Melanoma

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The goals of treatment depend on disease-specific factors (melanoma stage and location) and patient factors, such as age and comorbidities).

For early stage melanoma, the goals of treatment are excision of the primary tumour, followed by wide local excision to prevent local and distant recurrence. For metastatic disease, the goal is to prolong survival and improve quality of life.

Where available, enrolment in a clinical trial is encouraged for all patients with melanoma.[14] Patients should be managed by a specialist skin cancer multidisciplinary team.[56]

Early stage melanoma

Early stage melanomas are confined to the skin. This group includes melanoma in situ, stage I, and stage II disease.

Wide local excision

The standard of care is wide local excision (WLE) of the primary site, with an appropriate margin.[14] [ ]

The recommended surgical margin increases as tumour thickness increases.[14] A melanoma with greater thickness is more likely to extend wider and deeper than the clinically and histologically apparent tumour.[83]

Recommended excision margins are:[14][56][75]

Melanoma in situ (confined to the epidermis): margin 0.5-1 cm. Margins >0.5 cm may be needed for lentigo maligna subtype melanomas
Tumour thickness ≤1 mm: margin 1 cm
Tumour thickness 1-2 mm: margin 1-2 cm
Tumour thickness >2-4 mm: margin 2 cm
Tumour thickness >4 mm: margin 2 cm.

Excision with wider margins is not associated with a better clinical outcome.[84][85]

Typically, for invasive melanoma all tissue is removed to the depth of the fascia. The fascia itself is preserved, unless involved by tumour.[14] Peripheral resection margins may be modified to accommodate individual anatomical or functional considerations; however, narrower margins may increase the risk for margin positivity and/or local recurrence.[14]

Mohs' micrographic surgery

Mohs' micrographic surgery (MMS) may be considered for selected patients with minimally invasive tumours affecting anatomically constrained sites, such as the ears, face, or acral areas.[14]

Excised tissue is processed into frozen horizontal sections for immediate histopathological analysis. The process is repeated until the tumour is completely removed, enabling maximum conservation of healthy tissue.[86] However, permanent (paraffin-fixed) sections are the gold standard for histological evaluation of excised melanoma.[14]

Atypical melanocytes may be more difficult to interpret on frozen sections compared with permanent sections. If MMS is used, the central debulking specimen should be analysed as a permanent section to provide complete staging information. It may be appropriate to delay wound closure or reconstruction until histological evaluation of the excised tissue is complete.[14]

One systematic review of comparative studies concluded that survival and local recurrence rates are similar for patients with melanoma on the trunk and extremities who are treated with MMS or WLE.[87] However, a further systematic review which included both comparative and non-comparative studies found that the rate of local recurrence of melanoma was significantly reduced with MMS compared with WLE.[88]

MMS is not currently recommended for treatment of melanoma if standard excision margins can be obtained.[14]

Alternatives to surgery

Topical imiquimod or radiotherapy can be considered for select patients with melanoma in situ or locoregional melanoma with positive margins after biopsy to exclude invasive disease, or post surgical excision when further resection is not feasible.[14][56]

There is evidence that topical imiquimod is safe and well tolerated, with clearance rates ranging from 53% to 92% for patients with melanoma in situ, and can attain unstable locoregional control for patients with metastatic melanoma.[89][90]

Sentinel lymph node biopsy

Sentinel lymph node biopsy (SLNB) is based on the concept that a tumour will drain to a particular first lymph node with a lymph node basin. There may be multiple draining lymph node basins and multiple sentinel nodes, depending on individual lymphatic drainage patterns.

A radiotracer or a blue dye is injected intradermally at the site of the primary lesion (before WLE) to identify the sentinel node.[14]

SLNB may be performed for selected patients with stage I and stage II melanoma. It permits accurate staging of patients with no clinical or radiological evidence of nodal metastases, and provides prognostic information. Sentinel lymph node status is the most important prognostic indicator in this group, and can determine next steps in treatment.[14][91]

SLNB does not improve overall survival for patients with melanoma, but subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-I showed that SLNB improves the 10-year distant disease-free survival for patients with melanomas between 1.2 mm and 3.5 mm in thickness.[73] [ ]

UK guidelines recommend considering SLNB as a staging (rather than therapeutic) procedure for patients with a Breslow's thickness of 0.8 to 1.0 mm, with at least one of following features.[56]

Ulceration
Lymphovascular invasion
A mitotic index of 2 or more.

