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Deutsche Zeitschrift für Onkologie 2023; 55(04): 136-147
DOI: 10.1055/a-2192-6295
Forschung

Systemische Therapie der epithelialen serösen Ovarialkarzinome

Systemic Therapy of Epithelial Serous Ovarian Carcinomas
Viktoria Aivazova-Fuchs
1   Klinik Bad Trissl, Oberaudorf
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Zusammenfassung

Hintergrund Ovarialkarzinom (OC) ist nach dem Brustkrebs (BC) die häufigste gynäkologische Malignität und die häufigste Todesursache bei gynäkologischem Krebs. Ca. 1 von 72 Frauen (F) erkrankt im Laufe ihres Lebens an OC. Ca. 75% der Fälle werden in einem fortgeschrittenen Stadium diagnostiziert. Epithelialtumore machen ca. 90% aller Ovarialtumoren (OT) aus. Der häufigste histologische Subtyp des epithelialen OCs ist serös. Ungefähr 90% der serösen Karzinome sind hochgradig (high-grade (HG)) und 10% niedriggradig (low-grade (LG)). Das Tumorstadium bei Erstdiagnose des OCs und die Therapiequalität sind die wichtigsten Prognosefaktoren. Die aktuelle Übersicht der systemischen Therapie (T) von serösen OCen in neoadjuvanten, adjuvanten, rezidivierenden und metastasierenden Settings, ausgenommen intraperitoneale hypertherme Chemotherapie (CT) (HIPEC), wird hier besprochen.

Methode Selektive Literaturrecherche mit den Suchbegriffen „ovarian cancer“, „treatment“, „Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum“, S3-Leitlinie zur Diagnostik, Therapie und Nachsorge maligner Ovarialtumoren (Version 5.1, 2022), ASCO Berichte 2023.

Ergebnisse Die systemische T des OCs wird auf die neoadjuvante, adjuvante T des frühen und des fortgeschrittenen OCs, RezidivT und palliative T aufgeteilt. Bei Patientinnen (Pat.) mit frühem HG serösem OC (HGSOC) Stadium FIGO I–IIA, außer Stadium FIGO IA, G1 ist eine adjuvante platinhaltige CT indiziert. Bei fortgeschrittenem OC wird die Prognose der Pat. wesentlich durch das Ausmaß der Tumorreduktion bei der ersten Operation (OP) bestimmt. Pat. mit kompletter Tumorresektion haben ein signifikant längeres Überleben als Pat. mit Tumorrest am Ende der OP. Im Anschluss an die OP gilt die Kombinationstherapie aus Carboplatin (Carbo) und Paclitaxel (Pacli) über 6 Zyklen als Standard. Außerdem ist eine Erhaltungstherapie (ET) mit dem Angiogenese-Inhibitor Bevacizumab (Bev) ab FIGO Stadium IIIB und PARP-Inhibitoren (PARPi) wie Niraparib (Nira) alleine oder Olaparib (Ola) alleine oder in Kombination mit Bev je nach BRCA- und HRD-Status bei Pat. mit HGSOC ab FIGO Stadium III indiziert. In der Rezidivsituation wird zwischen platingeeignetem (PG) und nicht-platingeeignetem (NPG) Rezidiv (R) unterschieden. Bei PG R, nach Prüfung der OP-Indikation, wird eine platinhaltige KombinationsT, bestehend aus Carbo/pegiliertem liposomalem Doxorubicin (PLD), Carbo/Gemcitabin (Gem), Carbo/Pacli, empfohlen. Bei Pat. mit R eines HGSOCs nach Ansprechen auf eine platinhaltige RezidivT sollte eine ET mit einem PARPi Nira oder Ola bei fehlender Vortherapie mit PARPi angeboten werden. Außerdem besteht bei gutem Ansprechen auf die CT die Möglichkeit einer erneuten „PARPi nach PARPi“ ET mit Ola bei vorangegangener wirksamer PARPi-T nach Kostenübernahmezusage als Off-label use.

