|
你现在的位置: 首页 > 癌症医典(结直肠癌) > 结肠癌治疗
中文版 / English
结肠癌治疗(PDQ®)

结肠癌的基本信息

结肠癌的治愈率非常高，特别是局限性的结肠癌。外科手术是主要的治疗手段，治愈率约50%，手术后的复发是一个主要问题，也是导致患者死亡的常见原因。

发病率和死亡率

2020年美国结直肠癌的预期新发病例和死亡病例：

  • 新发病例：104610（仅结肠癌）。
  • 直肠癌新发病例：43340。
  • 死亡病例：53200（结肠癌和直肠癌）。

    • 据估计，2015年中国国结直肠癌的新发病例和死亡病例：

  • 新发病例：38.8万（结直肠癌）
  • 死亡病例：18.7万（结直肠癌）
    • 胃肠道间质瘤可发于结肠（更多信息，请参考PDQ摘要关于“胃肠道间质瘤治疗（成人）”部分内容。）

    解剖

    下消化道系统解剖。

    风险因素

    年龄的增长是大多数癌症的一个最重要的风险因素。结直肠癌的其他风险因素包括：

  • 直系亲属患结直肠癌的家族史。
  • 结直肠腺瘤、结直肠癌或卵巢癌的既往史。
  • 遗传性疾病，如家族性腺瘤性息肉病（FAP）和林奇综合征（遗传性非息肉样结直肠癌[HNPCC]）。
  • 长期慢性溃疡性结肠炎或克罗恩病的既往史。
  • 酗酒史。
  • 吸烟史。
  • 种族/民族：非裔美国人。
  • 肥胖。

    • 筛查

    鉴于结肠癌的发病率、高危险人群的鉴别能力、原发灶生长缓慢、早期患者较好的生存期以及筛查的简便性和准确性等因素，建议将结肠癌筛查作为50岁及以上成年人的常规体检项目，特别是有直系亲属结直肠癌家族史的人群。（更多信息，请参考PDQ摘要关于“结直肠癌筛查”部分内容。）

    预后因素

    结肠癌患者的预后明确与以下因素相关：

  • 肿瘤浸润肠壁的程度。
  • 有无淋巴结受累。
  • 有无远处转移。

    • 上述三点也是结肠癌所有分期体系的基础。

    影响预后的其他因素还包括：

  • 肠梗阻和肠穿孔常提示预后差。
  • 治疗前血清癌胚抗原（CEA）升高常提示预后不佳。

    • 曾有回顾性分析对结肠癌患者的预后指标进行研究，结果显示最常见的是18q染色体等位缺失、胸苷酸合成酶表达异常，但尚未得到前瞻性研究证实。

    一项以病例为基础的607例结直肠癌患者（年龄50岁以下）的研究结果显示，与HNPCC相关的微卫星不稳定常预示生存期良好，而与肿瘤的临床分期无关。

    在以病期分级的生存期分析中，HNPCC患者的预后优于散发性结肠癌患者。但由于此类研究的属于回顾性，而且可能选择了特定的因素，所以很难对结果进行合理解释。

    制定临床治疗决策是基于临床医生和患者个人的倾向以及疾病的临床分期，而与患者年龄无关。

    已有相关报道分析了种族对辅助治疗后总体生存期的影响，结果显示不同种族患者的无疾病生存期无明显差异。结果还指出在不同患者群体中，伴发病对生存具有重要意义。

    随诊和监测

    由于临床数据有限及缺少1级循证依据，很难指导患者和医生对术后和辅助治疗后进行监测和管理。美国临床肿瘤学会和美国综合癌症网络推荐有指定的监测和随诊方案。

    结肠癌治疗后，定期评估有助于早期发现和早期诊治肿瘤复发。

    仅有少数患者的转移灶较为局限，具有治愈可能，因此，对复发性结肠癌患者总体死亡率的监测意义非常有限。迄今为止，尚未有大规模的随机临床试验证实标准的术后监测能延长总体生存期，

    CEA是一类血清糖蛋白质，常见于结肠癌患者管理中。一篇综述就肿瘤标志物的临床应用，提出以下几点建议：

  • 由于大量CEA假阳性和假阴性的报告，CEA检测并不是结直肠癌的有效筛查手段。
  • 术后CEA检测应仅限于有可能行肝或肺转移瘤切除的患者。
  • 不建议仅将CEA水平作为监测临床治疗反应的常规手段。

    • 最佳随访方案和检查的频次尚未得到确定，主要是由于随访对患者生存期的影响并不清楚以及相关的数据的质量不高。

    复发的影响因素

    饮食和锻炼

    尚未有前瞻性随机临床试验证实特定的饮食和运动方案能改善患者的临床结局，但有队列研究提出饮食和锻炼方案可能会改善结局。队列研究含有潜在偏倚可能，应用此类数据时需谨慎。

    已有两项前瞻性观察性研究对癌症和白血病工作组B（临床试验 CALGB-89803[NCT00003835]）招募的患者进行分析，本项临床试验主要探索在III期结肠癌患者中应用辅助化疗。

    本项试验中，将处于西方饮食模式中最低五分之一层与最高五分之一层的患者进行对比，无病生存期的校正风险比（HR）为3.25（95% CI，2.04–5.19；P<0.001），总体生存期的风险比为2.32（95% CI，1.36–3.96；P<0.001）。此外，结果还显示，饮食血糖负荷最高的五分之一的III期结肠癌患者与饮食血糖负荷最低的五分之一的结肠癌患者相比，总体生存期的校正风险比为1.76（95% CI，1.22-2.54；P<0.001）。之后，在癌症预防研究II期营养学队列中， 2315例结肠癌患者发病前摄入红肉和加工肉可增加死亡风险（相对风险比[RR]，95% CI， 1.05-1.59；P=0.03），但确诊后摄入红肉与总体死亡率无相关性。

    [循证等级：3iiA]

    一项荟萃分析，共纳入7项评估结直肠癌患者确诊前后运动状况的前瞻性队列研究。结果显示，与从不运动的患者相比，确诊前常运动患者的结直肠癌特异性死亡率的RR为0.75（95% CI，0.65–0.87；P<0.001）。

    确诊前进行高强度运动癌症患者与低强度运动患者相比，其RR为0.70（95% CI，0.56–0.87；P=0.002）。确诊后常运动患者与不运动患者相比患者的结直肠癌特异死亡率RR为0.74（95% CI，0.58–0.95；P=0.02）。确诊后高强度运动患者与低强度运动患者相比，其RR为0.65（95% CI，0.47-0.92；P=0.01）。

    [循证等级：3iiB]

    阿司匹林

    一项前瞻性队列研究探讨了结直肠癌患者确诊后应用阿司匹林的影响。

    确诊结直肠癌后，常规使用阿司匹林的患者结肠直癌特异性死亡率的HR为0.71（95% CI，0.65–0.97），总体生存期的HR为0.79（95% CI，0.65–0.97）。

    [循证等级：3iiA] 护士健康研究和医务人员随诊研究针对964例结直肠癌患者进行了评估。

    结直肠癌伴PI3K突变的患者常规使用阿司匹林，其总体生存期的HR为0.54（95% CI，0.31-0.94，P=0.01）

    [循证依据等级：3iiA]

    相关摘要

    其他与结肠癌相关的PDQ总结还包括：

  • 结直肠癌预防
  • 结直肠癌筛查
  • 结直肠癌的基因组学
  • 儿童罕见癌症的治疗（儿童结肠癌）

    • 参考文献

  • American Cancer Society: Cancer Facts and Figures 2020. Atlanta, Ga: American Cancer Society, 2020. Available online. Last accessed January 17, 2020.
  • Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001.
  • Imperiale TF, Juluri R, Sherer EA, et al.: A risk index for advanced neoplasia on the second surveillance colonoscopy in patients with previous adenomatous polyps. Gastrointest Endosc 80 (3): 471-8, 2014.
  • Singh H, Nugent Z, Demers A, et al.: Risk of colorectal cancer after diagnosis of endometrial cancer: a population-based study. J Clin Oncol 31 (16): 2010-5, 2013.
  • Srinivasan R, Yang YX, Rubin SC, et al.: Risk of colorectal cancer in women with a prior diagnosis of gynecologic malignancy. J Clin Gastroenterol 41 (3): 291-6, 2007.
  • Mork ME, You YN, Ying J, et al.: High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer. J Clin Oncol 33 (31): 3544-9, 2015.
  • Laukoetter MG, Mennigen R, Hannig CM, et al.: Intestinal cancer risk in Crohn's disease: a meta-analysis. J Gastrointest Surg 15 (4): 576-83, 2011.
  • Fedirko V, Tramacere I, Bagnardi V, et al.: Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol 22 (9): 1958-72, 2011.
  • Liang PS, Chen TY, Giovannucci E: Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer 124 (10): 2406-15, 2009.
  • Laiyemo AO, Doubeni C, Pinsky PF, et al.: Race and colorectal cancer disparities: health-care utilization vs different cancer susceptibilities. J Natl Cancer Inst 102 (8): 538-46, 2010.
  • Lansdorp-Vogelaar I, Kuntz KM, Knudsen AB, et al.: Contribution of screening and survival differences to racial disparities in colorectal cancer rates. Cancer Epidemiol Biomarkers Prev 21 (5): 728-36, 2012.
  • Ma Y, Yang Y, Wang F, et al.: Obesity and risk of colorectal cancer: a systematic review of prospective studies. PLoS One 8 (1): e53916, 2013.
  • Steinberg SM, Barkin JS, Kaplan RS, et al.: Prognostic indicators of colon tumors. The Gastrointestinal Tumor Study Group experience. Cancer 57 (9): 1866-70, 1986.
  • Filella X, Molina R, Grau JJ, et al.: Prognostic value of CA 19.9 levels in colorectal cancer. Ann Surg 216 (1): 55-9, 1992.
  • McLeod HL, Murray GI: Tumour markers of prognosis in colorectal cancer. Br J Cancer 79 (2): 191-203, 1999.
  • Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331 (4): 213-21, 1994.
  • Lanza G, Matteuzzi M, Gafá R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79 (4): 390-5, 1998.
  • Griffin MR, Bergstralh EJ, Coffey RJ, et al.: Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 60 (9): 2318-24, 1987.
  • Johnston PG, Fisher ER, Rockette HE, et al.: The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12 (12): 2640-7, 1994.
  • Shibata D, Reale MA, Lavin P, et al.: The DCC protein and prognosis in colorectal cancer. N Engl J Med 335 (23): 1727-32, 1996.
  • Bauer KD, Lincoln ST, Vera-Roman JM, et al.: Prognostic implications of proliferative activity and DNA aneuploidy in colonic adenocarcinomas. Lab Invest 57 (3): 329-35, 1987.
  • Bauer KD, Bagwell CB, Giaretti W, et al.: Consensus review of the clinical utility of DNA flow cytometry in colorectal cancer. Cytometry 14 (5): 486-91, 1993.
  • Sun XF, Carstensen JM, Zhang H, et al.: Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma. Lancet 340 (8832): 1369-73, 1992.
  • Roth JA: p53 prognostication: paradigm or paradox? Clin Cancer Res 5 (11): 3345, 1999.
  • Gryfe R, Kim H, Hsieh ET, et al.: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342 (2): 69-77, 2000.
  • Watson P, Lin KM, Rodriguez-Bigas MA, et al.: Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 83 (2): 259-66, 1998.
  • Iwashyna TJ, Lamont EB: Effectiveness of adjuvant fluorouracil in clinical practice: a population-based cohort study of elderly patients with stage III colon cancer. J Clin Oncol 20 (19): 3992-8, 2002.
  • Chiara S, Nobile MT, Vincenti M, et al.: Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy. Cancer Chemother Pharmacol 42 (4): 336-40, 1998.
  • Popescu RA, Norman A, Ross PJ, et al.: Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 17 (8): 2412-8, 1999.
  • Dignam JJ, Colangelo L, Tian W, et al.: Outcomes among African-Americans and Caucasians in colon cancer adjuvant therapy trials: findings from the National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst 91 (22): 1933-40, 1999.
  • Meyerhardt JA, Mangu PB, Flynn PJ, et al.: Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 31 (35): 4465-70, 2013.
  • Benson AB, Bekaii-Saab T, Chan E, et al.: Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 11 (5): 519-28, 2013.
  • Martin EW, Minton JP, Carey LC: CEA-directed second-look surgery in the asymptomatic patient after primary resection of colorectal carcinoma. Ann Surg 202 (3): 310-7, 1985.
  • Bruinvels DJ, Stiggelbout AM, Kievit J, et al.: Follow-up of patients with colorectal cancer. A meta-analysis. Ann Surg 219 (2): 174-82, 1994.
  • Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Ann Surg 220 (2): 206-11, 1994.
  • Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Dis Colon Rectum 39 (3): 252-6, 1996.
  • Safi F, Link KH, Beger HG: Is follow-up of colorectal cancer patients worthwhile? Dis Colon Rectum 36 (7): 636-43; discussion 643-4, 1993.
  • Moertel CG, Fleming TR, Macdonald JS, et al.: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA 270 (8): 943-7, 1993.
  • Rosen M, Chan L, Beart RW, et al.: Follow-up of colorectal cancer: a meta-analysis. Dis Colon Rectum 41 (9): 1116-26, 1998.
  • Desch CE, Benson AB, Smith TJ, et al.: Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 17 (4): 1312, 1999.
  • Benson AB, Desch CE, Flynn PJ, et al.: 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 18 (20): 3586-8, 2000.
  • Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 14 (10): 2843-77, 1996.
  • Meyerhardt JA, Niedzwiecki D, Hollis D, et al.: Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA 298 (7): 754-64, 2007.
  • Meyerhardt JA, Sato K, Niedzwiecki D, et al.: Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst 104 (22): 1702-11, 2012.
  • McCullough ML, Gapstur SM, Shah R, et al.: Association between red and processed meat intake and mortality among colorectal cancer survivors. J Clin Oncol 31 (22): 2773-82, 2013.
  • Je Y, Jeon JY, Giovannucci EL, et al.: Association between physical activity and mortality in colorectal cancer: a meta-analysis of prospective cohort studies. Int J Cancer 133 (8): 1905-13, 2013.
  • Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302 (6): 649-58, 2009.
  • Liao X, Lochhead P, Nishihara R, et al.: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367 (17): 1596-606, 2012.
    • Colon Cancer Treatment (PDQ®)

    General Information About Colon Cancer

    Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of the patients. Recurrence following surgery is a major problem and is often the ultimate cause of death.

    Incidence and Mortality

    Estimated new cases and deaths from colon and rectal cancer in the United States in 2020:

  • New cases: 104,610 (colon cancer only).
  • New cases of rectal cancer: 43,340.
  • Deaths: 53,200 (colon and rectal cancers combined).

    • Gastrointestinal stromal tumors can occur in the colon. (Refer to the PDQ summary on Gastrointestinal Stromal Tumors Treatment (Adult) for more information.)

    Anatomy

    Anatomy of the lower gastrointestinal system.

    Risk Factors

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

  • Family history of colorectal cancer in a first-degree relative.
  • Personal history of colorectal adenomas, colorectal cancer, or ovarian cancer.
  • Hereditary conditions, including familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]).
  • Personal history of long-standing chronic ulcerative colitis or Crohn colitis.
  • Excessive alcohol use.
  • Cigarette smoking.
  • Race/ethnicity: African American.
  • Obesity.

    • Screening

    Because of the frequency of the disease, ability to identify high-risk groups, slow growth of primary lesions, better survival of patients with early-stage lesions, and relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults aged 50 years and older, especially for those with first-degree relatives with colorectal cancer. (Refer to the PDQ summary on Colorectal Cancer Screening for more information.)

    Prognostic Factors

    The prognosis of patients with colon cancer is clearly related to the following:

  • The degree of penetration of the tumor through the bowel wall.
  • The presence or absence of nodal involvement.
  • The presence or absence of distant metastases.

    • These three characteristics form the basis for all staging systems developed for this disease.

    Other prognostic factors include the following:

  • Bowel obstruction and bowel perforation are indicators of poor prognosis.
  • Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance.

    • Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated.

    Microsatellite instability, also associated with HNPCC, has been associated with improved survival independent of tumor stage in a population-based series of 607 patients younger than 50 years with colorectal cancer.

    Patients with HNPCC reportedly have better prognoses in stage-stratified survival analysis than patients with sporadic colorectal cancer, but the retrospective nature of the studies and possibility of selection factors make this observation difficult to interpret.

    Treatment decisions depend on factors such as physician and patient preferences and the stage of the disease, rather than the age of the patient.

    Racial differences in overall survival (OS) after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.

    Follow-up and Survivorship

    Limited data and no level 1 evidence are available to guide patients and physicians about surveillance and management of patients after surgical resection and adjuvant therapy. The American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend specific surveillance and follow-up strategies.

    Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.

    The impact of such monitoring on overall mortality of patients with recurrent colon cancer, however, is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, no large-scale randomized trials have documented an OS benefit for standard, postoperative monitoring programs.

    CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests the following:

  • A CEA level is not a valuable screening test for colorectal cancer because of the large numbers of false-positive and false-negative reports.
  • Postoperative CEA testing should be restricted to patients who would be candidates for resection of liver or lung metastases.
  • Routine use of CEA levels alone for monitoring response to treatment should not be recommended.

    • The optimal regimen and frequency of follow-up examinations are not well defined because the impact on patient survival is not clear and the quality of data is poor.

    Factors Associated with Recurrence

    Diet and exercise

    No prospective randomized trials have demonstrated an improvement in outcome with a specific diet or exercise regimen; however, cohort studies suggest that a diet or exercise regimen may improve outcome. The cohort studies contain multiple opportunities for unintended bias, and caution is needed when using the data from them.

    Two prospective observational studies were performed with patients enrolled on the Cancer and Leukemia Group B (CALGB-89803 [NCT00003835] trial), which was an adjuvant chemotherapy trial for patients with stage III colon cancer.

    In this trial, patients in the lowest quintile of the Western dietary pattern compared with those patients in the highest quintile experienced an adjusted hazard ratio (HR) for disease-free survival of 3.25 (95% confidence interval [CI], 2.04–5.19; P < .001) and an OS of 2.32 (95% CI, 1.36–3.96; P < .001). Additionally, findings included that stage III colon cancer patients in the highest quintile of dietary glycemic load experienced an adjusted HR for OS of 1.76 (95% CI, 1.22–2.54; P < .001) compared with those in the lowest quintile. Subsequently, in the Cancer Prevention Study II Nutrition Cohort, among 2,315 participants diagnosed with colorectal cancer, the degree of red and processed meat intake before diagnosis was associated with a higher risk of death (relative risk [RR], 1.29; 95% CI, 1.05–1.59; P = .03), but red meat consumption after diagnosis was not associated with overall mortality.

    [Level of evidence: 3iiA]

    A meta-analysis of seven prospective cohort studies evaluating physical activity before and after a diagnosis of colorectal cancer demonstrated that patients who participated in any amount of physical activity before diagnosis had a RR of 0.75 (95% CI, 0.65–0.87; P < .001) for colorectal cancer-specific mortality compared with patients who did not participate in any physical activity.

    Patients who participated in a high amount of physical activity (vs. a low amount) before diagnosis had a RR of 0.70 (95% CI, 0.56–0.87; P = .002). Patients who participated in any physical activity (compared with no activity) after diagnosis had a RR of 0.74 (95% CI, 0.58–0.95; P = .02) for colorectal cancer-specific mortality. Those who participated in a high amount of physical activity (vs. a low amount) after diagnosis had a RR of 0.65 (95% CI, 0.47–0.92; P = .01).

    [Level of evidence: 3iiB]

    Aspirin

    A prospective cohort study examined the use of aspirin after a colorectal cancer diagnosis.

    Regular users of aspirin after a diagnosis of colorectal cancer experienced an HR of colon cancer-specific survival of 0.71 (95% CI, 0.65–0.97) and an OS of 0.79 (95% CI, 0.65–0.97).

    [Level of evidence: 3iiA] One study evaluated 964 patients with rectal or colon cancer from the Nurse’s Health Study and the Health Professionals Follow-up Study.

    Among patients with PI3K-mutant colorectal cancer, regular use of aspirin was associated with an HR for OS of 0.54 (95% CI, 0.31–0.94; P = .01)

    [Level of evidence: 3iiiA]

    Related Summaries

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

  • Colorectal Cancer Prevention
  • Colorectal Cancer Screening
  • Genetics of Colorectal Cancer
  • Unusual Cancers of Childhood Treatment (childhood cancer of the colon)

    • ReferenceSection

  • American Cancer Society: Cancer Facts and Figures 2020. Atlanta, Ga: American Cancer Society, 2020. Available online. Last accessed January 17, 2020.
  • Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001.
  • Imperiale TF, Juluri R, Sherer EA, et al.: A risk index for advanced neoplasia on the second surveillance colonoscopy in patients with previous adenomatous polyps. Gastrointest Endosc 80 (3): 471-8, 2014.
  • Singh H, Nugent Z, Demers A, et al.: Risk of colorectal cancer after diagnosis of endometrial cancer: a population-based study. J Clin Oncol 31 (16): 2010-5, 2013.
  • Srinivasan R, Yang YX, Rubin SC, et al.: Risk of colorectal cancer in women with a prior diagnosis of gynecologic malignancy. J Clin Gastroenterol 41 (3): 291-6, 2007.
  • Mork ME, You YN, Ying J, et al.: High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer. J Clin Oncol 33 (31): 3544-9, 2015.
  • Laukoetter MG, Mennigen R, Hannig CM, et al.: Intestinal cancer risk in Crohn's disease: a meta-analysis. J Gastrointest Surg 15 (4): 576-83, 2011.
  • Fedirko V, Tramacere I, Bagnardi V, et al.: Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol 22 (9): 1958-72, 2011.
  • Liang PS, Chen TY, Giovannucci E: Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer 124 (10): 2406-15, 2009.
  • Laiyemo AO, Doubeni C, Pinsky PF, et al.: Race and colorectal cancer disparities: health-care utilization vs different cancer susceptibilities. J Natl Cancer Inst 102 (8): 538-46, 2010.
  • Lansdorp-Vogelaar I, Kuntz KM, Knudsen AB, et al.: Contribution of screening and survival differences to racial disparities in colorectal cancer rates. Cancer Epidemiol Biomarkers Prev 21 (5): 728-36, 2012.
  • Ma Y, Yang Y, Wang F, et al.: Obesity and risk of colorectal cancer: a systematic review of prospective studies. PLoS One 8 (1): e53916, 2013.
  • Steinberg SM, Barkin JS, Kaplan RS, et al.: Prognostic indicators of colon tumors. The Gastrointestinal Tumor Study Group experience. Cancer 57 (9): 1866-70, 1986.
  • Filella X, Molina R, Grau JJ, et al.: Prognostic value of CA 19.9 levels in colorectal cancer. Ann Surg 216 (1): 55-9, 1992.
  • McLeod HL, Murray GI: Tumour markers of prognosis in colorectal cancer. Br J Cancer 79 (2): 191-203, 1999.
  • Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331 (4): 213-21, 1994.
  • Lanza G, Matteuzzi M, Gafá R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79 (4): 390-5, 1998.
  • Griffin MR, Bergstralh EJ, Coffey RJ, et al.: Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 60 (9): 2318-24, 1987.
  • Johnston PG, Fisher ER, Rockette HE, et al.: The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12 (12): 2640-7, 1994.
  • Shibata D, Reale MA, Lavin P, et al.: The DCC protein and prognosis in colorectal cancer. N Engl J Med 335 (23): 1727-32, 1996.
  • Bauer KD, Lincoln ST, Vera-Roman JM, et al.: Prognostic implications of proliferative activity and DNA aneuploidy in colonic adenocarcinomas. Lab Invest 57 (3): 329-35, 1987.
  • Bauer KD, Bagwell CB, Giaretti W, et al.: Consensus review of the clinical utility of DNA flow cytometry in colorectal cancer. Cytometry 14 (5): 486-91, 1993.
  • Sun XF, Carstensen JM, Zhang H, et al.: Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma. Lancet 340 (8832): 1369-73, 1992.
  • Roth JA: p53 prognostication: paradigm or paradox? Clin Cancer Res 5 (11): 3345, 1999.
  • Gryfe R, Kim H, Hsieh ET, et al.: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342 (2): 69-77, 2000.
  • Watson P, Lin KM, Rodriguez-Bigas MA, et al.: Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 83 (2): 259-66, 1998.
  • Iwashyna TJ, Lamont EB: Effectiveness of adjuvant fluorouracil in clinical practice: a population-based cohort study of elderly patients with stage III colon cancer. J Clin Oncol 20 (19): 3992-8, 2002.
  • Chiara S, Nobile MT, Vincenti M, et al.: Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy. Cancer Chemother Pharmacol 42 (4): 336-40, 1998.
  • Popescu RA, Norman A, Ross PJ, et al.: Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 17 (8): 2412-8, 1999.
  • Dignam JJ, Colangelo L, Tian W, et al.: Outcomes among African-Americans and Caucasians in colon cancer adjuvant therapy trials: findings from the National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst 91 (22): 1933-40, 1999.
  • Meyerhardt JA, Mangu PB, Flynn PJ, et al.: Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 31 (35): 4465-70, 2013.
  • Benson AB, Bekaii-Saab T, Chan E, et al.: Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 11 (5): 519-28, 2013.
  • Martin EW, Minton JP, Carey LC: CEA-directed second-look surgery in the asymptomatic patient after primary resection of colorectal carcinoma. Ann Surg 202 (3): 310-7, 1985.
  • Bruinvels DJ, Stiggelbout AM, Kievit J, et al.: Follow-up of patients with colorectal cancer. A meta-analysis. Ann Surg 219 (2): 174-82, 1994.
  • Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Ann Surg 220 (2): 206-11, 1994.
  • Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Dis Colon Rectum 39 (3): 252-6, 1996.
  • Safi F, Link KH, Beger HG: Is follow-up of colorectal cancer patients worthwhile? Dis Colon Rectum 36 (7): 636-43; discussion 643-4, 1993.
  • Moertel CG, Fleming TR, Macdonald JS, et al.: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA 270 (8): 943-7, 1993.
  • Rosen M, Chan L, Beart RW, et al.: Follow-up of colorectal cancer: a meta-analysis. Dis Colon Rectum 41 (9): 1116-26, 1998.
  • Desch CE, Benson AB, Smith TJ, et al.: Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 17 (4): 1312, 1999.
  • Benson AB, Desch CE, Flynn PJ, et al.: 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 18 (20): 3586-8, 2000.
  • Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 14 (10): 2843-77, 1996.
  • Meyerhardt JA, Niedzwiecki D, Hollis D, et al.: Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA 298 (7): 754-64, 2007.
  • Meyerhardt JA, Sato K, Niedzwiecki D, et al.: Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst 104 (22): 1702-11, 2012.
  • McCullough ML, Gapstur SM, Shah R, et al.: Association between red and processed meat intake and mortality among colorectal cancer survivors. J Clin Oncol 31 (22): 2773-82, 2013.
  • Je Y, Jeon JY, Giovannucci EL, et al.: Association between physical activity and mortality in colorectal cancer: a meta-analysis of prospective cohort studies. Int J Cancer 133 (8): 1905-13, 2013.
  • Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302 (6): 649-58, 2009.
  • Liao X, Lochhead P, Nishihara R, et al.: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367 (17): 1596-606, 2012.
    • 结肠癌治疗(PDQ®)

    结肠癌的细胞学分类

    结肠癌的组织学分型包括：

  • 腺癌（结肠癌的主要类型）
  • 黏液（胶样）腺癌
  • 印戒细胞癌
  • 硬癌
  • 神经内分泌肿瘤。
  • 与单纯的腺癌类型相比，伴随神经内分泌样分化的肿瘤通常预后更差。

    • 参考文献

  • Saclarides TJ, Szeluga D, Staren ED: Neuroendocrine cancers of the colon and rectum. Results of a ten-year experience. Dis Colon Rectum 37 (7): 635-42, 1994.
    • Colon Cancer Treatment (PDQ®)

    Cellular Classification of Colon Cancer

    Histologic types of colon cancer include the following:

  • Adenocarcinoma (most colon cancers).
  • Mucinous (colloid) adenocarcinoma.
  • Signet ring adenocarcinoma.
  • Scirrhous tumors.
  • Neuroendocrine.
  • Tumors with neuroendocrine differentiation typically have a poorer prognosis than pure adenocarcinoma variants.

