The treatment of advanced cutaneous melanoma remains disappointing. Single-agent cytotoxic drugs usually produce response rates of less than 20%, though newer agents, particularly fotemustine and temozolomide, show some promise, especially in patients with brain metastases. Combination chemotherapy regimens yield response rates of 20% to 40%, but durable complete remissions are uncommon. Interferon-alfa and interleukin-2 alone produce response rates of 10% to 20%, 3% to 5% of which are durable. Vaccines and monoclonal antibodies have low level activity in advanced disease but may play a role in the adjuvant setting. The combinations of cisplatin-based regimens plus IFN-alfa and IL-2 have produced overall response rates of 50% to 60% and complete responses in 20% of patients, about half of which are durable. The toxicity of these regimens is severe, however, and their impact on survival remains to be established.
Cutaneous malignant melanoma is becoming a more common neoplasm. In 1995, an estimated 34,000 cases of melanoma will be diagnosed in the United States and 7,200 deaths due to melanoma will occur . By the year 2000, it is estimated that 1 of every 75 Americans will be diagnosed with melanoma.
Early primary melanoma is highly curable, but once the disease becomes widely disseminated, it is nearly always fatal. The survival time for patients with metastatic disease ranges from 6 to 9 months when metastases are detected in multiple organ sites. Patients with skin, subcutaneous tissue, and distant lymph node metastases have the longest survival, averaging 12 to 15 months, whereas patients with liver, brain, and bone metastases have a median survival of only 3 to 4 months .
The treatment of metastatic melanoma remains unsatisfactory, and thus far survival has been determined primarily by the extent and pace of the disease, rather than by the treatment strategy. In this article, we provide an overview of the systemic treatment options for advanced cutaneous melanoma, with emphasis on the more novel therapeutic approaches.
The only single agent approved for the treatment of melanoma is dacarbazine, which produces response rates of 10% to 20% but results in complete remission in less than 5% of treated patients . Responses have been observed mainly in soft tissues, ie, skin, subcutaneous tissue, lymph node, and lung metastases, and are usually short-lived, ranging from 3 to 6 months. Although complete responses are rare, approximately one-fourth of complete responders do attain long-term remissions .
The antitumor activity of the nitrosoureas currently available in the United States-carmustine (BCNU [BiCNU]), and lomustine (CCNU [CeeNu])-is similar to that of dacarbazine, with response rates ranging from 10% to 20% . Patients previously exposed to dacarbazine have an even lower response rate to the nitrosoureas than do untreated patients.
Fotemustine, a new agent of this class, has recently been studied in Europe. This novel chloroethyl nitrosourea with an amino acid-phosphonyl adduct has a mechanism of action involving rapid metabolic conversion and consequent alkylation of thioenzymes involved in DNA synthesis. In addition, it rapidly crosses the blood-brain barrier, possibly through an amino acid transport system. A multicenter phase II study of fotemustine with 153 assessable patients showed a response rate of 30% in previously untreated patients and 24% overall . Most importantly, a response rate of 20% was observed in 85 patients with brain metastases, and some of the responses were durable .
Other classes of chemotherapeutic agents with antitumor activity include the vinca alkaloids and platinum compounds, including cisplatin (Platinol) and carboplatin (Paraplatin), which have reported response rates of 10% to 20% . A new lipid-soluble dihydrofolate reductase inhibitor, piritrexim (taken orally), produced a response rate of 23% in 31 evaluable patients . Interestingly, responses were seen in previously treated as well as previously untreated patients.
Taxanes, including paclitaxel (Taxol) and docetaxel (Taxotere), agents that inhibit disassembly of the microtubule complex, have also been evaluated in metastatic melanoma. In two phase II trials, 3 complete responses and 4 partial responses were observed among 53 melanoma patients . Docetaxel has produced similar response rates, with 3 responders in 27 patients studied [6,7]. Further exploration of the taxanes in combination with other cytotoxic agents is warranted.
Another new agent, temozolomide, which is entering phase II studies in the United States, deserves special mention. This agent is an imidazotetrazine derivative that spontaneously converts in vivo to MTIC (methyl triazeno imidazole carboxamide), the active metabolite of dacarbazine, and crosses the blood-brain barrier efficiently in animal models. Temozolomide has shown significant antitumor activity in preclinical studies, and responses have been seen in phase I trials in patients with melanoma (with and without brain metastases) and in patients with primary brain tumors .
A recent European phase II study in 49 assessable patients with metastatic disease demonstrated a 6% complete response rate and a 21% total response rate . In this series, four patients had brain metastases, one of whom attained a partial response. The possible utility of this agent awaits further phase II data.
Based on the independent activity of dacarbazine and the nitrosoureas, several studies combining the two agents were performed in the late 1970s. These studies failed to show the superiority of the combination regimens over dacarbazine alone . Dacarbazine also has been combined with dactinomycin (Cosmegan), vinca alkaloids, cisplatin, and fotemustine. The observed response rates with the two-drug combinations have ranged from 20% to 35%, which are not clearly superior to response rates achieved with dacarbazine alone .
Combinations of three or more drugs with or without dacarbazine also have been investigated. A three-drug combination regimen of BCNU, hydroxyurea (Hydrea), and dacarbazine tested by the Southwest Oncology Group (SWOG) produced an overall response rate of 27% in 178 patients, with response duration averaging 6 months .
A regimen combining bleomycin, Oncovin, lomustine, and dacarbazine (BOLD), developed in the late 1970s at Duke University, produced a 40% response rate (9% complete responses) in a total of 72 assessable patients . Subsequent studies with the BOLD regimen failed to confirm these initial results, however; overall response rates in these later studies ranged from 4% to 20% .
Among combination chemotherapy regimens not including dacarbazine that were developed in the late 1970s and early '80s, a combination of bleomycin (Blenoxane), vinblastine, and cisplatin showed response rates ranging from 22% to 43% in several trials . More recently, various groups have reported their results combining dacarbazine, cisplatin, and a vinca alkaloid (either vinblastine or vindesine [Eldisine]) . The response rates achieved with this three-drug combination ranged from 24% to 45%, which appear to be superior to rates reported with dacarbazine alone.
Phase III Trials--Despite the abundance of phase II studies exploring different combinations of cytotoxic drugs, there have been only a limited number of phase III trials comparing dacarbazine alone with combination chemotherapy or comparing different combination regimens. The results of these phase III trials are summarized in
Table 1 [9-16]. Except for the SWOG study reported by Costanzi et al , which showed a significant improvement in response rate for combination chemotherapy vs dacarbazine, all the trials were extremely small and therefore had insufficient power to detect significant differences in response rate or survival. In addition, some of the studies combined dacarbazine with relatively inactive drugs. Thus, it is not surprising that none of the studies showed a significant difference in survival and only one study revealed a significant improvement in response rate.
The final results of the Cancer Community Oncology Program study, which compares dacarbazine alone with cis-platin, vinblastine, and dacarbazine (CVD) should be available in the near future . Also, investigators at Memorial Sloan-Kettering Cancer Center are currently evaluating the combination of cisplatin, BCNU, dacarbazine, and tamoxifen vs dacarbazine alone. Pending the results of these and other controlled studies, dacarbazine alone remains the standard for initial chemotherapy treatment of metastatic melanoma.
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