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Melanoma: HELP
Articles by Dr. Dirk Schadendorf
Based on 295 articles published since 2009
(Why 295 articles?)
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Between 2009 and 2019, D. Schadendorf wrote the following 295 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12
1 Guideline S3-guideline "diagnosis, therapy and follow-up of melanoma" -- short version. 2013

Pflugfelder, Annette / Kochs, Corinna / Blum, Andreas / Capellaro, Marcus / Czeschik, Christina / Dettenborn, Therese / Dill, Dorothee / Dippel, Edgar / Eigentler, Thomas / Feyer, Petra / Follmann, Markus / Frerich, Bernhard / Ganten, Maria-Katharina / Gärtner, Jan / Gutzmer, Ralf / Hassel, Jessica / Hauschild, Axel / Hohenberger, Peter / Hübner, Jutta / Kaatz, Martin / Kleeberg, Ulrich R / Kölbl, Oliver / Kortmann, Rolf-Dieter / Krause-Bergmann, Albrecht / Kurschat, Peter / Leiter, Ulrike / Link, Hartmut / Loquai, Carmen / Löser, Christoph / Mackensen, Andreas / Meier, Friedegund / Mohr, Peter / Möhrle, Matthias / Nashan, Dorothee / Reske, Sven / Rose, Christian / Sander, Christian / Satzger, Imke / Schiller, Meinhard / Schlemmer, Heinz-Peter / Strittmatter, Gerhard / Sunderkötter, Cord / Swoboda, Lothar / Trefzer, Uwe / Voltz, Raymond / Vordermark, Dirk / Weichenthal, Michael / Werner, Andreas / Wesselmann, Simone / Weyergraf, Ansgar J / Wick, Wolfgang / Garbe, Claus / Schadendorf, Dirk / Anonymous5740759. ·Department of Dermatology, University Hospital Tübingen, Germany. ·J Dtsch Dermatol Ges · Pubmed #23721604.

ABSTRACT: -- No abstract --

2 Editorial [Editorial]. 2016

Schilling, Bastian / Schadendorf, Dirk. · ·J Dtsch Dermatol Ges · Pubmed #26713629.

ABSTRACT: -- No abstract --

3 Review Adjuvant melanoma therapy with new drugs: should physicians continue to focus on metastatic disease or use it earlier in primary melanoma? 2018

Grob, Jean Jacques / Garbe, Claus / Ascierto, Paolo / Larkin, James / Dummer, Reinhard / Schadendorf, Dirk. ·Service de Dermatologie et Cancérologie Cutanée, Aix-Marseille University and APHM University Hospital, Marseille, France. Electronic address: jean-jacques.grob@ap-hm.fr. · Department of Dermatology, University Medical Center, Tuebingen, Germany. · Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy. · The Royal Marsden NHS Foundation Trust, London, UK. · Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. · Department of Dermatology and Comprehensive Cancer Centre, University Hospital Essen, Essen, Germany. ·Lancet Oncol · Pubmed #30507438.

ABSTRACT: It is important to differentiate between two concepts of adjuvant therapy in melanoma-what we have come to call late adjuvant and early adjuvant therapy. Early adjuvant therapy is defined as a medical intervention that is done after resection of a primary melanoma to eradicate possible undetectable minimal residual disease, whereas late adjuvant therapy is done when an overt metastatic disease (nodal or visceral) has been completely resected, to control disease better than if the same treatment were given at a later time, in the presence of multiple metastases. Early adjuvant therapy is thus a preventive treatment strategy, whereas late adjuvant therapy aims at anticipating treatment of metastatic disease. For patients with melanoma, 1-year treatment with targeted therapies and immunotherapy have only been assessed in late adjuvant settings, the outcomes of which more or less reproduce the same dramatic effect as they have in metastatic disease. However, early adjuvant therapy could provide greater benefits in terms of public health, since thin melanomas without nodal metastases are so common that they account for most deaths by melanoma. In the early adjuvant setting, a treatment course of less than 1 year might be sufficient to control the disease, with less toxicity and at reduced costs. In this Personal View, we discuss the potential benefit of short-term early adjuvant treatment in patients with stage II melanoma, with the hope that sentinel-node biopsy and the American Joint Committee on Cancer staging will soon be replaced by more relevant biomarkers to identify the most suitable candidates for early adjuvant therapy for this disease.

