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Bevacizumab, carboplatin, and paclitaxel in the first line treatment of advanced ovarian cancer patients: the phase IV MITO-16A/MaNGO-OV2A study
  1. Gennaro Daniele1,2,
  2. Francesco Raspagliesi3,
  3. Giovanni Scambia4,
  4. Carmela Pisano5,
  5. Nicoletta Colombo6,
  6. Simona Frezzini7,
  7. Germana Tognon8,
  8. Grazia Artioli9,10,
  9. Angiolo Gadducci11,
  10. Rossella Lauria12,
  11. Annamaria Ferrero13,
  12. Saverio Cinieri14,
  13. Andrea De Censi15,
  14. Enrico Breda16,
  15. Paolo Scollo17,
  16. Ugo De Giorgi18,
  17. Andrea Alberto Lissoni19,
  18. Dionyssios Katsaros20,
  19. Domenica Lorusso3,4,
  20. Vanda Salutari4,
  21. Sabrina Chiara Cecere5,
  22. Eleonora Zaccarelli6,
  23. Margherita Nardin21,
  24. Giorgio Bogani3,
  25. Mariagrazia Distefano4,
  26. Stefano Greggi22,
  27. Maria Carmela Piccirillo1,
  28. Roldano Fossati23,
  29. Gaia Giannone24,
  30. Laura Arenare1,
  31. Ciro Gallo25,
  32. Francesco Perrone1 and
  33. Sandro Pignata5
  1. 1Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
  2. 2Direzione Scientifica, Policlinico Universitario Agostino Gemelli, Roma, Italy
  3. 3Chirurgia Ginecologica, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
  4. 4Dipartimento Scienze della Salute della Donna e del Bambino, Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Roma, Italy
  5. 5Oncologia Clinica Sperimentale Uro-Ginecologica, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
  6. 6Istituto Europeo di Oncologia IRCCS, and Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Milano, Italy
  7. 7Oncologia Medica 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
  8. 8Divisione di Ostetricia e Ginecologia, ASST Spedali Civili di Brescia, Università degli Studi di Brescia, Brescia, Italy
  9. 9Oncologia ed Ematologia, U.L.S.S. 13, Mirano (VE), Italy
  10. 10Oncologia Medica, ULSS2 Marca Trevigiana, Treviso, Italy
  11. 11Dipartimento di Medicina Clinica e Sperimentale, UO Ginecologia e Ostetricia, Università degli Studi di Pisa Facolta di Medicina e Chirurgia, Pisa, Italy
  12. 12Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II Scuola di Medicina e Chirurgia, Napoli, Italy
  13. 13Divisione Universitaria di Ginecologia e Ostetricia, Azienda Ospedaliera Ordine Mauriziano di Torino, Torino, Italy
  14. 14Divisione di Oncologia Medica, Ospedale Antonio Perrino, Brindisi, Italy
  15. 15Oncologia Medica, Ospedali Galliera, Genova, Italy
  16. 16Dipartimento di oncologia, Ospedale San Giovanni Calibita Fatebenefratelli, Roma, Italy
  17. 17Divisione di Ostetricia e Ginecologia, Azienda Ospedaliera Cannizzaro, Catania, Italy
  18. 18Oncologia Medica, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
  19. 19Ginecologia Chirurgica, Ospedale San Gerardo, Monza, Italy
  20. 20Dipartimento di Scienze Chirurgiche, Ginecologia Oncologica, Ospedale Sant'Anna, Università di Torino, Torino, Italy
  21. 21Radiologia, Istituto Oncologico Veneto IRCCS, Università di Padova, Padova, Italy
  22. 22Ginecologia Oncologica, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
  23. 23Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
  24. 24Dipartimento di Oncologia, Università degli Studi di Torino e Istituto di Candiolo, FPO – IRCCS, Torino, Italy
  25. 25Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
  1. Correspondence to Professor Sandro Pignata, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli 80131, Italy; s.pignata{at}istitutotumori.na.it

Abstract

Objective To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab.

Methods A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m2) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints.

Results From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1–40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported.

Conclusions Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors.

Trial registration number EudraCT 2012-003043-29; NCT01706120.

  • ovarian cancer
  • medical oncology
  • ovarian neoplasms

Data availability statement

Data of this study will be shared with publication upon reasonable and motivated request to the Principal Investigator of the study (s.pignata@istitutotumori.na.it). The following IPD will be available for sharing: baseline characteristics of patients, treatment data, safety data, follow-up data. There will be no time limit for data sharing.

