Bethesda Handbook of Clinical Oncology, 2nd Edition

Digestive System

8

Colorectal Cancer

George P. Kim*

Chris H. Takimoto^†

Carmen J. Allegra^‡

*Gastrointestinal Cancer Section, Mayo Clinic Cancer Center, Jacksonville, Florida

^†Institute for Drug Development, Cancer, Therapy & Research Center, San Antonio, Texas

^‡Network for Medical Communication and Research, Atlanta, Georgia

EPIDEMIOLOGY

• Colorectal cancer (CRC) is the second overall, that is, men and women combined, leading cause of cancer death in the United States and is the third most common cause of cancer, separately, in men and in women.
• It was estimated that approximately 146,940 new cases of CRC would have been diagnosed in 2004 in the United States, and one-third of patients would have died as a result of the disease (1).
• The lifetime risk of developing CRC is 1:18.
• Surgery will cure almost 50% of all diagnosed patients, although almost 80,000 people develop metastatic CRC each year.
• 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.
• Between 1973 and 1998, the U.S. incidence of CRC continued to decline, and so did mortality, which declined by 23.5% during this interval.

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 cancer occur in patients older than 50 years.
• Gender:The incidence of colon cancer is higher in women, whereas rectal cancer is more common in men.
• Ethnicity:The occurrence of cancer is more common in African Americans than in whites, and mortality increases by 32% in African Americans.
• History of colorectal cancer or adenomas:
• –tubular adenomas (lowest risk)
• –tubulovillous adenomas (intermediate risk)
• –villous adenomas (highest risk).
• Tobacco use:About 2.5-fold increased risk of adenomas is observed in smokers.
• Obesity 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.

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• Micronutrient deficiency:Folate and vitamin E and D deficiency may increase the risk of cancer.
• Inflammatory bowel disease:Ulcerative colitis increases risk by 7-fold to 11-fold, especially with the duration of colitis (8 to 12 years) and with the detection of dysplasia. Crohn disease is associated with a twofold increased risk of CRC.
• Nonsteroidal antiinflammatory drugs:An American Cancer Society study reported 40% lower mortality in regular aspirin users, and similar reductions in mortality were seen in prolonged nonsteroidal antiinflammatory drug (NSAID) 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). Its role in the prevention of cancer development in nonheretidary cohorts is under investigation.
• 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 Adenomatous Polyposis Syndrome

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 ß-catenin.

Attenuated FAP: These FAPs are flat adenomas that arise at an older age than FAPs do; mutations tend to occur in the proximal and distal portions of the APC gene.

Gardner syndrome: This syndrome is associated with desmoid tumors, lipomas, and fibromas of the mesentery or abdominal wall.

Turcot syndrome: This syndrome involves tumors of the central nervous system (CNS).

Peutz–Jeghers syndrome: This syndrome shows nonneoplastic hamartomatous polyps throughout the gastrointestinal tract and perioral melanin pigmentation.

Juvenile polyposis: These are 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. Increased survival has been observed in patients despite colon cancer developing before 50 years, with a lifetime risk of cancer approximating 75%. The Lynch II or extracolonic individuals are susceptible to malignancies in the endometrium, ovary, stomach, hepatobiliary tract, small intestine, and genitourinary tract.

The “Amsterdam Criteria” 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 and
• At least one family member being diagnosed by 50 years.

Inclusion of extracolonic tumors and clinicopathological and age modifications were introduced by the “Bethesda Criteria” in 1997. Germline defects in DNA mismatch-repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) have been detected, and resultant microsatellite instability (MSI)

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can be identified in virtually all hereditary nonpolyposis colorectal cancer (HNPCC) kindreds and in 15% to 20% of sporadic colon cancers.

SCREENING

The American Cancer Society has developed screening guidelines for the early detection of colon cancer. There are a variety of available early detection tests for colon cancer. Starting at age 50, both men and women should discuss the full range of testing options with their physicians and choose one of the following:

• Yearly fecal occult blood test (FOBT)
• Flexible sigmoidoscopy every 5 years
• Yearly FOBT and flexible sigmoidoscopy every 5 years (preferred over either FOBT alone or flexible sigmoidoscopy alone)
• Double-contrast barium enema every 5 years
• Colonoscopy every 10 years.