4 Review Melanoma. 2018

Schadendorf, Dirk / van Akkooi, Alexander C J / Berking, Carola / Griewank, Klaus G / Gutzmer, Ralf / Hauschild, Axel / Stang, Andreas / Roesch, Alexander / Ugurel, Selma. ·Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. Electronic address: dirk.schadendorf@uk-essen.de. · Department of Surgical Oncology, Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, Netherlands. · Department of Dermatology and Allergy, University Hospital Munich, Munich, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Department of Dermatology, Hannover Medical School, Skin Cancer Centre Hannover, Hannover, Germany. · Department of Dermatology, University Hospital, Kiel, Germany. · Centre of Clinical Epidemiology, Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, Essen, Germany; Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA. ·Lancet · Pubmed #30238891.

ABSTRACT: Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)

5 Review The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. 2018

Knispel, Sarah / Zimmer, Lisa / Kanaki, Theodora / Ugurel, Selma / Schadendorf, Dirk / Livingstone, Elisabeth. ·a Skin Cancer Unit, Department of Dermatology , University Hospital Essen, University of Duisburg-Essen , Essen , Germany. ·Expert Opin Drug Saf · Pubmed #29050517.

ABSTRACT: INTRODUCTION: The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs. Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.

6 Review Update zum klinischen Einsatz von Inhibitoren mutierter Phosphokinasen beim Melanom. 2017

Cosgarea, Ioana / Ritter, Cathrin / Becker, Jürgen C / Schadendorf, Dirk / Ugurel, Selma. ·Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Essen, Universität Duisburg-Essen und Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen. ·J Dtsch Dermatol Ges · Pubmed #28872247.

ABSTRACT: Die Behandlungsstrategie beim metastasierten Melanom hat sich mit der Identifizierung therapeutisch angreifbarer molekularer Zielstrukturen innerhalb zellulärer Signalwege radikal geändert. Durch die Zulassung von Substanzen, die gezielt an den zentralen Schaltmolekülen, den Phosphokinasen, angreifen, können diese Signalwege selektiv abgeschaltet werden. Dies ist insbesondere bei denjenigen Tumoren von Interesse, deren Signalwege durch aktivierende Mutationen der für die Schaltmoleküle kodierenden Gene konstitutiv aktiviert sind. Aktuell ist diese therapeutische Strategie insbesondere für Patienten bedeutsam, deren Melanome eine Mutation im BRAF-Gen aufweisen. Diese Patienten können durch eine Kombinationstherapie aus Inhibitoren der Phosphokinasen BRAF und MEK langfristig mit sehr guter Krankheitskontrolle behandelt werden. Unter dieser Kombinationstherapie wird aktuell ein progressionsfreies Überleben von über zehn Monaten und ein Gesamtüberleben von mehr als zwei Jahren bei guter Lebensqualität erzielt. Da unter längerfristiger Therapie mit Kinaseinhibitoren jedoch bei einem Großteil der Patienten eine Resistenzbildung auftritt, sind aktuelle klinische Therapiestudien auf die Suche nach geeigneten Kombinationspartnern unter Blockierung anderer Signalwege oder unter Aktivierung der T-Zell-vermittelten Immunantwort ausgerichtet. Der vorliegende Übersichtsartikel stellt sowohl die aktuell verfügbaren als auch die in der klinischen Testung befindlichen zukünftigen Optionen der zielgerichteten Therapie des Melanoms dar.

7 Review Update on the clinical use of kinase inhibitors in melanoma. 2017

Cosgarea, Ioana / Ritter, Cathrin / Becker, Jürgen C / Schadendorf, Dirk / Ugurel, Selma. ·Department of Dermatology, Venereology, and Allergology, University Medical Center Essen, University of Duisburg-Essen, Germany, and German Cancer Consortium (DKTK), Essen, Germany. ·J Dtsch Dermatol Ges · Pubmed #28872233.

