Colorectal Cancer

EPIDEMIOLOGY

• Colorectal cancer (CRC) is the second leading cause of cancer death 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 149,030 new cases of CRC were diagnosed in 2008 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.
  
• U.S. mortality rates from CRC continue to decline (2.3% decrease from 1998 to 2004) as a result of effective screening programs, diagnosing early disease, and effective 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 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 is 10% higher in African Americans.
  
• Personal 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.
  
• Micronutrient deficiency: Folate, selenium, and vitamins 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 (8-12 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 (2).
  
• 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 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 (HNPCC) 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%. 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 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) can be identified in virtually all HNPCC 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 P.98
patients. The American Cancer Society 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.

TABLE 8.1. American Cancer Society Recommended Colorectal Cancer Screening Guidelines for asymptomatic average-risk individuals

Beginning at age 50, all patients should have one of the five screening options listed. Test Frequency Fecal Occult Blood Test (FOBT) Every year Flexible sigmoidoscopy Every 5 years FOBT plus flexible sigmoidoscopy (preferred option of the first three options) Every year Every 5 years Double-contrast barium enema Every 5 years Colonoscopy* Every 10 years * Colonoscopy should be done if the FOBT shows blood in the stool, if sigmoidoscopy results show a polyp, or if double-contrast barium enema studies show anything abnormal. If possible, all polyps should be completely removed during the colonoscopy.

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 polyps and cancer appear reasonable, but there is a wide range of sensitivities reported despite improved experience by providers and consistent technology (3). Patients still require bowel preparation and colonic distension as well as ingestion of oral contrast. Detected abnormalities require investigation with endoscopy. Additional studies are required before this technique can be recommended 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. It is routinely recommended in surveillance programs. 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 CRC is adenocarcinoma, 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 P.99
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
  
• 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

• 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.
  
• 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 abdomen and pelvis (with or without chest evaluation) are useful in initial cancer diagnosis and staging.
  
• In colon cancers, CT scan sensitivity for detecting distant metastasis is higher (75-87%) than for detecting nodal involvement (45-73%) 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.
  

Endoscopic rectal ultrasound is a valuable tool in the preoperative evaluation of rectal cancer, with high accuracy of determining the extent of the primary tumor (63-95%) and perirectal nodal status (63-82%). P.100
STAGING The American Joint Committee on Cancer staging of CRC using the TNM classification was updated in 2002 (Fig. 8.1 and Table 8.2). Patients with stage II and III disease have been further stratified, and vascular or lymphatic invasion has been included. The tumor designation, or T stage, defines the extent of bowel wall penetration, as opposed to tumor size. The Dukes or MAC staging system is no longer used. PROGNOSIS Pathologic staging remains the most important determinant of prognosis (Table 8.3). Stage for stage, rectal cancer confers a worse prognosis than colon cancer (4). 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
  

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 (TF). 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 histopathologic differentiation, vascular or lymphatic invasion, and a positive preoperative CEA value of >5 ng/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 T2 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).

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TABLE 8.2. TNM classification of colorectal cancer staging designated by the American Joint Committee on Cancer (AJCC), sixth edition (2002).

Primary tumor (T)a T0 No evidence of primary tumor Tis Carcinoma in situ—intraepithelial or invasion of the lamina propria T1 Invasion of submucosa T2 Invasion of muscularis propria T3 Invasion 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 peritoneum Lymph node status (N)b N0 No regional lymph node involvement N1 Metastases in one to three regional lymph nodes N2 Metastases in four or more regional lymph nodes Metastatic disease (M) M0 No distant metastases M1 Distant metastases present Stage grouping Stage T N M 0 Tis N0 M0 I T1-T2 N0 M0 IIA T3 N0 M0 IIB T4 N0 M0 IIIA T1-T2 N1 M0 IIIB T3-T4 N1 M0 IIIC T1-T4 N2 M0 IV T1-T4 N0-2 M1 Lymphadenectomy should contain at least 12 lymph nodes for adequate staging. aThe V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion. bSmooth metastatic nodules in the pericolic or perirectal fat are considered lymph node metastases and will be counted in the N status. 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.

