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Randomized trial of recombinant alpha 2b-interferon with or without indomethacin in patients with metastatic
R L Miller1, R G Steis, J W Clark
1Division of Cancer Treatment, Frederick Cancer Research Facility, Maryland 21701.
Abstract:
alpha-Interferon has antitumor activity in a variety of malignancies but is frequently associated with unacceptable toxic side-effects. The routine use of agents potentially capable of reducing these side-effects has not been recommended out of concern for possible reductions in the therapeutic activity of interferon. We conducted a prospective randomized trial of alpha-interferon given with or without indomethacin to patients with malignant melanoma to determine what effect, if any, indomethacin might have on the toxic, immunomodulatory, and therapeutic properties of interferon in this disease. 53 patients were stratified according to performance status and randomized to receive alpha 2b-interferon, 20 million units per m2 i.v., 5 days per week for 4 weeks followed by 10 million units per m2 s.c. three times per week, either with or without indomethacin, 25 mg orally three times a day. The overall major response rate was 13% (three complete responders and three partial responders among 47 evaluable patients) and was the same on both arms. The mean maximal temperature elevation induced by interferon was significantly reduced (from 102.1 to 100.7, P = 0.0002) by indomethacin, but the incidence and severity of interferon-related fatigue, reduction in performance status, headache, depression, confusion, elevations in liver function tests, and myelosuppression were no different in either arm of the study. Indomethacin did not reduce the frequency of dose reductions for toxic side-effects and did not permit the administration of higher interferon doses. Peripheral blood natural killer activity was significantly enhanced in patients during maintenance therapy whether or not they received indomethacin. Indomethacin appeared to inhibit augmentation of natural killer activity during high dose induction therapy. Immunological changes did not correlate with response status. We conclude that indomethacin can reduce the fever associated with interferon therapy in patients with malignant melanoma without interfering with its therapeutic or chronic immunomodulatory activities. Since fever is rarely the dose-limiting toxicity of interferon, indomethacin is of marginal benefit to patients with malignant melanoma receiving interferon at the doses outlined in this study.
Insights
Adding indomethacin to alpha-interferon therapy for malignant melanoma reduced fever but did not improve therapeutic response or other toxicities. This combination therapy showed marginal benefit in managing side effects for melanoma patients.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Alpha-interferon exhibits antitumor activity but causes significant toxic side effects.
- Concerns exist that agents reducing side effects might compromise interferon's therapeutic efficacy.
- Malignant melanoma treatment often involves interferon, necessitating strategies to manage its toxicity.
Purpose of the Study:
- To evaluate the effect of indomethacin on the toxicity, immunomodulatory properties, and therapeutic activity of alpha-interferon in malignant melanoma patients.
- To determine if indomethacin can mitigate interferon-induced side effects without compromising treatment outcomes.
Main Methods:
- A prospective randomized trial involving 53 malignant melanoma patients.
- Patients received alpha 2b-interferon with or without indomethacin.
- Interferon dosage: 20 million units/m2 i.v. for 4 weeks, then 10 million units/m2 s.c. thrice weekly; indomethacin: 25 mg orally thrice daily.
Main Results:
- The overall major response rate was 13% and was similar in both treatment arms.
- Indomethacin significantly reduced interferon-induced fever but did not alter other toxicities (fatigue, confusion, liver function, myelosuppression).
- Natural killer cell activity was enhanced during maintenance therapy, but indomethacin appeared to inhibit this during induction.
Conclusions:
- Indomethacin reduces fever associated with interferon therapy in malignant melanoma patients.
- Indomethacin does not interfere with the therapeutic or chronic immunomodulatory effects of interferon.
- Given that fever is rarely dose-limiting, indomethacin offers marginal benefit in this specific interferon regimen for malignant melanoma.