ABSTRACT: The identification of targetable molecules in cellular signaling pathways represents a milestone in the treatment of melanoma. Selective inhibitors of these molecules, known as phosphokinases, allow for individual signaling pathways to be "switched off". This is of particular importance for tumors in which these pathways are constitutively activated by mutations in genes encoding said molecules. Especially patients with BRAF-mutated melanomas significantly benefit from kinase inhibitor therapies, with the current standard of combined BRAF and MEK inhibition providing very good long-term disease control. Such regimens have been shown to achieve a progression-free survival of more than ten months and an overall survival of more than two years, along with good quality of life. Given that the majority of patients develop secondary resistance during long-term kinase inhibitor therapy, current clinical trials are geared towards finding suitable drug combinations including inhibitors of other signaling pathways as well as immune checkpoint inhibitors. The present review highlights targeted therapies for melanoma currently available as well as potential future options presently under clinical investigation.

8 Review Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. 2017

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Department of Dermatology, Timone Hospital and Aix-Marseille University, Marseille, France. · Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia, The University of Sydney, and Royal North Shore Hospital, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia and University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany. ·Eur J Cancer · Pubmed #28756137.

ABSTRACT: The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials.

9 Review Advances in the Treatment of Advanced Extracutaneous Melanomas and Nonmelanoma Skin Cancers. 2017

Komatsubara, Kimberly M / Jeter, Joanne / Carvajal, Richard D / Margolin, Kim / Schadendorf, Dirk / Hauschild, Axel. ·From the Columbia University Medical Center, New York, NY; Ohio State University Medical Center, Columbus, OH; City of Hope, Duarte, CA; Department of Dermatology, University Hospital Essen, Essen, Germany; Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. ·Am Soc Clin Oncol Educ Book · Pubmed #28561682.

ABSTRACT: Cutaneous malignancies make up the greatest proportion of all human cancers and include melanomas as well as nonmelanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), as well as less common Merkel cell carcinoma (MCC), cutaneous lymphomas, cutaneous adnexal tumors, Kaposi sarcomas, and other sarcomas. Each of these NMSCs differ significantly in biology, clinical behavior, and optimal treatment recommendations from each other and from cutaneous melanoma. Similarly, less common extracutaneous melanomas, such as mucosal (MMs) and uveal (UMs), are unique biologic and clinical entities that require distinct diagnostic and management considerations. In this review, we summarize recent advances in biology and treatment of extracutaneous melanomas and NMSCs, including MMs, UMs, cSCC, BCC, and MCC.

10 Review Immunotherapy in melanoma: Recent advances and future directions. 2017

Franklin, C / Livingstone, E / Roesch, A / Schilling, B / Schadendorf, D. ·Department of Dermatology, Venereology and Allergology, University Hospital, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. · Department of Dermatology, Venereology and Allergology, University Hospital, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: Bastian.Schilling@uk-essen.de. · Department of Dermatology, Venereology and Allergology, University Hospital, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. ·Eur J Surg Oncol · Pubmed #27769635.

ABSTRACT: Malignant melanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for treating physicians. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies. Monoclonal antibodies against different immune checkpoints have been revolutionizing the treatment of metastatic and unresectable melanoma. Ipilimumab, a monoclonal antibody against the cytotoxic T-lymphocyte antigen 4 (CTLA-4) as well as nivolumab and pembrolizumab which target the programmed cell death protein 1 (PD-1) have been shown to prolong overall survival in patients with advanced melanoma. The latter substances seem to have an increased response rate and more tolerable safety profile compared to ipilimumab. The combination of a CTLA-4 and a PD-1 inhibitor seems to be superior to the monotherapies, especially in patients with PD-L1 negative tumours. Checkpoint inhibitors are currently being tested in the adjuvant setting with initial data for ipilimumab suggesting efficacy in this context. Talimogene laherparepvec (TVEC) is the first oncolytic virus approved in the therapy of metastatic melanoma offering a treatment option especially for patients with limited disease. In this review, data on these recently developed and approved immunotherapies are presented. However, further studies are necessary to determine the optimal duration, sequencing and combinations of immunotherapies to further improve the outcome of patients with advanced melanoma.

11 Review Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents. 2016

Weber, Jeffrey S / Postow, Michael / Lao, Christopher D / Schadendorf, Dirk. ·Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA jeffrey.weber2@nyumc.org. · Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. · University Hospital Essen, Essen, Germany. ·Oncologist · Pubmed #27401894.

