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Incidence and Mortality
Estimated new cases and deaths from colon cancer in the United States in 2012:
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.
The prognosis of patients with colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. The American Joint Committee on Cancer 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.[4,5,6] 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.[7,8,9,10]
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.[11,12,13,14,15,16,17,18,19,20] Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (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. Treatment decisions depend on factors such as physician and patient preferences and the stage of the disease rather than the age of the patient.[22,23,24] Racial differences in overall survival 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.
Because of the frequency of the disease, ability to identify high-risk groups, demonstrated 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 or older, especially for those with first-degree relatives with colorectal cancer. Groups that have a high incidence of colorectal cancer include those with hereditary conditions, such as familial polyposis, HNPCC or Lynch syndrome variants I and II, and those with a personal history of ulcerative colitis or Crohn colitis.[26,27] Together, they account for 10% to 15% of colorectal cancers. 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.[Level of evidence: 3iiiA] More common conditions with an increased risk include a personal history of colorectal cancer or adenomas; first-degree family history of colorectal cancer or adenomas; and a personal history of ovarian, endometrial, or breast cancer.[29,30] These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers. (Refer to the PDQ summaries on Colorectal Cancer Prevention and Colorectal Cancer Screening for more information.)
Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.[32,33,34,35] 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 the efficacy of a standard, postoperative monitoring program.[36,37,38,39,40] 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:
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.[38,39,40] New surveillance methods, including CEA immunoscintigraphy  and positron emission tomography, are under clinical evaluation.
Gastrointestinal stromal tumors can occur in the colon. (Refer to the PDQ summary on Gastrointestinal Stromal Tumors Treatment for more information.)
Other PDQ summaries containing information related to colon cancer include the following:
Histologic types of colon cancer include the following:
Treatment decisions should be made with reference to the TNM classification  rather than to the older Dukes or the Modified Astler-Coller classification schema.
The American Joint Committee on Cancer (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.[2,3,4] 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.[5,6,7,8]
Definitions of TNM
The AJCC has designated staging by TNM classification to define colon cancer. The same classification is used for both clinical and pathologic staging.
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 [1,2,3,4] in the treatment of colon cancer has been examined in two studies. A multicenter, prospective, randomized, noninferiority trial (NCCTG-934653) compared laparoscopic-assisted colectomy (LAC) to 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; HR for death in LAC, 0.91; 95% CI, 0.68–1.21; P = .51) were similar in both groups for all stages of disease evaluated.[Level of evidence: 1iiA]. Tumor recurrence in surgical incisions was less than 1% for both groups. 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] The role of sentinel lymph node mapping is also under clinical evaluation.[8,9]
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.
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.[10,11,12] (Refer to the section of this summary on Stage II Colon Cancer for more information.)
Prior to 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. The addition of oxaliplatin to 5-FU and leucovorin has been shown to improve OS compared with 5-FU and leucovorin alone. (Refer to the sections of this summary on Stage III Colon Cancer and Stage IV and Recurrent Colon Cancer for more information.)
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 (T4, tumor location in immobile sites, local perforation, obstruction, and residual disease postresection).[13,14,15,16,17,18] 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 (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, though 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, though it may have a role for patients with residual disease.
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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Because of its localized nature, stage I colon cancer has a high cure rate.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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, complete obstruction, or with biologic characteristics such as aneuploidy, high S-phase analysis, or deletion of 18q),[5,6,7] evidence is inconsistent that adjuvant 5-fluorouracil (5-FU)–based chemotherapy is associated with an improved overall survival (OS) compared to surgery alone. Investigators from the National Surgical Adjuvant Breast and Bowel Project (NSABP) 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 (DFS) at 5 years when adjuvant therapy-treated patients treated with 5-FU-leucovorin are compared with untreated controls.[Level of evidence: 1iiDii
Recently, 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 where adjuvant chemotherapy was compared with observation for patients with stage II colon cancer. The mortality risk ratio was 0.87 (95% CI, 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."
Features in patients with stage II colon cancer that are associated with an increased risk of recurrence include inadequate lymph node sampling, T4 disease, involvement of the visceral peritoneum, and a poorly differentiated histology. The decision to use adjuvant chemotherapy for patients with stage II colon cancer is complicated and requires thoughtful consideration for both patients and their physicians.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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.
Drug combinations described in this section include the following:
Treatment options include the following:
The role of laparoscopic techniques [1,2,3,4] in the treatment of colon cancer was examined in a multicenter prospective randomized trial (NCCTG-934653, now closed) comparing laparoscopic-assisted colectomy (LAC) with open colectomy. The quality-of-life component of this trial has been published and reported minimal short-term quality-of-life benefits with LAC.[Level of evidence: 1iiC]
Based on results from the MOSAIC (NCT00275210) trial, adjuvant FOLFOX4 demonstrated prolonged overall survival (OS) for patients with stage III colon cancer compared with patients receiving 5-FU/leucovorin without oxaliplatin. The 6-year OS of patients with stage III colon cancer was 72.9% in the patients receiving FOLFOX and 68.9% in the patients receiving 5-FU/LV (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.65–0.97, P = .023).