    • ReferenceSection

  • Saclarides TJ, Szeluga D, Staren ED: Neuroendocrine cancers of the colon and rectum. Results of a ten-year experience. Dis Colon Rectum 37 (7): 635-42, 1994.
    • 结肠癌治疗(PDQ®)

    结肠癌的临床分期

    制定临床决策时，应参考TNM（肿瘤、淋巴结和转移癌）分类，

    而不是早期的Dukes或改良版Astler-Coller分类标准。

    AJCC和一个美国国家癌症研究院资助的专家组建议，结肠癌和直肠癌患者至少应检查12个淋巴结以确认是否有淋巴结转移。

    此推荐考虑到检出的淋巴结数目反映了外科切除时淋巴血管和肠系膜的受侵程度以及标本中淋巴结的病理鉴定。回顾性研究表明，结直癌肠手术检查的淋巴结数目可能与患者的预后有关。

    AJCC临床分期和TNM定义

    AJCC采用TNM分类方法对结肠癌进行临床分期。

    同样的分类方法适用于临床分期和病理分期。

    表1. TNM 0 阶段的定义表2. TNM I 阶段的定义表3. TNM IIA, IIB, IIC 阶段的定义表4. TNM IIIA, IIIB, IIIC 阶段的定义表5. TNM IVA, IVB, IVC 阶段的定义
    分期TNM说明图示
    分期TNM说明图示
    分期TNM说明图示
    分期TNM说明图示
    分期TNM定义图示
    0Tis, N0, M0Tis=原位癌，粘膜内层癌（侵犯固有层，但未穿透黏膜肌层）。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    分期TNM说明图示
    IT1, T2, N0, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不负责该范畴。）
    分期TNM说明图示
    IIAT3, N0, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    IIBT4a, N0, M0包括穿透肿瘤的严重肠穿孔，接着肿瘤通过炎症区域侵袭到脏层腹膜表层
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    IICT4b, N0, M0T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    分期TNM说明图示
    IIIAT1, N2a, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    N2a= 4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    T1–2, N1/N1c, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    IIIBT1–T2, N2b, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T2–T3, N2a, M0T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T3–T4a, N1/N1c, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    IIICT3–T4a, N2b, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4a, N2a, M0T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4b, N1–N2, M0T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2-3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    N2=4枚或以上区域淋巴结转移。
    –N2a= 4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    分期TNM定义图示
    IVA任何T、任何N、M1aTX=原发肿瘤无法评估。
    T0=无原发肿瘤证据。
    Tis=原位癌，粘膜内癌（侵犯固有层，但未穿透黏膜肌层）。
    T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，肿瘤通过炎症部位连续侵犯脏层腹膜表层）。
    –T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    NX=区域淋巴结无法评估。
    N0=无区域淋巴结转移。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2或3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现癌结节。
    N2=4枚或以上区域淋巴结转移。
    –N2a=4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M1a=单个部位或器官转移，未见腹膜转移。
    IVB任何T、任何N、M1b任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1b=2个或以上部位或器官转移，未见腹膜转移。
    IVC任何 T、任何 N、M1c任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1c=仅腹膜转移/伴随其他部位或器官转移。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    b T4中的直接侵犯，包括侵犯其他器官或穿透浆膜直接侵犯结直肠其他部位，并经内镜确诊（如通过盲肠癌侵犯乙状结肠），或腹膜后腹膜下癌，或穿透固有肌层直接侵犯其他器官和结构（如降结肠后壁肿瘤侵犯左肾或侧腹壁；或直肠中远端肿瘤侵犯前列腺、精索、宫颈和阴道）。
    c 肿瘤粘连于其他器官和结构，大体上归为cT4b。然而，如果镜下观察未见肿瘤粘连，按照肠壁侵犯深度归为pT1-4a。应将V和L分类标准用于鉴别是否伴血管和淋巴管侵犯，而PN预后影响因素应当用于神经侵犯。
    表2. TNM I 阶段的定义表3. TNM IIA, IIB, IIC 阶段的定义表4. TNM IIIA, IIIB, IIIC 阶段的定义表5. TNM IVA, IVB, IVC 阶段的定义
    分期TNM说明图示
    分期TNM说明图示
    分期TNM说明图示
    分期TNM定义图示
    IT1, T2, N0, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不负责该范畴。）
    分期TNM说明图示
    IIAT3, N0, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    IIBT4a, N0, M0包括穿透肿瘤的严重肠穿孔，接着肿瘤通过炎症区域侵袭到脏层腹膜表层
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    IICT4b, N0, M0T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    分期TNM说明图示
    IIIAT1, N2a, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    N2a= 4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    T1–2, N1/N1c, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    IIIBT1–T2, N2b, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T2–T3, N2a, M0T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T3–T4a, N1/N1c, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    IIICT3–T4a, N2b, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4a, N2a, M0T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4b, N1–N2, M0T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2-3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    N2=4枚或以上区域淋巴结转移。
    –N2a= 4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    分期TNM定义图示
    IVA任何T、任何N、M1aTX=原发肿瘤无法评估。
    T0=无原发肿瘤证据。
    Tis=原位癌，粘膜内癌（侵犯固有层，但未穿透黏膜肌层）。
    T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，肿瘤通过炎症部位连续侵犯脏层腹膜表层）。
    –T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    NX=区域淋巴结无法评估。
    N0=无区域淋巴结转移。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2或3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现癌结节。
    N2=4枚或以上区域淋巴结转移。
    –N2a=4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M1a=单个部位或器官转移，未见腹膜转移。
    IVB任何T、任何N、M1b任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1b=2个或以上部位或器官转移，未见腹膜转移。
    IVC任何 T、任何 N、M1c任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1c=仅腹膜转移/伴随其他部位或器官转移。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    b T4中的直接侵犯，包括侵犯其他器官或穿透浆膜直接侵犯结直肠其他部位，并经内镜确诊（如通过盲肠癌侵犯乙状结肠），或腹膜后腹膜下癌，或穿透固有肌层直接侵犯其他器官和结构（如降结肠后壁肿瘤侵犯左肾或侧腹壁；或直肠中远端肿瘤侵犯前列腺、精索、宫颈和阴道）。
    c 肿瘤粘连于其他器官和结构，大体上归为cT4b。然而，如果镜下观察未见肿瘤粘连，按照肠壁侵犯深度归为pT1-4a。应将V和L分类标准用于鉴别是否伴血管和淋巴管侵犯，而PN预后影响因素应当用于神经侵犯。
    表3. TNM IIA, IIB, IIC 阶段的定义表4. TNM IIIA, IIIB, IIIC 阶段的定义表5. TNM IVA, IVB, IVC 阶段的定义
    分期TNM说明图示
    分期TNM说明图示
    分期TNM定义图示
    IIAT3, N0, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    IIBT4a, N0, M0包括穿透肿瘤的严重肠穿孔，接着肿瘤通过炎症区域侵袭到脏层腹膜表层
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    IICT4b, N0, M0T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    N0=无区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    分期TNM说明图示
    IIIAT1, N2a, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    N2a= 4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    T1–2, N1/N1c, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    IIIBT1–T2, N2b, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T2–T3, N2a, M0T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T3–T4a, N1/N1c, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    IIICT3–T4a, N2b, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4a, N2a, M0T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4b, N1–N2, M0T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2-3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    N2=4枚或以上区域淋巴结转移。
    –N2a= 4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    分期TNM定义图示
    IVA任何T、任何N、M1aTX=原发肿瘤无法评估。
    T0=无原发肿瘤证据。
    Tis=原位癌，粘膜内癌（侵犯固有层，但未穿透黏膜肌层）。
    T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，肿瘤通过炎症部位连续侵犯脏层腹膜表层）。
    –T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    NX=区域淋巴结无法评估。
    N0=无区域淋巴结转移。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2或3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现癌结节。
    N2=4枚或以上区域淋巴结转移。
    –N2a=4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M1a=单个部位或器官转移，未见腹膜转移。
    IVB任何T、任何N、M1b任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1b=2个或以上部位或器官转移，未见腹膜转移。
    IVC任何 T、任何 N、M1c任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1c=仅腹膜转移/伴随其他部位或器官转移。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    b T4中的直接侵犯，包括侵犯其他器官或穿透浆膜直接侵犯结直肠其他部位，并经内镜确诊（如通过盲肠癌侵犯乙状结肠），或腹膜后腹膜下癌，或穿透固有肌层直接侵犯其他器官和结构（如降结肠后壁肿瘤侵犯左肾或侧腹壁；或直肠中远端肿瘤侵犯前列腺、精索、宫颈和阴道）。
    c 肿瘤粘连于其他器官和结构，大体上归为cT4b。然而，如果镜下观察未见肿瘤粘连，按照肠壁侵犯深度归为pT1-4a。应将V和L分类标准用于鉴别是否伴血管和淋巴管侵犯，而PN预后影响因素应当用于神经侵犯。
    表4. TNM IIIA, IIIB, IIIC 阶段的定义表5. TNM IVA, IVB, IVC 阶段的定义
    分期TNM说明图示
    分期TNM定义图示
    IIIAT1, N2a, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    N2a= 4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    T1–2, N1/N1c, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分）
    IIIBT1–T2, N2b, M0T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T2–T3, N2a, M0T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T3–T4a, N1/N1c, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    IIICT3–T4a, N2b, M0T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4a, N2a, M0T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，并通过炎症部位连续侵犯脏层腹膜表层）。
    N2a=4-6枚区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    T4b, N1–N2, M0T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2-3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现肿瘤沉积。
    N2=4枚或以上区域淋巴结转移。
    –N2a= 4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M0=影像检查等未见远处转移；未见远处部位或器官转移证据。（病理科医生不对M分期进行划分。）
    分期TNM定义图示
    IVA任何T、任何N、M1aTX=原发肿瘤无法评估。
    T0=无原发肿瘤证据。
    Tis=原位癌，粘膜内癌（侵犯固有层，但未穿透黏膜肌层）。
    T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，肿瘤通过炎症部位连续侵犯脏层腹膜表层）。
    –T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    NX=区域淋巴结无法评估。
    N0=无区域淋巴结转移。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2或3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现癌结节。
    N2=4枚或以上区域淋巴结转移。
    –N2a=4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M1a=单个部位或器官转移，未见腹膜转移。
    IVB任何T、任何N、M1b任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1b=2个或以上部位或器官转移，未见腹膜转移。
    IVC任何 T、任何 N、M1c任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1c=仅腹膜转移/伴随其他部位或器官转移。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    上标b和c的释义参见表5末尾。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    b T4中的直接侵犯，包括侵犯其他器官或穿透浆膜直接侵犯结直肠其他部位，并经内镜确诊（如通过盲肠癌侵犯乙状结肠），或腹膜后腹膜下癌，或穿透固有肌层直接侵犯其他器官和结构（如降结肠后壁肿瘤侵犯左肾或侧腹壁；或直肠中远端肿瘤侵犯前列腺、精索、宫颈和阴道）。
    c 肿瘤粘连于其他器官和结构，大体上归为cT4b。然而，如果镜下观察未见肿瘤粘连，按照肠壁侵犯深度归为pT1-4a。应将V和L分类标准用于鉴别是否伴血管和淋巴管侵犯，而PN预后影响因素应当用于神经侵犯。
    表5. TNM IVA, IVB, IVC 阶段的定义
    分期TNM定义图示
    IVA任何T、任何N、M1aTX=原发肿瘤无法评估。
    T0=无原发肿瘤证据。
    Tis=原位癌，粘膜内癌（侵犯固有层，但未穿透黏膜肌层）。
    T1=肿瘤侵犯黏膜下层（穿透黏膜肌层，但未穿透固有肌层）。
    T2=肿瘤侵犯固有肌层。
    T3=肿瘤穿透固有肌层进入结直肠旁组织。
    T4=肿瘤直接侵犯或粘连于相邻器官或结构。
    –T4a=肿瘤穿透脏层腹膜（包括肿瘤穿透肠壁，肿瘤通过炎症部位连续侵犯脏层腹膜表层）。
    –T4b=肿瘤直接侵犯或粘连于相邻器官或结构。
    NX=区域淋巴结无法评估。
    N0=无区域淋巴结转移。
    N1=1-3枚区域淋巴结转移（淋巴结内肿瘤≥0.2mm），或任意数目的淋巴结出现肿瘤沉积且可识别的淋巴结均为阴性。
    –N1a=1枚区域淋巴结转移。
    –N1b=2或3枚区域淋巴结转移。
    –N1c=无区域淋巴结转移，但浆膜下、肠系膜或无腹膜覆盖的结肠旁组织，或直肠旁/直肠系膜组织出现癌结节。
    N2=4枚或以上区域淋巴结转移。
    –N2a=4-6枚区域淋巴结转移。
    –N2b=7枚或以上区域淋巴结转移。
    M1a=单个部位或器官转移，未见腹膜转移。
    IVB任何T、任何N、M1b任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1b=2个或以上部位或器官转移，未见腹膜转移。
    IVC任何 T、任何 N、M1c任何T=见上述关于任何肿瘤、任何区域淋巴结、M1a TNM分期组中的T说明部分。
    任何N=见上述关于任何肿瘤、任何区域淋巴结1、M1a TNM分期组中的N说明部分。
    M1c=仅腹膜转移/伴随其他部位或器官转移。
    T=原发肿瘤；N=局部淋巴结；M=远处转移。
    AJCC复印许可：Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74。
    b T4中的直接侵犯，包括侵犯其他器官或穿透浆膜直接侵犯结直肠其他部位，并经内镜确诊（如通过盲肠癌侵犯乙状结肠），或腹膜后腹膜下癌，或穿透固有肌层直接侵犯其他器官和结构（如降结肠后壁肿瘤侵犯左肾或侧腹壁；或直肠中远端肿瘤侵犯前列腺、精索、宫颈和阴道）。
    c 肿瘤粘连于其他器官和结构，大体上归为cT4b。然而，如果镜下观察未见肿瘤粘连，按照肠壁侵犯深度归为pT1-4a。应将V和L分类标准用于鉴别是否伴血管和淋巴管侵犯，而PN预后影响因素应当用于神经侵犯。

    参考文献

  • Jessup J, Benson A, Chen V: Colon and Rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
  • Compton CC, Greene FL: The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54 (6): 295-308, 2004 Nov-Dec.
  • Nelson H, Petrelli N, Carlin A, et al.: Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 93 (8): 583-96, 2001.
  • Swanson RS, Compton CC, Stewart AK, et al.: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10 (1): 65-71, 2003 Jan-Feb.
  • Le Voyer TE, Sigurdson ER, Hanlon AL, et al.: Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 21 (15): 2912-9, 2003.
  • Prandi M, Lionetto R, Bini A, et al.: Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 235 (4): 458-63, 2002.
  • Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19 (1): 157-63, 2001.
    • Colon Cancer Treatment (PDQ®)

    Stage Information for Colon Cancer

    Treatment decisions can be made with reference to the TNM (tumor, node, metastasis) classification

    rather than to the older Dukes or the Modified Astler-Coller classification schema.

    The AJCC and a National Cancer Institute–sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor.

    This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.

    AJCC Stage Groupings and TNM Definitions

    The AJCC has designated staging by TNM classification to define colon cancer.

    The same classification is used for both clinical and pathologic staging.

    Table 1. Definitions of TNM Stage 0Table 2. Definitions of TNM Stage ITable 3. Definitions of TNM Stages IIA, IIB, and IICTable 4. Definitions of TNM Stages IIIA, IIIB, and IIICTable 5. Definitions of TNM Stages IVA, IVB, and IVC
    StageTNMDescription Illustration
    StageTNMDescriptionIllustration
    StageTNMDescriptionIllustration
    StageTNMDescription Illustration
    StageTNMDefinitionIllustration
    0Tis, N0, M0Tis = Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae).
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDescriptionIllustration
    IT1, T2, N0, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDescriptionIllustration
    IIAT3, N0, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIBT4a, N0, M0T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IICT4b, N0, M0T4b = Tumor directly invades or adheres to adjacent organs or structures.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDescription Illustration
    IIIAT1, N2a, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T1–2, N1/N1c, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIIBT1–T2, N2b, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T2–T3, N2a, M0T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T3–T4a, N1/N1c, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIICT3–T4a, N2b, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4a, N2a, M0T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4b, N1–N2, M0T4b = Tumor directly invades or adheres to adjacent organs or structures.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDefinitionIllustration
    IVAAny T, Any N, M1aTX = Primary tumor cannot be assessed.
    T0 = No evidence of primary tumor.
    Tis = Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae).
    T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    –T4b = Tumor directly invades or adheres to adjacent organs or structures.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M1a = Metastasis to one site or organ is identified without peritoneal metastasis.
    IVBAny T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1b = Metastasis to two or more sites or organs is identified without peritoneal metastasis.
    IVCAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1c = Metastasis to the peritoneal surface is identified alone or with other site or organ metastases.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    bDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
    cTumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN prognostic factor should be used for perineural invasion.
    Table 2. Definitions of TNM Stage ITable 3. Definitions of TNM Stages IIA, IIB, and IICTable 4. Definitions of TNM Stages IIIA, IIIB, and IIICTable 5. Definitions of TNM Stages IVA, IVB, and IVC
    StageTNMDescriptionIllustration
    StageTNMDescriptionIllustration
    StageTNMDescription Illustration
    StageTNMDefinitionIllustration
    IT1, T2, N0, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDescriptionIllustration
    IIAT3, N0, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIBT4a, N0, M0T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IICT4b, N0, M0T4b = Tumor directly invades or adheres to adjacent organs or structures.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDescription Illustration
    IIIAT1, N2a, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T1–2, N1/N1c, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIIBT1–T2, N2b, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T2–T3, N2a, M0T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T3–T4a, N1/N1c, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIICT3–T4a, N2b, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4a, N2a, M0T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4b, N1–N2, M0T4b = Tumor directly invades or adheres to adjacent organs or structures.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDefinitionIllustration
    IVAAny T, Any N, M1aTX = Primary tumor cannot be assessed.
    T0 = No evidence of primary tumor.
    Tis = Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae).
    T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    –T4b = Tumor directly invades or adheres to adjacent organs or structures.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M1a = Metastasis to one site or organ is identified without peritoneal metastasis.
    IVBAny T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1b = Metastasis to two or more sites or organs is identified without peritoneal metastasis.
    IVCAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1c = Metastasis to the peritoneal surface is identified alone or with other site or organ metastases.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    bDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
    cTumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN prognostic factor should be used for perineural invasion.
    Table 3. Definitions of TNM Stages IIA, IIB, and IICTable 4. Definitions of TNM Stages IIIA, IIIB, and IIICTable 5. Definitions of TNM Stages IVA, IVB, and IVC
    StageTNMDescriptionIllustration
    StageTNMDescription Illustration
    StageTNMDefinitionIllustration
    IIAT3, N0, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIBT4a, N0, M0T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IICT4b, N0, M0T4b = Tumor directly invades or adheres to adjacent organs or structures.
    N0 = No regional lymph node metastasis.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDescription Illustration
    IIIAT1, N2a, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T1–2, N1/N1c, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIIBT1–T2, N2b, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T2–T3, N2a, M0T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T3–T4a, N1/N1c, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIICT3–T4a, N2b, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4a, N2a, M0T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4b, N1–N2, M0T4b = Tumor directly invades or adheres to adjacent organs or structures.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDefinitionIllustration
    IVAAny T, Any N, M1aTX = Primary tumor cannot be assessed.
    T0 = No evidence of primary tumor.
    Tis = Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae).
    T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    –T4b = Tumor directly invades or adheres to adjacent organs or structures.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M1a = Metastasis to one site or organ is identified without peritoneal metastasis.
    IVBAny T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1b = Metastasis to two or more sites or organs is identified without peritoneal metastasis.
    IVCAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1c = Metastasis to the peritoneal surface is identified alone or with other site or organ metastases.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    bDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
    cTumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN prognostic factor should be used for perineural invasion.
    Table 4. Definitions of TNM Stages IIIA, IIIB, and IIICTable 5. Definitions of TNM Stages IVA, IVB, and IVC
    StageTNMDescription Illustration
    StageTNMDefinitionIllustration
    IIIAT1, N2a, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T1–2, N1/N1c, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIIBT1–T2, N2b, M0T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T2–T3, N2a, M0T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T3–T4a, N1/N1c, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    IIICT3–T4a, N2b, M0T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4a, N2a, M0T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    N2a = Four to six regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    T4b, N1–N2, M0T4b = Tumor directly invades or adheres to adjacent organs or structures.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M0 = No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
    StageTNMDefinitionIllustration
    IVAAny T, Any N, M1aTX = Primary tumor cannot be assessed.
    T0 = No evidence of primary tumor.
    Tis = Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae).
    T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    –T4b = Tumor directly invades or adheres to adjacent organs or structures.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M1a = Metastasis to one site or organ is identified without peritoneal metastasis.
    IVBAny T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1b = Metastasis to two or more sites or organs is identified without peritoneal metastasis.
    IVCAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1c = Metastasis to the peritoneal surface is identified alone or with other site or organ metastases.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    The explanations for superscripts b and c are at the end of Table 5.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    bDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
    cTumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN prognostic factor should be used for perineural invasion.
    Table 5. Definitions of TNM Stages IVA, IVB, and IVC
    StageTNMDefinitionIllustration
    IVAAny T, Any N, M1aTX = Primary tumor cannot be assessed.
    T0 = No evidence of primary tumor.
    Tis = Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae).
    T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
    T2 = Tumor invades the muscularis propria.
    T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
    T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure.
    –T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum).
    –T4b = Tumor directly invades or adheres to adjacent organs or structures.
    NX = Regional lymph nodes cannot be assessed.
    N0 = No regional lymph node metastasis.
    N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative.
    –N1a = One regional lymph node is positive.
    –N1b = Two or three regional lymph nodes are positive.
    –N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues.
    N2 = Four or more regional nodes are positive.
    –N2a = Four to six regional lymph nodes are positive.
    –N2b = Seven or more regional lymph nodes are positive.
    M1a = Metastasis to one site or organ is identified without peritoneal metastasis.
    IVBAny T, Any N, M1bAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1b = Metastasis to two or more sites or organs is identified without peritoneal metastasis.
    IVCAny T, Any N, M1cAny T = See T descriptions above in Any T, Any N, M1a TNM stage group.
    Any N = See N descriptions above in Any T, Any N1, M1a TNM stage group.
    M1c = Metastasis to the peritoneal surface is identified alone or with other site or organ metastases.
    T = primary tumor; N = regional lymph nodes; M = distant metastasis.
    aReprinted with permission from AJCC: Colon and rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
    bDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
    cTumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN prognostic factor should be used for perineural invasion.

