Gastroenterology
Volume 134, Issue 5 , Pages 1296-1310.e1, May 2008

Systemic Treatment of Colorectal Cancer

  • Brian M. Wolpin

      Affiliations

    • Department of Medicine, Harvard Medical School, Boston, Massachusetts
    • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    • ,
  • Robert J. Mayer

      Affiliations

    • Department of Medicine, Harvard Medical School, Boston, Massachusetts
    • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    • Dana-Farber Cancer Institute, Boston, Massachusetts
    • Corresponding Author InformationAddress requests for reprints to: Robert J. Mayer, MD, Center for Gastrointestinal Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115. fax: (617) 632-2260.

Received 31 January 2008; accepted 27 February 2008.

Wafik El-Diery and David Metz, Section Editors

Article Outline

Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Over the past 12 years, significant progress has been made in the systemic treatment of this malignant condition. Six new chemotherapeutic agents have been introduced, increasing median overall survival for patients with metastatic colorectal cancer from less than 9 months with no treatment to approximately 24 months. For patients with stage III (lymph node positive) colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy for the inclusion of oxaliplatin in such adjuvant treatment programs. For patients with stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at higher risk for disease recurrence. Ongoing randomized clinical trials are evaluating how best to combine currently available therapies, while smaller studies are evaluating new agents, with the goal of continued progress in prolonging life among patients with metastatic colorectal cancer and increasing cure rates among those with resectable disease.

Abbreviations used in this paper: ECOG, Eastern Cooperative Oncology Group, EGFR, epidermal growth factor receptor, FOLFIRI, infusional fluorouracil, leucovorin, and irinotecan, FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin, IFL, irinotecan, bolus fluorouracil, and leucovorin

 

Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. In 2008, an estimated 148,810 cases of colorectal cancer will be diagnosed and 49,960 people will die from this disease.1 Significant progress in the treatment of colorectal cancer has been achieved over the past 12 years, with the approval of 6 new therapeutic agents in the United States (Table 1). These compounds have greatly improved the outlook for patients diagnosed with resectable and metastatic disease. The current review focuses on advances in the systemic therapy of colorectal cancer.

Table 1. New Chemotherapeutic Agents in the Systemic Treatment of Colon Cancer
DrugCurrent indicationsa
Metastatic diseaseFDA-approval dateAdjuvant therapyFDA-approval date
Irinotecan (Camptosar)YesJune 1996No—
Capecitabine (Xeloda)YesApril 2001YesJune 2005
Oxaliplatin (Eloxatin)YesAugust 2002YesNovember 2004
Cetuximab (Erbitux)bYesFebruary 2004No—
Bevacizumab (Avastin)YesFebruary 2004No—
Panitumumab (Vectibix)bYesSeptember 2006No—

aUS Food and Drug Administration (FDA) data accessed at www.accessdata.fda.gov.

bApproved for use in patients with tumors that express the EGFR.

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Staging and Prognosis 

Pathologic stage represents the most important prognostic factor for patients with colorectal cancer. The tumor-node-metastasis (TNM) system, as defined by the American Joint Committee on Cancer, is the most commonly used staging system and is based on depth of invasion of the bowel wall, extent of regional lymph node involvement, and presence of distant sites of disease (Table 2).2, 3, 4 The depth of tumor invasion defines the T stage and increases from T1 (invasion of the submucosa) to T4 (invasion into the serosa or adjacent structures). As the depth of tumor invasion increases, the risk for nodal and distant spread also grows. Pathologic review of surrounding lymph nodes defines the 3 N categories: N0 (no lymph nodes involved), N1 (1–3 lymph nodes involved), and N2 (>3 lymph nodes involved). Current guidelines recommend the identification of 12 or more lymph nodes in the resected specimen2, 5 because the examination of fewer regional lymph nodes has been linked with poorer outcome in patients with node-negative and node-positive disease.6, 7, 8, 9, 10 The examination of fewer lymph nodes may reflect a less complete surgical procedure or an inadequate inspection of the pathologic specimen, mistakenly leading to understaging of the tumor and the subsequent omission of beneficial adjuvant therapy.

Table 2. TNM Staging System for Colorectal Cancer
Primary tumor (T)
TxPrimary tumor cannot be assessed
TisCarcinoma in situ
T1Tumor invades submucosa
T2Tumor invades muscularis propria
T3Tumor invades through the muscularis propria into the subserosa
T4Tumor directly invades other organs or structures, or perforates visceral peritoneum
Regional lymph nodes (N)
NxRegional lymph nodes cannot be assessed
N0No regional lymph node metastases
N1Metastases in 1–3 regional lymph nodes
N2Metastases in ≥4 regional lymph nodes
Distant metastases (M)
MxPresence or absence of distant metastases cannot be determined
M0No distant metastases detected
M1Distant metastases detected
Stage grouping and 5-year survival
StageTNM classification5-year survival
IT1–2, N0, M0>90%
IIAT3, N0, M080%–85%
IIBT4, N0, M070%–80%
IIIAT1–2, N1, M065%–80%
IIIBT3–4, N1, M050%–65%
IIICT1–4, N2, M025%–50%
IVT1–4, N0–2, M15%–8%

NOTE. Data from Greene et al,3, 4, 5 O'Connell et al,30 and Meyerhardt and Mayer.31

