％患者至少发生1例3或4级不良事件，其中最常见的是中性粒细胞减少症、低钠血症和贫血。
  • [证据等级：3iiiDiv]

    • 达拉非尼和曲美替尼联合治疗已获批用于治疗肿瘤携带BRAF V600E突变的NSCLC患者（通过FDA批准的试验检测）。

    免疫治疗

    纳武利尤单抗是一种完全人单克隆抗体，可抑制在肿瘤细胞和浸润性免疫细胞上表达的程序性死亡1（PD-1）共抑制免疫检查点。

    帕博利珠单抗是一种人源化单克隆抗体，可抑制肿瘤细胞上表达的PD-1共抑制性免疫检查点与浸润免疫细胞及其配体PD-L1和PD-L2之间的相互作用。

    阿替利珠单抗是一种阻断PD-L1的抗体。

    纳武利尤单抗

    证据（纳武利尤单抗）：

  • 在两项III期临床试验中，一项在铂类药物预治疗的晚期鳞状NSCLC患者中实施，另一项在非鳞状NSCLC患者中实施。在OS改善方面，纳武利尤单抗优效于既往多西他赛化疗标准治疗。
  • [证据等级：1iiA]此外，两项临床试验中纳武利尤单抗治疗组的3级和4级治疗相关毒性反应发生率明显低于多西他赛治疗组。值得注意的是，所有入组纳武利尤单抗III期临床研究的患者的ECOG PS为0或1；自身免疫性疾病、有症状的肺间质疾病或接受全身性免疫抑制治疗的患者不得入组。
  • 一项随机、开放性、III期临床试验中，随机分配了272例接受一种含铂化疗方案的晚期鳞状细胞NSCLC患者，接受纳武利尤单抗（3 mg / kg，每2周一次）或多西他赛（75 mg / m2，每3周一次），直至疾病进展。
  • 本研究的主要终点是OS。
  • 与多西他赛相比，纳武利尤单抗治疗后中位OS显著改善（9.2个月vs. 6个月；P < 0.001）。另外，在ORR（20％vs. 9％；P = 0.008）和中位PFS（3.5个月vs. 2.8个月； P <0.001）方面，纳武利尤单抗显优。
  • 纳武利尤单抗组治疗相关的毒性反应发生率显著低于多西他赛组（所有级别，纳武利尤单抗组为58％和多西他赛组为86％；3-4级，纳武利尤单抗组为7％，多西他赛组为55％）。
  • 一项随机、开放性、III期临床试验，随机分配了582例接受一种含铂化疗方案的晚期非鳞状NSCLC患者，接受纳武利尤单抗（3 mg / kg，每2周一次）或多西他赛（75 mg / m2，每3周一次），直至疾病进展。
  • 允许既往维持化疗后一线铂类药物双药治疗；允许EGFR突变或ALK易位的患者接受另一种TKI治疗方案。本研究的主要终点是OS。
  • 与多西他赛相比，纳武利尤单抗治疗后中位OS显著改善（12.2个月vs. 9.4个月；HR, 0.73；96% CI，0.59–0.89；P = 0.002）。本项研究显示，在ORR（19％vs. 12％；P = 0.02）方面，纳武利尤单抗治疗显优，但在中位PFS方面该药物不显优（纳武利尤单抗组为2.3个月，多西他赛组为4.2个月）。纳武利尤单抗组患者的中位DOR为17.2个月，多西他赛组为5.6个月。
  • 纳武利尤单抗组治疗相关的毒性反应发生率显著低于多西他赛组（所有级别，纳武利尤单抗组为69%和多西他赛组为88%；3-4级，纳武利尤单抗组为10%，多西他赛组为54%）。
  • 上述两项试验均显示2年预后具有长期临床获益。纳武利尤单抗组鳞状NSCLC患者的2年OS率为23％（95％CI，16–30），多西他赛组为8％（95％CI，4–13），纳武利尤单抗组非鳞状NSCLC患者的OS率为29％（95 ％CI，24–34），多西他赛组为16％（95％CI，12–20）。
  • 在2年内，我们观察了10例(37%)确诊的鳞状非小细胞肺癌应答者和56例非鳞状非小细胞肺癌应答者中的19例(34%)。在两项研究中，接受多西他赛治疗的患者均未出现持续反应。

    • 目前对于在一线含铂类药物化疗期间或之后出现疾病进展的转移性NSCLC患者来说，纳武利尤单抗是标准二线治疗。与多西他赛相比，纳武利尤单抗治疗后生存期延长，毒性反应发生率降低。但是，迄今为止，纳武利尤单抗的临床试验尚未招募有自身免疫疾病、间质性肺病病史或ECOG PS ＞1的患者。自身免疫疾病活跃的患者不能用纳武利尤单抗治疗。需要密切监测所有患者治疗中出现的自身免疫毒性反应。用于治疗自身免疫毒性反应的特定算法纳入纳武利尤单抗的FDA标签中。