    ReferenceSection

  • Jessup J, Benson A, Chen V: Colon and Rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 251–74.
  • Compton CC, Greene FL: The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54 (6): 295-308, 2004 Nov-Dec.
  • Nelson H, Petrelli N, Carlin A, et al.: Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 93 (8): 583-96, 2001.
  • Swanson RS, Compton CC, Stewart AK, et al.: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10 (1): 65-71, 2003 Jan-Feb.
  • Le Voyer TE, Sigurdson ER, Hanlon AL, et al.: Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 21 (15): 2912-9, 2003.
  • Prandi M, Lionetto R, Bini A, et al.: Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 235 (4): 458-63, 2002.
  • Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19 (1): 157-63, 2001.
    • 结肠癌治疗(PDQ®)

    结肠癌治疗方法概述

    表6.临床0–III期结肠癌的标准治疗方法表7.临床IV期和复发性结肠癌的治疗方法原发肿瘤的手术切除
    标准治疗方法
    治疗方法
    临床0期结肠癌
    临床I 期结肠癌
    临床II期结肠癌
    临床III期结肠癌
    治疗方法
    肝转移治疗
    临床IV期和复发性结肠癌的治疗
    表7.临床IV期和复发性结肠癌的治疗方法原发肿瘤的手术切除
    治疗方法
    肝转移治疗
    临床IV期和复发性结肠癌的治疗

    原发肿瘤的手术切除

    针对局部病变，结肠癌的标准治疗采用开腹手术切除原发病灶和区域淋巴结。

    腹腔镜技术的作用

    两项研究探讨了其在结肠癌中的治疗作用

    循证依据（腹腔镜技术）：

  • 一项多中心、前瞻性、随机的非劣性试验（NCCTG-934653 [NCT00002575]）对腹腔镜结肠切除术和开腹结肠切除术进行对比研究，共纳入872名病例。
  • 中位随诊时间4.4年，腹腔镜下结肠切除术组（LAC）和开腹结肠切除术组的3年复发率分别为16%和18%。复发的风险比为0.86（95%CI，0.63-1.17；P=0.32）。两组患者的3年总体生存率分别为86%和85%，LAC组死亡的风险比是0.91（95% CI，0.68–1.21； P=0.51），在各分期间均未发现差别。两组的手术切口复发率均低于1%。
  • [循证依据等级：1iiA]
  • LAC组住院时间5天，少于开腹组的6天（P<0.001）。LAC组镇痛药的使用也少于开腹组。LAC组有21%病例需要中转开腹。
  • 本项研究排除了局部进展期肿瘤、横结肠和直肠肿瘤以及穿孔的患者。66名外科医生参与了本项研究，每名医生至少进行了20例腹腔镜结肠切除术。在经过独立的手术录像评审后，以确保他们遵循肿瘤科和外科准则，这些医生才能参与本项研究。
  • 本试验的生活质量结果单独发表，据报道，LAC对短期生活质量的提高并不明显。
  • [循证依据等级：1iiC]
  • 一项针对219名患者的小型单中心随机研究显示，多因素分析显示，LAC手术与肿瘤复发率的降低是独立相关的。
  • [循证依据等级：1iiB]

    • 在严格挑选的可手术切除肝转移和肺转移的患者中，手术的治愈率为25%-40%。手术技术的提高和术前影像检查的进步有助于精准选择手术适应症。

    辅助化疗

    辅助化疗在临床II期结肠癌中的潜在价值尚存有争议。合并分析和荟萃分析表明，接受5-FU为基础的辅助治疗组比对照组的患者总体生存率高2%-4%。

    （更多信息，请参考本摘要“临床II期结肠癌治疗”部分内容。）

    2000年以前，5-FU是III期结肠癌辅助治疗中唯一有效的细胞毒性化疗药。自2000年以来，卡培他滨作为5-FU和亚叶酸钙（5-FU/LV）的替代药物，已获得临床肯定。与单用5-FU/LV相比，5-FU/LV联用奥沙利铂可延长患者总体生存期。（更多信息，请参考本摘要“临床III期结肠癌治疗”部分内容。）

    5-FU是III期结肠癌辅助治疗中唯一有效的细胞毒性化疗药。

    表8描述了用于结肠癌治疗的化疗方案。

    表8. 结肠癌治疗的联合用药方案辅助放疗
    方案名称联合应用的药物剂量
    AIO 或德国AIO 叶酸、5-FU、伊立替康伊立替康（100 mg/m2）和亚叶酸钙（500 mg/m2），静脉滴注2小时，第1天；随后5-FU（2000 mg/m2）静脉推注，输液泵持续静脉输注24小时，每年4次（52周）。
    CAPOX 卡培他滨联合奥沙利铂卡培他滨（1000 mg/m2），每日2次，第1-14天；奥沙利铂（70 mg/m2），第1天和第8天，每3周重复。
    Douillard 叶酸、5-FU、伊立替康伊立替康（180mg/m2），静脉滴注2小时，第1天；亚叶酸钙（200 mg/m2），静脉滴注2小时，第1天和第2天。随后负荷剂量5-FU（400 mg/m2）静脉推注，然后 5-FU（600 mg/m2）输液泵持续静脉输注22小时，第1天和第2天，每2周重复。
    FOLFIRI 叶酸、5-FU、伊立替康伊立替康（180 mg/m2）和亚叶酸钙（400 mg/m2），静脉滴注2小时，第1天；随后负荷剂量5-FU（400 mg/m2）静脉推注，第1天；然后 5-FU（2400-3000 mg/m2）输液泵持续静脉输注46小时，每2周重复。
    FOLFOX-4 奥沙利铂、叶酸、5-FU奥沙利铂（85 mg/m2），静脉滴注2小时，第1天；亚叶酸钙（200 mg/m2），静脉滴注2小时，第1天和第2天；随后负荷剂量5-FU（400 mg/m2）静脉推注，然后 5-FU（600 mg/m2）输液泵持续静脉输注22小时，第1天和第2天，每2周重复。
    FOLFOX-6 奥沙利铂、亚叶酸钙、5-FU奥沙利铂（85-100 mg/m2）、亚叶酸钙（400 mg/m2），静脉滴注2小时，第1天，随后负荷剂量5-FU（400 mg/m2）静脉推注，第1天；然后 5-FU（2400-3000 mg/m2）输液泵持续静脉输注46小时，每2周重复。
    FOLFOXIRI 伊立替康、奥沙利铂、亚叶酸钙、5-FU伊立替康（165 mg/m2）静脉滴注60分钟；同步滴注奥沙利铂（85mg/m2）和亚叶酸钙（200 mg/m2），静脉滴注超过120分钟；随后 5-FU（3200 mg/m2）静脉输注48小时。
    FUFOX5-FU、亚叶酸钙、奥沙利铂奥沙利铂（50 mg/m2）和亚叶酸钙（500 mg/m2）联用5-FU（2000 mg/m2）静脉输注22小时，第1、8、22、29天。每36天重复。
    FUOX 5-FU联合奥沙利铂5-FU（2250 mg/m2）静脉输注48小时，第1、8、15、22、29、36天。联用奥沙利铂（85mg/m2），第1、15、29天，每6周重复。
    IFL伊立替康、5-FU、亚叶酸钙伊立替康（125 mg/m2）联用5-FU（500 mg/m2）静脉推注，亚叶酸钙（20 mg/m2）静脉推注，周疗，连用4周，休息2周，每6周重复。
    XELOX 卡培他滨联合奥沙利铂口服卡培他滨（1000 mg/m2），每日2次，连用14天；奥沙利铂（130 mg/m2），第1天，每3周重复。
    5-FU = 5-氟尿嘧啶；AIO =肿瘤内科工作组；bid = 每日2次；IV = 静脉给药；LV = 亚叶酸钙。

    辅助放疗

    在直肠癌（腹膜返折以下）患者治疗中，化疗和放疗联合应用具有良好的临床疗效。辅助放疗在结肠癌（腹膜折返以上）的临床价值尚不明确。治疗方式分析和单中心回顾性综述显示放疗在特定的高危险结肠癌患者人群中具有一定的临床意义（如T4，肿瘤部位固定，局部侵透、梗阻和术后残留）。

    循证依据（辅助放疗）：

  • 这些观察结果促进了一项III期随机组间研究的开展，该研究旨在探索对选定的高危结肠癌患者（如T4；或T3，N1–N2升结肠和/或降结肠）在接受手术和5-FU-左旋咪唑方案化疗同时，辅助放疗的益处。
  • 这项临床试验因患者数量不足而提前结束，对222名登记患者（最初的目标是700名患者）的分析表明，尽管样本量和统计功效不足以排除获益，接受放射治疗的组无复发或OS获益。

    • 辅助放疗在残留癌的治疗中具有一定的临床意义。然而在治愈性切除的结肠癌中，尚未取得明确的临床价值。

    参考文献

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Schwenk W, Böhm B, Müller JM: Postoperative pain and fatigue after laparoscopic or conventional colorectal resections. A prospective randomized trial. Surg Endosc 12 (9): 1131-6, 1998.
  • Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350 (20): 2050-9, 2004.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
  • Lacy AM, García-Valdecasas JC, Delgado S, et al.: Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet 359 (9325): 2224-9, 2002.
  • Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 17 (5): 1356-63, 1999.
  • Gill S, Loprinzi CL, Sargent DJ, et al.: Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22 (10): 1797-806, 2004.
  • Mamounas E, Wieand S, Wolmark N, et al.: Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04) J Clin Oncol 17 (5): 1349-55, 1999.
  • Willett C, Tepper JE, Cohen A, et al.: Local failure following curative resection of colonic adenocarcinoma. Int J Radiat Oncol Biol Phys 10 (5): 645-51, 1984.
  • Willett C, Tepper JE, Cohen A, et al.: Obstructive and perforative colonic carcinoma: patterns of failure. J Clin Oncol 3 (3): 379-84, 1985.
  • Gunderson LL, Sosin H, Levitt S: Extrapelvic colon--areas of failure in a reoperation series: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 11 (4): 731-41, 1985.
  • Willett CG, Fung CY, Kaufman DS, et al.: Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 11 (6): 1112-7, 1993.
  • Willett CG, Goldberg S, Shellito PC, et al.: Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J Sci Am 5 (4): 242-7, 1999 Jul-Aug.
  • Schild SE, Gunderson LL, Haddock MG, et al.: The treatment of locally advanced colon cancer. Int J Radiat Oncol Biol Phys 37 (1): 51-8, 1997.
  • Martenson JA, Willett CG, Sargent DJ, et al.: Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 22 (16): 3277-83, 2004.
    • Colon Cancer Treatment (PDQ®)

    Treatment Option Overview for Colon Cancer

    Table 6. Standard Treatment Options for Stages 0–III Colon CancerTable 7. Treatment Options for Stage IV and Recurrent Colon CancerPrimary Surgical Therapy
    Standard Treatment Options
    Treatment Options
    Stage 0 Colon Cancer
    Stage I Colon Cancer
    Stage II Colon Cancer
    Stage III Colon Cancer
    Treatment Options
    Treatment of Liver Metastasis
    Treatment of Stage IV and Recurrent Colon Cancer
    Table 7. Treatment Options for Stage IV and Recurrent Colon CancerPrimary Surgical Therapy
    Treatment Options
    Treatment of Liver Metastasis
    Treatment of Stage IV and Recurrent Colon Cancer

    Primary Surgical Therapy

    Standard treatment for patients with colon cancer has been open surgical resection of the primary and regional lymph nodes for localized disease.

    The role of laparoscopic techniques

    in the treatment of colon cancer has been examined in two studies.

    Evidence (laparoscopic techniques):

  • A multicenter, prospective, randomized, noninferiority trial (NCCTG-934653 [NCT00002575]) compared laparoscopic-assisted colectomy (LAC) with open colectomy in 872 patients.
  • At a median follow-up of 4.4 years, 3-year recurrence rates (16% LAC vs. 18% open colectomy; hazard ratio [HR] for recurrence, 0.86; 95% confidence interval [CI], 0.63–1.17; P = .32) and 3-year overall survival (OS) rates (86% LAC vs. 85% open colectomy; HRdeath in LAC, 0.91; 95% CI, 0.68–1.21; P = .51) were similar in both groups for all stages of disease evaluated. Tumor recurrence in surgical incisions was less than 1% for both groups.
  • [Level of evidence: 1iiA]
  • Decreased hospital stay (5 days LAC vs. 6 days open colectomy, P < .001) and decreased use of analgesics were reported in the LAC group. A 21% conversion rate from LAC to open procedure was shown.
  • This study excluded patients with locally advanced disease, transverse colon and rectal tumor locations, and perforated lesions. Each of the 66 surgeons participating in the trial had performed at least 20 LACs and were accredited for study participation after independent videotape review assured appropriate oncologic and surgical principles were maintained.
  • The quality-of-life component of this trial was published separately and minimal short-term quality-of-life benefits with LAC were reported.
  • [Level of evidence: 1iiC]
  • One small, single-institution randomized study of 219 patients showed that the LAC procedure was independently associated with reduced tumor recurrence on multivariate analysis.
  • [Level of evidence: 1iiB]

    • Surgery is curative in 25% to 40% of highly selected patients who develop resectable metastases in the liver and lung. Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.

    Adjuvant Chemotherapy

    The potential value of adjuvant chemotherapy for patients with stage II colon cancer is controversial. Pooled analyses and meta-analyses have suggested a 2% to 4% improvement in OS for patients treated with adjuvant fluorouracil (5-FU)–based therapy compared with observation.

    (Refer to the Stage II Colon Cancer Treatment section of this summary for more information.)

    Before 2000, 5-FU was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer. Since 2000, capecitabine has been established as an equivalent alternative to 5-FU and leucovorin (5-FU/LV). The addition of oxaliplatin to 5-FU/LV has been shown to improve OS compared with 5-FU/LV alone. (Refer to the Stage III Colon Cancer Treatment section of this summary for more information.)

    Chemotherapy regimens

    Table 8 describes the chemotherapy regimens used to treat colon cancer.

    Table 8. Drug Combinations Used to Treat Colon CancerAdjuvant Radiation Therapy
    Regimen NameDrug CombinationDose
    AIO or German AIO Folic acid, 5-FU, and irinotecan Irinotecan (100 mg/m2) and LV (500 mg/m2) administered as 2-hour infusions on d 1, followed by 5-FU (2,000 mg/m2) IV bolus administered via ambulatory pump weekly over 24 h, 4 times a y (52 wk).
    CAPOX Capecitabine and oxaliplatin Capecitabine (1,000 mg/m2) bid on d 1–14, plus oxaliplatin (70 mg/m2) on d 1 and 8 every 3 wk.
    Douillard Folic acid, 5-FU, and irinotecan Irinotecan (180 mg/m2) administered as a 2-h infusion on d 1, LV (200 mg/m2) administered as a 2-h infusion on d 1 and 2, followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump over 22 h every 2 wk on d 1 and 2.
    FOLFIRI LV, 5-FU, and irinotecan Irinotecan (180 mg/m2) and LV (400 mg/m2) administered as 2-h infusions on d 1, followed by a loading dose of 5-FU (400 mg/m2) IV bolus administered on d 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump over 46 h every 2 wk.
    FOLFOX-4 Oxaliplatin, LV, and 5-FU Oxaliplatin (85 mg/m2) administered as a 2-h infusion on d 1, LV (200 mg/m2) administered as a 2-h infusion on d 1 and 2, followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump over 22 h every 2 wk on d 1 and 2.
    FOLFOX-6 Oxaliplatin, LV, and 5-FU Oxaliplatin (85–100 mg/m2) and LV (400 mg/m2) administered as 2-h infusions on d 1, followed by a loading dose of 5-FU (400 mg/m2) IV bolus on d 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump over 46 h every 2 wk.
    FOLFOXIRI Irinotecan, oxaliplatin, LV, 5-FU Irinotecan (165 mg/m2) administered as a 60-min infusion, then concomitant infusion of oxaliplatin (85 mg/m2) and LV (200 mg/m2) over 120 min, followed by 5-FU (3,200 mg/m2) administered as a 48-h continuous infusion.
    FUFOX5-FU, LV, and oxaliplatin Oxaliplatin (50 mg/m2) plus LV (500 mg/m2) plus 5-FU (2,000 mg/m2) administered as a 22-h continuous infusion on d 1, 8, 22, and 29 every 36 d.
    FUOX 5-FU plus oxaliplatin 5-FU (2,250 mg/m2) administered as a continuous infusion over 48 h on d 1, 8, 15, 22, 29, and 36 plus oxaliplatin (85 mg/m2) on d 1, 15, and 29 every 6 wk.
    IFL (or Saltz) Irinotecan, 5-FU, and LV Irinotecan (125 mg/m2) plus 5-FU (500 mg/m2) IV bolus and LV (20 mg/m2) IV bolus administered weekly for 4 out of 6 wk.
    XELOX Capecitabine plus oxaliplatin Oral capecitabine (1,000 mg/m2) administered bid for 14 d plus oxaliplatin (130 mg/m2) on d 1 every 3 wk.
    5-FU = fluorouracil; AIO = Arbeitsgemeinschaft Internistische Onkologie; bid = twice a day; IV = intravenous; LV = leucovorin.

    Adjuvant Radiation Therapy

    While combined modality therapy with chemotherapy and radiation therapy has a significant role in the management of patients with rectal cancer (below the peritoneal reflection), the role of adjuvant radiation therapy for patients with colon cancer (above the peritoneal reflection) is not well defined. Patterns-of-care analyses and single-institution retrospective reviews suggest a role for radiation therapy in certain high-risk subsets of colon cancer patients (e.g., T4, tumor location in immobile sites, local perforation, obstruction, and residual disease postresection).

    Evidence (adjuvant radiation therapy):

  • Such observations led to the development of a phase III randomized intergroup study designed to test the benefit of adding radiation therapy to surgery and chemotherapy with 5-FU-levamisole for selected high-risk colon cancer patients (e.g., T4; or T3, N1–N2 ascending and/or descending colon).
  • This clinical trial closed early secondary to inadequate patient accrual, and analysis of 222 enrolled patients (the original goal was 700 patients) demonstrated no relapse or OS benefit for the group receiving radiation therapy, although the sample size and statistical power were inadequate to exclude benefit.

    • Adjuvant radiation therapy has no current standard role in the management of patients with colon cancer following curative resection, although it may have a role for patients with residual disease.

    ReferenceSection

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Schwenk W, Böhm B, Müller JM: Postoperative pain and fatigue after laparoscopic or conventional colorectal resections. A prospective randomized trial. Surg Endosc 12 (9): 1131-6, 1998.
  • Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350 (20): 2050-9, 2004.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
  • Lacy AM, García-Valdecasas JC, Delgado S, et al.: Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet 359 (9325): 2224-9, 2002.
  • Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 17 (5): 1356-63, 1999.
  • Gill S, Loprinzi CL, Sargent DJ, et al.: Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22 (10): 1797-806, 2004.
  • Mamounas E, Wieand S, Wolmark N, et al.: Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04) J Clin Oncol 17 (5): 1349-55, 1999.
  • Willett C, Tepper JE, Cohen A, et al.: Local failure following curative resection of colonic adenocarcinoma. Int J Radiat Oncol Biol Phys 10 (5): 645-51, 1984.
  • Willett C, Tepper JE, Cohen A, et al.: Obstructive and perforative colonic carcinoma: patterns of failure. J Clin Oncol 3 (3): 379-84, 1985.
  • Gunderson LL, Sosin H, Levitt S: Extrapelvic colon--areas of failure in a reoperation series: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 11 (4): 731-41, 1985.
  • Willett CG, Fung CY, Kaufman DS, et al.: Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 11 (6): 1112-7, 1993.
  • Willett CG, Goldberg S, Shellito PC, et al.: Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J Sci Am 5 (4): 242-7, 1999 Jul-Aug.
  • Schild SE, Gunderson LL, Haddock MG, et al.: The treatment of locally advanced colon cancer. Int J Radiat Oncol Biol Phys 37 (1): 51-8, 1997.
  • Martenson JA, Willett CG, Sargent DJ, et al.: Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 22 (16): 3277-83, 2004.
    • 结肠癌治疗(PDQ®)

    临床0期结肠癌的治疗

    临床0期结肠癌是最表浅的一类病变，局限于黏膜层，未侵犯固有层。由于位置表浅，外科手术的作用较为受限。

    临床0期结肠癌的标准治疗

    手术

    临床0期结肠癌的标准治疗方法包括：

  • 局灶切除或息肉切除且切缘阴性。
  • 不适用局灶切除的较大病变需行结肠切除。

    • 当前的临床试验

    采用我们的临床试验高级搜索引擎，可查询正招募患者的NCI支持的癌症临床试验。搜索可按试验地点、治疗类型、药物名称及其他标准进行设置。还有一些临床试验相关的基本信息。

    Colon Cancer Treatment (PDQ®)

    Stage 0 Colon Cancer Treatment

    Stage 0 colon cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, the surgical procedure may be limited.

    Standard Treatment Options for Stage 0 Colon Cancer

    Surgery

    Standard treatment options for stage 0 colon cancer include the following:

  • Local excision or simple polypectomy with clear margins.
  • Colon resection for larger lesions not amenable to local excision.

    • 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.

    结肠癌治疗(PDQ®)

    临床I 期结肠癌的治疗

    由于局灶病变特征，临床I期结肠癌的治愈率较高。

    临床I期结肠癌的标准治疗

    手术

    临床I期结肠癌的标准治疗方法包括：

  • 广泛切除和吻合术。

    • 循证依据（腹腔镜技术）：

    腹腔镜的作用

    一项多中心前瞻性的随机临床试验（NCCTG-934653 [NCT00002575]）对腹腔镜在结肠癌治疗中的临床意义进行了探索，将腹腔镜下结肠切除术和开腹结肠切除术进行对比研究。

  • 两组患者的3年复发率和3年总体生存率无差异。（更多信息，请参考本摘要“结肠癌治疗概述”部分的“主手术疗法”部分内容。）
  • 本试验的生活质量结果单独发表，据报道，LAC对短期生活质量的益处微乎其微。
  • [循证依据等级：1iiC]

    • 当前的临床试验

    采用我们的临床试验搜索引擎，可查询正招募患者的NCI支持的癌症临床试验。搜索可按试验地点、治疗类型、药物名称及其他标准进行设置。还有一些临床试验相关的基本信息。

    参考文献

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Schwenk W, Böhm B, Müller JM: Postoperative pain and fatigue after laparoscopic or conventional colorectal resections. A prospective randomized trial. Surg Endosc 12 (9): 1131-6, 1998.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
    • Colon Cancer Treatment (PDQ®)

    Stage I Colon Cancer Treatment

    Because of its localized nature, stage I colon cancer has a high cure rate.

    Standard Treatment Options for Stage I Colon Cancer

    Surgery

    Standard treatment options for stage I colon cancer include the following:

  • Wide surgical resection and anastomosis.

    • Evidence (laparoscopic techniques):

    The role of laparoscopic techniques

    in the treatment of colon cancer was examined in a multicenter, prospective, randomized trial (NCCTG-934653 [NCT00002575]) comparing laparoscopic-assisted colectomy (LAC) with open colectomy.

  • Three-year recurrence rates and 3-year overall survival rates were similar in the two groups. (Refer to the Primary Surgical Therapy section in the Treatment Option Overview for Colon Cancer section of this summary for more information.)
  • The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.
  • [Level of evidence: 1iiC]

    • 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

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Schwenk W, Böhm B, Müller JM: Postoperative pain and fatigue after laparoscopic or conventional colorectal resections. A prospective randomized trial. Surg Endosc 12 (9): 1131-6, 1998.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
    • 结肠癌治疗(PDQ®)

    临床II期结肠癌的治疗

    临床II期结肠癌的标准治疗方法

    手术

    临床II期结肠癌的标准治疗方法包括：

  • 广泛切除和吻合术。

    • 循证依据（腹腔镜技术）：

    腹腔镜的作用

    一项多中心前瞻性的随机临床试验（NCCTG-934653 [NCT00002575]）对腹腔镜在结肠癌治疗中的临床意义进行了探索，将腹腔镜下结肠切除术和开腹结肠切除术进行对比研究。

  • 两组患者的3年复发率和3年总体生存率无差异。（更多信息，请参考本摘要“结肠癌治疗概述”部分的“主手术疗法”部分内容。）
  • 本试验的生活质量结果单独发表，据报道，LAC对短期生活质量的益处微乎其微。
  • [循证依据等级：1iiC]

    • 正处于临床评估阶段的治疗方法

    辅助化疗

    辅助化疗在临床II期结肠癌中的潜在临床价值尚有争议。尽管部分临床II期结肠癌亚群患者具有高于平均人群的复发风险（包括解剖学特征，如肿瘤粘连于相邻结构、穿孔以及完全梗阻），

    与单独手术相比，以5-FU为基础的辅助化疗并不能改善患者的总体生存期。

    临床II期结肠癌复发的影响因素包括：

  • 淋巴结样本不足。
  • T4疾病。
  • 侵犯脏层腹膜。
  • 组织学类型：低分化。

    • 将辅助化疗用于临床II期结肠癌的临床决策较为复杂，患者本人和临床医生均应谨慎考量。除非参与临床试验，否则大多数患者都不会建议采用辅助化疗。

    循证依据（辅助化疗）：

  • GRECCR-03 (NCT00046995) 和NCRI-QUASAR1 (NCT00005586)两项临床试验对全身化疗和局部化疗及生物治疗进行了对比研究。术后患者可考虑加入参加严格控制的临床试验。
  • 美国国家外科辅助治疗乳腺和肠道项目的研究人员指出，辅助治疗可降低临床II期结肠癌的复发风险，与辅助治疗在临床III期结肠癌中的临床获益相似，但总体生存期优势尚不明确。
  • 一项收录多个研究的1000例临床II期结肠癌患者的荟萃分析结果显示，5-FU/亚叶酸钙辅助化疗患者的5年无病生存率比未治疗的对照组高2%。
  • [循证依据等级：1iiDii]
  • 美国安大略省癌症护理实践指南倡议胃肠道癌癌症工作组发表了一篇荟萃分析的英文研究，其中包含多项有关辅助化疗用于临床II期结肠癌患者与对照组研究的随机临床试验。
  • 死亡率风险比为0.87 (95% CI，0.75–1.01；P =0 .07)。

    • 基于以上数据，美国临床肿瘤学会发布一项指南，提出“随机对照试验的直接证据并不支持辅助化疗在临床II期结肠癌患者中的常规应用”。

    当前的临床试验

    采用我们的临床试验搜索引擎，可查询正招募患者的NCI支持的癌症临床试验。搜索可按试验地点、治疗类型、药物名称及其他标准进行设置。还有一些临床试验相关的基本信息。

    参考文献

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
  • Lanza G, Matteuzzi M, Gafá R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79 (4): 390-5, 1998.
  • Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331 (4): 213-21, 1994.
  • Merkel S, Wein A, Günther K, et al.: High-risk groups of patients with Stage II colon carcinoma. Cancer 92 (6): 1435-43, 2001.
  • Moertel CG, Fleming TR, Macdonald JS, et al.: Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. J Clin Oncol 13 (12): 2936-43, 1995.
  • Mamounas E, Wieand S, Wolmark N, et al.: Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04) J Clin Oncol 17 (5): 1349-55, 1999.
  • Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 17 (5): 1356-63, 1999.
  • Harrington DP: The tea leaves of small trials. J Clin Oncol 17 (5): 1336-8, 1999.
  • Figueredo A, Charette ML, Maroun J, et al.: Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group. J Clin Oncol 22 (16): 3395-407, 2004.
  • Benson AB, Schrag D, Somerfield MR, et al.: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22 (16): 3408-19, 2004.
    • Colon Cancer Treatment (PDQ®)

    Stage II Colon Cancer Treatment

    Standard Treatment Options for Stage II Colon Cancer

    Surgery

    Standard treatment options for stage II colon cancer include the following:

  • Wide surgical resection and anastomosis.

    • Evidence (laparoscopic techniques):

    The role of laparoscopic techniques

    in the treatment of colon cancer was examined in a multicenter, prospective, randomized trial (NCCTG-934653 [NCT00002575]) comparing laparoscopic-assisted colectomy (LAC) to open colectomy.

