High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma

BACKGROUND. In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic a gents. In the current study, the authors examined whether high-dose tamoxif en (HDT) improved the overall and complete response in patients with metast atic melanoma who were treated with concurrent biochemotherapy. METHODS. Forty-nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin-2, interferon -alpha -2b, and tamoxifen. The study had a 2-step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate sa fety and tolerability, followed by Phase II accrual of 32 patients to HDT ( 320 mg) to assess clinical efficacy. Efficacy was compared with a similar m odified biochemotherapy regimen with low-dose tamoxifen (LDT). Pharmacokine tic studies were performed to determine in vivo tamoxifen levels. RESULTS. Tamoxifen dose escalation was completed without any reported dose- limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%-66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with tha t of patients recently treated with concurrent biochemotherapy and LDT. Ser um tamoxifen levels were found to correlate with the dose administered, wit h a mean of 0.9 muM at the 40-mg dose to 4.6 muM at the 320-mg dose. Ultraf iltered protein-free sera demonstrated low (< 0.01 <mu>M) concentrations of tamoxifen. CONCLUSIONS. The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reac hing the targeted plasma concentration. Unknown drug interactions or high p rotein binding of tamoxifen may account for the lack of clinical effectiven ess. Cancer 2001;92: 609-19. (C) 2001 American Cancer Society.