It should be noted that all positive tests 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 may need to undergo testing 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. A recent study demonstrated comparable sensitivity to conventional colonoscopy (88.7% versus 92.3% for polyps at least 6 mm in dimension). Earlier studies using two-dimensional technology and inexperienced radiologists observed equivocal results. Patients still require bowel preparation and colonic distension as well as ingestion of oral contrast. Additional studies are required before this technique can be used routinely.

Carcinoembryonic Antigen

Carcinoembryonic antigen (CEA) is not useful for general CRC screening purposes. CEA has a low positive predictive value whereby approximately 60% of cancers are missed.

K-ras Detection

The K-ras gene is mutated in 50% of CRCs, and its detection in stool represents a potential powerful screening strategy. This is currently an active area of clinical investigation.

PATHOPHYSIOLOGY

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). The loss of heterozygosity of chromosome 18q has prognostic significance.

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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 repeating DNA nucleotide units. This MSI contributes to the loss of growth inhibition mediated by transforming growth factor-ß (TGF-ß) 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 ß-catenin. Alterations in the APC gene occur early in tumor progression. Mutations in the protooncogene ras family, including K-ras and N-ras, are important for transformation and also are common in early tumor development.

More than 90% of CRCs are adenocarcinomas, with proximal tumors becoming increasingly more common. Left-sided cancers tend to be annular, leading to obstruction, whereas right-sided cancers are more commonly polypoid and clinically silent. One-third of patients will initially be seen with metastatic disease, whereas 50% will eventually develop metastases.

DIAGNOSIS

Signs and Symptoms

• Abdominal pain, typically intermittent and vague
• Weight loss
• Bowel changes, such as pencil stools
• Early satiety
• Gastrointestinal bleeding
• Fatigue
• Obstruction, perforation, acute or chronic bleeding, or liver metastasis, all of which contribute to symptom development
• Unusual presentations including patients with deep venous thrombosis, Streptococcus bovisbacteremia, and nephrotic-range proteinuria
• Clinical findings including anemia, weight loss, electrolyte abnormalities, and liver enzyme elevations.

Diagnostic Evaluation

• A double-contrast barium enema may be more cost effective as an initial evaluation, but endoscopic studies provide histologic information, potential therapeutic intervention, and overall greater sensitivity and specificity.
• Basic laboratory studies including complete blood count, electrolytes, and liver and renal function tests, chest radiograph, and CT scan of the abdomen and pelvis are useful in initial cancer diagnosis, although the relative contributions of these various modalities are undefined.
• CEA elevations occur in non–cancer-related conditions, reducing the specificity of CEA measurements in the initial detection of colon cancer.

STAGING

The American Joint Committee on Cancer (AJCC) (1) staging of colon cancer using the TNM classification was updated in 2003 (see Fig. 8.1). Patients with stage II and III disease have been further stratified, and vascular or lymphatic invasion has been included (see Table 8.1). The tumor designation, or T stage, defines the extent of bowel wall penetration, as opposed to tumor size. The AJCC staging system accounts for the number of lymph nodes involved as a significant predictor of survival. Four or more positive lymph nodes or gross versus microscopic bowel wall penetration lead to diminished survival. Some patients with stage

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II disease exhibit a heterogeneous outcome and are at high risk for relapse, with outcomes similar to those of node-positive patients (seeTable 8.2).

FIG. 8.1. Staging classification of colorectal cancer. Classification is based on modifications of Dukes' system. Stages B3 and C3 (not shown) signify invasion of contiguous organs or structures (T4). Prognosis is also determined by the number of positive lymph nodes: more than four (N2) lymph nodes predicts a worse outcome than one to three (N1) lymph nodes, and a poor histopathological differentiation, vascular or lymphatic invasion, and a positive preoperative CEA value of >5 ng per mL implies a worse outcome. According to the revised TNM classification system, stage I equals T1 or T2 N0 (Dukes' stage A and B1); stage II equals T3 or T4 N0 (Dukes' stage B2 and B3); stage III equals any T plus N1, N2, or N3 (Dukes' stage C1, C2 and C3); and stage IV equals any T any N plus M1 (Dukes' stage D).

