Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
2015; Elsevier BV; Volume: 26; Linguagem: Inglês
10.1093/annonc/mdv297
ISSN1569-8041
AutoresReinhard Dummer, Axel Hauschild, Nicole Lindenblatt, George Pentheroudakis, Ulrich Keilholz,
Tópico(s)Skin Protection and Aging
ResumoThe European incidence of malignant melanoma varies from 3 to 5/100 000/year in Mediterranean countries to 12–25 (and rising) in Nordic countries. Increased ultraviolet (UV) light exposure of a genetically predisposed population seems to be, at least in part, responsible for an ongoing increase in incidence with signs of stabilisation of mortality over recent decades, except in elderly males [1.Hollestein L.M. van den Akker S.A. Nijsten T. et al.Trends of cutaneous melanoma in The Netherlands: increasing incidence rates among all Breslow thickness categories and rising mortality rates since 1989.Ann Oncol. 2012; 23: 524-530Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. There is a disparity in the mortality-to-incidence ratios between Western and Eastern European countries [2.Forsea A.M. Del Marmol V. Stratigos A. Geller A.C. Melanoma prognosis in Europe: far from equal.Br J Dermatol. 2014; 171: 179-182Crossref PubMed Scopus (37) Google Scholar], implying a need to improve prevention, especially in Eastern Europe. UV irradiation was identified as a major carcinogen involved in melanoma genesis. Prevention of UV exposure, including the regular use of sunscreen, has been shown to diminish the incidence of primary cutaneous melanomas in an Australian population [3.Green A.C. Williams G.M. Logan V. Strutton G.M. Reduced melanoma after regular sunscreen use: randomized trial follow-up.J Clin Oncol. 2011; 29: 257-263Crossref PubMed Scopus (542) Google Scholar]. Suspicious lesions are characterised by Asymmetry, Border irregularities, Colour heterogeneity, Dynamics, (dynamics or evolution in colours, elevation or size) (‘ABCD rule’) [4.Dummer R. Guggenheim M. Arnold A.W. et al.Updated Swiss guidelines for the treatment and follow-up of cutaneous melanoma.Swiss Med Wkly. 2011; 141: w13320PubMed Google Scholar]. Today, many primary melanomas have a diameter of <5 mm [5.Bono A. Tolomio E. Trincone S. et al.Micro-melanoma detection: a clinical study on 206 consecutive cases of pigmented skin lesions with a diameter < or = 3 mm.Br J Dermatol. 2006; 155: 570-573Crossref PubMed Scopus (64) Google Scholar]. The ugly duckling ‘concept’ [6.Grob J.J. Bonerandi J.J. The ‘ugly duckling’ sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening.Arch Dermatol. 1998; 134: 103-104Crossref PubMed Google Scholar] helps to identify melanomas, because naevi in the same individual tend to resemble one another and melanomas often do not fit the individual's naevus pattern. Dermoscopy by an experienced physician enhances the diagnostic accuracy [II, B] [7.Kittler H. Pehamberger H. Wolff K. Binder M. Diagnostic accuracy of dermoscopy.Lancet Oncol. 2002; 3: 159-165Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar]. An automated video-dermoscopy system can provide improved diagnostic accuracy for patients with multiple atypical naevi in the follow-up. Diagnosis should be based on a full-thickness excisional biopsy with a minimal side margin. Processing by an experienced pathology institute is mandatory. The histology report should follow the American Joint Committee on Cancer (AJCC) classification [8.Balch C.M. Gershenwald J.E. Soong S.J. et al.Final version of 2009 AJCC melanoma staging and classification.J Clin Oncol. 2009; 27: 6199-6206Crossref PubMed Scopus (3646) Google Scholar], and include: information on the maximum thickness in millimetres (Breslow), information on mitotic rate in case of a tumour thickness below 1 mm, presence of ulceration, presence and extent of regression and clearance of the surgical margins [II, A]. In addition, information on anatomical site (including extra-cutaneous sites, such as mucosa, conjunctiva) and degree of sun damage is necessary. It should also include the melanoma type (superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma and others). In rare situations, melanomas may derive from dermal melanocytes (melanoma arising from giant congenital naevus, malignant blue naevus) [9.Whiteman D.C. Pavan W.J. Bastian B.C. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin.Pigment Cell Melanoma Res. 2011; 24: 879-897Crossref PubMed Scopus (201) Google Scholar]. Superficial spreading and nodular melanomas present a higher frequency of BRAF and NRAS mutations than other melanoma types [10.Bastian B.C. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia.Annu Rev Pathol. 2014; 9: 239-271Crossref PubMed Scopus (302) Google Scholar]. Acral lentiginous melanoma and mucosal melanomas of the genital region have a certain probability to present c-Kit mutations [11.Schoenewolf N.L. Bull C. Belloni B. et al.Sinonasal, genital and acrolentiginous melanomas show distinct characteristics of KIT expression and mutations.Eur J Cancer. 2012; 48: 1842-1852Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. Mutation testing for treatable mutations is mandatory in patients with advanced disease (unresectable stage III or stage IV, and highly recommended in high-risk resected disease stage IIc, stage IIIb–IIIc) [V, A]. If the tumour is BRAF-wild type, testing for NRAS mutations c-kit mutation should be considered [V, A]. Mutational testing of primary tumours without metastases is not recommended. Mutation analysis must be carried out in accredited (certified) institutes that have careful quality controls. Physical examination with special attention to other suspicious pigmented lesions, tumour satellites, in-transit metastases, regional lymph node (LN) and systemic metastases is mandatory. In low-risk melanomas (pT1a) no other investigations are necessary. In higher tumour stages (pT1b–pT3a), imaging (ultrasound for locoregional LN metastasis) and, in pT stages >pT3a, computed tomography (CT) or positron emission tomography (PET) scans are recommended before surgical treatment and sentinel node biopsy [III, C]. The refined version of the AJCC staging and classification system, which includes sentinel node staging, is the only internationally accepted classification system [8.Balch C.M. Gershenwald J.E. Soong S.J. et al.Final version of 2009 AJCC melanoma staging and classification.J Clin Oncol. 2009; 27: 6199-6206Crossref PubMed Scopus (3646) Google Scholar, 12.Hirakawa S. Kodama S. Kunstfeld R. et al.VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis.J Exp Med. 2005; 201: 1089-1099Crossref PubMed Scopus (582) Google Scholar] (Table 1).Table 1AJCC staging system of melanomaReprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved.T classificationThickness (mm)Ulceration status/mitosisT1≤1.0a: without ulceration and mitosis 4.0a: without ulcerationb: with ulcerationN classificationNo. of metastatic nodesNodal metastatic massN00N/AN11 nodea: micrometastasisab: macrometastasisbN22–3 nodesa: micrometastasisab: macrometastasisb c: in transit metastases/satellites ‘without’ metastatic nodesN34 or more metastatic nodes, or matted nodes, or in transit metastases/satellites ‘with’ metastatic nodesM classificationSiteSerum LDHM0No distant metastasisN/AM1aDistant skin, subcutaneous, or nodal metastasesNormalM1bLung metastasesNormalM1cAll other visceral metastasesAny distant metastasisNormalElevatedaMicrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if carried out).bMacrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.AJCC, American Joint Committee on Cancer; N/A, not applicable; LDH, lactate dehydrogenase. Open table in a new tab aMicrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if carried out). bMacrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension. AJCC, American Joint Committee on Cancer; N/A, not applicable; LDH, lactate dehydrogenase. Wide excision of primary tumours with safety margins of 0.5 cm for in situ melanomas, 1 cm for tumours with a thickness of up to 2 mm, and 2 cm for thicker tumours, is recommended [13.Thompson J.F. Scolyer R.A. Kefford R.F. Cutaneous melanoma.Lancet. 2005; 365: 687-701Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar] [II, B]. Modifications, with reduced safety margins, are acceptable for preservation of function in acral and facial melanomas and should be carried out with micrographic surgery. Elective lymphadenectomy or irradiation to the regional LNs should not be carried out routinely [II, B]. Sentinel LN biopsy in melanoma with a tumour thickness of >1 mm and >0.75 mm and additional risk factors such as ulceration or mitotic rate (pT1b) are recommended for precise staging [II, B] [14.Han D. Zager J.S. Shyr Y. et al.Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma.J Clin Oncol. 