ReviewBevacizumab in ovarian cancer: Focus on clinical data and future perspectives
Section snippets
Treatment landscape in ovarian cancer
The cornerstone of the management of ovarian cancer is primary cytoreductive surgery. After debulking surgery, patients receive front-line chemotherapy. For almost 15 years since the introduction of carboplatin–paclitaxel, most of the treatment strategies tested in the front-line setting yielded disappointing or controversial results. Substituting paclitaxel with other drugs in combination with carboplatin or adding a third drug to the carboplatin–paclitaxel regimen failed to improve outcomes (
Rationale for anti-angiogenic therapy in ovarian cancer
At the 2010 Consensus Conference on ovarian cancer, it was agreed that angiogenesis represents one of the most promising targets in ovarian cancer (Ledermann et al., 2011). One of the key mediators of angiogenesis is vascular endothelial growth factor (VEGF), a heparin-binding growth factor that selectively promotes proliferation and survival of vascular endothelial cells (Leung et al., 1989). VEGF also induces vascular permeability and angiogenesis in a variety of in vivo models (Ferrara, 2004
Clinical evaluation of bevacizumab
These preclinical properties, together with the proven efficacy of bevacizumab in a range of other solid tumour types and the known poor prognosis of patients with ovarian cancer overexpressing VEGF, led to clinical evaluation of bevacizumab in patients with recurrent ovarian cancer. The Gynecologic Oncology Group (GOG) carried out a series of phase II studies evaluating targeted agents, including bevacizumab, in patients with ovarian cancer. The activity demonstrated by bevacizumab in GOG 170D
GOG-0218
The double-blind, placebo-controlled randomised phase III GOG-0218 trial included 1873 patients with stage III (incompletely resected) or stage IV (any surgical outcome) epithelial ovarian, primary peritoneal or fallopian tube cancer (Burger et al., 2011) (Table 1). Patients were randomly assigned to one of three treatment groups: standard chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2) every 3 weeks for 6 cycles plus placebo from cycle 2 to cycle 22; the same chemotherapy for 6
Bevacizumab in recurrent ovarian cancer
Three further randomised phase III clinical trials have evaluated the efficacy and safety of bevacizumab in recurrent ovarian cancer: OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease) (Aghajanian et al., 2012a), GOG-0213 (Coleman et al., 2015) and AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) (Pujade-Lauraine et al., 2014).
In the placebo-controlled double-blind randomised phase
Ongoing evaluation of bevacizumab in ovarian cancer
A number of questions on the optimal use of bevacizumab in ovarian cancer remain unanswered, including the dose and the duration of bevacizumab treatment, the role and feasibility of combining bevacizumab with intraperitoneal chemotherapy, the selection of patients who can benefit most from bevacizumab, the optimal timing of bevacizumab initiation (front-line or at the time of relapse), strategies for patients previously treated with bevacizumab in the front-line setting and the most
Conclusions
Bevacizumab combined with chemotherapy provides a statistically and clinically significant improvement in PFS in the primary and recurrent advanced ovarian cancer settings. Exploratory analyses suggest an OS benefit in subgroups of patients defined according to residual disease and/or disease stage and have led to provocative hypotheses relating to patient selection, which need further evaluation and validation. Ongoing clinical trials are aiming to address currently unanswered questions, such
Author contributions
NC contributed in writing and revising the article. PFC, FR and GS contributed to drafting the manuscript. SP contributed to the conception and writing of the paper. All authors approved the final version for submission.
Conflict of interest
NC received research support and honoraria for lecturing and advisory boards from Roche, AstraZeneca, GSK, Clovis, MSD, Pharmamar and AMGEN. SP has received research grants from Roche, GSK and AstraZeneca, and honoraria from Roche and AstraZeneca. FR has received research support and honoraria for advisory boards from Roche, Pharmamar and AMGEN. PFC and GS declare that they have no conflict of interest.
Funding source
The funding source was not involved in analysis and interpretation of the data.
Acknowledgement
Medical writing and editorial support was funded by Roche Italy.
Nicoletta Colombo graduated in Medicine in 1980 and in 1984 she completed the Specialty in Obstetrics and Gynecology from the University of Milan, Italy. After a training period at Charing Cross Hospital and the Royal Marsden Hospital in London, she became a clinical research associate at the Kaplan Cancer Center, New York University, USA, where she worked from 1984 until 1986. She was Junior and later Senior Faculty at the Department of Obstetrics and Gynecology at the University of Milan from
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2019, International Journal of Biochemistry and Cell BiologyCitation Excerpt :In the clinical treatment of ovarian cancers, chemotherapies with the platinum and taxane classes of drugs have remained the major option for decades (Grunewald and Ledermann, 2016). However, recent advances in targeted therapies have significantly improved patient prognoses in the clinical management of ovarian cancers, and therefore drugs targeting the DNA damage repair pathway and the angiogenesis process in ovarian cancers have been approved by the Food and Drug Administration (FDA) (Crafton et al., 2016; Chase et al., 2017; Colombo et al., 2016). Inspired by the success of the PARP inhibitors, including olaparib, rucaparib, and niraparib, as well as the VEGF antibody bevacizumab, alternative therapeutic targets of ovarian cancers are under intensive investigations (Lin and Kraus, 2017; Staropoli et al., 2016).
