INTRODUCTION — Surgical excision is the treatment of choice for early cutaneous melanoma and is curative in most cases. However, some patients will subsequently relapse with disseminated disease. High-risk features in the primary tumor and regional lymph node metastasis define patient subsets that are at increased risk for recurrent disease.
The use of immunotherapy and targeted therapy as adjuvant treatment for high-risk melanoma will be reviewed here. The initial management of cutaneous melanoma and the management of patients with metastatic disease are discussed separately. (See "Initial surgical management of melanoma of the skin and unusual sites" and "Overview of the management of advanced cutaneous melanoma".)
GENERAL APPROACH TO ADJUVANT THERAPY
Staging, tumor characteristics, and prognosis — For patients who have undergone a complete resection of a cutaneous melanoma, the decision of whether or not to recommend adjuvant therapy depends upon the risk of disease recurrence, based upon the stage at diagnosis, along with a consideration of patient age, comorbidity, and personal preferences.
The extent and characteristics of the primary tumor and regional lymph node involvement allow classification of patients into different risk categories. The eighth edition of the tumor, nodes, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) (table 1A-B) incorporates the most important determinants of prognosis and is the basis for specific recommendations regarding adjuvant therapy [1,2]. In addition, the mutation status of the primary tumor may influence the choice of specific adjuvant therapy. (See "Tumor node metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)
●For the primary tumor (T), increasing tumor thickness, an increased mitotic rate, and the presence of ulceration (ie, the loss of the epidermal layer overlying the primary tumor) are associated with an increased risk of relapse (figure 1).
●The presence of lymph node involvement is associated with a significant increase in risk of recurrence, and this is further subdivided based upon the number and extent of lymph node disease (figure 2).
●The presence of a characteristic BRAF V600 mutation in the primary tumor may allow use of adjuvant targeted therapy rather than adjuvant immunotherapy.
Specific recommendations regarding the use of adjuvant therapy are summarized in this section for different risk groups. The clinical trial supporting data are discussed below.
Low-risk patients — The majority of patients diagnosed with melanoma present with stage I or IIA disease (≤2 mm in thickness with ulceration, or localized tumor ≤4 mm in thickness without ulceration) and a negative sentinel lymph node biopsy. In these patients, surgery is usually curative, and adjuvant therapy is not indicated except in the context of a formal clinical trial .
High-risk node-negative (stage IIB or IIC) disease — Patients without lymph node involvement but with high-risk features in their primary tumor are at increased risk for recurrence and disease dissemination. High-risk primary tumors include those that are >4 mm thick, or >2 mm thick with ulceration. High-risk node-negative patients were excluded from the phase III clinical trials evaluating nivolumab, ipilimumab, and targeted therapy with dabrafenib plus trametinib [4-6].
Adjuvant therapy with checkpoint inhibitors or targeted agents has not been evaluated in this patient population. Despite the increased risk of recurrence, adjuvant therapy is not generally recommended because of the toxicity associated with adjuvant therapy and the relatively favorable prognosis compared with those with lymph node involvement. Clinical trial enrollment with a checkpoint inhibitor or targeted therapy may be an alternative.
Stage III disease — Stage III in the eighth AJCC prognostic stage group system is defined by the presence of lymph node involvement and the absence of distant metastases (table 1A-B). For patients who have stage III melanoma, adjuvant immunotherapy with nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, is generally indicated. (See 'Nivolumab' below.)
For patients whose tumor contains a BRAF V600 mutation, dabrafenib and trametinib could be an alternative, particularly for patients with stage IIIA or IIIB disease or for those who are unable to take adjuvant immunotherapy due to active autoimmune disease or the need for immunosuppressive therapy. (See 'Dabrafenib plus trametinib' below.)
In patients with stage IIIA disease, the risk of disease recurrence is less than 20 percent and therefore observation should also be considered an option.
Pediatric and adolescent patients — As in adults, adjuvant therapy has generally been used for patients with localized disease at increased risk for disease dissemination due to regional lymph node disease or a high-risk primary tumor. However, data on the efficacy of adjuvant therapy in children and adolescents are lacking, and the treatment approach is generally based upon that used for adults.
CHECKPOINT INHIBITOR IMMUNOTHERAPY — Checkpoint inhibition immunotherapy has represented an important advance in the treatment of patients with metastatic melanoma. These results led to the evaluation of these agents in the adjuvant setting for patients at high risk for recurrence following initial surgery. (See "Principles of cancer immunotherapy" and "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Anti-PD-1 monoclonal antibodies'.)