ABSTRACT: : Immune checkpoint inhibitors have emerged as a mainstay of melanoma therapy and are playing an increasingly important role in the treatment of other tumor types. The clinical benefit afforded by these treatments can be accompanied by a unique spectrum of adverse events, called immune-related adverse events (irAEs), which reflect the drug's immune-based mechanism of action. IrAEs typically originate in the skin, gastrointestinal tract, liver, and endocrine system, although other organ systems may also be affected. This article provides an overview of irAEs associated with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab and pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab), followed by a discussion of irAEs of special clinical interest based on the potential for morbidity, frequent steroid use, and inpatient admission. We review clinical trial data and provide recommendations on how to manage irAEs associated with anti-PD-1 agents based on clinical experience and established management guidelines. We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab. A better understanding of the identification and management of irAEs will help inform health care providers about the risks associated with anti-PD-1 treatment, to ensure the safe and appropriate use of these important new treatments. IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitors have demonstrated significant clinical benefit in advanced melanoma and other tumor types. These treatments are associated with immune-related adverse events (irAEs), which most commonly affect the skin and gastrointestinal tract, and, to a lesser extent, the liver, endocrine system, and other organs. This review focuses on the management of irAEs after treatment with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab or pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab) in patients with advanced melanoma. A better understanding of the management of irAEs will help ensure the safe and appropriate use of anti-PD-1 agents in melanoma and other tumor types.

12 Review Treatment patterns of advanced malignant melanoma (stage III-IV) - A review of current standards in Europe. 2016

Harries, Mark / Malvehy, Josep / Lebbe, Céleste / Heron, Louise / Amelio, Justyna / Szabo, Zsolt / Schadendorf, Dirk. ·Guy's & St Thomas' Hospitals NHS Foundation Trust, London, UK. Electronic address: Mark.Harries@gstt.nhs.uk. · Servicio de Dermatología, Hospital Clínic de Barcelona, Catalonia, Spain. · Assistance Publique - Hôpitaux de Paris (AP-HP) Hôpital Saint-Louis, Dermatology Department Université Paris-Diderot, Sorbonne Paris Cité, INSERM UMR-S 976, Paris, France. · Adelphi Values, Bollington, UK. · Amgen Ltd., Uxbridge, London UK. · Amgen GmbH, Zug, Switzerland. · Klinik für Dermatologie, Universitätsklinikum Essen, Essen, Germany. ·Eur J Cancer · Pubmed #27118416.

ABSTRACT: AIMS AND BACKGROUND: With the recent emergence of immunotherapies and novel targeted treatments for advanced and metastatic melanoma such as selective B-Raf inhibitors and checkpoint inhibitors, the treatment landscape in Europe has changed considerably. The aim of this review was to provide an overview of current treatment pathways in Europe for the treatment of advanced melanoma, unresectable stage III-IV. METHODS: A literature search of four databases was conducted to identify publications reporting on the treatment patterns of advanced and metastatic melanoma (stage III-IV) in European populations. RESULTS: Seven full-text publications and two conference abstracts reported on observational studies of melanoma treatment practices in France, Italy and the United Kingdom. Treatment patterns were identified for two time periods: 2005-2009 and 2011-2012. Common treatments reported for both periods included chemotherapy with dacarbazine, fotemustine or temozolomide. The main differences between the two periods were the introduction and prescription of immunotherapy ipilimumab and targeted therapy vemurafenib between 2011 and 2012. Across the three countries studied, the types of treatments prescribed between 2005 and 2009 were relatively similar, however, with noticeable differences in the frequency and priority of administration. CONCLUSION: Treatment practices for advanced melanoma vary markedly across different European countries and continue to evolve with the introduction of new therapies. The results of this review highlight a considerable evidence gap with regards to recent treatment patterns for advanced melanoma in Europe, especially post-2011 after the introduction of novel therapeutic agents, and more recently with the introduction of programmed cell death 1 inhibitors.

13 Review Survival of patients with advanced metastatic melanoma: The impact of novel therapies. 2016

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · 28355 Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Dermatology Department, Timone Hospital and Aix-Marseille University, Marseille, France. · University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia and The University of Sydney, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University Tuebingen, 72074 Tuebingen, Germany. ·Eur J Cancer · Pubmed #26707829.

