Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.

Concurrent biochemotherapy for patients with advanced melanoma is capable of producing high CR and overall response rates and resulted in durable complete remissions in a small fraction of patients. Toxicity, although severe, was manageable in a routine inpatient hospital environment.

This study supports the use of stratification parameters that reflect the favorable prognostic impact of soft tissue or single visceral organ metastases and normal serum levels of LDH and albumin at time of enrollment in advanced melanoma trials. Improved survival over the prior decade probably reflects advances in diagnostic and palliative interventions.

The sequential combination of CVD with IL-2 + IFN-alpha appears to have produced an increase in the number of durable responses in patients with metastatic melanoma. The toxicity of this program, although severe, was manageable. The biochemotherapy regimen produced an apparent increase in the median survival compared to that observed with the CVD regimen. However, a prospective comparison of these two regimens will be required to confirm these observations.

Based on the independent activity of cisplatin, vinblastine, and dimethyl-triazeno-imidazole-carboxamide (DTIC) (CVD), a combination of these agents was used in the treatment of patients with advanced mel-anoma. Vinblastine was used in a dose of 1.6 mg/m2/d for 5 days, DTIC was used in a dose of 800 mg/ m2 intravenously (IV) on day I, and cisplatin was used in a dose of 20 mg/m2/d for 4 days starting on day 2 of chemotherapy. The courses of chemotherapy were repeated at 3-week intervals. All patients were premedicated with antiemetics, and IV hydration was used before cisplatin. Fifty-two consecutive patients were registered and 50 were evaluable for response. Two patients achieved a complete response (CR) and 18 patients had a partial response (PR) for an overall response rate of 40% (95% confidence interval, 27% to 55%). The median duration of response was 9 months and the median survival time of the responders was 12 months. The overall median survival time of patients treated on this protocol was 9 months. The treatment was associated with significant toxicity consisting of nausea, vomiting, diarrhea, and partial hair loss. Additionally, neutropenia with a median nadir granulocyte count of 500/~1 was observed, and significant anemia required blood transfusions in a majority of the patients after three to four courses of chemotherapy. The dose-limiting toxicity was peripheral neuropathy which required dis-continuation of cisplatin after six to eight courses of chemotherapy. We believe that this triple-drug regimen has significant activity that appears to be superior to the single-agent activity of these drugs, both in terms of increased response rate and duration of response.

Taxol is an investigational new drug which is currently undergoing Phase I1 evaluation in various tumors. It is a plant alkaloid extracted from the western Yew, Taxus brevifolia. In this study, patients with metastatic melanoma who were previously untreated, received Taxol at a starting dose of 250 mg/m2 delivered as a continuous intravenous (IV) infusion over 24 hours, at 3-week intervals. All patients were premedicated with oral dexamethasone and IV diphenhydramine hydrochloride as prophylaxis against allergic reactions. Three of 25 patients had a partial response (PR) for a response rate of 12% (CI, 3%-31%). In addition four patients had objective regression of tumor that failed to qualify for a PR but these responses were as durable, lasting 6 to 1 7 months. No patient experienced acute allergic reactions. The major toxicity of Taxol was neutropenia requiring dose reduction to 200 mg/m2 in a majority of the patients. Our data confirm that Taxol has definite although limited activity against metastatic melanoma. Cancer 65:2478-2481,1990.AXOL is a plant alkaloid derived from the needles T and bark of the western Yew, Taxus brevifolia.' It has a unique and complex structure which was delineated by Wani and Associates in 197 1 .' It is a potent inhibitor of cell replication in vitro, blocking the cells in G2/M phase of the cell cycle. In contrast to vinca alkaloids which inhibit the assembly of microtubules, Taxol promotes the polymerization of microtubules in an irreversible fashion.Taxol entered Phase I clinical trials in 1984 and was evaluated by several different dose schedule^.^-^ The doselimiting toxicity was myelosuppression of varying severity over the dosage range of 170 mg/m2 to 275 mg/m2 delivered in single or divided doses. The drug was generally well tolerated except for a significant incidence of hypersensitivity reactions in the form of skin rash, bronchospasm, and anaphylaxis which proved fatal in one in~t a n c e .~ This led to administration of Taxol as a slow infusion from 6 hours to 24 hours which appeared to be associated with a decrease in the frequency of allergic reFrom the University of Texas M. D.

Temozolomide (Temodar) has demonstrated clinical activity against melanoma equivalent to that of intravenous dacarbazine (DTIC). Phase I clinical studies have shown that low dose chronic administration of temozolomide permits the delivery of higher dose intensities than a 5 day dose schedule. Temozolomide is hydrolysed to its active metabolite monomethyltriazenoimidazole carboxamide (MTIC) upon absorption from the gastrointestinal tract, while DTIC is inactive until it is metabolized in the liver to MTIC. In view of this, a higher concentration of MTIC will pass through the liver during the first pass when its source is temozolomide rather than DTIC. To determine if these characteristics of temozolomide will translate into a higher response rate than that achieved with DTIC, we conducted a phase II clinical trial of temozolomide in patients with uveal melanoma metastatic to the liver. Temozolomide was administered orally at a starting dose of 75 mg/m2 per day for 21 days every 4 weeks. Fourteen patients were enrolled in the trial. No complete or partial responses were observed. Stabilization of disease was achieved in two patients. The treatments were well tolerated. We conclude that, like DTIC, temozolomide at the dose and schedule studied in this trial is not effective for the control of metastatic melanoma of uveal origin.

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