Jennifer M. Duff and Thomas J. George, Jr.
EPIDEMIOLOGY
■Colorectal cancer (CRC) is the second leading cause of cancer deaths among men and women combined in the United States and is the third most common cause of cancer, separately, in men and in women.
■Nearly 142820 new cases of CRC (72% colon; 28% rectal) were diagnosed in 2013 in the United States, and one-third will die as a result of the disease.
■The lifetime risk of developing CRC for both men and women is 5%.
■Surgery will cure almost 50% of all diagnosed patients; however, 40% to 50% of newly diagnosed CRC cases will eventually develop metastatic disease.
■The incidence of colon cancer is higher in the more economically developed regions, such as the United States or Western Europe, than in Asia, Africa, or South America.
■US incidence and mortality rates from CRC continue to decline (2.3% decrease from 1998 to 2004) as a result of prevention and early detection of disease through effective screening programs and effective adjuvant therapies.
RISK FACTORS
Although certain conditions predispose patients to develop colon cancer, up to 70% of patients have no identifiable risk factors:
■Age: More than 90% of colon cancers occur in patients older than 50 years.
■Gender: The incidence of colon cancer is similar in men and women, but rectal cancer is more prominent in men.
■Ethnicity: The occurrence of CRC is more common in African Americans than in whites, and mortality is nearly 45% higher in African Americans compared to whites.
■Personal history of CRC or adenomatous polyps:
•Tubular adenomas (lowest risk)
•Tubulovillous adenomas (intermediate risk)
•Villous adenomas (highest risk)
■Tobacco use is associated with increased incidence and mortality from CRC compared to never smokers. The association is stronger for rectal cancers.
■Obesity: Two prospective cohort studies show a 1.5-fold increased risk of CRC in people that have a high body mass index (BMI) compared to that in normal.
■Dietary factors: High-fiber, low caloric intake, and low animal fat diets may reduce the risk of cancer.
■Calcium deficiency: Daily intake of 1.25 to 2.0 g of calcium was associated with a reduced risk of recurrent adenomas in a randomized placebo-controlled trial. Oral bisphosphonate therapy for at least 1 year’s duration may also reduce CRC risk.
■Micronutrient deficiency: Selenium and vitamins E and D deficiency may increase the risk of cancer. The role of folate remains unclear.
■Inflammatory bowel disease: Ulcerative colitis increases the risk by 7- to 11-fold, especially with the duration of colitis (8 to 12 years) and with the detection of dysplasia. Crohn’s disease is associated with a twofold increased risk of CRC.
■Nonsteroidal anti-inflammatory drugs: An American Cancer Society study reported 40% lower mortality in regular aspirin users, and similar reductions in mortality were seen in prolonged nonsteroidal anti-inflammatory drug use in patients with rheumatologic disorders. The cyclooxygenase-2 (COX-2) inhibitor celecoxib is approved by the U.S. Food and Drug Administration (FDA) for adjunctive treatment of patients with familial adenomatous polyposis (FAP). Chemoprevention with selective COX-2 inhibitors must be balanced against increased cardiovascular risks.
■Family history: 80% of colon cancer cases are diagnosed in the absence of a positive family history. In the general population, if one first-degree relative develops cancer, it increases the relative risk for other family members to 1.72, and if two relatives are affected, the relative risk increases to 2.75. Increased risk is also observed when a first-degree relative develops an adenomatous polyp before age 60. True hereditary forms of cancer account for only 6% of CRCs.
FAMILIAL CANCER SYNDROMES
Familial Adenomatous Polyposis
FAP is an autosomal-dominant inherited syndrome with more than 90% penetrance, manifested by hundreds of polyps developing by late adolescence. The risk of developing invasive cancer over time is virtually 100%. Germline mutations in the adenomatous polyposis coli (APC) gene on chromosome 5q21 have been identified. The loss of the APC gene results in altered signal transduction with increased transcriptional activity of β-catenin. Several FAP variants with extraintestinal manifestations also exist:
■Attenuated FAP: This variant generates flat adenomas that arise at an older age. Mutations tend to occur in the proximal and distal portions of the APC gene.
■Gardner’s syndrome: Associated with desmoid tumors, osteomas, lipomas, and fibromas of the mesentery or abdominal wall.
■Turcot’s syndrome: Involves tumors (esp. medulloblastoma) of the central nervous system.
■Peutz–Jeghers syndrome: Includes non-neoplastic hamartomatous polyps throughout the gastrointestinal tract and perioral melanin pigmentation.
■Juvenile polyposis: Associated with hamartomas in colon, small bowel, and stomach.
Hereditary Nonpolyposis Colorectal Cancer
The Lynch syndromes, named after Henry T. Lynch, include Lynch I or the colonic syndrome, which is an autosomal-dominant trait characterized by distinct clinical features including proximal colon involvement, mucinous or poorly differentiated histology, pseudodiploidy, and the presence of synchronous or metachronous tumors. Patients develop colon cancer before 50 years, with a lifetime risk of cancer approximating 75%. In Lynch II or the extracolonic syndrome, individuals are susceptible to malignancies in the endometrium, ovary, stomach, hepatobiliary tract, small intestine, and genitourinary tract.
The Amsterdam criteria (3-2-1 rule) were established to identify potential kindreds and include
■Histologically verified CRC in at least three family members, one being a first-degree relative of the other two members
■CRC involving at least two successive generations
■At least one family member being diagnosed by 50 years
Inclusion of extracolonic tumors and clinicopathologic and age modifications was introduced by the Bethesda criteria in 1997 and subsequently revised to account for microsatellite instability (MSI). Lynch syndrome is characterized by germline defects in DNA mismatch–repair genes (e.g., hMSH2, hMLH1, hPMS1, and hPMS2). These defects result in alterations to the length of microsatellites, segments of DNA with repeating nucleotide sequences, thus making them unstable and detectable in diagnostic assays. This MSI can be identified in virtually all Lynch syndrome kindred and in 15% to 20% of sporadic colon cancers.
SCREENING
Several professional societies have developed screening guidelines for the early detection of colon cancer. There are a number of early detection tests for colon cancer in average-risk asymptomatic patients. The American Cancer Society and US Preventative Service Task Force screening guidelines (Table 8.1) are the most widely cited. Starting at age 50, both men and women should discuss the full range of testing options with their physician. Any positive or abnormal screening test should be followed up with colonoscopy. Individuals with a family or personal history of colon cancer or polyps, or a history of chronic inflammatory bowel disease, should be tested earlier and possibly more often.
