ABSTRACT: The 10-year survival rate for patients with metastatic melanoma is less than 10%. Although surgery and radiation therapy have a role in the treatment of metastatic disease, systemic therapy is the mainstay of treatment for most patients. Single-agent chemotherapy is well tolerated but is associated with response rates of only 5% to 20%. Combination chemotherapy and biochemotherapy may improve objective response rates but do not extend survival and are associated with greater toxicity. Immunotherapeutic approaches such as high-dose interleukin-2 are associated with durable responses in a small percentage of patients. In this article, we review the treatments for metastatic melanoma including promising investigational approaches.
Metastatic melanoma continues to be a challenging disease to treat, with an estimated 8,420 related deaths in the United States in 2008. The 10- year survival rate for patients with metastatic melanoma is less than 10%. More than 3 decades after its initial approval by the US Food and Drug Administration (FDA) in 1975, dacarbazine continues to be the standard of care for most patients with this disease. High-dose interleukin-2 (HD IL-2 [Proleukin]), approved by the FDA in 1998 for metastatic melanoma, benefits a small subset of patients. Attempts to improve upon the survival of patients with metastatic disease have met with failure, and the need for successful new therapies for metastatic melanoma cannot be overemphasized. However, our understanding of the biology of this disease is steadily increasing, and many promising therapeutic approaches are currently under investigation. We discuss the various systemic therapeutic approaches to the treatment of metastatic melanoma below.
Prognostic Factors for Metastatic Melanoma
Many factors have been proposed to influence the prognosis in patients with metastatic melanoma. The impact of the initial site of metastasis on survival was studied in a multivariate analysis of 1,521 patients with stage IV melanoma. Three groups of patients were identified: those with cutaneous, nodal, or gastrointestinal tract metastases; those with isolated pulmonary metastases; and those with liver, brain, or bone metastases. The median survivals in these three groups were 12.5, 8.3, and 4.4 months, respectively. The 5-year actuarial survivals were 14%, 4%, and 3%, respectively. In addition to the site of disease, the presence of an elevated serum lactate dehydrogenase (LDH) has also been associated with poor prognosis.[4,5] The 2002 American Joint Committee on Cancer (AJCC) staging system of cutaneous melanoma classifies patients with metastatic disease into three categories based on the site of metastases and serum LDH level (see Table 1).
Other factors that have been associated with shorter survival include older age, poor performance status, male sex, greater number of metastatic sites, shorter disease-free interval, hypoalbuminemia, pretreatment neutrophilia, and leukocytosis.[3-7] The identification of valid prognostic factors is important to the design and interpretation of clinical trials in metastatic melanoma.
Roles of Surgery, Radiation Therapy, and Systemic Therapy
The presence of distant metastases usually reflects hematogenous dissemination of melanoma cells. The cornerstone of treatment for metastatic melanoma is systemic therapy to address the subclinical sites of metastases as well. Locoregional treatment modalities such as surgery or radiation are usually reserved for palliation of symptoms due to local tumor growth.
Resection of distant metastases may also be considered for selected patients in whom a survival benefit might be expected with surgical rather than medical treatment. Surgery may potentially improve outcomes in patients with fully resectable oligometastatic disease.
In a report of 144 patients who underwent surgical resection of nonregional metastatic melanoma, the overall 5- and 10-year survival rates were 20% and 14%, respectively. Patients with a solitary metastasis confined to the subcutaneous, nonregional lymph nodes or lung were most likely to benefit from aggressive surgical intervention. In another series of 77 patients undergoing surgical resection of metastatic disease, the overall 5-year survival rate was 10%. Patients with solitary lesions had a 5-year survival rate of 12%, compared with 0% for patients with multiple lesions. Patients with complete resection had a 5-year survival rate of 15%, compared with 4% for patients with incomplete resection. Patients with complete resection of solitary lesions had a 5-year survival of 18%. However, the retrospective and nonrandomized nature of these reports makes it difficult to distinguish the true benefit of surgical intervention from the differences in natural history of disease.