    帕博利珠单抗

    证据（帕博利珠单抗）：

  • 在具有多个扩展队列的I期研究中，帕博利珠单抗在缓解率和DOR方面显示出显著的活性。
  • [证据等级：3iiiDiv]
  • 在这项研究中，495例患者接受了帕博利珠单抗2 mg / kg（每3周一次）、10 mg / kg（每3周一次）或10 mg / kg（每2周一次）治疗。在不同的治疗方案之间未见明显差异。关键排除标准是自身免疫病、肺炎病史、需要全身免疫抑制治疗以及PS ＞1。ORR为19.4％（95％CI，16.0–23.2），其中394例既往接受治疗的患者的缓解率达18.0％（95％CI，14.4–22.2），101例既往未接受治疗的患者缓解率为24.8％（95％CI，16.7–34.3）。 所有患者的中位PFS为3.7个月（95％CI，2.9-4.1），既往接受治疗的患者为3.0个月（95％CI，2.2-4.0），既往未接受治疗的患者为6.0个月（95％CI，4.1-8.6）。所有患者的中位DOR为12.5个月（1.0-23.3个月）。
  • 该研究评估了帕博利珠单抗在PD-L1高水平表达（通过抗PD-L1抗体克隆22C3评估）患者中的疗效。使用验证组73例患者的至少50％肿瘤细胞的膜染色截止值时，缓解率为45.2％（95％CI，33.5–57.3），该组的中位PFS为6.3个月（95％CI，2.9–12.5）。在发布时尚未达到中位OS。
  • 预估来自1143例筛选患者的PD-L1肿瘤染色率（其中824例患者样本可评价）如下所示：23.2％患者的肿瘤细胞染色率为50％或以上；37.6％患者的肿瘤细胞染色率为1％-49％；39.2％患者的肿瘤细胞染色率低于 1％。
  • 最常见的不良事件是乏力、瘙痒和食欲下降。在9.5％的患者中报告了3级或3级以上不良事件。超过2％的患者发生的炎症和免疫介导的不良事件为输液相关反应（3.0％）、甲状腺功能减退症（6.9％）和肺炎（3.6％）。
  • 在一项II/III期随机临床试验中，将既往接受过治疗且在至少1％肿瘤细胞上表达PD-L1的NSCLC患者随机分配（1:1:1），接受帕博利珠单抗（2 mg / kg）、帕博利珠单抗（10 mg / kg）或多西他赛（75 mg / m2）治疗，每3周一次。
  • [证据等级：1iiA]主要终点是总体人群中以及至少50％肿瘤细胞上PD-L1表达的患者的OS和PFS。该研究招募了1,034例患者；其中345例接受帕博利珠单抗（2 mg / kg）治疗；346例接受帕博利珠单抗（10 mg / kg）治疗；343接受多西他赛治疗。
  • 在总体人群中，帕博利珠单抗（2 mg / kg）组的中位OS为10.4个月，帕博利珠单抗（10 mg / kg）组的中位OS为12.7个月，多西他赛组的中位OS为8.5个月。帕博利珠单抗（2 mg / kg）组的OS显著长于多西他赛组（HR 0.71；95％CI，0.58–0.88；P = 0.0008），帕博利珠单抗（10 mg / kg）组的OS显著长于多西他赛组（HR，0.61；CI，0.49–0.75；P < 0.0001）。
  • 在总体人群中，与多西他赛组相比，帕博利珠单抗组的PFS未延长。
  • 在至少50％的肿瘤细胞上表达PD-L1的患者中，帕博利珠单抗（2 mg / kg）组的OS明显长于多西他赛组（中位值，14.9个月vs.8.2个月；HR，0.54；95％CI，0.38– 0.77；P = 0.0002），帕博利珠单抗（10 mg / kg）组的OS明显长于多西他赛组（中位值，17.3个月vs. 8.2个月；HR，0.50；CI，0.36-0.70；P < 0.0001）。
  • 在至少50％的肿瘤细胞上表达PD-L1的患者组中，帕博利珠单抗（2 mg / kg）组的PFS明显长于多西他赛组（中位值，5.0个月vs.4.1个月；HR，0.59；95％CI，0.44– 0.78；P = 0.0001），帕博利珠单抗（10 mg / kg）组的PFS明显长于多西他赛组（中位值，5.2个月vs. 4.1个月；HR，0.59；CI，0.45–0.78；P < 0.0001）。
  • 与多西他赛组相比，帕博利珠单抗组的3-5级治疗相关的不良事件不太常见（339例接受帕博利珠单抗（2 mg / kg）治疗的患者中43例[13％]、343例接受帕博利珠单抗（10 mg / kg）治疗的患者中55例[16％]、309例接受多西他赛治疗的患者中109例[35％]）。

    • 帕博利珠单抗已获得加速批准，作为NSCLC患者的二线治疗，其中该患者的肿瘤在一线化疗或一线化疗后出现PD-L1表达(经FDA批准的试验确定染色率＞50％)。在接受帕博利珠单抗之前，EGFR或ALK基因组肿瘤异常的患者应先行FDA批准的治疗确定疾病进展（参见FDA的帕博利珠单抗标签）。

    阿替利珠单抗

    证据（阿替利珠单抗）：

  • 两项国际、随机、开放性临床试验（OAK [NCT02008227]和POPLAR [NCT01903993]）证明了该药物在既往接受过铂类药物化疗的1137例NSCLC患者中的疗效和安全性。
  • [证据等级：[1iiA]与多西他赛相比，在预期的患者人群中使用阿替利珠单抗治疗可以使OSK研究的OS提高4.2个月，而POPLAR研究的OS提高2.9个月。
  • 在OAK试验中，阿替利珠单抗组的中位OS为13.8个月（95％CI，11.8-15.7），而多西他赛组的中位OS为9.6个月（95％CI，8.6-11.2）（HR = 0.74；95％CI，0.63-0.87；P = 0.0004）。
  • 在POPLAR试验中，阿替利珠单抗组的中位OS为12.6个月（95％CI，9.7–16.0），而多西他赛组的中位OS为9.7个月（95％CI，8.6-12.0）（HR = 0.69；95％CI，0.52–0.92）。
  • 尽管改善的程度与肿瘤细胞和浸润性免疫细胞上PD-L1免疫组化表达水平相关，但是在存在和不存在PD-L1表达的肿瘤患者中都观察到阿替利珠单抗的生存获益。
  • 在POPLAR试验中，接受阿替利珠单抗治疗的患者中最常见（≥20％）不良反应包括疲乏、食欲下降、呼吸困难、咳嗽、恶心、骨骼肌肉疼痛和便秘。
  • 在接受阿替利珠单抗治疗的患者中，最常见的（≥2％）3-4级不良事件包括呼吸困难、肺炎、低氧、低钠血症、疲乏、贫血、骨骼肌肉疼痛、天冬氨酸转氨酶升高、丙氨酸转氨酶升高、吞咽困难和关节痛。
  • 对于接受阿替利珠单抗治疗的患者，具有临床意义的免疫相关的不良事件包括肺炎、肝炎、结肠炎和甲状腺疾病。