  • Three-year recurrence rates and 3-year overall survival (OS) rates were similar in the two groups. (Refer to the Primary Surgical Therapy section in the Treatment Option Overview for Colon Cancer section of this summary for more information.)
  • The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.
  • [Level of evidence: 1iiC]

    • Treatment Options Under Clinical Evaluation

    Adjuvant chemotherapy

    The potential value of adjuvant chemotherapy for patients with stage II colon cancer remains controversial. Although subgroups of patients with stage II colon cancer may be at higher-than-average risk for recurrence (including those with anatomic features such as tumor adherence to adjacent structures, perforation, and complete obstruction),

    evidence is inconsistent that adjuvant 5-fluorouracil (5-FU)–based chemotherapy is associated with an improved OS compared with surgery alone.

    Features in patients with stage II colon cancer that are associated with an increased risk of recurrence include the following:

  • Inadequate lymph node sampling.
  • T4 disease.
  • Involvement of the visceral peritoneum.
  • A poorly differentiated histology.

    • The decision to use adjuvant chemotherapy for patients with stage II colon cancer is complicated and requires thoughtful consideration by both patients and their physicians. Adjuvant therapy is not indicated for most patients unless they are entered into a clinical trial.

    Evidence (adjuvant chemotherapy):

  • The GRECCR-03 (NCT00046995) and NCRI-QUASAR1 (NCT00005586) trials evaluated the use of systemic or regional chemotherapy or biologic therapy. Following surgery, patients can be considered for entry into a carefully controlled clinical trial.
  • Investigators from the National Surgical Adjuvant Breast and Bowel Project have indicated that the reduction in risk of recurrence by adjuvant therapy in patients with stage II disease is of similar magnitude to the benefit seen in patients with stage III disease treated with adjuvant therapy, though an OS advantage has not been established.
  • A meta-analysis of 1,000 stage II patients whose experience was amalgamated from a series of trials indicates a 2% advantage in disease-free survival at 5 years when adjuvant therapy–treated patients treated with 5-FU/leucovorin are compared with untreated controls.
  • [Level of evidence: 1iiDii];
  • The Cancer Care Ontario Practice Guideline Initiative Gastrointestinal Cancer Disease Site Group undertook a meta-analysis of the English language–published literature consisting of randomized trials in which adjuvant chemotherapy was compared with observation for patients with stage II colon cancer.
  • The mortality risk ratio was 0.87 (95% confidence interval, 0.75–1.01; P = .07).

    • Based on these data, the American Society of Clinical Oncology issued a guideline stating “direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer.”

    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

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
  • Lanza G, Matteuzzi M, Gafá R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79 (4): 390-5, 1998.
  • Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331 (4): 213-21, 1994.
  • Merkel S, Wein A, Günther K, et al.: High-risk groups of patients with Stage II colon carcinoma. Cancer 92 (6): 1435-43, 2001.
  • Moertel CG, Fleming TR, Macdonald JS, et al.: Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. J Clin Oncol 13 (12): 2936-43, 1995.
  • Mamounas E, Wieand S, Wolmark N, et al.: Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04) J Clin Oncol 17 (5): 1349-55, 1999.
  • Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 17 (5): 1356-63, 1999.
  • Harrington DP: The tea leaves of small trials. J Clin Oncol 17 (5): 1336-8, 1999.
  • Figueredo A, Charette ML, Maroun J, et al.: Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group. J Clin Oncol 22 (16): 3395-407, 2004.
  • Benson AB, Schrag D, Somerfield MR, et al.: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22 (16): 3408-19, 2004.
    • 结肠癌治疗(PDQ®)

    临床III期结肠癌的治疗

    临床III期结肠癌意味着淋巴结转移。有研究指出，淋巴结转移数目影响预后。1-3枚淋巴结转移患者的生存期明显优于4枚或以上淋巴结转移的患者。

    临床III期结肠癌的标准治疗方法

    临床III期结肠癌的标准治疗方法包括：

  • 手术。
  • 辅助化疗。

    • 手术

    临床III期结肠癌的手术治疗需范围较大的手术切除和吻合。

    循证依据（腹腔镜技术）：

    腹腔镜的作用

    一项多中心前瞻性的随机临床试验（NCCTG-934653 [NCT00002575]）对腹腔镜在结肠癌治疗中的临床意义进行了探索，将腹腔镜下结肠切除术和开腹结肠切除术进行对比研究。

  • 两组患者的3年复发率和3年总体生存率相似。（更多信息，请参考本摘要“结肠癌治疗概述”部分的“主手术疗法”部分内容。）
  • 本试验的生活质量结果单独发表，据报道，LAC对短期生活质量的益处微乎其微。
  • [循证依据等级：1iiC]

    • 辅助化疗

    2000年以前的化疗方案

    2000年以前，5-FU是III期结肠癌辅助治疗中唯一有效的细胞毒性化疗药。在早期随机研究中，没有证据表明5-FU辅助化疗能延长患者生存期。

    这些临床试验应用5-FU单药或5-FU/西莫司汀联合治疗。

    循证依据（5-FU单药和5-FU/西莫司汀联合治疗）：

  • 美国中北部癌症治疗组开展一项随机临床试验，将单独手术切除与术后左旋咪唑或左旋咪唑/5-FU治疗进行对比。
  • [循证依据等级：1iiA]
  • 采用左旋咪唑/5-FU治疗的临床III期结肠癌患者的无疾病生存期（DFS）明显延长，但总体生存期处于统计学意义的临界值。
  • 采用左旋咪唑/5-FU治疗的临床III期结肠癌患者的生存率具有明显优势，比对照组高约12%（49%比37%）。
  • 有一项大规模验证性组间试验，与单独手术组相比，术后采用左旋咪唑/5-FU治疗临床III期结肠癌可改善患者的无疾病生存期和总体生存期。
  • [循证依据等级：1iiA]左旋咪唑单药治疗无临床效果。
  • 随后有研究分析了 5-FU联合亚叶酸钙(5-FU/LV)在结肠癌术后患者辅助治疗中的作用。
  • 多项随机临床试验共纳入4000余例患者，将术后应用5-FU/LV或5-FU/司莫司汀/长春新碱方案与单独手术进行对比研究，结果显示辅助化疗组的死亡率降低22%-33%（3年总体生存率从71%–78%升至75%–84%）。
  • 已完成的组间临床试验0089（INT-0089 [NCT00201331]）将3794例高风险临床II或III期结肠癌患者随机给予以下四种治疗方案：
  • Mayo方案，共治疗6个周期。
  • Roswell Park方案，共治疗4个周期。
  • Mayo方案联合左旋咪唑，治疗6个周期。
  • 左旋咪唑，共治疗1年。

    • 结果：

  • Mayo方案联合左旋咪唑组的5年总体生存率为49%，Mayo方案治疗组为60%，两组差异无统计学意义。
  • [循证依据等级：1iiA]
  • 1997年11月，初步报告结果显示Mayo方案联合左旋咪唑组与左旋咪唑单药治疗组相比，总体生存期具有显著优势。随诊时间越长，两组间的差异越小。
  • 整体上，3级或3级以上的不良反应更常发生于Mayo方案组和Mayo方案联合左旋咪唑组。此外，Mayo方案联合左旋咪唑组的不良反应明显多于左旋咪唑单药组。
  • 所有四种治疗方案的死亡率从0.5%-1%不等。
  • 在美国，由于应用简便且不良反应少，Roswell Park方案是辅助化疗的首选方案。在随后的临床试验中，常被作为对照组进行研究。
  • 除了INT-0089，还有多项研究对5-FU/LV辅助化疗进行了改良，概括如下：
  • 选用亚叶酸钙，不用左旋咪唑。
  • 5-FU/LV辅助化疗6-8个月与12个月，其临床疗效无差别。
  • 5-FU/LV辅助化疗24周与36周，其临床疗效无差别。
  • 高剂量亚叶酸钙与低剂量无差别。
  • 一项纳入7项临床试验的荟萃分析显示，70岁及以下的癌症患者与70岁以上的患者相比，临床疗效与不良反应无显著差异。
  • 5-FU/LV静脉推注和静脉输注方案比Mayo方案的5-FU改良推注方法更安全。

    • 2000年以后的化疗方案

    卡培他滨是一种口服的氟嘧啶类药物。经过3步酶作用转化成5-FU，最后一步发生在肿瘤细胞中。对于转移性结肠癌患者，有两项研究显示卡培他滨的临床疗效与5-FU/LV等同。

    临床III期结肠癌患者，卡培他滨与静脉输注5-FU/LV的临床疗效无明显差异。

    循证依据（卡培他滨）：

  • 一项多中心欧洲研究将卡培他滨和Mayo5-FU方案组治疗临床III期结肠癌患者进行对比研究，其中卡培他滨（1250 mg/m2）每日2次，第1天到第14天，每21天重复，连用8个周期。Mayo方案组采用5-FU和低剂量亚叶酸钙。
  • 结果显示，两组的3年无疾病生存期无差别（危险比[HR] 0.87；P <0.001）。
  • [循证依据等级：1iiDii]
  • 手足综合征和高胆红素血症更常见于卡培他滨组，而腹泻、恶心、呕吐、胃炎、斑秃症和中性粒细胞减少症较为少见。
  • 采用卡培他滨治疗，57%患者需要调整剂量。
  • 临床III期结肠癌的治疗，卡培他滨可作为5-FU/LV的替代治疗方法。

    • 奥沙利铂联合5-FU/LV用于治疗转移性结肠癌具有显著的临床意义。

    循证依据（奥沙利铂）：

  • 在一项关于奥沙利铂/5-FU/LV用于结肠癌辅助化疗的多中心国际研究（MOSAIC [NCT00275210]）中，共纳入2246例临床II和III期可切除的患者，对FOLFOX-4（奥沙利铂/LV/5-FU）和5-FU/LV方案应用6个月后的不良反应和临床疗效进行评估。
  • 根据MOSAIC研究结果，与单纯5-FU/LV治疗相比，加用奥沙利铂的FOLFOX-4辅助化疗可延长临床III期结肠癌患者的总体生存期。
  • 随诊37个月的初步报告显示，FOLFOX-4治疗组的3年无疾病生存期优于对照组（77.8%比72.9%；P=0.01）.最初结果发表时，总体生存期未见明显差异。
  • [循证依据等级：1iiDii]
  • 6年随诊后，本研究中的两组患者的总体生存期（临床II和III期）未见明显差异（总体生存率，78.5%比76.0%；HR 0.84；95% CI，0.71-1.00）。在小组分析中，临床III期结肠癌患者的6年总体生存率在FOLFOX-4治疗组为72.9%，5-FU/LV组为68.7%（HR，0.80；95% CI，0.65-0.97；P=0.023）。
  • [循证依据等级：1iiA]
  • FOLFOX-4方案治疗组不良反应的发生率更高，主要有中性粒细胞减少症（41% >3级）、可逆的周围神经性病变（12.4% >3级）。
  • 在一项随机III期的研究（NSABP C-07 [NCT00004931]）中，将2407例临床II和III期结肠癌患者进行随机分组，一组给予5-FU/LV治疗，另一组采用FLOX方案治疗（5-FU/LV周疗，奥沙利铂第1、3、5周给药，每6周重复）。无病生存率作为研究主要终点。
  • 与5-FU/LV治疗组相比，FLOX方案治疗组的无病生存率明显延长，但总体生存期无明显差异。FLOX方案治疗组的无病生存率为69.4%，5-FU/LV治疗组为64.2%（HR，0.82；95% CI，0.72-0.93；P=0.0034）。
  • FLOX方案治疗组和5-FU/LV治疗组的总体生存率分别为80.2%和78.4%（HR，0.88；95% CI，0.75-1.02；P=0.08）。
  • [循证依据等级：1iiDii]
  • FLOX方案治疗组患者的3级和4级腹泻发生率为36.9%，3级和4级脱水发生率为16.1%。

    • 由于FLOX周疗出现不良反应，众多临床医生将FOLFOX方案作为标准治疗。FOLFOX方案已成为新一代III期结肠癌临床试验的参考标准。

    卡培他滨联合奥沙利铂

    卡培他滨联合奥沙利铂（CAPOX）是转移性结肠癌的标准治疗方法。

    循证依据（CAPOX）：

  • 曾有研究对CAPOX辅助化疗用于可切除的临床III期结肠癌进行评估（卡培他滨1000mg/m2，每日2次，第1到14天，每21天重复；奥沙利铂130mg/m2，每21天重复，共治疗8个周期）。
  • 一项随机III期临床试验(NO16968 [NCT00069121])将1886例临床III期结肠癌患者随机分为CAPOX组和5FU-LV静脉推注组（Roswell Park或Mayo方案）。
  • CAPOX组和5FU-LV组的7年无病生存率分别为63%和56%（HR，0.8；95% CI，0.69-0.93；P=0.004)。
  • CAPOX组和5FU-LV组的7年总体生存率分别为73%和67%（HR，0.83；95% CI，0.70-0.99；P=0.04)。
  • [循证依据等级：1iiA]

    • 基于本项研究，CAPOX已成为临床III期结肠癌患者的标准治疗方案。

    奥沙利铂的疗程

    由于致残性神经系统病变的高发率，奥沙利铂辅助治疗的时长尚无定论。

    循证依据（奥沙利铂的疗程）：

  • 国际辅助治疗持续时间评估(IDEA)协作组由6个独立的随机临床试验组成，对3个月和6个月以奥沙利铂为基础的辅助化疗进行评估。IDEA研究是对这些同时进行的研究的前瞻性、预计划的合并分析，以评估FOLFOX和CAPOX方案治疗3个月或6个月的非劣效性。如果HR二项式95%CI的上限低于1.12则被认定为非劣效性。

    • 2007年6月至2015年12月，6项同步开展的III期临床试验共招募13025例III期结肠癌患者，其中12834例患者符合意向性分析要求。中位随诊时间41.8个月，在调整的意向性人群中，3个月与6个月的非劣效性未得到肯定（3个月的治疗组，HR，1.07；95% CI，1.00-1.15，P=0.11）。

  • 3个月治疗组的3年无病生存率为74.6%，6个月治疗组为75.5%。
  • 2级及以上神经毒性反应的发生率，3个月治疗组（FOLFOX组16.6%， CAPOX14.2%）明显低于6个月治疗组（FOLFOX组47.7%， CAPOX44.9%）。而且，3个月治疗组的其他不良反应均低于6个月治疗组。
  • 亚组分析发现：
  • 采用FOLFOX治疗的患者中，6个月治疗组明显优于3个月治疗组（HR，1.16；95% CI，1.06–1.26；P=0.001）
  • 采用CAPOX治疗的患者中，3个月和6个月治疗组无明显差异（无疾病生存期HR，0.95；95% CI，0.85–1.06），达到预设的非劣效性边界。
  • N1患者（<4枚淋巴结转移）的HR为1.07(0.97-1.17)。N2患者（≥4枚淋巴结转移）的HR为1.07(0.96–1.19)。
  • T4患者3个月治疗组的临床疗效不如6个月治疗组（HR，1.16；95% CI，1.03-1.31）。
  • 低风险肿瘤患者（T1-3，N1），3个月治疗并不劣于6个月治疗（HR，1.01；95% CI，0.90-1.12）。3个月组3年无病生存率为83.1%，6个月组为83.3%。
  • 高风险肿瘤患者（T4或N2），6个月治疗组的临床疗效显著优于3个月治疗组（HR，1.12；95% CI，1.03–1.23；P=0.01）。

    • IDEA研究引发了诸多关于最佳治疗时长的争议。建议患者和临床医生权衡3个月降低临床疗效与升高的不良反应风险之间的利弊，特别是神经性病变。在辅助治疗中， CAPOX看似比FOLFOX方案稍微更有优势一些。

    正处于临床评估阶段的治疗方法

    如患者符合条件，可参加对比各种术后化疗方案的管控严格的临床试验。

    当前的临床试验

    采用我们的临床试验搜索引擎，可查询正招募患者的NCI支持的癌症临床试验。搜索可按试验地点、治疗类型、药物名称及其他标准进行设置。还有一些临床试验相关的基本信息。

    参考文献

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Schwenk W, Böhm B, Müller JM: Postoperative pain and fatigue after laparoscopic or conventional colorectal resections. A prospective randomized trial. Surg Endosc 12 (9): 1131-6, 1998.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
  • Panettiere FJ, Goodman PJ, Costanzi JJ, et al.: Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. J Clin Oncol 6 (6): 947-54, 1988.
  • Adjuvant therapy of colon cancer--results of a prospectively randomized trial. Gastrointestinal Tumor Study Group. N Engl J Med 310 (12): 737-43, 1984.
  • Higgins GA, Amadeo JH, McElhinney J, et al.: Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report. Cancer 53 (1): 1-8, 1984.
  • Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of colorectal cancer. Why we still don't know. JAMA 259 (24): 3571-8, 1988.
  • Laurie JA, Moertel CG, Fleming TR, et al.: Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 7 (10): 1447-56, 1989.
  • Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322 (6): 352-8, 1990.
  • Wolmark N, Rockette H, Fisher B, et al.: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11 (10): 1879-87, 1993.
  • Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 345 (8955): 939-44, 1995.
  • O'Connell M, Mailliard J, Macdonald J, et al.: An intergroup trial of intensive course 5FU and low dose leucovorin as surgical adjuvant therapy for high risk colon cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-552, 190, 1993.
  • Haller DG, Catalano PJ, Macdonald JS, et al.: Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol 23 (34): 8671-8, 2005.
  • Wolmark N, Bryant J, Smith R, et al.: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90 (23): 1810-6, 1998.
  • Wolmark N, Rockette H, Mamounas E, et al.: Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 17 (11): 3553-9, 1999.
  • Okuno SH, Woodhouse CL, Loprinzi CL, et al.: Phase III placebo-controlled clinical trial evaluation of glutamine for decreasing mucositis in patients receiving 5FU (fluorouracil)-base chemotherapy. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-256, 1998.
  • Andre T, Colin P, Louvet C, et al.: Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 21 (15): 2896-903, 2003.
  • Comparison of flourouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet 355 (9215): 1588-96, 2000.
  • Sargent DJ, Goldberg RM, Jacobson SD, et al.: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345 (15): 1091-7, 2001.
  • Van Cutsem E, Twelves C, Cassidy J, et al.: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19 (21): 4097-106, 2001.
  • Hoff PM, Ansari R, Batist G, et al.: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19 (8): 2282-92, 2001.
  • Twelves C, Wong A, Nowacki MP, et al.: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352 (26): 2696-704, 2005.
  • André T, Boni C, Mounedji-Boudiaf L, et al.: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350 (23): 2343-51, 2004.
  • André T, Boni C, Navarro M, et al.: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27 (19): 3109-16, 2009.
  • Yothers G, O'Connell MJ, Allegra CJ, et al.: Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 29 (28): 3768-74, 2011.
  • Schmoll HJ, Tabernero J, Maroun J, et al.: Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol 33 (32): 3733-40, 2015.
  • Grothey A, Sobrero AF, Shields AF, et al.: Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med 378 (13): 1177-1188, 2018.
  • Rougier P, Nordlinger B: Large scale trial for adjuvant treatment in high risk resected colorectal cancers. Rationale to test the combination of loco-regional and systemic chemotherapy and to compare l-leucovorin + 5-FU to levamisole + 5-FU. Ann Oncol 4 (Suppl 2): 21-8, 1993.
    • Colon Cancer Treatment (PDQ®)

    Stage III Colon Cancer Treatment

    Stage III colon cancer denotes lymph node involvement. Studies have indicated that the number of lymph nodes involved affects prognosis; patients with one to three involved nodes have a significantly better survival than those with four or more involved nodes.

    Standard Treatment Options for Stage III Colon Cancer

    Standard treatment options for stage III colon cancer include the following:

  • Surgery.
  • Adjuvant chemotherapy.

    • Surgery

    Surgery for stage III colon cancer is wide surgical resection and anastomosis.

    Evidence (laparoscopic techniques):

    The role of laparoscopic techniques

    in the treatment of colon cancer was examined in a multicenter, prospective, randomized trial (NCCTG-934653 [NCT00002575]) comparing laparoscopic-assisted colectomy (LAC) with open colectomy.

  • Three-year recurrence rates and 3-year overall survival (OS) rates were similar in the two groups. (Refer to the Primary Surgical Therapy section in the Treatment Option Overview for Colon Cancer section of this summary for more information.)
  • The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.
  • [Level of evidence: 1iiC]

    • Adjuvant chemotherapy

    Chemotherapy regimens before 2000

    Before 2000, 5-fluorouracil (5-FU) was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer. Many of the early randomized studies of 5-FU in the adjuvant setting failed to show a significant improvement in survival for patients.

    These trials employed 5-FU alone or 5-FU/semustine.

    Evidence (5-FU alone and 5-FU/semustine):

  • The North Central Cancer Treatment Group conducted a randomized trial comparing surgical resection alone with postoperative levamisole or levamisole/5-FU.
  • [Level of evidence: 1iiA]
  • A significant improvement in disease-free survival (DFS) was observed for patients with stage III colon cancer who received levamisole/5-FU, but OS benefits were of borderline statistical significance.
  • An absolute survival benefit of approximately 12% (49% vs. 37%) was seen in patients with stage III disease treated with levamisole/5-FU.
  • In a large confirmatory intergroup trial, levamisole/5-FU- prolonged DFS and OS in patients with stage III colon cancer compared with patients who received no treatment after surgery.
  • [Level of evidence: 1iiA] Levamisole alone did not confer these benefits.
  • Subsequent studies tested the combination of 5-FU/leucovorin (5-FU/LV) in the adjuvant treatment of patients with resected carcinoma of the colon.
  • Results of multiple randomized trials that have enrolled more than 4,000 patients comparing adjuvant chemotherapy with 5-FU/LV to surgery or 5-FU/semustine/vincristine demonstrate a relative reduction in mortality of between 22% and 33% (3-year OS of 71%–78% increased to 75%–84%).
  • The completed Intergroup trial 0089 (INT-0089 [NCT00201331]) randomly assigned 3,794 patients with high-risk stage II or stage III colon cancer to one of the following four treatment arms:
  • The Mayo Clinic regimen administered for a total of six cycles.
  • The Roswell Park regimen administered for a total of four cycles.
  • The Mayo Clinic regimen administered with levamisole for six cycles.
  • The levamisole regimen administered for a total of 1 year.

    • Results:

  • Five-year OS ranged from 49% for the Mayo Clinic regimen with levamisole to 60% for the Mayo Clinic regimen, and there were no statistically significant differences among treatment arms.
  • [Level of evidence: 1iiA]
  • A preliminary report in November 1997 demonstrated a statistically significant advantage for OS for the Mayo Clinic regimen with levamisole compared with the levamisole regimen. This difference became insignificant with longer follow-up.
  • Overall, grade 3 or greater toxicity occurred more frequently for the Mayo Clinic regimen and the Mayo Clinic regimen with levamisole. In addition, the Mayo Clinic regimen was significantly more toxic with levamisole than without levamisole.
  • The death rate for all four regimens ranged from 0.5% to 1%.
  • Because of its ease of use and its good toxicity profile, the Roswell Park regimen became the preferred adjuvant regimen used in the United States and was often the control arm in subsequent randomized studies.
  • In addition to INT-0089, multiple studies have refined the use of 5-FU/LV in the adjuvant setting and can be summarized as follows:
  • Levamisole is unnecessary when using leucovorin.
  • Treatment that includes 6 to 8 months of 5-FU/LV is equivalent to 12 months of therapy.
  • Treatment that includes 24 weeks of adjuvant 5-FU/LV is equivalent to 36 weeks of therapy.
  • High-dose leucovorin is equivalent to low-dose leucovorin.
  • A meta-analysis of seven trials revealed no significant difference in efficacy or toxicity among patients aged 70 years or younger compared with patients older than 70 years.
  • An infusional deGramont bolus and infusional 5-FU/LV schedule is safer than a bolus modified Mayo Clinic schedule of 5-FU/LV.

    • Chemotherapy regimens after 2000

    Capecitabine is an oral fluoropyrimidine that undergoes a three-step enzymatic conversion to 5-FU with the last step occurring in the tumor cell. For patients with metastatic colon cancer, two studies have demonstrated the equivalence of capecitabine to 5-FU/LV.

    For patients with stage III colon cancer, capecitabine provides equivalent outcome to intravenous 5-FU/LV.

    Evidence (capecitabine):

  • A multicenter European study compared capecitabine (1,250 mg/m2) administered twice daily for days 1 to 14, then given every 21 days for eight cycles against the Mayo Clinic schedule of 5-FU and low-dose LV for patients with stage III colon cancer.
  • The study demonstrated that DFS at 3 years is equivalent for patients who received capecitabine or 5-FU/LV (hazard ratio [HR], 0.87; P < .001).
  • [Level of evidence: 1iiDii]
  • Hand-foot syndrome and hyperbilirubinemia were significantly more common for patients receiving capecitabine, but diarrhea, nausea or vomiting, stomatitis, alopecia, and neutropenia were significantly less common.
  • Of patients receiving capecitabine, 57% required a dose modification.
  • For patients with stage III colon cancer in whom treatment with 5-FU/LV is planned, capecitabine is an equivalent alternative.

    • Oxaliplatin has significant activity when combined with 5-FU/LV in patients with metastatic colorectal cancer.

    Evidence (oxaliplatin):

  • In the 2,246 patients with resected stage II or stage III colon cancer in the completed Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC [NCT00275210]) study, the toxic effects and efficacy of FOLFOX-4 (oxaliplatin/LV/5-FU) were compared with the same 5-FU/LV regimen without oxaliplatin administered for 6 months.
  • Based on results from the MOSAIC trial, adjuvant FOLFOX-4 demonstrated prolonged OS for patients with stage III colon cancer compared with patients receiving 5-FU/LV without oxaliplatin.
  • The preliminary results of the study with 37 months of follow-up demonstrated a significant improvement in DFS at 3 years (77.8% vs. 72.9%; P = .01) in favor of FOLFOX-4. When initially reported, there was no difference in OS.
  • [Level of evidence: 1iiDii]
  • Further follow-up at 6 years demonstrated that the OS for all patients (both stage II and stage III) entered into the study was not significantly different (OS, 78.5% vs. 76.0%; HR, 0.84; 95% confidence interval [CI], 0.71–1.00). On subset analysis, the 6-year OS in patients with stage III colon cancer was 72.9% in the patients receiving FOLFOX-4 and 68.7% in the patients receiving 5-FU/LV (HR, 0.80; 95% CI, 0.65–0.97; P = .023).
  • [Level of evidence: 1iiA]
  • Patients treated with FOLFOX-4 experienced more frequent toxic effects consisting mainly of neutropenia (41% >grade 3) and reversible peripheral sensorial neuropathy (12.4% >grade 3).
  • In a randomized phase III study (NSABP C-07 [NCT00004931]), 2,407 patients with stage II or stage III colon cancer were randomly assigned to adjuvant 5-FU/LV or fluorouracil-leucovorin-oxaliplatin (FLOX) (weekly 5-FU/LV with oxaliplatin administered on weeks 1, 3, and 5 of each 6-week cycle). DFS was the primary endpoint of the study.
  • DFS was significantly longer in the treatment group who received FLOX, but OS was not significantly different. The DFS rate was 69.4% for patients who received FLOX and 64.2% for patients who received 5-FU/LV (HR, 0.82; 95% CI, 0.72–0.93; P = .0034).
  • The OS rate at 5 years was 80.2% for patients who received FLOX and 78.4% for patients who received 5-FU/LV (HR, 0.88; 95% CI, 0.75–1.02; P = .08).
  • [Level of evidence: 1iiD]
  • Grade 3 and grade 4 diarrhea was experienced by 36.9% of patients who received FLOX, and grade 3 and grade 4 dehydration was experienced by 16.1% of patients who received FLOX.