2013; 31: 4387-4393Crossref PubMed Scopus (178) Google Scholar]. A complete lymphadenectomy of regional LNs must be discussed with the patient, if the sentinel node was found positive for metastases [III, C]. However, this procedure offers just a relapse-free survival (RFS) benefit without proven effect on overall survival (OS) [15.Morton D.L. Thompson J.F. Cochran A.J. et al.Sentinel-node biopsy or nodal observation in melanoma.N Engl J Med. 2006; 355: 1307-1317Crossref PubMed Scopus (1490) Google Scholar]. Sentinel LN biopsy should be carried out only in experienced centres. Many well-designed clinical trials have investigated the impact of adjuvant therapy in patients with high-risk primary melanoma (stage IIB/C) or completely resected LN metastases (stage III) [6.Grob J.J. Bonerandi J.J. The ‘ugly duckling’ sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening.Arch Dermatol. 1998; 134: 103-104Crossref PubMed Google Scholar]. A number of prospective randomised trials have investigated adjuvant treatment with low, intermediate and high doses of interferon-α (IFN-α) [16.Eggermont A.M. Suciu S. Testori A. et al.Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991.Eur J Cancer. 2012; 48: 218-225Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 17.Kirkwood J.M. Ibrahim J.G. Sondak V.K. et al.High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.J Clin Oncol. 2000; 18: 2444-2458Crossref PubMed Scopus (791) Google Scholar]. A meta-analysis of 14 randomised, controlled trials, investigating adjuvant IFN therapy involving 8122 patients, showed statistically significant absolute improvement in both disease-free survival [hazard ratio (HR) 0.82] and OS (HR 0.89), with no clear indication to recommend a certain dose or treatment duration [18.Mocellin S. Pasquali S. Rossi C.R. Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis.J Natl Cancer Inst. 2010; 102: 493-501Crossref PubMed Scopus (428) Google Scholar]. Since pegylated IFN-α (PegIFN-α) is suitable for long-term therapy, the European Organisation for Research and Treatment of Cancer (EORTC) has initiated a large prospective randomised trial to investigate the protective effect of PegIFN-α-2b in the adjuvant setting [19.Eggermont A.M. Suciu S. Santinami M. et al.Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.Lancet. 2008; 372: 117-126Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. A total of 1256 patients with resected stage III melanoma were randomised to receive observation or PegIFN-α therapy [19.Eggermont A.M. Suciu S. Santinami M. et al.Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.Lancet. 2008; 372: 117-126Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness. The IFN group received an induction-IFN-weekly dose of 6 µg/kg for the first 8 weeks, and the dose was then reduced to 3 &mgr;g/kg per week for 5 years [19.Eggermont A.M. Suciu S. Santinami M. et al.Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.Lancet. 2008; 372: 117-126Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. At 3.8 years of median follow-up, RFS was significantly improved by 18% in the PegIFN-α-2b arm, compared with observation; the 4-year RFS rate was 45.6% versus 38.9%. OS was unchanged in the two groups. In stage III–N1a (micrometastases detected in the sentinel node), both RFS and distant metastases-free survival (DMFS) were prolonged in the PegIFNα-2b arm, whereas in stage III-N1b (macroscopic metastases), there was no benefit [19.Eggermont A.M. Suciu S. Santinami M. et al.Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.Lancet. 2008; 372: 117-126Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. An update of this trial, with median follow-up of 7.6 years, has shown that IFN therapy had a significant impact on RFS, DMFS and OS (HR 0.59 = 0.006) in a sub-population of patients with micrometastases and primary ulcerated melanomas [20.Eggermont A.M. Suciu S. Testori A. et al.Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma.J Clin Oncol. 2012; 30: 3810-3818Crossref PubMed Scopus (215) Google Scholar]. Therefore, while awaiting the results of prospective randomised trials, in this patient population, PegIFN-α can be recommended if the individual patient tolerates it well [II, B]. Adjuvant treatment in patients with resected macroscopic node involvement is preferentially applied in the context of randomised clinical trials in specialised centres. However, high-dose IFN-α-2b is an approved indication for this therapeutic situation. A meta-analysis on adjuvant therapy of melanoma with IFNs, however, did not demonstrate an improved efficacy of high-dose IFN compared with low- or intermediate-dose IFNs [18.Mocellin S. Pasquali S. Rossi C.R. Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis.J Natl Cancer Inst. 2010; 102: 493-501Crossref PubMed Scopus (428) Google Scholar]. Long-term therapy with ipilimumab, an antibody blocking CTLA4 and thus activating T lymphocytes to mount an immune response against tumour cells, has improved RFS (HR 0.75; median RFS 26.1 versus 17.1 months, with 3-year RFS rates of 46.5% versus 34.8%, P = 0.0013) in the adjuvant setting also for N1b and higher stages. However, the treatment with a dose of 10 mg/kg every 3 weeks for 4 doses, then every 3 months for up to 3 years, was associated with a number of severe and long-lasting adverse reactions including colitis and endocrinopathies. Therefore, additional trials are mandatory and the respective patient population should be referred to centres offering trial participation [21.Eggermont A.M. Chiarion-Sileni V. Grob J.J. et al.Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.Lancet. 2015; 16: 522-530Abstract Full Text Full Text PDF Scopus (899) Google Scholar]. Adjuvant chemotherapy, mistletoe extracts, viscum album and hormone therapies are not beneficial at all [22.Kleeberg U.R. Suciu S. Brocker E.B. et al.Final results of the EORTC 18871/DKG 80–1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis.Eur J Cancer. 2004; 40: 390-402Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar]. Adjuvant therapy with other cytokines including interleukin-2, tumour vaccination, immunochemotherapy and BRAF inhibitors is experimental and not to be used outside controlled clinical trials. The application of BRAF inhibitors is associated with cutaneous neoplasms such as keratoacanthomas, squamous cell carcinomas and melanomas [23.Oberholzer P.A. Kee D. Dziunycz P. et al.RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors.J Clin Oncol. 2012; 30: 316-321Crossref PubMed Scopus (345) Google Scholar, 24.Su F. Viros A. Milagre C. et al.RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.N Engl J Med. 2012; 366: 207-215Crossref PubMed Scopus (866) Google Scholar, 25.Zimmer L. Hillen U. Livingstone E. et al.Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition.J Clin Oncol. 2012; 30: 2375-2383Crossref PubMed Scopus (192) Google Scholar], which precludes use outside carefully monitored clinical trials. Radiotherapy for local tumour control should be considered in: cases of inadequate resection margins of lentigo maligna melanoma [26.Farshad A. Burg G. Panizzon R. Dummer R. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays.Br J Dermatol. 2002; 146: 1042-1046Crossref PubMed Scopus (153) Google Scholar], in R1 resections of melanoma metastases (when surgery is not adequate), or after resection of bulky disease [III, B]. A prospective randomised trial has demonstrated that postoperative irradiation after LN dissection reduces the risk for relapse in the irradiation field by ∼50%, but has no impact on RFS and OS [27.Burmeister B.H. Henderson M.A. Ainslie J. et al.Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.Lancet Oncol. 2012; 13: 589-597Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. Treatment decisions should be made in an interdisciplinary team. In the case of isolated locoregional LN metastases, surgical removal, including the surrounding LN region is indicated [III, C]; removal of the tumour-bearing LN alone is insufficient. In high-risk situations such as multiple bulky LN metastases, postoperative radiotherapy can improve local tumour control, but has no impact on RFS and OS [27.Burmeister B.H. Henderson M.A. Ainslie J. et al.Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.Lancet Oncol. 2012; 13: 589-597Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 28.Hong A. Fogarty G. Role of radiation therapy in cutaneous melanoma.Cancer J. 2012; 18: 203-207Crossref PubMed Scopus (21) Google Scholar]. However, before undertaking additional aggressive local surgical treatments, a detailed staging investigation, that includes high-resolution imaging techniques, such as PET, CT or magnetic resonance imaging is necessary to exclude distant metastases [4.Dummer R. Guggenheim M. Arnold A.W. et al.Updated Swiss guidelines for the treatment and follow-up of cutaneous melanoma.Swiss Med Wkly. 2011; 141: w13320PubMed Google Scholar] [III, B]. In unresectable in-transit cases, other locoregional approaches, such as electrochemotherapy [29.Campana L.G. Testori A. Mozzillo N. Rossi C.R. Treatment of metastatic melanoma with electrochemotherapy.J Surg Oncol. 