Published: August 2010
The primary treatment of early colorectal cancer is surgical resection of the primary tumor and regional lymph nodes. Surgery is curative in early stage tumors but, in more advanced stages, adjuvant therapy is recommended to prevent recurrence and improve survival. Stage IV disease will require systemic chemotherapy.
Primary treatment of stages I to III colon cancer is surgical resection of the primary tumor and regional lymph nodes. Adequate lymph node sampling is important, because the number of nodes examined significantly correlates with 5-year relapse-free and overall survival. At least 12 nodes should be examined to determine nodal status accurately.1
After surgical resection, adjuvant chemotherapy should be considered in patients with stage II or III disease to reduce the risk of disease recurrence, either as local or distant metastasis. There is no role for adjuvant chemotherapy in stage I disease.
Use of adjuvant therapy in patients with stage II colon cancer is actively debated. Many trials done to address the benefit of chemotherapy in a population consisting entirely or predominantly of stage II disease have been negative, or shown only a modest benefit in terms of disease-free survival (DFS) but not overall survival (OS). The American Society of Clinical Oncology (ASCO) recommends against routine administration of fluorouracil (5-FU)-based chemotherapy for patients with resected stage II colon cancer. However, they have suggested that adjuvant therapy be considered for medically fit patients who have inadequately sampled lymph nodes (fewer than 12 in the surgical specimen), T4 lesions, perforation, or poorly differentiated histology, despite the lack of direct data from randomized controlled trials to support the practice.2
Multiple studies have proven the benefit of adjuvant chemotherapy in patients with stage III disease. Adjuvant chemotherapy is associated with an approximately 30% reduction in the risk of disease recurrence, and a 22% to 32% reduction in mortality.3 The extent of benefit relates to tumor grade, invasion, and nodal involvement. The choice of chemotherapy in stage III is FOLFOX (oxaliplatin plus infusional 5-FU and leucovorin) regimen based on the MOSAIC trial.4 In this trial, 2246 patients with completely resected stage II or III colon cancer were randomized to a 6-month course of FOLFOX regimen or infusional 5-FU-leucovorin (LV). After a median follow-up of 38 months, 3-year DFS (the primary end point) was significantly higher with FOLFOX (78% vs. 73%; hazard ratio [HR], 0.77). Patients who have contraindications to oxaliplatin (e.g., preexisting neuropathy), 6 to 8 months of LV modulated 5-FU is an acceptable option. Recently, capecitabine (oral fluoropyrimidine) has been approved by the FDA for adjuvant therapy in stage III colon cancer based on the X-ACT study.5 In this study, capecitabine was at least as effective as 5-FU-LV, and there was some suggestion of superiority in terms of 3-year DFS (64.2% vs. 60.6%; P =.05) and OS (81.3% vs. 77.6%; P =.07). Currently, there are active trials looking at the impact of molecular factors (e.g., 18q deletion, thymidylate synthetase [TS] overexpression, p53 mutations, microsatellite instability, gene expression profile) on prognosis and the response to adjuvant chemotherapy in patients with stage II or III colorectal cancer.
When diagnosed as advanced metastatic disease, colorectal cancer (CRC) is traditionally associated with a poor prognosis, with 5-year survival rates in the range of 5% to 8%. The actual survival rate has remained unchanged over the past 35 to 40 years. However, during the past 5 years, significant advances have been made in chemotherapy treatment options, such that improvements in 2-year survival rates are now being reported—median survival rates of 21 to 24 months in patients with metastatic disease.
Chemotherapy has been the mainstay approach for patients with advanced colorectal cancer.6 For nearly 40 years, 5-FU was the only active anticancer agent available to treat advanced colorectal cancer in the first-line setting. In general, response rates to 5-FU in patients with advanced disease are low, in the range of 10% to 15%. To improve the clinical efficacy of 5-FU, the addition of certain biomodulating agents such as the reduced folate LV, a change in the schedule of administration of 5-FU from bolus to continuous infusion, or both have been actively investigated.7
Progress in the past five years has been made possible with the introduction of three cytotoxic agents—capecitabine, irinotecan, and oxaliplatin—and with the approval of two biologic agents, bevacizumab and cetuximab. During this time period, the median survival of patients with advanced metastatic disease has gone from 10 to 12 months to almost 24 months.
In the United States, the combination of irinotecan with bolus 5-FU-LV (IFL regimen) was approved for the initial therapy of metastatic CRC based on a randomized phase III study, which resulted in improved clinical efficacy in terms of higher response rate and greater overall and progression-free survival when compared with 5-FU-LV monotherapy.8 However, as a result of the increased incidence of diarrhea, dehydration, and myelosuppression, the IFL regimen is rarely used today. Instead, FOLFOX has now become the treatment of choice for most oncologists based on the Intergroup trial N9741.9 This pivotal study showed that FOLFOX had significantly greater clinical efficacy than IFL in terms of response rate (45% vs. 31%; P =.002), time to tumor progression (8.7 vs. 6.9 months; P =.0001), and median overall survival (19.5 vs. 14.8 months; P =.0001).