●Nivolumab, which targets programmed cell death protein 1 (PD-1), is the preferred agent for checkpoint inhibitor immunotherapy, based upon significant improvement in relapse-free survival (RFS) and decreased toxicity compared with ipilimumab in a large phase III trial. (See 'Nivolumab' below.)
●Ipilimumab, which targets cytotoxic T lymphocyte-associated protein 4 (CTLA-4), was approved for use in the adjuvant setting based upon a phase III trial that demonstrated improved disease-free and overall survival compared with interferon alfa. (See 'Ipilimumab' below.)
Although ipilimumab has been replaced by the more effective and less toxic nivolumab, it could be an option for patients who have BRAF WT disease that is resected after experiencing disease progression on or soon after nivolumab therapy.
Nivolumab — Nivolumab prolonged RFS while reducing toxicity in a phase III clinical trial in which 906 patients were randomly assigned to nivolumab (3 mg/kg every two weeks for one year) or ipilimumab (10 mg/kg every three weeks for four doses, and then every twelve weeks for up to one year) .
All patients had undergone a complete resection of stage IIIB, IIIC, or IV disease within 12 weeks prior to randomization. Patients with ocular melanoma were excluded, as were patients using systemic corticosteroids or those who had received prior systemic therapy for melanoma. Patients with acral and mucosal melanoma were allowed. Overall, 29 percent of patients had microscopic nodal involvement, while 71 percent had either macroscopic lymph node disease or resected stage IV disease. BRAF mutations were present in 42 percent, absent in 45 percent, and not determined in 4 percent.
●Recurrence-free survival, the primary endpoint of the trial, was significantly increased with nivolumab compared with ipilimumab (at 12 months, 70.5 versus 60.8 percent, and at 18 months, 66.4 versus 52.7 percent; hazard ratio [HR] 0.65, 95% CI 0.51-0.83). A similar benefit was seen with nivolumab both in those with programmed cell death ligand 1 (PD-L1) expression ≥5 percent and those with PD-L1 expression <5 percent.
•A similar degree of improvement with nivolumab was seen in the prespecified major subgroups, including stage III versus stage IV disease, the presence or absence of ulceration, the extent of lymph node involvement (microscopic versus macroscopic), PD-L1 status, and BRAF mutation status.
●Toxicity was significantly decreased with nivolumab, with grade 3 or 4 treatment-related adverse events reported in 14 percent of patients treated with nivolumab versus 46 percent of those assigned to ipilimumab.
●Additional follow-up will be required to assess the impact on overall survival.
Nivolumab was approved by the US Food and Drug administration in December 2017 for adjuvant treatment of patients who had undergone definitive resection of a cutaneous melanoma and had metastatic lymph node involvement, and for patients with stage IV disease who had undergone definitive resection of all sites of disease . The original approval of nivolumab as adjuvant therapy used a schedule of 240 mg every two weeks. Subsequently, an alternative schedule of nivolumab 480 mg every four weeks was approved based upon clinical pharmacology analyses and safety assessments .
Pembrolizumab — A phase III trial comparing pembrolizumab with placebo has completed accrual for patients with high-risk stage III melanoma following complete resection (NCT02362594). Results are pending. A phase III cooperative group trial (NCT02506153, Southwest Oncology Group S1404) comparing pembrolizumab with high-dose interferon or high-dose ipilimumab is ongoing in patients with high-risk stage III or IVA disease following complete resection.
Ipilimumab — The use of ipilimumab as an adjuvant for resected high-risk melanoma was based upon the results of a phase III trial in which ipilimumab significantly decreased the rate of recurrence and improved overall survival compared with placebo. Although there are no results directly comparing ipilimumab with interferon alfa (IFNa), the magnitude of the overall survival benefit with ipilimumab (on the 10 mg/kg schedule) made this the preferred agent for patients with stage III disease prior to the development of nivolumab as an adjuvant.
Efficacy and toxicity — In the European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial, 951 patients were randomly assigned to either ipilimumab or placebo [4,9]. All patients had stage III melanoma, and 80 percent had stage IIIB or IIIC disease. The other 20 percent had stage IIIA disease with melanoma >1 mm diameter in the sentinel lymph node.
Treatment with ipilimumab was given at a dose of 10 mg/kg every three weeks for four doses, then every three months for three years unless toxicity or relapse prevented its continuation. Placebo was given on the same schedule.
The primary endpoint of the trial was RFS; overall survival and distant metastasis-free survival (DMFS) were secondary endpoints. Results were updated at a median follow-up of 5.3 years :
●RFS was significantly better with ipilimumab compared with placebo (five-year RFS 40.8 versus 30.3 percent, HR 0.76, 95% CI 0.64-0.89).
●DMFS was significantly better with ipilimumab (five-year DMFS 48.3 versus 38.9 percent, HR 0.76, 95% CI 0.64-0.92).