In patients with resectable colorectal cancer, several other pathologic and clinical features have been identified that are associated with an increased risk for tumor recurrence. These include poorly differentiated histology, lymphovascular invasion, perineural invasion, T4 tumor penetration, bowel perforation, clinical bowel obstruction, and an increased preoperative plasma level of carcinoembryonic antigen.11, 12, 13, 14, 15 In contrast, hospitals and surgeons with higher patient volume have been associated with improved outcomes for resectable colorectal cancer.16, 17, 18

Microsatellite instability and loss of heterozygosity at chromosome 18q are the 2 best-defined molecular prognostic markers.19 Microsatellite instability results from mutations or promoter hypermethylation of DNA mismatch repair genes leading to errors in DNA replication and changes in short, repeated sequences of DNA. It is present in the vast majority of tumors from patients with hereditary nonpolyposis colon cancer, but also is found in 15% to 20% of patients with sporadic colon cancer.20, 21 Patients with tumors possessing a high degree of microsatellite instability have a more favorable prognosis than those patients whose tumors are microsatellite stable.20, 22 Loss of heterozygosity at chromosome 18q has been reported in approximately 50% of colon cancers and has been associated with a worse prognosis.23, 24 Although these factors provide prognostic information on the risk of tumor recurrence after primary resection, they have not been prospectively validated as predictive markers for altered outcome with administration of specific chemotherapeutic regimens.

The rectum is located within the pelvis and extends from the transitional mucosa of the anal dentate line to the sigmoid colon, which measures between 10 and 15 cm from the anal verge by rigid sigmoidoscopy. The bony constraints of the pelvis limit surgical access to the rectum, leading to a lower likelihood of achieving widely negative margins and a higher risk of local recurrence. Because of the increased risk of local recurrence, the local management of rectal cancer varies somewhat from that of colon cancer. Surgical resection of rectal cancer with sharp dissection of the mesorectum en bloc with the rectum, as part of a total mesorectal excision, has resulted in a lower likelihood of local recurrence.25, 26 The mesorectum is the rectal mesentery that contains the rectum's vascular supply and lymphatic drainage and is the initial site of spread for rectal cancer. In addition, radiotherapy administered preoperatively or postoperatively has been associated with a lower risk of local recurrence when compared with surgery alone, even when a total mesorectal excision has been performed.26, 27

Spread of tumor beyond the colorectum and regional lymph nodes defines the M stage of the American Joint Committee on Cancer classification system, with M1 indicating the presence of tumor metastases to distant sites. Approximately 20% of patients present with metastatic disease and 30% to 40% of patients with localized disease ultimately develop metastases. The liver reflects the most common initial site of disease spread, but metastases to other organs during the course of the disease are common, including to the lungs, peritoneum, and intra-abdominal lymph nodes. Patients with a small number of isolated, organ-confined metastases may be cured of their disease by surgical resection28; decisions regarding metastasectomy should be made by a medical oncologist working in close conjunction with an experienced surgeon. Most patients with metastatic disease are candidates for systemic chemotherapy to palliate symptoms and prolong life. As the American Joint Committee on Cancer stage increases from stage I to stage IV, the 5-year overall survival rates decline dramatically: stage I, greater than 90%; stage II, 70%–85%; stage III, 25%–80%; and stage IV, less than 10% (Table 2).2, 29, 30

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Fluoropyrimidines 

Intravenous Fluorouracil 

Fluorouracil remains the cornerstone of systemic treatment for colorectal cancer. It is a fluorinated pyrimidine that acts primarily through inhibition of thymidylate synthetase, the rate-limiting enzyme in pyrimidine nucleotide synthesis31 and is commonly administered with leucovorin, a reduced folate that is thought to stabilize fluorouracil's interaction with this enzyme.32, 33, 34, 35 A meta-analysis of 3300 patients from 19 randomized trials found that the likelihood of a greater than 50% tumor shrinkage by bidimensional product measurement doubles when fluorouracil is administered with leucovorin in patients with metastatic colorectal cancer, with a modest but statistically significant improvement in overall survival when compared with fluorouracil alone.36 Among patients with metastatic colorectal cancer receiving fluorouracil and leucovorin, approximately 20% will have a reduction in tumor size by 50% or more, and median survival is increased from approximately 6 months to about 12 months.36, 37

Fluorouracil can be administered by a variety of different schedules, with differing toxicity profiles. Neutropenia and stomatitis are the most frequent side effects when bolus fluorouracil and leucovorin are administered daily for 5 days every 4 to 5 weeks (the Mayo Clinic regimen). Higher rates of diarrhea are noted when bolus fluorouracil and leucovorin are administered weekly for 6 of 8 weeks (the Roswell Park regimen). Schedules that administer fluorouracil as a continuous infusion are associated with less hematologic and gastrointestinal toxicity, but have a greater incidence of hand-foot syndrome, a tender, erythematous rash involving the palms and soles.

