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Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

2012; Elsevier BV; Volume: 23; Linguagem: Inglês

10.1093/annonc/mds229

1569-8041

Reinhard Dummer, Axel Hauschild, Merlin Guggenheim, U. Keilholz, G. Pentheroudakis,

Skin Protection and Aging

The incidence of malignant melanoma varies from 3–5/100 000/year in Mediterranean countries to 12–20 in Nordic countries and is still rising [1.MacKie R.M. Bray C. Vestey J. et al.Melanoma incidence and mortality in Scotland 1979–2003.Br J Cancer. 2007; 96: 1772-1777Crossref PubMed Scopus (101) Google Scholar]. Increased ultraviolet (UV) light exposure of a genetically predisposed population seems to be at least in part responsible for an ongoing increase in incidence and mortality over recent decades [2.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]. UV light was identified as a major carcinogen involved in melanomagenesis. 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. et al.Reduced melanoma after regular sunscreen use: randomized trial follow-up.J Clin Oncol. 2011; 29: 257-263Crossref PubMed Scopus (546) Google Scholar]. Suspicious lesions are characterized by Asymmetry, Border irregularities, Color heterogeneity, Dynamics (Dynamics or evolution in colors, 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 us to identify melanomas, because nevi in the same individual tend to resemble one another and melanomas often do not fit in the individual nevus pattern. Dermoscopy by an experienced physician enhances the diagnostic accuracy (II, B). Diagnosis should be based on a full thickness excisional biopsy with a small side margin. Processing by an experienced pathology institute is mandatory. The histology report should follow the American Joint Committee on Cancer (AJCC) classification [7.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 (3684) Google Scholar] and includes information on the maximum thickness in millimeters (Breslow), information on the mitotic rate, presence of ulceration, presence and extent of regression and clearance of the surgical margins (II,A). In addition, information on the anatomical site (including extra cutaneous sites, such as mucosa and conjunctiva), and the degree of sun damage is necessary. It describes the melanoma type (superficial spreading melanoma, lentigo maligna melanoma, acrolentiginous melanoma, nodular melanoma, others). In rare situations, melanomas may derive from dermal melanocytes (melanoma arising from giant congenital nevus, malignant blue nevus) [8.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 (202) Google Scholar]. Superficial spreading and nodular melanomas present a much higher frequency of BRAF and NRAS mutations than other melanoma types. Acrolentiginous melanoma and mucosal melanomas of the genital region have a certain probability to present c-Kit mutations [9.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 (70) Google Scholar]. Mutation analysis for BRAF and optionally NRAS and c-Kit are necessary in the case of metastatic disease. Mutational testing of primary tumors without metastases is not recommended. Mutation analysis must be carried out in accredited (certified) institutes including careful quality controls. Physical examination with special attention to other suspicious pigmented lesions, tumor satellites, in-transit metastases, regional lymph node and systemic metastases is mandatory. In low-risk melanomas (pT1a), no other investigations are necessary. In higher tumor stages, imaging is recommended in order to allow proper staging (III, C). The refined version of the AJCC staging and classification system which includes a sentinel node staging is the only internationally accepted classification system [7.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 (3684) Google Scholar, 10.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 (583) Google Scholar] (Table 1).Table 1AJCC Staging system of melanoma [7.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 (3684) Google Scholar].ClassificationThickness (mm)Ulceration status/mitosesT TisNANA T1≤1.00(a) Without ulceration and mitosis < 1/mm²(b) With ulceration or mitoses ≥1/mm² T2≤2.00(a) Without ulceration(b) With ulceration T32.01–4.00(a) Without ulceration(b) With ulceration T4>4.00(a) Without ulceration(b) With ulcerationNNo. of Metastatic nodesNodal Metastatic BurdenN00NAN11(a) MicrometastasisaMicrometastases are diagnosed after sentinel lymph node biopsy.(b) MacrometastasisbMacrometastases are defined as clinically detectable nodal metastases confirmed pathologically.N22–3(a) MicrometastasisaMicrometastases are diagnosed after sentinel lymph node biopsy.(b) MacrometastasisbMacrometastases are defined as clinically detectable nodal metastases confirmed pathologically.