For people without adverse prognostic features, SLNB should be considered with a Breslow's thickness of greater than 1.0 mm.[56] Consider delaying SLNB for pregnant women until postnatal.

National Comprehensive Cancer Network (NCCN) guidelines advise that SLNB should be discussed with patients with stage IB or II disease with the following considerations:[14]

Tumour thickness <0.8 mm with ulceration
Tumour thickness 0.8 to 1.0 mm with or without ulceration

Tumour thickness >0.5 mm who have additional adverse prognostic features (e.g., age ≤42 years, head/neck location, lymphovascular invasion, and/ or mitotic index ≥2/mm²)

The probability of a positive SLNB is 5% to 10% for these patients, with an increased risk for patients with multiple adverse prognostic features.[14]

SLNB is not generally recommended for patients with tumours <0.8 mm thick without ulceration or adverse prognostic features, unless there is significant uncertainty about the adequacy of microstaging (e.g., positive deep margins or limited sampling of a larger lesion). The risk of positive SLNB in these patients is <5%.[14]

One phase 3 trial reported that SLNB does not improve overall survival for patients with melanoma, but subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-I showed that SLNB improves the 10-year distant disease-free survival for patients with melanomas between 1.2 mm and 3.5 mm in thickness.[73] [ ] However, subsequent evidence from a systematic review demonstrated that SLNB is associated with improved overall survival in patients with head and neck cutaneous melanoma.[74]

Adjuvant treatment for stage IIB and IIC melanoma

For patients with resected stage IIB or IIC melanoma with negative sentinel nodes, adjuvant therapy with a PD-1 inhibitor (pembrolizumab or nivolumab) is recommended for patients with resected stage IIB and IIC melanoma.[14][92][93]

Patients with resected stage IB, IIB, or IIC melanoma with positive sentinel nodes should be treated as patients with primary stage III tumours.[14] (See section - Stage IIIA/B/C/D with positive sentinel nodes.)

If considered, the benefit and toxicity of treatment should be discussed with the patient. Additionally patient age, performance status, personal or family history of autoimmune disease, and tolerance of risk should be assessed.[14]

The first interim analysis of the Keynote-716 trial reported that at median follow-up of 14.4 months, pembrolizumab significantly prolonged recurrence-free survival, compared with placebo (hazard ratio [HR] 0.65, 95% CI 0.46 to 0.92) in patients with resected high-risk stage II melanoma.[94] The 12-month recurrence-free survival rate was 90.5% in the pembrolizumab group and 83.1% in the placebo group. Grade 3-5 drug-related adverse events occurred in 78 (16.1%) patients in the pembrolizumab group and 21 (4.3%) patients in the placebo group; 74 (15.3%) versus 12 (2.5%) discontinued because of a drug-related adverse event.[95] Immune-mediated adverse events occurred in 36.2% of patients in the pembrolizumab group, compared with 8.4% in the placebo group. The most common immune-mediated adverse events were hypothyroidism and hyperthyroidism. Most were grade 1-2 in severity.[95] At the second interim analysis, median follow-up of 20.9 months, 15% of patients in the pembrolizumab group and 24% in the placebo group had a first recurrence or died (HR 0.61, 95% CI 0.45 to 0.82).[96]

The pre-specified third interim analysis of the secondary outcomes of the KEYNOTE-716 trial reported that adjuvant pembrolizumab significantly improved distant metastasis-free survival, and reduced the risk of recurrence, compared with placebo.[97]

Stage IIIB with microscopic satellites in biopsy from the primary lesion

Microsatellitosis represents microscopically identified lymphatic metastases and indicate an increased risk of recurrence.[14] When microsatellitosis is present in the initial biopsy, the pathological stage is at least N1c in AJCC TNM staging, and therefore these patients should be treated as having at least stage IIIB disease.[14] Patients should be offered sentinel node biopsy, the decision not to perform SLNB may be based on significant patient comorbidities, patient preference, or other factors such as advanced patient age and/or poor functional status.[14] BRAF mutation testing should be completed if adjuvant systemic therapy or clinical trial is being considered.[14]

Stage IIIA/B/C/D with negative sentinel nodes

For patients who are sentinel node negative, or did not undergo SNLB, treatment options post wide excision include adjuvant systemic therapy (preferred options nivolumab, pembrolizumab, or dabrafenib plus trametinib if BRAF V600 mutation positive), observation or entry into a clinical trial.[14]

Stage IIIA/B/C/D with positive sentinel nodes

For patients with stage IIIA/B/C/D sentinel node positive melanoma BRAFmutation testing should be considered for those future BRAF-directed therapy may be an option.[14][56]

When SLNB is positive, the patient may be a candidate for completion lymph node dissection.[14][56] This is the removal of all lymph nodes in the regional nodal basin.

