Jacobus Pfisterer1, Catherine M Shannon2, Klaus Baumann3, Joern Rau4, Philipp Harter5, Florence Joly6, Jalid Sehouli7, Ulrich Canzler8, Barbara Schmalfeldt9, Andrew P Dean10, Alexander Hein11, Alain G Zeimet12, Lars C Hanker13, Thierry Petit14, Frederik Marmé15, Ahmed El-Balat16, Rosalind Glasspool17, Nikolaus de Gregorio18, Sven Mahner19, Tarek M Meniawy20, Tjoung-Won Park-Simon21, Marie-Ange Mouret-Reynier22, Cristina Costan23, Werner Meier24, Alexander Reinthaller25, Jeffrey C Goh26, Tifenn L'Haridon27, Sally Baron Hay28, Stefan Kommoss29, Andreas du Bois5, Jean-Emmanuel Kurtz30. 1. Gynaecologic Oncology Center, Kiel, Germany. Electronic address: jacobus.pfisterer@googlemail.com. 2. Oncology Department, Mater Cancer Care Centre, Brisbane, QLD, Australia. 3. Gynaecology Department, Klinikum der Stadt Ludwigshafen am Rhein, Ludwigshafen, Germany. 4. Coordinating Center for Clinical Trials, Philipps-University, Marburg, Germany. 5. Department of Gynecology and Gynecological Oncology, Kliniken Essen-Mitte, Essen, Germany. 6. Gynaecology Department, Centre François Baclesse, Caen, France. 7. Department of Gynaecology, and European Competence Center for Ovarian Cancer, Charité - Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany. 8. Department of Gynaecology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 9. Technical University of Munich-Klinikum Rechts der Isar, Germany; Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 10. Gynaecological Oncology Department, St John of God Hospital, Subiaco, WA, Australia. 11. Gynaecology Department, Erlangen University Hospital, Erlangen, Germany. 12. Department of Obstetrics and Gynaecology, Innsbruck Medical University, Innsbruck, Austria. 13. Gynaecology Department, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. 14. Paul Strauss Cancer Center and Gynaecology Department, University of Strasbourg, Strasbourg, France. 15. Gynaecology Department, National Center for Tumor Disease, University of Heidelberg, Heidelberg, Germany; Department of Gynaecology and Obstetrics, University Hospital Mannheim, Mannheim, Germany. 16. Department of Gynaecology and Obstetrics, University of Frankfurt/Main, Frankfurt, Germany. 17. National Cancer Research Institute, Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, UK. 18. Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany. 19. Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Obstetrics and Gynaecology, University Hospital, Ludwig-Maximilian-University, Munich, Germany. 20. Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia. 21. Department of Gynaecology and Obstetrics, Medical University Hannover, Hannover, Germany. 22. Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France. 23. Department of Oncology, Hôpital Michallon, Grenoble, France. 24. Department of Gynaecology and Obstetrics, Evangelisches Krankenhaus Düsseldorf, Germany; Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany. 25. Department of Gynecology and Gynecologic Oncology, Comprehensive Cancer Centre, University Hospital for Gynaecology, Medical University Vienna, Vienna, Austria. 26. Royal Brisbane & Women's Hospital, Brisbane, QLD, Australia. 27. Centre Hospitalier Départemental les Oudairies, La Roche-Sur-Yon, France. 28. Women's Health, Royal North Shore Hospital, Sydney, NSW, Australia. 29. Department of Women's Health, Tübingen University Hospital, Tübingen, Germany. 30. Haematology-Oncology Department, Centre Hospitalier Régional et Universitaire de Strasbourg Hôpital Civil, Strasbourg, France.
Abstract
BACKGROUND: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab. METHODS: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. FINDINGS: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). INTERPRETATION: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. FUNDING: F Hoffmann-La Roche.
BACKGROUND: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab. METHODS: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. FINDINGS: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). INTERPRETATION: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. FUNDING: F Hoffmann-La Roche.
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