• Bowel obstruction or perforation at presentation
  
• Biochemical and molecular markers such as elevated thymidylate synthase, p53 mutations, or loss of heterozygosity of chromosome 18q (DCC gene) are associated with a poor prognosis (5,6). MSI caused by a defective DNA mismatch-repair system (altered MLH1, MSH2; associated with HNPCC) is associated with an improved outcome.
  

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.
  
• 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.
  
• The number of lymph nodes resected and pathologically examined is critical to accurate staging. The probability of determining true node negativity increases with the number of nodes sampled. At least 12 lymph nodes should be examined and reported.
  

TABLE 8.3. Prognosis by stage for colon and rectal cancers
5-Year overall survival (%) Stage Colon Rectal 0-I 93 90 IIA 85 75 IIB 72 65 IIIA 83 55 IIIB 64 35 IIIC 44 24 IV 8 6

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 utilized in rectal cancers to reduce local recurrence and improve resectability.
  

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 (7). 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 (8, 9). The results demonstrated that the 5-FU and leucovorin (LV) containing schedules (Mayo Clinic and Roswell Park) 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. P.103
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 (10). 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, 0.75-1.00; P = 0.0526). Toxicity was improved in all categories except hand-foot syndrome. 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 (11). 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 (12), which 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, 0.65-0.92; P = 0.002). With a median 6-year follow-up, the DFS advantage was confirmed with a trend toward improved OS (13). 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 1 year later (1%). 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 (14). The combination improved 3-year DFS (76.1% vs. 71.8%; HR 0.80; 95% CI, 0.69-0.93; P =0.003). Grade 3 diarrhea (38%) and peripheral neuropathy (8%) were significantly worse with FLOX without any difference in treatment-related mortality. CALGB 89803, PETACC-3, and ACCORD 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 (15). 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 cannot be recommended in the adjuvant setting. Adjuvant Chemotherapy Regimens for Colon Cancer Based on these studies, adjuvant chemotherapy is recommended for patients with stage III colon cancer. Several acceptable options exist (Table 8.4), with combination regimens offering increased efficacy and toxicity. The incorporation of biologic targeted therapy into the adjuvant setting is the topic of numerous, ongoing, large clinical trials.

TABLE 8.4. Acceptable adjuvant chemotherapy regimens for stage III colon cancer

Name Regimen and dose Repeated (days) Total cycles Mayo Clinic LV 20 mg/m2/day IV followed by 28 6 5-FU 425 mg/m2/day IV days 1-5 Roswell Park LV 500 mg/m2 IV followed by 8 wk 3-4 5-FU 500 mg/m2 IV weekly × 6 Capecitabine 1,250 mg/m2 PO twice daily × 14 days 21 8 FOLFOX4 Oxaliplatin 85 mg/m2 IV on day 1 followed by 14 12 LV 200 mg/m2/day IV on days 1 and 2 followed by 5-FU 400 mg/m2/day IV on days 1 and 2 followed by 5-FU 600 mg/m2/day CIVI for 22 hours on days 1 and 2 FOLFOX6 Oxaliplatin 85-100 mg/m2 IV on day 1 followed by 14 12 LV 400 mg/m2/day IV on day 1 followed by 5-FU 400 mg/m2/day IV on day 1 followed by 5-FU 2,400 mg/m2 CIVI for 46 hours FLOX LV 500 mg/m2 IV followed by 8 wk 3 5-FU 500 mg/m2 IV on days 1, 8, 15, 22, 29, 36 and Oxaliplatin 85 mg/m2 IV on days 1, 15 and 29 There is no role for biologic targeted therapy or irinotecan-containing regimens in the adjuvant setting at this time. LV, leucovorin; IV, intravenous; 5-FU, 5-fluorouracil; CIVI, continuous intravenous infusion.