Virtual Colonoscopy
A virtual colonoscopy, or computerized tomographic colonography, is an emerging technology in which a spiral computerized tomography (CT) scan of the colon is obtained and three-dimensional images are created and reviewed by a radiologist. Specificity for detection of large polyps and cancer appear reasonable, but there is a wide range of sensitivities reported despite improved experience by providers and consistent technology. Patients still require bowel preparation and colonic distension as well as ingestion of oral contrast. Detected abnormalities require investigation with endoscopy.
Carcinoembryonic Antigen
Carcinoembryonic antigen (CEA) is not useful for general CRC screening purposes. CEA has a low sensitivity whereby approximately 60% of cancers are missed. It is routinely recommended in surveillance programs after cancer has been confirmed.
K-ras Detection
The K-ras gene is mutated in 30% to 50% of CRCs, and the detection in stool represents a potentially powerful screening strategy. This is currently an active area of clinical investigation.
PATHOPHYSIOLOGY
More than 90% of CRCs are adenocarcinomas, the focus of this chapter. Other primary cancers of the colon and rectum include Kaposi’s sarcoma, non-Hodgkin’s lymphomas, small cell carcinoma, and carcinoid tumors. Although uncommon, metastases to the large bowel include melanoma, ovarian, and gastric cancer. Anatomic location and symptoms at presentation are the primary differences between right colon, left colon, and rectal adenocarcinomas.
Colon carcinogenesis involves progression from hyperproliferative mucosa to polyp formation, with dysplasia, and transformation to noninvasive lesions and subsequent tumor cells, with invasive and metastatic capabilities. CRC is a unique model of multistep carcinogenesis resulting from the accumulation of multiple genetic alterations. Stage-by-stage molecular analysis has revealed that this progression involves several types of genetic instability, including loss of heterozygosity, with chromosomes 8p, 17p, and 18q representing the most common chromosomal losses. The 17p deletion accounts for loss of p53 function, and 18q contains the tumor-suppressor genes deleted in colon cancer (i.e., DCC) and the gene deleted in pancreatic 4 (i.e., DPC4).
Colon carcinogenesis also occurs as a consequence of defects in the DNA mismatch–repair system. The loss of hMLH1 and hMSH2, predominantly, in sporadic cancers leads to accelerated accumulation of additions or deletions in DNA. This MSI contributes to the loss of growth inhibition mediated by transforming growth factor-β due to a mutation in the type II receptor. Mutations in the APC gene on chromosome 5q21 are responsible for FAP and are involved in cell signaling and in cellular adhesion, with binding of β-catenin. Alterations in the APC gene occur early in tumor progression. Mutations in the proto-oncogene ras family, including K-ras and N-ras, are important for transformation and also are common in early tumor development.
DIAGNOSIS
Signs and Symptoms
■Abdominal pain, typically intermittent, and vague
■Weight loss
■Bowel changes for left-sided colon and rectal cancers, including constipation, decreased stool caliber (pencil stools), and tenesmus
■Early satiety
■Fatigue
■Bowel obstruction, perforation, acute, or chronic bleeding, or liver metastasis, all of which contribute to symptom development
■Unusual presentations include deep venous thrombosis, Streptococcus bovis bacteremia or endocarditis, and nephrotic-range proteinuria
■Clinical findings include iron-deficiency anemia, weight loss, electrolyte abnormalities, and liver enzyme elevations
Diagnostic Evaluation
■Endoscopic studies provide histologic information, potential therapeutic intervention, and overall greater sensitivity, and specificity.
■CEA elevations occur in non–cancer-related conditions, reducing the specificity of CEA measurements alone in the initial detection of colon cancer.
■Basic laboratory studies including complete blood count, electrolytes, liver, and renal function tests, and CT scan of the chest, abdomen, and pelvis with IV contrast are useful in initial cancer diagnosis and staging.
■In colon cancers, CT scan sensitivity for detecting distant metastasis is higher (75% to 87%) than for detecting nodal involvement (45% to 73%) or the extent of local invasion (~50%). CT scanning is very sensitive for detection of malignant pelvic lymph nodes in rectal cancer as any perirectal adenopathy is presumed to be malignant, since benign adenopathy is not typically seen in this area.
■Contrast-enhanced magnetic resonance imaging (MRI) can help determine the status of suspicious lesions in the liver as well as the characteristics (not just size) of perirectal adenopathy.
■PET scanning adds little over conventional imaging in the initial staging and diagnosis of CRC in the absence of abnormalities seen on CT scan.
■Endoscopic rectal ultrasound (EUS) is a valuable tool in the preoperative evaluation of rectal cancer, with high accuracy of determining the extent of the primary tumor (63% to 95%) and perirectal nodal status (63% to 82%).
STAGING
The seventh edition of the American Joint Committee on Cancer Staging for CRC uses the TNM classification system. The Dukes or MAC staging systems are only of historic interest. The tumor designation, or T stage, defines the extent of bowel wall penetration including invasion into the submucosa (T1), muscularis propria (T2), pericolic tissue (T3), visceral peritoneal surface (T4a), or an adjacent organ or other structure (T4b). At least 12 lymph nodes must be sampled for accurate staging and represents an important quality control metric. The number of regional nodes involved varies from 1 to 3 (N1a/b) to 4 or more (N2a/b). N1c includes direct tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis. Metastases confined to one organ or site (M1a) have a better prognosis than metastases confined to the peritoneum or multiple sites (M1b).
PROGNOSIS
Pathologic staging remains the most important determinant of prognosis (Table 8.2) with similar outcomes for both colon and rectal cancers in the modern era. Other prognostic variables that have been proposed to be associated with an unfavorable outcome include
■Advanced age of patient
■High tumor grade
■High CEA level
■Bowel obstruction or perforation at presentation
■Several biochemical and molecular markers such as elevated thymidylate synthase, p53 mutations, or loss of heterozygosity of chromosome 18q (DCC gene) may be associated with a worse prognosis. MSI caused by a defective DNA mismatch–repair system (e.g., altered MLH1, MSH2; associated with Lynch Syndrome) is associated with an improved outcome for patients with node-negative disease
MANAGEMENT ALGORITHM
Surgery
■For colon cancers, the primary curative intervention requires en bloc extirpation of the involved bowel segment and mesentery, with pericolic and intermediate lymphadenectomy for both staging and therapeutic intent. Negative proximal, distal, and lateral surgical margins are of paramount importance. Laparoscopic techniques adhering to these surgical principles are an acceptable option.
■For rectal cancers, en bloc resection of the primary tumor with negative proximal, distal, and radial margins is critical as well as a sharp dissection of the mesorectum (total mesorectal excision) to optimally reduce local recurrence. The location of the tumor in relation to the anal sphincter is the primary determinant in a low anterior resection (LAR) versus an abdominoperineal resection (APR). The latter generates a permanent colostomy. For highly selected very early-stage rectal cancer cases, transanal endoscopic microsurgery may be a reasonable option.
