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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 patients. However, 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 2024:[
Gastrointestinal stromal tumors can occur in the colon. For more information, see Gastrointestinal Stromal Tumors Treatment.
Anatomy
Anatomy of the lower gastrointestinal (digestive) system.
Risk Factors
Increasing age is the most important risk factor for most cancers. Other risk factors for colorectal cancer include the following:
Screening
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. This recommendation is based on 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. For more information, see Colorectal Cancer Screening.
Prognostic Factors
The prognosis of patients with colon cancer is clearly related to:
These three characteristics form the basis for all staging systems developed for this disease.
Other prognostic factors for colon cancer include:
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.[
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 high-level 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.[
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 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
Although cohort studies have suggested that a diet or exercise regimen may improve outcomes, no prospective randomized trials have confirmed these findings. The cohort studies contained multiple opportunities for unintended bias, and caution is needed when using the data from them.
Two prospective observational studies were performed with patients enrolled in the Cancer and Leukemia Group B CALGB-89803 trial (NCT00003835), an adjuvant chemotherapy trial for patients with stage III colon cancer.[
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 an 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.[
Aspirin
A prospective cohort study examined the use of aspirin after a colorectal cancer diagnosis.[
References:
Histological types of colon cancer include:
References:
Treatment decisions can be made with reference to the TNM (tumor, node, metastasis) classification [
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.[
AJCC Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM classification to define colon cancer.[
Stage | TNMb,c | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph nodes; M = distant metastasis. | |||
a Reprinted 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. | |||
0 | Tis, N0, M0 | Tis = Carcinomain 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.) |
Stage | TNMb,c | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph nodes; M = distant metastasis. | |||
a Reprinted 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. | |||
I | T1, T2, N0, M0 | T1 = 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.) |
Stage | TNMb,c | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph nodes; M = distant metastasis. | |||
a Reprinted 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. | |||
IIA | T3, N0, M0 | T3 = 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.) | |||
IIB | T4a, N0, M0 | 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). | |
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.) | |||
IIC | T4b, N0, M0 | T4b = 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.) |
Stage | TNMb,c | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph nodes; M = distant metastasis. | |||
a Reprinted 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. | |||
IIIA | T1, N2a, M0 | T1 = 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, M0 | T1 = 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.) | |||
IIIB | T1–T2, N2b, M0 | T1 = 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, M0 | T2 = 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, M0 | 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). | |||
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.) | |||
IIIC | T3–T4a, N2b, M0 | 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). | |||
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, M0 | 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). | ||
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, M0 | T4b = 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.) |
Stage | TNMb,c | Definition | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph nodes; M = distant metastasis. | |||
a Reprinted 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. | |||
b Direct 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). | |||
c Tumor 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. | |||
IVA | Any T, Any N, M1a | TX = Primary tumor cannot be assessed. | |
T0 = No evidence of primary tumor. | |||
Tis = Carcinomain 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. | |||
IVB | Any T, Any N, M1b | Any 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. | |||
IVC | Any T, Any N, M1c | Any 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. |
References:
Stage (TNM Staging Criteria) | Treatment Options |
---|---|
Stage 0 Colon Cancer | Surgery |
Stage I Colon Cancer | Surgery |
Stage II Colon Cancer | Surgery |
Adjuvant chemotherapy(under clinical evaluation) | |
Stage III Colon Cancer | Surgery |
Clinical trials | |
Liver Metastasis | Surgery |
Neoadjuvant chemotherapy | |
Local ablation | |
Adjuvant chemotherapy | |
Intra-arterial chemotherapy | |
Clinical trials | |
Stage IV and Recurrent Colon Cancer | Surgery |
Systemic therapy | |
Immunotherapy | |
Clinical trials |
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 [
Evidence (laparoscopic techniques):
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.[
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. For more information, see the Treatment of Stage III Colon Cancer section.
Chemotherapy regimens
Table 7 describes the chemotherapy regimens used to treat colon cancer.
Regimen Name | Drug Combination | Dose |
---|---|---|
5-FU = fluorouracil; AIO = Arbeitsgemeinschaft Internistische Onkologie; bid = twice a day; IV = intravenous; LV = leucovorin. | ||
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. |
FUFOX | 5-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. |
Capecitabine and fluorouracil dosing
The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[
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):
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.
References:
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.
