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Future Directions in Adjuvant Therapy for Stage III Colon Carcinoma
Published on Physicians Practice (http://www.physicianspractice.com)
Future Directions in Adjuvant Therapy for Stage III Colon
Carcinoma
Review Article [1] | March 02, 2001
By Henry C. Pitot, MD [2] and Richard M. Goldberg, MD [3]
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
Introduction
olorectal 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.
C
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
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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 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.
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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 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.
Raltitrexed (Tomudex) is a quinazoline analog that began clinical development in the early 1990s.
The drug is a direct, specific inhibitor of thymidylate synthetase that undergoes intracellular
polyglutamination.[18] This increases the drug’s potency and allows for every-3-week dosing.
Raltitrexed has demonstrated less toxicity (stomatitis, diarrhea, and leukopenia) as compared with
5-FU and high-dose leucovorin in patients with advanced colorectal cancer.[19] Although response
and median survival rates were comparable, time to progression was statistically shorter in the
raltitrexed group.
Despite these results, the Pan-European Trials in Adjuvant Colon Cancer (PTACC) planned to enroll
more than 2,700 patients with resected node-positive colon cancer in a randomized trial comparing
raltitrexed and 5-FU/low-dose leucovorin. The trial opened in February 1998 and accrued more than
360 patients in the first 6 months. Unfortunately, an early safety analysis demonstrated excessive
toxicity in the raltitrexed arm, primarily related to cases of lethal toxicity in patients with
compromised renal function, and accrual was suspended (personal communication, D. Cunningham,
study chair, June 2000). Combination regimens that include raltitrexed may offer new avenues of
research for future trials of adjuvant therapy.[20]
Irinotecan
Irinotecan (CPT-11, Camptosar) is a potent inhibitor of topoisomerase I with demonstrated
single-agent activity in advanced colorectal cancer patients who have previously received 5-FU.[21]
In two studies, the combination of irinotecan with 5-FU and leucovorin resulted in a statistically
significant survival advantage over standard 5-FU and leucovorin regimens (Table 4).[22,23] Toxicity
was manageable in one study, with slightly more grade 3 diarrhea and vomiting and less mucositis,
grade 4 neutropenia, and neutropenic fevers in the irinotecan combination arm.[22]
The Cancer and Leukemia Group B (CALGB) is leading an NCI-sponsored phase III trial of irinotecan,
5-FU, and leucovorin vs 5-FU and high-dose leucovorin in resected node-positive patients. The
accrual goal is 1,260 patients over 3 years. Patients are stratified according to lymph node
involvement (1-3 vs ≥ 4), histology, and preoperative serum carcinoembryonic antigen levels. The
schedules both involve weekly chemotherapy administration of similar duration (30 vs 32 weeks,
respectively).
Two European trials will also evaluate irinotecan in combination with 5-FU in the adjuvant setting. A
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multicenter trial, with a planned enrollment of 1,800 patients with stage II and III disease, will
administer one of two 5-FU/leucovorin regimens commonly used in Europe (the infusional 5-FU de
Gramont regimen[24] and the high-dose 5-FU German AIO [German Cancer Society]
regimen).[24,25] Investigators may choose to use either of these 5-FU regimens, and patients will be
randomly assigned to receive additional irinotecan or no further therapy.
A smaller French study will evaluate irinotecan in high-risk stage III patients (more than four positive
nodes or any positive nodes with obstruction and/or perforation). A total of 400 patients will be
randomly assigned to the de Gramont regimen with or without irinotecan. The primary end point is
event-free survival at 3 years; secondary objectives are overall survival, toxicity, and quality of life.
Despite the use of three different standard regimens, nearly 3,500 patients will be included in these
randomized studies evaluating the role of irinotecan in resected colon cancer.
Oxaliplatin
Oxaliplatin is a diaminocyclohexane (DACH) platinum derivative that has demonstrated activity in
advanced colorectal carcinoma. Levi and colleagues first reported results combining oxaliplatin,
5-FU, and leucovorin in a chronomodulated fashion and observed a 55% response rate in 42 patients
with metastatic colorectal carcinoma.[26] These impressive phase II results led to subsequent phase
III trials in Europe comparing 5-FU plus leucovorin with or without oxaliplatin. In one trial, more than
200 patients received the combination regimen in a chronomodulated fashion (Table 5).[27] In the
second, larger trial, 5-FU and leucovorin were administered by bolus and short continuous infusion
(de Gramont schedule) for 2 days every 2 weeks with or without oxaliplatin.[28]
In both of these trials, response rates and median progression-free survivals (the primary end points
in each trial, respectively) were statistically significantly different in favor of the oxaliplatin arm.