    • 处于临床评估阶段的进展的复发性IV期NSCLC治疗选择（二线治疗）

    处于临床评估阶段的进展的复发性IV期NSCLC治疗选择（二线治疗）包括：

  • 临床试验可视为二线治疗。

    • 当前临床试验

    利用我们先进的临床试验检索工具查找NCI支持的癌症临床试验（当前正在招募患者）。可通过试验地点、治疗类型、药物名称和其他标准缩小检索范围。还可获得关于临床试验的基本信息。

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  • Clark GM, Zborowski DM, Culbertson JL, et al.: Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1 (8): 837-46, 2006.
  • Soria JC, Felip E, Cobo M, et al.: Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 16 (8): 897-907, 2015.
  • Mok TS, Wu Y-L, Ahn M-J, et al.: Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 376 (7): 629-640, 2017.
  • Kwak EL, Bang YJ, Camidge DR, et al.: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363 (18): 1693-703, 2010.
  • Shaw AT, Yeap BY, Solomon BJ, et al.: Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12 (11): 1004-12, 2011.
  • Shaw AT, Kim DW, Nakagawa K, et al.: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368 (25): 2385-94, 2013.
  • Shaw AT, Kim DW, Mehra R, et al.: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370 (13): 1189-97, 2014.
  • Shaw AT, Gandhi L, Gadgeel S, et al.: Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 17 (2): 234-42, 2016.
  • Ou SH, Ahn JS, De Petris L, et al.: Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 34 (7): 661-8, 2016.
  • Kim DW, Tiseo M, Ahn MJ, et al.: Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol 35 (22): 2490-2498, 2017.
  • Gainor JF, Shaw AT: Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18 (7): 865-75, 2013.
  • Shaw AT, Ou SH, Bang YJ, et al.: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371 (21): 1963-71, 2014.
  • Wu YL, Yang JC, Kim DW, et al.: Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 36 (14): 1405-1411, 2018.
  • Planchard D, Besse B, Groen HJM, et al.: Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 17 (7): 984-993, 2016.
  • Brahmer J, Reckamp KL, Baas P, et al.: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373 (2): 123-35, 2015.
  • Borghaei H, Paz-Ares L, Horn L, et al.: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373 (17): 1627-39, 2015.
  • Garon EB, Rizvi NA, Hui R, et al.: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372 (21): 2018-28, 2015.
  • Horn L, Spigel DR, Vokes EE, et al.: Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). J Clin Oncol 35 (35): 3924-3933, 2017.
  • Herbst RS, Baas P, Kim DW, et al.: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387 (10027): 1540-50, 2016.
  • Rittmeyer A, Barlesi F, Waterkamp D, et al.: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389 (10066): 255-265, 2017.
  • Fehrenbacher L, Spira A, Ballinger M, et al.: Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387 (10030): 1837-46, 2016.
    • Non-Small Cell Lung Cancer Treatment (PDQ®)

    Progressive Stage IV, Relapsed, and Recurrent NSCLC Treatment

    Standard Treatment Options for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)

    Standard treatment options for patients with progressive stage IV, relapsed, and recurrent non-small cell lung cancer (NSCLC) (second-line therapy and beyond) include the following:

  • Chemotherapy.
  • Docetaxel.
  • Docetaxel plus ramucirumab.
  • Pemetrexed.
  • Epidermal growth factor receptor (EGFR)-directed therapy.
  • EGFR-directed therapy after first-line chemotherapy.
  • Erlotinib.
  • Gefitinib.
  • Afatinib.
  • EGFR-directed therapy for acquired EGFR T790M mutations after prior EGFR-directed therapy.
  • Osimertinib.
  • Anaplastic lymphoma kinase (ALK)-directed tyrosine kinase inhibitors (TKI).
  • ALK-directed TKI after first-line chemotherapy.
  • Crizotinib.
  • ALK-directed TKI after prior ALK TKI therapy.
  • Ceritinib.
  • Alectinib.
  • Brigatinib.
  • ROS1-directed therapy.
  • Crizotinib.
  • BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations).
  • Dabrafenib and trametinib.
  • Immunotherapy.
  • Nivolumab.
  • Pembrolizumab.
  • Atezolizumab.

    • Chemotherapy

    The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.

    [Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.

    Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

    Docetaxel

    Evidence (docetaxel):

  • Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;
  • however, criteria for the selection of appropriate patients for second-line treatment are not well defined.
  • A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.
  • In that analysis, the following was shown:
  • Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test).
  • Significantly less severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both); however, no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.

    • Docetaxel plus ramucirumab

    Evidence (docetaxel plus ramucirumab):

  • In a double-blind, placebo-controlled, phase III study, 1,253 patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1 who had progressive disease after first-line chemotherapy were randomly assigned to receive docetaxel and placebo or docetaxel and ramucirumab.
  • [Level of evidence: 1iiA] Ramucirumab is a human immunoglobulin G1 monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2. The primary endpoint of the study was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and objective response rate (ORR). The study enrolled patients with either nonsquamous or squamous NSCLC; however, patients with poorly controlled hypertension, gastrointestinal perforation or fistulae, arterial thromboembolic event within 6 months (before random assignment), gross hemoptysis within 2 months, or grade 3 to 4 gastrointestinal bleeding within 3 months were excluded. In addition, the trial did not include patients with tumors that had major blood vessel involvement or intratumor cavitation.
  • The addition of ramucirumab to docetaxel compared with placebo plus docetaxel led to an increase in median OS (10.5 months vs. 9.1 months; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.98), ORR (23% vs. 14%), and PFS (4.5 months vs. 3 months). The improvement in OS from the addition of ramucirumab appeared consistent across subgroups including squamous and nonsquamous histologies.
  • Grade 3 to 4 treatment-related adverse events occurred in 79% of patients who received docetaxel and ramucirumab as compared with 71% of patients who received docetaxel and placebo. Febrile neutropenia, fatigue, and hypertension were among the toxicities that were more common with the addition of ramucirumab to docetaxel. There was no significant difference in the incidence of grades 3 to 4 hemorrhage between the groups.
  • On the basis of this study, the addition of ramucirumab to docetaxel chemotherapy can be considered for patients with good PS with advanced NSCLC who have progressive disease after first-line chemotherapy.

