Version May 2024
INTRODUCTION — Although the incidence of malignant melanoma is increasing, most cases are diagnosed at an early stage. Surgical excision is curative in most cases of early-stage disease, and patients at high risk of developing metastatic disease may benefit from adjuvant therapy with anti-programmed cell death receptor 1 (PD-1) inhibitors (eg, pembrolizumab or nivolumab) or MEK plus BRAF inhibitors (eg, dabrafenib plus trametinib) for BRAF V600 mutant melanoma. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)
Most patients with stage IV disease require systemic treatment (table 1A-B). For patients with extracranial metastatic melanoma, cytotoxic chemotherapy historically was widely used in patients who were not candidates for therapy with high-dose interleukin-2 (IL-2), although this approach was never demonstrated to improve survival. However, with the development of checkpoint inhibitor immunotherapy and targeted therapy for BRAF-mutated tumors, chemotherapy is now generally limited to second- or third-line settings and is frequently omitted altogether.
The clinical role of cytotoxic chemotherapy will be reviewed here. An overview of the management of advanced melanoma is presented separately.
●(See "Overview of the management of advanced cutaneous melanoma".)
●(See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)
●(See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)
CHOICE OF THERAPY FOR DISSEMINATED DISEASE — Approaches that have been shown to provide clinically important benefit for patients with disseminated melanoma in appropriately selected patients include immunotherapy with checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death receptor 1 (PD-1), and therapy targeting the mitogen-activated protein (MAP) kinase pathway with a combination of BRAF and MEK inhibitors in patients whose tumors contain a V600 mutation in the BRAF gene.
Cytotoxic chemotherapy does not have an established role in the management of patients with advanced melanoma. However, chemotherapy retains a role as therapy for patients whose disease can no longer be controlled with immunotherapy or targeted agents and who are not eligible or able to enroll in a clinical trial. Although chemotherapy has not been demonstrated to increase overall survival, combination regimens and single-agent chemotherapy have been associated with objective responses in a minority of patients. (See 'Combination regimens' below and 'Single-agent chemotherapy' below.)
The factors influencing the choice of therapy are discussed separately. (See "Overview of the management of advanced cutaneous melanoma".)
SINGLE-AGENT CHEMOTHERAPY — The most widely used chemotherapy agents for the treatment of advanced melanoma are dacarbazine and its prodrug temozolomide. Other agents that may have demonstrated at least some activity include nitrosoureas, platinum compounds, vinca alkaloids, and taxanes.
Dacarbazine and temozolomide
Dacarbazine — Dacarbazine has been widely used for the treatment of patients with metastatic melanoma. Although there are no phase III trials that have demonstrated a survival benefit for dacarbazine compared with a "no treatment" control, it is approved for this indication in the United States. Dacarbazine is generally considered to be the most active single agent in patients with metastatic melanoma, with a response rate of 8 to 20 percent. The vast majority of responses are only partial, and the median response duration is four to six months [1,2]. Long-term follow-up of patients treated with dacarbazine indicates that less than 2 percent of patients can be anticipated to survive six years [3].
Dacarbazine is generally well tolerated, with the major side effect being nausea and vomiting. Dacarbazine administration requires good venous access because of the potential for chemical phlebitis. Bone marrow suppression is usually only modest, and alopecia and fatigue are minimal, allowing most patients to maintain relatively normal function while receiving therapy.
Typical schedules for dacarbazine are 200 mg/m2 intravenously for five days or 850 to 1000 mg/m2 intravenously over one hour every two to four weeks. Response rates and response duration do not appear to be affected by the administration schedule. The availability of powerful antiemetic agents permits the more convenient, one day every three to four weeks schedule to be administered in an outpatient setting. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)
Clinical trials have consistently demonstrated a significant overall survival advantage for targeted therapies or checkpoint inhibitor immunotherapy over dacarbazine. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'BRAF V600 mutant disease'.)
Temozolomide — Temozolomide is an analog of dacarbazine that is chemically degraded at physiologic pH to MTIC, the active metabolite of dacarbazine [4]. In contrast to dacarbazine, temozolomide does not require metabolic activation. Unlike dacarbazine, temozolomide is orally absorbed; it can cross the blood brain barrier and may have some activity in brain metastases. (See "Management of brain metastases in melanoma".)
Temozolomide has been compared with dacarbazine in two randomized trials. In a phase III trial that included 305 patients with metastatic melanoma, treatment with temozolomide was associated with nonsignificant improvements in overall survival and progression-free survival compared with dacarbazine (median 7.7 versus 6.4 and 1.9 versus 1.5 months, respectively) [5]. Similarly, in a trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) in 859 patients with metastatic melanoma, there was no difference in overall or progression-free survival (median 9.1 versus 9.4 and 2.3 versus 2.2 months, respectively) [6].
Experimental approaches to augment the activity of temozolomide have not been successful, and the clinical data have not been sufficiently compelling to achieve US Food and Drug Administration (FDA) approval for the treatment of metastatic melanoma.
Fotemustine — The nitrosoureas fotemustine, carmustine (BCNU), and lomustine (CCNU) all have produced overall response rates of 13 to 18 percent in patients with metastatic melanoma [1,2,7]. Alopecia is more severe with these agents than with dacarbazine, and hematologic toxicity, particularly thrombocytopenia, is more prolonged.
In a phase III trial, 229 patients with advanced disease with or without brain metastases were randomly assigned to fotemustine or dacarbazine [7]. The objective response rate was twice as high with fotemustine compared with dacarbazine (15 versus 7 percent), but the median time to progression (1.9 and 1.8 months, respectively) and median survival (7.3 and 5.6 months, respectively) were not significantly different. Among patients without brain metastases, those randomly assigned to fotemustine had a lower risk of cerebral progression (18 versus 23 percent) and a significantly longer time to the development of brain metastases (22.7 versus 7.2 months) compared with those assigned to dacarbazine. This finding requires independent confirmation.