(c) In transit metastases/satellites without metastatic nodesN34+ metastatic nodes, or matted nodes, or in transit metastases/satellites with metastatic nodesMSiteSerum LDHM0No distant metastasesNAM1aDistant skin, subcutaneous or nodal metastasesNormalLung metastasesM1bAll other visceral metastasesNormalAny distant metastasesNormalM1cElevatedNA, not applicable; LDH, lactate dehydrogenase.a Micrometastases are diagnosed after sentinel lymph node biopsy.b Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically. Open table in a new tab NA, not applicable; LDH, lactate dehydrogenase. Wide excision of primary tumors with safety margins of 0.5 cm for in situ melanomas, of 1 cm for tumors with a Breslow thickness of up to 2 mm and 2 cm for thicker tumors is recommended [11.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 may be needed for preservation of function in acral and facial melanomas. Routine elective lymphadenectomy or irradiation to the regional lymph nodes is not recommended [II, B]. Sentinel lymph node biopsy in melanoma with a tumor thickness of >1 mm and/or ulceration is necessary for precise staging (II, B). It should be followed by a complete lymphadenectomy of regional lymph nodes, if the sentinel node was found positive for metastases (III, C). However, this procedure has no proven effect on overall survival (OS) [12.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 (1501) Google Scholar]. Sentinel lymph node biopsy should be carried out only by skilled teams in experienced centers. 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 lymph node 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 randomized trials have investigated adjuvant treatment with low, intermediate and high doses of IFN-α [13.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 (167) Google Scholar, 14.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 (795) Google Scholar]. The first trial that showed a positive effect in OS was ECOG 1684 [15.Kirkwood J.M. Strawderman M.H. Ernstoff M.S. et al.Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684.J Clin Oncol. 1996; 14: 7-17Crossref PubMed Scopus (1835) Google Scholar] which randomized 287 patients with node-positive melanoma to high-dose interferon-α (IFN-α) for 1 year versus observation. Five-year disease-free survival (DFS) was 37% versus 26% and OS was 46% versus 37% [15.Kirkwood J.M. Strawderman M.H. Ernstoff M.S. et al.Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684.J Clin Oncol. 1996; 14: 7-17Crossref PubMed Scopus (1835) Google Scholar]. On this basis, high-dose adjuvant IFN-α won US Food and Drug Administration (FDA) approval. A meta-analysis of 14 randomized, controlled trials investigating adjuvant IFN therapy involving 8122 patients showed statistically significant improvement in both DFS and OS [16.Mocellin S. Pasquali S. Rossi C.R. et al.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 (434) Google Scholar]. Since pegylated IFN-α (PegIFN-α) is suitable for long-term therapy, the European Organization for Research and Treatment of Cancer has initiated a large prospective randomized trial to investigate the protective effect of PegIFNα-2b in the adjuvant setting [17.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 (544) Google Scholar]. One thousand two hundred and fifty six patients with resected stage III melanoma were randomly assigned to receive observation or PegIFN-α therapy [17.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 (544) Google Scholar]. Randomization was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumor thickness. Relapse-free survival (RFS) (primary end-point), distant-metastases-free survival (DMFS) and OS were analyzed for the intent-to-treat population. The IFN group received an induction IFN dose of 6 μg/kg weekly for the first 8 weeks and then the dose was reduced to 3 μg/kg per week for 5 years [17.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 (544) Google Scholar]. At 3.8 years of median follow-up, RFS was substantially improved by 18% in the PegIFNα-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 (HR = 0.72, 57.7% versus 45.4%, P = 0.01) and DMFS (HR = 0.73, 60.5% versus 52.6%, P = 0.01) were prolonged in the PegIFNα-2b arm, whereas in stage III-N1b (macroscopic metastases) there was no benefit [17.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 (544) Google Scholar]. This trial showed that a prolonged adjuvant treatment with IFN-α improved the RFS period and DMFS in a subgroup of patients with low tumor burden [17.