    • Pemetrexed

    Evidence (pemetrexed):

  • A randomized, phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, PFS, or OS.
  • [Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel, and those with nonsquamous histologies appeared to benefit more from pemetrexed.

    • EGFR-directed therapy

    EGFR-directed therapy after first-line chemotherapy

    Erlotinib

    Evidence (erlotinib):

  • Two randomized, placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared with placebo
  • but does not improve survival compared with standard second-line chemotherapy with docetaxel or pemetrexed.
  • The trial of erlotinib versus best supportive care included 731 patients; 49% had received two previous chemotherapy regimens, and 93% had received platinum-based chemotherapy.
  • OS was 6.7 months among those who had received two previous chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.
  • [Level of evidence: 1iiA]
  • In the trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy after disease progression on first-line platinum combination therapy, 424 patients were randomly assigned.
  • There was no difference in the primary endpoint of OS (median OS, 5.3 months vs. 5.5 months; HR, 0.96; 95% CI, 0.78–1.19).
  • [Level of evidence: 1iiA]

    • Gefitinib

    Evidence (gefitinib):

  • A randomized phase III trial evaluated gefitinib versus placebo in 1,692 previously treated NSCLC patients and showed the following:
  • Gefitinib does not improve OS.
  • Median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; HR, 0.89; 95% CI, 0.77–1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 months vs. 5.4 months; HR, 0.84; CI, 0.68–1.03; P = .089).
  • Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49–0.92]; P = .012; median survival 8.9 months vs. 6.1 months) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48–0.91]; P = .01; median survival 9.5 months vs. 5.5 months).
  • [Level of evidence: 1iiA]
  • In a large, randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.
  • The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high EGFR gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day PO; n = 733) or docetaxel (75 mg/m2 IV every 3 weeks; n = 733).
  • Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR, 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR, 1.09; 95% CI, 0.78–1.51; P = .62).
  • In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
  • This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.

    • ORR to erlotinib and gefitinib are higher in patients who have never smoked, in females, in East Asians, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.

    Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the EGFR-

    and, with the absence of, KRAS mutations.

    [Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by fluorescence in situ hybridization studies,

    but the clinical utility of EGFR testing by immunohistochemistry has been questioned.

    Afatinib

    Evidence (afatinib):

  • Afatinib, an irreversible inhibitor of the ErbB-family of receptors, has been compared with erlotinib as second-line treatment in patients with advanced squamous cell carcinoma. In a randomized, controlled, phase III trial (LUX-Lung 8 [NCT01523587]), patients with stage IIIB/IV squamous cell NSCLC with disease progression after frontline platinum-based chemotherapy were randomly assigned in a 1:1 ratio to receive afatinib (398 patients, 40 mg PO qd) or erlotinib (397 patients, 150 mg PO qd).
  • [Level of evidence: 1iiDiii] The primary endpoint was PFS. Secondary endpoints included OS and response rate.
  • After a median follow-up of 6.7 months, the PFS was 2.4 months versus 1.9 months (HR, 0.82; 95% CI, 0.68–1.00).
  • After a median follow-up of 18.4 months, the median OS was significantly longer in the afatinib arm (7.9 months vs. 6.8 months; HR, 0.81; 95% CI, 0.69–0.95; P = .007). Survival at 6 months (63.6% vs. 54.6%; P = .009), 12 months (36.4% vs. 28.2%; P = .015), and 18 months (22% vs. 14.4%; P = .013) were all significantly better in patients who received afatinib.
  • There was no significant difference in response rate between the two arms (6% vs. 3%; P = .551).
  • The frequency of adverse events was similar between the two groups with 57% of the patients experiencing a rate of grade 3 or higher adverse events. Grade 3 treatment-related diarrhea and stomatitis occurred more frequently with afatinib; however, grade 3 rash or acne were more common in patients who received erlotinib.
  • Afatinib, as compared with erlotinib, represents another option for the second-line treatment of patients with stage IV squamous cell NSCLC.

    • EGFR-directed therapy for acquired EGFR T790M mutations after prior EGFR-directed therapy

    Osimertinib

    Evidence (osimertinib):

  • An open-label, phase III trial (AURA 3 [NCT02151981]) studied osimertinib in NSCLC patients with EGFR-sensitizing mutations whose disease had progressed after first-line EGFR inhibitors and who had the T790M EGFR resistance mutation as determined by the Cobas® EGFR Mutation Test.
  • The trial randomly assigned 419 patients (with a 2:1 ratio) to receive either osimertinib 80 mg PO qd or pemetrexed plus carboplatin or cisplatin IV every 3 weeks for up to six cycles; maintenance pemetrexed was allowed for the chemotherapy group. The primary endpoint was PFS.
  • Osimertinib was superior to chemotherapy in prolonging median PFS (10.1 months vs. 4.4 months; HR, 0.30; 95% CI, 0.23–0.41; P < .001).
  • The ORR was 71% with osimertinib versus 31% with platinum therapy (odds ratio for objective response, 5.39; 95% CI, 3.47–8.48; P < .001).
  • Among 144 patients with central nervous system (CNS) metastases, median PFS duration was 8.5 months with osimertinib versus 4.2 months with platinum therapy (HR, 0.32; 95% CI, 0.21–0.49).
  • Adverse events of grade 3 or greater occurred in 23% of osimertinib-treated patients versus 47% of platinum-treated patients.
  • [Level of evidence: 1iiDiii]

    • ALK-directed tyrosine kinase inhibitors (TKI)

    ALK-directed TKI after first-line chemotherapy

    Crizotinib

    Evidence (crizotinib):

