Clinical and Translational Oncology (2021) 23:948–960 https://doi.org/10.1007/s12094-020-02539-9 CLINICAL GUIDES IN ONCOLOGY SEOM clinical guideline for the management of cutaneous melanoma (2020) M. Majem1 · J. L. Manzano2 · I. Marquez‑Rodas3 · K. Mujika4 · E. Muñoz‑Couselo5 · E. Pérez‑Ruiz6 · L. de la Cruz‑Merino7,8 · E. Espinosa9 · M. Gonzalez‑Cao10 · A. Berrocal11 Accepted: 2 December 2020 / Published online: 2 March 2021 © The Author(s) 2021 Abstract Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I–III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immuno‑ therapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available. Keywords Melanoma · Adjuvant treatment metastatic treatment · Staging All authors have contributed equally to the present manuscript. All authors are members of the Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM). A. Berrocal * M. Majem berrocal.alf@gmail.com mmajem@santpau.cat 1 J. L. Manzano Department of Medical Oncology, Hospital de la Santa jmanzano@iconcologia.net Creu i Sant Pau, c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain I. Marquez‑Rodas 2 ivanpantic@hotmail.com Department of Medical Oncology, H. Germans Trias i Pujol, Catalan Institute of Oncology, ICO-Badalona, Badalona, K. Mujika Spain kmujika@onkologikoa.org 3 Department of Medical Oncology, Instituto de Investigación E. Muñoz‑Couselo Sanitaria Gregorio Marañón and CIBERONC, Madrid, Spain emunoz@vhio.net 4 Department of Medical Oncology, UGC de Oncología de E. Pérez‑Ruiz Gipuzkoa, OSI Donostialdea-Onkologikoa, Guipúzcoa, Spain eliperu@gmail.com 5 Department of Medical Oncology, Vall d’Hebron Institute L. de la Cruz‑Merino of Oncology (VHIO), Hospital Vall d’Hebron Barcelona, lucme12@yahoo.es Barcelona, Spain E. Espinosa 6 Department of Medical Oncology, Hospital Costa del Sol eespinosa00@hotmail.com and UGC Oncol, Instituto de Investigación Biomédica de M. Gonzalez‑Cao Málaga (IBIMA), Hospital Universitario Regional Virgen mgonzalezcao@oncorosell.com Victoria, Málaga, Spain 13 Vol:.(1234567890) Clinical and Translational Oncology (2021) 23:948–960 949 Methodology Diagnosis and pathology The authors have reviewed the published clinical guidelines, Clinical analysis of suspicious lesions includes three as well as clinical trials from which the aspects referred to aspects: (1) ABCD rule (Asymmetry, Border irregulari‑ in these guidelines can be concluded. Each author has been ties, Color heterogeneity, and Dynamics or evolution in responsible for reviewing a part of the guideline that has the color, size, or elevation), (2) the ugly duckling sign been shared and discussed among all the authors to reach a (the lesion is different from the rest in the same patient), consensus. Finally, the degrees of evidence and recommen‑ and (3) chronological analysis of changes: assessment of dation have been established based on the recommendations rapid growth in a previous lesion [13]. Dermatoscopy by for the development of guidelines [1, 2]. an experienced physician is recommended for the diagno‑ sis of pigmented lesions (Level of evidence 1b, grade of recommendation A) [14]. Whole-body photography and Incidence and epidemiology digital dermatoscopy are useful in people at high risk of melanoma, especially in early diagnosis (Level of evi‑ The annual incidence of melanoma in Europe dence 2b, grade of recommendation B) [15]. Reflectance is < 10–25/100.000, in the US is 20–30/100.000 and in Aus‑ confocal microscopy can be helpful in lesions difficult to tralia 50–60/100.000 [3]. It is expected an increase in the diagnose by visual inspection and dermatoscopy (Level of next years, and therefore, there is a need to improve preven‑ evidence 2b, grade of recommendation B) [16]. All suspi‑ tion and early diagnosis measures [4]. In Spain, an increase cious lesions must be confirmed histologically by exci‑ in the melanoma mortality rate was observed in the last dec‑ sional biopsy following the eighth edition of the American ades of the twentieth century; however, later, stabilization Joint Committee on Cancer (AJCC 8th edition) [17]. was observed in women and a decrease in middle age and young men [5, 6]. In 2020, the estimated new cases of mela‑ noma in Spain are 6179 [7]. Molecular testing Ultraviolet radiation is the most important risk factor, especially if intermittent sun exposure, particularly early Determination of BRAF V600 status is mandatory in in life [8]. Individuals with skin types I and II have the patients with resectable or unresectable stage III or IV highest