Melanoma is considered a relatively radioresistant tumor, but patients may derive clinical benefit from radiation of symptomatic metastases. Radiation therapy is usually used as an adjunct to the use of systemic therapy. Radiation therapy (whole-brain irradiation and/or stereotactic radiosurgery) is especially useful in patients with central nervous system (CNS) metastases, as most systemic therapies have limited penetration into the CNS.
Systemic therapy is the mainstay of therapy for most patients with stage IV melanoma. Systemic therapies include cytotoxic chemotherapy, immunotherapy, or a combination approach such as biochemotherapy. In addition, many novel therapies are currently under investigation.
Cytotoxic chemotherapy has been used for the treatment of metastatic melanoma for over 3 decades. Chemotherapeutic agents with modest antitumor efficacy in metastatic melanoma include alkylating agents (dacarbazine, temozolomide [Temodar], nitrosoureas), the platinum analogs, and the microtubular toxins. These agents have been used alone or in combination.
• Dacarbazine—An alkylating agent, dacarbazine (5-[3,3-dimethyl-1- triazenyl]-imidazole-4-carboxamide, or DTIC) is the only chemotherapeutic agent approved by the FDA for treatment of melanoma. A pooled analysis of 23 randomized, controlled trials showed that the objective response rate (ORR) for 1,390 patients receiving dacarbazine alone was 15.3%. The majority of these responses were partial (11.2% partial responses [PR], 4.2 % complete responses [CR]). Responses are seldom durable, and fewer than 2% of patients treated with dacarbazine alone are alive at 6 years. Since dacarbazine monotherapy has not been investigated in a placebo-controlled trial, there is insufficient evidence to suggest an overall survival benefit with dacarbazine. The primary purpose of dacarbazine therapy for metastatic melanoma is palliation.
Dacarbazine is typically administered intravenously at a dose of 150 to 200 mg/m2/d for 5 days or at a single dose of 800 to 1,000 mg/m2, with doses repeated every 3 to 4 weeks. The latter schedule is more convenient and is well tolerated by most patients. Common toxicities include mild nausea and vomiting, myelosuppression, and fatigue, and most patients are able to maintain their baseline quality of life.
Despite its modest efficacy and lack of data for survival benefit, dacarbazine continues to be the “standard treatment” of metastatic melanoma. No other therapy has yet been shown to have a significant survival benefit over dacarbazine.
• Temozolomide—An orally administered analog of dacarbazine, temozolomide has been extensively tested in melanoma. Like dacarbazine, temozolomide is converted to the active alkylating metabolite MTIC (3-methyl-[triazen-1-yl]-imidazole- 4-carboxamide). Unlike dacarbazine, however, this conversion is spontaneous, nonenzymatic, and occurs at a physiologic pH in all tissues to which the drug is distributed. Besides having excellent oral bioavailability, temozolomide penetrates into the CNS and may potentially prevent or treat melanoma brain metastases. These attractive features have prompted extensive investigation of temozolomide in metastatic melanoma.
A phase III trial randomized 305 patients to receive temozolomide (200 mg/m2/d orally for 5 days every 4 weeks) vs dacarbazine (250 mg/ m2/ d intravenously for 5 days every 3 weeks). The median overall survival (OS) and ORR for patients treated with temozolomide (7.7 months and 14%, respectively) were not statistically different from those treated with dacarbazine (6.4 months and 12%, respectively).
The results of another multicenter phase III trial that randomized 859 patients to receive dacarbazine vs an extended dosing schedule of temozolomide (150 mg/m2/d on 7 consecutive days every 14 days) were recently reported. The investigators found no significant differences between dacarbazine and temozolomide in ORR (10% and 14%, respectively), progression-free survival (PFS, 2.1 and 2.3 months, respectively), or OS (9.3 and 9.1 months, respectively).
Temozolomide has also been substituted for dacarbazine in various combination chemotherapy or biochemotherapy regimens in an effort to reduce the high rate of isolated CNS relapse in patients exhibiting major responses. However, the recently reported results of a phase III trial comparing cisplatin/IL-2/temozolomide vs cisplatin/IL-2/dacarbazine did not show any benefit of temozolomide in preventing brain metastases.
Hence, temozolomide has not proven to be superior to dacarbazine. The choice between the two drugs is usually guided by the desired route of administration, cost differences, and the presence or absence of brain metastases.