  • A study (NCT00585195) that screened 1,500 patients with NSCLC for ALK rearrangements identified 82 patients with advanced ALK-positive disease who were enrolled in a clinical trial that was an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib dual and ALK inhibitor of 250 mg bid in 28-day cycles.
  • Most of the patients had received previous treatment.
  • At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses, and one confirmed complete response); 27 patients (33%) had stable disease.
  • [Level of evidence: 3iiiD]
  • The estimated probability of 6-month PFS was 72%.
  • 1-year OS was 74% (95% CI, 63–82), and 2-year OS was 54% (40–66).
  • Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls identified from a different cohort given any second-line therapy (median OS not reached [95% CI, 14 months–not reached] vs. 6 months [95% CI, 4–17], 1-year OS, 70% [95% CI, 50–83] vs. 44% [95% CI, 23–64], and 2-year OS, 55% [33–72] vs. 12% [2–30]; HR, 0.36; 95% CI, 0.17–0.75; P = .004).
  • [Level of evidence: 3iiiD]
  • Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.
  • Patients with ALK rearrangements tended to be younger than those without the rearrangements; most of the patients had little or no exposure to tobacco; and the patients had adenocarcinomas.
  • In an open-label, randomized, phase III study, 347 patients with stage IIIB/IV NSCLC-harboring translocations in ALK, who had received one previous regimen of platinum-based chemotherapy, received either crizotinib (250 mg PO twice a day) or chemotherapy (pemetrexed 500 mg/m2 if pemetrexed-naïve or docetaxel 75mg/m2 IV every 21 days).
  • The primary endpoint was PFS. Median PFS was significantly longer in favor of crizotinib (7.7 months vs. 3.0 months, P < .001).
  • [Level of evidence: 1iiDiii]
  • OS, a secondary endpoint, was not significantly different, but there was significant crossover in the design.

    • ALK-directed TKI after prior ALK TKI therapy

    Ceritinib

    Evidence (ceritinib):

  • A single-arm, open-label trial enrolled 163 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression while receiving crizotinib or were intolerant to the drug.
  • The primary endpoint was ORR according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) with a secondary endpoint of duration of response (DOR). The ORR by blinded independent review was 43.6% (95% CI, 36–52), and the median DOR was 7.1 months (range, 5.6–not estimable).
  • [Level of evidence: 3iiiDiv]
  • Of note, 38% of patients required dose modification because of gastrointestinal toxicity; elevation of alanine transaminase to more than five times the upper limit of normal occurred in 27% of patients.

    • Alectinib

    Evidence (alectinib):

  • A phase II, open-label trial (NCT01871805) enrolled 87 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression after crizotinib treatment.
  • The primary endpoint was objective response according to RECIST (version 1.1). At the time of primary endpoint analysis of this ongoing study, 48% of patients (95% CI, 36–60) had a confirmed partial response, and 32% had stable disease by blinded independent review. The median DOR was 13.5 months (95% CI, 6.7–not estimable). The estimated median PFS was 8.1 months (95% CI, 6.2–12.6).
  • [Level of evidence: 3iiiDiv]
  • Sixteen patients had measurable CNS disease at baseline, of whom 11 had received prior radiation therapy. The CNS ORR was 75% (95% CI, 48–93), with 25% of the patients attaining complete response and 50% of the patients attaining partial response.
  • The most common side effects were grade 1 or 2 in severity; the most frequent adverse events, occurring in 23% to 36% of patients, were constipation, fatigue, myalgia, and peripheral edema. Dose interruption was needed in 36% of patients, and dose reduction occurred in 16%.
  • A second phase II, open-label trial enrolled 138 patients with ALK-positive stage IIIB/IV NSCLC who had disease progression on crizotinib.
  • The primary endpoint was ORR by independent central review. ORR was 50% (95% CI, 41–59). Median DOR was 11.2 months (95% CI, 9.6–not reached). Median PFS was 8.9 months (95% CI, 5.6–11.3).
  • [Level of evidence: 3iiiDiv]
  • CNS ORR in 35 patients with measurable CNS lesions was 57% (95% CI, 39–74).
  • Common adverse events that were mainly grade 1 or 2, which occurred in 25% to 33% of patients, were constipation, fatigue, and peripheral edema.

    • Brigatinib

    Evidence (brigatinib):

  • A phase II, open-label trial (NCT02094573) enrolled 222 patients with ALK-translocated locally advanced or metastatic NSCLC who had disease progression after crizotinib treatment. Patients were randomly assigned to receive 90 mg qd (n = 112; 109 treated) or 180 mg qd with a 7-day lead-in at 90 mg qd (n = 110).
  • The primary endpoint assessed by the investigators was ORR. ORR was 45% (97.5% CI, 34–56) for patients who received the 90 mg dose and 54% (97.5% CI, 43–65) for patients who received the 180 mg dose.
  • Median PFS was 9.2 months (95% CI, 7.4–15.6) for patients who received the 90 mg dose and 12.9 months (95% CI, 11.1–not reached) for patients who received the 180 mg dose.
  • At data cutoff, the median DOR was 13.8 months (95% CI, 5.6–13.8) for patients who received the 90 mg dose and 11.1 months (95% CI, 9.2–13.8) for patients who received the 180 mg dose.
  • [Level of evidence: 1iiDiv]
  • The CNS ORR in patients with measurable CNS lesions was 42% in patients receiving 90 mg qd (n = 26) and 67% in patients receiving 180 mg qd (n = 18).
  • Common adverse events, which were mainly grade 1 or 2 and occurred in 27% to 38% of patients at the higher dose, were nausea, diarrhea, headache, and cough. A subset of pulmonary adverse events with early onset (median onset, day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥3, 3%); none occurred after escalation to 180 mg. These events included dyspnea, hypoxia, cough, pneumonia, or pneumonitis. They were managed with dose interruption. Seven of the 14 patients were successfully retreated with brigatinib.
  • The U.S. Food and Drug Administration (FDA)-approved dose of brigatinib is 90 mg qd for 7 days; if tolerated, the dose is increased to 180 mg qd.