    • Most physicians have adopted FOLFOX as the standard of care because of toxicity concerns with weekly FLOX. FOLFOX has become the reference standard for the next generation of clinical trials for patients with stage III colon cancer.

    Capecitabine and Oxaliplatin

    The combination of capecitabine and oxaliplatin (CAPOX) is an accepted standard therapy in patients with metastatic colorectal cancer.

    Evidence (CAPOX):

  • CAPOX was evaluated in the adjuvant setting for patients with resected stage III colon cancer (capecitabine 1,000 mg/m2 bid on days 1 to 14 every 21 days and oxaliplatin 130 mg/m2 every 21 days for a total of 8 cycles).
  • A randomized phase III trial (NO16968 [NCT00069121]), randomly assigned 1,886 patients with stage III colon cancer to receive CAPOX or bolus 5FU-LV (Roswell Park or Mayo Clinic schedule).
  • The 7-year DFS rates were 63% for patients who received CAPOX and 56% for patients who received bolus 5-FU/LV (HR, 0.8; 95% CI, 0.69–0.93; P = .004).
  • The 7-year OS rates were 73% for patients who received CAPOX and 67% for patients who received a bolus 5-FU/LV (HR, 0.83; 95% CI, 0.70–0.99; P = .04).
  • [Level of evidence: 1iiA]

    • On the basis of this trial, CAPOX has become an acceptable standard regimen for patients with stage III colon cancer.

    Oxaliplatin Length of Therapy

    Given the high rate of disabling neuropathy, the duration of oxaliplatin adjuvant therapy became an open question.

    Evidence (length of therapy for oxaliplatin):

  • The International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration consisted of six separate randomized trials with regimens of 6 months versus 3 months of adjuvant oxaliplatin-based chemotherapy. The IDEA study was a prospective, preplanned pooled analysis of these concurrently conducted studies to evaluate the noninferiority of adjuvant therapy of either FOLFOX or CAPOX administered for 3 months versus 6 months. Noninferiority could be claimed if the upper limit of the two-sided 95% CI of the HR did not exceed 1.12.

    • From June 2007 through December 2015, 13,025 patients with stage III colon cancer were enrolled in six concurrent phase III trials. Of these patients, 12,834 patients met the criteria for intention-to-treat analysis. At a median follow-up of 41.8 months, noninferiority of 3 months versus 6 months was not confirmed in the modified intention-to-treat population (HR, 1.07; 95% CI, 1.00–1.15, P = .11 for noninferiority of 3 months).

  • The 3-year DFS rates were 74.6% in the 3-month group and 75.5% in the 6-month group.
  • Neurotoxicity of grade 2 or higher was lower in the 3-month group (16.6% for patients who received FOLFOX and 14.2% for patients who received CAPOX) than in the 6-month group (47.7% for patients who received FOLFOX and 44.9% for patients who received CAPOX). Moreover, all other toxicities were substantially lower with 3 months of treatment than with 6 months.
  • A subgroup analyses observed the following:
  • Among patients receiving FOLFOX, 6 months of therapy was superior to 3 months of therapy (HR, 1.16; 95% CI, 1.06–1.26; P = .001)
  • Among patients receiving CAPOX, 3 months of therapy was like 6 months of therapy (HR for DFS, 0.95; 95% CI, 0.85–1.06) and met the prespecified margin for noninferiority.
  • Among patients with N1 tumors (<4 positive nodes), the HR was 1.07 (0.97–1.17), and among those patients with N2 tumors (≥4 positive nodes), the HR was 1.07 (0.96–1.19).
  • Among patients with T4 tumors, a therapy duration of 3 months was inferior to a duration of 6 months (HR, 1.16; 95% CI, 1.03–1.31).
  • Among patients with low-risk tumors (T1–3, N1), 3 months of therapy was noninferior to 6 months of therapy (HR, 1.01; 95% CI, 0.90–1.12) with a 3-year DFS rate of 83.1% for patients who received 3 months of therapy and 83.3% for patients who received 6 months of therapy.
  • Among patients with high-risk tumors (T4 or N2), 6 months of therapy was superior to 3 months of therapy (HR, 1.12; 95% CI, 1.03–1.23; P = .01).

    • The IDEA study has generated much debate regarding the optimal length of therapy. It is recommended that patients and doctors weigh the pros and cons of potential diminished efficacy of 3 months of therapy versus the definite increased risk of toxicity, particularly neuropathy. CAPOX appears to be slightly more active than FOLFOX in the adjuvant setting.

    Treatment Options Under Clinical Evaluation

    Eligible patients can be considered for entry into carefully controlled clinical trials comparing various postoperative chemotherapy regimens.

    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

  • Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.
  • Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.
  • Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.
  • Schwenk W, Böhm B, Müller JM: Postoperative pain and fatigue after laparoscopic or conventional colorectal resections. A prospective randomized trial. Surg Endosc 12 (9): 1131-6, 1998.
  • Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.
  • Panettiere FJ, Goodman PJ, Costanzi JJ, et al.: Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. J Clin Oncol 6 (6): 947-54, 1988.
  • Adjuvant therapy of colon cancer--results of a prospectively randomized trial. Gastrointestinal Tumor Study Group. N Engl J Med 310 (12): 737-43, 1984.
  • Higgins GA, Amadeo JH, McElhinney J, et al.: Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report. Cancer 53 (1): 1-8, 1984.
  • Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of colorectal cancer. Why we still don't know. JAMA 259 (24): 3571-8, 1988.
  • Laurie JA, Moertel CG, Fleming TR, et al.: Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 7 (10): 1447-56, 1989.
  • Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322 (6): 352-8, 1990.
  • Wolmark N, Rockette H, Fisher B, et al.: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11 (10): 1879-87, 1993.
  • Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 345 (8955): 939-44, 1995.
  • O'Connell M, Mailliard J, Macdonald J, et al.: An intergroup trial of intensive course 5FU and low dose leucovorin as surgical adjuvant therapy for high risk colon cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-552, 190, 1993.
  • Haller DG, Catalano PJ, Macdonald JS, et al.: Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol 23 (34): 8671-8, 2005.
  • Wolmark N, Bryant J, Smith R, et al.: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90 (23): 1810-6, 1998.
  • Wolmark N, Rockette H, Mamounas E, et al.: Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 17 (11): 3553-9, 1999.
  • Okuno SH, Woodhouse CL, Loprinzi CL, et al.: Phase III placebo-controlled clinical trial evaluation of glutamine for decreasing mucositis in patients receiving 5FU (fluorouracil)-base chemotherapy. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-256, 1998.
  • Andre T, Colin P, Louvet C, et al.: Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 21 (15): 2896-903, 2003.
  • Comparison of flourouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet 355 (9215): 1588-96, 2000.
  • Sargent DJ, Goldberg RM, Jacobson SD, et al.: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345 (15): 1091-7, 2001.
  • Van Cutsem E, Twelves C, Cassidy J, et al.: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19 (21): 4097-106, 2001.
  • Hoff PM, Ansari R, Batist G, et al.: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19 (8): 2282-92, 2001.
  • Twelves C, Wong A, Nowacki MP, et al.: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352 (26): 2696-704, 2005.
  • André T, Boni C, Mounedji-Boudiaf L, et al.: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350 (23): 2343-51, 2004.
  • André T, Boni C, Navarro M, et al.: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27 (19): 3109-16, 2009.
  • Yothers G, O'Connell MJ, Allegra CJ, et al.: Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 29 (28): 3768-74, 2011.
  • Schmoll HJ, Tabernero J, Maroun J, et al.: Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol 33 (32): 3733-40, 2015.
  • Grothey A, Sobrero AF, Shields AF, et al.: Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med 378 (13): 1177-1188, 2018.
  • Rougier P, Nordlinger B: Large scale trial for adjuvant treatment in high risk resected colorectal cancers. Rationale to test the combination of loco-regional and systemic chemotherapy and to compare l-leucovorin + 5-FU to levamisole + 5-FU. Ann Oncol 4 (Suppl 2): 21-8, 1993.
    • 结肠癌治疗(PDQ®)

    临床IV期和复发性结肠癌的治疗

    临床IV期结肠癌常伴有远处转移。复发性结肠癌的治疗应根据体格检查和/或影像检查显示的复发部位而进行。除标准的影像学检查外，放射免疫显像检查还可能为临床处理提供更多信息。

    此类方法尚未被证实能改善患者的长期结果，如生存期。

    临床IV期和复发性结肠癌的治疗方法包括：

  • 局部复发癌采用手术切除。
  • 部分转移性肿瘤患者中，对于原发灶梗阻或出血，可采用外科切除吻合或粪便转流。
  • 部分肝转移患者可行手术切除（单个或多个转移癌行手术切除的5年治愈率超过20%）或消融治疗。
  • 部分患者的孤立性肺或卵巢转移癌，可行手术切除。
  • 姑息性放疗
  • 姑息性化疗
  • 靶向治疗
  • 临床试验评估新药和生物治疗
  • 临床试验对比各种化疗方案和生物治疗，单用或联合应用。

    • 肝转移治疗

    约50%的结肠癌患者出现肝转移，或在确诊时或在疾病复发时。仅有少数肝转移患者具有手术机会。不断改良的肿瘤消融术和局部化疗和全身化疗可作为临床治疗手段，包括：

  • 手术。
  • 新辅助化疗。
  • 局部消融。
  • 辅助化疗。
  • 动脉灌注化疗。

    • 手术

    肝转移可行手术切除，主要基于以下几方面因素：

  • 病灶数目少。
  • 肝内病灶。
  • 未侵犯大血管。
  • 无/少有肝外病灶。
  • 充分的肝储备功能。

    • 包括美国中北部癌症治疗组（NCCTG-934653 [NCT00002575]）在内的多项非随机的临床试验指出，具有手术可能的肝转移患者如肿瘤完全切除，其5年生存率可达25%-40%。

    [循证依据等级：3iiiDiv] 不断改进的手术技术和术前影像检查可有效筛选手术患者。此外，多项研究还显示多药联合化疗用于曾被认为不可手术的孤立的肝转移患者，部分患者可在化疗后行手术治疗。

    新辅助化疗用于不可切除的肝转移

    曾被认定为不可手术切除的肝转移患者如果临床化疗有效，则仍有手术机会。这些患者的5年生存率与可手术切除的患者无差异。

    目前尚未达成共识

    局部消融

    射频消融作为一种安全的治疗手段（术后并发症发生率2%，死亡率<1%），有可能会产生长期的控制肿瘤作用。

    射频消融和冷冻消融

    可用于不可手术切除及不宜行肝切除的患者。

    其他用于治疗肝转移瘤的局部消融技术包括栓塞和间质放射治疗。

    局限性肺转移患者以及肝肺同时转移患者还可以考虑手术切除，部分患者可存活5年。

    可切除肝转移的辅助或新辅助化疗

    辅助化疗在肝转移潜在治愈性手术切除后的作用尚不清楚。

    循证依据（可切除肝转移的辅助或新辅助化疗）：

    由于进度过慢，两项研究均提早关闭。

  • 173例患者（预期200例患者）
  • 化疗组和观察组的5年无疾病生存率分别为33.5%和26.7%（Cox多因素分析：复发率或死亡率OR值0.66；95% CI, 0.46-0.96；P=0.028）。两组患者的5年总体生存率无显著差异（化疗组51.1%，对照组41.1%；死亡率OR值，0.73；95% CI；0.48–1.10； P=0.13）。
  • 由于进度过慢，该研究提早关闭
  • 化疗组和单独手术的中位无进展生存期分别为27.9个月和18.8个月（HR，1.32；95% CI；1.00–1.76；P =0.058）。
  • 两组的中位总体生存期分别为62.2个月和47.3个月（HR，1.32；95% CI，0.95-1.82；P=0.095）。

    • 随后有两项研究对多药联合在结肠癌肝转移术后的辅助化疗中的作用进行了探索。

  • 一项III期临床试验将306例肝转移术后患者分为5-FU/LV组和FOLFIRI组。
  • 两组患者的无疾病生存期（5-FU/LV组21.6个月，FOLFIRI组24.7个月；HR，0.89；log-rank P=0.44）或总体生存期（HR，1.09；95%CI，0.72–1.64）均无差异。
  • 欧洲癌症研究和治疗组织（EORTC-40983 [NCT00006479]）将364例至少有4个及以上转移灶的患者随机分为围手术期 FOLFOX化疗组（术前和术后各6个周期）或单独手术组。
  • 单独手术组的无进展生存率为28.1% (95.66% CI，21.3–35.5) ，围手术期化疗组35.4% (28.1–42.7；HR 0.79；0.62–1.02；P=0.058)。两组患者的总体生存期无明显差别。随后分析显示，在采用适当的治疗后，两组患者的无进展生存率差距升至8.1%（28.1% [21.2–36.6]至36.2% [28.7–43.8]；HR, 0.77 [0.60–1.00]；P= 0.041）。在肝转移切除术的患者中，两组患者的无进展生存率差距升至9.2%（33.2% [25.3–41.2]至42.4% [34.0–50.5]；HR 0.73 [0.55–0.97]；P=0.025）。
  • 可逆性术后并发症更多见于化疗组，分别为化疗组（40/159，25%），单独手术组（27/170，16%）（P=0.04）

    • 还没有1级循证依据证实围手术期或术后化疗能改善肝转移患者的术后总体生存期。然而，根据EORTC研究的结果，部分临床医生认为围手术期或术后化疗具有一定的可行性。

    肝切除后动脉灌注化疗

    肝转移患者采用氟脲苷的动脉灌注化疗具有较好的临床疗效。与全身化疗相比，未观察到持续的生存期延长。

    荟萃分析

    循证依据（肝切除后动脉灌注化疗）：

    两项试验对肝切除术后的氟脲苷动脉灌注化疗的辅助治疗进行评估。

  • 有研究对氟脲苷和地塞米松肝动脉灌注联合5-FU/LV的全身化疗与仅5-FU/LV全身化疗进行对比。结果显示，联合治疗患者2年无进展生存率和总体生存率优于仅全身化疗。
  • [循证依据等级：1iiA]
  • 联合治疗组
  • 还有一项研究将109例结直癌伴1-3枚淋巴结转移的癌症患者在术前随机分配，一组未予治疗，另一组术后行肝动脉灌注化疗联合5-FU全身化疗。
  • 在这些随机病例中，有27%的病例在手术时被认为不符合要求，只有75例患者可进行复发和生存期评估。
  • 虽然肝癌复发风险降低，但两组患者的中位或4年生存期并无显著差异。

    • 需要进一步的研究来评估这种治疗方法，并确定是否有更有效的联合化疗方案，仅行全身化疗便可获得与肝动脉灌注化疗联合全身化疗相似的结果。

    多项研究显示肝动脉灌注化疗可增加局部不良反应，如肝功能异常和致命的胆道硬化症。

    临床IV期和复发性结肠癌的治疗

  • 手术。
  • 化疗和靶向治疗。

    • 手术

    复发性或晚期结肠癌患者的治疗取决于病灶部位。局部复发和/或仅肝/或仅肺转移的患者，如条件允许，应行手术治疗。这是一种潜在治愈的治疗方法。

    化疗和靶向治疗+D577:D589

    下面将介绍一些美国FDA批准的用于治疗转移性结直肠癌的临床药物，可单药使用，也可联合应用：

  • 5-FU。
  • 卡培他滨。
  • 伊立替康。
  • 奥沙利铂。
  • 贝伐珠单抗。
  • FOLFOXIRI（伊立替康、奥沙利铂、亚叶酸钙、5-FU）。
  • 西妥昔单抗。
  • 阿柏西普。
  • 雷莫芦单抗。
  • 帕尼单抗。
  • 抗上皮生长因子受体抗体（EGFR）与抗血管内皮生长因子（VEGF）抗体联合一线化疗。
  • 瑞戈非尼。
  • TAS-102。
  • 派姆单抗。

    • 5-FU

    在其他有效的化疗药上市前，5-FU是唯一一个有效的化疗药物，对局部晚期、不可手术切除、转移癌患者具有部分缓解作用，并能延长患者的疾病进展时间（TTP）。

    与支持治疗相比，还能改善患者的生存期和生活质量。

    多项临床试验对各种5-FU/LV方案（不同剂量和用药方式）的疗效和不良反应进行分析，结果显示在12个月内，中位生存期无明显差异。

    卡培他滨

    在多药联合化疗前，有两项随机试验提示卡培他滨的临床疗效等同于Mayo方案中的5-FU/LV方案。

    [循证依据等级：1iiA]

    伊立替康

    有3项随机研究结果显示，伊立替康或奥沙利铂联合5-FU/LV应用，可提高临床缓解率，改善PFS和OS。

    循证依据（伊立替康）：

  • 一项组间试验（NCCTG-N9741 [NCT00003594]）将伊立替康/5-FU/LV (IFL) 与奥沙利铂LV/5-FU (FOLFOX-4)作为转移性结直肠癌患者一线治疗方法进行对比研究。
  • FOLFOX-4患者无进展生存期和总体生存期均优于IFL组。IFL组和FOLFOX-4组患者的中位无进展生存期分别为6.9个月和8.7个月（P=0.014；HR，0.74；95% CI，0.61-0.89）。两组的总体生存期分别为15.0个月和19.5个月（P=0.001；HR，0.66；95% CI，0.54–0.82）。
  • 随后，两项试验对FOLFOX和FOLFIRI进行对比研究。两组患者如疾病出现进展，均可以互换一线治疗方案。
  • [循证依据等级：1iiDiii]
  • 两项研究的治疗组的无进展生存期和总体生存期相当。
  • 静脉推注、输注或卡培他滨联合-伊立替康-塞来昔布（BICC-C [NCT00094965）试验研究了数种以伊立替康为基础方案在不可切除的转移性结直肠癌中的应用，包括FOLFIRI、伊立替康联合静推5-FU/LV（mIFL）以及卡培他滨/伊立替康（CAPIRI）。
  • [循证依据等级：1iiA]
  • 该研究随机分配430例患者。由于入组过慢，该研究提早关闭。
  • FOLFIRI治疗组患者的无进展生存期高于mIFL组（7.6 个月比 5.9个月，P=0.004）和CAPIRI（7.6个月比5.8个月，P=0.015）。
  • CAPIRI 组的3级及以上的不良反应最多，如恶心、呕吐、腹泻、脱水和手足综合征。

    • 自这些研究成果发表以来，FOLFOX和FOLFIRI方案得到临床认可，用于一线治疗转移性结直肠癌。

    当采用以伊立替康为基础的方案作为转移性结直肠癌患者一线治疗方法时，FOLFIRI是首选。

    [循证依据等级：1iiDiii]

    奥沙利铂

    随机III期临床试验结果已提出可采用卡培他滨替代静脉输注5-FU。两项III期临床试验对5-FU/奥沙利铂 (FUOX) 与卡培他滨/奥沙利铂 (CAPOX)进行了对照研究。

    循证依据（奥沙利铂）：

  • AIO结直肠研究小组将474例患者随机分为5-FU/LV/奥沙利铂 (FUFOX)组和CAPOX组。
  • CAPOX组和FUFOX组的中位无进展生存期分别为7.1个月和8.0个月（HR，1.17；95% CI，0.96–1.43；P=0.117），HR位于预设的等值范围内。
  • 西班牙协作工作组随机将348例患者分为CAPOX组和FUOX组。
  • 循证依据等级：1iiDii
  • CAPOX组和FUOX组的疾病无进展期分别为8.9个月和9.5个月（P=0.153），符合预设的非劣效性范围。

    • 当采用以奥沙利铂为基础的方案作为转移性结直肠癌的一线治疗方法时，CAPOX方案并不劣于FUOX方案。

    在西妥昔单抗、帕尼单抗、贝伐珠单抗、阿柏西普作为二线治疗前，伊立替康作为二线化疗用于5-FU/LV一线治疗的患者。结果显示，与其他静脉输注5-FU或支持治疗相比，伊立替康的二线化疗能改善患者的总体生存期。

    同样，还有一项III期临床试验将伊立替康和5-FU/LV经治后出现进展的患者随机给予静推和静脉输注5-FU/LV （LV5FU2）、奥沙利铂单药治疗、FOLFOX-4方案。FOLFOX-4组和LV5FU2组的中位TTP分别为4.6个月和2.7个月（log-rank检测，二项式 P<0.001）。

    [循证依据等级：1iiDii]

    贝伐珠单抗

    贝伐珠单抗是一类与VEGF结合的人类单克隆抗体。可在FOLFIRI或FOLFOX方案中联用贝伐珠单抗，用于转移性结直肠癌的一线治疗。

    循证依据（贝伐珠单抗）：

  • 贝伐珠单抗批准使用后，BICC-C试验进行了修正。另有117例患者随机接受了FOLFIRI/贝伐珠单抗或mIFL/贝伐珠单抗治疗。
  • 虽然PFS作为主要终点未见明显差异，FOLFIRI/贝伐珠单抗组患者的总体生存期明显得到改善（尚未达到主要终点的中位随诊时间22.6个月比19.2个月，P=0.007）
  • 既往未经治的转移性结直肠癌患者随机被分为IFL组或IFL/贝伐珠单抗联合治疗组。
  • [循证依据等级：1iiA]
  • 结果显示，IFL/贝伐珠单抗联合治疗组的无进展生存期优于IFL/安慰剂组（10.6个月比6.2个月，疾病进展HR，0.54；P<0.001）。IFL/贝伐珠单抗联合治疗组总体生存期优于IFL/安慰剂组（20.3个月比15.6个月，死亡率HR, 0.66；P<0.001）。
  • 尽管直接数据不足，但在标准治疗中，根据NCCTG-N9741试验结果，贝伐珠单抗已与FOLFOX方案联合应用作为标准一线治疗方法。
  • 随后，在一项随机的III期研究中，采用2×2析因设计将未经治疗的临床IV期结直肠癌患者随机分配CAPOX和FOLFO+D635:D637X-4组，然后再将贝伐单抗和安慰剂对照研究。无进展生存期是主要终点。
  • 本项试验共纳入1401例患者。贝伐珠单抗治疗组患者的中位无进展生存期为9.4个月，安慰剂组患者为8.0个月（HR，0.83；97.5% CI，0.72–0.95；P=0.0023）。
  • [循证依据等级：1iiDii]
  • 贝伐珠单抗治疗组患者的中位总体生存期为21.3个月，安慰剂组患者为19.9个月（HR，0.89；97.5% CI，0.76–1.03；P=0.077）。
  • 含CAPOX方案的治疗组的中位无进展生存期（意向性分析）为8.0个月，FOLFOX-4组为8.5个月（HR，1.04；97.5% CI，0.93-1.16），97.5% CI的上限值低于预设非劣效性的界限值1.23。
  • 与最初的Hurwitz研究相比，贝伐珠单抗对患者总体生存期的影响可能会有所降低。
  • 美国东部肿瘤协作组织将5-FU/亚叶酸钙和伊立替康治疗后出现病情进展的患者随机给予FOLFOX或FOLFOX/贝伐珠单抗治疗。
  • FOLFOX/贝伐珠单抗组较FOLFOX组的无进展生存期（分别为7.43个月和4.7个月，HR，0.61；P<0.0001）和总体生存期（分别为12.9个月和10.8个月，HR，0.75；P=0.0011）明显改善，且有统计学意义。
  • [循证依据等级：1iiA]

    • 基于这些研究，贝伐珠单抗可合理加用到FOLFIRI或FOLFOX方案作为一线治疗用于转移性结直肠癌。一个主要问题是，当贝伐珠单抗作为一线治疗的组成药物时，在一线治疗后，还能否继续使用？随机对照试验数据在2012年美国临床肿瘤学会（ASCO）年会上发布。

    在这项临床试验中，在含贝伐珠单抗的一线化疗后病情出现进展的820例转移性结直肠癌患者被随机分为单纯化疗组和贝伐单抗联合化疗组。结果显示与单纯化疗组相比，贝伐单抗联合化疗组的中位总体生存期为11.2个月，单纯化疗组为9.8个月（HR，0.81；95% CI，0.69–0.94；log-rank检验，P=.0062）。接受贝伐单抗联合化疗组的中位无进展生存期为5.7个月，单纯化疗组为4.1个月（HR，0.68；95% CI，0.59-0.78；log-rank检验，P<0.0001）。

    [循证依据等级：1iiA]

    FOLFOXIRI

    循证依据（FOLFOXIRI）：

  • 一项随机III期临床试验，纳入508例未经治的转移性结直肠癌患者，将FOLFOXIRI联合贝伐珠单抗与FOLFIRI联合贝伐珠单抗进行对比研究。
  • [循证依据等级：1iiDiii]
  • FOLFOXIRI组的中位无进展生存期为12.1个月，FOLFIRI组为9.7个月（进展HR，0.75；95%CI，0.62–0.90；P=0.003）。两组的总体生存期无显著性差异（31.0个月比25.8个月；HR死亡率，0.79；95%CI，0.63-1.00；P=0.054）。
  • 3级和4级不良反应更多见于FOLFOXIRI治疗组，包括中性粒细胞减少症、口腔炎和周围神经病变。

    • 西妥昔单抗

    西妥昔单抗是一种抗EGFR的部分人源性单克隆抗体。由于西妥昔单抗可影响细胞膜表面的酪氨酸激酶信号通路，可导致激活EGFR下游通路的肿瘤突变，如KRAS突变，会使其对西妥昔单抗不敏感。在多药化疗中加用西妥昔单抗可提高结肠癌不伴KRAS突变（即KRAS野生型）患者的生存率。但重要的是，当西妥昔单抗加入含贝伐单抗的多药化疗方案时，KRAS突变型患者的临床预后可能更差。