risk of developing melanoma, as well as individu‑ melanoma (Level of evidence 1, grade of recommendation als with a high numbers of typical nevi, large congenital A). Determination of C-KIT and NRAS status is recom‑ nevi, and atypical nevi [9, 10]. About 10% of melanomas mended in BRAF wild-type patients (Level of evidence 2, occur in patients with familial history of melanoma and grade of recommendation C) [18, 19]. A new melanoma can present a germline mutation; CDKN2A is the main subtype with NF1 mutation has recently been defined, but gene involved [11]. Physical protection is the best preven‑ its clinical implications are unknown [20]. Programmed tion of melanoma, and regular use of sunscreen reduces death ligand 1 (PD-L1) expression can be tested in resect‑ the incidence of cutaneous melanoma (level of evidence able or unresectable stage III and IV, although its determi‑ 1, grade of recommendation A) [12]. nation is not mandatory, since negative cases can respond to anti-PD-1 treatments. 7 Department of Medical Oncology, Hospital Universitario Staging (Table 1) Virgen Macarena, Seville, Spain 8 Medicine Department, Universidad de Sevilla, Seville, Spain TNM staging in melanoma includes physical examination 9 Department of Medical Oncology, Hospital Universitario La of the entire body. In pT1b–pT4b melanoma, ultrasound Paz, CIBERONC, Madrid, Spain (US) for locoregional lymph-node metastasis, and/or com‑ 10 Oncology Department (IOR), Hospital Dexeus, Barcelona, puted tomography (CT) or positron emission tomography Spain (PET) scans and brain magnetic resonance imaging (MRI), 11 Department of Medical Oncology, Consorcio Hospital is recommended for proper tumor assessment (Level of General Universitario de Valencia, Valencia, Spain evidence 3, grade of recommendation A) [17]. 13 950 Clinical and Translational Oncology (2021) 23:948–960 Table 1  Melanoma staging AJCC 8th edition T category Thickness Ulceration status TX: Primary tumor thickness cannot be assessed (e.g., diagnosis by curettage) Not applicable Not applicable T0: No evidence of primary tumor (e.g., unknown primary or completely regressed Not applicable Not applicable melanoma) Tis (melanoma in situ) Not applicable Not applicable T1 ≤ 1.0 mm Unknown or unspecified T1a < 0.8 mm Without ulceration T1b < 0.8 mm With ulceration 0.8–1.0 mm With or without ulceration T2 > 1.0–2.0 mm Unknown or unspecified T2a > 1.0–2.0 mm Without ulceration T2b > 1.0–2.0 mm With ulceration T3 > 2.0–4.0 mm Unknown or unspecified T3a > 2.0–4.0 mm Without ulceration T3b > 2.0–4.0 mm With ulceration T4 > 4.0 mm Unknown or unspecified T4a > 4.0 mm Without ulceration T4b > 4.0 mm With ulceration N category No. of tumor-involved regional lymph nodes Presence of in-transit, satellite, and/or microsatellite metastases NX Regional nodes not assessed (e.g., sentinel lymph-node biopsy not performed, regional nodes No previously removed for another reason) Exception: pathological N category is not required for T1 melanomas, use clinical N information N0 No regional metastases detected No N1 One tumor-involved node or any number of in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes N1a One clinically occult (i.e., detected by SLN biopsy) No N1b One clinically detected No N1c No regional lymph-node disease Yes N2 Two or three tumor-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with one tumor-involved node N2a Two or three clinically occult (i.e., detected by SLN biopsy) No N2b Two or three, at least one of which was clinically detected No N2c One clinically occult or clinically detected Yes N3 Four or more tumor-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases N3a Four or more clinically occult (i.e., detected by SLN biopsy) No N3b Four or more, at least one of which was clinically detected, or the presence of any number of mat‑ No ted nodes N3c Two or more clinically occult or clinically detected and/or presence of any number of matted Yes nodes M category Anatomic site LDH level M0 No evidence of distant metastasis Not applicable M1 Evidence of distant metastasis See below M1a Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node Not recorded or unspecified M1a(0) Not elevated M1a (1) Elevated M1b Distant metastasis to lung with or without M1a sites of disease Not recorded or unspecified M1b(0) Not elevated M1b (1) Elevated 13 Clinical and Translational Oncology (2021) 23:948–960 951 Table 1  (continued) M category Anatomic site LDH level M1c Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease Not recorded