• Antimicrotubular Agents—Vinca alkaloids (inhibitors of microtubular assembly) such as vindesine and vinblastine, and taxanes (inhibitors of microtubule disassembly) such as paclitaxel have modest single-agent activity in patients with metastatic melanoma.[16,17] Vinblastine has been incorporated in various combination chemotherapy and biochemotherapy regimens. Paclitaxel, used as a single agent or in combination with other agents, has antitumor activity (ORR = 16%–26%) in patients with metastatic melanoma, including patients whose disease has progressed on prior chemotherapies.[17-19] Weekly administration of paclitaxel at a dose of 80 to 100 mg/m2 (on days 1, 8, and 15 every 4 weeks) is well tolerated by most patients. Alternatively, a higher dose can be administered once every 3 to 4 weeks.
Associated toxicities include fatigue, alopecia, myelosuppression, neuropathy, myalgias, and hypersensitivity reactions. An albumin-bound, nanoparticle form of paclitaxel (ABI-007, or Abraxane) had an ORR of 27% in 34 chemotherapy-naive patients with metastatic melanoma in a phase II trial.
• Platinum Analogs—Cisplatin and carboplatin have modest activity in patients with metastatic melanoma. Single-agent cisplatin given at conventional doses yields a response rate of less than 10%. However, a phase II study that used a higher dose (150 mg/m2) of cisplatin in combination with amifostine reported an ORR of 53%, although the responses were short-lived. A response rate of 19% was observed with carboplatin in a phase II study in chemotherapynaive patients with metastatic melanoma. Carboplatin has also been used in combination with paclitaxel in previously treated patients.
• Nitrosoureas—Nitrosoureas such as carmustine (BCNU), lomustine (CCNU), and fotemustine have single-agent activity comparable to dacarbazine, although they cause more myelosuppression and alopecia. Fotemustine rapidly crosses the blood-brain barrier and has been found to have encouraging activity in patients with brain metastases. When compared to dacarbazine in a phase III trial involving 229 patients with metastatic melanoma, fotemustine was associated with a higher ORR (15% vs 7%, respectively) and a trend toward improved survival (7.3 vs 5.6 months, respectively). In patients without brain metastases at inclusion, the median time to development of brain metastases was 22.7 months in the fotemustine arm vs 7.2 months in the dacarbazine arm. Fotemustine has not been approved by the FDA but is available in Europe.
The modest antitumor activity of the chemotherapeutic agents mentioned above led to investigation of combinations of these agents to improve outcomes. Single-institution studies suggested that combination chemotherapy might lead to an increase in the response rate and possibly survival.
The combination of cisplatin, dacarbazine, BCNU, and tamoxifen (CDBT), also known as the Dartmouth regimen, was initially reported to have an ORR of 55%.[25,26] However, a phase III multicenter trial that randomized 240 patients to the CDBT regimen vs dacarbazine monotherapy did not show a statistically significant benefit in favor of the combination. Despite a modest difference in ORR in favor of CDBT over dacarbazine (16.8% and 9.9%, respectively; P = .13), there was no significant difference in OS (7.7 and 6.3 months, respectively; P = .52). Myelosuppression, fatigue, nausea, and vomiting were significantly higher in the CDBT arm.
Another combination that includes cisplatin, vinblastine, and dacarbazine (CVD), had an ORR of 40% in a phase II study. The CVD regimen was later used as a backbone for combining with IL-2 and interferon to develop biochemotherapy regimens.
The combination of paclitaxel and carboplatin (PC) has been reported to have antitumor activity in patients with metastatic melanoma, including patients who have received prior chemotherapy.[ 19,30] The PC regimen was recently used as the comparator arm in two randomized, placebocontrolled, phase III trials testing PC vs PC plus sorafenib (Nexavar). In one of these trials involving patients who had received prior dacarbazine or temozolomide, patients who received PC alone had an ORR of 11%, median PFS of 17.9 weeks, and median OS of 42 weeks.
In summary, combinations of cytotoxic agents may yield somewhat higher response rates than dacarbazine monotherapy, but are associated with greater toxicity and do not extend survival significantly.
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