■Surgical intervention is indicated if polypectomy pathology reveals muscularis mucosal involvement or penetration.
■Surgical palliation may include colostomy or even resection of metastatic disease for symptoms of acute obstruction or persistent bleeding.
Radiation Therapy
■Routine administration of abdominal radiotherapy (RT) is limited by bowel-segment mobility, adjacent small bowel toxicity, previous surgery with adhesion formation, and other medical comorbidities.
■Local control and improved disease-free survival (DFS) have been reported in retrospective series of patients with T4 lesions or perforations, nodal disease, and subtotal resections, who have been treated with 5,000 to 5,400 cGy directed at the primary tumor bed and draining lymph nodes. However, there are no randomized data to support the routine use of RT in the management of colon cancer.
■In contrast, RT is routinely utilized in rectal cancers to reduce local recurrence and improve resectability.
Pivotal Adjuvant Chemotherapy Studies for Colon Cancer
Intergroup 0035
This large Intergroup trial of 5-fluorouracil (5-FU) and levamisole (Lev) is of historic importance because it reported a 41% reduction in the relapse rate and a 33% decrease in overall cancer mortality. This study resulted in the National Institutes of Health consensus panel recommending that 5-FU-based adjuvant therapy be administered to all patients with resected stage III colon cancer.
Intergroup 0089
Intergroup 0089 randomized 3,759 patients with stage II or III disease to one of four therapeutic arms. The results demonstrated that the 5-FU- and leucovorin (LV)-containing schedules (Mayo Clinic and Roswell Park regimens) were equivalent without the need for Lev. A 6-month schedule of the 5-FU and LV was similar to a protracted 12 months of therapy.
The 5-year DFS and overall survival (OS) for each of the four arms in the study were as follows:
■5-FU + Lev for 12 months; DFS = 56%, OS = 63%
■5-FU + high-dose LV (Roswell Park) for 8 months; DFS = 60%, OS = 66%
■5-FU + low-dose LV (Mayo) for 6 months; DFS = 60%, OS = 66%
■5-FU + LV + Lev; DFS = 60%, OS = 67%
X-ACT
Utilization of an oral fluoropyrimidine (capecitabine) was evaluated in patients with stage III disease. Capecitabine (1,250 mg/m2 b.i.d. for 14 days, every 3 weeks) was compared with the Mayo Clinic bolus of 5-FU and LV. The study was designed to demonstrate equivalency, with a primary endpoint of 3-year DFS. The capecitabine arm was noninferior and demonstrated a trend toward superiority in DFS (64% vs. 60%; HR 0.87; 95% CI 0.75 to 1.00; P = 0.0526). Toxicity was improved in all categories except hand–foot syndrome (HFS). A 3-year DFS endpoint was chosen because a retrospective analysis of more than 20,000 patients demonstrated equivalency to the conventional 5-year OS benchmark and serves as an acceptable endpoint.
MOSAIC
In Europe, 2,219 patients with stage II (40%) and III (60%) disease treated with infusional 5-FU with LV modulation versus the same combination with oxaliplatin (FOLFOX4) every 2 weeks for 6 months, demonstrated a 3-year DFS benefit favoring the FOLFOX4 combination over standard 5-FU with LV (78.2% vs. 72.9%; HR 0.77; 95% CI 0.65 to 0.92; P = 0.002). With a median 6-year follow-up, the OS advantage was confirmed in the patients with stage III disease (72.9% vs. 68.7%; HR 0.80; 95% CI 0.65 to 0.97; P = 0.023). No difference in OS was seen in the stage II population. Treatment with FOLFOX4 was well tolerated, with 41% patients having grade 3 and 4 neutropenia, with only 0.7% being associated with fever. Anticipated grade 3 peripheral neuropathy or paresthesias were observed (12%) which almost entirely resolved 2 years later (0.7%).
NSABP C-07
The addition of oxaliplatin to three cycles of adjuvant Roswell Park 5-FU with LV (FLOX) was evaluated in 2,407 stage II (30%) and III (70%) patients. The combination improved 3-year DFS (76.1% vs. 71.8%; HR 0.80; 95% CI 0.69 to 0.93; P = 0.003). Grade 3 diarrhea (38%) and peripheral neuropathy (8%) were significantly worse with FLOX without any difference in treatment-related mortality. MOSAIC and C-07 established doublet adjuvant chemotherapy with fluoropyrimidine and oxaliplatin as a standard of care.
Adjuvant Irinotecan
Unlike oxaliplatin, at least three studies failed to confirm a benefit for the use of adjuvant irinotecan. CALGB 89803 was a study of irinotecan with bolus 5-FU and LV (IFL) versus weekly 5-FU in patients with stage III disease. Increased grade 3 and 4 neutropenia and early deaths were observed in the experimental arm, and a higher number of patients withdrew from the study. Overall, IFL was not better than the 5-FU and LV arm. The two European studies (PETACC-3 and ACCORD) together randomized over 3,500 patients to infusional 5-FU with or without irinotecan. Both studies failed to reach their primary endpoint of 3-year DFS, although toxicities were less than in the IFL study. The use of irinotecan is not recommended in the adjuvant setting.
Adjuvant Biologics
Both cetuximab (cmab) and bevacizumab (bev) are biologic-targeted agents (see the metastatic CRC section) that have been shown to improve outcomes when combined with chemotherapy in metastatic CRC and have been definitively tested in the adjuvant setting.
Intergroup 0147 tested whether the addition of cmab to standard mFOLFOX6 adjuvant chemotherapy for resected stage III colon cancer improved outcomes. The protocol was amended to allow only patients with wild-type K-rastumors to be eligible. The study terminated early after a second interim analysis. Results demonstrated no benefit when adding cmab. Three-year DFS for patients with wild-type K-raswas 71.5% with mFOLFOX plus cmab and 74.6% with mFOLFOX alone (HR 1.21; 95% CI 0.98 to 1.49; P = 0.08), suggesting a trend toward harm. There were no subgroups that benefitted from cmab, with increased toxicity and greater detrimental differences in all outcomes in patients aged ≥70.
The addition of bev to mFOLFOX6 was tested in NSABP C-08. This randomized phase III trial assessed DFS in stage II (25%) and III patients. Bev was administered for the duration of the 6 months of chemotherapy and then for an additional 6 months beyond (total of 1 year of biologic therapy). mFOLFOX plus bev did not significantly improve 3-year DFS compared to mFOLFOX (77.4% vs. 75.5%; HR 0.89; 95% CI 0.76 to 1.04; P = 0.15). However, survival curve analysis suggested a time-dependent improvement in DFS with maximal separation of the curves occurring at 15 months, which correlated with 1 year of bev treatment followed by 3 months off drug. This benefit disappears with time. No OS benefit, unexpected toxicity, or difference in patterns of relapse was seen.