●Overall survival was significantly prolonged with ipilimumab (five-year overall survival 65.4 versus 54.4 percent, HR 0.72, 95% CI 0.58-0.88, p = 0.001). This benefit was seen despite the use of various systemic therapies in patients who subsequently developed recurrent disease.
●Toxicity associated with adjuvant ipilimumab was significant. Adverse events of any grade were observed in 98.7 percent of patients treated with ipilimumab, including 54.1 with grade 3 or 4 adverse events. Grade 3 or 4 immune-related adverse effects occurred in 41.6 percent of patients and led to treatment discontinuation or, rarely, death. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
•The most common immune-related adverse events included dermatologic, gastrointestinal, endocrine, and hepatic toxicity (grade 3 or higher in 4.2, 16.8, 7.8, and 10.9 percent of patients, respectively).
•There were five treatment-related deaths in patients treated with ipilimumab (three due to colitis, one to myocarditis, and one to multiorgan failure associated with Guillain-Barré syndrome).
●Quality of life was assessed using the EORTC Quality of Life Questionnaire version 3.0 (QLQ-C30) . There was a statistically significant decrement in global health status both during and after induction therapy, but the difference did not exceed the clinically relevant threshold.
Dose of ipilimumab — Based upon the initially reported results of the EORTC 18071 trial , ipilimumab was approved at a dose of 10 mg/kg for use as an adjuvant. The dose used in that trial (10 mg/kg) is different from the dose used for metastatic disease (3 mg/kg) and is associated with increased toxicity. However, in patients with metastatic disease, ipilimumab on the 10 mg/kg schedule has been shown to produce a superior three-year overall survival rate compared with ipilimumab 3 mg/kg (31 versus 23 percent) in patients with stage IV disease . (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Dose and schedule'.)
A second phase III trial in the adjuvant setting is comparing ipilimumab at one of two doses (the 10 mg/kg dose or 3 mg/kg dose) with high-dose IFN (E-1609, NCT01274338). It has overall survival and RFS as coprimary endpoints.
An unplanned exploratory analysis of the E-1609 trial was presented at the 2017 American Society of Clinical Oncology (ASCO) meeting . This was based on a 3.1 year follow-up of 773 concurrently randomized patients treated with ipilimumab at either 3 or 10 mg/kg. Toxicity was lower with the 3 mg/kg schedule compared with the 10 mg/kg schedule (all grade 3-4 adverse events 36.6 versus 56.5 percent and grade 3-4 immune-related adverse events 18.8 versus 34.0 percent). There was no difference in the three-year RFS (42.3 and 42.6 percent, respectively, HR 1.0), but longer follow-up is required.
In those situations where ipilimumab is used as an alternative to nivolumab (ie, for patients who have BRAF WT disease that is resected after experiencing disease progression on or soon after nivolumab therapy), the data are unclear whether use ipilimumab on a 10 mg/kg or 3 mg/kg schedule.
TARGETED THERAPY — For patients with metastatic melanoma and a BRAF V600 driver mutation, treatment targeting the mitogen-activated protein (MAP) kinase pathway with a combination of a BRAF inhibitor and a MEK inhibitor is an important treatment option. These results have led to the evaluation of this approach in the adjuvant setting. (See "Molecularly targeted therapy for metastatic melanoma", section on 'BRAF-mutated tumors'.)
Dabrafenib plus trametinib — In a phase III trial, 870 patients with completely resected BRAF V600 mutation-positive stage III melanoma were randomly assigned to the combination of dabrafenib (150 mg twice a day) plus trametinib (2 mg once a day) or to matching placebos for one year .
At a median follow-up of 2.8 years (minimum 2.5 years), results included the following:
●Relapse-free survival, the primary endpoint of the trial, was significantly longer with dabrafenib plus trametinib compared with placebo (three-year rate 58 versus 39 percent, HR 0.47, 95% CI 0.39-0.58).
●Overall survival was prolonged with the targeted therapy (three-year rate 86 versus 77 percent, HR 0.57, 95% CI 0.42-0.79).
Vemurafenib — In a phase III trial, 498 patients were randomly assigned to vemurafenib (960 mg twice daily) or placebo for one year . All patients had completely resected stage IIC or III melanoma.
The primary endpoint, disease-free survival in the 184 patients with stage IIIC disease, was not achieved with vemurafenib compared with placebo (median 23.1 versus 15.4 months, HR 0.80, 95% CI 0.0.54-1.18). In 314 patients with stage IIC, IIIA, or IIIB disease, median disease-free survival was prolonged with vemurafenib (median not reached versus 36.9 months, HR 0.54, 95% CI 0.37-0.78), but this result was a secondary endpoint and should be considered exploratory.
