Treatment of advanced colorectal cancer with 5-fluorouracil and interferon-α: An overview of clinical trials

Abstract

5-Fluorouracil (5-FU) is the most active single agent for treatment of advanced colorectal cancer, although objective responses occur in only 20% of patients, and there seems to be no impact on overall survival. Experimental findings suggesting that interferon-α (IFN-α) enhances 5-FU cytotoxicity have stimulated an increasing number of clinical trials to evaluate the therapeutic potential of this combination. This article summarises the possible mechanisms of interaction of 5-FU and IFN-α, and provides an overview of the current status of this approach in advanced colorectal cancer. A computerised (Medline) and manual search were performed to identify all trials using 5-FU and IFN-α for the treatment of advanced colorectal cancer published in the English literature between 1960 and 1994. Information abstracted included treatment regimen, number of patients, pretreatment status, complete and partial remissions, remission duration, overall survival, and toxicity. A total of 417 patients were enrolled in 16 trials using different regimens of 5-FU and IFN-α, and double modulation of 5-FU with leucovorin (LV) and IFN-α was investigated in nine trials involving 332 patients. The mean overall response rate in these phase II trials was only 31% (range 3–76) and 35% (range 0–54), respectively. Early results of six prospectively randomised studies of 5-FU or 5-FU/LV ± IFN-α also did not suggest a significant enhancement of the antitumour effectiveness with the addition of IFN-α. There is increasing evidence, however, that administration of IFN-α along with 5-FU enhances toxicity. Because of their modest therapeutic index, currently employed regimens of 5-FU ± LV plus IFN-α cannot be recommended for routine use at the present time. The combination of 5-FU plus LV represents an equally effective and less expensive alternative. Nevertheless, there is still hope that further attempts to elucidate the complex mechanisms of this potentially synergistic drug combination will allow the rational design of regimens with a superior therapeutic index.