Drs. Peeters and Haller provide a thorough review of the recent historical development, current state of knowledge, and future of adjuvant therapy for early-stage colon and rectal cancers. They provide reasonable recommendations for the management of patients with colon or rectal carcinoma that are based on the results of published clinical trials.
The authors point out that, for patients with colon and rectal cancer, there exist differences in survival that correlate with the pathologic stage (widely thought to be the most important prognostic indicator). Furthermore, they emphasize the importance of differences in the natural history of the two diseases and describe how these differences affect the clinicians approach to preventing recurrence (eg, rectal cancers require aggressive local control since local failures are common).
In addition, the authors briefly mention other risk factors for recurrence (perforation, obstruction, adjacent organ involvement, completeness of resection), as well as potential risk factors whose usefulness has yet to be established (DNA aneuploidy, tumor-thymidylate synthase activity, and reverse-transcriptasepolymerase chain reaction [RT-PCR] amplification of carcinoembryonic antigen [CEA] messenger RNA [mRNA]).
Peeters and Haller conclude that all stage III patients should be offered treatment with either 1 year of fluorouracil(Drug information on fluorouracil) (5-FU) plus levamisole(Drug information on levamisole) (Ergamisol) or 6 months of 5-FU plus folinic acid. This conclusion is based on the results of the second intergroup study (INT-0089), which compared four treatment groups (5-FU + low-dose folinic acid ± levamisole administered for a total of 6 months and 5-FU + high-dose folinic acid ± levamisole administered for 12 months); the National Surgical Adjuvant Breast and Bowel Project
(NSABP) C-04 study, which compared 5-FU + high-dose folinic acid ± levamisole for 1 year vs 5-FU + high-dose folinic acid for 8 months; and the North Central Cancer Treatment GroupNational Cancer Institute of Canada (NCCTG-NCIC) trial, which compared 5-FU + levamisole for either 6 or 12 months vs 5-FU+ low-dose folinic acid for either 6 or 12 months. Peeters and Haller emphasize the increased risk of toxicity associated with low-dose folinic acid and triple biomodulation regimens and the lack of benefit afforded by adding levamisole to 5-FU + folinic acid.
Low- vs High-Dose Folinic Acid
The authors make no comments concerning their preference for low- vs high-dose folinic acid. This is understandable, since at least seven randomized trials comparing high- and low-dose folinic acid regimens have yielded conflicting results. Most of these trials have found either a trend for superior benefit with high-dose folinic acid or at least equivalent efficacy of the high- and low-dose regimens.
Preclinical pharmacokinetic studies support the use of high-dose folinic acid even while the ambiguous results from clinical trials seem to imply equivalency between the two regimens (at least in terms of benefit). Toxicity analyses from these studies are also conflicting. Some researchers report varying spectra and higher overall treatment-related toxicities with low-dose folinic acid, while others reach similar conclusions about the high-dose regimens.
Recent Analysis of NSABP Trials
The NSABP recently concluded a comparison of results in patients with Dukes stage B or C colon cancer treated with postoperative adjuvant therapy on NSABP trials (C-01, C-02, C-03,C-04) from 1977 to 1990. The patient populations were remarkably similar, since the eligibility criteria and follow-up requirements were comparable.
Protocol C-01 compared adjuvant MOF (methyl-CCNU, Oncovin, and 5-FU) to operation alone. Protocol C-02 compared the perioperative administration of a portal venous infusion of 5-FU to surgery alone. Protocol C-03 compared adjuvant 5-FU + high-dose folinic acid to adjuvant MOF. Protocol C-04 compared adjuvant 5-FU + high-dose folinic acid to 5-FU + levamisole and to 5-FU + high-dose folinic acid + levamisole. Of the patients included in these four trials, 41% had Dukes stage B tumors.