or unspecified M1c(0) Not elevated M1c (1) Elevated M1d Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease Not recorded or unspecified M1d(0) Not elevated M1d (1) Elevated T N M Stage group Tis N0 M0 0 T1a N0 M0 IA T1b–T2a N0 M0 IB T2b–T3a N0 M0 IIA T3b–T4a N0 M0 IIB T4b N0 M0 IIC Any T, Tis ≥N1 M0 III Any T Any N M1 IV N+ : clinically lymph node EXCISIONAL BIOPSY SLN: sennel lymph node Pathological confirmaon pTis pT1a pT1b to pT4b cN0M0 Any cN+ cN0M0 cN0M0 Wide margin Wide margins Wide margins Wide margin 0.5 cm pT2 cN0M0 1 cm + 1cm pT3apT4b cN0M0 Lymphadenectomy 2 cm + SLN US-BASED FOLLOW UP or Lymphadenectomy Follow up SLN - SLN+ Systemic adjuvant therapy Fig. 1  Treatment algorithm for primary tumors and regional lymph notes Treatment of localized disease should extend to the fascia, whereas lateral margins will depend on Breslow thickness: 0.5 cm for in situ melano‑ Treatment of primary tumors mas, 1 cm for tumors with thickness of up to 2 mm, and 2 cm for > 2 mm (Level of evidence 1b, grade of recom‑ Excisional biopsy with a 2 mm lateral margin and deep mendation A) [21]. Figure 1 shows the treatment algorithm subcutaneous margin is indicated for any suspicious lesion for primary tumors. (Level of evidence 1a, grade of recommendation A). Upon Sentinel lymph-node biopsy is recommended for mela‑ pathological confirmation of the diagnosis, definitive sur‑ nomas with Breslow > 0.8 mm of thickness or < 0.8 mm gery with wide margins is performed. The deep margin with ulceration, i.e., melanomas with stage ≥ IB of the 13 952 Clinical and Translational Oncology (2021) 23:948–960 AJCC 8th edition classification (Level of evidence 2a, p < 0.0001, respectively) in patients with completely grade of recommendation A) [22–24]. resected stage IIIB, IIIC, or IV. Efficacy was observed both Complete lymph-node dissection in patients with posi‑ in BRAF mutant and wild-type patients. In the first report of tive sentinel lymph nodes carries severe morbidity and has overall survival, with fewer events than expected, OS rates shown no impact on survival compared with US-based were similar in both treatment groups (78% Nivolumab and follow-up (Level of evidence 1b, grade of recommendation 77% ipilimumab), taking into account that more patients A) [25, 26]. For this reason, complete dissection has been treated with ipilimumab received subsequent therapy, abandoned as routine practice. However, the procedure is including immunotherapy (57% with ipilimumab and 49% recommended in the case of clinically detected regional with nivolumab) [30, 31]. lymph-node metastases (Level of evidence 4, grade of rec‑ Pembrolizumab for 1 year has also shown prolonged ommendation C) [27]. RFS compared with placebo in patients with completely Resection of satellite or in-transit metastases is associ‑ resected stage III melanoma at 3.5-year follow-up (59′8% ated with a high risk of local and regional progression. vs. 41′4%, HR 0,59, p < 0.0001, respectively). Efficacy was With the advent of effective systemic therapies, this strat‑ observed both in BRAF mutant and wild-type patients. Pem‑ egy could only be considered in highly selected cases brolizumab also decreased the 3.5-year incidence of distant (Level of evidence 4, grade of recommendation C). metastases as first recurrence and locoregional recurrence only. The S1404 phase III trial compares pembrolizumab with high-dose interferon or high-dose ipilimumab in Adjuvant therapy patients with completely resected high-risk stage III–IVA disease; accrual is complete, and results are pending [32, Adjuvant radiotherapy 33]. Dabrafenib plus trametinib for 1 year showed a longer Adjuvant radiotherapy in the local tumor can be consid‑ RFS compared with placebo in completely resected stage III ered in cases of inadequate resection margins of lentigo BRAF V600 mutant melanoma at 5 year follow-up (52% vs. maligna when further resection is not advisable (Level of 36%, HR 0.51, 95% CI 0.42–0.61), irrespective of baseline evidence 3b, grade of recommendation B. The role of radi‑ factors. Overall survival, at a median follow-up of 2.8 years, otherapy for in-transit metastasis has not been established was prolonged with the targeted therapy, but remains imma‑ (Level of evidence 5, grade of recommendation D). Nodal ture [34–37]. adjuvant radiotherapy reduces the risk of regional recur‑ In summary, in patients with completely resected stage rence after resection of palpable regional lymph nodes or III or IV melanoma, adjuvant immunotherapy and targeted extracapsular