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 (544) Google Scholar]. An update of this trial with median follow-up of 7.6 years has shown that IFN therapy had a substantial impact on RFS, DMFS and OS (HR 0.59 = 0.006) in a subpopulation of patients with micrometastases and primary ulcerated melanomas. Therefore, in this patient population pegylated IFN 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 randomized clinical trials in specialized centers. However, high-dose IFN a2b is an approved indication for this therapeutic situation. A recent meta-analysis on adjuvant therapy of melanoma with IFN did not demonstrate an improved efficacy of high-dose IFN compared with low- or intermediate-dose IFN [16.Mocellin S. Pasquali S. Rossi C.R. et al.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 (434) Google Scholar]. Adjuvant chemotherapy, mistletoe extracts, viscum album and hormone therapies are not beneficial at all [18.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 (IL-2), tumor vaccination, immunochemotherapy and BRAF inhibitors are experimental and not to be used outside controlled clinical trials. The application of vemurafenib is associated with cutaneous neoplasms such as keratoakanthomas, squamous cell carcinomas and melanomas [19.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 (346) Google Scholar, 20.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 (875) Google Scholar, 21.Zimmer L. Hillen U. Livingstone E. et al.Atypical melanocytic proliferations and new primary melanomas in advanced melanoma patients undergoing selective BRAF inhibition.J Clin Oncol. 2012; 30: 2375-2383Crossref PubMed Scopus (194) Google Scholar]. Therefore, it is not recommended in patients without measurable tumor load. Radiotherapy for local tumor control should be considered in case of inadequate resection margins of lentigo maligna melanoma [22.Farshad A. Burg G. Panizzon R. et al.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 (154) Google Scholar] or R1 resections of melanoma metastases when surgery is not adequate (III, B). In the case of isolated locoregional lymph node metastases, surgical removal, including the surrounding lymph node region, is indicated (III, C); removal of the tumor-bearing lymph node alone is insufficient. In high-risk situations such as multiple bulky lymph node metastases, postoperative radiotherapy can improve local tumor control [23.Hong A. Fogarty G. Role of radiation therapy in cutaneous melanoma.Cancer J. 2012; 18: 203-207Crossref PubMed Scopus (21) Google Scholar]. Surgical removal is also recommended in the case of a single metastasis in parenchymal organs, including the central nervous system. However, before undertaking additional aggressive local surgical treatments, a detailed staging investigation, including imaging techniques such as Positron Emission Tomography (PET) and computed tomography (CT), is necessary to exclude the presence of further 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). Non-resectable in-transit metastases or inoperable primary tumors of the limbs without additional metastases may be treated with isolated limb perfusion using, e.g. melphalan and/or tumor necrosis factor-α [III, C]. Such treatment requires major surgery and should be restricted to centers of excellence. Radiation therapy may be used alternatively [V, C], although there are no data showing a positive effect on any outcome measure [23.Hong A. Fogarty G. Role of radiation therapy in cutaneous melanoma.Cancer J. 2012; 18: 203-207Crossref PubMed Scopus (21) Google Scholar, 24.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 (218) Google Scholar] (Table 2).Table 2Treatment modalities for melanoma metastases.Number and localization of the metastasesTreatment modalities (i) First choice(ii) Second choice(iii) Third choiceGrade of recommendationIn-transit metastases (few) (pTXN2cM0)(i) Surgical removalC(ii) RadiotherapyCIn-transit metastases (multiple, >5) (pTXN2cM0)(i) Perfusion of the extremityaThese therapies should be preferentially carried out at specialized centers.C(ii) RadiotherapyC(iii) Systemic therapyaThese therapies should be preferentially carried out at specialized centers.CLocoregional lymph nodes (pTxN1a,2a)(i) Resection and trial participationB(ii) Additional IFN-α treatmentaThese therapies should be preferentially carried out at specialized centers.BLocoregional lymph nodes (pTxN2b,2c,3)(i) Radical lymphadenectomy, in case of incomplete resection: irradiationC(ii) Consider trial participationCSolitary central nervous system metastases (pTxNxM3)(i) Neurosurgical removalC(ii) Stereotactic irradiationaThese therapies should be preferentially carried out at specialized centers. (according to localization this could also be the first choice)C(iii) Consider clinical trial participationSolitary lung metastases (pTxNxM1)(i) Surgical removalC(ii) Consider clinical trial participation(iii) Systemic therapyaThese therapies should be preferentially carried