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Summary The development of resistance to cisplatin (DDP) occurs rapidly both in vitro and in vivo, and constitutes a major obstacle to effective therapy. We have previously demonstrated that there is a highly synergistic interaction between tamoxifen (TAM) and DDP against cell lines representative of three different human cancers: melanoma, ovarian carcinoma and small-cell lung cancer. The purpose of these studies was to determine if TAM interferes with the development of resistance to DDP. T-289 Our previous clinical studies have demonstrated that tamoxifen (TAM) is an important component of a four-drug combination of dacarbazine, carmustine, DDP and TAM in the treatment of patients with metastatic melanoma (McClay et al., 1987). Omission of TAM from the regimen resulted in a decrease in the overall response rate from 51% to 10% (McClay et al., 1989). Reincorporation of TAM into the regimen resulted in a return of the response rate to more than 50% (McClay et al., 1992a). In a recent clinical study we demonstrated that, in patients with malignant melanoma documented to be resistant to single-agent DDP, the addition of TAM to the DDP programme on the next cycle resulted in a response rate of 30% (McClay et al., 1993a al., 1992b, 1993b). However, the DDP/TAM synergy was dependent on the sensitivity of the cell to TAM. DDP and TAM were still synergistic with respect to cytotoxicity in a DDP-resistant variant of the T-289 melanoma cell line, however they were not synergistic in killing a variant of the same cell line selected for resistance to TAM (McClay et al., 1993b). Synergy was also absent in another melanoma cell line that was 4-fold resistant to TAM (McClay et al., 1992b). (McClay et al., 1993c).Although the mechanism of synergy between TAM and DDP is not known at present, we hypothesised that if TAM can synergise with DDP to overcome DDP resistance then TAM may also be able to delay the development of DDP resistance by a similar mechanism. We report here that TAM can delay the development of DDP resistance in both T-289 and 2008 cells when given concurrently with DDP in cell culture.

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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