ABSTRACT: The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited.

14 Review Melanoma. 2015

Schadendorf, Dirk / Fisher, David E / Garbe, Claus / Gershenwald, Jeffrey E / Grob, Jean-Jacques / Halpern, Allan / Herlyn, Meenhard / Marchetti, Michael A / McArthur, Grant / Ribas, Antoni / Roesch, Alexander / Hauschild, Axel. ·Department of Dermatology, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Dermatology, University Tübingen, Tübingen, Germany. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Dermatology and Skin Cancers, APHM Timone Hospital Aix-Marseille University, Marseille, France. · Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania, USA. · Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. · Departments of Medicine, Surgery, and Medical and Molecular Pharmacology, University of California Los Angeles, Los Angeles, California, USA. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Kiel, Germany. ·Nat Rev Dis Primers · Pubmed #27188223.

ABSTRACT: Melanoma is a common cancer in the Western world with an increasing incidence. Sun exposure is still considered to be the major risk factor for melanoma. The prognosis of patients with malignant (advanced-stage) melanoma differs widely between countries, but public campaigns advocating early detection have led to significant reductions in mortality rates. As well as sun exposure, distinct genetic alterations have been identified as associated with melanoma. For example, families with melanoma who have germline mutations in CDKN2A are well known, whereas the vast majority of sporadic melanomas have mutations in the mitogen-activated protein kinase cascade, which is the pathway with the highest oncogenic and therapeutic relevance for this disease. BRAF and NRAS mutations are typically found in cutaneous melanomas, whereas KIT mutations are predominantly observed in mucosal and acral melanomas. GNAQ and GNA11 mutations prevail in uveal melanomas. Additionally, the PI3K-AKT-PTEN pathway and the immune checkpoint pathways are important. The finding that programmed cell death protein 1 ligand 1 (PDL1) and PDL2 are expressed by melanoma cells, T cells, B cells and natural killer cells led to the recent development of programmed cell death protein 1 (PD1)-specific antibodies (for example, nivolumab and pembrolizumab). Alongside other new drugs - namely, BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) - these agents are very promising and have been shown to significantly improve prognosis for patients with advanced-stage metastatic disease. Early signs are apparent that these new treatment modalities are also improving long-term clinical benefit and the quality of life of patients. This Primer summarizes the current understanding of melanoma, from mechanistic insights to clinical progress. For an illustrated summary of this Primer, visit: http://go.nature.com/vX2N9s.

15 Review Disease kinetics for decision-making in advanced melanoma: a call for scenario-driven strategy trials. 2015

Grob, Jean Jacques / Long, Georgina V / Schadendorf, Dirk / Flaherty, Keith. ·Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. Electronic address: jean-jacques.grob@ap-hm.fr. · Melanoma Institute Australia, University of Sydney, and Mater Hospital, Sydney, NSW, Australia. · University Hospital Essen and German Cancer Consortium, Essen, Germany. · Massachusetts General Hospital Cancer Center, Boston, MA, USA. ·Lancet Oncol · Pubmed #26433825.

ABSTRACT: In the past 5 years, the treatment of metastatic melanoma has changed from almost no effective treatment to the use of targeted and immune therapies with proven improvements in survival. The time has now come to define the optimal drug combinations, sequence of treatment, and drug regimens (intermittent vs continuous dosing) in the treatment of patients with metastatic melanoma. In view of the prevalence of advanced melanoma, finite resources, and the heterogeneity of disease characteristics, not all possibilities can be tested in therapeutic trials starting from an unselected population of patients with metastatic melanoma. In practice, clinicians rely on a few clinically derived signals, especially dynamic signals, to categorise patients into scenarios, from fast disease kinetics to slow disease kinetics, which drive clinicians' therapeutic decision making. The realistic goals of therapy are different in each scenario. We recommend that these scenarios are incorporated into clinical trials as either patient inclusion criteria or stratification factors. This approach is not only feasible but is also the only way to generate evidence for more effective and individualised treatment strategies for patients with metastatic melanoma.