out at specialized centers.CMultiple metastases (pTxNxM1a-1c)(i) Consider clinical trial participation(ii) Systemic therapyaThese therapies should be preferentially carried out at specialized centers.BPainful bone metastases (pTxNxM1a-1c)(i) Consider clinical trial participation(ii) RadiotherapyCa These therapies should be preferentially carried out at specialized centers. Open table in a new tab Recently new therapeutic strategies such as immunotherapy using Ipilimumab or anti-PD1 antibodies, selective BRAF inhibitors like vemurafenib and dabrafenib, c-Kit inhibitors and MAPK/ERK kinase (MEK) inhibitors [25.Flaherty K.T. Robert C. Hersey P. et al.Improved survival with MEK inhibition in BRAF-mutated melanoma.N Engl J Med. 2012; 367: 107-114Crossref PubMed Scopus (1735) Google Scholar, 26.Ascierto P.A. Berking C. Agarwala S.S. et al.Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations.J Clin Oncol. 2012; 30 (Abstr 8511)PubMed Google Scholar] have demonstrated impressive antitumor activity in clinical trials [27.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 (6153) Google Scholar, 28.Guo J. Si L. Kong Y. 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 (533) Google Scholar, 29.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 (11320) Google Scholar, 30.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 (3594) Google Scholar]. Ipilimumab and vemurafenib, dabrafenib and trametinib have substantially improved response rates and/or survival of the patient population included in prospective randomized trials [25.Flaherty K.T. Robert C. Hersey P. et al.Improved survival with MEK inhibition in BRAF-mutated melanoma.N Engl J Med. 2012; 367: 107-114Crossref PubMed Scopus (1735) Google Scholar, 27.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 (6153) Google Scholar, 29.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 (11320) Google Scholar, 30.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 (3594) Google Scholar]. Tumor tissues preferentially of metastatic lesions should be screened for mutations (BRAF, NRAS, c-Kit, GNA11, GNAQ) which help to direct patients to the appropriate clinical trials and in the long term to validate their prognostic relevance. Ipilimumab and in the presence of BRAF V600 mutation, vemurafenib, are optimal choices for first-line therapy of patients with metastatic melanoma (II, B). Phase III randomized, controlled trials resulted in the approval of vemurafenib by the United States Food & Drug Administration (FDA) and European Medicines Agency (EMA) and of ipilimumab for first- and second-line therapy (FDA) or as second-line therapy (EMA) of patients with advanced irresectable melanoma. If the patient suffers from symptomatic, bulky metastases from a BRAF V600 mutated melanoma, a selective inhibitor such as vemurafenib is preferred, because it has a high chance for a rapid response including improvement of the quality of life. There are no mature data to guide decision-making regarding the sequencing of ipilimumab and vemurafenib in patients with BRAF-mutant metastatic melanoma; however emerging data suggest that BRAF inhibition is effective even following immunotherapy. Currently, ipilimumab is only approved by EMA as second-line therapy for patients with advanced disease. Selective BRAF inhibitors can be safely used in patients with brain metastases and show promising efficacy in this compartment. Patients treated with vemurafenib should be carefully followed with special attention to skin [19.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 (346) Google Scholar, 21.Zimmer L. Hillen U. Livingstone E. et al.Atypical melanocytic proliferations and new primary melanomas in advanced melanoma patients undergoing selective BRAF inhibition.J Clin Oncol. 2012; 30: 2375-2383Crossref PubMed Scopus (194) Google Scholar] and other secondary neoplasms. In patients with BRAF wild-type melanomas ipilimumab, an agent blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and thus activating T-lymphocytes to mount an immune response against tumor cells, is a recommended second-line to first-(FDA) or second-line (FDA and EMA) therapeutic option. In the context of new developments and medical progress, there are continuously new experimental treatment options for patients with advanced metastatic melanoma. Therefore, these patients should be referred to tertiary centers providing a comprehensive clinical trial program. There are early signals that patients with metastatic melanomas carrying NRAS mutation will profit from MEK kinase inhibitor therapy [26.Ascierto P.A. Berking C. Agarwala S.S. et al.Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations.J Clin Oncol. 