The importance of tamoxifen to a cisplatin-containing regimen in the treatment of metastatic melanoma

Abstract

The combination of dacarbazine (DTIC, 220 mg/m2) and cisplatin (DDP, 25 mg/m2) IV daily for 3 days every 3 weeks, carmustine (BCNU, 150 mg/m2) IV every 6 weeks, and tamoxifen (TAM, 10 mg orally twice daily) produced a 50% objective response rate in patients with metastatic melanoma. Associated with this treatment, there was a high incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE). In an effort to reduce this toxicity, this regimen minus TAM was studied, and the results are reported. Twenty of twenty patients are evaluable for response and toxicity. There was one complete response (CR) lasting 5+ months and one partial response (PR) lasting 4+ months for an overall response rate of 10% (95% confidence limits, 1.23% to 31.70%). Two patients exhibited a mixed response and three patients developed disease stabilization lasting 4 to 10 months. Toxicity was similar to the original study except that no patients developed DVT or PE. This statistically significant (Fisher's exact test [two-tail] P = 0.008) decrease in the response rate by comparison with that achieved with the TAM-containing regimen may signal an essential role of TAM in this regimen. TAM may be acting in synergy with cisplatin through its calcium channel-blocking properties. TAM should be included as described in the initial reports, and the patients should be carefully observed for vascular complications.

Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis

“…So, on principle, the synergistic effect observed here could be dependent on modulation of P-gp activity. However, TAM was previously probed in vitro and in vivo (Hofmann et al, 1988;McClay et al, 1989;Scambia et al, 1992) as a synergistic agent for cisplatin, which induces a P-gp-independent resistance. Furthermore, our previous reports showed that, in contrast to other antioestrogens, such as ICI 182, 780, TAM was unable under our culture conditions to revert the MDR phenotype classically in terms of modulation of P-gp protein, MDR-1 mRNA expression or efflux activity as measured by rhodamine 123-based assay (De Vincenzo et al, 1996).…”

“…This combination was chosen on the basis of previous reports indicating that TAM can mediate a synergistic effect with cisplatin (McClay et al, 1989;Scambia et al, 1992), doxorubicin (Leonessa et al, 1994) and vinblastine (Trump et al, 1992) in oestrogen receptor (ER)-negative cell lines. Our results showed that this synergism occurred in the ER-negative MCF-7 ADRr, CEMVBLr and MDA-MB 231 cell lines, since a consistent increase in docetaxel activity was found in association with TAM, thereby suggesting a possible new approach for improving the therapeutic validity of the taxane family of anti-tumour drugs.…”

Tamoxifen delays the development of resistance to cisplatin in human melanoma and ovarian cancer cell lines

“…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).…”

“…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).…”

State of the science 60th anniversary review

“…124 This was just 1 harbinger of many failures of combination chemotherapy to demonstrate a clear advantage over DTIC alone. The widely used 4-drug ''Dartmouth regimen'' (DTIC, cisplatin, carmustine, and tamoxifen) 125 was prospectively compared with DTIC alone in a cooperative group study. Although the combination regimen had a slightly higher response rate (18.5% vs 10.2% for DTIC alone), overall survival was not impacted.…”