16 Review Integrating first-line treatment options into clinical practice: what's new in advanced melanoma? 2015

Dummer, Reinhard / Schadendorf, Dirk / Ascierto, Paolo A / Larkin, James / Lebbé, Celeste / Hauschild, Axel. ·aDepartment of Dermatology, University Hospital Zürich, Zürich, Switzerland bDepartment of Dermatology, University Hospital Essen, Essen cDepartment of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany dIstituto Nazionale Tumori Fondazione 'G. Pascale', Naples, Italy eRoyal Marsden NHS Foundation Trust, London, UK fAPHP Oncodermatology Unit, University Paris 7 Diderot U976, Paris, France. ·Melanoma Res · Pubmed #26426764.

ABSTRACT: Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients.

17 Review Systemic therapies for melanoma brain metastases: which drug for whom and when? 2015

Ramanujam, Sangeetha / Schadendorf, Dirk / Long, Georgina V. ·Melanoma Institute Australia, Sydney, Australia. · University Hospital Essen, Essen, Germany. · Melanoma Institute Australia and The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2060, Australia. georgina.long@sydney.edu.au. ·Chin Clin Oncol · Pubmed #26112811.

ABSTRACT: Melanoma brain metastases are common, difficult to treat, and are associated with a poor prognosis. Historically, due to the poor activity of chemotherapeutic agents in melanoma, the management of brain metastases was centred on local treatments such as surgery, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) depending on the clinical presentation. New systemic therapies have now evolved; kinase inhibitors targeting BRAF mutated melanoma cells and activating checkpoint inhibitors that activate an immune anti-tumour response, resulting in significantly improved survival and quality of life for patients with metastatic melanoma and these drugs have demonstrated activity in melanoma brain metastases. As the landscape shifts to incorporate these new systemic agents with the available local therapies, further research into using appropriate combinations or sequences of various treatments, especially for active or progressing melanoma brain metastasis, is required. This review will examine the evidence for systemic therapies in patients with active melanoma brain metastasis (untreated or treated and progressed) and highlight active and evolving clinical trials in this challenging field.

18 Review Treatment algorithms in stage IV melanoma. 2015

Espinosa, Enrique / Grob, Jean-Jacques / Dummer, Reinhard / Rutkowski, Piotr / Robert, Caroline / Gogas, Helen / Kefford, Richard / Eggermont, Alexander M M / Martin Algarra, Salvador / Hauschild, Axel / Schadendorf, Dirk. ·1Service of Oncology, Hospital La Paz, Madrid, Spain · 2Department of Dermatology, Hopital Ste Marguerite, Marseille, France · 3Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland · 4Department of Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland · 5Department of Dermatology (CR), and General Director (AE), Institute Gustave Roussy, Villejuif Cedex, France · 6First Department of Medicine, University of Athens Medical School, Athens, Greece · 7Department of Oncology, Westmead Hospital and Melanoma Institute Australia, University of Sydney, Sydney, Australia · 8Service of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain · 9Department of Dermatology, University of Kiel, Kiel, Germany · and 10Department of Dermatology, University Hospital Essen, Essen, Germany. ·Am J Ther · Pubmed #24413374.

ABSTRACT: The molecular classification of melanoma and the advent of new drugs are changing the paradigm of therapy for advanced melanoma. A review of the recent key studies was performed, followed by a discussion in an expert forum. The aim of this review was to generate a therapeutic algorithm for stage IV melanoma. Tumor genotyping for BRAF and/or KIT should be performed before selection of therapy. For most BRAF-mutated melanoma patients and particularly those with a high tumor load, vemurafenib or other BRAF inhibitors such as dabrafenib are the treatment of choice. KIT inhibitors can be effective in KIT-mutant tumors, especially in those patients with mutations at exons 11 and 13. Ipilimumab is a good option for patients with nontargetable or nondetected mutations and those who progress under therapy with vemurafenib or a KIT inhibitor. There is still a role for conventional chemotherapy either as first-line treatment in BRAF wild-type patients or as salvage therapy in second or third line, or after other treatment modalities. Participation in clinical trials is strongly encouraged, either in first or in subsequent lines. New therapeutic options for advanced melanoma are guided by tumor genotyping. The current therapeutic algorithm includes kinase inhibitors, anti-CTLA4 therapy, immunotherapy, and chemotherapy, depending on the tumor genotype and response to previous treatments. Participation in clinical trials should always be encouraged because the treatment goal is long-term survival and potential cure in a subset of patients.