    • ROS1-directed therapy

    ROS1 rearrangements occur in approximately 1% of patients with NSCLC.

    Crizotinib

    Crizotinib was approved for patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.

    Evidence (crizotinib):

  • In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.
  • ROS1 rearrangements were identified using break-apart fluorescence in situ hybridization or reverse-transcriptase-polymerase-chain-reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one previous treatment. The primary endpoint was response rate.
  • The overall response rate was 72% (95% CI, 58–84). Six percent of patients had a complete response, 66% had a partial response, and 18% had stable disease as their best response.
  • Median PFS was 19.2 months (95% CI, 14.4–not reached). The estimated DOR was 17.6 months (95% CI, 14.5–not reached).
  • [Level of evidence: 3iiiDiv]
  • In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.
  • Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary endpoint was objective response rate by independent review.
  • The objective response rate was 71.7% (95% CI, 63.0–79.3). Response rates were similar, irrespective of the number of previous therapies. Complete responses occurred in 13.4% of patients, while 58.3% of patients had partial responses and 16.5% of patients had stable disease as their best response.
  • [Level of evidence: 3iiiDiv]
  • Median PFS was 15.9 months (95% CI, 12.9–24). The duration of response was 19.7 months (95% CI, 14.1–not reached).
  • OS was 32.5 months (95% CI, 32.5–not reached).

    • BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations)

    BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas.

    Dabrafenib and trametinib

    Evidence (dabrafenib and trametinib):

  • In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 57 patients with progression after at least one to three previous platinum-containing regimens for treatment of metastatic NSCLC, who tested positive for BRAF V600E mutations, were treated with dabrafenib (a BRAF inhibitor) 150 mg bid and trametinib (a MEK inhibitor) 2 mg qd.
  • BRAF V600E mutations were ascertained by local testing. The primary endpoint was investigator-assessed overall response.
  • The overall response rate was 63.2% (95% CI, 49.3–75.6), as determined independently by investigator and independent review committee assessments. There were 2 out of 36 complete responses by investigator assessment; all responses were deemed partial by the independent review committee.
  • The median investigator-assessed PFS was 9.7 months (95% CI, 6.9–19.6 months). The estimated median DOR was 9.0 months (95% CI, 6.9–18.3). The OS data are immature.
  • Forty-nine percent of patients had at least one grade 3 or 4 adverse event, the most common of which were neutropenia, hyponatremia, and anemia.
  • [Level of evidence: 3iiiDiv]

    • The combination of dabrafenib and trametinib received approval for patients with NSCLC whose tumors harbor BRAF V600E mutations as detected by an FDA-approved test.

    Immunotherapy

    Nivolumab is a fully human monoclonal antibody that inhibits the programmed death-1 (PD-1) co-inhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells.

    Pembrolizumab is a humanized monoclonal antibody that inhibits the interaction between the PD-1 co-inhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells and its ligands, PD-L1 and PD-L2.

    Atezolizumab is a PD-L1–blocking antibody.

    Nivolumab

    Evidence (nivolumab):

  • In two phase III clinical trials, one conducted in patients with advanced platinum-pretreated squamous NSCLC and the other trial conducted in patients with nonsquamous NSCLC, nivolumab demonstrated a significant improvement in OS compared with the previous standard treatment of docetaxel chemotherapy.
  • [Level of evidence:1iiA] In addition, the rates of grade 3 and 4 treatment-related toxicity in both trials were significantly lower with nivolumab than with docetaxel. Of note, all patients enrolled in phase III studies of nivolumab had an ECOG PS of 0 or 1; patients with autoimmune disease, symptomatic interstitial lung disease, or those receiving systemic immunosuppression were excluded from enrollment.
  • A randomized, open-label, phase III trial randomly assigned 272 advanced squamous cell NSCLC patients who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.
  • The primary endpoint of this study was OS.
  • Nivolumab demonstrated a significant improvement in median OS compared with docetaxel (9.2 months vs. 6 months; P < .001). In addition, the ORR (20% vs. 9%; P = .008) and median PFS (3.5 months vs. 2.8 months; P < .001) favored nivolumab.
  • Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 58% for nivolumab vs. 86% for docetaxel; grades 3–4, 7% for nivolumab vs. 55% for docetaxel).
  • A randomized, open-label, phase III trial randomly assigned 582 advanced nonsquamous NSCLC patients who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.
  • Previous maintenance chemotherapy after first-line platinum-doublet was allowed; patients with EGFR mutations or ALK translocations were allowed to have received an additional regimen of therapy with a TKI. The primary endpoint of this study was OS.
  • Nivolumab demonstrated a significant improvement in patients in median OS compared with docetaxel (12.2 months vs. 9.4 months; HR, 0.73; 96% CI, 0.59–0.89; P = .002). In this study, ORR (19% vs. 12%; P = .02) but not median PFS (2.3 months for nivolumab vs. 4.2 months for docetaxel) favored nivolumab. The median DOR in patients was 17.2 months for nivolumab and 5.6 months for docetaxel.
  • Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 69% for nivolumab vs. 88% for docetaxel; grades 3–4, 10% for nivolumab vs. 54% for docetaxel).
  • Both of these trials demonstrated long-term clinical benefit at the 2-year outcomes. The OS rates for nivolumab at 2 years compared with docetaxel in squamous NSCLC were 23% (95% CI, 16–30) versus 8% (95% CI, 4–13), and OS rates in nonsquamous NSCLC were 29% (95% CI, 24–34) versus 16% (95% CI, 12–20).
  • Ongoing responses at 2 years were observed in 10 (37%) confirmed responders with squamous NSCLC and 19 (34%) of 56 responders with nonsquamous NSCLC. No patient treated with docetaxel in either study had an ongoing response.

