Future Directions in Adjuvant Therapy for Stage III Colon Carcinoma

Introduction

Colorectal cancer is the second leading cause of cancer-related death in the United States. It is the most common cause of cancer-related death in nonsmokers.[1] The estimated number of new colon cancers diagnosed in 2000 was 93,800, and that of new rectal cancers was 36,400.[2] Most patients presenting with this disease can undergo complete gross resection with the possibility of negative microscopic margins. Any residual cancer is likely microscopic in nature. Adjuvant therapy generally refers to the administration of chemotherapy and/or radiation therapy following surgery of curative intent. The goal of postoperative chemotherapy is to eradicate the invisible micrometastases that are responsible for postoperative relapses.

Despite many clinical trials from the 1950s to the 1980s, there was no convincing evidence that effective adjuvant therapy existed for patients with resected colon cancer. A meta-analysis published in 1988 showed a nonsignificant survival benefit in patients who received adjuvant treatment with fluorouracil(Drug information on fluorouracil) (5-FU) that ranged from a 2.3% to 5.7% difference in 5-year overall survival for treated patients over surgical controls.[3]

A small study by the North Central Cancer Treatment Group (NCCTG) published in 1989 reported on the possible benefits of levamisole(Drug information on levamisole) (Ergamisol) in combination with 5-FU for patients with surgically treated stage II and III colon cancer.[4] Subsequent trials were performed to confirm and build upon this experience. With the introduction of many new active agents for the treatment of advanced colorectal cancer, current and future adjuvant trials will be testing a variety of new regimens. This article will briefly review clinical trials of treatments for colorectal cancer that were reported in the past decade and then focus on ongoing and future studies.

Past Trials of Adjuvant Therapy

The first Intergroup trial to confirm the efficacy of 5-FU and levamisole set a new standard for treatment of patients with resected node-positive colon cancer (Table 1).[5] The trial enrolled patients over 3.5 years through October 1987. The benefits of 5-FU plus levamisole in stage III disease translated into an absolute reduction in risk of recurrence of 15% with a relative-risk reduction of 41% (P < .0001). The death rate was reduced by 33% (P = .0007). No benefit was noted for the group receiving levamisole alone. Final results after a median follow-up of 6.5 years showed no loss of protection from recurrence over time.[6] Based on the initial results, the National Cancer Institute (NCI) issued a clinical update in October 1989 that stated "the therapeutic option of postsurgical observation (‘no treatment’ control groups) is no longer justifiable for NCI-sponsored adjuvant studies for Dukes’ C patients." A subsequent National Institutes of Health (NIH) consensus conference in 1990 confirmed this recommendation but concluded that optimal adjuvant therapy "has not yet been devised" and encouraged continued efforts to discover more active regimens.[7]

The next generation of trials all included 5-FU and levamisole administered for 12 months as the control arm. An NCCTG trial addressed the important issue of whether 6 or 12 months of adjuvant therapy were required for patients with resected colon carcinoma.[8] After a median follow-up of 5.1 years, results showed a significant duration-by-regimen interaction. Specifically, the standard 5-FU plus levamisole was inferior to 5-FU/levamisole plus leucovorin when treatment was given for 6 months (P < .01). The authors concluded that 5-FU plus levamisole for 6 months should not be used in clinical practice. The three-drug regimen for 6 months was as effective as 12 months of standard 5-FU and levamisole.

The largest study of adjuvant therapy for colon cancer that has been conducted in the United States is Intergroup-0089. Of 3,759 patients enrolled, 80% had stage III colon cancer. The trial initially had a surgery-alone control arm that was discontinued in 1989 and replaced by standard 5-FU plus levamisole for 12 months. At the same time, a three-drug regimen of 5-FU, levamisole, and leucovorin for 6 months was added. The other two original study arms prescribed 5-FU with leucovorin either in the high-dose weekly leucovorin regimen developed at Roswell Park Cancer Institute or the regimen of low-dose leucovorin daily for 5 days in a row each month developed at the Mayo Clinic.

