Tamoxifen modulation of cisplatin resistance in patients with metastatic melanoma : a biologically important observation

Background. Treatment with the four-drug combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and tamoxifen (TAM) has resulted in an overall response rate of more than 50% in patients with metastatic melanoma. Deletion of TAM from the regimen resulted in a decrease in the response rate to 10%, suggesting an important role for TAM. The authors have subsequently demonstrated that TAM is highly synergistic with DDP in a human melanoma cell line, T-289, which supports the clinical observation that TAM is important in this regimen. The authors conducted a clinical trial to determine whether the addition of TAM can overcome established DDP resistance in patients with malignant melanoma. Methods. Patients with metastatic melanoma were initially treated with DDP 100 mg/m2 alone until they demonstrated DDP resistance. On the next cycle of treatment, patients received TAM 40 mg by mouth four times a day on the day before DDP treatment followed by 20 mg by mouth daily for the rest of the 3-week cycle plus the same dose of DDP. Results. Among 24 patients treated with DDP alone there were one complete and two partial responses. Twenty patients, in whom single-agent DDP failed, were treated with the combination of TAM and DDP. Of these 20 patients, 19 were evaluable for response. Among these 19 patients, there were three partial responses (16%) and three mixed responses (16%), for an overall response rate of 32% (0% was expected) (P < 0.001). If the three mixed responses are eliminated, the statistical significance is of borderline significance (P = 0.058). Conclusions. The addition of TAM to DDP can overcome established DDP resistance in a subset of patients with metastatic melanoma.