    循证依据（西妥昔单抗）：

  • 一项随机的II期研究纳入了应用伊立替康治疗后疾病进展的患者，将患者随机分为西妥昔单抗单药组或伊立替康/西妥昔单抗联合治疗组。
  • [循证依据等级：3iiiDiv]
  • 西妥昔单抗单药治疗组患者的中位疾病进展期为1.5个月，而伊立替康/西妥昔单抗联合治疗组为4.2个月。
  • [循证依据等级：1iiDii]
  • 基于这项研究，西妥昔单抗被批准用于5-FU和伊立替康耐药的转移性结直肠癌。
  • Crystal研究（EMR 62202-013[NCT 00154102]）随机将1198例临床IV期结直肠癌患者分为FOLFIRI组和FOLFIRI/西妥昔单抗联合治疗组。
  • [循证依据等级：1iiDii]
  • FOLFIRI联用西妥昔单抗可改善患者的无进展生存期（HR，0.85；95%CI，0.72–0.99；log rank检验 P=.048），但对患者的总体生存期无影响。
  • 对转移性结直肠癌患者的回顾性研究表明，抗EGFR抗体治疗仅对野生型KRAS（如KRAS基因第12或13密码子缺乏激活性突变）的患者有效。
  • 在Crystal研究中，对不同KRAS状态的作用进行了亚组分析。KRAS突变状态与肿瘤治疗的临床疗效显著相关性（P=0.03），而对无进展生存期无影响（P=0.07）。在KRAS野生型肿瘤患者中，FOLFIRI/西妥昔单抗联合或更具有临床意义（HR，0.68；95%CI，0.50-0.94）。
  • 在一项随机试验中，转移性结直肠癌患者采用卡培他滨/奥沙利铂/贝伐单抗联合或不联合西妥昔单抗治疗。
  • [循证依据等级：1iiDii]
  • 西妥昔单抗联合组的中位无进展生存期为9.4个月，未采用西妥昔单抗治疗组的中位无进展生存期为10.7个月（P=.01）。
  • 在亚组分析中，采用西妥昔治疗的KRAS突变型患者比野生型KRAS肿瘤患者采无进展生存期显著减少（8.1个月比10.5个月；P=0.04）。
  • 与未采用西妥昔单抗治疗的KRAS突变患者相比，采用西妥昔单抗治疗的突变型KRAS肿瘤患者的无进展生存期更短（8.1个月比12.5个月；P=0.003），总体生存期也显著缩短（17.2个月比24.9个月；P=0.03）。
  • 医学研究委员会（MRC）（COIN[NCT00182715]试验）探讨了在氟尿嘧啶和奥沙利铂联合化疗的一线治疗中加用西妥昔单抗治疗KRAS野生型肿瘤能否有临床意义的问题。
  • 此外，MRC还对间歇化疗与持续化疗的疗效进行评估。将1630名患者随机分成三个治疗组：
  • A组：氟尿嘧啶/奥沙利铂。
  • B组：氟尿嘧啶/奥沙利铂/西妥昔单抗。
  • C组：氟尿嘧啶/奥沙利铂交替用药。
  • 分别对A和B组以及和A和C组进行对比分析，并将研究成果单独发表。
  • 在KRAS野生型肿瘤患者中（A组，n=367；B组，n=362），两组总体生存期无差异（中位生存期，对照组17.9个月[IQR为10.3-29.2]，西妥昔单抗组为17.0个月[IQR为9.4-30.1]；HR为1.04；95%CI0.87-1.23；P=0.67）。同样，两组患者无进展生存期无差异（对照组8.6个月[IQR，5.0-12.5]，西妥昔单抗组8.6个月[IQR，5.1-13.8]；HR，0.96；95%CI，0.82-1.12；P=0.60）。
  • [循证依据等级：1iiA]
  • 联用西妥昔单抗的临床意义不大，其原因尚不清楚。亚组分析表明，卡培他滨的使用与不良预后具有相关性，西妥昔单抗很少作为二线治疗。
  • 持续治疗组（A组）和间歇治疗组（C组）两组患者间未见差异。意向性治疗患者（两组均为815）的中位生存期为A组15.8个月（IQR，9.4-26.1），C组14.4个月（IQR，8.0-24.7）（HR，1.084；80%可信区间，1.008-1.165）。符合治疗方案的患者中包括治疗12周无疾病进展的患者，以及随机分配继续治疗或处于化疗间歇的患者（A组，n=467；C组，n=511），A组的中位生存期为19.6个月（IQR，13.0-28.1），C组为18.0个月（IQR，12.1-29.3）（HR，1.087；95%CI，0.986-1.198）。在这两个分析中，HR可信区间的上限都超过预设的非劣效性阈值。间歇化疗被认为不具有非劣效性，其在患者预后方面临床意义不大。
  • OPUS研究是一项开放随机多中心的II期临床试验，旨在分析表达EGFR的转移性结直肠癌患者，来评估一线治疗中应用FOLFOX方案联合西妥昔单抗对临床疗效的影响。
  • 在该试验中，将344名患者随机分配，单独应用FOLFOX-4治疗或FOLFOX-4/西妥昔单抗联合治疗。结果显示两组患者的临床有效率和无进展生存期无统计学差异。
  • 在亚组分析中，对KRAS野生型肿瘤患者分别进行分析。在KRAS野生型患者中，两组的临床有效率（61%比37%，P=0.011）和无进展生存期（7.7个月比7.2个月，P=0.0163）有显著统计学差异。
  • 在亚组分析中，采用FOLFOX-4/西妥昔单抗治疗的KRAS突变患者的无进展生存期更差，劣于采用FOLFOX-4单一方案治疗的KRAS突变患者（5.5个月比8.6个月，P=0.0192）。
  • [循证依据等级：1iiD]

    • 阿柏西普

    阿柏西普是一种新型抗VEGF分子制剂，常被用于转移性结直肠癌的二线治疗。

    循证依据（阿柏西普）：

  • 在一项试验中，将1226名患者随机分为两组，一组阿柏西普（4mg/kg，静脉滴注），另一组安慰剂，每2周联合FOLFIRI化疗。
  • [循证依据等级：1A]
  • 采用阿柏西普/FOLFIRI联合治疗患者的总体生存率显著高于安慰剂/FOLFIRI组，联合治疗组的中位生存期为13.50个月，安慰剂组为12.06个月（HR，0.817；95.34%CI，0.713–0.937；P=.0032）。
  • 阿柏西普/FOLFIRI联合治疗患者的无进展生存率明显延长，中位无进展生存期为6.90个月，安慰剂组为4.67个月（HR，0.758；95%CI，0.661-0.869；P<0.0001）。
  • 根据这些结果，阿柏西普/FOLFIRI联合用药可被作为二线治疗方案，用于FOLFOX方案治疗后的患者。在二线治疗中，是继续贝伐单抗，还是将阿柏西普作为初始二线治疗，尚未缺少临床研究及相关数据。

    • 雷莫芦单抗

    雷莫芦单抗是一种与血管内皮生长因子受体2结合的完全人源化单克隆抗体。

    循证依据（雷莫芦单抗）：

  • 在随机、非盲性III期RAISE（NCT 01183780）研究中，将纳入1072例经一线化疗进展的临床IV期结直肠癌患者随机分配，FOLFIRI单方案治疗组或FOLFIRI/雷莫芦单抗联合治疗组。
  • [循证依据等级：1iiA]
  • 与FOLFIRI单方案治疗组相比，FOLFIRI/雷莫芦单抗联合治疗组患者的中位总体生存期（13.3个月比11.7个月；HR，0.84；P=0.0219）和无进展生存期（5.7个月比4.5个月；HR，0.793；P=0.0005）具有明显优势。
  • 3级不良反应在FOLFIRI/雷莫芦单抗联合治疗组更为常见，包括3级中性粒细胞减少症。
  • 根据这些数据，FOLFIRI/雷莫芦单抗可作为二线治疗方案，用于FOLFOX/贝伐单抗治疗后的患者。在二线治疗中，是继续沿用贝伐单抗，还是将雷莫芦单抗作为初始二线治疗，尚未得到临床试验的验证。

    • 帕尼单抗

    帕尼单抗是一种抗EGFR的完全人源化抗体。FDA批准帕尼单抗用于化疗无效的转移性结直肠癌。

    在临床试验中，帕尼单抗作为单药或联合治疗均具有一定的临床疗效。该药对PFS和OS影响与西妥昔单抗相似。二者或有一致的阶级效应。

    循证依据（帕尼单抗）：

  • 在III期临床试验中，随机将化疗耐受的结直肠癌患者分为帕尼单抗组和最佳支持治疗组。
  • [循证依据等级：1iiDiii]
  • 帕尼单抗治疗组患者的无进展生存期得到明显改善（8周比7.3周；HR，0.54；95%CI，0.44-0.66；P<0.0001）。
  • 两组患者的总体生存期无差异，这有可能与最佳治疗组中76%的患者采用帕尼单抗治疗有关。
  • 帕尼单抗联合化疗用于转移性结直肠癌进行疗效评估的临床试验中[NCT00364013]，将1183例患者随机分配，FOLFOX-4单方案治疗和FOLFOX-4/帕尼单抗联合治疗分别作为转移性结直肠癌的一线治疗。该研究不断修正以扩大样本量，分别统计KRAS野生型和突变型的患者数量。
  • [循证依据等级：1iiDiii]
  • 对于KRAS野生型肿瘤患者，与FOLFOX-4单方案治疗组相比，帕尼单抗/FOLFOX-4联合治疗组患者的无进展生存期显著延长，具有统计学意义（HR，0.80；95%CI，0.66–0.97；P=0.02，分层log-rank检验）。
  • 帕尼单抗/FOLFOX-4联合治疗组的中位无进展生存期为9.6个月（95% CI，9.2-11.1个月），FOLFOX-4单方案治疗组为8.0个月（95%CI，7.5-9.3个月）。两组患者的总体生存期无显著差异（HR，0.83；95% CI，0.67–1.02；P=.072）。
  • 对于KRAS突变患者，联合帕尼单抗会不能提高无进展生存期（HR，1.29；95%CI，1.04-1.62；P=0.02，分层log-rank检验）。
  • 帕尼单抗/FOLFOX-4联合治疗组和FOLFOX-4单方案治疗组的中位无进展生存期分别为7.3个月（95% CI，6.3-8.0个月）和8.8个月（95% CI，7.7-9.4个月）。
  • 随后，一项回顾性分析对野生型KRAS基因的外显子2进行检测，来鉴别KRAS突变和BRAF突变。
  • [循证依据等级：3iiiA]
  • 在最初被确认为KRAS第2外显子没有突变的620名患者中，108名患者（17%）发现了额外的RAS突变，53名患者（8%）发现了BRAF突变。在回顾性分析中，与FOLFOX-4/panitumab组相比，没有RAS或BRAF突变的患者应用FOLFOX-4/panitumab组可以获得更长的PFS（10.8个月vs.9.2个月，P=0.002）和OS（28.3个月vs.20.9个月，P=0.02）。
  • 同样，在无KRAS突变的转移性结肠癌患者中，与单独使用FOLFOX /贝伐单抗的方案相比，在FOLFOX /贝伐单抗的方案中添加帕尼单抗导致PFS缩短和毒性反应加重（HR分别为11.4个月和10.0个月，HR） ，1.27； 95％CI，1.06-1.52）。
  • [循证依据等级：1iiDiii]
  • 在另一项研究（NCT00339183）中，将转移性结直肠癌且经氟尿嘧啶治疗的患者随机分为两组，一组给予FOLFIRI单方案治疗，另一组行FOLFIRI/帕尼单抗联合治疗。
  • [循证依据等级：1iiDiii]
  • 在随后分析中，KRAS野生型肿瘤患者具有显著的无进展生存期优势（HR，0.73；95%CI，0.59–0.90；P=0.004，分层log-rank）。
  • 帕尼单抗/FOLFIRI联合治疗组患者的中位无进展生存期为5.9个月（95%CI，5.5-6.7个月），FOLFIRI单方案组为3.9个月（95%CI，3.7-5.3个月）。
  • 两组患者的总体生存期无显著差异。突变型KRAS肿瘤患者没有从帕尼单抗中获益。

    • 抗EGFR抗体与抗VEGF抗体联合一线化疗的对比研究

    在临床IV期结直肠癌患者的治疗中，KRAS野生型患者是否应采用抗EGFR抗体联合化疗或抗VEGF抗体联合化疗，目前尚不清楚。有两项临床试验尝试对此进行研究。

    循证依据（抗EGFR抗体与VEGF抗体联合化疗的比较）

  • FIRE-3[NCT00433927]研究将592例KRAS外显子2野生型未经治的癌症患者进行随机分配，一组给予FOLFIRI/西妥昔单抗（297例），另一组给予FOLFIRI/贝伐珠单抗治疗（295例）。研究的主要终点是客观缓解率。
  • [循证依据等级：1iiA]
  • 两组间的客观缓解率无显著差异。FOLFIRI/西妥昔单抗治疗组的客观缓解率为62.0%（95%CI 56.2-67.5），FOLFIRI/贝伐珠单抗治疗组为58.0%（95%CI 52.1-63.7；OR 1.18；95%CI 0.85-1.64；P=0.18）。
  • 西妥昔单抗组的中位无进展生存期为10.0个月（95%CI，8.8-10.8），贝伐单抗组为10.3个月（95%CI，9.8-11.3）（HR，1.06；95%CI，0.88-1.26；P=0.55）。
  • 西妥昔单抗组的中位总体生存期为28.7个月（95% CI，24.0-36.6），贝伐单抗组为25.0个月（22.7-27.6）（HR为0.77；95%CI，0.62-0.96；P=0.017）。
  • 随后对RAS野生型肿瘤患者进行分析（KRAS和NRAS基因突变热点的测序，包括外显子2密码子12和13；外显子3密码子59和61；外显子4密码子117和146），西妥昔单抗组的中位总体生存期为33.1个月（95%CI，24.5-39.4），贝伐单抗组为25.0个月（95%CI，23.0-28.1）（HR，0.70；95%CI，0.54–0.90；P=.0059）。
  • 值得注意的是，贝伐单抗组52%患者随后采用了西妥昔单抗或帕尼单抗治疗。
  • 癌症和白血病B组组间研究80405[NCT00265850]在2014年ASCO会议上发布。该研究纳入2334例KRAS野生型未治的患者，将患者随机分为化疗（FOLFOX或FOLFIRI）联合贝伐单抗治疗组或化疗/西妥昔单抗治疗组。总体生存期是主要终点。
  • [循证依据等级：1iiDiii]
  • 贝伐单抗组和西妥昔单抗组患者的总体生存期无统计学差异。化疗/贝伐单抗组的总体生存期为29.04 [25.66–31.21]个月，化疗/西妥昔单抗为29.93 [27.56–31.21]个月（HR，0.92[0.78，1.09]；P=0.34）。

    • 根据这两项研究，化疗联合贝伐单抗或西妥昔单抗用于KRAS野生型的转移性结直肠癌患者无明显差异。然而，在KRAS野生型患者的临床治疗中，联用抗EGFR抗体可有效改善患者的总体生存期。

    瑞戈非尼

    瑞戈非尼是多种酪氨酸激酶途径的抑制剂，包括血管内皮生长因子。2012年9月，FDA批准瑞戈非尼用于既往治疗失败的患者。

    循证依据（瑞戈非尼）

  • 一项单中心的760例经治的转移性结直肠癌患者的临床研究对瑞戈非尼的安全性和有效性进行了探索。按照2:1的比例，将患者随机分为瑞戈非尼或安慰剂联合最佳支持治疗组。
  • 瑞戈非尼治疗组患者的总体生存期得到明显改善。瑞戈非尼组为6.4个月，安慰剂组为5.0个月（HR为0.77；95% CI0.64-0.94；P=0.0052）。

    • TAS-102

    TAS-102（Lonsurf）是一种口服的胸腺嘧啶核苷类似物、曲氟尿苷、胸腺嘧啶磷酸化酶抑制剂、盐酸替吡拉西的复合制剂。曲氟尿苷，以三磷酸形式抑制胸苷酸合成酶，具有抗肿瘤作用。盐酸替吡拉西是胸苷磷酸化酶的有效抑制剂，能有效降解曲氟尿苷。曲氟尿苷和替吡拉西结合可升高血浆中曲氟尿苷水平。

    循证依据（TAS-102）：

  • 一项 III期双盲研究（RECOURSE[NCT 01607957]）随机分配了800例临床IV期已经对两种治疗产生耐药的结直肠癌患者。患者必须既往采取过5-FU、奥沙利铂、伊立替康、贝伐单抗治疗。如果患者KRAS野生型，则必须接受过西妥昔单抗或帕尼妥单抗治疗。按2:1比例将患者随机分配，一组采用最佳支持治疗联合TAS-102（n=534），另一组最佳支持治疗联合安慰剂（n=266）。患者的中位年龄为63岁，大多数患者（60%-63%）曾接受过四种或以上的治疗方案。所有患者既往均曾采用过氟尿嘧啶、伊立替康、奥沙利铂和贝伐单抗治疗。另外，其中有52%患者采用过EGFR抑制剂治疗。约20%患者曾接受瑞戈非尼治疗。
  • [循证依据等级：1iiA]
  • TAS-102，用药剂量为35mg/m2，每日两次，每次5天，休息2天，连用2周，然后休息14天。
  • 研究主要终点是总体生存期。TAS-102治疗组患者的中位总体生存期为7.1个月，安慰剂组为5.3个月（HR，0.68；P<0.0001）。
  • TAS-102组中位无进展生存期为2个月，安慰剂组为1.7个月（HR，0.48；P<0.0001）。
  • 研究的次要终点是无进展生存期、总有效率和疾病控制率。
  • TAS-102治疗组的总有效率为1.6%，其中1例完全缓解，1例部分缓解。安慰剂的总有效率为0.4%（P=0.29）。

    • 基于RECOURSE临床试验结果，FDA批准TAS-102用于治疗转移性结直肠癌。

    派姆单抗

    约4%IV期结直肠癌患者的肿瘤有微卫星不稳定；这也被称为高度微卫星不稳定（MSI-H）。MSI-H表型与MLH1、MSH2、MSH6和PMS2基因的胚系缺陷有关，是遗传性非息肉样结直肠癌（HNPCC）或林奇综合征患者中常见的表型。由于上述某个基因在DNA甲基化后沉默，患者也出现MSI-H表型。可采用分子遗传学检测微卫星不稳定性，在肿瘤组织中观察微卫星不稳定性，或者通过免疫组化检测检测错配修复蛋白的缺失。

    2017年5月，FDA批准派姆单抗，即程序性细胞死亡蛋白1（PD-1）抗体，用于治疗微卫星不稳定性肿瘤。

  • FDA批准该药的依据是149例MSI-H或DNA错配修复缺失患者的数据，这些患者来源于5项无对照组、多队列、多中心、单臂临床试验。其中90例结直肠癌，59例被诊断为其他癌症（14种癌症）。派姆单抗有两种用药方式，一种是每次200mg，每3周重复；另一种10mg/kg，每2周重复。持续治疗，直到出现不可耐受的不良反应或疾病进展。主要疗效观察指标为客观缓解率，由单盲独立中心的影像科医生根据实体瘤反应评价标准（RECIST）1.1和疗效持续时间进行评价。
  • 客观缓解率为39.6%（95% CI，31.7–47.9）。
  • 78%患者采用派姆单抗治疗，临床疗效可持续6个月甚或更长。完全缓解11例，部分缓解48例。
  • 虽然肿瘤类型不同，但客观缓解率相近。结直肠癌为36%，其他类型肿瘤（14种）为46%。

    • 正处于临床评估阶段的治疗方法

    正处于临床评估阶段用于临床IV期和复发性结肠癌的方法，包括：

  • 临床试验评估新药和生物治疗
  • 临床试验对比各种化疗方案和生物治疗，单用或联合应用。

    • 当前的临床试验

    采用我们的临床试验搜索引擎，可查询正招募患者的NCI支持的癌症临床试验。搜索可按试验地点、治疗类型、药物名称及其他标准进行设置。还有一些临床试验相关的基本信息。

    参考文献

  • Serafini AN, Klein JL, Wolff BG, et al.: Radioimmunoscintigraphy of recurrent, metastatic, or occult colorectal cancer with technetium 99m-labeled totally human monoclonal antibody 88BV59: results of pivotal, phase III multicenter studies. J Clin Oncol 16 (5): 1777-87, 1998.
  • Wagman LD, Kemeny MM, Leong L, et al.: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 8 (11): 1885-93, 1990.
  • Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 77 (11): 1241-6, 1990.
  • Scheele J, Stangl R, Altendorf-Hofmann A, et al.: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110 (1): 13-29, 1991.
  • Adson MA, van Heerden JA, Adson MH, et al.: Resection of hepatic metastases from colorectal cancer. Arch Surg 119 (6): 647-51, 1984.
  • Coppa GF, Eng K, Ranson JH, et al.: Hepatic resection for metastatic colon and rectal cancer. An evaluation of preoperative and postoperative factors. Ann Surg 202 (2): 203-8, 1985.
  • Gayowski TJ, Iwatsuki S, Madariaga JR, et al.: Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 116 (4): 703-10; discussion 710-1, 1994.
  • Fernández-Trigo V, Shamsa F, Sugarbaker PH: Repeat liver resections from colorectal metastasis. Repeat Hepatic Metastases Registry. Surgery 117 (3): 296-304, 1995.
  • Jaeck D, Bachellier P, Guiguet M, et al.: Long-term survival following resection of colorectal hepatic metastases. Association Française de Chirurgie. Br J Surg 84 (7): 977-80, 1997.
  • Taylor M, Forster J, Langer B, et al.: A study of prognostic factors for hepatic resection for colorectal metastases. Am J Surg 173 (6): 467-71, 1997.
  • Elias D, Cavalcanti A, Sabourin JC, et al.: Resection of liver metastases from colorectal cancer: the real impact of the surgical margin. Eur J Surg Oncol 24 (3): 174-9, 1998.
  • Girard P, Ducreux M, Baldeyrou P, et al.: Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. J Clin Oncol 14 (7): 2047-53, 1996.
  • Hughes KS, Simon R, Songhorabodi S, et al.: Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery 100 (2): 278-84, 1986.
  • Schlag P, Hohenberger P, Herfarth C: Resection of liver metastases in colorectal cancer--competitive analysis of treatment results in synchronous versus metachronous metastases. Eur J Surg Oncol 16 (4): 360-5, 1990.
  • Rosen CB, Nagorney DM, Taswell HF, et al.: Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 216 (4): 493-504; discussion 504-5, 1992.
  • Fong Y, Fortner J, Sun RL, et al.: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230 (3): 309-18; discussion 318-21, 1999.
  • Leonard GD, Brenner B, Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 23 (9): 2038-48, 2005.
  • Rossi S, Buscarini E, Garbagnati F, et al.: Percutaneous treatment of small hepatic tumors by an expandable RF needle electrode. AJR Am J Roentgenol 170 (4): 1015-22, 1998.
  • Solbiati L, Livraghi T, Goldberg SN, et al.: Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 221 (1): 159-66, 2001.
  • Lencioni R, Goletti O, Armillotta N, et al.: Radio-frequency thermal ablation of liver metastases with a cooled-tip electrode needle: results of a pilot clinical trial. Eur Radiol 8 (7): 1205-11, 1998.
  • Curley SA, Izzo F, Delrio P, et al.: Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 230 (1): 1-8, 1999.
  • Oshowo A, Gillams A, Harrison E, et al.: Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases. Br J Surg 90 (10): 1240-3, 2003.
  • Livraghi T, Solbiati L, Meloni F, et al.: Percutaneous radiofrequency ablation of liver metastases in potential candidates for resection: the "test-of-time approach". Cancer 97 (12): 3027-35, 2003.
  • Pawlik TM, Izzo F, Cohen DS, et al.: Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients. Ann Surg Oncol 10 (9): 1059-69, 2003.
  • Jarnagin WR, Fong Y, Ky A, et al.: Liver resection for metastatic colorectal cancer: assessing the risk of occult irresectable disease. J Am Coll Surg 188 (1): 33-42, 1999.
  • Ravikumar TS, Kaleya R, Kishinevsky A: Surgical ablative therapy of liver tumors. Cancer: Principles and Practice of Oncology Updates 14 (3): 1-12, 2000.
  • Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 228 (2): 201-8, 1998.
  • Bageacu S, Kaczmarek D, Lacroix M, et al.: Cryosurgery for resectable and unresectable hepatic metastases from colorectal cancer. Eur J Surg Oncol 33 (5): 590-6, 2007.
  • Thomas DS, Nauta RJ, Rodgers JE, et al.: Intraoperative high-dose rate interstitial irradiation of hepatic metastases from colorectal carcinoma. Results of a phase I-II trial. Cancer 71 (6): 1977-81, 1993.
  • Ravikumar TS: Interstitial therapies for liver tumors. Surg Oncol Clin N Am 5 (2): 365-77, 1996.
  • McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 53 (5): 780-5; discussion 785-6, 1992.
  • Headrick JR, Miller DL, Nagorney DM, et al.: Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 71 (3): 975-9; discussion 979-80, 2001.
  • Portier G, Elias D, Bouche O, et al.: Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 24 (31): 4976-82, 2006.
  • Mitry E, Fields AL, Bleiberg H, et al.: Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol 26 (30): 4906-11, 2008.
  • Ychou M, Hohenberger W, Thezenas S, et al.: A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol 20 (12): 1964-70, 2009.
  • Nordlinger B, Sorbye H, Glimelius B, et al.: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 371 (9617): 1007-16, 2008.
  • Kemeny N, Daly J, Reichman B, et al.: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 107 (4): 459-65, 1987.
  • Chang AE, Schneider PD, Sugarbaker PH, et al.: A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206 (6): 685-93, 1987.
  • Rougier P, Laplanche A, Huguier M, et al.: Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 10 (7): 1112-8, 1992.
  • Kemeny N, Cohen A, Seiter K, et al.: Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer. J Clin Oncol 11 (2): 330-5, 1993.
  • Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Meta-Analysis Group in Cancer. J Natl Cancer Inst 88 (5): 252-8, 1996.
  • Mocellin S, Pilati P, Lise M, et al.: Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol 25 (35): 5649-54, 2007.
  • Kemeny N, Huang Y, Cohen AM, et al.: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341 (27): 2039-48, 1999.
  • Kemeny MM, Adak S, Gray B, et al.: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. J Clin Oncol 20 (6): 1499-505, 2002.
  • Petrelli N, Herrera L, Rustum Y, et al.: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5 (10): 1559-65, 1987.
  • Petrelli N, Douglass HO, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol 7 (10): 1419-26, 1989.
  • Scheithauer W, Rosen H, Kornek GV, et al.: Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306 (6880): 752-5, 1993.
  • Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. J Clin Oncol 10 (6): 904-11, 1992.
  • Buyse M, Thirion P, Carlson RW, et al.: Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 356 (9227): 373-8, 2000.
  • Leichman CG, Fleming TR, Muggia FM, et al.: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 13 (6): 1303-11, 1995.
  • Van Cutsem E, Twelves C, Cassidy J, et al.: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19 (21): 4097-106, 2001.
  • Hoff PM, Ansari R, Batist G, et al.: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19 (8): 2282-92, 2001.
  • Saltz LB, Cox JV, Blanke C, et al.: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343 (13): 905-14, 2000.
  • de Gramont A, Figer A, Seymour M, et al.: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18 (16): 2938-47, 2000.
  • Douillard JY, Cunningham D, Roth AD, et al.: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355 (9209): 1041-7, 2000.
  • Tournigand C, André T, Achille E, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22 (2): 229-37, 2004.
  • Colucci G, Gebbia V, Paoletti G, et al.: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23 (22): 4866-75, 2005.
  • Fuchs CS, Marshall J, Mitchell E, et al.: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25 (30): 4779-86, 2007.
  • Díaz-Rubio E, Tabernero J, Gómez-España A, et al.: Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 25 (27): 4224-30, 2007.
  • Porschen R, Arkenau HT, Kubicka S, et al.: Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 25 (27): 4217-23, 2007.
  • Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14 (4): 1128-35, 1996.
  • Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14 (3): 709-15, 1996.
  • Rougier P, Van Cutsem E, Bajetta E, et al.: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352 (9138): 1407-12, 1998.
  • Cunningham D, Pyrhönen S, James RD, et al.: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352 (9138): 1413-8, 1998.
  • Rothenberg ML, Oza AM, Bigelow RH, et al.: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21 (11): 2059-69, 2003.
  • Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (23): 2335-42, 2004.
  • Sanoff HK, Sargent DJ, Campbell ME, et al.: Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 26 (35): 5721-7, 2008.
  • Saltz LB, Clarke S, Díaz-Rubio E, et al.: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26 (12): 2013-9, 2008.
  • Cassidy J, Clarke S, Díaz-Rubio E, et al.: Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26 (12): 2006-12, 2008.
  • Giantonio BJ, Catalano PJ, Meropol NJ, et al.: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. [Abstract] J Clin Oncol 23 (Suppl 16): A-2, 1s, 2005.
  • Arnold D, Andre T, Bennouna J, et al.: Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). [Abstract] J Clin Oncol 30 (Suppl 15): A-CRA3503, 2012.
  • Loupakis F, Cremolini C, Masi G, et al.: Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371 (17): 1609-18, 2014.
  • Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 (4): 337-45, 2004.
  • Van Cutsem E, Köhne CH, Hitre E, et al.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360 (14): 1408-17, 2009.
  • Tol J, Koopman M, Cats A, et al.: Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360 (6): 563-72, 2009.
  • Maughan TS, Adams RA, Smith CG, et al.: Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377 (9783): 2103-14, 2011.
  • Adams RA, Meade AM, Seymour MT, et al.: Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 12 (7): 642-53, 2011.
  • Bokemeyer C, Cutsem EV, Rougier P, et al.: Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 48 (10): 1466-75, 2012.
  • Van Cutsem E, Tabernero J, Lakomy R, et al.: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30 (28): 3499-506, 2012.
  • Tabernero J, Yoshino T, Cohn AL, et al.: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16 (5): 499-508, 2015.
  • Van Cutsem E, Peeters M, Siena S, et al.: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25 (13): 1658-64, 2007.
  • Douillard JY, Siena S, Cassidy J, et al.: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28 (31): 4697-705, 2010.
  • Douillard JY, Oliner KS, Siena S, et al.: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369 (11): 1023-34, 2013.
  • Hecht JR, Mitchell E, Chidiac T, et al.: A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27 (5): 672-80, 2009.
  • Peeters M, Price TJ, Cervantes A, et al.: Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28 (31): 4706-13, 2010.
  • Heinemann V, von Weikersthal LF, Decker T, et al.: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (10): 1065-75, 2014.
  • Venook AP, Niedzwiecki D, Lenz HJ, et al.: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). [Abstract] J Clin Oncol 32 (Suppl 5): A-LBA3, 2014.
  • Stintzing S, Modest DP, Rossius L, et al.: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 17 (10): 1426-1434, 2016.
  • Modest DP, Stintzing S, von Weikersthal LF, et al.: Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer. J Clin Oncol 33 (32): 3718-26, 2015.
  • Grothey A, Sobrero AF, Siena S, et al.: Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. [Abstract] J Clin Oncol 30 (Suppl 4): A-LBA385, 2012.
  • Grothey A, Van Cutsem E, Sobrero A, et al.: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381 (9863): 303-12, 2013.
  • Mayer RJ, Van Cutsem E, Falcone A, et al.: Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372 (20): 1909-19, 2015.
    • Colon Cancer Treatment (PDQ®)