Although treatment programs that involve infusional fluorouracil were initially thought to be less convenient and more expensive than bolus regimens, little difference has been noted in quality of life or cost between these 2 types of regimens.38, 39, 40 In addition, a meta-analysis of 6 randomized trials has shown a modest improvement in response rate and median overall survival among patients with metastatic colorectal cancer who received infusional fluorouracil when compared with patients who received a more rapid, bolus approach.37

Oral Fluoropyrimidines 

Initial attempts to administer fluoropyrimidines orally were unsuccessful. A randomized comparison of oral vs intravenous fluorouracil in patients with metastatic colorectal cancer favored the intravenous route in terms of tumor response rate and mean duration of tumor response.41 These differences in response were thought to result from erratic intestinal absorption of fluorouracil, owing to differing mucosal concentrations of dihydropyrimidine dehydrogenase, a major catabolic enzyme of the drug. Two strategies have been used to circumvent this problem: the administration of an absorbable fluorouracil prodrug that is not catabolized by dihydropyrimidine dehydrogenase42 and the co-administration of an inhibitor of dihydropyrimidine dehydrogenase with oral fluorouracil.43

Capecitabine (Xeloda; Roche, Nutley, NJ) is an oral prodrug of fluorouracil that is absorbed intact through the gastrointestinal mucosa and undergoes a 3-step enzymatic conversion to fluorouracil.42 The side-effect profile of this drug is similar to that seen with continuous infusion fluorouracil, with the hand-foot syndrome being most prominent. Studies have shown capecitabine to be equivalent therapeutically to bolus fluorouracil and leucovorin (Mayo Clinic schedule) as initial therapy in metastatic colorectal cancer, with no significant differences in median time to tumor progression or median overall survival.44, 45

Tegafur uracil (Orzel; Bristol-Myers Squibb, New York, NY) circumvents the erratic intestinal absorption of fluorouracil by the co-administration of an oral fluoropyrimidine (tegafur) with an inhibitor of dihydropyrimidine dehydrogenase (uracil), thereby allowing for a more uniform absorption and bioavailability of tegafur.46 In 2 randomized studies of patients with metastatic colorectal cancer, treatment with tegafur uracil and oral leucovorin resulted in similar rates of response and median survival as parental fluorouracil and leucovorin.47, 48 Although available in Europe and Asia, tegafur uracil is not available in the United States.

Although capecitabine, at the recommended dose of 1250 mg/m2 twice daily, appears therapeutically similar to monthly bolus fluorouracil and leucovorin with a somewhat less severe toxicity profile, it is uncertain whether the differences in toxicity profile would remain if capecitabine were compared with a more tolerable schedule of parenteral fluorouracil (ie, Roswell Park or infusional schedule). In addition, results from recent studies of capecitabine administered with other intravenous chemotherapies, such as oxaliplatin and irinotecan, call into question the more favorable convenience and cost-effectiveness profile that have been reported with single-agent capecitabine.49, 50, 51

Adjuvant Therapy With Fluoropyrimidines for Stage III Colon Cancer 

Fluorouracil was thought for many years to be ineffective as adjuvant treatment for colon cancer52, 53, 54, 55; a meta-analysis of randomized trials published before 1987 showed only a small, statistically insignificant benefit for such treatment.56 In retrospect, these randomized trials suffered from heterogeneous patient populations, inadequate sample size, and poor compliance with therapy. Two subsequent approaches to adjuvant therapy for colon cancer revived interest in fluorouracil.

In an attempt to reduce the incidence of subsequent liver metastases, several clinical trials evaluated the administration of fluorouracil into the portal circulation during the immediate postoperative period.57, 58, 59, 60, 61, 62 Although these studies failed to reduce tumor spread to the liver, a meta-analysis of 10 such trials did show a modest overall survival benefit, supporting the value of a short exposure to adjuvant fluorouracil when compliantly administered.63

In addition, the merits of adjuvant treatment with fluorouracil were reassessed when levamisole, an antihelminthic, was examined as a putative immunomodulating agent.64, 65, 66 Because levamisole eventually was shown to be inactive, these studies actually represented a reassessment of the adjuvant administration of fluorouracil. A large trial of 1296 patients conducted by the Eastern Cooperative Oncology Group (ECOG) showed that adjuvant fluorouracil (and levamisole) reduced the risk of recurrence by 41% and the risk of death by 33% compared with surgery alone in patients with stage III disease.67 After a median follow-up period of 6.5 years, overall survival was increased from 47% to 60% by the addition of postoperative fluorouracil (and levamisole).68

Because the antitumor activity of fluorouracil was enhanced in the metastatic setting when administered with leucovorin,36 the combination of fluorouracil and leucovorin was evaluated in the adjuvant setting, where it was found to improve disease-free and overall survival.69, 70, 71, 72 A pooled analysis of 7 randomized trials of postoperative fluorouracil-based therapy vs surgery alone showed an increase in 5-year disease-free survival from 42% to 58% and a 5-year overall survival from 51% to 61% in patients with stage III disease.73 Subsequent studies showed that adjuvant fluorouracil and leucovorin administered for 6 months was equivalent to fluorouracil and levamisole administered for 12 months, and that the addition of levamisole to fluorouracil and leucovorin did not provide added benefit.72, 74, 75 Furthermore, none of the various administration schedules of fluorouracil was found to be superior to any other in the adjuvant setting,76, 77, 78, 79 although different side-effect profiles were noted, similar to those observed in patients treated for metastatic disease.