In the UK, routine completion lymph node dissection would not be offered to patients with stage III melanoma with micrometastatic nodal disease detected by SLNB unless:

there are factors that might make recurrent nodal disease difficult to manage; for example, for patients with melanoma of the head, neck for whom stage III adjuvant therapies are contraindicated, or when regular follow-up is not possible; and
after discussion with the patient and specialist skin cancer multidisciplinary team.

Complete therapeutic lymph node dissection is recommended for patients with palpable stage IIIB to IIID melanoma, or cytologically or histologically confirmed nodal disease.[56]

In the US, the preferred primary treatment for patients with stage III/B/C/D sentinel node positive melanoma is active nodal basin ultrasound or other radiographic surveillance without completion lymph node dissection if institutional expertise is available.[14]

In select clinical scenarios, for example, inability to adhere to clinical and imaging surveillance, or when primary tumour characteristics and SLN tumour burden predict a high likelihood of additional positive nodes, completion lymph node dissection may be considered for regional disease control.[14]

With or without completion node dissection, it is recommended that adjuvant systemic therapy be considered based on the risk of recurrence.[14] Preferred regimens include nivolumab, pembrolizumab, dabrafenib plus trametinib if BRAF v600 positive.[14]

In patients with very low tumour volume stage IIIA disease (T1a/b–T2a/N1a or N2a), the toxicity of adjuvant therapy may outweigh the benefit.[14]

T1b–T2a/N1a or N2a pathological stage IIIA melanoma and SLN tumour deposits ≥0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy. Stage IIIA patients with SLN deposits <0.3 mm in maximum dimension demonstrate 5-year MSS similar to those with pathological stage IB (T2aN0) melanoma, with consideration for less intensive radiological surveillance and follow-up.[14]

Stage III melanoma with clinically positive nodes

Clinically positive (i.e., palpable) lymph nodes are associated with a worse prognosis than non-palpable lymph nodes with microscopic evidence of melanoma only.[14] Treatment for patients with stage III clinical nodal disease include wide local excision with or without neoadjuvant systemic therapy, followed by adjuvant systemic treatment and/or locoregional therapy, or observation.[14] The choice of observation versus adjuvant systemic treatment should take into consideration the patient’s risk of melanoma recurrence and the risk of treatment toxicity.[14]

Neoadjuvant systemic therapy for resectable advanced stage III melanoma - nodal disease

Preferred regimens for neoadjuvant systemic therapy for patients with resectable stage III nodal disease include pembrolizumab, nivolumab plus ipilimumab, or dabrafenib plus trametinib for patients who are BRAF V600 mutation positive.[14][92]

Several trials of neoadjuvant therapy are underway, with preliminary results indicating a promising role for this treatment approach in those who achieve pathological complete response at the time of surgery.[98][99][100][101][102][103] One phase 3 trial of patients with resectable, macroscopic stage III melanoma reported that neoadjuvant nivolumab plus ipilimumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab.[104]

Surgery for resectable advanced stage III melanoma - nodal disease

Wide local excision of the primary lesion should be performed for all patients with advanced stage III nodal disease either post neoadjuvant systemic therapy or as initial treatment.[14] Surgery may include therapeutic lymph node dissection if not performed earlier.[14]

Adjuvant systemic treatments for resectable advanced stage III melanoma - nodal disease

After surgery, patients should be offered adjuvant treatment with a PD-1 inhibitor (nivolumab or pembrolizumab). BRAF/MEK inhibition with dabrafenib plus trametinib is an alternative adjuvant treatment option for patients with an activating BRAF-V600 mutation.[14][92]

If patients have received neoadjuvant pembrolizumab, it is recommended that pembrolizumab is given as adjuvant treatment.[92] In the UK, pembrolizumab or nivolumab are recommended as an option for the adjuvant treatment of completely resected stage III melanoma with lymph node involvement in adults.[105][106]

Adjuvant treatment has been demonstrated to improve the rate of recurrence-free survival, compared with patients managed without adjuvant treatment.[107][108]

PD-1 inhibitors

Antibodies to programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) block the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumour cells, thus facilitating anti-tumour immunity. They have demonstrated superior efficacy and a more favourable toxicity profile than the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, ipilimumab.