The AVANT trial also tested bev in a three-arm study that randomized 3,451 patients with high-risk stage II (17%) or stage III colon cancer to either FOLFOX4, FOLFOX4 plus bev, or XELOX plus bev. The 3-year DFS was not significantly different between the groups with 5-year OS hazard ratio for FOLFOX 4 plus bev versus FOLFOX4 (HR 1.27; 95% CI 1.03 to 1.57; P = 0.02), and XELOX plus bev versus FOLFOX4 (HR 1.15; 95% CI 0.93 to 1.42; P= 0.21) suggesting a potential detriment.
Adjuvant Chemotherapy Regimens for Colon Cancer
Based on these studies, 6 months of adjuvant chemotherapy is recommended for patients with stage III colon cancer. Several acceptable options exist (Table 8.3), with combination regimens offering increased efficacy and toxicity. The use of irinotecan or biologic-targeted therapies in the adjuvant setting is not recommended. Adjuvant chemotherapy should be started within 8 weeks of surgery, if at all possible, with data supporting a delay beyond 2 months may compromise the effectiveness of adjuvant treatment.
Fluoropyrimidines
Reasonable options include 5-FU with LV via the Mayo Clinic or Roswell Park regimen or capecitabine. The toxicity profile of the regimens differs. Myelosuppression and oral mucositis are more common with the daily Mayo Clinic regimen, whereas diarrhea may be more severe with the weekly Roswell Park schedule. Cryotherapy with ice held in the mouth during the 5-FU infusion may help lessen the mucositis associated with the therapy. HFS and diarrhea are primary toxicities of capecitabine.
Oxaliplatin Combinations
Increased efficacy as well as toxicity is seen with the addition of oxaliplatin to either bolus or infusional 5-FU and LV. FOLFOX6 represents a modification to FOLFOX4, which omits the day 2 bolus 5-FU and LV and gives more continuously infused 5-FU over 46 hours, and appears to have activity equivalent to that of FOLFOX4 in the advanced disease setting. It has been incorporated into numerous adjuvant clinical trials given the improved ease of administration.
Adjuvant Chemotherapy for Stage II Colon Cancer
Despite the 75% 5-year survival with surgery alone, some patients with stage II disease have a higher risk of relapse, with outcomes being similar to those of node-positive patients. Adjuvant chemotherapy provides up to 33% relative risk reduction in mortality, resulting in an absolute treatment benefit of approximately 5%.
Several analyses have reported varying outcomes in patients with stage II disease who received adjuvant treatment:
■The National Surgical Adjuvant Breast and Bowel Project (NSABP) summary of protocols (C-01 to C-04) of 1,565 patients with stage II disease reported a 32% relative reduction in mortality (cumulative odds, 0.68; 95% CI 0.50 to 0.92; P = 0.01). This reduction in mortality translated into an absolute survival advantage of 5%.
■A meta-analysis by Erlichman et al. detected a nonsignificant 2% benefit (82% vs. 80%; P = 0.217) in 1,020 patients with high-risk T3 and T4 cancer treated with 5-FU and LV for 5 consecutive days.
■Schrag et al. reviewed Medicare claims for chemotherapy within the Surveillance, Epidemiology, and End Results (SEER) database and identified 3,700 patients with resected stage II disease among whom 31% received adjuvant treatment. No survival benefit was detected with 5-FU compared to surgery alone (74% vs. 72%) even with patients considered to be at high risk because of obstruction, perforation, or T4 lesions.
■The Quasar Collaborative Group study reported an OS benefit of 3.6% in 3,239 patients (91% Dukes B colon cancer) prospectively randomized to chemotherapy versus surgery alone. With a median follow-up of 5.5 years, the risk of recurrence (HR 0.78; 95% CI 0.67 to 0.91; P = 0.001) and death (HR 0.82; 95% CI 0.70 to 0.95; P = 0.008) favored 5-FU and LV chemotherapy.
■In the MOSAIC study, FOLFOX4 chemotherapy showed nonsignificant benefits in DFS over 5-FU and LV in patients with stage II disease (86.6% vs. 83.9%; HR 0.82; 95% CI 0.57 to 1.17).
■The American Society of Clinical Oncology Panel concluded that the routine use of adjuvant chemotherapy for patients with stage II disease could not be recommended. A review of 37 randomized controlled trials and 11 meta-analyses found no evidence of a statistically significant survival benefit with postoperative treatment of stage II patients. However, treatment should be considered for specific subsets of patients (e.g., T4 lesions, perforation, poorly differentiated histology, or inadequately sampled nodes), and patient input is critical.
■For stage II patients without high-risk features, molecular analysis can provide improved recurrence risk determination.
•MSI is a surrogate marker for defects in the mismatch–repair system (Lynch Syndrome). When these occur at a high frequency (MSI-high) in node-negative colon cancer, it portends a favorable prognosis. There is controversy as to whether MSI-high tumors benefit from adjuvant fluoropyrimidine chemotherapy. Given the more favorable outcome and questionable response to adjuvant chemotherapy, it is recommended to test this molecular marker in all stage II patients to aid in personalized treatment decisions.
•A commercially available and validated microarray gene expression profile (Oncotype Dx™; Genomic Health, Inc) examines formalin-fixed paraffin-embedded tissue samples from resected colon cancer. Using an 18-gene signature, and excluding patients with MSI-high tumors, a recurrence score can be generated for an individual patient with stage II disease that classify them as low risk (score less than 30; recurrence risk 12%), intermediate risk (score 30 to 40; risk 18%), or high risk (score ≥41; risk 22%). Several other expression profiles are also currently under development or validation.
Perioperative Treatment for Rectal Cancer
In contrast to colon cancer, local treatment failures after potentially curative resections represent a major clinical problem. Combined-modality chemotherapy with RT (chemoRT) is the standard therapy for patients with stage II and III rectal cancer (T3, T4, and nodal involvement).
Intergroup 0114
A four-arm study of 1,695 patients compared 5-FU alone, 5-FU and LV combination, 5-FU and Lev combination, and 5-FU and LV and Lev combination. Two cycles of chemotherapy were administered before and after chemotherapy in combination with 5,040 cGy of external beam RT (4,500 cGy with 540 cGy boost). The chemotherapy during the RT was given as a bolus with or without LV. The DFS and OS were similar in all treatment arms, leading to the conclusion that 5-FU alone was as effective as other combinations.
NCCTG
Both DFS and OS advantages were observed in patients receiving continuous infusion of 5-FU during RT when compared with those receiving bolus 5-FU. This survival benefit has led to continuous infusion of 5-FU during RT being considered as a standard.