TABLE 8.1. American Joint Committee on Cancer (AJCC) Staging Classification (2003)

a Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. b Direct invasion in T4 includes invasion of other segments of the colorectum through the serosa, for example, invasion of the sigmoid colon by a carcinoma of the cecum. c Tumor that is macroscopically adherent to other organs or structures is classified T4. However, if no tumor is present in the adhesion microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion. d Smooth metastatic nodules in the pericolic or perirectal fat are considered lymph node metastases and will be counted in the N staging. In contrast, irregularly contoured metastatic nodules in the peritumoral fat are considered as a vascular invasion and will be coded as an extension of the T category as either V1 (microscopic vascular invasion) if it is only microscopically visible or as V2 (macroscopic vascular invasion) if it is grossly visible. Primary tumor: T    TX: Primary tumor cannot be assessed    T0: No evidence of primary tumor    Tis: Carcinoma in situ—intraepithelial or invasion of the lamina propriaa    T1: Tumor invades submucosa    T2: Tumor invades muscularis propria    T3: Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissues    T4: Tumor directly invades other organs or structures, and/or perforates visceral peritoneumb,c   Regional lymph nodes: Nd    NX: Regional nodes cannot be assessed    N0: No regional lymph node metastasis    N1: Metastasis in 1 to 3 regional lymph nodes    N2: Metastasis in 4 or more regional lymph nodes   Distant metastases: M    MX: Presence of distant metastases cannot be assessed    M0: No distant metastases    M1: Distant metastases are present. Metastasis in the external iliac or common iliac lymphnode is classified as M1   Stage grouping Dukes'/MAC   Stage 0: Tis N0 M0   Stage I T1 N0 M0—A A T2 N0 M0—A B1   Stage IIA T3 N0 M0—B B2   Stage IIB T4 N0 M0—B B3   Stage IIIA T1—T2 N1 M0—C C1   Stage IIIB T3–T4 N1 M0—C C2/C3   Stage IIIC Any T N2 M0—C C1/C2/C3   Stage IV Any T Any N M1—D   ·   Stage group II is subdivided into IIA and IIB on the basis of whether the primary tumor is T3 or T4, respectively ·   Stage III is subdivided into IIIA (T1–2 N1 M0), IIIB (T3–4 N1 M0), or IIIC (any T N2 M0)   Stage at initial diagnosis:   Stage I 14%   Stage II/III 65%   Stage IV 21%

TABLE 8.2. Five-year Survival Prognosis by Stage

Stage 0–I >90% Stage II 70–85% Stage III 55–70% Stage IV <10%

PROGNOSIS

Adverse Prognostic Factors

The adverse prognostic factors include:

• Advanced stage
• Serosal penetration
• Advanced age of patient
• High tumor grade
• More than four lymph nodes being involved
• Bowel obstruction or perforation at presentation
• MSI caused by a defective DNA mismatch-repair system (altered MLH1, MSH2), which is associated with an improved outcome
• Biochemical and molecular markers such as elevated thymidylate synthase, p53 mutations, or loss of heterozygosity of chromosome 18q, which are associated with a poor prognosis (2,3).

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MANAGEMENT ALGORITHM

Surgery

• The primary curative intervention requires en bloc extirpation of the involved bowel segment along with mesentery by laparotomy, with pericolic and intermediate lymphadenectomy for both staging and therapeutic intent. Negative proximal, distal, and lateral surgical margins are of paramount importance.
• 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.
• The number of lymph nodes resected and pathologically examined is critical to accurate staging. The probability of true node negativity in T1 or T2 tumors is less than 25% when at least 18 nodes are examined, whereas in T3 and T4 tumors, fewer than 10 nodes need to be evaluated to achieve the same probability. On average, at least 12 to 14 lymph nodes should be examined.