In the CheckMate-238 trial, patients (n=906) with stage IIIB/IIIC and resected stage IV melanoma were randomised to nivolumab or ipilimumab for 1 year.[109] Nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab.

Keynote-054 examined the use of adjuvant pembrolizumab in patients with resected stage III melanoma.[110][111] Patients (n=1019) were randomised to either pembrolizumab or placebo for 1 year. At a median follow-up of 15 months, treatment with pembrolizumab resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified.[110] Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival (a secondary endpoint) at a 3·5-year median follow-up.[112]

BRAF and MEK inhibition

The combination of dabrafenib (a BRAF inhibitor) plus trametinib (a MEK inhibitor) was explored in the COMBI-AD study.[113][114] Patients (n=870) with fully resected stage III melanoma with BRAF V600E or V600K mutations and no prior radiotherapy or systemic therapy were randomised to either dabrafenib plus trametinib or two matched placebos, for 12 months. The trial met its primary endpoint of relapse-free survival, both at the time of the primary interim analysis at 2.8 years and in a subsequent analysis at 5 years. At 5 years of follow-up, relapse-free survival was 52% in the adjuvant dabrafenib plus trametinib group, compared with 36% in the placebo group (hazard ratio 0.51, 95% CI 0.42 to 0.61).[115] This result was consistent across all patient subgroups, regardless of stage III substage and the specific BRAF mutation.

Approximately 41% of patients receiving adjuvant dabrafenib plus trametinib experienced grade 3-4 adverse events, compared with 14% in the placebo group.[113] Furthermore, 26% of patients prematurely ceased adjuvant dabrafenib-trametinib because of toxicity, although no long-term toxicity or treatment-related deaths were reported.[113]

The BRIM8 trial examined the use of adjuvant vemurafenib (a BRAF inhibitor) in patients (n=498) with BRAF mutant stage IIC/III melanoma.[116] Patients were grouped into two cohorts; cohort 1 included patients with stage IIC, IIIA, and IIIB melanoma, while cohort 2 included stage IIIC disease. Patients in each cohort were randomised to vemurafenib or placebo. The trial's primary endpoint was disease-free survival, with prespecified hierarchical testing, wherein disease-free survival was tested in cohort 2 before cohort 1. The trial did not meet statistical significance in cohort 2, thereby also rendering cohort 1 data statistically insignificant. This trial is likely to have not met its endpoint of relapse-free survival because of the lack of combination BRAF and MEK inhibition, as dual agent therapy is required for successful blockade of the mitogen-activated protein (MAP) kinase pathway. The use of adjuvant single-agent BRAF inhibitors in patients with stage III BRAF mutant melanoma is not recommended.

Adjuvant radiotherapy for resectable advanced stage III melanoma - nodal disease

Radiotherapy (RT) to the nodal basin may be considered instead of or in addition to adjuvant systemic therapy in select patient who are at high risk for nodal recurrent based on the location, size, and number of involved nodes, and gross and/or histological extracapsular extension.[14]

Adjuvant nodal basin RT has been demonstrated to reduce lymph node field recurrence but no improvement has been shown in recurrence-free survival or overall survival in patients with advanced nodal melanoma.[14] Potential toxicities such as limb lymphoedema or oropharyngeal complications should be considered against the benefits of treatment.[14]

Unresectable stage III melanoma - nodal disease

For patients with unresectable nodal stage III melanoma who have undergone previous lymph node dissection, treatment options include: systemic treatment, and/or palliative radiotherapy, and or intralesional talimogene laherparepvec and/or best supportive care.[14]

See section - Limited resectable stage III melanoma - satellite/in-transit metastases for further information on systemic and localised treatment options.

For patients with unresectable nodal disease, consider treatment with systemic therapy followed by resection, or treat as stage IV distant metastatic melanoma.[14]

See section - Stage IV distant metastatic melanoma.

Limited resectable stage III melanoma - satellite/in-transit metastases

Lymphatic metastases can be characterised as clinically, radiologically, or pathologically detectable satellite metastases (dermal and/or subcutaneous intralymphatic metastases occurring within 2 cm from the primary melanoma), or in-transit metastases (identified between 2 cm from the primary melanoma and the regional nodal basin). The 2-cm cutoff is consistent with AJCC staging definitions, but satellite and in-transit lymphatic metastases are biologically and prognostically similar.[14]

Initial treatment pathways for limited resectable satellite/in-transit metastases, include:[14]

neoadjuvant systemic therapy followed by complete excision to clear margins,
initial complete excision to clear margins,
talimogene laherparepvec intralesional therapy, or
systemic therapy followed by clinical and pathological assessment to determine treatment response.