19 Review Expression of stress ligands of the immunoreceptor NKG2D in melanoma: regulation and clinical significance. 2014

Paschen, Annette / Baingo, Jolanthe / Schadendorf, Dirk. ·Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen and German Cancer Consortium (DKTK), Germany. Electronic address: annette.paschen@uk-essen.de. · Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen and German Cancer Consortium (DKTK), Germany. ·Eur J Cell Biol · Pubmed #24629838.

ABSTRACT: Tumor cells, in particular melanoma cells, can be detected as abnormal self by cytotoxic lymphocytes of the innate and adaptive immune system. Of major importance in this process is the activating lymphocyte receptor NKG2D that in humans binds to MIC and ULBP surface molecules on tumor cells. Expression of NKG2D ligands (NKG2DL) is an early event in malignant transformation, induced by stress-associated and oncogene-driven pathways. Thus NKG2DL expression is considered as an innate barrier against tumor development. However, tumor cells can overcome this barrier by shedding of NKG2DL. Ligand shedding leads to elevated levels of soluble ligands in sera of tumor patients that in case of melanoma are of strong prognostic relevance. Here we review important aspects of NKG2DL expression and regulation in tumor cells with a focus on melanoma, and discuss their clinical relevance and potential in immunotherapy.

20 Review Genetic alterations and personalized medicine in melanoma: progress and future prospects. 2014

Griewank, Klaus G / Scolyer, Richard A / Thompson, John F / Flaherty, Keith T / Schadendorf, Dirk / Murali, Rajmohan. ·Affiliations of authors: Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany (KGG, DS) · Royal Prince Alfred Hospital, Camperdown, NSW, Australia (RAS) · University of Sydney, Camperdown, NSW, Australia (RAS, JFT) · Melanoma Institute Australia, North Sydney, NSW, Australia (RAS, JFT) · Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, MA (KTF) · Department of Pathology, and Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (RM). ·J Natl Cancer Inst · Pubmed #24511108.

ABSTRACT: High-throughput sequencing technologies are providing new insights into the genetic alterations involved in melanomagenesis. It appears likely that most genetic events important in the pathogenesis of melanoma will be discovered over the next few years. Genetic analysis is also increasingly being used to direct patient care. In parallel with the discovery of new genes and the elucidation of molecular pathways important in the development of melanoma, therapies targeting these pathways are becoming available. In other words, the age of personalized medicine has arrived, characterized by molecular profiling of melanoma to identify the relevant genetic alterations and the abnormal signaling mechanisms involved, followed by selection of optimal, individualized therapies. In this review, we summarize the key genetic alterations in melanoma and the development of targeted agents against melanomas bearing specific mutations. These developments in melanoma serve as a model for the implementation of personalized medicine for patients with all cancers.

21 Review Melanoma in 2013: Melanoma--the run of success continues. 2014

Schadendorf, Dirk / Hauschild, Axel. ·Department of Dermatology, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. · Departments of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany. ·Nat Rev Clin Oncol · Pubmed #24419300.

ABSTRACT: -- No abstract --

22 Review New developments in biomarkers for melanoma. 2013

Griewank, Klaus G / Ugurel, Selma / Schadendorf, Dirk / Paschen, Annette. ·Department of Dermatology, University Hospital Essen, Essen, Germany. ·Curr Opin Oncol · Pubmed #23334230.

ABSTRACT: PURPOSE OF REVIEW: Therapy of malignant melanoma recently experienced remarkable advances with the introduction of two treatment regimens, gene mutation-based therapies with signaling pathway inhibitors (kinase inhibitors) and treatments with immune modulators. Both strategies prolong patients' survival but still have specific limitations, demanding the identification of additional genetic and immunological biomarkers as predictors of treatment response and prognosis. New developments in that field are summarized in this review. RECENT FINDINGS: Activating oncogene mutations are important melanoma biomarkers. They predict responsiveness to kinase inhibitor therapies and have therapy independent prognostic relevance. Epigenetic alterations (DNA methylation, chromatin remodeling, and noncoding RNA) in melanoma are emerging as potentially valuable biomarkers. With the successful introduction of immunotherapies for melanoma, interest in immunological biomarkers has grown. Tumor-reactive cytotoxic T cells from patients' peripheral blood were recently proposed to predict prognosis and response to immunotherapy. A superior immune profile assessment could be achieved by combining a detailed characterization of a tumor's immune cell infiltrate with its (immune) gene signature. SUMMARY: Genetic melanoma markers have already become clinically relevant. We expect both their role and that of immunological biomarkers to increase significantly in the next few years, enabling personalized therapy with optimal treatment selection for individual tumors.

