SEOM clinical guideline for the management of malignant melanoma (2017)

All melanoma suspected patients must be confirmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams.

## Surgical management of melanoma
Excisional biopsy with a 2 mm lateral margin and deep subcutaneous margin is indicated for any suspicious lesion (Grade recommendation A; Level of Evidence 1a). Once the diagnosis is confirmed by the pathologist, definitive surgery is done to obtain wide margins. The deep margin should extend to the fascia (Grade recommendation B; Level of Evidence 2b), whereas lateral margins will be determined by Breslow thickness: 1 cm if Breslow up to 1 mm; 1-2 cm for Breslow 1-2 mm; and 2 cm if Breslow [ 2 mm (Grade recommendation A; Level of Evidence 1a). Wider margins do not provide benefit regarding recurrence or melanoma-related death rates [bib_ref] Long term follow up of survival in a randomised trial of wide..., Hayes [/bib_ref].
Sentinel lymph node biopsy is recommended in melanomas over 1 mm depth (Grade recommendation A; Level of Evidence 1a). It can also be considered for melanomas with Breslow 0.75-1 mm of Breslow and any risk factor such as ulceration, Clark level IV, regression, increased mitotic rate or age less than 40 (Grade recommendation B; Level of Evidence 1a) [bib_ref] Melanoma thickness and histology predict sentinel lymph node status, Nguyen [/bib_ref]. Complete lymph node dissection of the involved nodal basin must be performed if sentinel node is positive or there are clinically positive nodes (stages IIB or IIIC) (Grade recommendation A; Level of Evidence 2a).
Surgical excision of solitary metastases is indicated whenever possible. Data from retrospective studies demonstrated survival rates of 20-30% at 5 years after surgical removal of single metastases (Grade recommendation B; Level of Evidence 2b).

## Adjuvant therapy
There is high risk of relapse for patients with stages IIB-C (T4 or with ulceration) and stage III (N positive). High-risk patients are considered candidates for adjuvant treatment. Interferon alpha high dose scheme (Induction treatment with 20 MU/m 2 iv 9 5 days/week 9 4 weeks, followed by maintenance treatment with 10 MU/m 2 sc 9 3 days/ week 9 11 months) demonstrated a significant benefit in relapse-free survival versus observation. Although initially this benefit extended to overall survival, a follow-up superior to 12 years showed no significant differences [bib_ref] A pooled analysis of eastern cooperative oncology group and intergroup trials of..., Kirkwood [/bib_ref]. After that, many studies have evaluated the efficacy and toxicity profile of this drug relative to other agents or different schemes and dosage. Low-dose interferon significantly improves RFS for stages II, but not significant in overall survival. However, evaluated in the global context of high-risk population (stages II and III) they are clearly inferior to high doses [bib_ref] High-and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial..., Kirkwood [/bib_ref]. With all of these conflicting results about benefit in OS, recently several meta-analyses have tried to answer this question. Whereas one of them confirmed the significant improvement in RFS, but not for OS [bib_ref] Disease Site G. Adjuvant interferon therapy for patients at high risk for..., Petrella [/bib_ref] , other meta-analyses have demonstrated a significant benefit in OS [bib_ref] Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma, Mocellin [/bib_ref]. Nevertheless, none of them have been able to respond the answer about the optimal IFNa treatment scheme and which subgroup of patients will be the best candidates to receive it.
Given these results, high-risk melanoma patients could be offered interferon adjuvant therapy unless there is a better treatment (Grade recommendation A; Level of Evidence 1a).
Adjuvant Ipilimumab at 10 mg/kg schedule has demonstrated in a phase III clinical trial (EORTC 18,071) an improvement in RFS and OS compared with placebo in resected stage III melanoma. More than 50% of patients experienced grade 3-4 adverse events, with a discontinuation rate of 32% in patients treated with ipilimumab, including 5 toxic deaths [bib_ref] Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy, Eggermont [/bib_ref]. This indication is not approved in Europe, therefore no recommendation can be made.
A change is expected in the therapeutic scene in the next years with the publication of the results of trials evaluating new immunotherapy agents, such as nivolumab or pembrolizumab, and BRAF/MEK inhibitors.

