PURPOSE: Registration of new anticancer drugs is usually based on results of randomized controlled trials (RCTs) showing improved efficacy when compared with standard therapy. There is relatively less emphasis on toxicity. In our study, we analyze serious toxicities of newly approved anticancer drugs reported in pivotal RCTs used for drug registration. PATIENTS AND METHODS: We identified RCTs evaluating agents for the treatment of solid tumors approved by the US Food and Drug Administration between 2000 and 2010. Odds ratios (OR) and 95% CI were computed for three end points of safety and tolerability: treatment-related death, treatment-discontinuation related to toxicity, and grade 3 or 4 adverse events (AEs). These were then pooled in a meta-analysis. Correlations between these end points and the hazard ratios for overall survival (OS) and progression-free survival (PFS) were also assessed. RESULTS: Thirty-eight RCTs were analyzed. Compared with control groups, the odds of toxic death was greater for new agents (OR, 1.40; 95% CI, 1.15 to 1.70; P < .001) as were the odds of treatment-discontinuation (OR, 1.33; 95% CI, 1.22 to 1.45, P < .001). Grade 3 or 4 AEs (OR, 1.52; 95% CI, 1.35 to 1. 71; P < .001) were also more common with new agents, especially nonhematologic AEs such as diarrhea, skin reactions, and neuropathy. There were no significant correlations between safety end points and OS or PFS. CONCLUSION: New anticancer agents that lead to improvements in time-to-event end points also increase morbidity and treatment-related mortality. The balance between efficacy and toxicity may be less favorable in clinical practice because of selection of fewer patients with good performance status and limited comorbidities. Patients' baseline health characteristics should be considered when choosing therapy.
PURPOSE: Registration of new anticancer drugs is usually based on results of randomized controlled trials (RCTs) showing improved efficacy when compared with standard therapy. There is relatively less emphasis on toxicity. In our study, we analyze serious toxicities of newly approved anticancer drugs reported in pivotal RCTs used for drug registration. PATIENTS AND METHODS: We identified RCTs evaluating agents for the treatment of solid tumors approved by the US Food and Drug Administration between 2000 and 2010. Odds ratios (OR) and 95% CI were computed for three end points of safety and tolerability: treatment-related death, treatment-discontinuation related to toxicity, and grade 3 or 4 adverse events (AEs). These were then pooled in a meta-analysis. Correlations between these end points and the hazard ratios for overall survival (OS) and progression-free survival (PFS) were also assessed. RESULTS: Thirty-eight RCTs were analyzed. Compared with control groups, the odds of toxic death was greater for new agents (OR, 1.40; 95% CI, 1.15 to 1.70; P < .001) as were the odds of treatment-discontinuation (OR, 1.33; 95% CI, 1.22 to 1.45, P < .001). Grade 3 or 4 AEs (OR, 1.52; 95% CI, 1.35 to 1. 71; P < .001) were also more common with new agents, especially nonhematologic AEs such as diarrhea, skin reactions, and neuropathy. There were no significant correlations between safety end points and OS or PFS. CONCLUSION: New anticancer agents that lead to improvements in time-to-event end points also increase morbidity and treatment-related mortality. The balance between efficacy and toxicity may be less favorable in clinical practice because of selection of fewer patients with good performance status and limited comorbidities. Patients' baseline health characteristics should be considered when choosing therapy.