2012; 30 (Abstr 8511)PubMed Google Scholar]. If clinical trials or the approved new targeted compounds are not available, cytotoxic drugs such as dacarbazine (DTIC), temozolomide, taxanes, fotemustine, platin derivatives or others, cytokines ( IFN, IL-2) or combinations may be applied. Dacarbazine is still considered a reference drug in this situation. In aggressive metastastic disease, multi-agent polychemotherapy containing paclitaxel and carboplatin or cisplatin, vindesine and dacarbazine produce partial response rates and stabilizations in a meaningful number of patients. Despite a better initial control rate, no survival benefit has been shown with polychemotherapy when compared with monochemotherapy, and therefore, polychemotherapies are not considered an established first-line therapy. Despite a minor increase in progression-free survival, bevacizumab therapy is rarely used in metastatic melanoma [31.von Moos R. Seifert B. Simcock M. et al.First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07).Ann Oncol. 2011; 23: 531-536Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 32.Kim K.B. Sosman J.A. Fruehauf J.P. et al.BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma.J Clin Oncol. 2012; 30: 34-41Crossref PubMed Scopus (138) Google Scholar]. There are no randomized clinical trials for IL-2 monotherapy. Some centers still use IL-2 as first-line therapy when disease burden is low [33.Petrella T. Quirt I. Verma S. et al.Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review.Cancer Treat Rev. 2007; 33: 484-496Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 34.Hamm C. Verma S. Petrella T. et al.Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review.Cancer Treat Rev. 2008; 34: 145-156Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]. Several randomized trials did not show any survival benefit for the very intensive biochemotherapy including IL-2. Surgery of visceral metastases may be appropriate for selected cases with good performance status and isolated tumor manifes-tations. In principal, the goal is R0-resections in these patients. Palliative radiotherapy should be considered, especially for symptomatic brain or localized and painful bone metastases. Stereotactic irradiation is preferred in case of few brain metastases [23.Hong A. Fogarty G. Role of radiation therapy in cutaneous melanoma.Cancer J. 2012; 18: 203-207Crossref PubMed Scopus (21) Google Scholar]. In general, stage IV melanoma patients need to be treated and discussed in an interdisciplinary tumor board at centers with broad experience in this disease. Melanoma patients should be instructed on avoidance of sunburns, extended unprotected solar or artificial UV exposure and on lifelong regular self-examinations of the skin and peripheral lymph nodes. Patients must be aware that family members have an increased melanoma risk (III, B). There is no necessity for genetic testing. During melanoma follow-up, patients are clinically monitored in order to detect a relapse and to recognize additional skin tumors, especially secondary melanomas, as early as possible [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). However, it is unproven if this policy leads to improved survival rates. Eight percent of all melanoma patients develop a secondary melanoma within 2 years of their initial diagnosis [35.Titus-Ernstoff L. Perry A.E. Spencer S.K. et al.Multiple primary melanoma: two-year results from a population-based study.Arch Dermatol. 2006; 142: 433-438Crossref PubMed Scopus (83) Google Scholar]. Melanoma patients also have increased risks of other skin tumors. In patients with lentigo maligna melanomas, 35% of the patients developed another cutaneous malignancy within 5 years [22.Farshad A. Burg G. Panizzon R. et al.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 (154) Google Scholar]. There is currently no consensus on the frequency of follow-up and the use of imaging techniques. In recent series, most relapses have been detected by the patients themselves, questioning the usefulness and cost-effectiveness of follow-up visits every 3 months during the first 3 years and every 6–12 months thereafter. The above recommendations were solely based on the relapse-risk profile over time [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]. Intervals between controls tailored according to individual risk may reduce false-positive findings and suffice for psychological support of the patients [36.Turner R.M. Bell K.J. Morton R.L. et al.Optimizing the frequency of follow-up visits for patients treated for localized primary cutaneous melanoma.J Clin Oncol. 