There is a rising incidence of malignant melanoma world-wide and, despite major improvements in i t s early diagnosis and treatment, the 10-year death rate remains at 20-25%. Evidence that the immune system has a role in the control of melanoma growth has encouraged immunological intervention. The results of phase II trials of recombinant interferon alfa-2a in advanced melanoma justified further studies. A review of trials of various interferons used as sole agents showed an overall objective response rate of 16.3%, one-third of the responses being complete responses of long duration. The use of cimetidine together with recombinant interferon alfa-2a remains controversial. Trials of both beta-and gamma-interferons are incomplete and information on their effect in advanced melanoma is not yet available. Recombinant interferon alfa-2a in combination with chemotherapy is now being used in trials and the early results are encouraging. In a combined series from Brisbane and Newcastle, Australia involving 44 patients treated with recombinant interferon alfa-2a and DTIC, 13 objective responses including 6 complete responses have been obtained. These response rates compare favourably with those of earlier trials using interferon alone. Further work is necessary t o determine the best combined dosage and method of administration for optimum immunobiological effect.
Advanced malignant melanoma, unsuitable for surgical treatment, shows a poor response to both chemotherapy and immunotherapy (Terry, 1980). Analysis of the published results of trials showed a maximum response rate of 28% for treatment with single agents, and 40% for combined therapies (Table I). The median survival of patients with metastatic disease (including regional disease) is 12 months. It was, therefore, decided that the effect of recombinant interferon alfa-2a (IFN alfa-2a) on this disease should be evaluated.
Recombinant IFN alfa-2a has been shown to be active in the treatment of advanced malignant melanoma in a number of clinical trials, which commenced in 1982 and have now been completed (McLeod, 1987). The 6 trials analysed used various dosages and frequencies of administration of recombinant IFN alfa-2a, and gave response rates of 10-22.6% (Table I). Those in which higher dosages were used required more frequent dose reduction due to toxicity but, overall, patient acceptance of the treatment and maintenance of quality of life were good. The overall objective response rate was 16.3% (Table I), a rate apparently comparable to that for the chemotherapeutic agents used in melanoma.
Studies in which cimetidine was added to an IFN regimen differed in their results. Flodgren et al. (1983, 1985) reported good response rates with human alpha-IFN (Le) in combination with cimetidine; 5 of 8 patients with metastatic skin lesions responded after an initial failure to respond with IFN alone. Creagan er al. (1985) found response rates to recombinant IFN alfa-2a in combination with cimetidine to be no better than with recombinant IFN alfa-2a as sole therapy. Trials with recombinant IFN alfa-2b and cimetidine also failed to show enhancement of activity (Ernstoff et al., 1984; Lipton et al., 1984).
The study to be reported here involved combined DTIC and recombinant IFN alfa-2a therapy. This was chosen because the toxic effects of DTIC are mainly gastrointestinal and haematological, whereas those of recombinant IFN alfa-2a are mainly constitutional with some haematological effects at high dosages. It was hoped that the combination could be administered without an excessive increase in toxic effects.
PATIENTS AND METHODS
Patients eligible for inclusion in this open-ended prospective study were males and females, aged 18-75 years, with confirmed metastatic melanoma which was measurable and evaluable but not suitable for surgery or irradiation. Patients were ineligible if there was evidence of cerebral metastases or of other cancers, or if there had been serious infection, the use of cytotoxics, radiotherapy to a marker lesion or surgery in the previous 28 days. Other factors causing exclusion were pregnancy, prior IFN therapy, cardiac failure or myocardial infarction in the past 6 months and current therapy with steroids or non-steroidal anti-inflammatory agents.