However, median overall survival was not significantly different. Several explanations for these
findings have been proposed, including (1) use of oxaliplatin or irinotecan in secondary salvage
chemotherapy regimens, (2) use of aggressive salvage surgery in select patients enrolled in these
trials, and (3) use of too small a sample to detect a survival difference.
The clinical data on oxaliplatin in advanced disease have led investigators to assess oxaliplatin in the
adjuvant setting. The NSABP C-07 study was initiated to compare weekly 5-FU and high-dose
leucovorin with and without oxaliplatin in stage II and III colon cancer. Each study arm will consist of
three 8-week cycles of 5-FU and high-dose leucovorin with oxaliplatin (85 mg/m2) given on days 1,
15, and 19 of each cycle. The projected accrual is approximately 2,500 patients over 3 years.
In Europe, approximately 1,500 of a planned accrual of 2,000 patients with stages II and III disease
have been enrolled in a multicenter international study of oxaliplatin/5-FU and leucovorin as
adjuvant therapy for colon cancer (MOSAIC). The trial is comparing the de Gramont regimen of 5-FU
and leucovorin to the same schedule with the addition of oxaliplatin (FOLFOX-4). Results of this trial
will be eagerly awaited by the oncology community in the coming years.
Monoclonal Antibody 17-1A
Use of adjuvant immunotherapy has been an intriguing concept that has been tested in many colon
cancer trials. Interferon-alpha combined with 5-FU and leucovorin was tested in NSABP C-05; the
regimen only increased toxicity without improving outcomes for patients treated with
immunotherapy.[29] Riethmuller and colleagues reported 7-year results of a study of monoclonal
antibody therapy in patients with resected Dukes’ C colorectal cancer.[30] Monoclonal antibody
17-1A recognizes a 34-kd glycoprotein on the cell membrane of epithelial cells. The trial included
189 patients, 70 of whom had rectal cancer.
Patients were randomly assigned to an observation arm or to receive monoclonal antibody
treatment. After 7 years of follow-up, overall mortality was reduced by 32% (P ≤ .01) and recurrence
rate decreased by 23% (P < .04). The benefits observed in this small trial were of the same order of
magnitude as in the initial 5-FU and levamisole study,[5] with the therapeutic effect maintained after
long-term follow-up.
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Based on these results, a large international study was initiated. As of early 1999, more than 2,700
patients were enrolled and the trial was closed to accrual. Patients were randomly assigned to one of
three treatment arms: 5-FU and low-dose leucovorin (six cycles), monoclonal antibody 17-1A (five
infusions), or the combination 5-FU/leucovorin and monoclonal antibody 17-1A. This trial and a study
being performed in North America of monoclonal antibody 17-1A vs no treatment in stage II patients
will help determine whether monoclonal antibody 17-1A is effective adjuvant therapy and whether
chemotherapy alters or enhances the immune effects of monoclonal antibody 17-1A.
Carcinoembryonic Antigen Vaccine
Vaccines offer an innovative approach to cancer therapy. Foon and colleagues have demonstrated
clinical and immune responses in patients receiving an anti-idiotype antibody (termed CeaVac) that
is an internal image of carcinoembryonic antigen (CEA).[31] Patients with CEA-positive resected or
incompletely resected stage II-IV disease were treated with subcutaneous injections of CeaVac. Of 32
patients, 14 received concurrent 5-FU-based chemotherapy. All patients generated high-titer IgG
(immunoglobulin G) and T-cell proliferative immune responses against CEA. The use of 5-FU did not
change the quantitative or qualitative effect of the immune response.
Several of these patients fared "remarkably well" according to the authors, even though patients
were allowed to enter the trial up to 1 year after surgical resection. In an ideal world, adjuvant
therapy would begin immediately after surgery. Thus, a cooperative group in the United States is
considering conducting a large-scale clinical trial of CeaVac as adjuvant therapy for resected colon
cancer, in which patients would be randomly assigned to receive 5-FU and leucovorin with or without
CeaVac. Results of this trial may address whether specific immunization against the
tumor-associated antigen in humans will result in beneficial immunotherapeutic antitumor effects.
Summary
In summary, adjuvant therapy for colon cancer is now widely accepted as a standard of care for
patients with node-positive disease. The most commonly used regimens involve approximately 6
months of 5-FU and low- or high-dose leucovorin. New chemotherapy agents and immunotherapy
agents offer the potential for less toxicity and/or improved overall survival for patients with stage III
disease. In the coming years, thousands of patients with resected colon cancer will be enrolled in
randomized clinical trials evaluating these new agents. Many of these trials will incorporate a
translational component, which will help focus future innovative clinical research. With the multitude
of treatment opportunities available to patients with colon cancer, the oncology community can
hopefully move beyond 5-FU and leucovorin during the next decade.
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