Oral fluoropyrimidines also have been evaluated in the adjuvant therapy of colon cancer. In the Xeloda in Adjuvant Colon Cancer Trial, capecitabine (1250 mg/m2 administered twice daily on days 1–14 every 3 weeks) was shown to be equally effective when compared with the Mayo Clinic regimen of bolus fluorouracil and leucovorin in a cohort of patients with stage III colon cancer.80 A large randomized trial comparing tegafur uracil and leucovorin with intravenous fluorouracil and leucovorin as adjuvant therapy also showed similar rates of disease-free survival and overall survival between the 2 treatment arms.81

Although nearly 75% of patients diagnosed with colon cancer are 65 years of age or older,82 such patients have been underrepresented in clinical trials and are less likely to receive adjuvant therapy.83, 84 Pooled data analyses and population-based studies have repeatedly shown a consistent and equivalent survival benefit for adjuvant therapy in all age groups,85, 86, 87, 88, 89 without an increase in treatment-related toxicity among older patients.86, 89, 90, 91, 92 When disease outcomes have been analyzed by ethnicity, higher colorectal cancer–specific mortality has been noted in African American than in Caucasian patients.93 Differences in comorbid disease, sociodemographic factors, stage at presentation, tumor biology, and receipt of treatment have been investigated as underlying reasons for the discrepancy in outcomes.87, 94, 95, 96, 97 Subset analyses of randomized treatment trials have shown similar disease-free survival among African American and Caucasian patients,98, 99 suggesting that African Americans derive a similar degree of benefit from appropriately administered therapy as do Caucasians.

Adjuvant Therapy With Fluoropyrimidines for Stage II Colon Cancer 

The benefit of adjuvant fluorouracil-based therapy in patients with stage II colon cancer is less clear. Subset analyses of trials that have included patients with stage II and III disease have repeatedly failed to show a statistically significant survival benefit for stage II patients receiving adjuvant therapy. A pooled analysis of 7 studies showed a 5-year overall survival of 81% in patients who received fluorouracil-based adjuvant therapy and 80% in patients who underwent surgery alone (P = .11).73

Two studies have been cited in favor of the use of adjuvant therapy in patients with stage II disease. A retrospective subset analysis of 4 consecutive National Surgical Adjuvant Breast and Bowel Project trials noted a similar proportional survival benefit for patients with stage II and stage III disease who received fluorouracil-based therapy,100 although the statistical approach taken in this analysis has been questioned.101 The Quick and Simple and Reliable study, a complex comparison of 4 different fluorouracil-based regimens with observation alone, showed a statistically significant 3.7% improvement in overall survival (80.8% vs 77.1%) among patients with predominantly stage II colon and rectal cancer who received adjuvant treatment.102 Interpretation of these data is clouded by the lack of central pathologic review to verify tumor stage; a heterogeneous patient population with inclusion of patients with both colon (71%) and rectal (29%) cancers, patients with stage III disease (8%), and patients who also received radiotherapy or portal vein infusion; multiple different chemotherapy regimens in the treatment arm; and a somewhat lower than expected survival in the 2 arms, when compared with other recently published adjuvant studies.103

After systematically reviewing the available literature, the Cancer Care Ontario Program in Evidence-Based Care,104 an expert panel convened by the American Society of Clinical Oncology,105 and the National Comprehensive Cancer Network106 independently recommended against the routine administration of adjuvant therapy in patients with stage II disease. In addition, the American Society of Clinical Oncology panel determined that a sample size of 9680 patients per group would be required to detect a 2% survival difference between treatment and control arms, with 90% power and a significance level of 0.05.105

It has been proposed that adjuvant chemotherapy may provide benefit to those patients with stage II disease and adverse clinical characteristics, such as T4 tumor penetration, bowel perforation, or clinical bowel obstruction.105 Although this hypothesis has not yet been validated in a prospective, randomized clinical trial, a retrospective subset analysis of patients with stage II disease enrolled in the previously noted ECOG study that examined the adjuvant value of fluorouracil and levamisole suggested a survival benefit for postoperative therapy in these high-risk patient subgroups.14 Although other high-risk features, such as inadequate lymph node sampling, lymphovascular or perineural invasion, poorly differentiated histology, microsatellite stability, and loss of heterozygosity at chromosome 18q also are known to carry a higher risk of recurrence,11 the potential benefit of chemotherapy has not been examined prospectively in patients with these risk factors.

Adjuvant Therapy With Fluoropyrimidines for Stage II and Stage III Rectal Cancer 

Several clinical trials performed in the 1980s showed that the addition of systemic chemotherapy to postoperative radiation reduced the risk of local recurrence and improved overall survival after the resection of stage II and stage III rectal cancers.107, 108, 109 In a subsequent study, the administration of infusional fluorouracil with radiotherapy was noted to be more effective than similar radiotherapy with concurrent bolus fluorouracil.110 More recently, the German Rectal Cancer Study Group showed that preoperative combined chemoradiation therapy improved local control, decreased toxicity, and reduced the need for a colostomy when compared with postoperative chemotherapy and radiation among patients assessed by preoperative endoscopic ultrasound and thought to have stage II and stage III rectal cancer.111 No differences in disease-free or overall survival were observed between the preoperative and postoperative treatment arms. Therefore, the standard of care for stages II and III rectal cancer generally is considered to be preoperative combined modality therapy with radiation and chemotherapy, followed by surgical resection with total mesorectal excision. Perhaps to parallel the 6 months of adjuvant therapy used among patients with resected colon cancer, an additional 4 months of postoperative fluorouracil-based chemotherapy typically is administered to patients with stage II or III rectal cancer.