2014; 109: 301-307Crossref PubMed Scopus (41) Google Scholar] or intralesional therapy with replicating herpes virus [Talimogene laherparepvec (T-Vec)] [30.Andtbacka R.H. Kaufman H.L. Collichio F. et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.J Clin Oncol. 2015; ([Epub ahead of print])Crossref PubMed Scopus (1585) Google Scholar], preferentially in the context of a clinical trial, should be considered. Surgical removal or stereotactic irradiation therapy might be curative in a few patients and is recommended in the case of a single metastasis in parenchymal organs, including the central nervous system. Non-resectable in-transit metastases or inoperable primary tumours of the limbs, without additional metastases, may be treated with isolated limb perfusion using melphalan and/or tumour necrosis factor-α [III, C]. Such treatment requires major surgery and should be restricted to centres of excellence. Radiation therapy, electrochemotherapy [29.Campana L.G. Testori A. Mozzillo N. Rossi C.R. Treatment of metastatic melanoma with electrochemotherapy.J Surg Oncol. 2014; 109: 301-307Crossref PubMed Scopus (41) Google Scholar] or intralesional therapy, with replicating T-Vec [30.Andtbacka R.H. Kaufman H.L. Collichio F. et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.J Clin Oncol. 2015; ([Epub ahead of print])Crossref PubMed Scopus (1585) Google Scholar], may also be used [V, D], [27.Burmeister B.H. Henderson M.A. Ainslie J. et al.Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.Lancet Oncol. 2012; 13: 589-597Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 28.Hong A. Fogarty G. Role of radiation therapy in cutaneous melanoma.Cancer J. 2012; 18: 203-207Crossref PubMed Scopus (21) Google Scholar]. New therapeutic strategies, such as immunotherapy, that utilise antibodies that bind to checkpoint inhibitors of T-cell activation, have demonstrated impressive efficacy. CTLA-4 blocking agents like ipilimumab, the anti PD-1 antibodies, such as nivolumab and pembrolizumab, as well as selective BRAF inhibitors, such as vemurafenib, encorafenib and dabrafenib (used alone and/or in combination with MEK inhibitors like binimetinib, cobimetinib and trametinib [31.Flaherty K.T. Hennig M. Lee S.J. et al.Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials.Lancet Oncol. 2014; 15: 297-304Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 32.McArthur G.A. Chapman P.B. Robert C. et al.Safety and efficacy of vemurafenib in BRAF (V600E) and BRAF (V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.Lancet Oncol. 2014; 15: 323-332Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar]), have demonstrated impressive anti-tumour activity [33.Chapman P.B. Hauschild A. Robert C. et al.Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011; 364: 2507-2516Crossref PubMed Scopus (6115) Google Scholar, 34.Guo J. Si L. Kong Y. Flaherty K.T. et al.Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification.J Clin Oncol. 2011; 29: 2904-2909Crossref PubMed Scopus (527) Google Scholar, 35.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11189) Google Scholar, 36.Robert C. Thomas L. Bondarenko I. et al.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364: 2517-2526Crossref PubMed Scopus (3568) Google Scholar, 37.Long G.V. Stroyakovskiy D. Gogas H. et al.Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.N Engl J Med. 2014; 371: 1877-1888Crossref PubMed Scopus (1276) Google Scholar, 38.Robert C. Karaszewska B. Schachter J. et al.Improved overall survival in melanoma with combined dabrafenib and trametinib.N Engl J Med. 2015; 372: 30-39Crossref PubMed Scopus (1824) Google Scholar, 39.Robert C. Long G.V. Brady B. et al.Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015; 372: 320-330Crossref PubMed Scopus (4027) Google Scholar]. Therefore, immunotherapy and kinase inhibitors are the backbone of systemic therapy. Chemotherapy is considered a second-line or bridging treatment option. Tumour tissues, preferentially of metastatic lesions, should be screened for mutations of BRAF V600. If that is negative, further molecular testing can be carried out for NRAS, c-Kit (mucosal and acrolentigenous primaries) GNA11 or GNAQ (uveal primary); this helps to direct patients to the appropriate targeted treatment or clinical trial. There are early signals from a phase II clinical trial that patients with metastatic melanomas, carrying NRAS mutation, may benefit from MEK kinase-inhibitor therapy [40.Ascierto P.A. Schadendorf D. Berking C. et al.MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study.Lancet Oncol. 2013; 14: 249-256Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar]. The additional analysis for PDL-1 expression helps to enrich the population of patients who benefit from anti-PD1 therapy, but is not powerful enough to exclude patients from anti-PD1 treatment [39.Robert C. Long G.V. Brady B. et al.Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015; 372: 320-330Crossref PubMed Scopus (4027) Google Scholar, 41.Larkin J. Ascierto P.A. Dréno B. et al.Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.N Engl J Med. 2014; 371: 1867-1876Crossref PubMed Scopus (1497) Google Scholar]. The recommendations for first-line treatment of metastatic disease are under debate. Reasonable approaches include anti-PD1 therapies and, for BRAF-mutated melanomas, combinations of BRAF inhibitors with MEK inhibitors. BRAFi/MEKi inhibitor combos offer high response rates (70%) and rapid response induction associated with symptom control, with a progression-free survival (PFS) of ∼12 months. Anti-PD1 therapy, and to a lesser extent ipilimumab, offer lower response rates in the range, but many responses are durable [42.Robert C. Schachter J. Long G.V. et al.Pembrolizumab versus ipilimumab in advanced melanoma.N Engl J Med. 2015; 372: 2521-2532Crossref PubMed Scopus (4050) Google Scholar]. In patients with BRAF-wild-type (wt) disease, ipilimumab has been the standard treatment based on a survival benefit with a ∼10% higher survival rate at 1, 2 and 3 years [36.Robert C. Thomas L. Bondarenko I. et al.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364: 2517-2526Crossref PubMed Scopus (3568) Google Scholar]. Based on very recent randomised trial results, comparing anti-PD1 antibody therapies to ipilimumab, anti-PD1 antibody therapy is the preferred first-line treatment of patients with BRAF-wt disease [42.Robert C. Schachter J. Long G.V. et al.Pembrolizumab versus ipilimumab in advanced melanoma.N Engl J Med. 2015; 372: 2521-2532Crossref PubMed Scopus (4050) Google Scholar]. These therapies also demonstrate efficacy for patients with other BRAF mutations [37.Long G.V. Stroyakovskiy D. Gogas H. et al.Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.N Engl J Med. 2014; 371: 1877-1888Crossref PubMed Scopus (1276) Google Scholar]. Anti-PD1 therapies are also recommended as a second-line treatment, after ipilimumab failure [43.Weber J.S. D'Angelo S.P. Minor D. et al.Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4-treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2015; 16: 375-384Abstract Full Text Full Text PDF PubMed Scopus (2012) Google Scholar, 44.Dummer R. Daud A. Puzanov I. et al.A randomized controlled comparison of pembrolizumab and chemotherapy in patients with ipilimumab-refractory melanoma.J Transl Med. 2015; 13: 05Crossref PubMed Scopus (0) Google Scholar]. The anti-PD1 antibody nivolumab was compared with the reference chemotherapy dacarbazine in a double-blind randomised clinical trial with BRAF-wt patients. This trial showed a 1-year survival rate of 72.9% in the nivolumab group, compared with 42.1% in the dacarbazine group (HR for death, 0.42; P < 0.001) [39.Robert C. Long G.V. Brady B. et al.Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015; 372: 320-330Crossref PubMed Scopus (4027) Google Scholar]. Nivolumab and pembrolizumab present an excellent safety profile, resulting in a favourable risk/benefit ratio. The most frequent adverse events included fatigue, pruritus and nausea. Both molecules have been compared with standard chemotherapies in a second-line setting after ipilimumab therapy. They demonstrated favourable efficacy, with prolonged PFS and better response rates, than the chemotherapy option [43.Weber J.S. D'Angelo S.P. Minor D. et al.Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4-treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2015; 16: 375-384Abs
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