Radiation Therapy

• Administration of radiotherapy is limited by bowel-segment mobility. Small bowel toxicity, in particular, limits abdominal radiation, and patients with comorbidities such as diabetes, previous surgery with adhesion formation, and previous 5-fluorouracil (5-FU) exposure are at higher risk than patients without comorbidities. Bowel toxicity ranging from 4% to 8% is expected.
• 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 use of radiation in the management of colon cancer.

Adjuvant Chemotherapy for Colon Cancer

Intergroup 035

This large Intergroup trial of 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 (4). 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 is a landmark study that randomized 3,759 patients with stage II or III disease to one of four arms (5). The results demonstrated that the 5-FU and leucovorin (LV)–containing schedules (Mayo Clinic and Roswell Park) were equivalent and that the three-drug combination

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only increased toxicity. The 5-FU and Lev arm was effective but required 12 months of treatment versus the 6-month schedules of the 5-FU and LV arm.

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; DFS = 60%, OS = 66%
• 5-FU + low-dose LV; DFS = 60%, OS = 66%
• 5-FU + LV + Lev; DFS = 60%, OS = 67%.

MOSAIC

A European study of 2,219 patients with stage II (40%) and III (60%) disease who were treated with infusional 5-FU with LV modulation versus the same combination with oxaliplatin (FOLFOX4) every 2 weeks for 6 months (6) demonstrated a 3-year DFS benefit favoring the FOLFOX4 combination [78.2% for 5-FU and LV versus 72.9% for FOLFOX4, hazard ratio (HR) 0.77; 95% CI, 0.65 to 0.92, p = 0.002], although the OS between the two arms was not statistically different when the study was reported. A 3-year disease-free endpoint was chosen because a recent retrospective analysis of more than 17,400 patients demonstrated that the 3-year disease-free endpoint is equivalent to the conventional 5-year OS benchmark. Treatment with FOLFOX4 was well tolerated, with 41% patients having grade 3 and 4 neutropenia, with only 0.7% being associated with fever. Anticipated peripheral neuropathy or paresthesias were observed (grade 2–32% and grade 3–12%) but was almost entirely resolved 1 year later (grade 2–5% and grade 3–1%).

X-ACT

A 1987 study of patients with stage III disease compared capecitabine (1,250 mg per m² b.i.d. for 14 days, every 3 weeks) with the Mayo Clinic bolus of 5-FU and LV (7). The study was designed to demonstrate equivalency, with a primary endpoint of 3-year DFS. The capecitabine arm demonstrated a trend toward superiority in this endpoint (64.2% versus 60.6%, HR 0.87; 95% CI, 0.75 to 1.00, Log-rankp = 0.0526).

CALGB 89803

CALGB 89803 was a study of irinotecan with bolus 5-FU and LV (IFL) versus weekly 5-FU in patients with stage III disease (8). 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 use of the IFL regimen in the adjuvant setting cannot be recommended at present. An important study of irinotecan in combination with infusional 5-FU or FOLFIRI (continuous infusion 5-FU with biweekly irinotecan) has completed accrual of 1,800 patients, and preliminary analyses report no significant increases in treatment-related toxicity.

Adjuvant Chemotherapy Regimens for Colon Cancer

On the basis of these adjuvant chemotherapy studies, the use of one of the following regimens is recommended for patients with stage III colon cancer. The results with capecitabine are promising in the adjuvant setting.

5-fluorouracil and Calcium Leucovorin:

• Mayo Clinic (bolus) regimen: 5-FU, 425 mg per m²daily for 5 days; preceded by LV, 20 mg per m² daily every 4 weeks for six cyclesOR
• Roswell Park (weekly) regimen: 5-FU, 500 mg per m²with LV, 500 mg per m² weekly for 6 weeks, repeated every 8 weeks for 8 months.

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The toxicity profile of these two regimens differs. Myelosuppression and oral mucositis are more common with the daily Mayo Clinic regimen, whereas diarrhea may be more severe with the weekly schedule. Cryotherapy with ice held in the mouth during the 5-FU infusion may help lessen the mucositis associated with the therapy.