Authors: Julia H Rowland; Erin E Kent; Laura P Forsythe; Jon Håvard Loge; Lars Hjorth; Adam Glaser; Vittorio Mattioli; Sophie D Fosså Journal: Cancer Date: 2013-06-01 Impact factor: 6.860
Authors: Shing M Lee; Daniel Backenroth; Ying Kuen Ken Cheung; Dawn L Hershman; Diana Vulih; Barry Anderson; Percy Ivy; Lori Minasian Journal: J Clin Oncol Date: 2016-02-29 Impact factor: 44.544
Authors: John K Chan; Tuyen K Kiet; Bradley J Monk; Nichole Young-Lin; Kevin Blansit; Daniel S Kapp; Idoroenyi Amanam Journal: Oncologist Date: 2014-03-05
Authors: Keith I Block; Charlotte Gyllenhaal; Leroy Lowe; Amedeo Amedei; A R M Ruhul Amin; Amr Amin; Katia Aquilano; Jack Arbiser; Alexandra Arreola; Alla Arzumanyan; S Salman Ashraf; Asfar S Azmi; Fabian Benencia; Dipita Bhakta; Alan Bilsland; Anupam Bishayee; Stacy W Blain; Penny B Block; Chandra S Boosani; Thomas E Carey; Amancio Carnero; Marianeve Carotenuto; Stephanie C Casey; Mrinmay Chakrabarti; Rupesh Chaturvedi; Georgia Zhuo Chen; Helen Chen; Sophie Chen; Yi Charlie Chen; Beom K Choi; Maria Rosa Ciriolo; Helen M Coley; Andrew R Collins; Marisa Connell; Sarah Crawford; Colleen S Curran; Charlotta Dabrosin; Giovanna Damia; Santanu Dasgupta; Ralph J DeBerardinis; William K Decker; Punita Dhawan; Anna Mae E Diehl; Jin-Tang Dong; Q Ping Dou; Janice E Drew; Eyad Elkord; Bassel El-Rayes; Mark A Feitelson; Dean W Felsher; Lynnette R Ferguson; Carmela Fimognari; Gary L Firestone; Christian Frezza; Hiromasa Fujii; Mark M Fuster; Daniele Generali; Alexandros G Georgakilas; Frank Gieseler; Michael Gilbertson; Michelle F Green; Brendan Grue; Gunjan Guha; Dorota Halicka; William G Helferich; Petr Heneberg; Patricia Hentosh; Matthew D Hirschey; Lorne J Hofseth; Randall F Holcombe; Kanya Honoki; Hsue-Yin Hsu; Gloria S Huang; Lasse D Jensen; Wen G Jiang; Lee W Jones; Phillip A Karpowicz; W Nicol Keith; Sid P Kerkar; Gazala N Khan; Mahin Khatami; Young H Ko; Omer Kucuk; Rob J Kulathinal; Nagi B Kumar; Byoung S Kwon; Anne Le; Michael A Lea; Ho-Young Lee; Terry Lichtor; Liang-Tzung Lin; Jason W Locasale; Bal L Lokeshwar; Valter D Longo; Costas A Lyssiotis; Karen L MacKenzie; Meenakshi Malhotra; Maria Marino; Maria L Martinez-Chantar; Ander Matheu; Christopher Maxwell; Eoin McDonnell; Alan K Meeker; Mahya Mehrmohamadi; Kapil Mehta; Gregory A Michelotti; Ramzi M Mohammad; Sulma I Mohammed; D James Morre; Vinayak Muralidhar; Irfana Muqbil; Michael P Murphy; Ganji Purnachandra Nagaraju; Rita Nahta; Elena Niccolai; Somaira Nowsheen; Carolina Panis; Francesco Pantano; Virginia R Parslow; Graham Pawelec; Peter L Pedersen; Brad Poore; Deepak Poudyal; Satya Prakash; Mark Prince; Lizzia Raffaghello; Jeffrey C Rathmell; W Kimryn Rathmell; Swapan K Ray; Jörg Reichrath; Sarallah Rezazadeh; Domenico Ribatti; Luigi Ricciardiello; R Brooks Robey; Francis Rodier; H P Vasantha Rupasinghe; Gian Luigi Russo; Elizabeth P Ryan; Abbas K Samadi; Isidro Sanchez-Garcia; Andrew J Sanders; Daniele Santini; Malancha Sarkar; Tetsuro Sasada; Neeraj K Saxena; Rodney E Shackelford; H M C Shantha Kumara; Dipali Sharma; Dong M Shin; David Sidransky; Markus David Siegelin; Emanuela Signori; Neetu Singh; Sharanya Sivanand; Daniel Sliva; Carl Smythe; Carmela Spagnuolo; Diana M Stafforini; John Stagg; Pochi R Subbarayan; Tabetha Sundin; Wamidh H Talib; Sarah K Thompson; Phuoc T Tran; Hendrik Ungefroren; Matthew G Vander Heiden; Vasundara Venkateswaran; Dass S Vinay; Panagiotis J Vlachostergios; Zongwei Wang; Kathryn E Wellen; Richard L Whelan; Eddy S Yang; Huanjie Yang; Xujuan Yang; Paul Yaswen; Clement Yedjou; Xin Yin; Jiyue Zhu; Massimo Zollo Journal: Semin Cancer Biol Date: 2015-12 Impact factor: 15.707