The Combination of Vinorelbine and Tamoxifen is Active in Malignant Melanoma
ABSTRACT & COMMENTARY
Synopsis: Vinorelbine 30 mg/m2 weekly for 13 weeks then every other week combined with tamoxifen 10 mg twice a day achieved a response rate of 20% in patients with malignant melanoma.
Source: Feun LG, et al. Cancer 2000;88:584-588.
Feun and colleagues from the sylvester comprehensive Cancer Center in Miami enrolled 31 patients in a trial of malignant melanoma. Eligible patients may have had one prior chemotherapy regimen. Their Karnofsky performance status was greater than 70%. Controlled central nervous system metastases were allowed. Tamoxifen was administered at 10 mg orally twice a day. The vinorelbine was started at 30 mg/m2 over 6-10 minutes weekly for 13 doses and then continued at the same dose but given every other week.
There were six partial and no complete responses for a response rate of 20%. These responses lasted for two, four, nine, 12, 14, and 20 or more months. There were three patients with stable disease lasting up to 12 months. As might be expected, toxicity was mild and acceptable. Only eight patients had received prior chemotherapy but 16 of the 31 patients had received prior biologic therapy.
COMMENT BY KENNETH W. KOTZ, MD
Vinorelbine was selected by the authors for evaluation in malignant melanoma because of a promising response noted in a patient on a phase I study,1 as well as the known activity of other vinca alkaloids including vincristine, vinblastine, and vindesine. Vinorelbine has also been demonstrated to have antiproliferative effects against melanoma cell lines.2 When combined with paclitaxel, a single study showed vinorelbine is active in patients with metastatic malignant melanoma.3 Other clinical trials of the use of vinorelbine in patients with metastatic melanoma have not been reported.
The role of tamoxifen in patients with melanoma is undetermined even though there is preclinical and clinical evidence to support a synergistic effect with chemotherapy.4 Much of the excitement for its use was generated by a randomized study from the Italian Oncology Group. Published in 1992, the addition of 20 mg/m2 of tamoxifen to dacarbazine increased the response rate from 12% to 28%, and more impressively, the survival from 29 to 48 weeks.5
However, more recent randomized studies have cast doubt on the role of tamoxifen in malignant melanoma. For example, a Canadian, randomized, double-blind, placebo-controlled study of the "Dartmouth Regimen" (BCNU, cisplatin, and dacarbazine) with or without tamoxifen showed no improvement in either the response rate or survival.6 This was confirmed by a Mayo Clinic study.7 In addition, the Eastern Cooperative Oncology Group performed a four-arm study of: 1) dacarbazine alone; 2) dacarbazine with interferon; 3) dacarbazine with tamoxifen; or 4) dacarbazine with both interferon and tamoxifen. The power of the study was increased by its 2 × 2 factorial design. Neither survival nor time to treatment failure was improved by the addition of tamoxifen.8
It is reasonable to add vinorelbine to the list of drugs with palliative activity in malignant melanoma. Although the study by Feun et al had no complete responses, the response rate of 20% is similar to what has been reported with other chemotherapy drugs. While palliative chemotherapy will always have an important role in melanoma, it is hoped that alternative strategies such as vaccines or biologic approaches will offer patients with melanoma a better opportunity for significant, long-term disease-free survival.
References
1. Donehower L, et al. Proc Am Soc Clin Oncol 1992;1:111.
2. Photiou A, et al. J Cancer Res Clin Oncol 1992;118:249-254.
3. Retsas S, et al. Anticancer Drugs 1996;7:161-165.
4. Toma S, et al. Int J Oncol 1999;15:321-327.
5. Cocconi G, et al. N Engl J Med 1992;327:516-523.
6. Rusthoven J, et al. J Clin Oncol 1996;14:2083-2090.
7. Creagan E, et al. J Clin Oncol 1999;17:1884-1890.
8. Falkson C, et al. J Clin Oncol 1998;16:1743-1751.
Which of the following is true?
a. CNS metastases responded to the combination of vinorelbine and tamoxifen 20% of the time.
b. In the study by Feun et al, the addition of tamoxifen to vinorelbine was critical for a response.
c. Vinorelbine is the only vinca alkaloid that has shown activity in malignant melanoma.
d. The combination of vinorelbine and tamoxifen has a response rate of 20% in melanoma.
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