@article{6c6641f96fe647e1a4a763af083fafb7,
title = "Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial: The Lancet Oncology",
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 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. {\textcopyright} 2021 Elsevier Ltd",
keywords = "alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bevacizumab, bilirubin, carboplatin, cholesterol, doxorubicin, gamma glutamyltransferase, gemcitabine, paclitaxel, platinum complex, antineoplastic agent, macrogol, abdominal pain, acne, adult, adult respiratory distress syndrome, aged, allergic reaction, anaphylaxis, anemia, anorexia, anus fistula, aphonia, area under the curve, arthralgia, Article, bilirubin blood level, cancer growth, cancer recurrence, cancer staging, catheter infection, cerebrovascular accident, cholesterol blood level, clinical outcome, clinical practice, colon fistula, colon obstruction, colon perforation, confusion, constipation, controlled study, dental caries, depression, device infection, diarrhea, doublet chemotherapy, drug dosage form comparison, drug response, drug safety, dysarthria, dyspnea, enzyme blood level, epistaxis, erythroderma, faintness, fatigue, febrile neutropenia, female, fever, follow up, fracture, functional status, gastrointestinal symptom, hand foot syndrome, headache, heart disease, heart failure, heart left ventricle ejection fraction, heart muscle ischemia, hemorrhoid, human, hyperglycemia, hyperkalemia, hypertension, hypokalemia, hyponatremia, hypotension, infection, intention to treat analysis, kidney colic, left ventricular systolic dysfunction, leukocyte count, leukocytosis, leukoencephalopathy, maculopapular rash, maintenance therapy, major clinical study, median survival time, mortality rate, mucosa inflammation, multicenter study, multiple cycle treatment, musculoskeletal disease, nausea, neutrophil count, open study, ovary cancer, overall survival, pain, pancreatitis, pelvic inflammatory disease, pericardial effusion, phase 3 clinical trial, platelet count, pleura effusion, priority journal, progression free survival, proteinuria, randomized controlled trial, rectum hemorrhage, respiratory tract disease, second cancer, seizure, sensory neuropathy, sepsis, side effect, skin disease, small intestine obstruction, small intestine perforation, stomach hemorrhage, thromboembolism, vasculitis, vertigo, vomiting, clinical trial, disease exacerbation, disease free survival, drug resistance, middle aged, ovary tumor, pathology, tumor recurrence, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carboplatin, Disease Progression, Disease-Free Survival, Doxorubicin, Drug Resistance, Neoplasm, Female, Humans, Middle Aged, Neoplasm Recurrence, Local, Ovarian Neoplasms, Paclitaxel, Polyethylene Glycols",
author = "S. Pignata and D. Lorusso and F. Joly and C. Gallo and N. Colombo and C. Sessa and A. Bamias and V. Salutari and F. Selle and S. Frezzini and {De Giorgi}, U. and P. Pautier and A. Bologna and M. Orditura and C. Dubot and A. Gadducci and S. Mammoliti and I. Ray-Coquard and E. Zafarana and E. Breda and L. Favier and A. Ardizzoia and S. Cinieri and R. Largillier and D. Sambataro and E. Guardiola and R. Lauria and C. Pisano and F. Raspagliesi and G. Scambia and G. Daniele and F. Perrone and MITO16b/MANGO-OV2/ENGOT-ov17 Investigators",
note = "Cited By :7 Export Date: 1 October 2021 CODEN: LOANB Correspondence Address: Pignata, S.; Dipartimento Urogenitale, Italy; email: s.pignata@istitutotumori.na.it Chemicals/CAS: alanine aminotransferase, 9000-86-6, 9014-30-6; alkaline phosphatase, 9001-78-9; aspartate aminotransferase, 9000-97-9; bevacizumab, 216974-75-3, 1438851-35-4; bilirubin, 18422-02-1, 635-65-4; carboplatin, 41575-94-4; cholesterol, 57-88-5; doxorubicin, 23214-92-8, 25316-40-9; gamma glutamyltransferase, 85876-02-4; gemcitabine, 103882-84-4; paclitaxel, 33069-62-4; macrogol, 25322-68-3; Bevacizumab; Carboplatin; Doxorubicin; liposomal doxorubicin; Paclitaxel; Polyethylene Glycols Manufacturers: Hoffmann La Roche Funding details: Amgen Funding details: Bristol-Myers Squibb, BMS Funding details: Pfizer Funding details: Astellas Pharma US Funding details: AstraZeneca Funding details: Bayer Funding details: GlaxoSmithKline, GSK Funding details: Novartis Funding details: Roche Funding details: Celgene Funding details: Merck Sharp and Dohme, MSD Funding details: Sandoz Funding details: Les Laboratories Pierre Fabre Funding details: Cilag Funding text 1: SP reports grants and personal fees from Roche, during the conduct of the study; personal fees from AstraZeneca, Merck Sharp & Dohme, and Clovis; and non-financial support from Tesaro (GlaxoSmithKline), outside of the submitted work. DL reports personal fees from Immunogen and Genmab; grants and personal fees from Clovis and Merck; personal fees and travel and accomodation support from AstraZeneca and Amgen; and grants, personal fees, and travel and accomodation support from Roche, Tesaro (GlaxoSmithKline), and