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Irinotecan 

Irinotecan (Camptosar; Pfizer, New York, NY) is a semisynthetic derivative of the natural alkaloid camptothecin that is converted by carboxylesterases to SN-38.112 By inhibiting topoisomerase I, an enzyme that catalyzes breakage and rejoining of DNA strands during DNA replication, SN-38 causes DNA fragmentation and programmed cell death.113 Metabolism of SN-38 occurs predominantly in the liver, where it is inactivated by glucuronidation and excreted through the biliary system. A polymorphism in the uridine diphosphate glucuronosyltransferase isoform 1A1 (UGTA1A) gene, which is responsible for glucuronidation of SN-38, has been identified and leads to decreased inactivation of SN-38 with resultant increases in treatment-related toxicity.114 A diagnostic test for this genetic polymorphism is available, although not widely used in the clinic. Increased serum bilirubin levels also have been associated with excess irinotecan-mediated toxicity and this drug is not typically administered to patients with hyperbilirubinemia.115 The most commonly observed toxicities associated with irinotecan are diarrhea, myelosuppression, and alopecia.116, 117

Randomized trials have shown improvements in progression-free and overall survival when irinotecan has been added to either infusional (FOLFIRI)118 or bolus (IFL)119 fluorouracil and leucovorin in the initial treatment of patients with metastatic colorectal cancer. More recently, a randomized trial comparing FOLFIRI, IFL, and irinotecan plus capecitabine showed that those patients receiving FOLFIRI experienced longer progression-free and overall survival times, supporting the superiority of the infusional approach.120 In addition, irinotecan plus capecitabine was associated with approximately twice the rates of serious vomiting, diarrhea, and dehydration when compared with the 2 regimens that included intravenous fluorouracil.

Based on the encouraging results with irinotecan in patients with metastatic disease, it was anticipated that irinotecan would be an effective addition to adjuvant treatment programs for colon cancer. Three randomized trials of adjuvant irinotecan with either bolus or infusional fluorouracil and leucovorin have examined this premise.121, 122, 123 Surprisingly, each of these studies showed increased toxicity without a meaningful improvement in outcome among patients receiving irinotecan. This unanticipated failure of irinotecan to prove beneficial in the adjuvant setting has not been well explained, but underscores the importance of conducting rigorous, randomized clinical trials before making changes in clinical practice.124

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Oxaliplatin 

Oxaliplatin (Eloxatin; Sanofi-Aventis, Bridgewater, NJ) is a diaminocyclohexane platinum compound that forms DNA adducts, leading to impaired DNA replication and cellular apoptosis.125, 126 In patients with metastatic colon cancer, single-agent oxaliplatin has limited efficacy, but clinical benefit has been observed when it is administered with fluorouracil and leucovorin,127, 128, 129, 130, 131, 132 possibly as a result of oxaliplatin-induced down-regulation of thymidylate synthetase.133 A cumulative sensory neuropathy, characterized by paresthesias of the hands and feet, is the primary toxicity associated with oxaliplatin.

In 2 randomized clinical trials in patients with metastatic colorectal cancer, the addition of oxaliplatin to infusional fluorouracil and leucovorin (FOLFOX) increased tumor response rates and disease-free survival, with a trend towards an improvement in overall survival.129, 130 Further studies have compared the efficacy of oxaliplatin-containing and irinotecan-containing combinations. In one such trial of patients with newly diagnosed metastatic disease, FOLFOX was associated with prolongations of progression-free and overall survival when compared with IFL or a combination of irinotecan and oxaliplatin.134 Because this outcome may have been influenced by the superiority of infusional fluorouracil (as included in FOLFOX) over bolus fluorouracil (as included in IFL),37, 120 2 further studies have compared oxaliplatin and irinotecan in combination with an infusional fluorouracil schedule.132, 135 In both of these studies, tumor response rate, progression-free survival, and overall survival were statistically indistinguishable among patients receiving FOLFOX or FOLFIRI as first-line therapy. Importantly, patients receiving all 3 of these drugs—fluorouracil, oxaliplatin, and irinotecan—were noted to have a median overall survival of approximately 20 months.132, 135, 136 Recent randomized studies have examined whether capecitabine can replace fluorouracil and leucovorin in combination with oxaliplatin as initial therapy among patients with metastatic disease.137, 138, 139 These trials have shown the 2 combinations to have similar therapeutic benefit and toxicity, but the capecitabine-containing regimens to be more expensive because of the high cost of capecitabine.51