The outcome of initial treatment will determine any subsequent therapy.[14]

For further information on neoadjuvant systemic treatment options, see section - Resectable advanced stage III melanoma - nodal disease.

Excision to clear margins

Excision to clear margins is recommended, rather than wide excision, as there are no clinical data to support wider surgical margins for satellite/intransit metastasis; however, clear histological margins should be achieved.[14]

Systemic therapy for limited resectable stage III melanoma - satellite/in-transit metastases

Combination systemic therapy is preferred, recommended regimens include nivolumab plus ipilimumab or nivolumab/relatlimab, but monotherapy with pembrolizumab or nivolumab can be considered for patients who do not want to take on a higher risk of toxicity, or who have comorbidities or autoimmune processes that would elevate the risk of immune-related adverse events.[14]

For patients with BRAF V600 mutation combination regimens include dabrafenib plus trametinib, vemurafenib plus cobimetinib, encorafenib plus binimetinib or pembrolizumab plus ipilimumab.[14]

Nivolumab plus ipilimumab

Nivolumab plus ipilimumab has been shown to have superior efficacy to ipilimumab monotherapy with ipilimumab for patients with advanced melanoma.[117][118][119]

The CheckMate 204 open-label trial reported that nivolumab plus ipilimumab significantly improved intracranial response rates, overall survival rates, and progression-free survival rates in patients with asymptomatic brain metastases.[120][121]

The CheckMate 067 trial compared nivolumab plus ipilimumab, nivolumab alone, and ipilimumab alone in patients with previously untreated, unresectable stage III or IV melanoma.[119] Median overall survival after a minimum follow-up of 6.5 years was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median melanoma-specific survival was not reached, 58.7 months, and 21.9 months, respectively. Overall survival rates at 6.5 years were 57%, 43%, and 25% in patients with BRAF-mutant tumours, and 46%, 42%, and 22% in those with BRAF wild-type tumours, respectively.[119] One indirect comparison demonstrated that nivolumab plus ipilimumab, and nivolumab/relatlimab have similar progression-free survival and overall survival rates in patients with advanced melanoma.[122]

Early data suggest that those who derive greater benefit from combined nivolumab and ipilimumab than from nivolumab monotherapy have tumours that do not express PD-L1.[118]

Nivolumab/relatlimab

Fixed-dose combination of nivolumab/relatlimab has been demonstrated to improve progression-free survival at 12 months, and at 3 years compared with nivolumab alone patients with advanced melanoma.[123][124]

One network meta-analysis reported that for patients with advanced melanoma combination therapy with nivolumab/relatlimab demonstrated similar benefits for progression-free survival and overall response rate as patients treated with nivolumab plus ipilimumab.[125]

Available data on the use of nivolumab/relatlimab demonstrated a median progression-free survival of 10.1 months in the first-line setting.[126] This benefit was seen more frequently in patients with PD-L1 <1% and LAG-3 ≥1%.[126]

Immune-related adverse effects are common in patients treated with nivolumab/relatlimab compared to nivolumab alone.[123] Grade 3 or 4 treatment-related adverse effects are reported to occur in approximately 19% of patients treated with nivolumab/relatlimab compared with ~10% of patients receiving nivolumab alone.[123]

PD-1 inhibitor monotherapy

The PD-1 inhibitors nivolumab and pembrolizumab have demonstrated greater efficacy than standard chemotherapy with dacarbazine, and CTLA-4 inhibition with ipilimumab.[127][128]

A 5-year analysis of nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma confirmed the significant benefit of nivolumab monotherapy over dacarbazine for all endpoints including long-term survival.[129] Objective response rates are approximately 40% (although an estimated 60% of patients have some degree of tumour regression) and survival can be durable.[127][128][130]