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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. Hand-foot syndrome (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: P.105

• 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, 0.50-0.92; P = 0.01). This reduction in mortality translated into an absolute survival advantage of 5% (16).
  
• A meta-analysis by Erlichman et al. (17) 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 (18). 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 (19). With a median follow-up of 5.5 years, the risk of recurrence (HR 0.78; 95% CI, 0.67-0.91; P = 0.001) and death (HR 0.82; 95% CI, 0.70-0.95; 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, 0.57-1.17).
  
• The American Society of Clinical Oncology Panel concluded in 2004 that the routine use of adjuvant chemotherapy for patients with stage II disease could not be recommended (20). 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.
  
• Utilization of molecular prognostic markers in stage II disease is being incorporated into active clinical trial protocols to help determine which patients may maximally benefit from adjuvant therapy.
  

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 radiation therapy (chemoRT) is now the standard therapy for patients with stages 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 (21). Two cycles of chemotherapy were administered before and after chemotherapy in combination with 5,040 cGy of external beam radiation (4,500 cGy with 540 cGy 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 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 (22). This survival benefit has led to continuous infusion of 5-FU during radiation 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 (23). In both groups, 5-FU was administered in a continuous fashion during the first and fifth weeks of radiation. All patients received an additional four cycles of adjuvant 5-FU after chemoRT and surgery. Results of P.106
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 approach to patients with rectal cancer. Combined-Modality Options for Rectal Cancer 1. Following initial treatment with surgery:

• Intravenous 5-FU bolus (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 5-FU bolus (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.
  

2. Neoadjuvant therapy:

• Intravenous 5-FU continuous infusion (1,000 mg/m2/day) given daily for 5 days during the first and fifth week of radiation therapy, which is given in 180 cGy fractions to a total dose of 5,040 cGy.
  

3. Followed by surgery:

• Upon recovery from surgery, intravenous 5-FU bolus (500 mg/m2/day) on days 1 to 5 repeated every 28 days for 4 cycles.
  