In contrast to the experience with irinotecan, 2 randomized trials have shown an improvement in disease-free survival when oxaliplatin has been added to fluorouracil and leucovorin in the adjuvant setting.140, 141 Both the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer study and the C-07 study of the National Surgical Adjuvant Breast and Bowel Project have shown a 20% reduction in the rate of colon cancer recurrence with the addition of oxaliplatin. With 6 years of follow-up evaluation, the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer study also has shown a statistically significant 4.4% improvement in overall survival for those patients with stage III disease (73.0% vs 68.6%).103 No such survival benefit was observed in patients with stage II colon cancer, for whom the likelihood of survival after 6 years was 87% in both treatment arms. However, a nonsignificant 26% reduction in disease recurrence with the addition of oxaliplatin was observed in patients with high-risk stage II disease, defined as the presence of T4 tumor stage, bowel obstruction, perforation, poorly differentiated histology, venous invasion, or examination of less than 10 lymph nodes in the resected specimen. The addition of oxaliplatin to fluorouracil and leucovorin in these trials did result in increased rates of neutropenia and neurotoxicity. Of note, approximately 10% of patients who received oxaliplatin continued to have symptomatic neuropathy 2 years after completing treatment on these clinical trials.103, 142

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Angiogenesis Inhibitors 

A more recently recognized strategy to control malignant proliferation and spread involves the inhibition of neoangiogenesis, or new blood vessel formation.143 Currently, the most successful anti-angiogenic strategy has focused on inhibiting the vascular endothelial growth factor, a soluble protein that stimulates blood vessel proliferation.144 Bevacizumab (Avastin; Genetech, South San Francisco, CA) is a humanized monoclonal antibody directed against vascular endothelial growth factor that has been examined in combination with chemotherapy in patients with advanced colorectal cancer (Table 3). In these patients, bevacizumab has been relatively well tolerated, with reversible hypertension and proteinuria representing 2 of the most common toxicities. Nonetheless, rare, yet serious side effects have been observed with bevacizumab, including a 1%–2% risk of bowel perforation, a 3% risk of serious bleeding events, a 2%–3% risk of arterial embolic events, and a less than 1% risk of reversible posterior leukoencephalopathy syndrome.145, 146, 147

Table 3. Trials of Targeted Therapies in Metastatic Colorectal Cancer
StudyStudy typeNo. of patientsResponse rate, %Median DFS, moMedian OS, mo
Cetuximab
Cunningham et al160Phase IIa
Cetuximab 111111.56.9
Cetuximab + irinotecan 218234.18.6
NCIC CO.17159Phase IIIb
Best supportive care 2850—4.6
Cetuximab 2878—6.1
CRYSTAL167Phase IIIc
FOLFIRI 609398.0—
FOLFIRI + cetuximab 608478.9—
Panitumumab
Van Cutsem et al168Phase IIIb
Best supportive care 23201.8—
Panitumumab 231102.0—
Bevacizumab
Hurwitz et al145Phase IIIc
IFL 402356.215.6
IFL + bevacizumab 4114510.620.3
ECOG E3200150Phase IIId
FOLFOX 29194.710.8
FOLFOX + bevacizumab 286237.312.9
Bevacizumab + anti-EGFR
BOND-2123Phase IIa
Cetuximab + bevacizumab 40204.911.4
Irinotecan + cetuximab + bevacizumab 43377.314.5
Panitumumab Advanced Colorectal Cancer Evaluation177Phase IIIc
FOLFOX + bevacizumab 4104611.020.6
FOLFOX + bevacizumab + panitumumab 413459.519.3

DFS, disease-free survival; OS, overall survival.

aSecond- or third-line therapy after progressive disease on an irinotecan-containing regimen.

bAfter progressive disease on a fluoropyrimidine, irinotecan, and oxaliplatin.

cFirst-line therapy in previously untreated patients.

dSecond-line therapy after progressive disease on an irinotecan-containing regimen.

Initial studies of bevacizumab showed improvements in tumor response rate and progression-free survival among patients with metastatic colorectal cancer when bevacizumab was added to fluorouracil and leucovorin.148, 149 In subsequent randomized trials, bevacizumab was shown to prolong median overall survival (20.3 vs 15.6 mo) in combination with IFL145 as initial treatment, and FOLFOX150 after the failure of a prior irinotecan-containing regimen (12.9 vs 10.8 mo). Further studies have confirmed improved response rates and progression-free survival times with the addition of bevacizumab to FOLFIRI or FOLFOX in patients with untreated, metastatic colorectal cancer.120, 151

Given the efficacy of bevacizumab in patients with metastatic colorectal cancer, the role of bevacizumab in adjuvant therapy currently is being examined in several randomized trials (Table 4). In the United States, the C-08 study of the National Surgical Adjuvant Breast and Bowel Project is randomizing patients with stage II or III colon cancer to FOLFOX with or without bevacizumab, and a similar study of oxaliplatin-containing regimens with or without bevacizumab is ongoing in Europe. In addition, investigators of the ECOG have incorporated molecular markers into a large, randomized study of FOLFOX vs FOLFOX and bevacizumab in patients with high-risk stage II colon cancer. Until the results of these trials are available, it is premature to recommend the incorporation of bevacizumab into adjuvant treatment programs for colon cancer.

Table 4. Ongoing Trials of Targeted Therapies in Resected Colon Cancer
Clinical trialAmerican Joint Committee on Cancer stageRandomization
National Surgical Adjuvant Breast and Bowel Project C-08II, IIIFOLFOX ± bevacizumab
AVANTII, IIIFOLFOX vs FOLFOX + bevacizumab vs capecitabine + oxaliplatin + bevacizumab
ECOG E5202IIMolecular high risk (MSS or MSI-L and 18q LOH): FOLFOX ± bevacizumab
Standard risk: observation
North Central Cancer Treatment Group N0147IIIFOLFOX ± cetuximab
PETACC-8IIIFOLFOX ± cetuximab

MSS, microsatellite stable; MSI-L, microsatellite instability—low; 18q LOH, loss of heterozygosity at chromosome 18q.

