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.

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.

In their Table 2, which lists randomized trials of chemotherapy vs biochemotherapy in metastatic melanoma, the authors include tamoxifen as a component of regimens along with chemotherapy. It should be pointed out that tamoxifen is now considered an inactive drug in this setting and should no longer be used.

Immunotherapy

Immunotherapeutic approaches are an essential component of treatment for metastatic melanoma. At least three immunotherapeutic drugs (interferon alfa [Intron A, Roferon- A], IL-2, and ipilimumab) has each produced response rates of 10% to 15%, the same frequency of response rates as reported with single-agent cytotoxic therapy.

IL-2 therapy is currently underutilized in the management of patients with metastatic melanoma because of concerns about severe adverse events associated with the administration of high-dose IL-2 therapy. It should be noted that IL-2 can also be administered by continuous infusion (at 18 million IU/m2 daily × 5 days), which has shown equivalent activity but less toxicity than that of conventional high-dose IL-2 therapy. In fact, we have shown in a phase II study that the dose of IL-2 can be lowered to 12 million IU/m2/d × 5 with similar levels of antitumor activity.[2] This was the basis for utilizing an IL-2 dose of 9 million IU/m2 per day × 4 to 5 days, which clearly contributed to the higher response rate observed with BCT vs combination chemotherapy (CVD regimen), in studies reported by investigators from the M.D. Anderson Cancer Center.[3,4]

Although controversy surrounds the use of biochemotherapy based on a poorly conducted Eastern Cooperative Oncology Group (ECOG) trial, where the doses of drugs and the number of cycles of BCT were compromised, I believe that BCT is currently a better choice of treatment for the large majority of metastatic melanoma patients who are young and physically fit.

Brain Metastases

The article by Bhatia et al neglects to mention another major hurdle in the treatment of metastatic melanoma- the common occurrence of central nervous system (CNS) metastases once the disease has disseminated to stage IV. Patients with metastatic melanoma are best categorized at their initial evaluation as having either oligometastatic disease or polymetastatic disease. For patients with solitary metastases, including CNS metastases, surgical resection should be considered, because long-term cure is possible in a small minority of such patients. Postoperative whole-brain radiotherapy is advised for such patients in order to control subclinical metastases in other parts of the brain. Polymetastatic disease is associated with a grimmer prognosis.

All patients with stage IV disease should also have a magnetic resonance imaging (MRI) scan of the brain as part of their initial staging workup so that patients without brain metastases can be managed more aggressively. Those with multiple brain metastases should be managed with a primary focus on the brain lesions as opposed to extracranial disease, because CNS metastases invariably represent the leading edge of the disease course and limit patient survival typically to less than 6 months. Systemic therapy offers no significant benefit against CNS metastases.

Given that the incidence of brain metastases approaches 50% to 60% during the lifetime of patients with metastatic melanoma, monitoring for brain metastases is advised throughout the course of the disease, with MRI scans of the brain-a better test than computed tomography (CT) scanning-repeated at 6- to 9-week intervals.

Final Thoughts

Despite relatively limited progress in the treatment of metastatic melanoma during the past 3 decades, it is the only common solid tumor for which some patients with stage IV disease can still be cured with the judicious use of currently available therapies. This is why an aggressive approach to treatment should be undertaken, especially in patients with a surgically resectable (solitary) metastasis, regardless of its location. That said, nearly 80% of patients with a surgically resectable metastasis will develop disease progression within 1 year of surgery. Results in these patients may improve with the administration of neoadjuvant therapy using a combination of two or three cytotoxic agents or BCT.

Finally, molecularly targeted drugs are under intensive investigation. Although these drugs have shown only limited antitumor activity when used as single agents, ongoing efforts are aimed at developing combinations of novel molecularly targeted agents, with and without cytotoxic agents, thereby blocking multiple pathways of cellular proliferation simultaneously.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Fecher LA, Cummings SD, Keefe MJ, et al: Toward a molecular classification of melanoma. J Clin Oncol 25:1606-1620, 2007.
2. Legha SS, Gianan MA, Plager C, et al: Evaluation of interleukin-2 administered by continuous infusion in patients with metastatic melanoma. Cancer 77:89-96, 1996.
3. Legha SS, Ring S, Eton O, et al: Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 16:1752-1759, 1998.
4. Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 20:2045- 2052, 2002.