## Radiotherapy
Adjuvant radiotherapy is rarely necessary for excised local melanoma and can be considered in the case of inadequate resection margins in lentigo maligno, desmoplastic neurotropic melanommma and also in the case of R1 resections of metastases when wide margins cannot be obtained (Grade of recommendation B; level of evidence 2b).
Adjuvant radiotherapy improves lymph-node field control with no effect on OS or RFS in patients at high risk of lymph node relapse following a lymphadenectomy for regional node involvement [bib_ref] Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field..., Burmeister [/bib_ref]. This strategy may be considered in selected patients with clinically appreciable nodes and features of high risk of nodal relapse such as extranodal tumor extension, C 3 lymph nodes involvement and/or size of nodal metastasis C 3 cm (Grade of recommendation C; level of evidence 1b). Its benefits should be weighed against potential long-term skin and regional toxicities.
Radiotherapy is an alternative for patients with in-transit metastases (Grade of recommendation C; level of evidence 4).

## Locorregional metastases
Patients with satellite and in-transit metastases should be treated within the context of clinical studies if possible.
Surgical therapy of in-transit metastases shall be performed when there is a possibility of macroscopic and microscopic complete removal of the metastatic lesions (Grade of recommendation B, level of evidence 4).
Intralesional therapy with Talimogene Laherparepvec has shown improvement in overall survival and locorregional control in patients with in patients with injectable lesions and unresectable stage IIIb/c or Iva specially when used as first line therapy [bib_ref] Talimogene laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref] (Grade of recommendation B, level of evidence 1b).
In the presence of multiple, inoperable, locorregional cutaneous/subcutaneous metastases on an extremity, regional chemotherapy as isolated limb perfusion comes into consideration (Grade of recommendation B, level of evidence 4). Other procedures such as intralesional injection of interleukin-2 (Grade of recommendation B, level of evidence 4) or radiation therapy, electrochemotherapy, cryosurgery, or laser destruction may also be applied for local tumor control (Grade of recommendation C, level of evidence 4). Fundamental superiority of one over the other has not been proven and their use depends on individuals factors.

## Treatment of metastatic disease
All tumours should be tested for BRAF-V600 mutation (Grade of recommendation A, level of evidence 1a). Validated BRAF-V600E/K test methods are tissue based and provide qualitative data (positive or negative). Participation in clinical trials is strongly encouraged.

## First line therapy in braf-mutant, advanced (unresectable stages iiic/iv) melanoma
The standard of care in this setting is the combination of a BRAF inhibitor and a MEK inhibitor (Grade of recommendation A, level of evidence 1a). Three phase III trials have demonstrated that combined therapy is more active than single agent BRAF inhibitor [bib_ref] Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma, Long [/bib_ref] [bib_ref] Improved overall survival in melanoma with combined dabrafenib and trametinib, Robert [/bib_ref] [bib_ref] Combined vemurafenib and cobimetinib in BRAF-mutated melanoma, Larkin [/bib_ref]. Over two-thirds of patients achieve an objective response, time to progression lies in the range of 10-12 months and median overall survival is around 25 months. The combination of encorafenib and binimetinib has also shown increased progression-free survival with regard to vemurafenib alone in an ongoing phase III study.
Single agent BRAF inhibitors (vemurafenib or dabrafenib) can be considered (response rate 50%, time to progression 6-8 months, median overall survival 16-18 months) if the combination with their companion MEK inhibitor cannot be used [bib_ref] Improved survival with vemurafenib in melanoma with BRAF V600E mutation, Chapman [/bib_ref] (Grade of recommendation A, level of evidence 1a).
BRAF inhibitors are also active in patients with brain metastases: response rate 30-39%, overall survival 8 months [bib_ref] Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the..., Long [/bib_ref]. Concomitant use with radiotherapy is not recommended due to the risk of increased toxicity (Grade of recommendation A, level of evidence 2a). The combination of BRAF and MEK inhibitors is currently being tested in this setting.
The anti-PD1 antibodies nivolumab and pembrolizumab are active in BRAF-mutant disease, although results seem to be inferior to those obtained in the BRAF-wild type population. Data come from phase III studies comparing pembrolizumab vs. Ipilimumab [bib_ref] Pembrolizumab versus ipilimumab in advanced melanoma, Robert [/bib_ref] and nivolumab vs. nivolumab plus ipilimumab vs. ipilimumab [bib_ref] Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, Larkin [/bib_ref]. Anti-PD1 therapy can be considered in patients with good performance status who do not need a rapid response (Grade of recommendation B, level of evidence 2a).
There is limited experience with ipilimumab in this setting but as chemotherapy is a suboptimal treatment for first line in this population and should not considered as first line treatment.