Bei Pat. mit erstem PG R und ohne vorherige VEGFR-gerichtete T sind die Kombinationen (K) aus Carbo/Gem/Bev oder Carbo/Pacll/Bev mit anschließender ET mit Bev zugelassen. Bei NPG R, definiert als R<3 bis 6 Monate nach letzter platinhaltigen CT, bei keiner sinnvollen OP-Indikation, kommen Mono-CTen, wie Pacli, PLD, Topotecan (Topo), Gem ggf. in K mit Bev, außer PLD, falls keine anti-angiogene Vortherapie erfolgte, in Frage. Die in Deutschland noch nicht zugelassene T mit einem Antibody Drug Conugate (ADC) (Folat-Rezeptor-alfa Antagonisten) Mirvetuximab Soravtansin bei positivem FR-alpha Status wäre auch eine Option bei NPG R.

Zur HIPEC liegen derzeit nur wenige Daten vor, daher kann diese T-Option außerhalb von klinischen Studien nicht empfohlen werden.

Die low grade serösen OC (LGSOC) gelten als weniger chemosensibel. Bei bestehender Indikation wird in der Primärtherapie die K aus Carbo/Pacli mit anschließender endokriner Erhaltungstherapie (EnET) oder alleinige EnT bei Östrogenrezeptor (ER) positiven Tumoren eingesetzt. Für F mit LGSOC R können mögliche sekundäre zytoreduktive OP, CT (unter Verwendung von Standarddefinitionen für PG- oder NPG-Erkrankungen), EnT oder zielgerichtete Wirkstoffe (z. B. Trametinib oder Bev) durchgeführt werden.

Diskussion Diese Übersichtsarbeit dient als Orientierung, den Patientinnen mit epithelialen serösen OCen eine stadiengerechte moderne T bei der Ersterkrankung und auch beim Rezidiv anbieten zu können. Die Ergebnisse internationaler Studien und Metaanalysen zur systemischen T sowie die aktuellen Empfehlungen der S3-Leitlinie und klinisch relevante ASCO-Ergebnisse von 2023 wurden in dieser Arbeit berücksichtigt. Durch die optimale T soll mittel- und langfristig die Mortalität der Pat. mit malignen OT gesenkt und die Lebensqualität (LQ) erhöht werden. Trotz Entwicklung eines umfangreichen, operativen Therapiekonzeptes und moderner medikamentöser T ist die Prognose im Verhältnis zu anderen Krebserkrankungen der Geschlechtsorgane eher schlecht. Das relative 5-Jahres-Überleben liegt derzeit bei ca. 43% über alle Stadien.

Schlussfolgerung Eine optimale leitliniengerechte T verbessert das Überleben der Pat. signifikant und sollte somit als Standard eingesetzt werden, dabei sollten aber auch neue Entwicklungen und Therapiemöglichkeiten stets berücksichtigt werden.

Abstract

Objective Ovarian cancer (OC) is the most common gynecological malignancy after breast cancer (BC) and the leading cause of death from gynecological cancer. Approx. 1 in 72 women will develop OC in their lifetime. Approximately 75% of cases are diagnosed at an advanced stage. Epithelial tumors account for approximately 90% of all ovarian tumors (OT). The most common histologic subtype of epithelial OC is serous. Approximately 90% of serous carcinomas are high-grade (HG) and 10% are low-grade (LG). The tumor stage at initial diagnosis of OC and the quality of therapy (T) are the most important prognostic factors. The current overview of systemic T of serous OC in neoadjuvant, adjuvant, recurrent and metastatic settings, excluding heated intraperitoneal (IP) chemotherapy (HIPEC), is discussed here.

Method Selective literature search using the search terms “ovarian cancer”, “treatment”, “Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum”, S3 guidelines for the diagnosis, therapy and follow-up of malignant ovarian tumors (version 5.1), published in Year 2022, ASCO reports 2023.