A randomised controlled trial compared pembrolizumab monotherapy with ipilimumab (a fully human immunoglobulin G1 [IgG1] monoclonal antibody that blocks CTLA-4) monotherapy for patients with advanced melanoma.[127] Patients treated with pembrolizumab had a better response rate, 6-month progression-free survival, and 12-month survival, compared with patients treated with ipilimumab. Six-month progression-free survival was approximately 47% in the two pembrolizumab groups (2 weeks vs. 3 weeks dosing interval), compared with 27.5% in the ipilimumab group. Serious treatment-related adverse events were less common in the pembrolizumab groups, compared with the ipilimumab groups.[127] Further analysis after 22 months demonstrated a persistent survival benefit with pembrolizumab, compared with ipilimumab.[131] The 7-year follow-up study reported that pembrolizumab improved survival rates compared with ipilimumab (median overall survival of 32.7 months vs. 15.9 months, respectively; HR 0.70; 95% CI 0.58 to 0.83; 7-year overall survival of 37.8% and 25.3%).[132]

Adverse events of immunotherapeutic agents for advanced melanoma may include thyroiditis, skin reactions, colitis, pneumonitis, hepatitis, arthropathies, and cardiac and neurological toxicities.[133] Immunotherapy-related adverse events can affect any organ and presentation can vary greatly between patients.

Localised treatments for for limited resectable stage III melanoma - satellite/in-transit metastases

Some evidence suggests that talimogene laherparepvec, a modified herpes virus that induces tumour lysis and localised expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in tumour lesions, in combination with systemic treatment may increase the effectiveness of the systemic agents.[134] However, one phase 3 trial reported the talimogene laherparepvec did not significantly improve progression-free survival or overall survival when added to pembrolizumab compared with placebo/pembrolizumab in patients with advanced melanoma.[135]

Direct injection of an agent into in-transit metastases has been shown to produce local ablative effects and occasionally a systemic host response with tumour reduction in non-injected metastases.[136]

Unresectable/borderline resectable stage III melanoma - satellite/in-transit metastases

For patients with unresectable/borderline resectable stage III melanoma with satellite/in-transit metastases initial treatment options include systemic therapy, or regional therapy options, such as talimogene laherparepvec, radiotherapy, palliation of symptomatic disease (limited excision, local ablation therapy) or isolated limb infusion/perfusion with melphalan-based regimen in certain circumstances.[14][56] Further treatment will be determined by pathological and assessment imaging to evaluate response to initial treatment.[14]

Limited excision surgery

In the UK, limited excision surgery should be offered as a first-line option to patients with stage III in-transit metastases.[56] US guidelines recommend systemic therapies as the preferred initial treatment.[14]

Systemic therapy for unresectable/borderline resectable stage III melanoma - satellite/in-transit metastases

Preferred systemic therapy regimens include nivolumab plus ipilimumab, or nivolumab/relatlimab, or monotherapy with pembrolizumab or nivolumab in certain circumstances, e.g., for patients with low-volume in-transit disease, the high risk of toxicities associated with combination regimens may outweigh the benefits.[14]

For patients with BRAF V600 mutation combination regimens include dabrafenib plus trametinib, vemurafenib plus cobimetinib, encorafenib plus binimetinib or pembrolizumab plus ipilimumab.[14]

For patients who have previously received systemic therapy, either as active treatment or adjuvant therapy, the selection of the systemic therapy regimen should be informed by prior response.[14] Patients who experience disease progression during or shortly after a prior therapy should consider a different class of systemic agent. For patients who experience disease control on a prior systemic therapy, and have no residual toxicity, but subsequently experienced disease progression/relapse >3 months after treatment discontinuation, systemic therapy with the same agent or same class of agents may be considered.[14]

Radiotherapy for unresectable/borderline resectable stage III melanoma - satellite/in-transit metastases

Definitive or palliative RT can be considered for unresectable melanoma, depending on the goal of treatment. Definitive RT has the intent of durable irradiated tumour control. Palliative RT has the intent of relieving symptoms caused by tumour.[14]

Localised treatments for unresectable/borderline resectable stage III melanoma - satellite/in-transit metastases

Talimogene laherparepvec has been associated with a response rate (lasting ≥6 months) of 16% in highly selected patients with unresectable metastatic melanoma.[14] Efficacy was demonstrated in AJCC 7th Edition stage IIIB and IIIC disease, and was more likely to be seen in patients who were treatment naïve. Talimogene laherparepvec has shown similar efficacy across clinically detected/macroscopic AJCC 8th Edition stage III disease.[14] In the UK, talimogene laherparepvec is only recommended for patients with unresectable melanoma in adults with systemic therapy is not suitable.[56][137]