In all four studies, an overall improvement in disease-free survival and recurrence-free survival improvement was noted for all patients with either Dukes stage B or C disease. When the relative efficacy of chemotherapy was examined within stage, there was always an observed reduction in mortality, recurrence, or disease-free survival from chemotherapy, irrespective of stage. Furthermore, in most cases, the reduction was as great or greater for Dukes stage B patients than for Dukes stage C patients. This was true for each individual trial and also when data from all four trials were examined in a combined analysis (a 31% mortality reduction in Dukes stage B patients occurred irrespective of the presence or absence of adverse prognostic factors).
As alluded to by Peeters and Haller, the nonsignificant, 32% reduction in recurrence (P = .10) in INT 0035 may be explained by the fact that the study did not have sufficient statistical power to detect reductions in recurrence of less than 50%. For this reason, in terms of recurrence, the results of the NSABP cross-study analysis and those of INT 0035 are not discordant.
Likewise, although there was no difference in overall survival in the treatment groups in INT 0035, there was a nonsignificant, 20% reduction in the rate of colon cancerrelated deaths in the group receiving 5-FU + levamisole. It is likely that the lack of an overall survival benefit was due to the relatively high noncancer-related death rate among the Dukes stage B patients.
Even if the predicted absolute 5-year survival advantage is small for Dukes stage B patients, the abbreviated duration of adjuvant therapy (6 months), the emergence of effective oral adjuvant therapies (uracil/tegafur [UFT] + folinic acid [Orzel]), the dire consequences of recurrence, and the lack of correlation with identified adverse prognostic factors lead me to conclude that, at this time, all Dukes stage B patients should be offered adjuvant therapy. In the future, as more reliable predictors of prognosis and relapse become apparent, subsets of Dukes stage B patients may be identified, which will allow us to further refine this recommendation.
Treatment of Early Rectal Cancer
I agree with the authors recommendations concerning the treatment of early rectal cancer. Questions regarding the timing and duration of radiation therapy, the use of preoperative or postoperative radiation therapy, combined-modality therapy with chemotherapy and radiation, and the ability of these manipulations to improve sphincter preservation, local control rate, disease-free survival, and overall survival are far from definitively answered.
The current Dutch (CKVO 95-04) and Scandinavian trials are designed to answer the questions of whether
short-course radiotherapy prior to surgery offers a local control and survival advantage, and whether postoperative 5-FUbased chemotherapy adds additional benefit for patients with Dukes stage B or C disease.[5,6]
In addition, one American randomized trial that is currently accruing patients (NSABP protocol R-03) is comparing preoperative and postoperative combine- modality therapy in this population of patients. (Another American trial was terminated early due to a lack of accrual). The primary end points of R-03 are to determine disease-free survival and overall survival in patients treated with preoperative combined-modality therapy, but important information will also be obtained concerning tumor downstaging, local recurrence rates, sphincter preservation, and primary tumor response rate.
A preliminary report of this study indicates that sphincter-sparing rates may be lower than expected. At present, this study is also accruing patients slowly, and steps are being taken to encourage a larger accrual and to expand the population sampled. Until the results of R-03 are available, it is safe to say that the roles of preoperative or postoperative combined-modality therapy will remain uncertain.
The article by Peeters and Haller represents a thorough, yet concise review of the treatment of patients with early colon and rectal cancers. The authors offer treatment recommendations based on the results of current clinical trials that are widely accepted as credible. They also briefly review the possible roles of new treatment modalities and chemotherapeutic agents that will likely be available shortly as part of the routine treatment armamentarium.
Their treatment of these complex data is balanced and well-founded. With the exception of an admittedly debatable disagreement about the treatment of Dukes stage B colon cancer patients, I found this review to be useful and timely.
It is important to remember that, in the absence of randomized trials, clinical experience is all that treating physicians have to rely on to determine the best treatments for their patients. Peeters and Haller do an admirable job of interpreting pertinent clinical trials to the full extent possible, arriving at judicious conclusions (and acknowledging the limitations of those conclusions), and then using these conclusions to make practical recommendations for treatment.