Capecitabine is a rationally designed oral fluoropyrimidine carbamate that is absorbed intact through the intestinal wall and then converted to 5-FU in three sequential enzymatic reactions. Studies have shown similar efficacy of capecitabine compared with infusional 5-FU and leucovorin.10 Capecitabine has been approved by the U.S. Food and Drug Administration (FDA) for first-line treatment of metastatic CRC in the setting of irinotecan- and oxaliplatin- intolerant patients. There have been studies designed to determine whether capecitabine can be substituted for infusional 5-FU in combination with irinotecan and oxaliplatin.11
Bevacizumab is a recombinant humanized monoclonal antibody that targets all forms of vascular endothelial growth factor A (VEGF-A). Bevacizumab was granted FDA approval in February 2004 as a first-line treatment for metastatic colorectal cancer in combination with any IV fluoropyrimidine-containing regimen based on a phase III trial.12 The trial has shown that patients with colorectal cancer who received bevacizumab plus standard chemotherapy with the bolus weekly IFL regimen had longer progression-free survival (10.6 vs. 6.2 months; P <.00001) and improved median overall survival (20.3 vs. 15.6 months; P =.00003) compared with those receiving IFL chemotherapy plus placebo. Today, the greatest use of bevacizumab has been in combination with FOLFOX-based regimens because of the poor toxicity profile of the IFL regimen.
Cetuximab is a chimeric monoclonal antibody directed against the external cell surface of the epidermal growth factor receptor (EGFR). EGFR is a member of the erb-B family of growth factor receptors, and is overexpressed in up to 85% of colorectal tumors. Moreover, its expression has been correlated with metastatic disease and poor prognosis. Currently, cetuximab is approved, in combination with irinotecan, for the treatment of metastatic CRC in patients refractory to irinotecan, and for use as a single agent in the treatment of recurrent metastatic CRC in patients intolerant of irinotecan-based chemotherapy.13
Surgical resection is the cornerstone of curative treatment in rectal cancer. Usually, tumors in the upper and middle rectum can be managed with low anterior resection (LAR), coloanal anastomosis, and preservation of the anal sphincter. Distal rectal cancer will require abdominoperineal resection (APR) and entails a permanent colostomy, which maybe burdensome to patients. Total mesorectal excision (TME) has been used in conjunction with APR and LAR and has been associated with decreased local recurrence. TME is a surgical technique that involves sharp dissection along the mesorectal fascia, with removal of the rectum and all tissue invested by the adjacent visceral fascia, including fatty tissue, lymph nodes, and lymphatic vessels.
The use of perioperative chemoradiation therapy (CRT) for rectal cancer continues to evolve. A 1990 NIH Consensus Development Conference recommended that postoperative 5-FU-based chemotherapy combined with irradiation should be standard clinical practice for stages II and III rectal cancer because of its proven decreases in local recurrence, cancer-related deaths, and overall mortality.14 The success of combined modality treatment in the postoperative setting has led to its use for the preoperative treatment of rectal cancer. Neoadjuvant CRT has many advantages, including tumor downstaging and a higher rate of sphincter preservation.
The German Rectal Cancer Study Group has completed a large, prospective, randomized trial that compared preoperative with postoperative chemoradiation.15 In this pivotal study, 823 patients with clinically staged T3 to T4 or node-positive rectal cancer were randomized to the same chemoradiotherapy (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-FU) regimen administered preoperatively or postoperatively. It was concluded that although there is no difference in overall survival between the two groups, there is a significant reduction in the local recurrence rate (6% vs. 13%; P =.006) and treatment toxicity in the preoperative group (27% vs. 40%; P =.001). Based on this trial, neoadjuvant CRT should be considered standard treatment for patients with stage II or III rectal cancer. Surgical resection is generally deferred until 6 to 8 weeks following completion of therapy to allow maximal tumor response and to allow patients to recover from the chemoradiation.
No trials have conclusively demonstrated the benefits of postoperative chemotherapy for patients who have already received neoadjuvant CRT. However, preliminary data from EORTC trial 22921 has suggested that there may be improvement in outcomes for patients receiving postoperative adjuvant 5-FU–based chemotherapy.16 Guidelines from the NCCN (National Comprehensive Cancer Network, www.nccn.org) recommend that all patients receive 5-FU–containing chemotherapy, even if they have a pathologic complete remission (pCR) to neoadjuvant CRT.