Neue molekulare Therapien bei fortgeschrittenem differenziertem Schilddrüsenkarzinom

Zusammenfassung

Die akzeptierte Standardbehandlung des fortgeschrittenen, sich vom Follikelepithel ableitenden, Schilddrüsenkarzinoms (DTC) ist die Radioiodtherapie. Sind die Karzinome dagegen resistent und nicht kurativ resezierbar, gibt es aktuell keine etablierte Standardtherapie. Allerdings konnten in den letzten Jahren zunehmend molekulare Zielstrukturen (z. B. BRAF- und RAS-Mutationen oder RET-PTC-Rearrangement) identifiziert werden, die Grundlage für neue Therapieansätze darstellen. Diese aktivierenden Mutationen führen unter anderen zu einer Zunahme der Zellproliferation. Zusätzlich exprimieren viele Schilddrüsenkarzinome vermehrt Rezeptoren für Wachstumsfaktoren (z. B. den Vascular endothelial growth factor receptor (VEGF-R) und den Epidermal growth factor receptor (EGF-R)), die ebenfalls therapeutisch angegangen werden können. Die besten klinischen Ergebnisse liegen aktuell zu Multityrosinkinasehemmern (z. B. Sorafenib und Axitinib) vor, die in Phase-II-Studien bei vielen Patienten die Progression der Erkrankung aufhalten konnten. Eine weitere potenzielle Zielstruktur ist der Somatostatinrezeptor. Die ersten Erfahrungen einer entsprechenden Radiopeptidtherapie beim fortgeschrittenen DTC weisen auf ein gewisses Ansprechen hin, bedürfen jedoch weiterer Bestätigung. Für Patienten mit aggressivem Tumorverlauf gibt es erste vielversprechende Ergebnisse mit neueren zytotoxischen Substanzen wie Pemetrexed (in Kombination mit Paclitaxel). Ob eine Redifferenzierungstherapie (z. B. mit PPRγ-Agonisten) in Kombination mit Radioiodgabe erfolgversprechender ist als die Behandlung mit Retinsäure, bleibt abzuwarten. Zusammenfassend wurden in den letzten Jahren zahlreiche neue zielgerichtete Behandlungsmethoden für das radioiodresistente DTC entwickelt und erprobt. Patienten mit fortgeschrittenem DTC sollten nach Möglichkeit in laufende klinische Studien eingeschlossen werden. In Anbetracht der neuen Möglichkeiten erscheint es wichtig, die richtige Behandlung unter Berücksichtigung der Aggressivität der Erkrankung gegen den potenziellen Nutzen und die Nebenwirkungen der Behandlung abzuwägen.

Abstract

Accepted standard of care for advanced differentiated thyroid cancer (DTC) derived from follicular epithelium is the treatment with radioiodine. If the tumor is irresectable and resistant against radioiodine, no standard approach for systemic treatment is established. In the last years increasingly new targets, like BRAF/RAS mutations and RET/PTC rearrangement, could be identified in DTC, which constitutes the basis for new therapeutic approaches. Those activating point mutations lead to an increased cell proliferation. Furthermore, DTC have an increased expression of receptors for growth factors, like the vascular endothelial growth factor receptor (VEGF-R) and the epidermal growth factor receptor (EGF-R) which may also be used as therapeutic target. Currently the best clinical results are available for multityrosinekinase inhibitors like Sorafenib and Axitinib, which were able to stop progression of advanced DTC in several patients in recent phase II clinical trials. Another potential target is the somatostatin receptor. First experiences of using radiopeptide therapy in advanced thyroid cancer indicate a potential benefit, with acceptable side effects, but need to be confirmed. For patients with a very aggressive course of the disease, first preliminary promising results are available using new cytotoxic substances like pemetrexed (in combination with paclitaxel). If new redifferentiating therapies (e. g. PPRγ agonists) in combination with radioiodine will be more successful than retinoic acid is still unclear. As a conclusion, in the last years many new targeted treatments for advanced radioiodine resistant DTC have been developed and are still being tested. If possible, patients should be enrolled in clinical studies. Given those choices it is important to select the most suitable drug/therapy by weighing the aggressiveness of the disease against the potential benefit for the patient and the side effects of the drug.

Schlüsselwörter

molekulare Substanzen - Tyrosinkinaseinhibitoren - Schilddrüsenkarzinom - systemische Therapie

Key words

targeted therapies - tyrosinekinase inhibitors - thyroid cancer - systemic therapy

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