Diagnostik und Therapie des Melanoms im Wandel der letzten 25 Jahre

Zusammenfassung

Im zurückliegenden Vierteljahrhundert hat sich unser Verständnis maligner Melanome enorm erweitert, und dies führte zu einer Vielzahl neuer Diagnostik- und Behandlungsstrategien.

Nach einer als erfolgreich bewerteten Pilotphase in Schleswig-Holstein wurde wegen der hohen und ständig noch steigenden Hautkrebsinzidenz 2008 die Hautkrebsfrüherkennung auf Kosten der gesetzlichen Krankenkassen deutschlandweit eingeführt.

Die Früherkennung und -beseitigung regionärer Lymphknotenmetastasen von Patienten mit mitteldicken und dicken Hautmelanomen gelang durch die Etablierung und innerhalb weniger Jahre erreichten Optimierung der Sentinel-Lymphonodektomie. Dabei erweist sich zudem die mikromorphometrische Klassifikation des Sentinel-Lymphknotenbefalls als erstrangiges Prognose- und Therapieleitkriterium, etwa für die Indikation zur radikalen Komplettierungsdissektion oder zur adjuvanten Interferon-alpha-Therapie.

In fortgeschrittenen Metastasierungsstadien stehen erstmals erfolgreichere Systemtherapien als die Dacarbazin-Monotherapie zur Verfügung. Bei knapp 50 % der Melanome findet sich in der BRAF-Kinase des MAPK-Signaltransduktionsweges eine aktivierende V600-Mutation, die sich wirksam mit den oral verfügbaren Medikamenten Vemurafenib oder Dabrafenib blockieren lässt. Die so rasch erzielbare Metastasenregression wird durch Kombination mit einem MEK-Inhibitor (z. B. Trametinib) noch nachhaltiger. Von den Immuntherapien erreichten Antikörper gegen die immunbremsenden T-Zell-Rezeptoren CTLA4 und PD-1 die besten Therapieergebnisse. Obwohl es darunter selten zu Vollremissionen kommt, können bei einem Teil der Patienten in fortgeschrittenen Melanomstadien anhaltende Tumorkontrollen erzielt werden. Die höchste Tumorkontrollrate ergab sich in Studien mit der Kombination des PD-1-Antikörpers Nivolumab und des CTLA4-Antikörpers Ipilimumab.

Die sinnvolle Nutzung und Kombination dieser innovativen therapeutischen Eingriffe eröffnet erstmals die Chance, die Melanommortalität trotz weiter steigender Inzidenz zu senken. Schon jetzt zeichnet sich allerdings ab, dass dies nicht ohne präzise Charakterisierung von Melanomsubentitäten sowie die sorgfältige Herausarbeitung von Prognosekriterien gelingen wird. Eine derartig differenzierte Patientenversorgung lässt sich sowohl aus medizinischer als auch ökonomischer Sicht am besten durch interdisziplinäre Kooperation im Rahmen von Hautkrebszentren realisieren.

Abstract

Our knowledge about malignant melanomas has enormously grown within the last 25 years, resulting in a variety of new diagnostic and therapeutic strategies.

The high and still increasing incidence of skin cancer and a successful pilot phase in Northern Germany (Schleswig-Holstein) have led to a nation-wide screening program for skin cancer in Germany in 2008, paid by the medicare insurances. Its effects are under evaluation now.

The early recognition and elimination of regional lymph node metastases has been optimized by the sentinel node technique. It is regularly applied for melanomas of intermediate and high Breslow thickness. In addition, the micromorphometric classification of sentinel node metastases represents a first-rank prognosticator and the best indicator whether a completion lymph node dissection is needed and whether adjuvant treatment with interferon-alpha might be helpful or not.

For patients in advanced stages of metastasis, more successful systemic therapies compared with dacarbazin have become available. Nearly 50 % of all cutaneous melanomas have an activating V600 mutation in the BRAF kinase, which is part of the MAPK pathway. Vemurafenib and Dabrafenib are orally given drugs, which block the BRAF activity in case of V600 mutation. They usually achieve a quick regression of metastases in the respective patients, and this effect can be stabilized and prolonged by combining one of the BRAF inhibitors with a MEK inhibitor, e. g. Trametinib. Among the immunotherapies, antibodies against downregulating checkpoint receptors on T cells (CTLA4 and PD-1) have shown the best results. While complete remissions of the metastases were rare, continuing tumor control was achieved in a considerable percentage of the patients. The highest percentage was observed in a trial that combined the PD-1 antibody nivolumab with the CTLA4 antibody ipilimumab.

The rational use of all these innovations and – last not least – the optimized collaboration of multiple disciplines in skin cancer centers open the chance, that the melanoma-related mortality might decrease despite a still growing incidence of melanomas.

For this purpose we must learn to find the best “tailored” therapy for each of the upcoming melanoma subentities and for each of the prognostic categories to be defined.

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