## Second line therapy in braf-mutant advanced melanoma
If patient received immunotherapy as first line, the activity of BRAF and MEK inhibitors after immunotherapy has not been clearly prospectively studied, but seems to be similar to that obtained in first line in terms of response rate [bib_ref] Sequential treatment with immunotherapy and BRAF inhibitors in BRAF-mutant advanced melanoma, Aya [/bib_ref] (Grade of recommendation A, level of evidence 2b). Data from COLUMBUS trial (encorafenib ? binimetinib), where BRAF mutant patients could have been treated previously with immune therapy, showed that these patients still benefit from the combination versus monotherapy (Grade of recommendation A, level of evidence 2a).
If the patient received BRAF/MEK inhibitors as first line therapy, the anti-PD1 antibodies nivolumab and pembrolizumab are superior to chemotherapy in second line. Data are limited in patients previously treated with BRAF inhibitors, but nivolumab and pembrolizumab yield more responses than chemotherapy in patients who have also received ipilimumab [bib_ref] Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4..., Weber [/bib_ref] (Grade of recommendation A, level of evidence 2a). Ipilimumab can be considered after anti PD-1 failure. Finally chemotherapy can be considered for patients who have exhausted other options (Grade of recommendation D, level of evidence 2b).

## Treatment of braf wild type, advanced (iiic/iv) melanoma
Randomized trials have demonstrated the superiority of nivolumab and pembrolizumab in monotherapy in terms of response, PFS and OS compared to chemotherapy in untreated advanced melanoma patients [bib_ref] Nivolumab in previously untreated melanoma without BRAF mutation, Robert [/bib_ref] or Ipilimumab in first and second line treatment [bib_ref] Pembrolizumab versus ipilimumab in advanced melanoma, Robert [/bib_ref] , with a favourable toxicity profile. Survival rates at 2 years were around 50%, and response rates of 44-37% for both anti-PD-1 inhibitors. These treatments must be considered as the first line treatment (Grade of recommendation A, level of evidence 1a).
In addition, the combination of nivolumab and ipilimumab and nivolumab monotherapy improved responses and PFS in patients with untreated advanced melanoma compared to ipilimumab [bib_ref] Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, Larkin [/bib_ref]. Response rates are higher than with anti PD-1 alone, but also the toxicity that reaches 58.5% of grades 3-4. Nivolumab and Ipilimumab combination could also be considered as first line treatment but we can't recommend witch population if any has better outcome (Grade of recommendation A, level of evidence 1a). The optimal duration of therapy, long-term results with these agents or criteria for the selection of patients for monotherapy vs combination immunotherapy are not yet known.
The value of Ipilimumab after anti PD-1 theray has not been assessed in clinical trials. Some reports on the patients that progressed in the first line trial with anti PD-1 therapies suggest that Ipilimumab maintains its response rate as second line and may add increased survival for patients progressing Anti PD-1(Grade of recommendation C Level of evidence 2b).
Several chemotherapeutic agents (dacarbazine, temozolamide, fotemustine, carboplatin, cisplatin, and paclitaxel among others) have been tested in randomized clinical trials with similar response rates (5-12%) and suvival (\ 5%) results and should not be offered unless other treatment options are exhausted.
In patients with brain metastases, immunotherapy with ipilimumab or anti-PD1 antibodies have demonstrated some degree of activity, although evidence is extremely scarce up to now. In this situation, locoregional approaches (surgical resection, stereotactic radiosurgery and/or whole brain radiation) must be taken into consideration upfront. If the previous ones are discarded, then systemic therapies may be introduced judiciously [bib_ref] Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain..., Goldberg [/bib_ref].
Results from case reports and a phase II study of KIT inhibitor imatinib suggest that some patients with KIT mutations (more common in acral lentiginous and mucosal melanomas) may respond (10-20%) to KIT kinase inhibitor therapy (Grade of recommendation C, level of evidence 2b), but these agents have not been approved for this indication KIT as a therapeutic target in metastatic melanoma [bib_ref] KIT as a therapeutic target in metastatic melanoma, Carvajal [/bib_ref]. Same can be said for MEK inhibitors such as binimetinib in NRAS mutant melanoma, which have shown a superior PFS in comparison with DTIC (2.8 vs. 1.5 m), but with no effect on OS [bib_ref] Binimetinib versus dacarbazine in patients with advanced NRASmutant melanoma (NEMO): a multicentre,..., Dummer [/bib_ref]. This indication is under evaluation, therefore no recommendation can be made.