Oxaliplatin, 5-fluorouracil (Infusional and Bolus), and Leucovorin (FOLFOX4):

• Oxaliplatin 85 mg per m²on day 1 only, followed by bolus 5-FU 400 mg per m² on days 1 and 2, with LV 200 mg per m² on days 1 and 2. Infusional 5-FU 600 mg per m² is then given for 22 hours on days 1 and 2.

FOLFOX6, which omits the day 2 bolus 5-FU and LV, uses 2,400 mg per m² of continuous 5-FU over 46 hours and appears to have activity equivalent to that of FOLFOX4 in the advanced disease setting. The oxaliplatin dose is increased to 100 mg per m², but ongoing studies are evaluating the 85 mg per m² dose.

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% OS advantage, 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% (9).
• A meta-analysis by Erlichman et al. (10) detected a nonsignificant 2% benefit (82% versus 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 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 (11). No survival benefit was detected with 5-FU compared to surgery alone (74% versus 72%) even with patients considered to be at high risk because of obstruction, perforation, or T4 lesions.
• In the recent MOSAIC study, FOLFOX4 chemotherapy showed benefits in patients with stage II disease (40%), although this was not statistically significant [86.6% versus 83.9% 5-FU and LV, HR 0.82 (0.57–1.17), relative risk reduction, 18%].
• The Quasar Collaborative Group study reported an OS benefit of 1% to 5% in 3,238 patients (91% Dukes B colon cancer) randomized to chemotherapy versus surgery alone. With a median follow-up of 4.2 years, the risk of death (HR 0.88; 95 % CI, 0.75 to 1.05; p= 0.15) and recurrence rate (HR 0.82; 95% CI, 0.70 to 0.97; p = 0.02) favored 5-FU and LV chemotherapy.
• The American Society of Clinical Oncology Panel recently concluded that the routine use of adjuvant chemotherapy for patients with stage II disease could not be recommended (12). A review of 37 randomized controlled trials and 11 meta-analyses found no evidence of a statistically significant survival benefit with postoperative treatment. Treatment needed to be considered for specific subsets of patients (e.g., T4 lesions, perforation, poorly differentiated histology, or inadequately sampled nodes), and patient input was critical.

Immunotherapy (Edrecolomab, 17-1A)

Riethmuller et al. (13) treated 189 patients postoperatively with the monoclonal antibody edrecolomab, resulting in a 27% decrease in recurrence rate and a 30% reduction in mortality

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rate. In a comparison of patients with stage III disease treated with 5-FU–based chemotherapy without or with edrecolomab, a survival advantage was suggested for the latter (HR 0.785; 95% CI, 0.638 to 0.967). The results from a study of edrecolomab in patients with stage II disease are pending.

Adjuvant Treatment for Rectal Cancer

In contrast to colon cancer, treatment failures after potentially curative resections tend to occur more locally in 10% to 18% of patients. Combined-modality adjuvant chemotherapy and radiation therapy is now the standard therapy for patients with stages II and III rectal cancer (T3, T4, and nodal disease N+).

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 (14). Two cycles of chemotherapy was administered before and after chemotherapy in combination with external beam radiation (50.4 Gy to 45 Gy with 5.4 Gy boost). The chemotherapy during the radiation was given as a bolus with or without LV. The DFS and OS was similar in all treatment arms, leading to the conclusion that 5-FU alone was as effective as other combinations.

NCCTG 86-47-51

Both DFS and OS advantages were observed in patients receiving continuous infusion of 5-FU during radiation when compared with those receiving bolus 5-FU (15). This survival benefit has led to continuous infusion 5-FU during radiation being considered as the standard.