INTERFERON ALFA — Prior to the development of checkpoint inhibitor immunotherapy, high-dose interferon alfa (IFNa) was the only option for adjuvant treatment of high-risk melanoma that had demonstrated an improvement in overall survival. The use of high-dose IFNa was supported by the results of the Eastern Cooperative Oncology Group (ECOG) 1684  and Intergroup E1694 trials , as well as a meta-analysis that included results from trials with various schedules and doses of IFNa .
Approaches to improve the therapeutic index of high-dose IFNa included the use of low or intermediate doses of IFNa [17-19], the use of combinations of IFNa with various chemotherapy regimens , and the use of pegylated IFN [21,22]. However, none of these approaches was superior to high-dose IFNa in terms of overall survival.
Furthermore, administration of adjuvant high-dose IFNa was associated with numerous serious side effects, including acute constitutional symptoms, chronic fatigue, myelosuppression, hepatotoxicity, and neurologic and psychologic effects, which were experienced to some degree by the majority of patients (table 2) .
IFNa no longer has a well-defined role in the adjuvant setting for cutaneous melanoma. The use of high-dose IFNa for high-risk node-negative disease may occasionally be an alternative, but its use should be discouraged in favor of clinical trial participation or observation.
RECURRENCE AFTER ADJUVANT THERAPY — For patients who recur with metastatic disease after initial adjuvant therapy, options include treatment with an alternative active systemic therapy or inclusion in a clinical trial. (See "Overview of the management of advanced cutaneous melanoma", section on 'After adjuvant therapy'.)
CLINICAL TRIAL PARTICIPATION — Despite the advances in adjuvant therapy, multiple clinical trials for adjuvant therapy are currently in progress with other promising approaches, especially combination approaches. Clinical trial participation (ClinicalTrials.gov) should be considered whenever possible.
OLDER EXPERIMENTAL APPROACHES — Biochemotherapy , bevacizumab [25,26], and granulocyte-macrophage colony-stimulating factor (GM-CSF)  were previous approaches with some data supporting their use, but these are no longer considered appropriate options given the new data with checkpoint inhibitors.
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
●Patients who have undergone a definitive resection of cutaneous melanoma generally do well. However, subsets of patients at increased risk of recurrence can be defined based upon the characteristics of the primary tumor (thickness, mitotic rate, ulceration) or the presence of lymph node metastases. (See 'General approach to adjuvant therapy' above.)
●Patients with lymph node involvement (American Joint Committee on Cancer [AJCC] stage III (table 1A-B)) and those with stage IV disease who have undergone definitive resection of all sites of disease are at significantly increased risk for recurrence and death from melanoma, and adjuvant immunotherapies and targeted therapies are now available that have been shown to improve survival in these patients. Selection of a specific agent depends largely on BRAF mutation status and toxicity profiles. (See 'Stage III disease' above.)
●In most patients whose tumor contains a BRAF V600 mutation, we suggest adjuvant nivolumab rather than targeted therapy (Grade 2C). Both have been shown to improve survival, but they have not been compared directly. Our preference for nivolumab in most patients is based on the safety and tolerability profile. (See 'Nivolumab' above and 'Targeted therapy' above.)
●In patients with stage IIIA disease, regardless of BRAF mutation status, the chance of disease recurrence is less than 20 percent, and therefore, observation should also be considered an option. (See 'General approach to adjuvant therapy' above.)
●Patients at increased risk of recurrence with stage II melanoma (primary tumor >4 mm, or >2 mm with ulceration) were also excluded from the phase III ipilimumab and nivolumab versus ipilimumab trials. Adjuvant therapy with checkpoint inhibitors or targeted agents has not been evaluated in this patient population. Despite the increased risk of recurrence, adjuvant therapy is not generally recommended because of the toxicity associated with adjuvant therapy and the relatively favorable prognosis compared with those with lymph node involvement, as well as the relatively high likelihood of significant benefit from systemic therapy in the small subset of patients who do ultimately relapse. (See 'High-risk node-negative (stage IIB or IIC) disease' above.)
Clinical trial enrollment with a checkpoint inhibitor or targeted therapy may be an alternative.
●For patients at low risk of recurrence (no lymph node involvement and tumor ≤4 mm in thickness without ulceration or ≤2 mm in thickness with ulceration, stage IIA (table 1A-B)), there is a high probability of cure. There is no evidence that adjuvant therapy improves the prognosis, and adjuvant therapy is not indicated. (See 'Low-risk patients' above.)
●Patients should be enrolled in formal clinical trials whenever feasible.