Interferon-a Adds Toxicity Without Improving the Treatment Outcome of 5- Fluorou
Interferon-a Adds Toxicity Without Improving the Treatment Outcome of 5- Fluorouracil and Leucovorin Adjuvant Therapy
Abstract & Commentary
Synopsis: Strong scientific rationale and phase II clinical trial results suggest that interferon-a is capable of improving the antitumor effects of 5-fluorouracil and leucovorin in the setting of metastatic colorectal cancer. National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-05 compared 5-fluorouracil plus leucovorin with or without interferon as adjuvant therapy for patients with Dukes’ stage B or C colon cancer. No significant improvement in disease-free or overall survival was noted but the addition of interferon increased the toxicity of the therapy.
Source: Wolmark N, et al. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol C-05. J Natl Cancer Inst 1998; 90:1810-1816.
The potential mechanisms for interferon to augment the antitumor effects of 5-fluorouracil are numerous. Interferon prevents the upregulation of the enzyme that 5-fluorouracil inhibits, namely thymidylate synthase. Cells develop 5-fluorouracil resistance in part by increasing the expression of the target enzyme. Thus, interferon can slow the development of 5-fluorouracil resistance. In addition, 5-fluorouracil is metabolized in part by thymidine phosphorylase and the expression of this enzyme, too, is inhibited by interferon. Pharmacokinetic studies have shown that interferon can decrease 5-fluorouracil clearance in vivo in patients with colon cancer.
Clinical experience with interferon plus 5-fluorouracil has produced conflicting results. While Wadler and colleagues1 noted a 76% response rate in a small series of previously untreated patients with metastatic colon cancer, phase II studies in the cooperative group setting documented responses in about 42% of such patients.2 Grem and colleagues put interferon together with both 5-fluorouracil and leucovorin and reported a 54% response rate among 44 assessable patients with metastatic colon cancer.3 Based upon these findings, the National Surgical Adjuvant Breast and Bowel Project (NSABP) undertook a randomized trial comparing 5-fluorouracil plus leucovorin to the same drugs plus interferon in patients surgically rendered free of disease with Dukes’ B or C colon cancer.
More than 2000 patients were randomly assigned to receive one of the following two treatment programs: 5-fluorouracil and leucovorin included six 28-day cycles with leucovorin (500 mg/m2) given as a 30-minute infusion followed by 5-fluorouracil (370 mg/m2) given by bolus one hour after completing leucovorin; these drugs were given daily for 5 days; 5-fluorouracil and leucovorin and interferon included the same dose and schedule of 5-fluorouracil and leucovorin but interferon-a. (5 x 106 U/m2) was given subcutaneously 24 hours before the first dose of chemotherapy, daily just before administration of chemotherapy, and a final dose 24 hours after the day 5 chemotherapy. Results were reported with a median follow-up of 54 months.
The disease-free survival at four years of patients treated without interferon was 69%; for patients treated with interferon, four-year disease-free survival was 70%. Similarly, overall survival at four years was 80% for the group not receiving interferon and 81% for those receiving interferon. By contrast, the group receiving interferon had significantly greater toxicity from the treatment than did those receiving 5-fluorouracil and leucovorin without interferon. Grade 3 or higher diarrhea occurred in 28.8% of patients not receiving interferon and in 43.2% of those receiving interferon. Interferon-related flu-like symptoms were obviously more common in patients receiving interferon and 49% of patients receiving interferon developed fever, compared to 14.5% of patients on the control arm. Hematologic toxicity was less severe on the interferon arm. More patients randomly assigned to interferon stopped treatment and more dose modifications were made on the interferon arm. Thus, no advantage was seen from adding interferon to 5-fluorouracil and leucovorin in the adjuvant treatment of colon cancer.
Commentary
This study deals another blow to those of us hoping that rational combinations of agents will improve treatment outcome. The scientific rationale for adding interferon to 5-fluorouracil and leucovorin is strong. The preclinical data suggest meaningful enhancement of antitumor effects. Even the phase II clinical trials seemed to show better results from the combination of interferon and 5-fluorouracil and leucovorin than would have been expected from 5-fluorouracil and leucovorin. Given these findings, it seemed highly promising that the combination would show significant benefits in the adjuvant setting. Why didn’t it work?
Many possibilities suggest themselves. We do not really know whether the dose and schedule of interferon given on this study were sufficient to influence the expression of the target and metabolizing enzymes. The toxicities of interferon are less tolerable in the adjuvant setting than in the metastatic disease setting. In this study, the patients receiving interferon received considerably less 5-fluorouracil and leucovorin than did patients receiving the 5-fluorouracil and leucovorin regimen. Could a small improvement in outcome have been blurred by the required dose reductions?
Regardless of what happened here, the result is a disappointing one. Given that adjuvant therapy currently benefits only a small fraction of treated patients, it seemed possible that significant improvements in outcome could emerge from rather small improvements in antitumor efficacy. This negative study may serve as an impetus to go back to the laboratory and figure out other methods of delivering the combination of interferon and 5-fluorouracil in a combination that is less toxic and maximizes the enhanced antitumor effects.
References
1. Wadler S, et al. J Clin Oncol 1989;7:1769-1775.
2. Wadler S, et al. J Clin Oncol 1991;9:1806-1810.
3. Grem JL, et al. J Clin Oncol 1991;9:1737-1745.
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