German Rectal Cancer Study Group
The benefit of delivering chemoRT in a preoperative (neoadjuvant) fashion was evaluated in 421 patients compared to 401 similar patients randomized to receive postoperative chemoRT. In both groups, 5-FU was administered in a continuous fashion during the first and fifth weeks of RT. All patients received an additional four cycles of adjuvant 5-FU after chemoRT and surgery. Results of neoadjuvant treatment provided improvement in local recurrence (6% vs. 13%; P = 0.006), but no difference in 5-year OS. Both acute toxic effects (27% vs. 40%; P = 0.001) and long-term toxicities (14% vs. 24%; P = 0.01) were less common with neoadjuvant treatment. Preoperative chemoRT followed by surgical resection with postoperative 5-FU-based chemotherapy represents a standard for patients with rectal cancer.
NSABP R-04
This phase III, 2 × 2 noninferiority trial evaluated the substitution of oral capecitabine for infusional 5-FU as well as the intensification of radiosensitization by adding oxaliplatin in stage II and III rectal carcinoma. Over 1,500 patients were randomized into one of four neoadjuvant chemoRT arms. There was no increase in grade 3 to 4 diarrhea with capecitabine versus 5-FU alone, but the addition of oxaliplatin did significantly increase the risk of grade 3 to 4 diarrhea (6.6% vs. 15.4%; P < 0.0001). Both fluoropyrimidine alone arms had similar rates of pathologic complete responses, surgical downstaging, and sphincter sparing surgeries, suggesting that capecitabine has similar efficacy to infusional 5-FU. The primary endpoint of local-regional relapse and other survival data is anticipated shortly after press. Additional European studies have also demonstrated similar outcomes for using capecitabine as a substitute for infusional 5-FU in rectal cancer patients without benefit from intensification by adding oxaliplatin. “Attempts to identify novel radiosensitizers with companion biomarkers for rectal cancer are ongoing.”
Combined-Modality Options for Rectal Cancer
1.Neoadjuvant therapy (chemoRT):
•Continuous infusion 5-FU (1,000 mg/m2/day) given daily for 5 days during the first and fifth week of radiation therapy OR 225 mg/m2/day given Monday through Friday continuously throughout RT OR oral capecitabine 825 mg/m2 twice daily given Monday through Friday on days of RT concurrent with external beam RT given in 180 cGy fractions to a total dose of 5,040 cGy
2.Followed by surgery adhering to total mesorectal excision standards
3.Adjuvant systemic therapy for 4 months upon recovery from surgery:
•5-FU bolus (500 mg/m2/day) on days 1 to 5 repeated every 28 days for four cycles. Given the previously discussed data for adjuvant chemotherapy regimens in colon cancer, several different regimens (see Table 8.3) may also be considered in select cases as components of the systemic adjuvant chemotherapy phase of therapy in rectal cancer
FOLLOW-UP AFTER ADJUVANT TREATMENT
Eighty percent of recurrences are seen within 2 years of initial therapy. The American Cancer Society recommends total colonic evaluation with either colonoscopy or double-contrast barium enema within 1 year of resection, followed every 3 to 5 years if findings remain normal. Synchronous cancers must be excluded during initial surgical extirpation, and metachronous malignancies in the form of polyps must be detected and excised before more malignant behavior develops.
History and physical evaluations with serum CEA measurements should be performed every 3 to 6 months for the first few years after therapy. These evaluations can be further reduced during subsequent years. Surveillance imaging should be reserved for those individuals who would be considered operable candidates if localized metastases were to be identified. Elevations of CEA postoperatively may suggest residual tumor or early metastasis. Patients with initially negative levels of CEA can subsequently exhibit positive levels; therefore, serial CEA measurements after completion of treatment may identify patients who are eligible for a curative surgery, in particular, patients with oligometastatic liver or lung recurrence.
TREATMENT FOR ADVANCED COLORECTAL CANCER
Unprecedented improvements in OS have been recognized during the past decade with systemic chemotherapy in advanced or metastatic disease. Median survival has improved from 6 months with best supportive care to over 2 years with incorporation of all active agents. Based upon clinical practice and supported by total cancer genomic analyses, there are no differences in the molecular characteristics or systemic management of metastatic colon or rectal cancers. Data also support proceeding with systemic therapy without surgical intervention on the primary tumor, as long as the intact primary tumor is asymptomatic.
Fluoropyrimidine-Based Chemotherapy
5-FU inhibits thymidylate synthase, an enzyme critical in thymidine generation. LV potentiates this inhibition. 5-FU and LV chemotherapy regimens in advanced CRC have objective response rates of 15% to 20%, with median survival of 8 to 12 months. Toxicity is predictable and manageable.
The activity of continuous infusion of 5-FU may be equivalent to or slightly better than that of bolus 5-FU and LV and is generally well tolerated despite the inconvenience of a prolonged intravenous ambulatory infusion apparatus. Toxicities include mucositis and palmar–plantar erythrodysesthesia (HFS); however, myelosuppression is less common. Continuous infusions of 5-FU may have activity in patients who have progressed with bolus 5-FU.
Capecitabine, an oral fluoropyrimidine prodrug, undergoes a series of three enzymatic steps in its conversion to 5-FU. The final enzymatic step is catalyzed by thymidine phosphorylase, which is overexpressed in tumor tissues and upregulated by RT. Two phase 3 studies have compared single-agent capecitabine to the Mayo Clinic 5-FU and LV regimen and demonstrated higher response rates for the former but equivalent time to progression and median survival. Capecitabine was associated with decreased gastrointestinal and hematologic toxicities and fewer hospitalizations, but with an increased frequency of HFS and hyperbilirubinemia.
Oxaliplatin
Oxaliplatin is an agent that differs structurally from other platinums in its 1,2-diaminocyclohexane (DACH) moiety, but acts similarly by generating DNA adducts. Oxaliplatin exhibits synergy with 5-FU with response rates as high as 66% even in patients who are refractory to 5-FU. Despite its unique toxicities (i.e., peripheral neuropathy, laryngopharyngeal dysesthesias, and cold hypersensitivities), oxaliplatin lacks the emetogenic and nephrogenic toxicities of cisplatin.
Oxaliplatin was initially approved for second-line therapy in metastatic CRC based on a study comparing FOLFOX4 with oxaliplatin alone and with infusional or bolus 5-FU and LV. In this study, response rate, time to progression, and relief of tumor-related symptoms were improved with FOLFOX4, when compared to the other treatment arms. Despite the improved time to progression, the OS difference was not statistically significant (9.8 vs. 8.7 and 8.1 months, respectively).