2011; 29: 4641-4646Crossref PubMed Scopus (73) Google Scholar]. Since patients with a thin primary melanoma have only a small risk of relapse, routine imaging techniques are definitively not recommended for this patient population. In high-risk patients, e.g. those with thick primary tumors or following treatment of metastases ultrasound of lymph nodes, computed tomography (CT) or whole body positron emission tomography scans (PET)/PET–CT scans may lead to an earlier diagnosis of regional or systemic relapses [37.Bastiaannet E. Wobbes T. Hoekstra O.S. et al.Prospective comparison of [18F]fluorodeoxyglucose positron emission tomography and computed tomography in patients with melanoma with palpable lymph node metastases: diagnostic accuracy and impact on treatment.J Clin Oncol. 2009; 27: 4774-4780Crossref PubMed Scopus (74) Google Scholar]. However, an impact of radiological exams upon survival has not been demonstrated so far [38.Nieweg O.E. Kroon B.B. The conundrum of follow-up: should it be abandoned?.Surg Oncol Clin N Am. 2006; 15: 319-330Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. Rising serum S-100 has a higher specificity for disease progression than lactate dehydrogenase (LDH) and therefore is the most accurate blood test in the follow-up of melanoma patients [39.Beyeler M. Waldispuhl S. Strobel K. et al.Detection of melanoma relapse: first comparative analysis on imaging techniques versus S100 protein.Dermatology. 2006; 213: 187-191Crossref PubMed Scopus (29) Google Scholar], if any blood test is recommended at all (IV, D).Table 3Summary of recommendationsDiagnosis should be based on a full thickness excisional biopsy with a small side margin (II, A)The histology report should include at least information on the type of melanoma, actinic damage, maximum thickness in millimeters (Breslow), information on the mitotic rate in case of pT1, presence of ulceration, presence and extent of regression and clearance of the surgical margins (II,A)Physical examination with special attention to other suspicious pigmented lesions, tumor satellites, in-transit metastases, regional lymph node and systemic metastases is mandatory. In low-risk melanomas (pT1a), no other investigations are necessary. In higher tumor stages, imaging is recommended in order to allow proper staging (III, C)Wide excision of primary tumors with safety margins of 0.5 cm for in situ melanomas, of 1 cm for tumors with a Breslow thickness of up to 2 mm and 2 cm for thicker tumors is recommended (II, B)Sentinel lymph node biopsy in melanoma with a tumor thickness of >1 mm and/or ulceration is necessary for precise staging (II, B)Patients with resected stage III melanomas should be evaluated for adjuvant therapy with either high-dose IFN-α2b for 1 year or with pegylated weekly PegIFN-α for up to 5 years (II, B). Subgroup analyses suggest that patients with microscopic regional nodal involvement and/or ulcerated primaries are the ones most likely to benefit from adjuvant IFN-α. Participation in clinical trials should be encouragedSurgical removal of locoregional recurrence or single distant metastasis should be considered in fit patients as a therapeutic option offering potential for long-term disease control (III, C)Patients with metastatic melanoma should have a metastasis (preferably) or the primary screened for the presence of BRAF V600 mutation. Treatment options for the first- and second-line setting include ipilimumab, an anti-CTLA4 antibody, for all patients and vemurafenib, a BRAF inhibitor, for patients with BRAF-mutant melanoma (II, B). Ipilimumab is approved only as 2nd line therapy by EMAIf clinical trials or the approved new targeted compounds are not available, cytotoxic drugs such as DTIC, temozolomide may be applied, with modest activity shown (II, C)Melanoma patients should be instructed on avoidance of sunburns, extended unprotected solar or artificial UV exposure and on lifelong regular self-examinations of the skin and peripheral lymph nodes (III, B)There is no consensus on optimal schedule, frequency of follow-up visits neither on the utility of imaging and blood tests for patients with resected melanoma Open table in a new tab Prof. Dummer has reported: research funding from AstraZeneca, Novartis, Cephalon, Merck Sharp & Dohme, Transgene, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Bayer; consultant or advisory board relationship with AstraZeneca, Novartis, Cephalon, Merck Sharp & Dohme, Transgene, Genta, Bayer, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Spirig. Prof. Hauschild has reported: consultancy/honoraria for advisory board, speakers' bureau and lecture support from Amgen, AstraZeneca, Biovex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eisai, GlaxoSmithKline, IGEA, Lilly, Medec, MelaSciences, Merck Sharpe & Dohme/Merck, Novartis, Roche Pharma, SOBI, Vical, Janssen. Prof. Keilholz has reported: speakers' bureau for GlaxoSmithKline and Bristol-Myers Squibb. Other authors have reported no potential conflicts of interest.