Clinical and pharmacological studies of interferon and chemotherapy in gastrointestinal and breast cancer

The interferons enhance the cytotoxicity of antimetabolites, alkylating agents, and plant antibiotics against cultured human tumours in vitro and in vivo. Five clinical trials in humans with advanced colorectal carcinoma have demonstrated responses ranging from 26 to 63% in patients treated with 5-fluorouracil (5-FU) plus interferon-α (FN-α), suggesting improved response with the combination as compared with 5-FU alone. In addition, responses have been observed in patients with adenocarcinomas of the lung, pancreas, breast, and kidney, squamous cell carcinoma of the oesophagus, and urothelial carcinoma treated with 5-FU/IFN-α. However, enhanced 5-FU-related toxicity was observed in these studies, as has been observed when 5-FU is combined with other modulating agents, such as leucovorin. While some studies suggested that enhanced 5-FU-related toxicity was associated with an IFN-α-induced reduction in 5-FU clearance when 5-FU was given as an intravenous (i.v.) bolus (750mg/m² IV weekly) or as a high-dose five-day continuous infusion (CI) (750mg/m²/day x 5 days), another study found enhanced 5-FU toxicity in the absence of pharmacokinetic perturbation when 5-FU was given as a low-dose prolonged CI (300mg/m²/day x 28 or more days). IFN-α-induced reduction in 5-FU clearance was observed at higher (5-10 x 10⁶ units/m²) but not lower (3 x 10⁶ units/m²) doses of IFN-α in two studies when used concomitantly with 5-FU given as an i.v. bolus, but was also observed at low doses of IFN-α (0.5, 1.0, 3.0 x 10⁶ units/m²) when administered in conjunction with 5-FU given as a high dose five-day CI. Furthermore, the IFN-α-induced reduction in 5-FU clearance is abrogated by the concomitant administration of leucovorin, and conversely leucovorin clearance is also impaired by IFN-α, potentially confounding the interpretation of trials investigating the addition of leucovorin to the 5-FU/IFN-α combination. The interaction between 5-FU and IFN-α, therefore, appears to be quite complex. Further research is required to determine the optimal dose and schedule of 5-FU and IFN-α administration, the biochemical basis for their interaction, the effectiveness of the combination relative to 5-FU used either alone or in combination with other modulating agents, and the potential for combining IFN-α with other cytotoxic agents in the treatment of carcinomas arising at other sites.