The North Central Cancer Treatment Group (NCCTG-9741) conducted a trial comparing first-line FOLFOX4 versus IFL versus IROX (irinotecan in combination with oxaliplatin). Higher 60-day mortality was detected in the IFL arm, resulting in a dose reduction in the protocol. The response rate, time to progression, and OS were significantly better in the FOLFOX4 arm than in the modified IFL arm. However, imbalances in the second-line chemotherapy administered to patients in this study may confound the survival differences. Approximately 60% of the oxaliplatin failures were treated with irinotecan, whereas only 24% of patients who are refractory to irinotecan received oxaliplatin. In addition, the study was not designed to address the effect of infusional 5-FU. The observed toxicities in the study were reflective of the specific drug combinations and included grade 3 or higher paresthesias (18%) in the FOLFOX arm and a 28% incidence of diarrhea in the IFL arm. Despite a higher degree of neutropenia (60% in FOLFOX vs. 40% in IFL) with FOLFOX, febrile neutropenia was significantly greater in the IFL arm. IROX also exhibited significant toxicities. Oxaliplatin was approved by the FDA for use in the first-line treatment of patients with metastatic CRC largely based on this study.
Although FOLFOX is clearly a superior regimen compared to IFL, the use of infusional 5-FU with irinotecan (FOLFIRI) may produce results similar to those seen using FOLFOX. Tournigand et al. reported an equivalent median survival of 21.5 months with FOLFIRI followed by FOLFOX and a median survival of 20.6 months with the opposite sequence (P = 0.99). Similar survival is observed in patients receiving either sequence and both are acceptable first-line therapies for advanced disease.
Irinotecan
Irinotecan is a topoisomerase I inhibitor, with activity in advanced CRC deemed refractory to 5-FU. As a single agent, response rates as high as 20% are observed, and an additional 45% of patients achieve disease stabilization. Significant survival advantages have been shown for irinotecan as second-line therapy after 5-FU compared with supportive care or with continuous-infusion 5-FU regimens. Several schedules are typically administered with and without 5-FU; however, the cumulative data suggest that irinotecan should not be utilized with bolus 5-FU (i.e., IFL) due to excessive treatment-related mortality.
Irinotecan obtained FDA approval based on a study comparing IFL to the 5-FU bolus Mayo Clinic regimen. A higher response rate (39% vs. 21%; P = 0.0001) and OS (14.8 vs. 12.6 months; P = 0.042) were observed favoring IFL.
Delayed-onset diarrhea is common and requires close monitoring and aggressive management (high-dose loperamide, 4 mg initially and then 2 mg every 2 hours until diarrhea stops for at least 12 hours). Neutropenia, mild nausea, and vomiting are common. This combination of toxicities can be severe and life-threatening, which was evident in NCCTG 9741 (see previous oxaliplatin section). A higher 60-day mortality was observed (4.5% vs. 1.8%), and the dose of irinotecan required reduction.
Infusional 5-FU with biweekly irinotecan offered improvements in response (35% vs. 22%; P < 0.005), median survival (17.4 vs. 14.1 months; P = 0.031), and quality of life over 5-FU. Neutropenia was equivalent to that found in the weekly irinotecan regimen, although febrile neutropenia and diarrhea were markedly reduced.
As monotherapy, irinotecan every 3 weeks produced responses in 13.7% of patients and stable disease in another 44% of cases. In patients who are refractory to 5-FU, a median survival of 10.5 months was reported. Administration of weekly irinotecan alone has also been reported by Pitot et al. In patients receiving 5-FU earlier, a 13% response rate and an 7.7 median response duration were observed.
Anti-VEGF Therapies
Bevacizumab is a recombinant humanized antivascular endothelial cell growth factor (VEGF) monoclonal antibody with amino acid sequence similarity of 97% to that of human IgG1. Bev blocks VEGF-induced angiogenesis with a high affinity for VEGF, preventing it from binding to VEGF receptors. One of the initial trials with bev in untreated CRC patients combined bev with weekly bolus 5-FU and LV. Interestingly, a 40% response rate and 21.5-month median survival was observed. The major toxicities included arterial thrombosis (13 patients with three treatment discontinuations and one patient death), proteinuria, and hypertension. Updated toxicity data reveal that full-dose anticoagulation can be administered with bev and that there is no increased risk of deep venous thrombus formation. When added to IFL, bev increased the response rate (45% vs. 35%; P = 0.004) and had a longer median survival (20.3 vs. 15.6 months; P < 0.001). When added to FOLFOX in the second-line setting, response rates are again increased (23% vs. 9%; P < 0.001) along with OS (12.9 vs. 10.8 months; P = 0.0011). Bev has been approved by the FDA for the treatment of patients with advanced CRC in combination with any intravenous 5-FU-based regimen. The optimal duration of treatment remains controversial but continuation of anti-VEGF therapy through lines of sequential therapy may provide a slight improvement in disease control.
Ziv-aflibercept is a fully humanized recombinant fusion protein that blocks angiogenesis by binding to VEGFA, VEGFB, and placental growth factor and preventing their interaction with endogenous receptors. It is FDA approved for use in combination with FOLFIRI for second-line treatment in metastatic CRC based on results from the VELOUR study. This phase III, placebo-controlled trial randomized 1,226 metastatic patients with CRC after an oxaliplatin-based regimen to second-line therapy with FOLFIRI plus ziv-aflibercept or placebo. Median survival of FOLFIRI plus ziv-aflibercept was statistically superior to FOLFIRI (13.5 vs. 12 months; HR 0.87; 95% CI 0.713 to 0.937; P = 0.0032) as was progression-free survival (6.9 vs. 4.7 months; P < 0.0001).
The first and currently only approved oral multikinase inhibitor for metastatic CRC is regorafenib. This agent blocks several kinases involved in angiogenic and oncogenic survival pathways including VEGFR1, VEGFR2, VEGFR3, TIE2, KIT, RET, RAF1, BRAF, PDGFR, and FGFR. The CORRECT trial randomized heavily pretreated metastatic CRC patients who progressed within 3 months after treatment with all currently available standard therapies to oral regorafenib versus placebo. Median OS was found to be improved with regorafenib compared to placebo (6.4 vs. 5 months; HR 0.77; P = 0.0052).
Antiepidermal Growth Factor Therapies
The epidermal growth factor receptor (EGFR) and pathway represent another targeted approach in advanced CRC therapy. Two monoclonal antibodies are FDA approved for use in patients with metastatic CRC. Importantly, tumor EGFR positivity by immunohistochemistry staining does not correlate with treatment response; however, K-ras, and likely B-raf, mutational status does. Both intracellular signal transduction proteins exist in either a wild-type (normal functional) or mutated (via activating mutation resulting in continuous overactivity) state. Mutations in K-ras (40%) and B-raf (6%) have high concordance between primary and metastatic CRC tumors (in excess of 90%), with recommendations for testing these at the time of metastatic diagnosis. Of note, B-raf mutation also appears to be prognostic with a more aggressive clinical course, shortened progression-free intervals, and overall reduced survival. Commercial testing for both mutations is available.