Pharmamar, outside of the submitted work. FJ reports travel and accomodation support from Pfizer, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Astellas, Janssen, Bayer, Sanofi, Ipsen, Roche, GlaxoSmithKline, and Clovis, outside of the submitted work. NC reports personal fees from Roche, Pharmamar, AstraZeneca, Clovis, Tesaro (GlaxoSmithKline), Merck Sharp & Dohme, Pfizer, Amgen, Takeda, Immunogen, and Biocad, outside of the submitted work. ABa reports grants and personal fees from Roche and AstraZeneca, outside of the submitted work. VS reports personal fees from AstraZeneca, Merck Sharp & Dohme, Roche, Tesaro (GlaxoSmithKline), and Pharmamar, outside of the submitted work. FS reports personal fees from Clovis and GlaxoSmithKline; and personal fees and non-financial support from Roche, AstraZeneca, Tesaro (GlaxoSmithKline), Merck Sharp & Dohme, and PharmaMar, outside of the submitted work. UDG reports grants from AstraZeneca; personal fees from Astellas, Bayer, Novartis, Merck Sharp & Dohme, and Pharmamar; grants and personal fees from Sanofi; grants and non-financial support from Roche; and personal fees and non-financial support from Janssen-Cilag, Pfizer, Bristol Myers Squibb, and Ipsen, outside of the submitted work. PP reports personal fees and travel and accomodation support from Roche, AstraZeneca, and Tesaro (GlaxoSmithKline); and travel and accomodation support from Clovis, outside of the submitted work. IR-C reports personal fees from Roche, Clovis, and GlaxoSmithKline; and grants and personal fees from AstraZeneca and Bristol Myers Squibb, outside of the submitted work. FR reports grants from Roche, Merck Sharp & Dohme, and Pharmamar; and grants and personal fees from GlaxoSmithKline, outside of the submitted work. GD reports personal fees from Bei Gene; and grants and travel and accomodation support from Roche, outside of the submitted work. FP reports grants from Roche and Pfizer; personal fees from Sandoz, Celgene, Pierre Fabre, and Janssen Cilag; grants and personal fees from Incyte and AstraZeneca; and grants, personal fees, and non-financial support from Bayer, outside of the submitted work. All other authors declare no competing interests. References: Burger, R.A., Brady, M.F., Bookman, M.A., Incorporation of bevacizumab in the primary treatment of ovarian cancer (2011) N Engl J Med, 365, pp. 2473-2483; Perren, T.J., Swart, A.M., Pfisterer, J., A phase 3 trial of bevacizumab in ovarian cancer (2011) N Engl J Med, 365, pp. 2484-2496; Aghajanian, C., Blank, S.V., Goff, B.A., OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer (2012) J Clin Oncol, 30, pp. 2039-2045; Pujade-Lauraine, E., Hilpert, F., Weber, B., Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial (2014) J Clin Oncol, 32, pp. 1302-1308; Bennouna, J., Sastre, J., Arnold, D., Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial (2013) Lancet Oncol, 14, pp. 29-37; Vergote, I., Pujade-Lauraine, E., Pignata, S., European Network of Gynaecological Oncological Trial Groups' requirements for trials between academic groups and pharmaceutical companies (2010) Int J Gynecol Cancer, 20, pp. 476-478; Schemper, M., Smith, T.L., A note on quantifying follow-up in studies of failure time (1996) Control Clin Trials, 17, pp. 343-346; Marubini, E., Valsecchi, M.G., Analysing survival data from clinical trials and observational studies (1995), Wiley Hoboken, NJ; Eisenhauer, E.A., Therasse, P., Bogaerts, J., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) (2009) Eur J Cancer, 45, pp. 228-247; Coleman, R.L., Brady, M.F., Herzog, T.J., Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial (2017) Lancet Oncol, 18, pp. 779-791; Pfisterer, J., Shannon, C.M., Baumann, K., Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial (2020) Lancet Oncol, 21, pp. 699-709; Gonz{\'a}lez-Mart{\'i}n, A., Pothuri, B., Vergote, I., Niraparib in patients with newly diagnosed advanced ovarian cancer (2019) N Engl J Med, 381, pp. 2391-2402; Ray-Coquard, I., Pautier, P., Pignata, S., Olaparib plus bevacizumab as first-line maintenance in ovarian cancer (2019) N Engl J Med, 381, pp. 2416-2428; Pfisterer, J., Dean, A.P., Baumann, K., Carboplatin/pegylated liposomal doxorubicin/bevacizumab (CD-BEV) vs. carboplatin/gemcitabine/bevacizumab (CG-BEV) in patients with recurrent ovarian cancer: a prospective randomized phase III ENGOT/GCIG-Intergroup study (AGO study group, AGO-Austria, ANZGOG, GINECO, SGCTG) (2018) Ann Oncol, 29, pp. viii332-viiii333; Roncolato, F.T., Gibbs, E., Lee, C.K., Quality of life predicts overall survival in women with platinum-resistant ovarian cancer: an AURELIA substudy (2017) Ann Oncol, 28, pp. 1849-1855; Stark, D., Nankivell, M., Pujade-Lauraine, E., Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial (2013) Lancet Oncol, 14, pp. 236-243",
year = "2021",
doi = "10.1016/S1470-2045(20)30637-9",
language = "English",
volume = "22",
pages = "267--276",
journal = "Lancet Oncol.",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "2",
}