A Phase 3 Trial of Bevacizumab in Ovarian Cancer

Perren, Timothy J.; Swart, Ann Marie; Pfisterer, Jacobus; Ledermann, Jonathan A.; Pujade-Lauraine, Éric; Kristensen, Gunnar B.; Carey, Mark; Beale, Philip; Cervantes, Andrés; Kurzeder, Christian; Bois, Andreas du; Sehouli, Jalid; Kimmig, Rainer; Stähle, A.; Collinson, Fiona; Essapen, Sharadah; Gourley, Charlie; Lortholary, Alain; Selle, Frédèric; Mirza, Mansoor Raza; Leminen, Arto; Plante, Marie; Stark, Dan; Qian, Wendi; Parmar, Mahesh; Oza, Amit M.; Investigators, Icon

doi:10.1056/nejmoa1103799

Cited by 1,909 publications

(1,567 citation statements)

References 22 publications

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“…The dose of bevacizumab (7.5 mg/kg) was half of that used in GOG 218 [59]. AEs were reported as consistent with previous bevacizumab trials, and included hypertension, proteinuria, thromboembolic events and GI perforations.…”

Section: Phase 2 Studiesmentioning

confidence: 87%

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Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

Eskander

Tewari

2014

Gynecologic Oncology

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Section: Phase 2 Studiesmentioning

confidence: 87%

“…(Table 1), bevacizumab (Avastin) was the first anti-angiogenesis agent to be advanced into the phase 3 randomized trial design for advanced EOC. To date, four pivotal trials have been completed, two in the primary setting and two for patients with recurrent disease (Table 2) [57][58][59][60][61][62][63][64][65][66].…”

Section: Phase 2 Studiesmentioning

confidence: 99%

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

Eskander

Tewari

2014

Gynecologic Oncology

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“…The negative short‐term impact of second‐line chemotherapy plus cediranib contrasts with QOL improvements observed during first‐line chemotherapy combined with antiangiogenic agents 13, 25. Treating relapsed ovarian cancer before symptom development has previously been found detrimental to QOL,26 but 87% of ICON6 patients were symptomatic at randomization.…”

Section: Discussionmentioning

confidence: 99%

Quality of life with cediranib in relapsed ovarian cancer: The ICON6 phase 3 randomized clinical trial

Stark

Cook

Brown

et al. 2017

Cancer

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BACKGROUNDThe ICON6 trial showed that cediranib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, improved clinical outcomes for patients with platinum‐sensitive relapsed ovarian cancer when it was used with chemotherapy and was continued as maintenance therapy. This study describes health‐related quality of life (QOL) during the first year of treatment.METHODSFour hundred fifty‐six women were randomly allocated to receive standard chemotherapy only, chemotherapy with concurrent cediranib, or chemotherapy with cediranib administered concurrently and continued as maintenance. Patients completed QOL questionnaires until disease progression every 3 weeks during chemotherapy and then every 6 weeks to 1 year. Patients alive with disease progression completed a QOL form 1 year after randomization. The primary QOL endpoint was the global score from the Quality of Life Questionnaire Core 30 (of the European Organization for Research and Treatment of Cancer) at 1 year, with the standard chemotherapy group compared with the concurrent‐maintenance cediranib group.RESULTSThe rate of questionnaire compliance was 90% at the baseline and 76% at 1 year and was similar across the 3 groups. The mean global QOL score at 1 year was 62.6 points for the standard chemotherapy group and 68.7 points for the concurrent‐maintenance group (+4.5; 95% confidence interval, –2.0 to 11.0; P = .18). Sensitivity analyses suggested that this finding was robust to the effect of missing data, and the improvement became statistically significant after adjustments for self‐reported diarrhea.CONCLUSIONSThe 6th study by the International Collaboration in Ovarian Neoplasm (ICON6) showed a significant improvement in progression‐free survival with cediranib as concurrent and maintenance therapy. No QOL detriment with cediranib was found 1 year after treatment was commenced. The maintenance of QOL along with prolonged cancer control suggests that cediranib has a valuable role in the treatment of relapsed ovarian cancer. Cancer 2017;123:2752‐61. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Most recently, antiangiogenic agents have demonstrated effectiveness in EOC clinical trials 7, 8. The progressive introduction of these agents in trials and in routine care during the conduct of the majority of the EOC trials published within the last decade may well have caused actual survival to deviate from historical controls.…”

Section: Discussionmentioning

confidence: 99%

“…This coupled with improved access to standard therapy and surgery has resulted in survival gains both in the first‐line setting and among patients with recurrent disease. In contrast to trials performed in the early 1980s, in which the median survival in phase 2 and 3 trials ranged from 15 to 24 months,5, 6 the median survival times published in the last decade have ranged from 36 to 40 months 7, 8…”

Section: Introductionmentioning

confidence: 92%

Estimation of expectedness: Predictive accuracy of standard therapy outcomes in randomized phase 3 studies in epithelial ovarian cancer

Castonguay

Wilson

Díaz-Padilla

et al. 2014

Cancer

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BACKGROUNDThe anticipated clinical outcome of the standard/control arm is an important parameter in the design of randomized phase 3 (RP3) trials to properly calculate sample size, power, and study duration. Changing patterns of care or variation in the study population enrolled may lead to a deviation from the initially anticipated outcome. The authors hypothesized that recent changes in patterns of care in epithelial ovarian cancer (EOC) have led to challenges in correctly estimating the outcome of control groups.METHODSA systematic review of the literature was conducted for RP3 trials of EOC published between January 2000 and December 2010. The expected outcome of the control arm as well as the actual outcome achieved by this cohort was collected and a ratio (actual‐over‐expected ratio) was calculated. The estimation of outcome was deemed accurate if the outcome of the control arm was between 0.75 to 1.25 times the anticipated outcome.RESULTSA total of 35 trials were eligible for analysis. Fifteen trials had survival as the primary endpoint whereas 20 had a progression‐based primary endpoint. In total, 12 of 15 trials with a survival‐based endpoint significantly underestimated the outcome of the control arm, whereas only 4 of 20 trials with a progression‐based endpoint did. Studies with a survival endpoint underestimated outcome more frequently than those with a progression endpoint (P<.001).CONCLUSIONSSurvival of the control arm has frequently been underestimated in recent EOC RP3 trials. This underestimation means that the initial statistical assumptions of these trials may have been inaccurate. Underestimating the outcome of the control arm may result in trials being underpowered to demonstrate the absolute benefit they were designed to show. Cancer 2015;121:413–422. © 2014 American Cancer Society.

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A Phase 3 Trial of Bevacizumab in Ovarian Cancer

Cited by 1,909 publications

References 22 publications

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

Quality of life with cediranib in relapsed ovarian cancer: The ICON6 phase 3 randomized clinical trial

Estimation of expectedness: Predictive accuracy of standard therapy outcomes in randomized phase 3 studies in epithelial ovarian cancer

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