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Epidermal Growth Factor Receptor Inhibitors 

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that interacts with signaling pathways affecting cellular growth, proliferation, and programmed cell death,152 and is expressed in malignancies of multiple tissues, including those of the colon, lung, breast, and head and neck.153 In colorectal cancer, EGFR expression on the tumor cell surface has been shown in up to 80% of tumors154, 155 and tumors that express EGFR carry a poorer prognosis.156 Antibodies directed against the extracellular domain of EGFR and small molecular inhibitors of the intracellular tyrosine kinase domain have been developed to inhibit the function of this transmembrane receptor. Thus far, only the anti-EGFR monoclonal antibodies, cetuximab (Erbitux; ImClone Systems, Brachburg, NJ) and panitumumab (Vectibix; Amgen, Thousand Oaks, CA), have definitively shown efficacy in colorectal cancer (Table 3).157 Although small molecule inhibitors of the intracellular tyrosine kinase domain of EGFR, such as erlotinib (Tarceva; Genetech), are effective in other solid tumors, they appear to be inactive in patients with colorectal cancer.158

In a study of patients whose disease had progressed on a fluoropyrimidine, irinotecan, and oxaliplatin, weekly cetuximab showed improvements in progression-free and overall survival (6.1 vs 4.6 mo) when compared with those treated with best supportive care alone.159 Other studies of cetuximab in patients with irinotecan-refractory, metastatic colorectal cancer have confirmed tumor response rates of approximately 10% with cetuximab alone and 20% with cetuximab and irinotecan,160, 161, 162 indicating an ability of cetuximab to overcome irinotecan resistance in tumor cells. The main side effects of treatment with cetuximab are acneiform rash, hypomagnesemia, and infusion reactions, with approximately 3% of patients experiencing serious hypersensitivity reactions to cetuximab infusion. The presence of an acneiform rash has been associated positively with an improved response to cetuximab, among patients with metastatic colorectal cancer.163 Although initial studies mandated the immunohistochemical detection EGFR on the surface of tumor cells as a prerequisite for enrollment, the degree of surface EGFR expression has been found to correlate poorly with tumor response, and responses to cetuximab have been noted among patients without detectable EGFR by immunohistochemistry.164, 165

Two further studies have evaluated the addition of cetuximab to first-line regimens in patients with previously untreated metastatic colorectal cancer.166, 167 Initial results from a trial conducted by the Cancer and Leukemia Group B (CALGB) have shown an improvement in tumor response rate (RR) with the addition of cetuximab to FOLFIRI or FOLFOX (RR, 52% vs 38%).166 The CRYSTAL trial, a randomized evaluation of FOLFIRI with or without cetuximab, has shown improvements in tumor response rate (RR, 47% vs 39%) and progression-free survival (PFS) (median, 8.9 vs 8.0 mo) among those patients receiving cetuximab.167 Although these results do support the efficacy of including cetuximab in first-line treatment programs, how these regimens compare with bevacizumab-containing regimens is currently unknown. Several ongoing studies, described later, have been designed to investigate this question.

The role of cetuximab in the adjuvant therapy of colon cancer has not yet been defined. The North Central Cancer Treatment Group and the European Organization for Research and Treatment of Cancer are each registering more than 2000 patients with resected stage III colon cancer and randomizing them to receive FOLFOX alone or FOLFOX with cetuximab (Table 4). Until the results of these trials become available, the inclusion of cetuximab in adjuvant treatment programs cannot be recommended outside of a clinical trial.

Panitumumab is a humanized monoclonal antibody to EGFR that has shown similar single-agent activity as cetuximab in metastatic colorectal cancer, but with a biweekly (rather than weekly) administration schedule.157, 168 In an initial study, 9% of patients whose cancers had progressed after treatment with fluorouracil and either irinotecan or oxaliplatin experienced a tumor response to panitumumab.169 In a randomized trial of 463 patients previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin, single-agent panitumumab improved progression-free survival when compared with best supportive care (median PFS, 8.0 vs 7.3 wk),168 similar to the previously described experience with cetuximab.159 Two ongoing studies are evaluating the addition of panitumumab to FOLFOX and FOLFIRI in patients with metastatic colorectal cancer. Panitumumab has not yet been tested in adjuvant treatment programs among patients with colon cancer, and cannot be recommended in this setting.

Because only a subset of patients' tumors treated with cetuximab or panitumumab will respond to this drug, the identification and characterization of molecular markers to predict tumor response is an area of active investigation. Two such tumor characteristics have emerged from initial studies: EGFR copy number as determined by fluorescence in situ hybridization and K-ras gene mutation status. Among patients treated with cetuximab or panitumumab, high EGFR gene copy number by fluorescence in situ hybridization has been associated with higher tumor response rates and prolongation of disease-free and overall survival.170, 171 In contrast, patients with tumors having mutations in K-ras appear to be relatively resistant to treatment with cetuximab172, 173, 174 or panitumumab,175 with lower response rates and poorer survival. These and other molecular features may help define a subset of patients who will derive benefit from treatment with an inhibitor of EGFR.

