Future Directions in Adjuvant Therapy for Stage III Colon Carcinoma

Future Directions in Adjuvant Therapy for Stage III Colon Carcinoma

ABSTRACT: The current recommendation for adjuvant chemotherapy for patients with newly diagnosed stage III colon cancer involves 6 months of fluorouracil (5-FU) plus low- or high-dose leucovorin. In clinical trials performed throughout the world, several drugs have demonstrated either improved toxicity profiles or antitumor activity for patients with advanced colorectal carcinoma. Uracil and tegafur (UFT) and capecitabine (Xeloda) are two examples of new oral chemotherapy compounds with acceptable side-effect profiles in early adjuvant or advanced disease trials. Irinotecan (CPT-11, Camptosar) and oxaliplatin, when administered intravenously in combination with a 5-FU regimen, have both demonstrated significant antitumor effects for patients with advanced-stage disease. Other immunotherapies, including monoclonal antibodies and cancer vaccines, are being evaluated to help stimulate immune responses in patients with resected colon cancer. These agents are just a few examples of the new compounds being tested in the next generation of clinical trials for resected stage III colon cancer. Future and ongoing investigations will look to integrate these new therapies as we attempt to move beyond the era of 5-FU and leucovorin. [ONCOLOGY 15(Suppl 5):31-36, 2001]


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 (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
(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

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
).[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

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


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 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
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


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 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.


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