    • Nivolumab is now considered a standard second-line therapy for patients with metastatic NSCLC with progression on or after first-line platinum-based chemotherapy and is associated with improved survival and lower rates of toxicity than docetaxel. However, clinical trials of nivolumab to date have not enrolled patients with a history of autoimmune disease, interstitial lung disease, or an ECOG PS higher than 1. Patients with active autoimmune conditions cannot be treated with nivolumab. Closely monitoring all patients for autoimmune toxicities from treatment is required. Specific algorithms for the management of autoimmune toxicity are included in the FDA label for nivolumab.

    Pembrolizumab

    Evidence (pembrolizumab):

  • In a phase I study with multiple expansion cohorts, pembrolizumab demonstrated significant activity with respect to response rate and DOR.
  • [Level of evidence: 3iiiDiv]
  • In the study, 495 patients received either pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. No significant differences were seen among the different treatment schedules. Key exclusion criteria were autoimmune disease, history of pneumonitis, requirement for systemic immunosuppressive therapy, and a PS higher than 1. The ORR was 19.4% (95% CI, 16.0–23.2), which included a response rate of 18.0% (95% CI, 14.4–22.2) in 394 previously treated patients and 24.8% (95% CI, 16.7–34.3) in 101 previously untreated patients. Median PFS was 3.7 months (95% CI, 2.9–4.1) for all patients, 3.0 months (95% CI, 2.2–4.0) for previously treated patients, and 6.0 months (95% CI, 4.1–8.6) for previously untreated patients. The median DOR was 12.5 months (range, 1.0–23.3 months) in all patients.
  • The study evaluated the efficacy of pembrolizumab in patients with high levels of PD-L1, as assessed by the anti-PD-L1 antibody clone 22C3. Using the cutoff of membranous staining in at least 50% of tumor cells in a validation group of 73 patients, the response rate was 45.2% (95% CI, 33.5–57.3), and the median PFS in this group was 6.3 months (95% CI, 2.9–12.5). Median OS was not reached at the time of publication.
  • The estimated prevalence of PD-L1 tumor staining from 1,143 screened patients, of whom 824 had evaluable samples, is as follows: 23.2% had 50% or more tumor cells with staining; 37.6% had between 1% and 49% tumor cells with staining; and 39.2% had less than 1% of tumor cells with staining.
  • The most common adverse events were fatigue, pruritus, and decreased appetite. Grade 3 or higher adverse events were reported in 9.5% of patients. Inflammatory and immune-mediated adverse events that occurred in more than 2% of patients were infusion-related reactions (3.0%), hypothyroidism (6.9%), and pneumonitis (3.6%).
  • In a phase II/III randomized clinical trial, patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells were randomly assigned (1:1:1) to receive pembrolizumab (2 mg/kg), pembrolizumab (10 mg/kg), or docetaxel (75 mg/m2) every 3 weeks.
  • [Level of evidence: 1iiA] The primary endpoints were OS and PFS in the total population and in patients with PD-L1 expression on at least 50% of tumor cells. This study enrolled 1,034 patients; 345 of them were allocated to pembrolizumab (2 mg/kg); 346 were allocated to pembrolizumab (10 mg/kg); and 343 were allocated to docetaxel.
  • In the total population, median OS was 10.4 months with pembrolizumab (2 mg/kg), 12.7 months with pembrolizumab (10 mg/kg), and 8.5 months with docetaxel. OS was significantly longer for pembrolizumab (2 mg/kg) versus docetaxel (HR 0.71; 95% CI, 0.58–0.88; P = .0008) and for pembrolizumab (10 mg/kg) versus docetaxel (HR, 0.61; CI, 0.49–0.75; P < .0001).
  • In the total population, PFS was not prolonged in the pembrolizumab groups compared with the docetaxel group.
  • Among patients with at least 50% of tumor cells expressing PD-L1, OS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 14.9 months vs. 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P = .0002) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 17.3 months vs. 8.2 months; HR, 0.50; CI, 0.36–0.70; P < .0001).
  • In the group of patients with at least 50% of tumor cells expressing PD-L1, PFS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 5.0 months vs. 4.1 months; HR, 0.59; 95% CI, 0.44–0.78; P = .0001) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 5.2 months vs. 4.1 months; HR, 0.59; CI, 0.45–0.78; P < .0001).
  • Grade 3 to 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given pembrolizumab (2 mg/kg), 55 [16%] of 343 patients given pembrolizumab (10 mg/kg), and 109 [35%] of 309 patients given docetaxel).

    • Pembrolizumab received accelerated approval as a second-line therapy for patients with NSCLC whose tumors express PD-L1 (>50% staining as determined by an FDA-approved test) with progression on or after first-line chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapies before receiving pembrolizumab (refer to the FDA label for pembrolizumab).

    Atezolizumab

    Evidence (atezolizumab):

  • Two international, randomized, open-label clinical trials (OAK [NCT02008227] and POPLAR [NCT01903993]) demonstrated efficacy and safety in a total of 1,137 patients with NSCLC who previously received platinum chemotherapy.
  • [Level of evidence: 1iiA] Compared with docetaxel, treatment with atezolizumab in the intended patient population resulted in improved OS rates of 4.2 months in the OAK study and 2.9 months in the POPLAR study.
  • In the OAK trial, the median OS was 13.8 months in the atezolizumab arm (95% CI, 11.8–15.7) compared with 9.6 months in the docetaxel arm (95% CI, 8.6–11.2) (HR = 0.74; 95% CI, 0.63–0.87; P = .0004).
  • The median OS in the POPLAR trial was 12.6 months in the atezolizumab arm (95% CI, 9.7–16.0) and 9.7 months in the docetaxel arm (95% CI, 8.6–12.0) (HR, 0.69; 95% CI, 0.52–0.92).
  • Although the magnitude of improvement correlated with PD-L1 immunohistochemistry expression on tumor cells and tumor-infiltrating immune cells, survival benefit with atezolizumab was seen in patients with tumors with and without PD-L1 expression.
  • In the POPLAR trial, the most common (≥20%) adverse reactions were in patients treated with atezolizumab and included fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation.
  • The most common (≥2%) grade 3 to 4 adverse events in patients treated with atezolizumab were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia.
  • Clinically significant immune-related adverse events for patients receiving atezolizumab included pneumonitis, hepatitis, colitis, and thyroid disease.