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Nicoletta Colombo graduated in Medicine in 1980 and in 1984 she completed the Specialty in Obstetrics and Gynecology from the University of Milan, Italy. After a training period at Charing Cross Hospital and the Royal Marsden Hospital in London, she became a clinical research associate at the Kaplan Cancer Center, New York University, USA, where she worked from 1984 until 1986. She was Junior and later Senior Faculty at the Department of Obstetrics and Gynecology at the University of Milan from 1986 to 1994. In September 1994 she became Deputy Director, and in July 2001 Director of the Gynecologic Oncology Unit, Division of Gynecology, European Institute of Oncology, Milan, Italy. Since October 2002 she has been Associate Professor of Obstetrics and Gynecology at the University of Milan-Bicocca. Prof. Colombo has authored several publications in the field of gynaecological oncology and is a member of various professional societies such as the American Society of Clinical Oncology (ASCO), the Society of Gynecologic Oncologists (SGO) and the International Gynecological Cancer Society (IGCS). She is also Past President of the European Society of Gynecologic Oncology (ESGO) and Senior Editor of the International Journal of Gynecological Cancer.
Pier Franco Conte is Chief of the Division of Medical Oncology 2 at the Istituto Oncologico Veneto, IRCCS I Padua, Italy. He received his MD in 1974, and a Speciality in Clinical Oncology in 1977, both from Turin University, Italy. He specialised further in Clinical Immunology in 1980 and Hematology in 1984 at Milan and Genoa Universities. Prof. Conte was Founder and Chairman of the Gruppo Oncologico Nord-Ovest, and is currently a member of the Steering Committee of the International Cancer Cooperative Group (ICCG), a Faculty Member of the European Society for Medical Oncology (ESMO), and Founder and Chairman of Association Translation Research Oncology (ASTRO) and Association Research Education Oncology (AREO). He has authored over 320 scientific papers and sits on the Editorial Boards of several journals, including the Journal of Clinical Oncology, Clinical Breast Cancer and The Oncologist. In 2007 Prof. Conte received the Claude Jacquillat Award for Achievement in Clinical Oncology.
Sandro Pignata was born in Naples, Italy, in 1962. He took his MD degree in 1986 at Naples University and his PhD degree in Gastroenterological Science at the University of Rome in 1990. Since 1993 he has been on the Staff at the National Cancer Institute in Naples, where he is now Head of the Uro-Gynecological Department. Prof. Pignata is the President of the Multicenter Italian Trial in Ovarian cancer and gynecologic malignancies (MITO) group, which is involved in several randomised trials of the treatment of gynaecological cancer with results published in important international journals. He is a member of the educational committee of the European Society for Medical Oncology (ESMO) and of the executive board of the European Network of Gynaecological Oncological Trial Groups (ENGOT) and of the Gynecologic Cancer InterGroup (GCIG).
Francesco Raspagliesi graduated in Medicine in 1981 and is a Specialist in obstetrics, gynaecology and oncology. Since 1999 he has been Director of the Gynecologic Oncology Unit at the Fondazione IRCCS Istituto Nazionale Tumori of Milan, Italy, and Professor at the School of Specialization in Obstetrics and Gynecology at the University of Milan. He was President of the Italian Society of Gynecologic Oncology and is a member of the European Board and Council of Obstetrics and Gynecology. He has authored several papers on gynaecological oncology and is a peer reviewer for journals including Gynecologic Oncology, the International Journal of Reproductive Medicine, Cancer, Oncology Topics, the European Journal of Obstetrics & Gynecology and Reproductive Biology.
Giovanni Scambia received his degree in Medicine and Surgery in 1983 from the Catholic University of Rome. He did his residency at the Department of Obstetrics and Gynecology at the Catholic University of the Sacred Heart (UCSC) from 1983 to 1987, and then a Fellowship in Gynecologic Oncology at the Department of Obstetrics and Gynecology at the Catholic University of Rome from 1987 to 1990. Since 1992 he has been Head of the Research Laboratory, Department of Gynecology at UCSC, and in addition has been in charge of the management of clinical trials since 1997. He became a Full Professor of Gynaecology and Obstetrics at the Catholic University in 2007, and is currently Head of the Departments of Women’s and Children’s Health at UCSC, Director of Gynecology and Obstetrics Post Graduate School and Scientific Director of Cure and Research at Giovanni Paolo II in Campobasso, Italy. Prof. Scambia has authored over 730 scientific publications and is a member of the Italian Department of Health, on the Board of Directors of Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO), and a member of various societies including the European Society of Gynecologic Oncology (ESGO), the Gynecologic Cancer Cooperative Group and the International Gynecological Cancer Society (IGCS).