Cetuximab(cmab) is a chimerized IgG1 antibody that prevents ligand binding to the EGFR and its heterodimers through competitive displacement. Panitumumab (pmab) is a fully humanized IgG2 antibody also targeting EGFR in a similar manner. These agents both block receptor dimerization, tyrosine kinase phosphorylation, and subsequent downstream signal transduction. Both can cause a skin rash, diarrhea, hypomagnesemia, and infusion reactions, but to a less degree with pmab for the latter two toxicities. A correlation between the intensity of the skin rash and survival has been consistently noted with agents in this class with investigation underway to prospectively test the dose-to-rash response relationship.
Cmab was initially FDA approved based on a study in irinotecan-refractory advanced disease. Patients were randomized to the combination of cmab and irinotecan versus cmab alone with improvements in the response rate (22.9% vs. 10.8%; P = 0.0074) and time to progression (4.1 vs. 1.5 months; P < 0.0001) favoring the combination. Despite manageable toxicity, no improvements in survival outcomes were observed, but tumor resensitization to irinotecan was clearly demonstrated. Cmab is also approved for use as first-line metastatic treatment for patients with wild-type K-ras tumors. The CRYSTAL phase III trial randomized 1,217 patients to FOLFIRI with or without cmab. FOLFIRI plus cmab demonstrated a 15% relative reduction in the risk of recurrence (HR 0.85; 95% CI 0.72 to 0.99; P = 0.048) with an improvement in the median PFS (8.9 vs. 8 months). The addition of cmab produced significantly more skin reactions, diarrhea, and infusional reactions. Median progression-free survival directly correlated with increased grade of skin rash. K-ras status was available on a subgroup analysis of 540 tissue samples. Patients with wild-type K-ras had a favorable outcome on response rate, OS and PFS (HR 0.68). However, mutated K-ras tumors were associated with a decrease in OS and response rates, particularly with cmab addition, confirming that this mutation is a negative predictor of response to EGFR inhibition.
Panitumumab is FDA approved as monotherapy given improvement in progression-free survival over best supportive care in heavily pretreated patients (HR 0.54; 95% CI 0.44 to 0.66; P < 0.0001), although no OS advantage was noted. This agent also has data supporting improvements in PFS when combined with FOLFIRI in the second-line treatment.
CHEMOTHERAPY REGIMENS FOR METASTATIC CRC
See Tables 8.3 and 8.4. Investigations into the optimal timing, role of maintenance therapy, and sequence of treatment combinations both with and without EGFR and VEGF inhibition continue.
OLIGOMETASTATIC DISEASE
The liver is the most common site for metastasis, with one-third of cases involving only the liver. Approximately 25% of liver metastases are resectable, with certain patient subsets showing 30% to 40% 5-year survival after resection and 3% to 5% operative morbidity and mortality. Nonoperative ablative techniques (i.e., cryoablation, radiofrequency ablation, stereotactic RT, and hepatic artery embolization with or without chemotherapy) have not shown consistent durable prospective survival benefits. Intraoperative ultrasound is the most sensitive test for initial detection, followed by CT scan or MRI. PET scanning can help identify occult extrahepatic disease in select patients being considered for resection.
Patients with unresectable disease limited to the liver can be treated with locoregional hepatic artery infusion (HAI) or systemic chemotherapy. Kemeny et al. reported a 4-year DFS and hepatic disease-free benefit in patients with resected liver metastases who had received intra-arterial floxuridine with systemic 5-FU compared to those who did not receive any postoperative therapy, although there was no statistically significant difference in OS (62% vs. 53%; P = 0.06). Such an approach has typically been reserved for select centers and its utility has been challenged by the advent of more effective systemic chemotherapy.
The feasibility of converting initially unresectable disease to a potentially curative disease has been investigated by Bismuth and colleagues. Resection was possible in 99 patients with either downstaged or stable disease, and the 3-year survival was encouraging (58% for responders, 45% for patients with stable disease). Similar observations have been reported by Alberts using preoperative FOLFOX4 on 41% of patients undergoing resection with an observed median survival of 31.4 months (95% CI 20.4 to 34.8) for the entire cohort. Indeed, current management of resectable liver disease typically includes appropriate patient selection, adequate imaging to confirm isolated and limited disease burden, multidisciplinary clinical collaboration, and consideration of perioperative systemic chemotherapy. The latter recommendation is based, in part, on the results of a European study showing a progression-free survival advantage to the use of 3 months of FOLFOX4 chemotherapy pre- and postresection compared to surgery alone. However, attention must be paid to the potential hepatotoxicity and surgical complications from prolonged perioperative chemotherapy. Importantly, systemic chemotherapy fails to sterilize hepatic metastases, even if radiographic complete response is noted. The role of targeted therapies in the perioperative setting is an area of active investigation.
REVIEW QUESTIONS
1.A 64-year-old woman complains of fatigue and 10 lb weight loss over the last 4 months. She denies any cough or abdominal pain, but reports occasional bright red blood per rectum after a bowel movement that she attributes to hemorrhoids. She is otherwise healthy and family history is noncontributory. She is a lifelong nonsmoker but has not seen a physician in 10 years. Her physical examination is unremarkable, except for some external nonbleeding hemorrhoids noted on digital rectal examination. Her lab tests including the comprehensive metabolic panel are within normal limits. A complete blood count shows hemoglobin 10.2 g/dL, mean corpuscular volume (MCV) of 73 fL, platelets 600,000/µL, and normal WBC count and differential. What is the next best test that should be performed?
A.Mammogram
B.Bone marrow biopsy
C.Colonoscopy
D.Positron emission tomography (PET) scan
E.Stool fecal occult blood test (FOBT or FIT)
2.A 43-year-old male presents with 2 months of intermittent dark-colored stools and shortness of breath with exertion. His personal medical history is unremarkable. His father was diagnosed with colon cancer at age 55, his paternal uncle died from colon cancer at age 52, and his sister had endometrial cancer at age 48. He has a microcytic anemia. Esophagogastricduodenoscopy is unremarkable. Colonoscopy reveals a 3 cm, friable, lesion on the right side of the colon near the hepatic flexure; there are no polyps noted on examination. A biopsy confirms poorly differentiated adenocarcinoma. Which of the following genetic deficiencies is most likely present?
A.BRCA 1 gene
B.APC gene
C.STK11 gene
D.CDH1 (E-cadherin) gene
E.DNA mismatch–repair gene
3.A 61-year-old male underwent surgical resection 4 weeks ago with end-to-end anastomosis for a sigmoid colon adenocarcinoma. The tumor was 2.5 cm across and extended into the muscularis propria, margins were negative. Fifteen lymph nodes were resected; four were positive for adenocarcinoma. A CT scan of the chest, abdomen, and pelvis showed no evidence of distant metastatic disease. He has healed well and is referred to oncology. Which of the following treatment is recommended after surgery?
