- Email: [email protected]
Discordance between the results and conclusions of ICON7
Correspondence
Discordance between the results and conclusions of ICON7 In their Article on the overall survival results of the ICON7 trial on the use of chemotherapy plus bevacizumab for first-line treatment of patients with newly diagnosed ovarian cancer, Amit Oza and colleagues concluded, “our data strongly support early use of bevacizumab, based on risk and disease burden”.1 We believe it is premature to derive such strong conclusions from this study for several reasons. First, the overall survival benefit of bevacizumab in patients with poor prognosis disease in this trial is derived from a subgroup analysis. This trial is itself an unmasked trial, not a placebo controlled trial. So this positive finding should be separately validated in another study before such strong conclusions can be derived. Second, benefit of improved progression-free survival, but not overall survival, can also be obtained with bevacizumab in the relapsed setting.2,3 We do not know yet whether the early use of bevacizumab is better than use of the drug at relapse or progression with chemotherapy. The evidence therefore equally supports use of chemotherapy alone in the firstline setting and with an addition of bevacizumab at relapse. In fact, the trials with bevacizumab in relapse settings2,3 have better hazard ratios and shorter duration of bevacizumab needed for a similar gain in progression-free survival compared with this trial. Third, because the JGOG 3016 trial4 showed significant benefit in progressionfree survival and overall survival with the use of dose-dense paclitaxel alone, early use of bevacizumab is not needed. This benefit in survival with dose-dense paclitaxel was especially pronounced in those with a residual disease of more than 1 cm, classified as patients with poor prognosis disease in ICON7, in whom the authors strongly recommend early use of bevacizumab. Although the conclusion of JGOG www.thelancet.com/oncology Vol 16 October 2015
3016 has been put into doubt by the MITO-7 results,5 the in-progress ICON8 trial (ISRCTN10356387) will hopefully provide a definitive answer. With the absence of an improvement in overall survival and the toxic effects associated with bevacizumab, not to mention the high cost, we disagree with the authors’ conclusion to “strongly support early use of bevacizumab”. Surprisingly, the authors also cite three references6–8 to help support their conclusion. However, none of the studies showed a significant overall survival benefit for bevacizumab. In fact, the article6 by Timothy Perren and colleagues is the first report of the same ICON7 study. Although improvement in the survival of patients is the foremost goal of clinical oncology research, clinicians should also assume responsibilities in addressing the financial burden of modern anticancer drugs. Exaggeration of marginal and questionable benefits with expensive therapies will be detrimental to society, not just financially, but also ethically. In scenarios in which these expensive drugs cannot be used because of unaffordability or the absence of regulatory approval, patients might be misled to believe that they have been deprived of an important drug, when in truth, the evidence does not suggest much benefit. YA reports grants from Sanofi, Torii Pharmaceutical Co, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co Ltd, grants and personal fees from Chugai Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Daiichi Sankyo Co Ltd, Kyowa Hakko Kirin Co Ltd, Eisai Co Ltd, Taiho Pharmaceutical Co Ltd, Nippon Kayaku Co Ltd, Yakult Honsya Co Ltd, Merck Serono Co Ltd, Hisamitsu Pharmaceutical Co Inc, and personal fees from Ono Pharmaceutical Co Ltd, Eli Lilly Japan KK, Pfizer Inc, Novartis Pharma KK, Janssen Pharmaceutical KK, AstraZenaca KK, GlaxoSmithKline plc, ASKA Pharmaceutical Co Ltd, Terumo Corporation, Bayel Holding Ltd, Meiji Seika Pharma Co Ltd, Arkray Marketing Inc, CBC Radio Co Ltd, Igaku-shoin Ltd, Vigorous-Med Inc, Nakayama Shoten Co Ltd, Nanzando Co Ltd, Benesse Style Care Co Ltd, Tokyo Kagaku Dojin Co Ltd, Kowa Pharmaceutical Co Ltd, Boehringer Ingelheim Co Ltd, and Bristol-Myers Squibb, outside the submitted work. BG and TS declare no competing interests.
*Bishal Gyawali, Tomoya Shimokata, Yuichi Ando [email protected]
Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Showa-ku Nagoya 466-8550, Japan 1
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Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015; 16: 928–36. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 2014; 32: 1302–08. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebocontrolled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 2039–45. Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013; 14: 1020–06. Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014; 15: 396–405. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–96. Witteveen P, Lortholary A, Fehm T, et al. Late breaking abstract: final overall survival (OS) results from AURELIA, an open-label randomised phase III trial of chemotherapy (CT) with or without bevacizumab (BEV) for platinum-resistant recurrent ovarian cancer (OC). Eur J Cancer 2013; 49 (suppl 3): S3–S4. Coleman R, Brady M, Herzog T, et al. A phase III randomised controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer (GOG-0213). Gynecol Oncol 2015; 137 (suppl 1): 3.