extension [28]. However, it increases the risk therapies have shown to improve RFS (Level of evidence 1, of regional toxicity—particularly lymphedema—with no grade of recommendation A). Although in all these pivotal impact on overall survival, so it is not longer routinely clinical trials, lymphadenectomy was required as an inclu‑ recommended (Level of evidence 2b, grade of recom‑ sion criteria, the impact of avoiding a lymphadenectomy on mendation B) [29]. Radiotherapy may be discussed in the results of adjuvant treatment is unknown, leaving the resected head and neck melanoma with palpable lymph decision whether or not performing it before in the context nodes, where local control is critical and has a lower risk of a discussion with the patient (Level of evidence 3, grade of lymphedema. of recommendation C). Finally, stage IIIA AJCC v7 patients were included in COMBI-AD and Keynote 054 trials with Adjuvant systemic therapy the inclusion criteria of sentinel lymph nodes > 1 mm; regu‑ latory approvals of FDA, EMA, and AEMPS admit to extend For patients with complete resection of a cutaneous mela‑ the use of adjuvant systemic treatment to with anti-PD-1 noma, to recommend adjuvant systemic therapy depends antibodies all stage III, including stage IIIA, but there is upon the risk of disease recurrence, based on the stage at no clear evidence of its use in IIIA with < 1 mm (Level of diagnosis, along with a consideration of patient age, comor‑ evidence 3, grade of recommendation B–C). Selection of a bidity, and personal preferences. For patients with stage III specific agent depends largely on BRAF mutation status and melanoma, adjuvant immunotherapy with nivolumab or toxicity profiles (Level of evidence 3–4, grade of recommen‑ pembrolizumab is indicated; and dabrafenib and trametinib dation B). Figure 2 shows adjuvant treatment algorithm in are an alternative for patients with BRAF V600 mutation. high-risk melanoma. In patients with completely resected stage IV, adjuvant For patients who relapse with metastatic disease after nivolumab is also indicated. initial adjuvant therapy, options include treatment with an Nivolumab for 1 year prolonged RFS at 4-year follow- alternative active systemic therapy or inclusion in a clinical up compared with ipilimumab (52% vs. 41%, HR: 0.71, trial (Level of evidence 3, grade of recommendation C) [38]. 13 Clinical and Translational Oncology (2021) 23:948–960 953 HIGH RISK ADJUVANT MELANOMA TREATMENT TARGETED THERAPY COMBI-AD iBRAF+ iMEK: - dabrafenib/trametinib vs placebo - stage IIIA, IIIB, IIIC Stage III, IV IMMUNOTHERAPY resected AJCC v8 CHECKMATE 238: - nivolumab vs BRAF status ipilimumab - stage IIIB; IIIC, IV BRAF WT BRAF MUTANT resected - 42% BRAF mutant KEYNOTE 054: - pembrolizumab vs placebo IMMUNOTHERAPY TARGETED IMMUNOTHERAPY - stage IIIA, IIIB, IIIC THERAPY - 41% BRAF mutant Fig. 2  Adjuvant treatment algorithm in high-risk melanoma Table 2  Main characteristics of the pivotal trials of immunotherapy in advanced melanoma Treatment Considerations PFS (median OS (median months, 95% IC) Update overall survival (%) months 95% IC) Nivolumab [3, 4] BRAF WT patients 5.1 (3.5–10.8) NR (survival rate at 1 year 51.2% at 3 years CheckMate 066 Control arm: DTIC 72.9% (65.5–78.9) Protocol amendment: cross over nivolumab Pembrolizumab [5, 6] Control arm: ipilimumab 4.1 (2.9 a 6.9)* NR (survival rate at 1 year 32.7 (24.5–41.6) at 5 years** KEYNOTE-006 34% second-line treatment 68.4%) 36% BRAF mutant Ipilimumab + nivolumab Control arm: ipilimumab 11.5 (8.9–16.7) 64% survival rate at 2 years 58% at 3 years; 52% at 5 years [7, 8] 31.5% BRAF mutant CheckMate 067 NR not reached, NC unknown *At dose 10 mg/kg every 3 weeks **Combined pembrolizumab groups Treatment of advanced disease Systemic treatment of unresectable advanced/m1 disease Oligometastatic disease Treatment options in first line Some stage IV patients present with a resectable, oligomet‑ astatic disease and surgical excision or stereotactic radio‑ Immunotherapy Immunotherapy based on immune check‑ surgery (SRS) of solitary metastases should be considered point inhibitors has demonstrated its superiority over chem‑ whenever feasible. One-third of patients with resected otherapy in terms of response, PFS and OS in first-line treat‑ metastasis may become long-term survivors (Level of evi‑ ment (Level of evidence 1, grade of recommendation A). dence 2b, grade of recommendation B) [39]. Surgery may be This option, unlike that occurs with targeted therapy against the preferred option for