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Conrad Notes
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N. Wolmark, MD, University of Pittsburgh, Penn and coinvestigators found added alpha interferon (INF) did not improve the efficacy of 5-fluorouracil (5-FU)/leucovorin (LV). This well-controlled clinical trial included over 2000 advanced CRC patients. INF increased toxicity and decreased compliance with 5-FU/FV therapy. Survival curves at 4 years' follow-up were virtually identical. The results require reexamination of the rationale for adding INF to 5-FU reginens.
Rationale for megatrial INF significantly decreased the breakdown of 5-FU in blood mononuclear cells of patients with gastrointestinal (GI) adenocarcinoma (J Natl Cancer Inst 1992;84:1820). A pilot study in 31 patients with metastatic GI adenocarcinoma showed comedication with INF increased 5-FU toxicity and decreased 5-FU clearance. Reported toxicity included mucositis, diarrhea and thrombocytopenia (J Clin Oncol 1991;9:1811).

Comparative Phase II studies, published during 1989-1991, did not give a definitive answer on the contribution of IFN in patients treated with 5-FU for advanced CRC (J Clin Oncol 1989;7:1769; Cancer 1990;66:2470; and J Clin Oncol 1991;9:1806). Prolonged overall and disease-free survival by 5-FU/LV treatment of CRC, reported in Clin Oncol 1993;11: 1879, prompted evaluation of added INF as a means of increasing efficacy.

Study CO5 protocol Patients with Dukes' B and C carcinoma of the colon entered to receive 5-FU/FV alone (control) or with added INF (test). Both arms consisted of six 28-day cycles:
  • Control = 5-FU as 370 mg/msq x 5 days
                    LV as 500 mg/msq x 5 days
  • Test = same as control plus INF given on day before
               and after as 80 giga units/msq totaling 7 days
Between October 1991 and February 1994, some 2176 CRC patients entered this trial. There were 2129 evaluable patients on study for an average of 54 months. Treatment toxicity led to discontinuation in 22% test and 6% control patients. Twenty individuals could not tolerate INF and were not enrolled. Six cycles of assigned therapy were completed by 77% test and 88% control patients.
Results on 2129 evaluable patients Wolmark reported nearly identical distributions in both groups for age, gender, Dukes' classification, and treatment-related deaths. Survival curves for both arms were virtually superimposable covering 4 years' follow-up. Overall and disease-free survival rates were:
Survival 5-FU/LV(%) Plus INF(%)
Overall 80 81
Disease-free 69 70
The relative risk (RR) calculations were similar from data on patients who actually started assigned treatment or using the amount of 5-FU/LV taken. Decreased consumption of 5-FU/LV by patients comedicated with INF did not account for the responses seen in the test group, according to Wolmark.
Remarks of invited discussant C. Erlichman, MD, Mayo Clinic, Rochester, Minn, found the negative results answered the original question: Does INF add anything to 5-FU/LV efficacy in CRC? The Phase III protocol did not require dose adjustment of 5-FU in the control arm because of drug toxicity from accumulation. More research is needed to evaluate modulation of 5-FU catabolism by INF as a method for increasing efficacy.

Eugene A. Conrad

Presented at the American Society of Clinical Oncology (ASCO) Meeting, May 16-19, 1998
Copyright © 1998 Conrad Group Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / June 1998
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