Results Systemic T of OC is divided into neoadjuvant, adjuvant T of early and advanced OC, relapse T and palliative T. In patients (Pat.) with early OC stages FIGO I–IIA, except stage FIGO IA, G1, adjuvant platinum-containing chemotherapy (CT) is indicated. In advanced OC, the patient’s prognosis is largely determined by the extent of tumor reduction during the first operation (OP). Patients with complete tumor resection have a significantly longer survival than Pat. with residual tumor at the end of the operation (OP). Following the OP, the combination (K) of carboplatin (Carbo) and paclitaxel (Pacli) over 6 cycles is considered standard. In addition, maintenance therapy (ET) with the angiogenesis inhibitor bevacizumab (Bev) from FIGO stage IIIB and PARP inhibitors (PARPi) such as niraparib (Nira) alone or olaparib (Ola) alone or in combination with bevacizumab (Bev) is recommended depending on BRCA and HRD status by patients with high-grade serous OC (HGSOC) from FIGO stage III. In the recurrence situation, a distinction is made between platinum-suitable (PG) and non-platinum-suitable (NPG) recurrences (R). In PG R, after checking the indication for surgery, a platinum-containing combination T consisting of Carbo/pegilated liposomal doxorubicin (PLD), Carbo/Gemcitabine (Gem), Carbo/Pacli, is recommended. In patients with a relapse of a high-grade OC after a response to a platinum-containing relapse T, ET with a PARPi Nira or Ola should be offered if pretherapy with PARPi is missing. In addition, if the response to CT is good, there is the possibility of a new “PARPi after PARPi” ET with Ola Analog OREO study in the case of previous effective PARPi therapy after agreement to cover costs as off-label use.

For patients with first PG R and no previous VEGFR-directed T, the combinations of Carbo/Gem/Bev or Carbo/PacIi/Bev with subsequent ET with Bev are approved. In the case of NPG R, defined as R<3 to 6 months after the last platinum-containing CT, with no meaningful indication for surgery, mono-CTs such as Pacli, PLD, Topotecan (Topo), Gem may be used in combination with Bev, except PLD, if no anti -angiogenic pretherapy was questioned. T with an antibody drug conjugate (ADC) (folate receptor alfa antagonist) mirvetuximab soravtansine, for Pat. with positive FR-alpha status, which is not yet approved in Germany, can also be an option for NPG relapse.

There is currently limited data on HIPEC, so this T option cannot be recommended outside of clinical trials.

Low grade serous OC (LGSOC) are considered to be less chemosensitive. If there is an existing indication, the combination of Carbo/Pacli with subsequent endocrine maintenance therapy (EnET) or EnT alone for estrogen receptor (ER) positive tumors is used in primary T. For Pat. with LGSOC R secondary cytoreductive surgery, CT (using standard definitions for PG or NPG diseases), EnT or targeted agents (e. g., trametinib or Bev) are possible.

Discussion This review article serves as a guide to be able to offer Pat with epithelial serous OC appropriate modern T for the initial illness and also for R. The results of international studies and meta-analyses on systemic T as well as the current recommendations of the S3 guideline and clinically relevant ASCO results from 2023 were considered in this work. The optimal T is intended to reduce the mortality of Pat with malignant OT in the medium and long term and increase the quality of life (LQ). The prognosis of OC in relation to other cancers of sexual organs is rather bad despite the development of an extensive, surgical T concept and modern drug T. The relative 5-year survival is currently approximately 43% across all stages.

Conclusion Guideline-based T significantly improves Pat survival and should therefore be used as standard, but new developments and treatment options should always be considered.

Schlüsselwörter

Ovarialkarzinom - Therapie - Rezidiv - epithelial - serös - metastasiert - low grade - high grade - PARPi

Key words

ovarian cancer - therapy - recurrence - epithelial - serous - metastatic - low grade - high grade - PARPi


Publication History

Article published online:
04 December 2023

© 2023. Thieme. All rights reserved.

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