Adjuvant Combined-modality Regimens for Rectal Cancer

• 5-FU by intravenous bolus injection at 500 mg/m²/day on days 1 to 5 and on days 36 to 40, followed by
• –radiation therapy given in 180-cGy fractions over 5 weeks, starting day 64, to a total dose of 4,500 to 5,400 cGy along with 5-FU, 225 mg/m²/day, by ambulatory infusion pump during the entire 5-week period of radiation therapy, followed by
• –intravenous bolus of 5-FU, 450 mg/m²/day, given daily for 5 days on days 134 to 138 and on days 169 to 173 for a total treatment period of 6 months.
• On the basis of the improvements in these earlier studies and in the adjuvant chemotherapy for colon cancer, one can consider the administration of either Mayo Clinic or Roswell Park regimen 2 months before 5-FU chemotherapy–radiation, followed by an additional two cycles.
• Studies have shown that preoperative chemoradiation (preop chemoRT) is better than postoperative chemoradiation (postop chemoRT) for survival and preservation of anal function. Many physicians in the United States now use preop chemoRT followed by surgery and by additional chemoRT to complete a 6-month course of chemotherapy, that is, approximately 4 months of treatment after surgery.
• Capecitabine, which mimics infusional 5-FU, is being investigated in conjunction with radiation, and no increased toxicity has been observed. Additionally, oxaliplatin is being evaluated as a radiation sensitizer for patients with rectal disease.

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

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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.

TREATMENT FOR ADVANCED DISEASE

5-fluorouracil–Based Chemotherapy

Single-arm phase II studies of 5-FU and LV chemotherapy regimens in advanced CRC have reported response rates ranging from 0% to 70%, but most larger studies have observed objective response rates of 15% to 20%, with median survival of 8 to 12 months.

Continuous Infusion of 5-fluorouracil

The efficiency 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 infusion apparatus (16,17). 5-FU at 300 mg/m²/day is infused continuously by an ambulatory infusion pump. Toxicities include mucositis; however, myelosuppression is less common. Palmar–plantar erythrodysesthesia (hand–foot syndrome) is common and may respond to pyridoxine, 50 to 150 mg/m²/day. Continuous infusions of 5-FU may have modest activity in patients who have progressed on a bolus 5-FU regimen.

Oxaliplatin

Oxaliplatin is an agent that differs structurally from other platinums in its 1,2-diaminocyclohexane (DACH) moiety. At doses resulting in equivalent cytotoxicity, oxaliplatin forms fewer DNA adducts than does cisplatin, suggesting that oxaliplatin lesions are more lethal than cis-platinum adducts. Oxaliplatin exhibits synergy with 5-FU because increased response rates as high as 66% have been observed even in patients who are refractory to 5-FU. Despite its unique toxicities (i.e., reversible peripheral neuropathy, laryngopharyngeal dysesthesias, and cold hypersensitivities), oxaliplatin lacks the emetogenic and nephrogenic toxicities of cisplatin.

Oxaliplatin was approved for second-line therapy in metastatic patients on the basis of 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 versus 8.7 and 8.1 months, respectively).

The North Central Cancer Treatment Group (N9741) conducted a trial comparing first-line FOLFOX4 versus IFL versus IROX (irinotecan in combination with oxaliplatin). The study, designed by Richard Goldberg et al. (18), originally consisted of six arms, but three were eliminated on the basis of changes in the standard of care or toxicity. In addition, a higher 60-day mortality was detected in

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the IFL arm, resulting in a dose reduction to 100 mg per m². The response rate, time to progression, and OS were significantly better in the FOLFOX4 arm than in the IFL arm. Interestingly, survival in the patients on IROX regimen was better than in the IFL-treated patients and was not significantly different from those on the FOLFOX combination. 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 (50% in FOLFOX versus 40% in IFL) with FOLFOX, febrile neutropenia was significantly greater in the IFL arm (15% with FOLFOX versus 4% with IFL). IROX also exhibited significant toxicities. Oxaliplatin has been approved by the FDA for use in the first-line treatment of patients with metastatic CRC largely on the basis of this study.

Although FOLFOX is clearly a superior regimen compared to IFL, the use of infusional 5-FU with irinotecan 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) (19). The conclusion is that similar survival is observed in patients receiving either sequence. Other investigators have suggested that the use of all active agents results in the best survival in patients with advanced CRC.