Chemotherapy regimens prior to 2000
Prior to 2000, 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.[8,9,10,11] These trials employed 5-FU alone or 5-FU-semustine (methyl-CCNU). The North Central Cancer Treatment Group (NCCTG) conducted a randomized trial comparing surgical resection alone with postoperative levamisole or 5-FU-levamisole.[Level of evidence: 1iiA] A significant improvement in disease-free survival (DFS) was observed for patients with stage III colon cancer who received 5-FU-levamisole, 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 5-FU-levamisole.
In a large, confirmatory intergroup trial, 5-FU-levamisole 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 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-leucovorin 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%).[14,15,16]
The completed, Intergroup trial 0089 (INT-0089 [EST-2288]) randomly assigned 3,794 patients with high-risk stage II or stage III colon cancer to one of four treatment arms:
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-leucovorin in the adjuvant setting and can be summarized as follows:
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-leucovorin.[24,25] A multicenter European study compared capecitabine (1250 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 leucovorin for patients with stage III colon cancer. The study demonstrated that disease-free survival (DFS) at 3 years is equivalent for patients receiving capecitabine or 5-FU-leucovorin (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-leucovorin is planned, capecitabine is an equivalent alternative.
Oxaliplatin has significant activity when combined with 5-FU-leucovorin in patients with metastatic colorectal cancer. In the 2,246 patients with resected stage II or stage III colon cancer in the MOSAIC study, the toxic effects and efficacy of FOLFOX4 were compared with the same 5-FU-leucovorin regimen without oxaliplatin administered for 6 months. 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 FOLFOX4. 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% 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 and 68.9% 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 FOLFOX4 experienced more frequent toxic effects consisting mainly of neutropenia (41% >grade 3) and reversible peripheral sensorial neuropathy (12.4% >grade 3). FOLFOX has become the reference standard for the next generation of clinical trials for patients with stage III colon cancer.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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.
Approximately 50% of colon cancer patients will be diagnosed with hepatic metastases, either at the time of initial presentation or as a result 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 a number of treatment options.
Hepatic metastasis may be considered to be resectable based on the following:[5,7,13,14,15,16]
For patients with hepatic metastasis considered to be resectable, a negative margin resection has resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the NCCTG-934653 trial.[5,7,13,14,15,16] Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.
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. Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide for long-term tumor control.[18,19,20,21,22,23,24] Radiofrequency ablation and cryosurgical ablation [25,26,27,28] 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.[29,30] 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.[12,31,32]
The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain. A trial of hepatic arterial floxuridine and dexamethasone plus systemic fluorouracil (5-FU) and leucovorin compared to systemic 5-FU plus leucovorin alone showed improved 2-year progression-free survival (57% vs. 42%, P = .07) and overall survival (OS) (86% vs. 72%, P = .03) but did not show a significant statistical difference in median survival, compared with systemic 5-FU therapy alone. Median survival in the combined therapy arm was 72.2 months versus 59.3 months in the monotherapy arm (P = .21).[Level of evidence: 1iiA]
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 recurrence was decreased, median or 4-year survival was not significantly different. Further studies are required to evaluate this treatment approach and to determine if more effective systemic combination chemotherapy alone may provide similar results compared with hepatic intra-arterial therapy plus systemic treatment.
Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy.[2,35,36,37,38,39] Controversy regarding the efficacy of regional chemotherapy led to initiation of a large multicenter phase III trial (CALGB-9481, now completed) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation. Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.
Treatment of Patients With Stage IV Disease
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.
For patients with hepatic metastasis considered to be resectable, a negative margin resection has been associated with 5-year survival rates of 25% to 40% in mostly nonrandomized studies.[41,42,43,44,45][Level of evidence: 3iiiDiv] Better 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.
Currently, there are seven active and approved drugs for patients with metastatic colorectal cancer:
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 [46,47] as well as improved survival and quality of life for patients receiving chemotherapy, compared with the best supportive care.[48,49,50] Several trials have analyzed the activity and toxic effects of various 5-FU-leucovorin regimens using different doses and administration schedules and showed essentially equivalent results with a median survival time in the 12-month range. Prior to 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-leucovorin.[52,53][Level of evidence: 1iiA]
First-line Multiagent Chemotherapy
Three randomized studies demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin.[54,55,56] An intergroup study (NCCTG-N9741) then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced an improved PFS (median, 6.9 months vs. 8.7 months; P = .014; hazard ratio [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.[Level of evidence: 1iiA] Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over upon progression on first-line therapy, respectively.[57,58][Level of evidence: 1iiDiii] PFS and OS were identical between the treatment arms in both studies. 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.