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Data availability statement

Data of this study will be shared with publication upon reasonable and motivated request to the Principal Investigator of the study (s.pignata@istitutotumori.na.it). The following IPD will be available for sharing: baseline characteristics of patients, treatment data, safety data, follow-up data. There will be no time limit for data sharing.

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Footnotes

  • FP and SP are co-last authorship.

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  • Contributors Gennaro Daniele, Ciro Gallo, Francesco Perrone and Sandro Pignata, wrote the protocol and the first draft of the manuscript. Ciro Gallo, Gennaro Daniele, Laura Arenare and Francesco Perrone did the statistical analyses. Francesco Raspagliesi, Giovanni Scambia, Carmela Pisano, Nicoletta Colombo, Simona Frezzini, Germana Tognon, Grazia Artioli, Angiolo Gadducci, Rossella Lauria, Annamaria Ferrero, Saverio Cinieri, Andrea De Censi, Enrico Breda, Paolo Scollo, Ugo De Giorgi, Andrea Alberto Lissoni, Dionissyos Katsaros, Domenica Lorusso, Vanda Salutari, Sabrina Chiara Cecere, Eleonora Zaccarelli, Margherita Nardin, Giorgio Bogani, Mariagrazia Distefano, Stefano Greggi, Maria Carmela Piccirillo, Roldano Fossati, and Gaia Giannone contributed to the results’ interpretation and to the final version of the manuscript.

  • Funding The MITO-16A/MaNGO-OV2A is a multicenter, national, academic trial sponsored by NCI Naples. Roche Italy provided bevacizumab and partial funding for trial activities and for the translational project. AIRC (Associazione Italiana per la Ricerca sul Cancro) supported translational studies with the IG 5776. AIOM (Associazione Italiana di Oncologia Medica) supported biomarker analysis with a grant. Roche, AIRC and AIOM did not play any role in study design, protocol writing, data collection, data analysis and interpretation, and manuscript writing. The corresponding author had full access to all of the data and the final responsibility to submit for publication.

  • Competing interests Dr Daniele reports travel and accommodations from Roche, outside the submitted work. Dr Raspagliesi reports grants from Roche, grants from GSK, grants from MSD, grants from Pharmamar, outside the submitted work. Dr Colombo reports personal fees from Roche, personal fees from Pharmamar, personal fees from AstraZeneca, personal fees from MSD, personal fees from Tesaro, personal fees from GSK, personal fees from Clovis, personal fees from Amgen, personal fees from Pfizer, personal fees from Biogen, personal fees from BIOCAD, outside the submitted work. Dr De Giorgi reports personal fees from Astellas - Pharma, personal fees from Bayer, personal fees and non-financial support from Bristol Myers-Squibb, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Janssen, personal fees and non-financial support from Pfizer, grants and personal fees from Sanofi, personal fees from Novartis, personal fees from MSD, grants and non-financial support from Roche, grants from AstraZeneca, personal fees from Pharmamar, outside the submitted work. Dr Lorusso reports grants, personal fees and non-financial support from Pharmamar, grants and personal fees from MSD, grants and personal fees from Clovis, grants, personal fees and non-financial support from GSK, personal fees and non-financial support from AstraZeneca, personal fees from Merck Serono, personal fees from Amgen, non-financial support from Roche, outside the submitted work. Dr Salutari reports personal fees from MSD, personal fees from GSK, personal fees from Tesaro, personal fees from AstraZeneca, personal fees from Roche, personal fees from Eisai, personal fees from Clovis, outside the submitted work. Dr Piccirillo reports personal fees from Daichii Sankyo, personal fees from GSK, personal fees from MSD, grants from Roche, grants and personal fees from AstraZeneca, non-financial support from Bayer, outside the submitted work. Dr Perrone reports grants from Roche, during the conduct of the study; grants, personal fees and non-financial support from Bayer, personal fees from Sandoz, grants and personal fees from Incyte, personal fees from Celgene, grants and personal fees from AstraZeneca, personal fees from Pierre Fabre, personal fees from Janssen Cilag, grants from Roche, grants from Pfizer, outside the submitted work. Dr Pignata reports grants from Roche, during the conduct of the study; personal fees from AZ, personal fees from MSD, personal fees from Clovis, personal fees and non-financial support from Tesaro GSK, personal fees from Roche, outside the submitted work. The other authors do not declare conflicts of interests.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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