Irinotecan/CPT-11

Irinotecan is a topoisomerase I–targeting agent, with activity in patients with advanced CRC and in patients deemed refractory to 5-FU. 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:

• The first schedule followed the IFL regimen (20)—irinotecan is infused at a dose of 125 mg per m²over 90 minutes weekly for 4 weeks followed by a 2-week rest. In a phase III study comparing this regimen to the 5-FU bolus Mayo Clinic regimen, a higher response rate (39% versus 21%, p = 0.0001) and OS (14.8 versus 12.6 months, p = 0.042) were observed for this regimen.

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 and mild nausea and vomiting also are common. This combination of toxicities can be severe and life threatening, which was evident in a large phase III study, NCCTG 9741, comparing irinotecan and oxaliplatin combination regimens (see subsequent text). A higher 60-day mortality was observed (4.5% versus 1.8%), and the dose of the irinotecan weekly regimen reduced to 100 mg per m².

• A second schedule administered 350 mg per m²of irinotecan over a 90-minute period once every 3 weeks and produced responses in 13.7% of patients and stable disease in another 44% of patients (21). In patients who are refractory to 5-FU, a median survival of 10.5 months was reported.
• A third schedule combined infusional 5-FU with biweekly irinotecan, as reported by Douillard et al. (22). Improvements in response (35% versus 22%, p<0.005), median survival (17.4 versus 14.1 months, p= 0.031), and quality of life were observed in the irinotecan-treated arm. Neutropenia was equivalent to that found in the weekly irinotecan regimen, although febrile neutropenia and diarrhea were markedly reduced in this third regimen.
• Finally, the administration of weekly irinotecan alone has been reported by Pitot et al. (23) In patients receiving 5-FU earlier, a 13% response rate and an 7.7 median response duration were observed.

Capecitabine

Capecitabine, the 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 than in normal tissues. Subsequently, the tumor tissue achieves higher concentrations of 5-FU, with thymidine phosphorylase preferentially activating the tumor tissue. Two phase III studies have compared single-agent capecitabine to the Mayo Clinic 5-FU

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and LV regimen and demonstrated higher response rates for the former but equivalent time to progression and median survival (24). The toxicity profile favored the capecitabine arm because decreased gastrointestinal and hematologic toxicities and fewer hospitalizations were observed in this arm. An increased frequency of hand–foot syndrome and hyperbilirubinemia were noted with capecitabine. Early phase II studies with capecitabine in combination with either oxaliplatin or irinotecan demonstrated promising response rates as high as 50% to 65%, and several large phase III studies are ongoing.

Bevacizumab

Bevacizumab (BV) is a recombinant humanized anti–vascular endothelial cell growth factor (anti-VEGF) monoclonal antibody with amino acid sequence similarity of 97% to that of human IgG1. BV blocks VEGF-induced angiogenesis with an exceptionally high affinity for VEGF. One of the initial trials with BV in untreated CRC patients combined BV (doses of either 5 or 10 mg per kg every 2 weeks) with weekly 500–mg per m² dose of 5-FU and LV. Interestingly, a 40% response rate and 21.5-month median survival was observed in the 5–mg per kg cohort. The major toxicities included thrombosis (13 patients with three treatment discontinuations and one patient death), proteinuria, and hypertension. Updated toxicity data reveals that full-dose anticoagulation can be administered with BV and that there is no increased risk of deep venous thrombus formation. The intriguing results presented by Hurwitz et al. (25) also reports a higher response rate (45% versus 35%, p<0.0029) and a longer median survival (20.3 versus 15.6 months) when BV is combined with IFL. A large phase III trial combining BV with FOLFOX as second-line treatment is awaited. BV has been approved by the FDA, largely on the basis of the results of these trials, for the treatment of patients with advanced CRC in combination with any intravenous 5-FU–based regimen.