selected patients if feasible, prefer‑ BRAF, is not based on any biomarker such as the expression entially combined with adjuvant systemic therapies as previ‑ of the programmed death-ligand 1 (PD-L1) (Level of evi‑ ously commented. dence I, grade of recommendation B) or tumor mutational 13 954 Clinical and Translational Oncology (2021) 23:948–960 Table 3  Randomized trials with of BRAF and MEK inhibitors in advanced BRAF mutant melanoma Combination Progression-free survival Overall survival (median Patients alive at 3, 4, and References (median months, 95% IC) months, 95% IC) 5 years (%) Dabrafenib + trametinib 11.1 (9.5–12.8) 25.9 (22.6–31.5) 44,37,34 [1] Vemurafenib + cobimetinib 12.6 (9.5–14.7) 22.5 (20.3–28.8) 38.5, 34.7, NA [2] Encorafenib + binimetinib 14.9 (11.0–20.2) 33.6 (24.4–39.2) 47, 39, NA [3] burden (TMB) (Level of evidence IV, grade of recommen‑ Direct comparison among the three different combos dation C). Ipilimumab, an anti-CTLA-4 (cytotoxic T-lym‑ does not exist, and similar efficacy with small differences phocyte-associated protein 4) antibody, was the first treat‑ in the toxicity profile has been described. When selecting ment to show an improvement in overall survival in patients the combination, patient preferences, drug availability, and with metastatic melanoma [40, 41]. This option has been efficiency criteria should be taken into account (Level of exchanged in favor to PD-1 inhibitors such as nivolumab evidence 4, grade of recommendation C). [42, 43], pembrolizumab [44, 45], or the combination of ipilimumab plus nivolumab [46, 47]. Table 2 summarizes First‑line selection in BRAFm The best treatment sequence the main characteristics of the pivotal trials of immunother‑ for BRAF mutant patients is unknown, since no direct com‑ apy in advanced melanoma. parison exists. First-line decision between targeted thera‑ The clinical criteria that can help us to choose the pies or immunotherapy is currently being studied in pro‑ best first-line treatment option with immune checkpoint spective trials (SECOMBIT, NCT02631447) to define the inhibitors (monotherapy or combination) or the duration best sequencing combination treatment in terms of OS, the of treatment are not yet established. Different studies have primary efficacy variable. Meanwhile, the decision should proposed several clinical markers such as LDH (lactate be based on patient’s profile (comorbidities, ECOG, symp‑ dehydrogenase), lymphocytes, leukocytes, or eosinophils toms, and life expectancy) and on melanoma characteristics count that could predict the response to ICI, but data are (tumor burden, site of metastasis, and level of LDH) [52, inconclusive (Level of evidence IV, grade of recommenda‑ 53] (Level of evidence 2, grade of recommendation B). tion C) [48]. Most studies have demonstrated a higher number of On the other hand, there is other type of immunother‑ events during the first 12 months with immunotherapy than apy such as Talimogene Laherparepvec, an intralesional with targeted therapy and, by contrast, patients with immu‑ virotherapy that has shown an improvement in durable notherapy have better survival beyond the first year [50, 54]. response rate, overall survival, and loco-regional control With all the aforementioned, it can be advised that in those respect to GM-CSF in patients with injectable lesions and patients where the first months of treatment can be admin‑ unresectable stage IIIB–C or IV melanoma, specially when istered safely (for example, those who will not progress used as first-line therapy (Level of evidence 1, grade of quickly, or where immediate response is not required due recommendation B) [49]. to involvement of an organ or its function) would be good candidates for immunotherapy, reserving targeted therapy Targeted therapy Currently, there are three different for later lines (Level of evidence 2, grade of recommenda‑ combinations of BRAF and MEK inhibitors based in four tion B). randomized phase III clinical trials that improve both pro‑ gression-free survival and overall survival in comparison with BRAF inhibitors alone (Table 3) [50, 51]. The com‑ Treatment options in second line bination of BRAF and MEK inhibitors should be the ther‑ apy of choice when targeted therapy is considered, unless Treatment options in second line depend on the treatment absolute contraindication for MEK inhibitors is present administered in the first line, as well as, on the mutational (Level of evidence 1, grade of recommendation A). status. For the BRAF wild-type patients, options