Treatment Options for Stage 0 Colon Cancer
Treatment options for stage 0 colon cancer include:
Surgery
Surgical options include local excision or simple polypectomy with clear margins, or colon resection for larger lesions not amenable to local excision.
Current Clinical Trials
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Because of its localized nature, stage I colon cancer has a high cure rate.
Treatment Options for Stage I Colon Cancer
Treatment options for stage I colon cancer include:
Surgery
Evidence (laparoscopic techniques):
Current Clinical Trials
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References:
Treatment Options for Stage II Colon Cancer
Treatment options for stage II colon cancer include:
Surgery
Evidence (laparoscopic techniques):
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 anatomical features such as tumor adherence to adjacent structures, perforation, and complete obstruction),[
Features in patients with stage II colon cancer that are associated with an increased risk of recurrence include:
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):
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
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References:
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.
Treatment Options for Stage III Colon Cancer
Treatment options for stage III colon cancer include:
Surgery
Surgery for stage III colon cancer is wide surgical resection and anastomosis.
Evidence (laparoscopic techniques):
Adjuvant chemotherapy
Chemotherapy regimens before 2000
Before 2000, 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.[
Evidence (5-FU alone and 5-FU/semustine):
Results:
Chemotherapy regimens after 2000
Capecitabine
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):
Oxaliplatin
Oxaliplatin has significant activity when combined with 5-FU/LV in patients with metastatic colorectal cancer.
Evidence (oxaliplatin):
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):
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):
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 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.
Current Clinical Trials
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References:
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.[
Treatment options for stage IV colon cancer, recurrent colon cancer, and liver metastases include:
Treatment Options for 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:
Surgery
Hepatic metastasis may be considered to be resectable based on the following factors:[
For patients with resectable hepatic metastasis, 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]).[
For patients with unresectable liver metastases, excellent outcomes have been achieved with liver transplant. The optimal patient cohort for this therapy is still being determined, but in general, the goal is to achieve good initial systemic control with chemotherapy, followed by transplant. In one study of 91 patients, 11% underwent live donor liver transplant. At a median follow-up of 1.5 years after transplant, the recurrence-free survival rate was 62% and the overall survival (OS) rate was 100%.[
In the TRANSMET study (NCT02597348), published in abstract form, 94 patients were randomly assigned to receive either chemotherapy and liver transplant (n = 47) or chemotherapy alone (n = 47). In an intent-to-treat analysis, the 5-year OS rate was 57% in the chemotherapy-and-liver transplant arm and 13% in the chemotherapy-alone arm. In a per-protocol analysis, the 5-year OS rate was 73% in the chemotherapy-and-liver transplant arm and 9% in the chemotherapy-alone arm.[
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.[
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.[
Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[
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 (leucovorin calcium [LV], fluorouracil [5-FU], and oxaliplatin) and FOLFIRI (5-FU/LV/irinotecan), two trials attempted to randomly assign patients after resection of liver metastases to 5-FU/LV or observation, but both studies were closed early because of poor accrual.
In the era of multiagent chemotherapy, two subsequent studies evaluated its role in the adjuvant setting following resection of liver metastases from colorectal cancer.
There is no high-level 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.[
Evidence (intra-arterial chemotherapy after liver resection):
Two trials evaluated hepatic arterial floxuridine in the adjuvant setting after liver resection.
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 Options for Stage IV and Recurrent Colon Cancer
Treatment of patients with recurrent or advanced colon cancer depends on the location of the disease.
Surgery
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.
Systemic therapy
The following drugs are used alone and in combination with other drugs for patients with metastatic colorectal cancer:
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,[
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.[
Irinotecan
Three randomized studies demonstrated improved response rates, PFS, and OS when irinotecan or oxaliplatin was combined with 5-FU/LV.[
Evidence (irinotecan):
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.[
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):
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 ziv-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).[
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):
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.[
FOLFOXIRI
Evidence (FOLFOXIRI):
Cetuximab
Cetuximab is a partially humanized monoclonal antibody against 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):
The comparisons between arms A and B and arms A and C were analyzed and published separately.[
Ziv-aflibercept
Ziv-aflibercept is an anti-VEGF molecule and has been evaluated as a component of second-line therapy in patients with metastatic colorectal cancer.
Evidence (ziv-aflibercept):
Ramucirumab
Ramucirumab is a fully humanized monoclonal antibody that binds to vascular endothelial growth factor receptor-2.
