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Combination Therapy with Temozolomide and Thalidomide May Increase Survival in Advanced-Stage Metastatic Melanoma Patients

The combination of temozolomide and thalidomide administered orally on a low-dose daily schedule has significant clinical activity in patients with advanced-stage metastatic melanoma, say researchers.

Advanced-stage metastatic melanoma is associated with a poor prognosis, with no improvement in overall survival associated with current treatment options. Two orally bioavailable agents, temozolomide and thalidomide, offer favourable side effect profiles and anti-tumour activity that hypothetically may be enhanced when the drugs are combined.

To investigate the efficacy and safety of such a treatment combination, Wen-Jen Hwu, MD, PhD, and colleagues of Memorial Sloan-Kettering Cancer Centre in New York, United States, performed an open label, phase II study of 38 patients with metastatic melanoma without brain metastases.

Patients with histologically confirmed stage IV or IIIc metastatic melanoma were enrolled in the study. All patients received concomitant doses of temozolomide (75 mg/m²/day) and thalidomide (200 mg/day with dose escalation to 400 mg/day for patients < 70 years old or 100 mg/day with dose escalation to 250 mg/day for patients >/= 70 years old).

Treatment was continued in 6-week cycles (after which temoxolomide treatment was interrupted for 2 weeks) until disease progression occurred or unacceptable toxicity levels were reached. The primary efficacy endpoint was complete (CR) or partial (PR) tumour response.

Intent-to-treat analysis showed that 12 (32%) patients had an objective tumour response, including 11 patients with a PR and 1 patient with a CR continuing past 25 months. Of the patients achieving PR, 5 with a greater than 90% disease reduction were converted to a CR with surgery.

Overall, 9 patients survived to a median follow up of 24.3 months. Median survival for responders was 24.1 months from time of first response, and median survival for non-responders 4.1 months.

Brain metastases developed in 9 patients after a median follow up of 24.3 months, leading the researchers to hypothesize that the combination regimen might function to reduce central nervous system progression.

Treatment was generally well tolerated. Lymphopaenia and leukopaenia were the primary haematologic adverse effects. Non-haematologic adverse effects included rash, constipation, vomiting, dizziness, dyspnoea, fatigue, nausea, headache, and infection, most of which were manageable. A total of 14 patients discontinued therapy due to adverse effects or other complications.

"The combination of temozolomide plus thalidomide appears to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study," the investigators conclude.





J Clin Oncol 2003 Sep 1;21:17:3351-6. "Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic Melanoma"

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