Although there were some initially encouraging results when lomustine was administered via the hepatic artery, a randomized trial failed to demonstrate any improvement in survival when compared with intravenous administration [8]. (See "Metastatic uveal melanoma", section on 'Locoregional therapies'.)
Although fotemustine is considered first-line chemotherapy in some European countries, it is not available in the United States.
Platinum compounds — Cisplatin and carboplatin have shown only modest activity in patients with metastatic melanoma. Single-agent cisplatin has been tested at doses up to 200 mg/m2, with response rates ranging from 0 to 53 percent (mean 15 to 20 percent) [1]. Single-arm studies have provided evidence for some dose dependency. In one study, for example, single-agent cisplatin was given at doses up to 150 mg/m2 in combination with amifostine, a thiol derivative with protective effects on bone marrow and renal tissue. Tumor responses were noted in 53 percent of patients, but all were partial and the median response duration was only four months [9].
Carboplatin has been less extensively tested [10], and its activity compared with other single agents is uncertain. It has been primarily tested in combination with paclitaxel. Platinum compounds have also been extensively studied in biochemotherapy combinations.
Nanoparticle albumin-bound paclitaxel — Nanoparticle albumin-bound paclitaxel (nabpaclitaxel) showed evidence of activity in a phase II clinical study, with response rates of 22 and 3 percent in chemotherapy-naïve and previously treated patients [11].
Based upon this, a phase III trial was conducted in which 529 previously untreated patients with metastatic melanoma were randomly assigned to nabpaclitaxel or dacarbazine [12]. Progression-free survival, the primary endpoint, was significantly increased with nabpaclitaxel (median 4.8 versus 2.5 months, hazard ratio [HR] 0.79, 95% CI 0.63-0.99). The difference in overall survival was not statistically significant between nabpaclitaxel and dacarbazine (median 12.6 versus 10.5 months, HR 0.9, 95% CI 0.74-1.09, p = 0.27]), and the difference in objective response rate on independent review was not statistically significant (15 versus 11 percent). Subsequent analyses indicated that nabpaclitaxel had similar activity in those with wild-type BRAF and those with mutated BRAF [13].
Other agents — Microtubule toxins, such as vinca alkaloids [14], and agents that interfere with microtubule disassembly, such as taxanes [15-17], have shown only modest activity in patients with metastatic melanoma. These agents have been studied primarily in combinations.
COMBINATION REGIMENS — There are no randomized trials that have established the superiority of combination chemotherapy or biochemotherapy regimens compared with single-agent dacarbazine or temozolomide in patients with metastatic melanoma. However, combination regimens may have a role in patients whose disease can no longer be controlled with immunotherapy and/or targeted therapy.
Dacarbazine or temozolomide combinations — Phase III trials have not confirmed a survival advantage for various dacarbazine-based or temozolomide-based combinations compared with single-agents.
The lack of improvement in survival is illustrated by results from a multicenter trial in which 240 patients were randomly assigned to either dacarbazine or a combination of cisplatin, dacarbazine, carmustine, and tamoxifen (CDBT) [18]. Although the response rate with CDBT was marginally improved (19 versus 10 percent compared with dacarbazine alone, p = 0.09), median survival was seven months on both treatment arms. Toxicity (myelosuppression, nausea, vomiting, fatigue) was more severe with the combination regimen.
Carboplatin paclitaxel — The combination of carboplatin and paclitaxel has not been directly compared with single-agent dacarbazine or temozolomide, but this regimen has activity and may be useful as second- or third-line therapy [19,20]. The most extensive data come from a phase III trial in which carboplatin paclitaxel was compared with carboplatin paclitaxel plus sorafenib as first-line therapy in 823 patients with metastatic melanoma [19]. Although the addition of sorafenib did not improve outcomes, the objective response rate for the entire cohort was 18 to 20 percent, and the median overall survival was 11 months on both treatment arms.
Carboplatin paclitaxel bevacizumab — The addition of bevacizumab to carboplatin paclitaxel may improve disease control compared with carboplatin paclitaxel alone. In the phase II BEAM trial, the combination of carboplatin paclitaxel and bevacizumab was compared with carboplatin paclitaxel alone in 214 patients with metastatic melanoma [21]. In the entire study population, there was a trend toward improved overall survival (median 12.3 versus 8.6 months, hazard ratio [HR] 0.67, 95% CI 0.46-0.98), although this benefit was not statistically significant with longer follow-up (table 1A).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Checkpoint immunotherapy targeting programmed cell death receptor 1 (PD-1) and/or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and therapy targeting the mitogen-activated protein (MAP) kinase pathway with BRAF and MEK inhibitors are preferred modalities for the initial systemic treatment of patients with advanced melanoma. (See "Overview of the management of advanced cutaneous melanoma" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)
●For patients who are not candidates for further immunotherapy or targeted therapy, who are not candidates for inclusion in a formal clinical trial, and who are interested in additional therapy, chemotherapy may be an option. These approaches have not been proven to increase overall survival, but they are associated with objective responses in a minority of patients.
•In these patients, we suggest a combination of carboplatin and paclitaxel (Grade 2C). (See 'Carboplatin paclitaxel' above.)
•Single-agent chemotherapy (dacarbazine, temozolomide, fotemustine, nanoparticle albumin-bound paclitaxel [nabpaclitaxel]) is an appropriate alternative. (See 'Single-agent chemotherapy' above.)
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