Cetuximab

Cetuximab is a chimerized IgG1 antibody that prevents ligand binding to the epidermal growth factor receptor (EGFR) and its heterodimers. Cetuximab exhibits higher affinity (subnanomolar) or approximately 1-log greater binding than the natural ligands for EGFR. The agent blocks receptor dimerization, tyrosine kinase phosphorylation, and subsequent downstream signal transduction. Cetuximab is administered at a dose of 400 mg per m² in the first week and then at a 250 mg per m² dose each week thereafter.

In a study with patients refractory to irinotecan who were treated with the combination of cetuximab and irinotecan versus cetuximab alone, improvements in the response rate (22.9% versus 10.8%, 0.0074) and time to progression (4.1 versus 1.5 months, <0.0001) were reported (26). Despite manageable toxicity, no improvements in survival outcomes were observed. A correlation between the intensity of the skin rash and median survival was noted. Cetuximab has been approved by the FDA for the treatment of patients with EGFR-positive advanced CRC that is refractory to or intolerant of irinotecan.

CHEMOTHERAPY REGIMENS FOR METASTATIC COLORECTAL CANCER

First Line

• Oxaliplatin based: FOLFOX4 or 6 or CAPOX
• Irinotecan based: FOLFIRI
• BV in combination with intravenous 5-FU regimen: 5-FU and LV, IFL, FOLFIRI, or FOLFOX.

Other Regiments

• Capecitabine alone
• Irinotecan alone (350 mg/m²) or IFL
• XELOX (Oxaliplatin and capacitabine)

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• XELIRI (Irinotecan and capacitabine)
• 5-FU alone as continuous infusion.

Second Line

• Any alternative, non–cross resistant regimen to first-line treatment (i.e., FOLFOX followed by FOLFIRI)
• Cetuximab either alone or in combination with irinotecan.

CONTROVERSIES

Carcinoembryonic Antigen

CEA is an acid glycoprotein localized to the cell membrane, facilitating release into blood and surrounding body fluids. CEA is elevated in nonneoplastic processes such as smoking and inflammatory bowel disease and in cancers involving the breast, lungs, or pancreas. The degree of tumor differentiation correlates with CEA expression; up to 30% of colon cancers, in particular poorly differentiated tumors, exhibit no CEA elevation. Elevation is typically defined as a concentration >5 ng per mL and is associated with increased recurrence rate and decreased survival. A measurement of concentration >25 ng per mL is highly suggestive of metastatic disease. In patients preoperatively evaluated with CEA measurements, a sensitivity of 43% and a specificity of 90% were reported.

Persistent elevation of CEA postoperatively may suggest residual tumor or early metastasis. The routine use of CEA alone for evaluating treatment response is not recommended because up to 20% of patients exhibit conflicting declines in CEA levels despite disease progression. Patients with initially negative levels of CEA can subsequently exhibit positive levels. Serial CEA measurements after completion of postoperative chemotherapy may identify patients who are eligible for a curative resection, in particular, patients with a solitary liver or lung metastasis, but this is rare. Data from studies such as the Ohio State study report a 31% 5-year survival in select populations with aggressive CEA surveillance and second-look laparotomy to detect early recurrences. A joint National Institutes of Health (NIH) and U.K. trial failed to demonstrate survival differences with serial CEA measurements. The American Society of Clinical Oncology recommends CEA testing in patients with previous CRC diagnoses who would be eligible or be considered for surgical resection.

Hepatic-only Metastasis

The liver is the most common site for metastasis, with one third of instances involving only the liver; liver is involved in two-thirds of patients dying from colon cancer. 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. Intraoperative ultrasound is the most sensitive test for initial detection, followed by CT scan or magnetic resonance imaging (MRI).

Nonresectable patients with disease limited to the liver can be treated with locoregional [by hepatic artery infusion (HAI)] or systemic chemotherapy. Postoperative chemotherapy trials have exhibited some benefit. Kemeny et al. (27) reported a 4-year DFS and hepatic disease-free benefit in patients with resected liver metastases who had received intraarterial 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% versus 53%, p = 0.06).

The feasibility of converting an initially unresectable disease to a potentially curative disease has been investigated by Bismuth and colleagues (28). Metastectomy was possible in 99 patients with either down-staged 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

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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 (29).

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