While TAM as a single agent is minimally active in treating patients with metastatic melanoma, when it is combined with DTIC, BCNU, and DDP, a marked improvement in the overall response rate is observed. Although a prospective randomized trial has yet to be completed, it appears that this four-drug combination has a higher overall and complete response (CR) rate when compared with single-agent DTIC. In light of the relatively modest toxicity observed with this regimen, the combination of DBDT represents a reasonable alternative to single-agent DTIC as first-line therapy for patients with metastatic melanoma.

The adjuvant treatment of high-risk malignant melanoma remains problematic. Previously we reported moderate success in the treatment of metastatic disease using tamoxifen, cisplatin, dacarbazine and carmustine. Based upon data that suggested tamoxifen and cisplatin were the active agents in this regimen, we initiated a phase II trial of this combination in the adjuvant setting. We treated 153 patients with 4 cycles of tamoxifen (160 mg day–1, days 1–7) and cisplatin (100 mg m–2, day 2) for 28-day intervals. Patients received an anti-nausea regimen of dexamethasone with ondansetron or granisetron. During the first 2 years of follow-up, patients were evaluated every 2 months with a history, physical exam, laboratory work and computed tomography scans of the chest, abdomen and pelvis every 4 months. Thereafter, patients were evaluated every 3 months and radiographic studies were performed if necessary. Currently, with a median follow-up of 36 months, the disease-free survival (DFS) is 68.4% and overall survival (OS) is 84.5%. Kaplan–Meier analysis predicts a 5-year DFS of 62% with an OS of 79%. Relapses after 20 months have been rare. No effect of gender or number of positive lymph nodes was noted, however, stage of disease prior treatment was a factor. The major toxicity proved to be gastrointestinal in nature with nausea the most prevalent symptom. Minimal renal, haematologic and neurologic toxicity occurred. These preliminary results suggest that there is a positive impact of tamoxifen and cisplatin on both the DFS and OS of high-risk malignant melanoma patients. The 5-year projected DFS and OS compare favourably with those reported for the ECOG 1684 trial and warrant confirmation in a prospective randomized trial. © 2000 Cancer Research Campaign

We have previously demonstrated that the combination of tamoxifen and cisplatin has activity in patients with metastatic melanoma. In vitro studies have demonstrated that tamoxifen and cisplatin exhibit cytotoxic synergy in human melanoma cells and that this interaction is dependent on a tamoxifen effect. The mechanism of this effect is currently under investigation in in vitro studies. In an attempt to improve the complete response rate of this regimen, we initiated a phase II trial to determine the effect of the use of high dose tamoxifen and weekly cisplatin on the complete response rate, disease-free survival and overall survival. Tamoxifen was started on day 1 initially at a dose of 240 mg/day and continued until the patient was taken off treatment. This dose was subsequently lowered to 200 mg/day. Cisplatin (80 mg/m2) was begun on day 2 and repeated weekly for a total of 3 weeks. During week 4, the patient was not treated with cisplatin but was evaluated for response. If disease stabilization or regression was documented, the patient received a second 3 week cycle of cisplatin and was then re-evaluated for response. Patients with progressive disease at any evaluation were removed from the study. In 28 consecutive patients, the overall response rate was 32% (95% confidence interval 15.88-52.35%). One patient achieved a complete remission that lasted 22 months. All other responses were partial in nature. Toxicity was primarily nausea and vomiting. Two patients developed grade 2 renal toxicity. There were no episodes of deep venous thrombosis. This phase II study demonstrates that this combination has modest activity in patients with metastatic melanoma. However, this study failed to confirm our hypothesis that high dose tamoxifen would increase the complete response rate of this combination. While this combination has activity, the overall response rate is not significantly better that that observed with the original Dartmouth regimen and the toxicity is substantial. We do not recommend this dose and schedule for routine clinical use.

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Background. Although somewhat controversial, there are data to suggest that patients with ovarian cancer may experience a survival advantage if the dose intensity of platinum‐containing regimens can be maximized. Administration of chemotherapeutic agents via the intraperitoneal route offers the opportunity to increase dose intensity of several chemotherapeutic agents. Methods. The authors conducted a Phase I trial of intraperitoneal carboplatin and etoposide in combination with granulocyte macrophage colony stimulating factor (GM‐CSF) in an attempt to determine the maximum tolerated dose of carboplatin. The starting dose for carboplatin was 300 mg/m2 and for etoposide 400 mg/m2. The dose of carboplatin was escalated while the etoposide was maintained at the initial dose. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one‐third of the total dose. On day 1 of therapy, onethird of the dose was mixed in 2 liters of dextrose (D5 W) and administered intraperitoneally (IP) as rapidly as possible. On Days 2 and 3, one‐third of the dose was mixed in 1 liter of D5 W and administered similarly. GM‐CSF was begun on Day 4 as a subcutaneous injection at a dose of 500 mg/m2/d. Results Unacceptable hematologic toxicity was encountered at a carboplatin dose of 800 mg/m2; therefore, a carboplatin dose of 600 mg/m2 is recommended for Phase II studies. An overall response rate of 54% with a complete response rate of 17% was observed in patients with ovarian cancer. The overall response rate for all patients was 45%. Conclusion. Because of the significant toxicity encountered in this study, it is recommended that this regimen be used only in the context of a clinical study. The recommended Phase II study dose for this combination is carboplatin 600 mg/M2 and a total dose of etoposide 400 mg/M2 total dose given as three equal parts IP over 3 days. GM‐CSF should begin on Day 4 at a dose of 500 mg/m2/day subcutaneously and should continue until the absolute neutrophil count is greater than 1000 granulocytes on 3 successive days. Cancer 1994; 74: 664‐9