Elsevier

Clinics in Dermatology

Volume 31, Issue 3, May–June 2013, Pages 290-297
Clinics in Dermatology

Chemotherapy in the management of advanced cutaneous malignant melanoma

https://doi.org/10.1016/j.clindermatol.2012.08.016Get rights and content

Abstract

The recent past has witnessed unprecedented clinical progress in the treatment of advanced malignant melanoma through targeting of mutant BRAF in approximately 50% of patients and immune check point blockade in all patients. As has been well documented, responses to targeted therapy are of limited duration, and rates of clinical benefit to immunotherapy are modest. Given these factors, palliation of patients with chemotherapy remains an essential aspect of melanoma oncology. Many chemotherapeutics (and combinations with other agents, such as immunotherapy) have been evaluated in melanoma, although no chemotherapy regimen has been documented to provide an overall survival benefit in a prospective, randomized, well-controlled phase III study. We provide an overview of the development of the most common chemotherapy regimens for melanoma, discuss the clinical trial evidence supporting and contrasting them, and highlight appropriate clinical situations in which they might be used. We also discuss the future of chemotherapy for melanoma, noting the potential for combinations of chemotherapy with either targeted or immunotherapeutic agents.

Introduction

Major advancements in the treatment of metastatic melanoma have recently been achieved with the approval of the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blocking monoclonal antibody ipilimumab and BRAFV600E kinase inhibitor vemurafenib by the Food and Drug Administration (FDA). These treatments represent the only approvals of drugs for melanoma other than dacarbazine (1975), interferon-alpha (INF-α) (1995), and interleukin (IL)-2 (1998). These new drugs represent a shift away from treatment with cytotoxic agents; however, chemotherapy continues to be an important tool in the treatment of melanoma. Although not having demonstrated an overall survival (OS) benefit, chemotherapy has a clear role for palliation of patients with melanoma. Before the development of ipilimumab and vemurafenib, the only treatment known to lead to long-term remissions in patients with melanoma was high-dose IL-2. Unfortunately, this treatment approach is relevant to a select patient population, given its toxicity and many of these patients eventually receive chemotherapy as well.

Even in the era of CTLA-4 blockade and targeted therapies, chemotherapy remains an essential treatment option. Many patients are ineligible for treatment with ipilimumab or do not harbor a BRAFV600E mutation. Additionally, even if eligible for treatment, many patients treated with ipilimumab obtain no benefit and all patients treated with small molecule kinase inhibitors eventually relapse from therapy. In this review, we focus on the available clinical trial evidence underlying the use of chemotherapy in melanoma and highlight the clinical circumstances in which it may be most appropriately used.

Section snippets

Dacarbazine and temozolomide

Multiple chemotherapeutics have been evaluated in the treatment of advanced melanoma; however, only dacarbazine has been approved for use by the FDA. Dacarbazine and the analog drug temozolomide are alkylating agents that damage DNA by introducing alkyl groups to guanine bases, eventually causing cell death via apoptosis and other cell death mechanisms. Upon administration, dacarbazine is hepatically demethylated to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and subsequently to

Combination chemotherapy

Given the modest RRs observed with single-agent chemotherapy, there has been historical interest in the development of combination chemotherapy regimens. Similar rationale has led to the development of more effective strategies in many other solid tumors; however, this has not been widely efficacious in malignant melanoma. Initial development of combination chemotherapy regimens suggested that the RRs, and possibly survival, could be improved with the addition of further agents to dacarbazine

Adjuvant and neoadjuvant chemotherapy

With the lack of an OS benefit from chemotherapy in the metastatic setting, it now seems intuitive that there would not be a standard role for chemotherapy in the adjuvant or neoadjuvant setting. This realization has not been generally understood until relatively recently. Many chemotherapies,74 chemotherapy combinations,75., 76. and chemoimmunotherapies77., 78. have been leveraged in adjuvant clinical trials without success.

Most recently, TMZ was evaluated in a neoadjuvant phase II study.

Clinical decision making and future directions in chemotherapy for melanoma

With the development of vemurafenib and ipilimumab, the first-line treatment of melanoma is now associated with an OS benefit for the first time. In patients who harbor BRAFV600E mutations or who are candidates for ipilimumab, these agents should be used preferentially to chemotherapy. Additionally, in highly selected patients, IL-2 continues to be a treatment option associated with long-term benefit. Many patients, unfortunately, do not fit these criteria in the first-line setting and most

Conclusions

There are developments on the clinical horizon that may alter this therapeutic landscape in the relatively near future. Nab-paclitaxel is an interesting agent that may become a new first-line chemotherapeutic treatment option when combined with carboplatin or bevacizumab. These combinations may also eventually come into the general clinical setting as salvage regimens. Novel agents and combinations of chemotherapy with other targeted therapies and immunotherapies, such as anti-PD-1, -PD-L1,

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