Adjuvant Intraperitoneal 5-Fluoruracil May Reduce Recurrence for Stage II Colon Cancer
ABSTRACT & COMMENTARY
Synopsis: A French multicenter trial of short-term intraperitoneal 5-FU after resection of stage II or III colon cancer demonstrated low toxicity and long-term advantages for certain subgroups (particularly those with stage II disease at diagnosis). The findings raise the question of the value of this approach in an era in which longer term, systemic therapy has become standard of care.
Source: Vaillant J.C, et al. Ann Surg 2000;231:449-456.
The objective of this study was to evaluate in a prospective, randomized, multicenter clinical trial, the benefits of immediate adjuvant 5 Fluorouracil (5-FU) administered intraperitoneally shortly after resection of stages II and III colon cancers. The study, performed at several French sites, included 267 patients randomized into two groups. Group 1 patients (n = 133) underwent resection followed by intraperitoneal administration of 5-FU (0.6 g/m2/d) for six days (day 4 to day 10). These patients also received an initial intraoperative dose of 5-FU intravenously (1 g). Group 2 patients (n = 134) underwent resection alone.
There was no statistical difference in pathological stage, or operative morbidity or mortality between the two groups. Toxicity of chemotherapy was slight, with only 3% having treatment discontinued due to drug effect. Of the 133 group 1 patients, 103 received the planned total dose. The majority of those who failed to complete the treatment did so because of catheter-related technical problems.
After a median follow-up of 58 months, five-year overall survival was 74% in group 1 (treatment) and 69% in group 2 (control). The survival curves were nearly identical until year 3, but began to diverge thereafter. For those who did develop recurrence in the liver, the mean time to relapse was 21 months for group 1 and 11 months for group 2. This delay in recurrence was also noticed for those who relapsed with lung metastases (42 mos. vs 19mos.) but not for those who relapsed locally (15 mos. vs 17 mos.) or in the peritoneum (13.5 mos. vs 14 mos).
Analysis by stage revealed a significant survival advantage for treated (group 1) patients who were stage II, but no survival benefit of therapy for Stage III patients. Thus, Vaillant and associates conclude that intraperitoneal 5-FU administered during a short period after surgery was well tolerated and reduced the risk of recurrence for Stage II patients. They suggested that this approach, coupled with systemic chemotherapy, might further reduce both local and distant recurrences in patients with resected colon cancers.
COMMENT by WILLIAM B. ERSHLER, MD
These days, adjuvant systemic chemotherapy is considered standard care for patients with Stage II or III colon cancer.1 Local, or regional therapy, although previously tested, had not proven to offer additional benefit.2 The publication of this trial might change this thinking somewhat. The study is unusual in that it contained a no-treatment arm, which of course was fully justified at the time of initiation before which there was no proven benefit to adjuvant systemic chemotherapy for colon cancer. In fact, Vaillant et al are to be commended for terminating the trial early once it became clear that enrolled patients (particularly in the control arm) were being denied systemic adjuvant therapy. Thus, the trial is somewhat smaller than planned, and the modest findings might have been more apparent with larger numbers.
Nonetheless, the demonstration of a response to short-term adjuvant therapy apparent five years later further supports the rationale for early chemotherapy. Current, more intensive systemic approaches show a clear benefit in both disease-free survival and overall survival for stage III patients. In this light, it is interesting to speculate that the immediate intraperitoneal approach might be more specifically useful for those with smaller primary tumors, without nodal metastases. Perhaps those with fewer residual malignant cells will have demonstrable efficacy with a short-term course of therapy. And, using similar logic, those with more residual disease, such as expected with those with stage III lesions, are unlikely to have demonstrable benefit with limited chemotherapy.
Thus, the actual benefit of an intraperitoneal approach was not established with this study. It might have been had there been a control group receiving short-term systemic therapy. Accordingly, such an approach (short-term, intraperitoneal chemotherapy) can not be recommended as sufficient postoperative therapy for colon cancer (of any stage). However, the findings are of sufficient interest that it would seem a good idea to follow up with a second multicenter trial comparing short-term, postoperative intraperitoneal chemotherapy plus a full course (one half year) of systemic therapy vs. the full course of systemic therapy alone.
References
1. Moertel CG, et al. N Engl J Med 1990;322:358.
2. Sugarbaker PH, et al. Sem Oncol 1989;16(Suppl 6):83.
Which of the following statements about adjuvant chemotherapy for colon cancer is true?
a. Using an intraperitoneal approach immediately after surgery was shown to be superior to systemic therapy for patients with stage II disease.
b. Using an intraperitoneal approach immediately after surgery was shown to be superior to systemic therapy for patients with stage III disease.
c. Using an intraperitoneal approach immediately after surgery was shown to be superior to no therapy for patients with stage II disease.
d. Using an intraperitoneal approach immediately after surgery was shown to be superior to no therapy for patients with stage II and III disease. ::::
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