for a sec‑ There are certain subgroups that of poor progno‑ ond-line treatment are limited, and inclusion in clinical trials sis, being the most important factors an elevated LDH, is a priority. When the first line was an anti-PD-1 antibody, ECOG > 1 and high tumor burden (expressed in number ipilimumab (Level of evidence 2, grade of recommenda‑ of organs involved) [50, 52]. However, a combination of tion B) and the combination of nivolumab and ipilimumab BRAF and MEK inhibitor would be the first option over (Level of evidence 4, grade of recommendation B) are two monotherapy (Level of evidence 2, grade of recommenda‑ valid options [55]. Finally, chemotherapy (Dacarbazine tion B). and Temozolomide) can be considered for patients who 13 Clinical and Translational Oncology (2021) 23:948–960 955 exhausted other options (Level of evidence 2, grade of rec‑ of recommendation A), although the role of SRS has been ommendation D). tested for up to 15 brain metastasis [61]. Adjuvant SRS In the BRAF mutant population treated with an anti-PD-1 yields the same overall survival but with fewer declines in antibody in first line, the combination of BRAF and MEK cognitive function, so SRS on the surgical cavity and not inhibitors is the preferred option. Although their activity WBRT is recommended after excision of brain metastases has not been prospectively studied after progression to anti- (Level of evidence 1b, grade of recommendation A) [62]. PD-1, it seems to be similar to the first line of treatment in Whole brain radiation therapy (WBRT) is discouraged terms of response (Level of evidence 2, grade of recom‑ except in the palliative setting when other options are not mendation A) [56]. Data from the Columbus Study, where feasible (Level of evidence 4, grade of recommendation BRAF mutant patients may have previously received immu‑ C) [59]. notherapy, showed that these patients also benefited from the When locoregional strategies are discarded, systemic combination (Level of evidence 2, grade of recommendation therapies must be considered. At this point, two main A) [57]. clinical situations emerge. In asymptomatic, previously In the BRAF mutant population treated with the combi‑ untreated brain metastasis patients, combination immuno‑ nation of BRAF and MEK inhibitors in first line, anti-PD-1 therapy with nivolumab and ipilimumab has demonstrated antibody and the combination of nivolumab and ipilimumab outstanding results with intracranial response rates rang‑ are valid options. ing from 46 to 57% and median PFS and DOR not reached with a median follow-up of 20.6 months [63]. Pembroli‑ zumab, nivolumab, and ipilimumab as single therapies also Treatment beyond progression show some degree of activity (ORR around 20%) [64]. In BRAF mutant patients, BRAF and MEK inhibitors obtain Treatment beyond progression might be an option in selected high intracranial responses, which rises up to 58% with the patients both on targeted as well as on immunotherapy based combination of dabrafenib and trametinib [65]. However, on retrospective data [58]. No randomized data are avail‑ these responses seem to be shorter than those obtained in able at this time. Treatment beyond progression is generally extracranial sites. Aforementioned results make reasonable not recommended unless there is a suspicion of pseudo- advising nivolumab plus ipilimumab as the preferred first- progression, bearing in mind that the analysis of these data line treatment for patients with asymptomatic brain metas‑ is subject to many biases related to patient status. tasis not amenable to surgery or SRS, irrespective of BRAF status, whenever possible (Level of evidence 3, grade of rec‑ Management of brain metastasis ommendation A). In BRAF-mutated patients, combination of BRAF and MEK inhibitors remains a good alternative It is estimated that up to 50–60% of metastatic melanoma option in first and second lines (Level of evidence 3, grade patients will develop brain metastasis. First, a stepwise of recommendation B). and multidisciplinary approach is highly recommended Unfortunately, symptomatic and/or previously treated to design an individualized plan for every patient (Level patients obtain poorer results, especially with immunother‑ of evidence 4, grade of recommendation A) [59]. In an apy, and new approaches are eagerly needed in this setting effort to classify patients into similar prognostic groups, [59]. some key clinical factors such as Karnofsky Performance Score (KPS), number of brain metastases, extracranial