    Stage IV and Recurrent Colon Cancer Treatment

    Stage IV colon cancer denotes distant metastatic disease. Treatment of recurrent colon cancer depends on the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. In addition to standard radiographic procedures, radioimmunoscintography may add clinical information that may affect management.

    Such approaches have not led to improvements in long-term outcome measures such as survival.

    Treatment options for stage IV and recurrent colon cancer include the following:

  • Surgical resection of locally recurrent cancer.
  • Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases.
  • Resection of liver metastases in selected metastatic patients (5-year cure rate for resection of solitary or combination metastases exceeds 20%) or ablation in selected patients.
  • Resection of isolated pulmonary or ovarian metastases in selected patients.
  • Palliative radiation therapy.
  • Palliative chemotherapy.
  • Targeted therapy.
  • Clinical trials evaluating new drugs and biological therapy.
  • Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

    • Treatment of Liver Metastasis

    Approximately 50% of colon cancer patients will be diagnosed with hepatic metastases, either at the time of initial presentation or because of disease recurrence. Although only a small proportion of patients with hepatic metastases are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy administration provide for several treatment options. These include the following:

  • Surgery.
  • Neoadjuvant chemotherapy.
  • Local ablation.
  • Adjuvant chemotherapy.
  • Intra-arterial chemotherapy.

    • Surgery

    Hepatic metastasis may be considered to be resectable based on the following factors:

  • Limited number of lesions.
  • Intrahepatic locations of lesions.
  • Lack of major vascular involvement.
  • Absent or limited extrahepatic disease.
  • Enough functional hepatic reserve.

    • For patients with hepatic metastasis that is considered to be resectable, a negative margin resection resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the North Central Cancer Treatment Group trial (NCCTG-934653 [NCT00002575]).

    [Level of Evidence: 3iiiDiv] Improved surgical techniques and advances in preoperative imaging have improved patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of chemotherapy.

    Neoadjuvant chemotherapy for unresectable liver metastases

    Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.

    There is no consensus on the best regimen to use to convert unresectable isolated liver metastases to resectable liver metastases.

    Local ablation

    Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide for long-term tumor control.

    Radiofrequency ablation and cryosurgical ablation

    remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.

    Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.

    Patients with limited pulmonary metastases, and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly-selected patients.

    Adjuvant or neoadjuvant chemotherapy for resectable liver metastases

    The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain.

    Evidence (adjuvant or neoadjuvant chemotherapy for resectable liver metastases):

    In the era before the use of FOLFOX (folinic acid [LV], 5-fluorouracil [5-FU], and oxaliplatin) and FOLFIRI (5-FU/leucovorin [LV]/irinotecan), two trials attempted to randomly assign patients after resection of liver metastases to 5-FU/ or observation, but both studies were closed early because of poor accrual.

  • The FFCD-9902 [NCT00304135] trial randomly assigned 173 patients (200 patients were planned) to postoperative 5-FU/LV, which is the Mayo Clinic regimen, or observation.
  • The 5-year disease-free survival (DFS) rate was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio (OR) for recurrence or death, 0.66; 95% confidence interval [CI], 0.46–0.96; P = .028). The 5-year overall survival (OS) was not significantly different between the groups (chemotherapy group, 51.1% vs. the control group, 41.1%; ORdeath, 0.73; 95% CI, 0.48–1.10; P = .13).
  • The European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada/Gruppo Interdisciplinare Valutazione Interventi in Oncologia (EORTC/NCIC/GIVIO) International trial attempted a similar random assignment of patients after surgical resection of liver metastases. The study closed because of poor accrual, and a combined analysis of the study and the FFCD-9902 study was done instead. In the combined analysis, 278 patients (138 of whom received chemotherapy; 14 of whom received surgery alone) were included.
  • Median progression-free survival (PFS) was 27.9 months in the chemotherapy arm and 18.8 months in the surgery alone arm (hazard ratio [HR], 1.32; 95% CI, 1.00–1.76; P = .058).
  • Median OS was 62.2 months in the chemotherapy arm compared with 47.3 months in the surgery-alone arm (HR, 1.32; 95% CI, 0.95–1.82; P = .095).

    • In the era of multiagent chemotherapy, two subsequent studies evaluated its role in the adjuvant setting following resection of liver metastases from colorectal cancer.

  • A phase III study randomly assigned 306 patients to 5-FU/LV or FOLFIRI after a resection of liver metastases.
  • There was no difference in DFS (21.6 months for 5-FU/LV vs. 24.7 months for FOLFIRI; HR, 0.89; log-rank P = .44) or OS (HR, 1.09; 95% CI, 0.72–1.64).
  • The EORTC (EORTC-40983 [NCT00006479]) trial randomly assigned 364 patients with up to four resectable liver metastases to perioperative FOLFOX (six cycles presurgery and six cycles postsurgery) or surgery alone.
  • The PFS was 28.1% (95.66% CI, 21.3–35.5) for the surgery-alone group and 35.4% (28.1–42.7; HR 0.79; 0.62–1.02; P = .058) for the perioperative chemotherapy group. There was no difference in OS. Subsequent post hoc analysis demonstrated that the difference in PFS in truly eligible patients rose 8.1% (from 28.1% [21.2–36.6] to 36.2% [28.7–43.8]; HR, 0.77 [0.60–1.00]; P = .041). In patients who underwent resection of liver metastases, the difference in PFS rose 9.2% (from 33.2% [25.3–41.2] to 42.4% [34.0–50.5]; HR, 0.73 [0.55–0.97]; P = .025).
  • Reversible postoperative complications occurred more often after chemotherapy than after surgery (40 [25%] of the 159 complications vs. 27 [16%] of the 170 complications; P = .04). After surgery, there were two deaths in the surgery-alone group and one in the perioperative chemotherapy group.

    • There is no level 1 evidence to demonstrate that perioperative or postoperative chemotherapy improves OS for patients undergoing resection of liver metastases. Nevertheless, on the basis of post hoc subset analyses of the EORTC study, some physicians feel perioperative or postoperative therapy is reasonable in this setting.

    Intra-arterial chemotherapy after liver resection

    Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy.

    A meta-analysis of the randomized studies, which were all done in the era when only fluoropyrimidines were available for systemic therapy, did not demonstrate a survival advantage.

    Evidence (intra-arterial chemotherapy after liver resection):

    Two trials evaluated hepatic arterial floxuridine in the adjuvant setting after liver resection.

  • A trial of hepatic arterial floxuridine and dexamethasone plus systemic 5-FU/LV compared with systemic 5-FU/LV alone showed improved 2-year PFS (57% vs. 42%, P = .07) and OS (86% vs. 72%, P = .03) for patients in the combined therapy arm but did not show a significant statistical difference in median survival compared with systemic 5-FU therapy alone.
  • [Level of evidence: 1iiA]
  • Median survival in the combined therapy arm was 72.2 months versus 59.3 months in the monotherapy arm (P = .21).
  • A second trial preoperatively randomly assigned 109 patients who had one to three potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU.
  • Of those randomly assigned patients, 27% were deemed ineligible at the time of surgery, which left only 75 patients evaluable for recurrence and survival.
  • While liver cancer recurrence was decreased, median or 4-year survival was not significantly different between the patient groups.

    • Further studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone may provide similar results compared with hepatic intra-arterial therapy plus systemic treatment.

    Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

    Treatment of Stage IV and Recurrent Colon Cancer

  • Surgery.
  • Chemotherapy and targeted therapy.

    • Surgery

    Treatment of patients with recurrent or advanced colon cancer depends on the location of the disease. For patients with locally recurrent and/or liver-only and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment.

    Chemotherapy and targeted therapy

    The following are active U.S. Food and Drug Administration (FDA)-approved drugs that are used alone and in combination with other drugs for patients with metastatic colorectal cancer:

  • 5-FU.
  • Capecitabine.
  • Irinotecan.
  • Oxaliplatin.
  • Bevacizumab.
  • FOLFOXIRI (irinotecan, oxaliplatin, LV, and 5-FU).
  • Cetuximab.
  • Aflibercept.
  • Ramucirumab.
  • Panitumumab.
  • Anti-epidermal growth factor receptor (EGFR) antibody versus anti-vascular endothelial growth factor (VEGF) antibody with first-line chemotherapy.
  • Regorafenib.
  • TAS-102.
  • Pembrolizumab.

    • 5-FU

    When 5-FU was the only active chemotherapy drug, trials in patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,

    and improved survival and quality of life for patients who received chemotherapy versus best supportive care.

    Several trials have analyzed the activity and toxic effects of various 5-FU/LV regimens using different doses and administration schedules and showed essentially equivalent results with a median survival time in the 12-month range.

    Capecitabine

    Before the advent of multiagent chemotherapy, two randomized studies demonstrated that capecitabine was associated with equivalent efficacy when compared with the Mayo Clinic regimen of 5-FU/LV.

    [Level of evidence: 1iiA]

    Irinotecan

    Three randomized studies demonstrated improved response rates, PFS, and OS when irinotecan or oxaliplatin was combined with 5-FU/LV.

    Evidence (irinotecan):

  • An intergroup study (NCCTG-N9741 [NCT00003594]) compared irinotecan/5-FU/LV (IFL) with oxaliplatin/LV/5-FU (FOLFOX-4) in first-line treatment for patients with metastatic colorectal cancer.
  • Patients assigned to FOLFOX-4 experienced an improved PFS (median, 6.9 months vs. 8.7 months; P = .014; HR, 0.74; 95% confidence interval [CI], 0.61–0.89) and OS (15.0 months vs. 19.5 months, P = .001; HR, 0.66; 95% CI, 0.54–0.82) compared with patients randomly assigned to IFL.
  • Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over upon progression on first-line therapy, respectively.
  • [Level of evidence: 1iiDiii]
  • PFS and OS were identical between the treatment arms in both studies.
  • The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C [NCT00094965]) trial evaluated several different irinotecan-based regimens in patients with previously untreated metastatic colorectal cancer, including FOLFIRI, irinotecan plus bolus 5-FU/LV (mIFL), and capecitabine/irinotecan (CAPIRI).
  • [Level of evidence: 1iiA]
  • The study randomly assigned 430 patients and was closed early because of poor accrual.
  • The patients who received FOLFIRI had a better PFS than the patients who received either mIFL (7.6 months vs. 5.9 months, P = .004) or CAPIRI (7.6 months vs. 5.8 months, P = .015).
  • Patients who received CAPIRI had the highest grade 3 or higher rates of nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome.

    • Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.

    When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.

    [Level of evidence: 1iiDiii]

    Oxaliplatin

    Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated 5-FU/oxaliplatin (FUOX) versus capecitabine/oxaliplatin (CAPOX).

    Evidence (oxaliplatin):

  • The AIO Colorectal Study Group randomly assigned 474 patients to either 5-FU/LV/oxaliplatin (FUFOX) or CAPOX.
  • The median PFS was 7.1 months for the CAPOX arm and 8.0 months for the FUFOX arm (HR, 1.17; 95% CI, 0.96–1.43; P = .117), and the HR was in the prespecified equivalence range.
  • The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX.
  • Level of evidence: 1iiDiii
  • The TTP was 8.9 months versus 9.5 months (P = .153) and met the prespecified range for noninferiority.

    • When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.

    Before the availability of cetuximab, panitumumab, bevacizumab, and aflibercept as second-line therapy, second-line chemotherapy with irinotecan in patients treated with 5-FU/LV as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.

    Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU/LV to bolus and infusional 5-FU/LV (LV5FU2), single-agent oxaliplatin, or FOLFOX-4. The median TTP for FOLFOX-4 versus LV5FU2 was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).

    [Level of evidence: 1iiDiii]

    Bevacizumab

    Bevacizumab is a partially humanized monoclonal antibody that binds to VEGF. Bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.

    Evidence (bevacizumab):

  • After bevacizumab was approved, the BICC-C trial was amended, and an additional 117 patients were randomly assigned to receive FOLFIRI/bevacizumab or mIFL/bevacizumab.
  • Although the primary endpoint of PFS was not significantly different, patients who received FOLFIRI/bevacizumab had a significantly better OS (not yet reached with a median follow-up of 22.6 months vs. 19.2 months, P = .007).
  • Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL/bevacizumab.
  • [Level of evidence: 1iiA]
  • The patients randomly assigned to IFL/bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL/bevacizumab, as compared with 6.2 months in the group given IFL/placebo; HRdisease progression, 0.54; P < .001) and OS (20.3 months in the group given IFL/ bevacizumab, as compared with 15.6 months in the group given IFL/ and placebo corresponding to an HRdeath , 0.66; P < .001).
  • Despite the lack of direct data, in standard practice, bevacizumab was added to FOLFOX as a standard first-line regimen based on the results of the NCCTG-N9741 trial.
  • Subsequently, in a randomized phase III study, patients with untreated, stage IV, colorectal cancer were randomly assigned in a 2 × 2 factorial design to CAPOX versus FOLFOX-4, then to bevacizumab versus placebo. PFS was the primary endpoint.
  • In this trial, 1,401 patients were randomly assigned, and the median PFS was 9.4 months for patients receiving bevacizumab and 8.0 months for the patients receiving placebo (HR, 0.83; 97.5% CI, 0.72–0.95; P = .0023).
  • [Level of evidence: 1iiDiii]
  • Median OS was 21.3 months for patients receiving bevacizumab and 19.9 months for patients receiving placebo (HR, 0.89; 97.5% CI, 0.76–1.03; P = .077).
  • The median PFS (intention-to-treat analysis) was 8.0 months in the pooled CAPOX-containing arms versus 8.5 months in the FOLFOX-4-containing arms (HR, 1.04; 97.5% CI, 0.93–1.16), with the upper limit of the 97.5% CI being below the predefined noninferiority margin of 1.23.
  • The effect of bevacizumab on OS is likely to be less than what was seen in the original Hurwitz study.
  • Investigators from the Eastern Cooperative Oncology Group randomly assigned patients who had progressed on 5-FU/leucovorin and irinotecan to either FOLFOX or FOLFOX /bevacizumab.
  • Patients randomly assigned to FOLFOX/bevacizumab experienced a statistically significant improvement in PFS (7.43 months vs. 4.7 months, HR, 0.61; P < .0001) and OS (12.9 months vs. 10.8 months, HR, 0.75; P = .0011).
  • [Level of evidence: 1iiA]

    • Based on these studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer. A major question was whether the use of bevacizumab after first-line therapy was warranted when bevacizumab was used as a component of first-line therapy. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, data were presented from a randomized, controlled trial.

    In the trial, 820 patients with metastatic colorectal cancer, after progressing on first-line chemotherapy that included bevacizumab, were randomly assigned to chemotherapy without bevacizumab or chemotherapy with bevacizumab. Patients who received bevacizumab experienced an improved OS compared with the patients who did not receive bevacizumab. Median OS was 11.2 months for patients who received bevacizumab/chemotherapy and 9.8 months for patients who received chemotherapy without bevacizumab (HR, 0.81; 95% CI, 0.69–0.94; unstratified log-rank test, P = .0062). Median PFS was 5.7 months for patients who received bevacizumab/chemotherapy and 4.1 months for those who received chemotherapy without bevacizumab (HR, 0.68; 95% CI, 0.59–0.78; unstratified log-rank test, P < .0001).

    [Level of evidence: 1iiA]

    FOLFOXIRI

    Evidence (FOLFOXIRI):

  • The combination of FOLFOXIRI with bevacizumab was compared with FOLFIRI with bevacizumab in a randomized, phase III study of 508 patients with untreated metastatic colorectal cancer.
  • [Level of evidence: 1iiDiii]
  • The median PFS was 12.1 months in the FOLFOXIRI group, compared with 9.7 months in the FOLFIRI group (HRprogression, 0.75; 95% CI, 0.62–0.90; P = .003). OS was not significantly different between the groups (31.0 vs. 25.8 months; HRdeath, 0.79; 95% CI, 0.63–1.00; P = .054).
  • Patients who received FOLFOXIRI had significantly more grade 3 and 4 toxicities, including neutropenia, stomatitis, and peripheral neuropathy.

    • Cetuximab

    Cetuximab is a partially humanized monoclonal antibody against the EGFR. Because cetuximab affects tyrosine kinase signaling at the surface of the cell membrane, tumors with mutations causing activation of the pathway downstream of the EGFR, such as KRAS mutations, are not sensitive to its effects. The addition of cetuximab to multiagent chemotherapy improves survival in patients with colon cancers that lack a KRAS mutation (i.e., KRAS wild type). Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab.

    Evidence (cetuximab):

  • For patients who have progressed on irinotecan-containing regimens, a randomized, phase II study was performed using either cetuximab or irinotecan and cetuximab.
  • [Level of evidence: 3iiiDiv]
  • The median TTP for patients who received cetuximab was 1.5 months, compared with the median TTP of 4.2 months for patients receiving irinotecan/cetuximab.
  • [Level of evidence: 1iiDiii]
  • On the basis of this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.
  • The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.
  • [Level of evidence: 1iiDii]
  • The addition of cetuximab was associated with an improved PFS (HR, 0.85; 95% CI, 0.72–0.99; P = .048, by a stratified log rank test) but not OS.
  • Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-EGFR antibody therapy are confined to patients with tumors that harbor wild types of KRAS (i.e., lack activating mutations at codon 12 or 13 of the KRAS gene).
  • A subset analysis evaluating efficacy vis-à-vis KRAS status was done in patients enrolled on the Crystal Study. There was a significant interaction for KRAS mutation status and treatment for tumor response (P = .03) but not for PFS (P = .07). Among patients with KRAS wild-type tumors, the HR favored the FOLFIRI/cetuximab group (HR, 0.68; 95% CI, 0.50–0.94).
  • In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.
  • [Level of evidence: 1iiDiii]
  • The median PFS was 9.4 months in the group who received cetuximab and 10.7 months in the group who did not receive cetuximab (P = .01).
  • In a subset analysis, cetuximab-treated patients with tumors bearing a mutated KRAS gene had significantly decreased PFS compared with cetuximab-treated patients with wild-type KRAS tumors (8.1 months vs. 10.5 months; P = .04).
  • Cetuximab-treated patients with mutated KRAS tumors had a significantly shorter PFS compared with patients with mutated KRAS tumors who did not receive cetuximab (8.1 months vs. 12.5 months; P = .003) and a significantly shorter OS (17.2 months vs. 24.9 months; P = .03).
  • The Medical Research Council (MRC) (COIN [NCT00182715] trial) sought to answer the question of whether adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with first-line KRAS wild-type tumors was beneficial.
  • In addition, the MRC sought to evaluate the effect of intermittent chemotherapy versus continuous chemotherapy. The 1,630 patients were randomly assigned to three treatment groups:
  • Arm A: fluoropyrimidine/oxaliplatin.
  • Arm B: fluoropyrimidine/oxaliplatin/cetuximab.
  • Arm C: intermittent fluoropyrimidine/oxaliplatin.
  • The comparisons between arms A and B and arms A and C were analyzed and published separately.
  • In patients with KRAS wild-type tumors (arm A, n = 367; arm B, n = 362), OS did not differ between treatment groups (median survival, 17.9 months [interquartile range (IQR) 10.3–29.2] in the control group vs. 17.0 months [IQR, 9.4–30.1] in the cetuximab group; HR, 1.04; 95% CI, 0.87–1.23; P = .67). Similarly, there was no effect on PFS (8.6 months [IQR, 5.0–12.5] in the control group versus 8.6 months [IQR, 5.1–13.8] in the cetuximab group; HR, 0.96; 95% CI, 0.82–1.12; P = .60).
  • [Level of evidence: 1iiA]
  • The reasons for lack of benefit in adding cetuximab are unclear. Subset analyses suggest that the use of capecitabine was associated with an inferior outcome, and the use of second-line therapy was less frequent in patients treated with cetuximab.
  • There was no difference between the continuously treated patients (arm A) and the intermittently treated patients (arm C). Median survival in the intent-to-treat population (n = 815 in both groups) was 15.8 months (IQR, 9.4–26.1) in arm A and 14.4 months (IQR, 8.0–24.7) in arm C (HR, 1.084; 80% CI, 1.008–1.165). In the per-protocol population, which included only those patients who were free from progression at 12 weeks and randomly assigned to continue treatment or go on a chemotherapy holiday (arm A, n = 467; arm C, n = 511), median survival was 19.6 months (IQR, 13.0–28.1) in arm A and 18.0 months (IQR, 12.1–29.3) in arm C (HR, 1.087; 95% CI, 0.986–1.198). The upper limits of CIs for HRs in both analyses were greater than the predefined noninferiority boundary. While intermittent chemotherapy was not deemed noninferior, there appeared to be clinically insignificant differences in patient outcomes.
  • The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-labeled, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.
  • In the trial, 344 patients were randomly assigned to receive FOLFOX-4 alone or FOLFOX-4/cetuximab. There was no statistically significant difference in response rate or PFS.
  • On subset analysis, patients with KRAS wild-type tumors were analyzed separately. In the KRAS wild-type tumor population, there was a statistically significant improvement in response rate (61% vs. 37%, P = .011) and PFS (7.7 months vs. 7.2 months, P = .0163).
  • On subset analysis, patients with KRAS mutant tumors receiving FOLFOX-4/cetuximab had a statistically significant worse PFS than patients with KRAS mutant tumors receiving FOLFOX-4 (5.5 months vs. 8.6 months, P = .0192).
  • [Level of evidence: 1iiD]

    • Aflibercept

    Aflibercept is a novel anti-VEGF molecule and has been evaluated as a component of second-line therapy in patients with metastatic colorectal cancer.