Mature results of Intergroup-0089 showed that 5-year disease-free and overall survival rates were not significantly different for the various treatment strategies and schedules, except for the comparison between 5-FU and levamisole vs 5-FU, leucovorin, and levamisole.[9] Toxicity data revealed important differences among the various treatments. Regimens containing 5-FU plus low-dose leucovorin (with or without levamisole) had significantly higher incidences of stomatitis than the 5-FU/levamisole or 5-FU/high-dose leucovorin regimens (Table 2).[10] Conversely, diarrhea was more common with 5-FU and high-dose leucovorin than with 5-FU plus levamisole or 5-FU plus low-dose leucovorin.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-04 trial, more than 2,100 patients with stage II and III colon cancer were randomly assigned to receive one of three different 5-FU regimens (Table 1).[11] The results indicated that 5-FU and high-dose leucovorin given for 8 months conferred a small disease-free survival advantage (P = .04) and a prolongation in overall survival of borderline significance (P = .07) as compared with 5-FU and levamisole for 12 months. The addition of levamisole to the 5-FU and leucovorin regimen provided no additional benefit.

Based on results from these studies, clinicians treating patients with stage III colon cancer who are not enrolled in a clinical trial may choose from a variety of regimens with apparently equivalent efficacy and overall treatment durations of 6 to 12 months. Because Intergroup-0089 has shown that either of the 5-FU plus leucovorin regimens given for approximately 6 months is equivalent to 5-FU and levamisole given for 12 months, there is little reason for clinicians to use 5-FU and levamisole outside of a clinical trial setting.

Current and Future Trials of Adjuvant Therapy

Researchers assessing current and future directions for adjuvant treatment of resected colon cancer are using two possible approaches: Some investigators seek to improve on the toxicity profile of current standard regimens by incorporating new orally administered fluorinated pyrimidine compounds into adjuvant therapy trials. Others will investigate new chemotherapy or immunotherapy agents that have demonstrated activity in colorectal carcinoma patients.

UFT

A series of new orally administered fluorinated pyrimidine compounds are of particular interest in colon cancer. UFT, which was developed in the 1970s, is a combination of uracil and tegafur(Drug information on tegafur) in a 4:1 molar concentration. Tegafur is a 5-FU prodrug, and uracil competes with 5-FU as a substrate for dihydropyrimidine dehydrogenase, an enzyme responsible for the catabolism of 5-FU. In phase II studies of UFT administered orally with the biochemical modulator leucovorin (calcium folinate) to metastatic colon cancer patients, response rates ranged from 25% to 43%.[12,13] In a phase III trial of more than 800 patients with advanced disease, UFT and oral leucovorin had similar response rates and survival to a standard intravenous (IV) regimen.[14] Use of UFT was associated with a significant decrease in grade 4 stomatitis and hematologic toxicity. The toxicity profiles observed in these studies were considered acceptable for treatment in the adjuvant setting.

The NSABP C-06 study is comparing the relative efficacies of 5-FU and high-dose leucovorin to UFT plus oral leucovorin. In this phase III trial, patients with resected stage II and III colon carcinoma were stratified by number of positive lymph nodes before random assignment to one of the regimens. The accrual goal of more than 1,450 patients has been satisfied and the study is currently closed with analysis pending. Preliminary toxicity assessment involving more than 470 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles (Table 3).[15] The toxicity profile is favorable in that the oral regimen is not associated with any significant increase in hematologic or nonhematologic toxicity. This study is important because an oral treatment with efficacy equal to that of IV approaches would be preferred by many patients and physicians in the adjuvant setting.

Capecitabine

Capecitabine (Xeloda) is a prodrug of 5-FU that is currently approved in the United States as third-line therapy for advanced breast cancer.[16] Capecitabine(Drug information on capecitabine) is converted to 5-FU in a series of four enzymatic activation steps. In the first activation step, capecitabine is converted to 5-deoxy-5-fluorocytidine by carboxylesterase in the liver while the final activation step occurs in tumor tissue and in normal cells by the enzyme thymidine phosphorylase. Capecitabine is thought to be selectively activated to 5-FU in tumor cells because of increased amounts of thymidine phosphorylase in tumor tissue relative to normal tissue. This preferential activation in the tumor cell may increase its therapeutic index, resulting in higher cytotoxicity in colon cancer cells than in normal tissue. Ongoing trials are assessing its efficacy in patients with advanced colon cancer.[17] Capecitabine would be an excellent agent to test as adjuvant treatment of patients with resected colorectal carcinoma.