A.Additional resection with removal of more lymph nodes
B.Adjuvant chemotherapy with a fluoropyrimidine-based regimen followed by radiation to the surgical bed
C.Adjuvant chemotherapy with a fluoropyrimidine-based regimen
D.Adjuvant RT to the surgical bed
E.No further treatment indicated
4.A 58-year-old male is evaluated for several months of fatigue, abdominal pain, lower back tenderness, and 25 lb unintentional weight loss. Examination is notable for tender hepatomegaly and no focal neurologic deficits. Laboratory tests reveal a total bilirubin 3 mg/dL, direct bilirubin 2.2 mg/dL, AST 72 units/L, ALT 65 units/L, alkaline phosphatase 212 units/L, creatinine 0.8 mg/dL. CEA is elevated at 478. A CT chest, abdomen, and pelvis shows multiple, hypodense lesions in the right and left hepatic lobes; small, bilateral pulmonary nodules; and scattered destructive lesions in the lumbar vertebrae. A biopsy of a liver lesion confirms poorly differentiated adenocarcinoma, CK20 positive, CK7 negative, CDX2 positive, supporting the diagnosis of a colorectal malignancy. A mutational analysis confirms wild-type K-ras. He is offered palliative chemotherapy for metastatic colon cancer. Which is NOT an approved biologic agent for this patient’s metastatic colon cancer?
A.Bevacizumab
B.Rituximab
C.Panitumumab
D.Cetuximab
E.Regorafenib
5.A 54-year-old woman complains of difficulty passing stool and rectal fullness for 2 months. Her medical history is otherwise negative. Her heme-occult stool test is positive. A colonoscopy shows a 4 cm rectal mass located 8 cm from the anal verge, and biopsy confirms adenocarcinoma. An endoscopic ultrasound shows the lesion penetrates through the muscularis propria and four regional lymph nodes are involved. A CT of chest, abdomen, and pelvis does not reveal any overt distant metastases. What is the recommended treatment for her rectal cancer?
A.Surgical resection followed by adjuvant chemotherapy and radiation
B.Neoadjuvant combined chemotherapy and radiation followed by surgical resection
C.Definitive chemotherapy and radiation therapy
D.Neoadjuvant combined chemotherapy and radiation, surgical resection, then postoperative chemotherapy
E.Transanal mucosal resection of cancer
Suggested Readings
1.Alberts SR, Donohue JH, Mahoney MR, et al. Liver resection after 5-fluorouracil, leucovorin and oxaliplatin for patients with metastatic colorectal cancer (MCRC) limited to the liver: a North Central Cancer Treatment Group (NCCTG) Phase II Study. 2003 ASCO Annual Meeting (abstract 1053).
2.Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012;307(13):1383-1393.
3.Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29(1):11-16.
4.Allegra CJ, Yothers G, O’Connell MJ, et al. Bevacizumab in stage II-III colon cancer: 5 year update of the NSABP C-08 Trial. J Clin Oncol. 2013; 31(3): 359-364.
5.American Cancer Society. Colorectal Cancer Facts and Figures 2011. http://www.cancer.org. Accessed December 20, 2012.
6.Andre T, Boni C, Mounedji-Boudiaf L, et al. Multicenter international study of oxaliplatin/5-fluorouracil/leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med.2004;350:2343-2351.
7.André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27(19):3109-3116.
8.Benson AB, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408-3419.
9.Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg. 1996;224:509-520.
10.Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345.
11.Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413-1418.
12.de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012;13(12):1225-1233.
13.Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041-1047.
14.Falcone A, Allegrini G, Lenconi M, et al. Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a Phase II study. Cancer Chemother Pharmacol. 1999;44:159-163.
15.George TJ Jr, LaPlant KD, Walden EO, et al. Managing Cetuximab Hypersensitivity-Infusion Reactions: Incidence, Risk Factors, Prevention, and Retreatment. J Support Oncol. 2010 Mar-Apr;8(2):72-7. PMID: 20464886
16.Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol.2007;25(12):1539-1544.
17.Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23-30.
18.Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomized, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
19.Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004;22(7):1209-1214.
20.Gunderson LL, Jessup JM, Sargent DJ, et al. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol. 2010;28(2):264-271.
21.Haller DG, Catalano PJ, MacDonald JS, et al. Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: five-year final report of INT-0089. Proc Am Soc Clin Oncol. 1998;16:256a.
22.Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005;23(34):8671-8678.
23.Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342.
24.International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999;17(5):1356–1363.
25.Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy—an Intergroup study. J Clin Oncol. 2002;20:1499-1505.
26.Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991;324:709-715.
27.Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25(16):2198-2204.
28.Leichman CG, Fleming TR, Muggia FM, et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol. 1995;13:1303-1311.
29.Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C01, C02, C03, and C04). J Clin Oncol. 1999;17:1349-1355.
30.Martínez ME, Giovannucci E, Spiegelman D, et al. Leisure-time physical activity, body size, and colon cancer in women. Nurses’ Health Study Research Group. J Natl Cancer Inst. 1997;89(13):948.
31.McCahill LE, Yothers G, Sharif S, et al. Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10. J Clin Oncol. 2012;30(26):3223-3228.
32.Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352-358.
33.NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. http://www.nccn.org/professionals/physician_ gls/pdf/colon.pdf. Accessed December 29, 2012.
34.Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer. Lancet. 2008;371(9617):1007-1016.
35.O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994;331:502-507.
36.Pasty BM, Potter JD. Risks and benefits of celecoxib to prevent recurrent adenomas. N Engl J Med. 2006;355:950-952.
37.Pitot HC, Wender DB, O’Connell MJ, et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol. 1997;15(8):2910-2919.
38.Quasar Collaborative Group, Gray R, Barnwell J, McConkey C, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370(9604):2020-2029.
39.Roh MS, Yothers GA, O’Connell MJ, et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin Oncol. 2011;29:Abstract 3503.
40.Saltz LB, Cox JV, Blanke C, et al. Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000;343:905-914.
41.Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (CALGB C89803). J Clin Oncol. 2007;25(23):3456-3461.
42.Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2005;23(34):8664-8670.
43.Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740.
44.Schrag D, Rifas-Shiman S, Saltz L, et al. Adjuvant chemotherapy use for Medicare beneficiaries with stage II colon cancer. J Clin Oncol. 2002;20:3999-4005.
45.Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-237.
46.Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-2704.
47.Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004;90:1190-1197.
48.Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408-1417.
49.Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658-1664.
50.Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499-3506.