Follow‑up metastases, age, and BRAF status constitute the basis of the specific graded prognostic assessment (GPA) index On average, 20–30% of early stage melanoma patients will for melanoma (Melanoma-mol GPA) [60] and could be develop a recurrence within 5 years [66]. For stage I–II extremely helpful to guide clinical decision-making (Level melanomas, recurrences will be in 50% of cases at regional of evidence 3, grade of recommendation B). lymph nodes, 30% as distant metastasis and 20% will be Among locoregional strategies, surgery must be con‑ local relapses or in-transit metastasis. For stage III mela‑ sidered to treat symptomatic and large brain metastasis, noma, up to 95% occur during the first 3 years of follow-up especially in the case of solitary brain metastasis and when [66], and up to 50% will be distant recurrences, 25% regional a pathological and/or molecular diagnosis is needed (Level and 25% local relapses. About 2–10% will have a second of evidence 4, grade of recommendation B) [61]. SRS is primary melanoma, most of them during the first year after generally recommended in patients with 1–4 brain metas‑ initial diagnosis [67]. tases with less than 3–4 cm (Level of evidence 3, grade 13 956 Clinical and Translational Oncology (2021) 23:948–960 Self-examination is an essential component of the follow- distant metastases in the extremities (Grade of recommen‑ up and can lead to early recognition of recurrences and new dation C; level of evidence 4) [72]. For earlier stages I–IIA melanomas [68]. Patients should receive instructions on self- where the risk of relapse is lower, radiological follow-up examination (Level of evidence 3, grade of recommendation with body CT scan and brain MRI is optional (Grade of B). Over the last few years, several skin cancer detection appli‑ recommendation C; level of evidence 4). cations for smartphones have been developed through analysis of artificial intelligence algorithms. Further studies are needed Summary of recommendations and evidence before implementing these techniques in the general popula‑ tion (Level of evidence 4, grade of recommendation C). Physical examination has proven to be an effective proce‑ dure for early recurrence detection [68] and should be per‑ Level of Grade of formed in all melanoma patients during follow-up (Level evidence recommen‑ of evidence 2, grade of recommendation A). Physical exam dation must include skin and nodes exam. Total body photography, Physical protection and regular use of sun‑ 1 A sequential digital dermatoscopy imaging, and reflectance screen reduce the incidence of cutaneous confocal microscopy, must be helpful in patients with a high melanoma number of moles or presence of clinical atypical nevi (Level Diagnosis and pathology 1b A of evidence 3, grade of recommendation A). For stage I–IIA Dermatoscopy by an experienced physi‑ melanomas, the frequency of physical exams should be, at cian is recommended for the diagnosis of pigmented lesions least, annually, life-long, but it depends on the risk factors Whole-body photography and digital 2b B of each patient (Level of evidence 3, grade of recommenda‑ dermatoscopy are useful in people at high tion A). For patients with stage IIB–IV melanomas, physical risk of melanoma, especially in early examinations should be performed every 3–6 months during diagnosis the first 2 years, and then every 3–6 months for 3 years, and Determination of BRAF V600 status is 1 A after 5 years, they could be done annually (Level of evidence mandatory in patients with resectable or unresectable stage III or IV melanoma 3, grade of recommendation A). Staging Routine blood testing is optional, as few recurrences are In pT1b–pT4b melanoma, US for locore‑ 3 A detected by increased LDH and S-100 levels [68] (Level gional LN metastasis, CT or PET-TC and of evidence 4, grade of recommendation C). Liquid biopsy brain MRI, is recommended for melanoma screening using the determination of BRAF Treatment of primary tumor mutation in cfDNA from blood or other body fluids is a Excisional biopsy is recommended on all 1a A promising technique, but it is not routinely indicated yet suspicious lesions (Level of evidence 4, grade of recommendation C). Safety surgical margins should be Breslow- 1b A Lymph-node sonography has proven to be the most adapted sensitive and most specific procedure for the detection SLN is indicated if Breslow > 0.8 mm 2a A or < 0.8 mm with ulceration of locoregional lymph-node metastases [69]. In patients Routine CLND is not recommended for 1b