Electrochemotherapy, a local injection of chemotherapeutic agents (e.g., bleomycin) followed by an electrical impulse, is not recommended in the US.[14] However, a European guideline suggests that it may be proposed as part of a clinical trial for patients with satellite/in-transit metastases.[138] While in the UK, electrochemotherapy should only be considered as part of palliative treatment.[56] There is evidence to suggest that electrochemotherapy is effective for the treatment of metastatic cutaneous melanoma.[139][140][141][142][143]

Regional treatments for unresectable/borderline resectable stage III melanoma - satellite/in-transit metastases

Isolated limb infusion or perfusion (ILI/ILP) is primarily used for patients with limb only disease with progression on/ contraindications to standard therapies.[14] This procedure should only be done at centres with experience with ILI/ILP. In the UK, ILI/ILP would only be considered for patients in whom surgery is not feasible, or who have recurrent in-transit metastases.[56]

Stage IV distant metastatic melanoma

For patients with distant metastatic melanoma, BRAF mutation testing should considered if not previously performed on a metastatic lesion.[14] Treatment options differ depending on whether patients have oligometastasis or widely disseminated distant metastases.[14]

Oligometastatic distant metastases

Initial treatment for oligometastatic disease includes metastasis-directed therapy options such as resection, stereotactic ablative therapy, talimogene laherparepvec intralesional therapy (for accessible lesions), or systemic therapy.[14] Preferred systemic options include:[14]

Nivolumab plus ipilimumab
Nivolumab/relatlimab
Pembrolizumab
Nivolumab

Combinations for BRAF V600 mutation include:[14]

Dabrafenib plus trametinib
Vemurafenib plus cobimetinib
Encorafenib plus binimetinib
Pembrolizumab plus ipilimumab

Considerations for using combination therapy versus monotherapy include:

Patient’s desire for potentially improved efficacy and willingness to take on a higher risk of toxicity.
Absence of comorbidities or autoimmune processes that would elevate the risk of immune-related adverse effects.
Tumour burden and patient social support and preparedness to work with medical team to handle toxicities.

In the UK, surgery or other ablative treatment to prevent or control symptoms of oligometastatic stage IV melanoma should be considered.[56]

Treatment plans should be discussed by a multidisciplinary team.[14][56]

For evidence on systemic therapy see sections - Limited resectable stage III melanoma - satellite/in-transit metastases and Resectable advanced stage III melanoma - nodal disease.

For evidence on talimogene laherparepvec see section - Limited resectable stage III melanoma - satellite/in-transit metastases.

Widely disseminated distant metastases

Treatment for patients with widely disseminated distant metastases is determined on whether they have brain metastases or not.[14]

Without brain metastases

Initial treatment options for patients with widely disseminated distant metastases without brain metastasis include systemic therapy, palliative resection and/or radiotherapy and/or intralesional talimogene laherparepvec for symptomatic extracranial disease, or best supportive/palliative care.[14]

For preferred systemic therapy regimens please see section - Oligometastatic distant metastases

With brain metastases

For patients with brain metastases a multidisciplinary evaluation (i.e., neurosurgery, radiation oncology, medical oncology) prior to initiation of treatment is strongly recommended.[14]

The management of symptoms for patients with brain metastases includes corticosteroids (lowest dose possible), and may include standard first-line anticonvulsants for patients who experience seizures.[14]

Patients with a higher burden of intracranial disease associated with symptoms will often require brain-directed therapies, e.g., surgery, radiotherapy (stereotactic radiosurgery (SRS)), palliative whole-body radiation treatment (WBRT).[14]

In patients with lower volume of asymptomatic brain metastases as well as those with extensive extracranial disease, an initial course of systemic therapy may be preferred.[14]

It is likely that many patients presenting with brain metastases will need both systemic therapy and local brain-directed therapy over their course of treatment.[14]

The selection of initial treatment will depend on a combination of clinical factors, such as:[14]

The extent of intracranial disease, including factors such as the size, number, and location of metastases, guides the initial treatment of brain metastases.
Brain-directed therapy is preferred for patients with symptomatic metastases as there are sparse data supporting the efficacy of upfront systemic therapy.
In patients with other high-risk clinical scenarios (e.g., haemorrhage, eloquent cortex, brainstem), brain-directed therapy may be preferred over systemic therapy.
The context in which the brain metastases developed should be considered when selecting initial treatment. In patients who develop brain metastases while on systemic therapy, brain-directed therapy may be preferred.