    Evidence (aflibercept):

  • In one trial, 1,226 patients were randomly assigned to receive aflibercept (4 mg/kg IV) or placebo every 2 weeks in combination with FOLFIRI.
  • [Level of evidence: 1A]
  • Patients who received aflibercept/FOLFIRI had significantly improved OS rates, with median survival times of 13.50 months compared with patients who received placebo/FOLFIRI, with median survival times of 12.06 months (HR, 0.817; 95.34% CI, 0.713–0.937; P = .0032).
  • Patients who received aflibercept/FOLFIRI also had significantly improved PFS rates, with median PFS rates of 6.90 months compared with patients who received placebo/FOLFIRI, with median PFS rates of 4.67 months (HR, 0.758; 95% CI, 0.661–0.869; P < .0001).
  • On the basis of these results, the use of aflibercept/FOLFIRI is an acceptable second-line regimen for patients previously treated with FOLFOX-based chemotherapy. Whether to continue bevacizumab or initiate aflibercept in second-line therapy has not been addressed yet in any clinical trial, and there are no data available.

    • Ramucirumab

    Ramucirumab is a fully humanized monoclonal antibody that binds to vascular endothelial growth factor receptor-2.

    Evidence (ramucirumab):

  • In the randomized, unblinded, phase III RAISE (NCT01183780) study, 1,072 patients with stage IV colorectal cancer who had progressed on first-line chemotherapy were randomly assigned to FOLFIRI with or without ramucirumab (8 mg/kg).
  • [Level of evidence: 1iiA]
  • Patients assigned to FOLFIRI/ramucirumab had a significant improvement in median OS (13.3 months vs. 11.7 months; HR, 0.84; P = .0219) and PFS (5.7 months vs. 4.5 months; HR, 0.793; P = .0005).
  • Grade 3 adverse events were more common in the ramucirumab group, including grade 3 neutropenia.
  • On the basis of this data, FOLFIRI/ramucirumab is an acceptable second-line regimen for patients previously treated with FOLFOX/bevacizumab. Whether to continue bevacizumab in second-line chemotherapy or use ramucirumab in second-line chemotherapy has not yet been addressed in a clinical trial.

    • Panitumumab

    Panitumumab is a fully humanized antibody against the EGFR. The FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.

    In clinical trials, panitumumab demonstrated efficacy as a single agent or in combination therapy, which was consistent with the effects on PFS and OS with cetuximab. There appears to be a consistent class effect.

    Evidence (panitumumab):

  • In a phase III trial, patients with chemotherapy-refractory colorectal cancer were randomly assigned to panitumumab or best supportive care.
  • [Level of evidence: 1iiDiii]
  • Patients who received panitumumab experienced an improved PFS (8 weeks vs. 7.3 weeks; HR, 0.54; 95% CI, 0.44–0.66; P < .0001).
  • There was no difference in OS, which was thought to be the result of 76% of patients on best supportive care crossing over to panitumumab.
  • In the Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) [NCT00364013] study, 1,183 patients were randomly assigned to FOLFOX-4 with or without panitumumab as first-line therapy for metastatic colorectal cancer. The study was amended to enlarge the sample size to address patients with the KRAS wild-type tumors and patients with mutant KRAS tumors separately.
  • [Level of evidence: 1iiDiii]
  • For patients with KRAS wild-type tumors, a statistically significant improvement in PFS was observed in those who received panitumumab/FOLFOX-4 compared with those who received only FOLFOX-4 (HR, 0.80; 95% CI, 0.66–0.97; P = .02, stratified log-rank test).
  • Median PFS was 9.6 months (95% CI, 9.2 months–11.1 months) for patients who received panitumumab/FOLFOX-4 and 8.0 months (95% CI, 7.5 months–9.3 months) for patients who received FOLFOX-4. OS was not significantly different between the groups (HR, 0.83; 95% CI, 0.67–1.02; P = .072).
  • For patients with mutant KRAS tumors, there was worse PFS with the addition of panitumumab (HR, 1.29; 95% CI, 1.04–1.62; P = .02, stratified log-rank test).
  • Median PFS was 7.3 months (95% CI, 6.3 months–8.0 months) for panitumumab/FOLFOX-4 and 8.8 months (95% CI, 7.7 months–9.4 months) for FOLFOX-4 alone.
  • Subsequently, a retrospective analysis evaluated patients with wild-type KRAS exon 2 status for other KRAS and BRAF mutations.
  • [Level of evidence: 3iiiA]
  • Of the 620 patients who were initially identified as not having a mutation in exon 2 of KRAS, 108 patients (17%) were found to have additional RAS mutations and 53 patients (8%) were found to have BRAF mutations. In a retrospective analysis, patients without any RAS or BRAF mutations had a longer PFS (10.8 months vs. 9.2 months, P = .002) and OS (28.3 months vs. 20.9 months, P = .02) when assigned to the FOLFOX-4/panitumumab arm than the patients assigned to the FOLFOX-4 arm.
  • Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared with a regimen of FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic colon cancer (11.4 months vs. 10.0 months, HR, 1.27; 95% CI, 1.06–1.52).
  • [Level of evidence: 1iiDiii]
  • In another study (NCT00339183), patients with metastatic colorectal cancer who had already received a fluoropyrimidine regimen were randomly assigned to either FOLFIRI or FOLFIRI/panitumumab.
  • [Level of evidence: 1iiDiii]
  • In a post hoc analysis, patients with KRAS wild-type tumors experienced a statistically significant PFS advantage (HR, 0.73; 95% CI, 0.59–0.90; P = .004, stratified log-rank).
  • Median PFS was 5.9 months (95% CI, 5.5 months–6.7 months) for panitumumab/FOLFIRI and 3.9 months (95% CI, 3.7 months–5.3 months) for FOLFIRI alone.
  • OS was not significantly different. Patients with mutant KRAS tumors experienced no benefit from the addition of panitumumab.

    • Anti-EGFR antibody versus anti-VEGF antibody with first-line chemotherapy

    In the management of patients with stage IV colorectal cancer, it is unknown whether patients with KRAS wild-type cancer should receive an anti-EGFR antibody with chemotherapy or an anti-VEGF antibody with chemotherapy. Two studies attempted to answer this question.

    Evidence (anti-EGFR antibody vs. anti-VEGF antibody with first-line chemotherapy)

  • The FIRE-3 [NCT00433927] study randomly assigned 592 patients with KRAS exon 2 wild-type tumors who were previously untreated to FOLFIRI/cetuximab (297 patients) or FOLFIRI/bevacizumab (295 patients). The primary endpoint of the study was objective response rate.
  • [Level of evidence: 1iiA]
  • The objective response rate was not significantly different between the groups (objective response rate, 62.0%; 95% CI, 56.2–67.5 vs. objective response rate, 58.0%; 95% CI, 52.1–63.7; OR, 1.18; 95% CI, 0.85–1.64; P = .18).
  • Median PFS was 10.0 months (95% CI, 8.8–10.8) in the cetuximab group and 10.3 months (95% CI, 9.8–11.3) in the bevacizumab group (HR, 1.06; 95% CI, 0.88–1.26; P = .55).
  • Median OS was 28.7 months (95% CI, 24.0–36.6) in the cetuximab group compared with 25.0 months (22.7–27.6) in the bevacizumab group (HR, 0.77; 95% CI, 0.62–0.96; P = .017).
  • In a post hoc analysis of patients with expanded RAS wild-type tumors (sequencing for mutational hot spots within KRAS and NRAS genes, including exon 2 codons 12 and 13; exon 3 codons 59 and 61; and exon 4 codons 117 and 146), the median OS was 33.1 months (95% CI, 24.5–39.4) in the cetuximab group compared with 25.0 months (95% CI, 23.0–28.1) in the bevacizumab group (HR, 0.70; 95% CI, 0.54–0.90; P = .0059).
  • Of note, only 52% of patients assigned to the bevacizumab arm subsequently received cetuximab or panitumumab.
  • The Cancer and Leukemia Group B Intergroup study 80405 [NCT00265850] was presented at the ASCO meeting in 2014. This study randomly assigned 2,334 previously untreated patients with KRAS wild-type cancer to chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab or chemotherapy/cetuximab. OS was the primary endpoint.
  • [Level of evidence: 1iiDiii]
  • There was no statistically significant difference in OS among the patients assigned to bevacizumab or cetuximab (for OS differences, chemotherapy/bevacizumab = 29.04 [25.66–31.21] months vs. chemotherapy/cetuximab = 29.93 [27.56–31.21] months; HR, 0.92 [0.78, 1.09]; P = .34).

    • On the basis of these two studies, no apparent significant difference is evident about starting treatment with chemotherapy/bevacizumab or chemotherapy/cetuximab in patients with KRAS wild-type metastatic colorectal cancer. However, in patients with KRAS wild-type cancer, administration of an anti-EGFR antibody during the course of management improves OS.

    Regorafenib

    Regorafenib is an inhibitor of multiple tyrosine kinase pathways including VEGF. In September 2012, the FDA granted approval for the use of regorafenib in patients who had progressed on previous therapy.

    Evidence (regorafenib):

  • The safety and effectiveness of regorafenib were evaluated in a single, clinical study of 760 patients with previously treated metastatic colorectal cancer. Patients were randomly assigned in a 2:1 fashion to receive regorafenib or a placebo in addition to the best supportive care.
  • Patients treated with regorafenib had a statistically significant improvement in OS (6.4 months in the regorafenib group vs. 5.0 months in the placebo group; HR, 0.77; 95% CI, 0.64–0.94; one-sided P = .0052).

    • TAS-102

    TAS-102 (Lonsurf) is an orally administered combination of a thymidine-based nucleic acid analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluridine, in its triphosphate form, inhibits thymidylate synthase; therefore, trifluridine, in this form, has an anti-tumor effect. Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase, which actively degrades trifluridine. The combination of trifluridine and tipiracil allows for adequate plasma levels of trifluridine.

    Evidence (TAS-102):

  • A phase III, double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 stage IV colorectal cancer patients whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus TAS-102 (n = 534) or placebo (n = 266). The median age of patients was 63 years, and most patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.
  • [Level of evidence: 1iiA]
  • TAS-102 was administered at 35 mg/m2 twice daily with meals for 5 days, with 2 days of rest for 2 weeks, followed by a 14-day rest period.
  • The primary endpoint of the study was OS. The median OS for patients with metastatic colorectal cancer who received TAS-102 was 7.1 months compared with 5.3 months for those who received a placebo (HR, 0.68; P < .0001).
  • The median PFS time in the TAS-102 arm was 2 months versus 1.7 months with a placebo (HR, 0.48; P < .0001).
  • Secondary endpoints focused on PFS, overall response rate, and disease control rate.
  • The overall response rate was 1.6% with TAS-102, which consisted of a complete response in one patient and partial responses in other patients. The overall response rate with a placebo was 0.4% (P = .29).

    • TAS-102 was approved by the FDA for the treatment of metastatic colorectal cancer patients, based on the results of the RECOURSE trial.

    Pembrolizumab

    Approximately 4% of patients with stage IV colorectal cancer will have tumors that are microsatellite unstable; this designation is also known as microsatellite-high (MSI-H). The MSI-H phenotype is associated with germline defects in the MLH1, MSH2, MSH6, and PMS2 genes and is the primary phenotype observed in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Patients can also have the MSI-H phenotype because one of these genes was silenced via a process called DNA methylation. Testing for microsatellite instability can be done with molecular genetic tests, which look for microsatellite instability in the tumor tissue or with immunohistochemistry, which looks for the loss of mismatch repair proteins.

    In May 2017, the FDA granted approval for using pembrolizumab, a programmed cell death protein 1 (PD-1) antibody, in patients with microsatellite unstable tumors.

  • The approval was based on data from 149 patients with MSI-H or DNA mismatch repair cancers enrolled across 5 uncontrolled, multicohort, multicenter, single-arm clinical trials. Ninety patients had colorectal cancer, and 59 patients were diagnosed with one of 14 other cancer types. Patients received either 200 mg of pembrolizumab every 3 weeks or 10 mg/kg of pembrolizumab every 2 weeks. Treatment continued until unacceptable toxicity or disease progression. The major efficacy outcome measures were objective response rate, which was assessed by blinded independent central radiologists’ review in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and response duration.
  • Objective response rate was 39.6% (95% CI, 31.7–47.9).
  • Responses lasted 6 months or longer for 78% percent of those who responded to pembrolizumab. There were 11 complete responses and 48 partial responses.
  • Objective response rate was similar whether patients were diagnosed with colorectal cancer (36%) or a different cancer type (46% across the 14 other cancer types).

    • Treatment Options Under Clinical Evaluation

    Treatment options under clinical evaluation for stage IV and recurrent colon cancer include the following:

  • Clinical trials evaluating new drugs and biological therapy.
  • Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

    • 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

  • Serafini AN, Klein JL, Wolff BG, et al.: Radioimmunoscintigraphy of recurrent, metastatic, or occult colorectal cancer with technetium 99m-labeled totally human monoclonal antibody 88BV59: results of pivotal, phase III multicenter studies. J Clin Oncol 16 (5): 1777-87, 1998.
  • Wagman LD, Kemeny MM, Leong L, et al.: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 8 (11): 1885-93, 1990.
  • Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 77 (11): 1241-6, 1990.
  • Scheele J, Stangl R, Altendorf-Hofmann A, et al.: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110 (1): 13-29, 1991.
  • Adson MA, van Heerden JA, Adson MH, et al.: Resection of hepatic metastases from colorectal cancer. Arch Surg 119 (6): 647-51, 1984.
  • Coppa GF, Eng K, Ranson JH, et al.: Hepatic resection for metastatic colon and rectal cancer. An evaluation of preoperative and postoperative factors. Ann Surg 202 (2): 203-8, 1985.
  • Gayowski TJ, Iwatsuki S, Madariaga JR, et al.: Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 116 (4): 703-10; discussion 710-1, 1994.
  • Fernández-Trigo V, Shamsa F, Sugarbaker PH: Repeat liver resections from colorectal metastasis. Repeat Hepatic Metastases Registry. Surgery 117 (3): 296-304, 1995.
  • Jaeck D, Bachellier P, Guiguet M, et al.: Long-term survival following resection of colorectal hepatic metastases. Association Française de Chirurgie. Br J Surg 84 (7): 977-80, 1997.
  • Taylor M, Forster J, Langer B, et al.: A study of prognostic factors for hepatic resection for colorectal metastases. Am J Surg 173 (6): 467-71, 1997.
  • Elias D, Cavalcanti A, Sabourin JC, et al.: Resection of liver metastases from colorectal cancer: the real impact of the surgical margin. Eur J Surg Oncol 24 (3): 174-9, 1998.
  • Girard P, Ducreux M, Baldeyrou P, et al.: Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. J Clin Oncol 14 (7): 2047-53, 1996.
  • Hughes KS, Simon R, Songhorabodi S, et al.: Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery 100 (2): 278-84, 1986.
  • Schlag P, Hohenberger P, Herfarth C: Resection of liver metastases in colorectal cancer--competitive analysis of treatment results in synchronous versus metachronous metastases. Eur J Surg Oncol 16 (4): 360-5, 1990.
  • Rosen CB, Nagorney DM, Taswell HF, et al.: Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 216 (4): 493-504; discussion 504-5, 1992.
  • Fong Y, Fortner J, Sun RL, et al.: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230 (3): 309-18; discussion 318-21, 1999.
  • Leonard GD, Brenner B, Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 23 (9): 2038-48, 2005.
  • Rossi S, Buscarini E, Garbagnati F, et al.: Percutaneous treatment of small hepatic tumors by an expandable RF needle electrode. AJR Am J Roentgenol 170 (4): 1015-22, 1998.
  • Solbiati L, Livraghi T, Goldberg SN, et al.: Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 221 (1): 159-66, 2001.
  • Lencioni R, Goletti O, Armillotta N, et al.: Radio-frequency thermal ablation of liver metastases with a cooled-tip electrode needle: results of a pilot clinical trial. Eur Radiol 8 (7): 1205-11, 1998.
  • Curley SA, Izzo F, Delrio P, et al.: Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 230 (1): 1-8, 1999.
  • Oshowo A, Gillams A, Harrison E, et al.: Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases. Br J Surg 90 (10): 1240-3, 2003.
  • Livraghi T, Solbiati L, Meloni F, et al.: Percutaneous radiofrequency ablation of liver metastases in potential candidates for resection: the "test-of-time approach". Cancer 97 (12): 3027-35, 2003.
  • Pawlik TM, Izzo F, Cohen DS, et al.: Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients. Ann Surg Oncol 10 (9): 1059-69, 2003.
  • Jarnagin WR, Fong Y, Ky A, et al.: Liver resection for metastatic colorectal cancer: assessing the risk of occult irresectable disease. J Am Coll Surg 188 (1): 33-42, 1999.
  • Ravikumar TS, Kaleya R, Kishinevsky A: Surgical ablative therapy of liver tumors. Cancer: Principles and Practice of Oncology Updates 14 (3): 1-12, 2000.
  • Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 228 (2): 201-8, 1998.
  • Bageacu S, Kaczmarek D, Lacroix M, et al.: Cryosurgery for resectable and unresectable hepatic metastases from colorectal cancer. Eur J Surg Oncol 33 (5): 590-6, 2007.
  • Thomas DS, Nauta RJ, Rodgers JE, et al.: Intraoperative high-dose rate interstitial irradiation of hepatic metastases from colorectal carcinoma. Results of a phase I-II trial. Cancer 71 (6): 1977-81, 1993.
  • Ravikumar TS: Interstitial therapies for liver tumors. Surg Oncol Clin N Am 5 (2): 365-77, 1996.
  • McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 53 (5): 780-5; discussion 785-6, 1992.
  • Headrick JR, Miller DL, Nagorney DM, et al.: Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 71 (3): 975-9; discussion 979-80, 2001.
  • Portier G, Elias D, Bouche O, et al.: Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 24 (31): 4976-82, 2006.
  • Mitry E, Fields AL, Bleiberg H, et al.: Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol 26 (30): 4906-11, 2008.
  • Ychou M, Hohenberger W, Thezenas S, et al.: A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol 20 (12): 1964-70, 2009.
  • Nordlinger B, Sorbye H, Glimelius B, et al.: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 371 (9617): 1007-16, 2008.
  • Kemeny N, Daly J, Reichman B, et al.: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 107 (4): 459-65, 1987.
  • Chang AE, Schneider PD, Sugarbaker PH, et al.: A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206 (6): 685-93, 1987.
  • Rougier P, Laplanche A, Huguier M, et al.: Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 10 (7): 1112-8, 1992.
  • Kemeny N, Cohen A, Seiter K, et al.: Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer. J Clin Oncol 11 (2): 330-5, 1993.
  • Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Meta-Analysis Group in Cancer. J Natl Cancer Inst 88 (5): 252-8, 1996.
  • Mocellin S, Pilati P, Lise M, et al.: Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol 25 (35): 5649-54, 2007.
  • Kemeny N, Huang Y, Cohen AM, et al.: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341 (27): 2039-48, 1999.
  • Kemeny MM, Adak S, Gray B, et al.: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. J Clin Oncol 20 (6): 1499-505, 2002.
  • Petrelli N, Herrera L, Rustum Y, et al.: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5 (10): 1559-65, 1987.
  • Petrelli N, Douglass HO, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol 7 (10): 1419-26, 1989.
  • Scheithauer W, Rosen H, Kornek GV, et al.: Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306 (6880): 752-5, 1993.
  • Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. J Clin Oncol 10 (6): 904-11, 1992.
  • Buyse M, Thirion P, Carlson RW, et al.: Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 356 (9227): 373-8, 2000.
  • Leichman CG, Fleming TR, Muggia FM, et al.: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 13 (6): 1303-11, 1995.
  • Van Cutsem E, Twelves C, Cassidy J, et al.: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19 (21): 4097-106, 2001.
  • Hoff PM, Ansari R, Batist G, et al.: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19 (8): 2282-92, 2001.
  • Saltz LB, Cox JV, Blanke C, et al.: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343 (13): 905-14, 2000.
  • de Gramont A, Figer A, Seymour M, et al.: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18 (16): 2938-47, 2000.
  • Douillard JY, Cunningham D, Roth AD, et al.: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355 (9209): 1041-7, 2000.
  • Tournigand C, André T, Achille E, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22 (2): 229-37, 2004.
  • Colucci G, Gebbia V, Paoletti G, et al.: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23 (22): 4866-75, 2005.
  • Fuchs CS, Marshall J, Mitchell E, et al.: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25 (30): 4779-86, 2007.
  • Díaz-Rubio E, Tabernero J, Gómez-España A, et al.: Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 25 (27): 4224-30, 2007.
  • Porschen R, Arkenau HT, Kubicka S, et al.: Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 25 (27): 4217-23, 2007.
  • Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14 (4): 1128-35, 1996.
  • Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14 (3): 709-15, 1996.
  • Rougier P, Van Cutsem E, Bajetta E, et al.: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352 (9138): 1407-12, 1998.
  • Cunningham D, Pyrhönen S, James RD, et al.: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352 (9138): 1413-8, 1998.
  • Rothenberg ML, Oza AM, Bigelow RH, et al.: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21 (11): 2059-69, 2003.
  • Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (23): 2335-42, 2004.
  • Sanoff HK, Sargent DJ, Campbell ME, et al.: Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 26 (35): 5721-7, 2008.
  • Saltz LB, Clarke S, Díaz-Rubio E, et al.: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26 (12): 2013-9, 2008.
  • Cassidy J, Clarke S, Díaz-Rubio E, et al.: Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26 (12): 2006-12, 2008.
  • Giantonio BJ, Catalano PJ, Meropol NJ, et al.: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. [Abstract] J Clin Oncol 23 (Suppl 16): A-2, 1s, 2005.
  • Arnold D, Andre T, Bennouna J, et al.: Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). [Abstract] J Clin Oncol 30 (Suppl 15): A-CRA3503, 2012.
  • Loupakis F, Cremolini C, Masi G, et al.: Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371 (17): 1609-18, 2014.
  • Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 (4): 337-45, 2004.
  • Van Cutsem E, Köhne CH, Hitre E, et al.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360 (14): 1408-17, 2009.
  • Tol J, Koopman M, Cats A, et al.: Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360 (6): 563-72, 2009.
  • Maughan TS, Adams RA, Smith CG, et al.: Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377 (9783): 2103-14, 2011.
  • Adams RA, Meade AM, Seymour MT, et al.: Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 12 (7): 642-53, 2011.
  • Bokemeyer C, Cutsem EV, Rougier P, et al.: Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 48 (10): 1466-75, 2012.
  • Van Cutsem E, Tabernero J, Lakomy R, et al.: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30 (28): 3499-506, 2012.
  • Tabernero J, Yoshino T, Cohn AL, et al.: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16 (5): 499-508, 2015.
  • Van Cutsem E, Peeters M, Siena S, et al.: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25 (13): 1658-64, 2007.
  • Douillard JY, Siena S, Cassidy J, et al.: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28 (31): 4697-705, 2010.
  • Douillard JY, Oliner KS, Siena S, et al.: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369 (11): 1023-34, 2013.
  • Hecht JR, Mitchell E, Chidiac T, et al.: A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27 (5): 672-80, 2009.
  • Peeters M, Price TJ, Cervantes A, et al.: Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28 (31): 4706-13, 2010.
  • Heinemann V, von Weikersthal LF, Decker T, et al.: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (10): 1065-75, 2014.
  • Venook AP, Niedzwiecki D, Lenz HJ, et al.: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). [Abstract] J Clin Oncol 32 (Suppl 5): A-LBA3, 2014.
  • Stintzing S, Modest DP, Rossius L, et al.: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 17 (10): 1426-1434, 2016.
  • Modest DP, Stintzing S, von Weikersthal LF, et al.: Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer. J Clin Oncol 33 (32): 3718-26, 2015.
  • Grothey A, Sobrero AF, Siena S, et al.: Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. [Abstract] J Clin Oncol 30 (Suppl 4): A-LBA385, 2012.
  • Grothey A, Van Cutsem E, Sobrero A, et al.: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381 (9863): 303-12, 2013.
  • Mayer RJ, Van Cutsem E, Falcone A, et al.: Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372 (20): 1909-19, 2015.
    • 结肠癌治疗(PDQ®)

    最新更新日期：2020.01.22

    PDQ癌症信息定期评估和及时更新最新内容。这一部分会收录相关内容的最新信息（截至更新日期）。

    2020年新发病例和死亡病例均采用最新资料（摘自美国癌症学会，见参考文献1）。

    本篇内容由PDQ成人治疗编委会进行撰写和维护，编委会独立于NCI。本篇内容的选取立场公正，不代表NCI和NIH任何政治观点。有关本篇内容的政策及编委会在PDQ维护中的作用等更多信息，请参考PDQ摘要以及PDQ®-NCI综合癌症数据库页面内容。

    Colon Cancer Treatment (PDQ®)

    Changes to This Summary (01/22/2020)

    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.

    结肠癌治疗(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 colon 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 Colon Cancer Treatment are:

  • Russell S. Berman, MD（纽约大学医学院）
  • Valerie Lee, MD（霍普金斯大学）
  • David P. Ryan, MD（麻省总医院）

    • 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 Colon Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq. Accessed . [PMID: 26389297]

    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.

    Colon 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 colon 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 Colon Cancer Treatment are:

  • Russell S. Berman, MD (New York University School of Medicine)
  • Valerie Lee, MD (Johns Hopkins University)
  • David P. Ryan, MD (Massachusetts General Hospital)

    • 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 Colon Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq. Accessed . [PMID: 26389297]

    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 >
    目录
    章 节
    结肠癌的基本信息 结肠癌的细胞学分类 结肠癌的临床分期 结肠癌治疗方法概述 临床0期结肠癌的治疗 临床I 期结肠癌的治疗 临床II期结肠癌的治疗 临床III期结肠癌的治疗 临床IV期和复发性结肠癌的治疗 最新更新日期：2020.01.22 About This PDQ Summary
    地址：北京市朝阳区潘家园南里17号中国医学科学院肿瘤医院科研楼216、217室  邮编：100021  电话：010-87788070、010-87788069  邮箱：bjzlxh8746@163.com

    Copyright by 北京肿瘤学会 All rights reserved. 京ICP .备案：18036179号﹣1号