Sandro Pignata1, Domenica Lorusso2, Florence Joly3, Ciro Gallo4, Nicoletta Colombo5, Cristiana Sessa6, Aristotelis Bamias7, Vanda Salutari8, Frédèric Selle9, Simona Frezzini10, Ugo De Giorgi11, Patricia Pautier12, Alessandra Bologna13, Michele Orditura14, Coraline Dubot15, Angiolo Gadducci16, Serafina Mammoliti17, Isabelle Ray-Coquard18, Elena Zafarana19, Enrico Breda20, Laure Favier21, Antonio Ardizzoia22, Saverio Cinieri23, Rémy Largillier24, Daniela Sambataro25, Emmanuel Guardiola26, Rossella Lauria27, Carmela Pisano28, Francesco Raspagliesi29, Giovanni Scambia8, Gennaro Daniele30, Francesco Perrone31. 1. Dipartimento Urogenitale, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS Fondazione Pascale, Naples, Italy. Electronic address: s.pignata@istitutotumori.na.it. 2. Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Dipartimento di Chirurgia, SC Chirurgia Ginecologica, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy. 3. Département recherche, enseignement, innovation, Centre François Baclesse, Caen, France; Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France. 4. Dipartimento di Salute Mentale Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy. 5. Istituto Europeo di Oncologia IRCCS, Milan, Italy; Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Milan, Italy. 6. Unità tumori ginecologici, Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland. 7. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece. 8. Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Ginecologia Oncologica-Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore di Roma, Rome, Italy. 9. Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France; Service Oncologie, Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France. 10. Oncologia Medica II, Istituto Oncologico Veneto IRCCS, Padua, Italy; Dipartimento di Oncologia, University of Padova, Padua, Italy. 11. Oncologia Medica, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy. 12. Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France; Department de Medecine, Institut Gustave Roussy, Université Paris Saclay, Villejuif, France. 13. Oncologia, Azienda Unità Sanitaria Locale di Reggio Emilia-IRCCS, Reggio Emilia, Italy. 14. Dipartimento DAI di Internistica Polispecialistica-Oncologia Medica ed Ematologia, Azienda Ospedaliera Universitaria, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy. 15. Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France; Oncologie Médicale, Institut Curie Saint-Cloud, Saint-Cloud, France. 16. Dipartimento di Medicina Clinica e Sperimentale, UO Ginecologia e Ostetricia, Università di Pisa, Pisa, Italy. 17. Oncologia Medica 1, IRCCS San Martino IST, Genova, Italy. 18. Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France; Département d'Oncologie Médicale, Centre Léon Bérard, Lyon, France. 19. Dipartimento Oncologico, SOC Oncologia Medica-Prato, Nuovo Ospedale di Prato Santo Stefano, Azienda USL Toscana Centro, Prato, Italy. 20. Dipartimento di Oncologia, Ospedale San Giovanni Calibita Fatebenefratelli, Rome, Italy. 21. Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France; Service d'oncologie médicale, L'HôpitalPrivé du Confluent, Nantes, France. 22. Dipartimento Oncologico, Ospedale Alessandro Manzoni-ASST Lecco, Lecco, Italy. 23. Oncologia Medica-Ospedale Senatore Antonio Perrino, Brindisi, Italy. 24. Centre Azuréen de Cancérologie, Mougins, France. 25. Oncologia Medica, A O Garibaldi-Nesima, Catania, Italy. 26. Service d'oncologie médicale-hématologie, Centre Hospitalier de la Dracénie, Draguignan, France. 27. Dipartimento DAI di Oncoematologia, Diagnostica per Immagini e Morfologica e Medicina Legale, Oncologia Medica-Azienda Ospedaliera Universitaria Policlinico Universitario Federico II, Naples, Italy. 28. Dipartimento Urogenitale, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS Fondazione Pascale, Naples, Italy. 29. Dipartimento di Chirurgia, SC Chirurgia Ginecologica, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy. 30. Dipartimento di Ricerca Traslazionale, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS Fondazione Pascale, Naples, Italy; Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. 31. Dipartimento di Ricerca Traslazionale, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS Fondazione Pascale, Naples, Italy.
Abstract
BACKGROUND:Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in thebevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in thebevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.
RCT Entities:
BACKGROUND:Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.
Authors: Alexandra Lainé; Travis T Sims; Olivia Le Saux; Isabelle Ray-Coquard; Robert L Coleman Journal: Curr Oncol Rep Date: 2021-11-09 Impact factor: 5.075
Authors: Ignace Vergote; Antonio Gonzalez-Martin; Domenica Lorusso; Charlie Gourley; Mansoor Raza Mirza; Jean-Emmanuel Kurtz; Aikou Okamoto; Kathleen Moore; Frédéric Kridelka; Iain McNeish; Alexander Reuss; Bénédicte Votan; Andreas du Bois; Sven Mahner; Isabelle Ray-Coquard; Elise C Kohn; Jonathan S Berek; David S P Tan; Nicoletta Colombo; Rongyu Zang; Nicole Concin; Dearbhaile O'Donnell; Alejandro Rauh-Hain; C Simon Herrington; Christian Marth; Andres Poveda; Keiichi Fujiwara; Gavin C E Stuart; Amit M Oza; Michael A Bookman Journal: Lancet Oncol Date: 2022-08 Impact factor: 54.433
Authors: Gabriel Osborn; Chara Stavraka; Rebecca Adams; Ahmad Sayasneh; Sharmistha Ghosh; Ana Montes; Katie E Lacy; Rebecca Kristeleit; James Spicer; Debra H Josephs; James N Arnold; Sophia N Karagiannis Journal: Clin Exp Immunol Date: 2022-07-22 Impact factor: 5.732