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Abstract & Commentary
Synopsis: Temozolomide and DTIC had similar efficacy in this prospective, randomized study. However, overall treatment results for this patient population remain dismal and discovery of new treatment approaches for patients with metastatic melanoma is greatly needed.
Source: Middleton MR, et al. J Clin Oncol 2000;18: 158-166.
The success of various chemotherapy strategies for patients with metastatic melanoma has been limited. The use of single-agent dacarbazine (DTIC) has been a "standard" treatment, but the modest response rate of 15-20%, with most of the responses being of brief duration, certainly leaves ample room for improvement.1 A recent study from the Eastern Cooperative Oncology Group (ECOG) randomized 258 eligible patients with metastatic melanoma to receive treatment with dacarbazine either alone or combined with tamoxifen, interferon-alpha, or both tamoxifen and interferon-alpha. There was no difference between time-to-treatment failure (median of 2.6 months) or overall survival (median of 8.9 months) between any of the four treatment groups.2 Thus, neither tamoxifen, interferon-alpha, nor the combination of tamoxifen and interferon-alpha were able to improve response rate, time-to-treatment failure, or survival of melanoma patients when these treatments were added to single-agent therapy with dacarbazine. Several additional chemotherapy regimens have been evaluated for patients with metastatic melanoma, but results from these studies have not yet identified a chemotherapy regimen that is clearly better than single-agent dacarbazine. Thus, discovery of new drugs with clinical activity against melanoma is greatly needed.
Temozolomide, like DTIC, is a pro-drug of the active alkylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide (MTIC). However, temozolomide, unlike DTIC, is active following oral administration.3 In addition, temozolomide can penetrate the blood-brain barrier and has shown activity against primary brain tumors.4 Initial phase II evaluation of temozolomide in metastatic melanoma revealed an objective response rate of 21% and a median survival time of 5.5 months.5 Thus, the study by Middleton and colleagues was initiated to compare overall survival of patients with advanced melanoma treated with either temozolomide or DTIC and to compare the safety of these treatments. Middleton et al conclude that temozolomide has efficacy equal to that of DTIC and provides an oral alternative for patients with advanced metastatic melanoma.
COMMENT By Mark R. Albertini, MD
Malignant melanoma remains an increasingly common disease. Recent estimates from the American Cancer Society are that there will be 47,700 new cases of melanoma in the United States in the year 2000.6 Since 7700 deaths due to melanoma are expected to occur this year, this is an important clinical problem. Many of these patients will be young, as the average age at diagnosis of patients with melanoma is approximately 50 years.7 While early melanoma can be a curable disease, the successful treatment of patients with metastatic disease remains elusive. The average survival for patients with metastatic melanoma is about seven months, and the percentage of patients with metastatic melanoma alive at five years is approximately 6%.8 Thus, further improvements in our treatment are critically needed.
The study by Middleton et al demonstrates the comparable activity of temozolomide and DTIC for patients with advanced metastatic melanoma and no CNS involvement. Overall survival and objective response rates were similar in the two treatment groups. Middleton et al describe a significant increase in progression-free survival (PFS) in patients treated with temozolomide (1.9 months) compared with patients treated with DTIC (1.5 months). However, this minimal increase could easily be explained by the difference in timing of disease status assessment for patients, as the DTIC treated patients had assessment for disease progression two weeks earlier than did the temozolomide treated patients. Overall, safety parameters of the treatments were similar, and a slight benefit in quality-of-life parameters assessed by a questionnaire at week 12 was present in the temozolomide group. Thus, the current study supports comparable activity of temozolomide and DTIC for patients with metastatic melanoma. However, overall results for both treatment groups remain poor.
Several nonrandomized, single institution, phase II studies have evaluated Interleukin-2 (IL-2) given together with interferon-alpha and combination chemotherapy for patients with metastatic melanoma. These biochemotherapy regimens have included both inpatient and outpatient regimens, and response rates of 40-60% have been reported.9-11 In addition, up to 10% of these patients have achieved a durable complete response. An intergroup, phase 3, randomized study is now ongoing to compare chemotherapy with dacarbazine, cisplatin, and vinblastine either alone or in combination with IL-2, Interferon-a2b, and G-CSF for patients with metastatic melanoma. The aim of that study is to determine whether immunotherapy adds additional benefit to a chemotherapy regimen for patients with metastatic melanoma.
There remains no standard treatment for patients with metastatic melanoma. Various options including no treatment, surgery, radiation therapy, chemotherapy, immunotherapy, biochemotherapy, and an increasing number of experimental options may be appropriate considerations for an individual patient. Given the limited results from "standard" treatments, participation in a well-designed clinical trial remains a valuable option for patients with this disease.
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a. Antitumor activity is similar to DTIC.
b. Objective response rates are significantly higher than DTIC.
c. Overall survival is significantly improved compared to DTIC.
d. Significantly fewer adverse events occur with temozolomide than with DTIC.