The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial evaluated several different irinotecan-based regimens in patients with previously untreated metastatic colorectal cancer: FOLFIRI, mIFL, and capecitabine/irinotecan (CAPIRI). The study randomly assigned 430 patients and was closed early due to 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. 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, PFS, was not significantly different, patients receiving 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). When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[Level of evidence: 1iiDiii] (Refer to the PDQ summary on Nausea and Vomiting and for information on diarrhea and dehydration, refer to the PDQ summary on Gastrointestinal Complications.)
Randomized, phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[60,61] The AIO Colorectal Study Group randomly assigned 474 patients to either 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. The TTP was 8.9 months versus 9.5 months (P = .153) and met the prespecified range for noninferiority.[Level of evidence: 1iiDiii] When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.
The Addition of Targeted Therapy to Multiagent Chemotherapy
Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL and bevacizumab. The patients randomly assigned to IFL and bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL and bevacizumab, as compared with 6.2 months in the group given IFL and placebo; HR for disease progression, 0.54; P < .001) and OS (20.3 months in the group given IFL and bevacizumab, as compared with 15.6 months in the group given IFL and placebo corresponding to an HR for death, 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 NCCTG-N9741. 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 FOLFOX4, 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% confidence interval [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 FOLFOX4-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.[64,65] 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 (ECOG) randomly assigned patients who had progressed on 5-FU-leucovorin and irinotecan to either FOLFOX or FOLFOX and bevacizumab. Patients randomly assigned to FOLFOX and 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 two studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.
There are currently no completed randomized controlled studies evaluating whether continued use of bevacizumab in the second line or third line after progressing on a first-line bevacizumab regimen is worthwhile.
Cetuximab/panitumumab and second-line chemotherapy
Second-line chemotherapy with irinotecan in patients treated with 5-FU-leucovorin as first-line therapy demonstrated improved OS when compared to either infusional 5-FU or supportive care.[67,68,69,70] Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU-leucovorin to bolus and infusional 5-FU-leucovorin (LV5FU2), single-agent oxaliplatin, or FOLFOX4. The median TTP for FOLFOX4 versus LV5FU2 was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[Level of evidence: 1iiDiii]
Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). For patients who have progressed on irinotecan-containing regimens, a randomized phase II study was performed of either cetuximab or irinotecan and cetuximab. The median TTP for patients receiving cetuximab was 1.5 months, and the median TTP for patients receiving irinotecan and cetuximab was 4.2 months.[Level of evidence: 3iiiDiv] 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 (NCT00154102) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab. 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.[Level of Evidence: 1iiDii] 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 a 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).
Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab. In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab. The median PFS was 9.4 months in the group receiving cetuximab and 10.7 months in the group not receiving 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 not receiving cetuximab (8.1 months vs. 12.5 months; P = .003) as well as OS (17.2 months vs. 24.9 months; P = .03).[Level of evidence: 1iiDiii]
Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial, patients with chemotherapy refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced an improved PFS (8 weeks vs. 7.3 weeks, HR, 0.54; 95% CI, 0.44–0.66; P <.0001).[Level of evidence: 1iiDiii] 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. The FDA-approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.
In the PRIME (NCT00364013) study, 1,183 patients were randomly assigned to FOLFOX4 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. For patients with KRAS wild-type tumors, a statistically significant improvement in PFS was observed in those who received panitumumab-FOLFOX4 compared with those who received only FOLFOX4 (HR, 0.80; 95% CI, 0.66–0.97; P = .02, stratified log-rank test).[Level of evidence: 1iiDiii] Median PFS was 9.6 months (95% CI, 9.2 months–11.1 months) for patients who received panitumumab-FOLFOX4 and 8.0 months (95% CI, 7.5 months–9.3 months) for patients who received FOLFOX4. 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-FOLFOX4 and 8.8 months (95% CI, 7.7 months–9.4 months) for FOLFOX4 alone.
Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared to 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 plus panitumumab. 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).[Level of evidence: 1iiDiii] 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.
The Medical Research Council (MRC) (UKM-MRC-COIN-CR10 [NCT00182715] or COIN 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.[79,80] 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:
The comparisons between arms A and B and arms A and C were analyzed and published separately.[79,80]
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 vs. 8.6 months [IQR, 5.1–13.8] in the cetuximab group; HR, 0.96; 0.82–1.12, P = .60).[79,80][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 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.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV colon cancer and recurrent colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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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.
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National Cancer Institute: PDQ® Colon Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/colon/HealthProfessional. Accessed <MM/DD/YYYY>.
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