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|Articles|May 13, 2009

Oncology

  • ONCOLOGY Vol 23 No 6
  • Volume 23
  • Issue 6

Treating Metastatic Melanoma: Further Considerations

The article by Bhatia and colleagues focuses on the treatment of patients with metastatic melanoma using standard therapies, but it also includes a brief outline of recent treatment approaches using investigational agents. In addition, the authors describe prognostic factors for metastatic melanoma, highlighting the impact of the extent of tumor and the site of metastasis (eg, soft-tissue vs visceral metastases) on survival.

The article by Bhatia and colleagues focuses on the treatment of patients with metastatic melanoma using standard therapies, but it also includes a brief outline of recent treatment approaches using investigational agents. In addition, the authors describe prognostic factors for metastatic melanoma, highlighting the impact of the extent of tumor and the site of metastasis (eg, soft-tissue vs visceral metastases) on survival.

Treatment Options

The authors describe the role of surgical resection in selected patients with metastatic disease and the palliative role for which radiotherapy is sometimes useful. They provide a fairly detailed description about the efficacy of systemic therapies including single-agent chemotherapy and combination chemotherapy, and address the role of immunotherapy and biochemotherapy(BCT). They appropriately conclude that combination chemotherapy has not produced significant increases in survival compared to that achieved with single-agent therapy with dacarbazine. The efficacy of interleukin-2 (IL-2, Proleukin) is well summarized, and the serious toxicities associated with high-dose IL-2 therapy are emphasized. Referencing various meta-analyses in this setting, the authors highlight the pivotal randomized trials of chemotherapy vs BCT in patients with metastatic disease. They conclude that BCT is sometimes associated with a high response rate, but this has not resulted in significant improvement in overall survival.

The authors also address selected novel therapies under investigation including the two anti-CTLA-4 antibodies (ipilimumab and tremelimumab), molecularly targeted therapies such as augmerosen (Genasense) plus dacarbazine, and the recently reported phase III study of sorafenib (Nexavar) combined with paclitaxel plus carboplatin. A brief section is devoted to adoptive cell therapy, describing the results of phase II studies showing high response rates. The authors conclude with an encouraging note stating that many novel therapeutic approaches appear promising, and recommending that participation in clinical trials be considered the standard of care. The article is generally well written and lists most of the important publications dealing with the treatment of metastatic melanoma.

Importance of Disease Heterogeneity

Although I am in general agreement with this paper, I would like to expand on several important principles that need to be taken into consideration when recommending treatment for patients with metastatic melanoma.

To begin with, there is a huge heterogeneity in the patterns of disease among patients with metastatic melanoma. Those with cutaneous melanoma (90% of patients diagnosed with melanoma) have a different biology than those with two less common subtypes-mucosal melanoma and uveal (choroidal) melanoma. Increasingly, various molecular subtypes of cutaneous melanoma are being recognized[ 1] and will become the focus of attention for developing future therapies that target abnormalities in the signal transduction pathways.

Common pathways that develop abnormalities and control the growth of melanoma include activating mutations in the BRAF kinase found in nearly 60% of patients and dysfunction of the PI3K/PTEN/Akt/mTOR pathway. In addition, c-KIT mutations are especially common in patients with mucosal and acral melanomas, and clinical trials are evaluating imatinib (Gleevec) in this setting. The molecular biology of uveal melanoma is entirely different from that of cutaneous melanoma. This will influence the choice of future treatments and may provide an explanation as to why metastatic uveal melanoma patients have more resistant disease, rarely responding to available chemotherapy or immunotherapy with IL-2.

Relative Response Rates

The authors state that single-agent dacarbazine is a standard of care for the treatment of metastatic melanoma. Unfortunately, dacarbazine has fairly low activity against the disease, with typical response rates ranging from 10% to 15%. Moreover, the duration of response to single-agent chemotherapy is typically quite short, lasting no more than 3 to 4 months. Several other cytotoxic drugs-eg, cisplatin, carboplatin, paclitaxel, and fotemustine-have shown a similar range of low response rates (10%–15%). Although the combinations of multiple chemotherapy agents have not produced a significant increase in median survival, their associated response rates are invariably higher, ranging from 20% to 30% with an average expected response rate of 25%. Therefore, if a decision to use chemotherapy has been made, a response rate of 25% ought to be more attractive than the infrequent responses expected from the use of any of the single agents such as dacarbazine.

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