Authors’ reply We thank Bishal Gyawali and colleagues for raising important points relating to our analysis of bevacizumab in the treatment of newly-diagnosed ovarian cancer. The ICON7 trial1 recruited patients with high-risk early stage ovarian cancer and patients with more advanced disease. We reported no improvement in overall survival in the overall trial population, but e478
Discordance between the results and conclusions of ICON7 In their Article on the overall survival results of the ICON7 trial on the use of chemotherapy plus bevacizumab for first-line treatment of patients with newly diagnosed ovarian cancer, Amit Oza and colleagues concluded, “our data strongly support early use of bevacizumab, based on risk and disease burden”.1 We believe it is premature to derive such strong conclusions from this study for several reasons. First, the overall survival benefit of bevacizumab in patients with poor prognosis disease in this trial is derived from a subgroup analysis. This trial is itself an unmasked trial, not a placebo controlled trial. So this positive finding should be separately validated in another study before such strong conclusions can be derived. Second, benefit of improved progression-free survival, but not overall survival, can also be obtained with bevacizumab in the relapsed setting.2,3 We do not know yet whether the early use of bevacizumab is better than use of the drug at relapse or progression with chemotherapy. The evidence therefore equally supports use of chemotherapy alone in the firstline setting and with an addition of bevacizumab at relapse. In fact, the trials with bevacizumab in relapse settings2,3 have better hazard ratios and shorter duration of bevacizumab needed for a similar gain in progression-free survival compared with this trial. Third, because the JGOG 3016 trial4 showed significant benefit in progressionfree survival and overall survival with the use of dose-dense paclitaxel alone, early use of bevacizumab is not needed. This benefit in survival with dose-dense paclitaxel was especially pronounced in those with a residual disease of more than 1 cm, classified as patients with poor prognosis disease in ICON7, in whom the authors strongly recommend early use of bevacizumab. Although the conclusion of JGOG www.thelancet.com/oncology Vol 16 October 2015
3016 has been put into doubt by the MITO-7 results,5 the in-progress ICON8 trial (ISRCTN10356387) will hopefully provide a definitive answer. With the absence of an improvement in overall survival and the toxic effects associated with bevacizumab, not to mention the high cost, we disagree with the authors’ conclusion to “strongly support early use of bevacizumab”. Surprisingly, the authors also cite three references6–8 to help support their conclusion. However, none of the studies showed a significant overall survival benefit for bevacizumab. In fact, the article6 by Timothy Perren and colleagues is the first report of the same ICON7 study. Although improvement in the survival of patients is the foremost goal of clinical oncology research, clinicians should also assume responsibilities in addressing the financial burden of modern anticancer drugs. Exaggeration of marginal and questionable benefits with expensive therapies will be detrimental to society, not just financially, but also ethically. In scenarios in which these expensive drugs cannot be used because of unaffordability or the absence of regulatory approval, patients might be misled to believe that they have been deprived of an important drug, when in truth, the evidence does not suggest much benefit. YA reports grants from Sanofi, Torii Pharmaceutical Co, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co Ltd, grants and personal fees from Chugai Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Daiichi Sankyo Co Ltd, Kyowa Hakko Kirin Co Ltd, Eisai Co Ltd, Taiho Pharmaceutical Co Ltd, Nippon Kayaku Co Ltd, Yakult Honsya Co Ltd, Merck Serono Co Ltd, Hisamitsu Pharmaceutical Co Inc, and personal fees from Ono Pharmaceutical Co Ltd, Eli Lilly Japan KK, Pfizer Inc, Novartis Pharma KK, Janssen Pharmaceutical KK, AstraZenaca KK, GlaxoSmithKline plc, ASKA Pharmaceutical Co Ltd, Terumo Corporation, Bayel Holding Ltd, Meiji Seika Pharma Co Ltd, Arkray Marketing Inc, CBC Radio Co Ltd, Igaku-shoin Ltd, Vigorous-Med Inc, Nakayama Shoten Co Ltd, Nanzando Co Ltd, Benesse Style Care Co Ltd, Tokyo Kagaku Dojin Co Ltd, Kowa Pharmaceutical Co Ltd, Boehringer Ingelheim Co Ltd, and Bristol-Myers Squibb, outside the submitted work. BG and TS declare no competing interests.
*Bishal Gyawali, Tomoya Shimokata, Yuichi Ando [email protected]
Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Showa-ku Nagoya 466-8550, Japan 1
2
3
4
5
6
7
8
Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015; 16: 928–36. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 2014; 32: 1302–08. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebocontrolled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 2039–45. Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013; 14: 1020–06. Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014; 15: 396–405. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–96. Witteveen P, Lortholary A, Fehm T, et al. Late breaking abstract: final overall survival (OS) results from AURELIA, an open-label randomised phase III trial of chemotherapy (CT) with or without bevacizumab (BEV) for platinum-resistant recurrent ovarian cancer (OC). Eur J Cancer 2013; 49 (suppl 3): S3–S4. Coleman R, Brady M, Herzog T, et al. A phase III randomised controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer (GOG-0213). Gynecol Oncol 2015; 137 (suppl 1): 3.
Authors’ reply We thank Bishal Gyawali and colleagues for raising important points relating to our analysis of bevacizumab in the treatment of newly-diagnosed ovarian cancer. The ICON7 trial1 recruited patients with high-risk early stage ovarian cancer and patients with more advanced disease. We reported no improvement in overall survival in the overall trial population, but e478