## Follow up
The objective of follow-up is the early detection of recurrences and secondary melanomas. The optimal duration of follow-up remains controversial. Studies in stage I-III showed that 47% of recurrences occurred within the first year after diagnosis and 32 and 80% within the second and third years, respectively, and thorough follow-up is advocated for this time period. Late recurrences are well documented, but only 5% of recurrences occur after 10 years. Thus, a 10-year follow-up appears to be reasonable (Grade of recommendation B; level of evidence 1b). Patients with a primary melanoma are at increased risk for developing a second primary melanoma. Estimates of that increased risk range from 8 to 10%. Although the most secondary melanomas occur within the first two years after the primary diagnosis of melanoma may even occur more than 30 years after, suggesting a need for life-long, regular dermatologic examinations (Grade of recommendation B; level of evidence 3b). Self-examinations by the patient are an essential component of follow-up and can lead to early recognition of recurrences of new melanomas. The patients should receive instructions on self-examination to detect a new melanoma or recognize a recurrence themselves (Grade of recommendation B; level of evidence 3b).
Physical examinations in stage I-III disease have proven to be the most effective procedure for early recurrence detection [bib_ref] Detection of first relapse in cutaneous melanoma patients: implications for the formulation..., Francken [/bib_ref] and shall be performed in all melanoma patients during follow-up (Grade of recommendation A; level of evidence 2b).
Routine blood testing to detect recurrence is not recommended (Grade of recommendation D; level of evidence 4). Early detection of locoregional lymph node metastases is of particular significance. In a meta-analysis of 74 trials, lymph node sonography proved to be the most sensitive and most specific procedure for the detection of locoregional lymph node metastases and is the particular interest in patients with and equivocal lymph node physical exam, patients without sentinel lymph node biopsy (SLNB) or patients with a positive SLNB who did not undergo complete lymph node disection (Grade of recommendation A; level of evidence 1a).
Overall, a general recommendation about imaging procedure is not possible, because there are no studies assessing how the early detection of a recurrence could have an impact in the overall survival with the new treatments, as immunotherapy. In view of the current data, it is possible that an early detection of recurrence could have an impact in the response and evolution with the new treatments. Individual follow-up exams may be conducted in a risk-adapted fashion, trimonthly intervals in high risk of recurrence and in patients with decreasing risk, follow-up intervals may be extended from 6 to 12 months. Ethical approval This article does not contain any studies with human participants performed by any of the authors.
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[table] Recommendations table: SurgeryAll melanoma suspected lesion must be biopsied A 1aSurgery can be used for in transit metastases C 4Isolated limb perfusion can be used for in transit metastasesC 4 T-VEC can be used in locorregional disease B 1a Metastatic disease B-RAF determination should be done for all metastatic patients A 1a Combined B-RAF/MEK inhibition should be offered for BRAF mutated patients A 1a Anti-PD1 containing therapy is the first option for BRAF wild type patients A 1a BRAF inhibitors may be used in brain metastases A 2a Anti PD1 based therapy can be an alternative for BRAF mutated patients whose disease is not aggressively progressing B 2a Chemotherapy is an option if no other therapy could be available A 1A Patients treated with immunotherapy must be offered BRAF/MEK therapy as second line A 2b Patients treated with BRAF/MEK inhibitors must be offered anti-PD1 based therapy A 2a KIT mutated melanomas may be offered KIT kinase inhibitors C 2b NRAS mutated melanomas may be offered encorafenib C 2b Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. [/table]