The oral fluoropyrimidine capecitabine mimics infusional 5-FU and has been investigated in conjunction with radiation. Additionally, oxaliplatin is being evaluated as a radiation sensitizer for patients with rectal disease. Given the previously discussed data for adjuvant chemotherapy regimens in colon cancer, several different regimens (see Table 8.4) may 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 reresection, in particular, patients with a solitary liver or lung metastasis. TREATMENT FOR ADVANCED COLORECTAL CANCER Unprecedented improvements in survival 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 (24). 5-Fluorouracil-Based Chemotherapy 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. P.107
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 (25, 26). Toxicities include mucositis and palmar-plantar erythrodysesthesia (hand-foot syndrome); however, myelosuppression is less common. Continuous infusions of 5-FU may have activity in patients who have progressed on a bolus 5-FU regimen. Capecitabine 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 expressed in tumor tissues. 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 (27). The toxicity profile favored the capecitabine arm with decreased gastrointestinal and hematologic toxicities and fewer hospitalizations. An increased frequency of hand-foot syndrome and hyperbilirubinemia were noted with capecitabine. Oxaliplatin Oxaliplatin is an agent that differs structurally from other platinums in its 1,2-diaminocyclohexane (DACH) moiety, but acts similary 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., reversible 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 (28) comparing first-line FOLFOX4 versus IFL versus IROX (irinotecan in combination with oxaliplatin). Of the original six arms in the study, three were eliminated based on changes in the standard of care or toxicity. In addition, 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) (29). The conclusion is that similar survival is observed in patients receiving either sequence. Irinotecan/CPT-11 Irinotecan is a topoisomerase I inhibitor, with activity in patients with advanced CRC and in patients deemed refractory to 5-FU. As a single agent, response rates as high as 20% are observed, and an P.108
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 (30) 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 the 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 (31). 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 (32). 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 (33). In patients receiving 5-FU earlier, a 13% response rate and an 7.7 median response duration were observed. Bevacizumab Bevacizumab (BEV) 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 an exceptionally high affinity for VEGF. 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 reveals 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) (34). 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) (35). 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 and under intense investigation. Cetuximab and Panitumumab The epidermal growth factor receptor (EGFR) and pathway represent a targeted approach to CRC therapy. Two monoclonal antibodies are FDA approved for use in patients with metastatic CRCs. Importantly, tumor EGFR positivity by immunohistochemistry staining does not correlate with treatment response; however, K-ras mutational status does. K-ras is an intracellular tyrosine kinase involved in the EGFR signal transduction pathway. There appears to be no clinical benefit to the use of EGFR inhibition if K-ras is mutated (i.e., not wild-type), which is the case in approximately 40% of patients (36). Commercial testing for K-ras mutational status is available. Cetuximab is a chimerized IgG1 antibody that prevents ligand binding to the EGFR and its heterodimers. Cetuximab exhibits higher affinity (subnanomolar) or approximately 1-log greater binding than the natural ligands for EGFR. Panitumumab is a fully humanized IgG2 antibody also targeting EGFR. These agents block receptor dimerization, tyrosine kinase phosphorylation, and subsequent downstream signal transduction. Both agents can cause a skin rash and diarrhea, but are without P.109
myelosuppression. A correlation between the intensity of the skin rash and survival has been consistently noted. Cetuximab is FDA approved based on a study in patients refractory to irinotecan. They were randomized to the combination of cetuximab and irinotecan versus cetuximab 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 (37). Despite manageable toxicity, no improvements in survival outcomes were observed. 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, 0.44-0.66; P < 0.0001), although no overall survival advantage was noted (38). Attempts to combine this agent with FOLFOX or FOLFIRI plus BEV in first-line management of advanced disease did not provide benefit over placebo for unclear reasons. CHEMOTHERAPY REGIMENS FOR METASTATIC COLORECTAL CANCER See Tables 8.4 and 8.5. Investigations into the optimal timing and sequence of treatment combinations both with and without EGFR and VEGF inhibition continue. CONTROVERSIES Hepatic-only Metastasis 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, and hepatic artery embolization with or without chemotherapy) have not shown consistent durable 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. Optimal therapy to improve survival after surgical resection is controversial. Patients with unresectable disease limited to the liver can be treated with locoregional hepatic artery infusion (HAI) or systemic chemotherapy. Kemeny et al. (39) reported a 4-year DFS and hepatic P.110
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.

TABLE 8.5. Select chemotherapy regimens for advanced colorectal canceraa

Name Regimen and dose Repeated (days) XELOX Oxaliplatin 100-130 mg/m2 IV on day 1 21 Capecitabine 850 mg/m2 PO twice daily on days 1-14 Irinotecan 300-350 mg/m2 IV 21 Irinotecan 125 mg/m2 IV on days 1, 8, 15, and 22 6 wk FOLFIRI Irinotecan 180 mg/m2 IV on day 1 followed by 14 LV 400 mg/m2/day IV on day 1 followed by 5-FU 400 mg/m2/day IV on day 1 followed by 5-FU 2,400 mg/m2 CIVI for 46 hours Bevacizumabb 5 mg/kg IV on day 1 14 Cetuximabc 400 mg/m2 IV on day 1 followed by weekly 250 mg/m2 IV weekly thereafter Panitumumab 6 mg/kg IV 14 LV, leucovorin; IV, intravenous; 5-FU, 5-fluorouracil; CIVI, continuous intravenous infusion. aThese are in addition to those presented in Table 8.4. bIn combination with any 5-FU-containing regimen. cAlone or in combination with irinotecan.

The feasibility of converting initially unresectable disease to a potentially curative disease has been investigated by Bismuth and colleagues (40). 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, 20.4-34.8) for the entire cohort (41). Indeed, current management of resectable liver disease typically includes perioperative systemic chemotherapy. This 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 post-resection compared to surgery alone (42). However, attention must be paid to the potential hepatotoxicity and surgical complications from perioperative chemotherapy. The role of targeted therapies in the perioperative setting is an area of active investigation.