23 Review Brain metastasis: opportunity for drug development? 2012

Preusser, Matthias / Berghoff, Anna S / Schadendorf, Dirk / Lin, Nancy U / Stupp, Roger. ·Department of Medicine I and Comprehensive Cancer Center CNS Unit, Medical University of Vienna, Vienna, Austria. Matthias.preusser@meduniwien.ac.at ·Curr Opin Neurol · Pubmed #23108247.

ABSTRACT: PURPOSE OF REVIEW: Brain metastases are a common clinical problem, and only limited treatment options exist. We review recent advances in medical brain metastasis research with a focus on the most common tumor types associated with secondary brain colonization: melanoma, breast cancer and lung cancer. We speculate on opportunities for drug development in patients with brain metastases, both as a treatment of established disease and as an adjuvant and prophylactic strategy. RECENT FINDINGS: BRAF inhibitors and the immunomodulatory anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab have shown clinically meaningful activity in melanoma patients with brain metastases. In breast cancer, current studies on drug treatment of brain metastases are mainly focusing on human epidermal growth factor receptor 2 targeting agents such as lapatinib. Emerging data seem to implicate a potential role of targeted agents including antiangiogenic compounds, pazopanib, and epithelial growth factor receptor inhibitors for prevention of brain metastasis formation in breast cancer or nonsmall cell lung cancer. SUMMARY: Novel drugs are beginning to enter clinical practice for selected patients with brain metastases. The promising findings from recent studies may fuel more research on brain metastases and their optimal drug treatment.

24 Review [Immunotherapy of melanomas]. 2012

Zimmer, L / Vaubel, J / Schadendorf, D. ·Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Essen, Hufelandstr. 55, 45133, Essen, Deutschland. ·Hautarzt · Pubmed #23097082.

ABSTRACT: Even early clinical studies showed that adjuvant chemotherapy achieved no therapeutic benefit for melanomas so that in the current guidelines its use is only recommended within the framework of clinical studies. For over 30 years interferons have been used in the adjuvant treatment of primary high risk melanomas as well as in the treatment of metastasized melanomas. They function in an antiviral, immune modulating and antitumor fashion. Direct and indirect effects on tumor cells could be demonstrated for interferons. In Europe low dosage interferon therapy is approved and has become widely established for stage II melanomas, whereas in the USA high dosage therapy for stage III and since March 2011 therapy with pegylated interferon in stage III are also approved. In this article the most important study results will be dealt with in detail. In summary, according to the current study situation therapy with interferon should be offered especially to patients with ulcerated primary melanoma and microscopic lymph node infiltration. Many attempts have been made in the last decades to positively influence the survival time of distant metastasized melanoma by systemic therapy. The recent development of the antibody ipilimumab against cytotoxic T-lymphocyte protein 4 (CTLA-4) could show for the first time a survival advantage in the therapy of melanoma patients in advance stage disease. The licensing of ipilimumab has meant that there is now a new standard available for the second line therapy of malignant melanoma which will be included in the guidelines on therapy of malignant melanoma. A further interesting option for adjuvant therapy is currently vaccination with the recombinant melanoma-associated protein 3 (MAGE-A3) protein in combination with the adjuvant AS015.

25 Review Current advances and perspectives in the treatment of advanced melanoma. 2012

Livingstone, Elisabeth / Zimmer, Lisa / Vaubel, Julia / Schadendorf, Dirk. ·Department of Dermatology, Skin Cancer Center, University Hospital Essen, Germany. ·J Dtsch Dermatol Ges · Pubmed #22432863.

ABSTRACT: Melanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti-CTLA-4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF-inhibitor vemurafenib, which has shown a significant impact on progression-free survival and overall survival in patients with the BRAF(V600E) mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.

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