    • Treatment Options under Clinical Evaluation for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)

    Treatment options under clinical evaluation for progressive stage IV, relapsed, and recurrent NSCLC (second-line therapy) include the following:

  • Clinical trials can be considered as second-line therapy.

    • Current Clinical Trials

    Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  • Ciuleanu T, Stelmakh L, Cicenas S, et al.: Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 13 (3): 300-8, 2012.
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  • Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22 (6): 1103-9, 2004.
  • Paez JG, Jänne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (5676): 1497-500, 2004.
  • Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (21): 2129-39, 2004.
  • Pao W, Miller V, Zakowski M, et al.: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (36): 13306-11, 2004.
  • Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2 (1): e17, 2005.
  • Tsao MS, Sakurada A, Cutz JC, et al.: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 353 (2): 133-44, 2005.
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  • Clark GM, Zborowski DM, Culbertson JL, et al.: Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1 (8): 837-46, 2006.
  • Soria JC, Felip E, Cobo M, et al.: Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 16 (8): 897-907, 2015.
  • Mok TS, Wu Y-L, Ahn M-J, et al.: Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 376 (7): 629-640, 2017.
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  • Kim DW, Tiseo M, Ahn MJ, et al.: Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol 35 (22): 2490-2498, 2017.
  • Gainor JF, Shaw AT: Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18 (7): 865-75, 2013.
  • Shaw AT, Ou SH, Bang YJ, et al.: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371 (21): 1963-71, 2014.
  • Wu YL, Yang JC, Kim DW, et al.: Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 36 (14): 1405-1411, 2018.
  • Planchard D, Besse B, Groen HJM, et al.: Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 17 (7): 984-993, 2016.
  • Brahmer J, Reckamp KL, Baas P, et al.: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373 (2): 123-35, 2015.
  • Borghaei H, Paz-Ares L, Horn L, et al.: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373 (17): 1627-39, 2015.
  • Garon EB, Rizvi NA, Hui R, et al.: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372 (21): 2018-28, 2015.
  • Horn L, Spigel DR, Vokes EE, et al.: Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). J Clin Oncol 35 (35): 3924-3933, 2017.
  • Herbst RS, Baas P, Kim DW, et al.: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387 (10027): 1540-50, 2016.
  • Rittmeyer A, Barlesi F, Waterkamp D, et al.: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389 (10066): 255-265, 2017.
  • Fehrenbacher L, Spira A, Ballinger M, et al.: Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387 (10030): 1837-46, 2016.
    • 非小细胞肺癌治疗(PDQ®)

    该总结变更内容（01/27/2020）

    定期审查PDQ癌症信息总结内容，并在获得最新信息后进行更新。 本章节描述了截至上述日期对本总结所做的最新变更。

    更新了2020年估计的新发病例和死亡病例的统计数据（引用美国癌症协会的数据作为参考文献1）。

    本总结由PDQ成人治疗编辑委员会撰写并维护，其编辑内容独立于NCI。 总结反映了独立审查文献，不代表NCI或NIH的政策声明。 如需了解更多关于总结政策和PDQ编辑委员会在维护PDQ总结内容中作用的信息，请参见有关“本PDQ总结”和“PDQ®-NCI综合癌症数据库”页。

    Non-Small Cell Lung Cancer Treatment (PDQ®)

    Changes to This Summary (01/27/2020)

    The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

    Updated statistics with estimated new cases and deaths for 2020 (cited American Cancer Society as reference 1).

    This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

    非小细胞肺癌治疗(PDQ®)

    About This PDQ Summary

    Purpose of This Summary

    This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

    Reviewers and Updates

    This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

    Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

    • Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

    The lead reviewers for Non-Small Cell Lung Cancer Treatment are:

  • Janet Dancey, MD, FRCPC（加拿大安大略省癌症研究所与NCIC临床试验组）
  • Patrick Forde, MD（约翰霍普金斯大学Sidney Kimmel综合癌症中心）
  • Raymond Mak, MDHa（哈佛医学院）
  • Arun Rajan, MD（美国国家癌症研究所）
  • Eva Szabo, MD（美国国家癌症研究所）

    • Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

    Levels of Evidence

    Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

    Permission to Use This Summary

    PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

    The preferred citation for this PDQ summary is:

    PDQ® Adult Treatment Editorial Board. PDQ Non-Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Accessed . [PMID: 26389304]

    Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

    Disclaimer

    Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

    Contact Us

    More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

    Non-Small Cell Lung Cancer Treatment (PDQ®)

    About This PDQ Summary

    Purpose of This Summary

    This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

    Reviewers and Updates

    This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

    Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

    • Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

    The lead reviewers for Non-Small Cell Lung Cancer Treatment are:

  • Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
  • Patrick Forde, MD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins)
  • Raymond Mak, MD (Harvard Medical School)
  • Arun Rajan, MD (National Cancer Institute)
  • Eva Szabo, MD (National Cancer Institute)

    • Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

    Levels of Evidence

    Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

    Permission to Use This Summary

    PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

    The preferred citation for this PDQ summary is:

    PDQ® Adult Treatment Editorial Board. PDQ Non-Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Accessed . [PMID: 26389304]

    Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

    Disclaimer

    Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

    Contact Us

    More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

    < 1 2 3 4 5 6 7 8 9 10 11 12 13 14 >
    目录
    章 节
    非小细胞肺癌（NSCLC）的基本信息 NSCLC的细胞学分类 NSCLC的分期信息 NSCLC的治疗选择概述 隐匿性NSCLC治疗 0期NSCLC治疗 IA与IB期NSCLC治疗 IIA与IIB期NSCLC治疗 IIIA期NSCLC治疗 IIIB与IIIC期NSCLC治疗 新诊断的复发性IV期NSCLC治疗 进展的复发性IV期NSCLC治疗 该总结变更内容（01/27/2020） About This PDQ Summary
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