A with stage IIC–III melanomas, lymph-node sonography of SLN + patients regional areas must be performed regularly, and it should CLND is recommended for clinically 4 C be performed every 4 months during the first 2 years, detected regional lymph nodes and every 6 months during the next 3 years, especially in Adjuvant therapy patients with positive sentinel lymph nodes without lymph- Adjuvant radiotherapy is not recommended, 2b B node dissection (Grade of recommendation A; level of evi‑ but it may be considered for selected cases dence 1). Adjuvant anti-PD-1 treatment with 1 A General recommendation about imaging procedures is not nivolumab and pembrolizumab or targeted therapies with dabrafenib and trametinib possible, since no prospective studies have assessed if early are recommended in resected stage III–IV recurrence detection impacts in the overall survival. Some melanoma studies in IIC–III melanoma patients have demonstrated Oligometastatic disease that an extensive follow-up including CT body scan and Surgical excision or SRS of solitary metas‑ 2b B brain MRI detects almost 50%, and 8% of recurrences [70, tases should be considered 71], so imaging follow up every 3 months is recommended Management of advanced disease (Grade of recommendation B; level of evidence 3). Routine First line advanced/M1 disease follow-up with PET–CT is not recommended, although some studies have demonstrated a higher sensitivity for detecting 13 Clinical and Translational Oncology (2021) 23:948–960 957 Level of Grade of Compliance with ethical standards evidence recommen‑ dation Conflict of interest MMT reports grants and personal fees from BMS; personal fees from Astra Zeneca, Novartis, Roche, MSD, Boehringer Anti-PD-1 treatment (nivolumab or 1 A Ingelheim, Takeda, Pierre-Fabre and Bayer; non-financial support pembrolizumab) or ipilimumab and from Astra Zeneca, MSD, Boehringer Ingelheim outside the submitted nivolumab are a standard of care for all work. JLM reports personal fees from Novartis, Roche, Pierre-Fabre, patients with advanced melanoma BMS, MSD and grants from; Merck, Roche, Abbvie, Astra Zeneca Intralesional T-VEC is also an option for 1 C outside the submitted work. I.M.-R. has received grants as advisory unresectable stage IIIB–C or IV board member and travel and congress accommodation from BMS, In BRAF V600 melanoma, BRAF and 1 A MSD, Roche, Novartis, Amgen, Pierre Fabre, Merck Serono, Sanofi, MEK inhibitors (dabrafenib–trametinib, Regeneron, Incyte, AstraZeneca, and Bioncotech. LCM reports grants vemurafenib–cobimetinib, encorafenib– and personal fees from BMS, Roche, MSD-Merck, and Amgen, per‑ binimetinib) are additional first-line sonal fees from Pierre Fabre, Novartis, and grants from Celgene, out‑ options side the submitted work. EE reports personal fees from BMS, MSD, Novartis, Pierre Fabre, and Roche. MGC reports personal fees from Second line and beyond advanced/M1 NOVARTIS, BMS, and Roche. AB reports personal fees and non-fi‑ disease nancial support from BMS, MSD, Roche, Novartis, Sanofi, and Mer‑ In BRAF wild-type melanoma, 2, 4 B ck-Pfizer, and personal fees from Pierre Fabre and Incyte, outside the ipilimumab and the combination of submitted work. KM, EPR, and EMC have nothing to disclose. nivolumab and ipilimumab are two valid options after an anti-PD-1 treatment Ethical approval The current study has been performed in accordance In BRAFV600 melanoma, BRAF and 2 A with the ethical standards laid down in the 1964 Declaration of Hel‑ MEK inhibitors are the preferred option sinki and its later amendments. after an anti-PD-1 treatment In BRAFV600 melanoma treated with 2 A Informed consent Not applicable. BRAF and MEK inhibitors in first line, anti-PD-1 treatment (nivolumab Open Access This article is licensed under a Creative Commons Attri‑ or pembrolizumab) or ipilimumab and bution 4.0 International License, which permits use, sharing, adapta‑ nivolumab are valid options tion, distribution and reproduction in any medium or format, as long Chemotherapy can be considered for 2 D as you give appropriate credit to the original author(s) and the source, patients who exhausted other options provide a link to the Creative Commons licence, and indicate if changes Brain metastases were made. The images or other third party material in this article are Multidisciplinary approach is highly recom‑ 4 A included in the article’s Creative Commons licence, unless indicated mended otherwise in a credit line to the material. 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