Evidence (ramucirumab):
Panitumumab
Panitumumab is a fully humanized antibody against the EGFR. The FDA approved
Evidence (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)
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.
Trifluridine-tipiracil
Trifluridine-tipiracil (
Evidence (trifluridine-tipiracil):
The FDA approved trifluridine-tipiracil for the treatment of patients with metastatic colorectal cancer, based on the results of the RECOURSE trial.
Evidence (combination of trifluridine-tipiracil and bevacizumab):
The FDA approved the combination of trifluridine-tipiracil and bevacizumab for the treatment of patients with previously treated metastatic colorectal cancer based on the results of the SUNLIGHT trial.
Regorafenib
Regorafenib is an inhibitor of multiple tyrosine kinase pathways, including VEGF. In 2012, the FDA approved regorafenib for patients who had progressed on previous therapy.
Evidence (regorafenib):
With the improved OS from the combination of trifluridine-tipiracil and bevacizumab discussed above, regorafenib is now often considered a fourth-line or later option for treatment of patients with metastatic colorectal cancer.
Encorafenib with cetuximab in patients withBRAFV600E mutations
BRAF V600E mutations occur in about 10% of metastatic colorectal cancers and are an indicator of poor prognosis. Unlike in melanoma, BRAF inhibitor monotherapy has not shown a benefit in colorectal cancer, and multiple studies have evaluated concurrent targeting of the EGFR-MAPK pathway.
Evidence (encorafenib with cetuximab in patients with BRAF V600E mutations):
Based on these data, the FDA approved the combination of encorafenib with cetuximab for patients with previously treated BRAF V600E-mutated metastatic colon cancer in 2020.
Sotorasib with panitumumab for patients withKRASG12C mutations
KRAS G12C mutations are found in approximately 4% of patients with colorectal cancer and are associated with poor prognosis.[
The primary end point was PFS assessed by blinded independent central review according to RECIST 1.1. Secondary end points included OS and objective response rate.
Immunotherapy
Approximately 4% of patients with stage IV colorectal cancer have tumors that are mismatch repair deficient (dMMR) or microsatellite unstable/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 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. MSI-H status has historically been prognostic of increased survival for patients with earlier-stage disease and since 2015, has also been found to predict tumor response to checkpoint inhibition.
The FDA approved pembrolizumab for patients with treatment-naïve, metastatic, dMMR/MSI-H colorectal cancer in 2020. Studies regarding first-line treatment with dual checkpoint inhibitors are ongoing. The FDA approved the anti-programmed cell death protein 1 (PD-1) antibodies pembrolizumab and nivolumab in 2017 for patients with microsatellite-unstable tumors who had previously received 5-FU, oxaliplatin, and irinotecan-based therapy. In 2018, the FDA granted accelerated approval for the combination of nivolumab with ipilimumab (a CTLA-4 inhibitor) to treat MSI-H colorectal cancers that progressed on prior 5-FU, oxaliplatin, and irinotecan-based therapies.
First-line immunotherapy
Pembrolizumab monotherapy
Evidence (pembrolizumab monotherapy):
Nivolumab and ipilimumab
Evidence (nivolumab and ipilimumab):
Second-line immunotherapy
Pembrolizumab monotherapy
Evidence (pembrolizumab monotherapy):
Nivolumab monotherapy
Evidence (nivolumab monotherapy):
Nivolumab and ipilimumab
Evidence (nivolumab and ipilimumab):
Current Clinical Trials
Use our
References:
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.
Treatment of Stage IV and Recurrent Colon Cancer
Added text about outcomes for patients with unresectable liver metastases who undergo liver transplant. The optimal patient cohort for this therapy is still being determined, but in general, the goal is to achieve good initial systemic control with chemotherapy, followed by transplant (cited Hernandez-Alejandro et al. as reference 18 and level of evidence C3).
Added text about the results of the TRANSMET study, which randomly assigned 94 patients to receive either chemotherapy and liver transplant or chemotherapy alone (cited Adam et al. as reference 19 and level of evidence A1).
Added text about the results of the CheckMate 8HW study, which randomly assigned 303 patients to receive either nivolumab and ipilimumab or chemotherapy alone (cited Lenz et al. as reference 107).
This summary is written and maintained by the
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 in the care of their 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
Board members review recently published articles each month to determine whether an article should:
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:
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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.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Colon Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at:
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Last Revised: 2024-09-06
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