For patients with <3 cm asymptomatic brain metastases, who do not require corticosteroids, and have had no prior systemic treatment may be considered for systemic therapy, no brain-directed therapy may be required in the absence of intracranial progression.[14]

For patients with symptomatic brain metastases initially requiring corticosteroids, surgical resection, SRS, or BRAF/MEK inhibition, it may be useful to reduce corticosteroid dose prior to transitioning to immunotherapy.[14]

The American Society for Clinical Oncology suggests that SRS, whole-brain radiation (WBRT), or a combination of SRS plus WBRT may all be considered as options for patients with more than four unresected brain metastases, with a KPS ≥70. For patients with a better prognosis, or if effective systemic therapy is available, SRS may be the preferred option.[144]

Surgery

Surgery is the preferred option for large, symptomatic lesions or single lesions in resectable areas, particularly when there is diagnostic uncertainty or when additional tissue sampling may drive future therapeutic decisions.[14]

Post-operative radiation to the resection cavity may be considered to decrease the risk of local recurrence.
Adjuvant WBRT is not recommended after resection for melanoma brain metastases.

Stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT)

SRS is the preferred radiation modality for treating melanoma brain metastases, and is used to deliver high-dose radiation to multiple lesions, usually in the brain or spine.[14]

Large lesions should be treated with fractionated SRS to decrease the risk of radionecrosis.
Adjuvant WBRT is not recommended after SRS/SRT for melanoma brain metastases.

SRS may be offered to patients with resected brain metastases depending on the size of the cavity (<5 cm).[14][144]

Cavities larger than 5 cm can be treated with SRT.[14]

SRS, as either gamma knife or linear accelerator radiosurgery, has shown a survival benefit in brain metastases treated with either modality.[145] These techniques seem to have comparable efficacy in both survival rates and decreased size of tumour, with a lower adverse effect profile compared with whole-brain irradiation.[146]

For patients with melanoma brain metastasis (MBM), radiotherapy combined with immune checkpoint inhibitors improves the effective rate of treatment.[147] Evidence has demonstrated that immune checkpoint inhibitors plus radiotherapy significantly improves overall survival for patients with MBM.[148][149][150][151] The addition of radiotherapy may enhance the immune checkpoint inhibitor efficacy and induce more durable response via the abscopal effect.[152][153] One study reported that immune checkpoint inhibitors plus radiotherapy non-significantly increased ≥3 neurological adverse effects, and ≥3 radiation necrosis compared with radiotherapy alone for patients with MBM.[149]

Metastatic or unresectable melanoma

For patients with unresectable melanoma, systemic therapy is the preferred treatment and/or palliative radiotherapy, and/or intralesional talimogene laherparepvec, and/or best supportive care.[14]

For preferred systemic therapy regimens please see section - Oligometastatic distant metastases.

BRAF/MEK inhibitors for unresectable melanoma

One phase 3 trial in patients with treatment-naive BRAFV600-mutant metastatic melanoma demonstrated that initial treatment with nivolumab plus ipilimumab followed by dabrafenib plus trametinib at disease progression significantly improved 2-year overall survival rates compared with initial treatment with dabrafenib plus trametinib, followed by nivolumab plus ipilimumab at disease progression.[154]

Nonetheless, because of the higher overall response rates and favourable time to response associated with BRAF/MEK inhibitors, they may be preferred when rapid disease control is required (e.g., compromise or imminent compromise of critical organs). In settings of low disease burden, slow progression, or where organ compromise is not imminent, immunotherapy is the preferred first-line treatment.[138][155]

Combination BRAF and MEK inhibitor therapy has been shown to be superior to BRAF inhibitor monotherapy.[114][156][157][158][159][160][161] Dabrafenib plus trametinib, and encorafenib plus binimetinib, have been demonstrated to significantly improve response and survival rates in patients with BRAF V600 melanoma compared with placebo or vemurafenib monotherapy.[156][157][160]

Cutaneous squamous cell carcinoma and other skin toxicities are reduced with combination therapy.[156][157] Incidence of grade 3 toxicity is similar between combination and single agents; however, the profile of adverse events tends to differ.[157][160] An open-label follow-up study reported that encorafenib plus binimetinib continued to have long-term benefits and a consistent safety profile at 5 years.[162]

Staging of melanoma

The American Joint Committee on Cancer (AJCC) staging system describes the extent of disease based on the following anatomic factors: size and extent of the primary tumour (T); regional lymph node involvement (N); and presence or absence of distant metastases (M). Non-anatomic prognostic factors (e.g., tumour grade, biomarkers) may be used to supplement the staging of certain cancers.[62]

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