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Combined Targeted Therapy 

Several ongoing studies are assessing the efficacy of combined treatment with monoclonal antibodies to vascular endothelial growth factor and EGFR in patients with metastatic colorectal cancer (Table 3). Initial data supporting this treatment approach arose from 2 studies in which patients received combinations of irinotecan, cetuximab, and bevacizumab.160, 176 Those patients receiving both cetuximab and bevacizumab had improvements in tumor response rate and progression-free survival.

In the Panitumumab Advanced Colorectal Cancer Evaluation trial, patients with previously untreated, metastatic colorectal cancer received FOLFOX and bevacizumab with or without panitumumab.177 Surprisingly, the first planned efficacy interim analysis showed an inferior outcome for those patients receiving panitumumab, with shorter survival times and increased side effects. Because patients receiving panitumumab experienced greater treatment-related toxicity, it remains uncertain whether the combination is therapeutically inferior or whether the toxic effects resulted in less exposure to active drugs. This question should be answered by an ongoing randomized trial coordinated by the National Cancer Institute (CALGB/SWOG 80405), in which patients with previously untreated, metastatic colorectal cancer are receiving FOLFOX or FOLFIRI with the addition of cetuximab; bevacizumab; or cetuximab and bevacizumab.

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Summary and Future Directions 

Currently available data in 2008 support the use of a fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab, and either cetuximab or panitumumab, in the treatment of patients with metastatic colorectal cancer. The optimal sequence of administration of these drugs remains under investigation, but patients who receive all of these available therapies can now expect a median overall survival of approximately 2 years (Figure 1). The success of chemotherapy in prolonging survival in the metastatic setting also is translating to improved cure rates among patients with stage III disease. The goal of ongoing adjuvant trials evaluating bevacizumab and cetuximab is to increase even further the improved rates of survival provided by fluorouracil, leucovorin, and oxaliplatin (Table 5).

Table 5. Postoperative Treatment of Patients With Resected Stage II and Stage III Colon Cancer
Stage III disease
Randomized clinical trials support 6 months of postoperative fluorouracil, leucovorin, and oxaliplatin
Capecitabine and intravenous bolus fluorouracil and leucovorin appear to have similar efficacy, if a fluoropyrimidine is to be used alone as postoperative therapy
Current data do not support the use of irinotecan, cetuximab, or bevacizumab in postoperative treatment programs
Stage II disease
Randomized clinical trials have not shown a clear survival benefit to postoperative therapy in patients with standard risk stage II disease
Although certain features can predict an increased risk for disease recurrence, the benefit of postoperative therapy in patients with high-risk stage II disease has not been validated prospectively in clinical trials

Over the past 15 years, deaths from colorectal cancer in the United States have decreased by approximately 13%.1, 178 This decline in mortality highlights the advances made in screening, prevention, and treatment for colorectal cancer, brought about by the collaboration of gastroenterologists, medical oncologists, pathologists, primary care physicians, and surgeons. Although this progress has occurred relatively rapidly, such cancer care and new chemotherapeutic agents, in particular, have not come without a significant cost to the health care system (Table 6).179, 180 In the near future, physicians and society may be faced with difficult decisions regarding resource allocation and innovative cancer treatment, as we work to maintain our current trajectory of progress.180

Table 6. Costs of Systemic Treatments for Colorectal Cancer
RegimenCost per 6 mo, $a
Bolus fluorouracil/leucovorin (Mayo Clinic schedule)96
Infusional fluorouracil/leucovorin352
Capecitabine11,648
Irinotecan (every 3 weeks)30,100
FOLFIRI23,572
FOLFOX29,989
Bevacizumab23,897
Cetuximab52,131
Panitumumab44,720

NOTE. Adapted with permission from Meropol and Schulman.180

aOnly drug costs included. Costs based on average sales price for a 70-kg patient with a body-surface area of 1.7 m2. Wholesale acquisition costs provided for panitumumab.

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Supplementary data 

Supplemental Table. Glossary of Relevant Terms
TermDefinition
AJCC TNM systemAmerican Joint Committee on Cancer, Tumor-Node-Metastasis Cancer Staging System
Adjuvant treatmentTreatment delivered after resection of the primary tumor, with the goal of reducing the risk of tumor recurrence by eliminating micrometastatic disease
IFLIrinotecan, bolus Fluorouracil (5-FU), and Leucovorin (LV)
FOLFIRIInfusional 5-FU, LV, and Irinotecan
CAPIRICapecitabine and Irinotecan
FOLFOXInfusional 5-FU, LV, and Oxaliplatin
XELOXCapecitabine (Xeloda®) and Oxaliplatin
Targeted therapyTherapeutic agents designed to perturb specific molecular pathways critical for tumor cell growth and survival
EGFREpidermal growth factor receptor – a transmembrane protein on the surface of tumor cells, targeted by cetuximab and panitumumab
VEGFVascular endothelial growth factor – a serum protein involved in stimulating new blood vessel formation, targeted by bevacizumab

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 The authors wish to cite NIH support from grant numbers T32CA09001 and IP50CA127003-01.

PII: S0016-5085(08)00450-2

doi:10.1053/j.gastro.2008.02.098

Gastroenterology
Volume 134, Issue 5 , Pages 1296-1310.e1, May 2008

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