Chemotherapy in the management of advanced cutaneous malignant melanoma☆
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,
References (79)
- et al.
Metastatic melanoma: chemotherapy
Semin Oncol
(2002) - et al.
Systemic chemotherapy for the treatment of metastatic melanoma
Semin Oncol
(2002) - et al.
Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032)
Eur J Cancer
(2011) - et al.
Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group
Eur J Cancer
(1994) - et al.
Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha
Ann Oncol
(1996) - et al.
Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma
Ann Oncol
(2006) - et al.
LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951)
Eur J Cancer
(2009) - et al.
Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide
J Invest Dermatol
(2009) - et al.
Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice
J Invest Dermatol
(2007) - et al.
Hedgehog signaling in skin cancers
Cell Signal
(2011)
Overexpression of Notch ligand Dll1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization
Cancer Lett
Phase II trial of neoadjuvant temozolomide in resectable melanoma patients
Ann Oncol
Systemic treatments for metastatic cutaneous melanoma
Cochrane Database Syst Rev
Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma
J Clin Oncol
MGMT gene silencing and benefit from temozolomide in glioblastoma
N Engl J Med
Temozolomide chemoresistance heterogeneity in melanoma with different treatment regimens: DNA damage accumulation contribution
Melanoma Res
Effect of single and multiple administration of an O6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model
Cancer Chemother Pharmacol
MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
Br J Cancer
Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors
Clin Cancer Res
Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma
J Clin Oncol
Phase II study of extended-dose temozolomide in patients with melanoma
J Clin Oncol
Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects
Cancer
Metronomic cyclophosphamide regimen selectively depletes CD4+CD25 + regulatory T cells and restores T and NK effector functions in end stage cancer patients
Cancer Immunol Immunother
Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model
Cancer Immunol Immunother
Selective CD4 + lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications
J Clin Oncol
CD8 + T cell immunity against a tumor/self-antigen is augmented by CD4 + T helper cells and hindered by naturally occurring T regulatory cells
J Immunol
Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8 + T cells
J Exp Med
The role of cytotoxic chemotherapeutic agents either alone or in combination with biological response modifiers
Chemotherapy for metastatic melanoma
Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study
J Clin Oncol
Vindesine in patients with metastatic malignant melanoma: a Southwest Oncology Group study
J Clin Oncol
Vindesine for metastatic malignant melanoma. A phase II trial
Am J Clin Oncol
A pilot study with vincristine sulfate liposome infusion in patients with metastatic melanoma
Melanoma Res
A Phase II trial of vinorelbine tartrate in patients with disseminated malignant melanoma and one prior systemic therapy: a Southwest Oncology Group study
Cancer
Phase II trial of vinorelbine tartrate in patients with treatment-naive metastatic melanoma
Anticancer Drugs
A phase II study of taxol in patients with malignant melanoma
Invest New Drugs
Phase 2 open-label study of weekly docosahexaenoic acid-paclitaxel in cutaneous and mucosal metastatic melanoma patients
Melanoma Res
Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel
Clin Cancer Res
A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma
Cancer
Cited by (74)
Caramel: A web-based QSAR tool for melanoma drug discovery[Formula presented]
2024, Software ImpactsMetastasectomy for metastatic melanoma in the era of effective systemic therapy
2023, American Journal of SurgeryRuthenium and iridium complexes bearing porphyrin moieties: PDT efficacy against resistant melanoma cells
2022, Dyes and PigmentsCitation Excerpt :Currently, the development of therapeutic agents for a successful treatment, minimizing the damage in patients, is a challenge for researchers from several scientific fields around the world [1,6,8,9]. Depending on cancer localization, genetic profile, and stage, different therapeutic approaches are commonly used to fight it, namely targeted therapy [10,11], chemotherapy [12], radiotherapy [13], immunotherapy [6], or surgical resection. However, these approaches evidence some drawbacks such as adverse events due to immune reactions leading to skin and gastrointestinal toxicity, lack of specificity for cancer cells, reduced efficiency, and resistance to immune-, chemo- and targeted therapies or functional/mechanical and esthetical alterations.
Decoding the synergistic potential of MAZ-51 and zingerone as therapy for melanoma treatment in alignment with sustainable development goals
2024, Cell Biochemistry and Function
- ☆
Drug Names: vemurafenib: Zelboraf. ipilimumab: Yervoy. temozolomide: Temodar. docetaxel: Taxotere. nab-paclitaxel: Abraxane. interleukin-2: Proleukin. interferon-alpha: Intron A. bevacizumab: Avastin. sorafenib: Nexavar.
- 1
Currently affiliated: Melanoma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.