Eric J Chow1, Richard Aplenc2, Lynda M Vrooman3, David R Doody1, Yuan-Shung V Huang2, Sanjeev Aggarwal4, Saro H Armenian5, K Scott Baker1, Smita Bhatia6, Louis S Constine7, David R Freyer8, Lisa M Kopp9, Wendy M Leisenring1, Barbara L Asselin7, Cindy L Schwartz10, Steven E Lipshultz11. 1. Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, Seattle, Washington. 2. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 3. Dana-Farber Cancer Institute, Boston Children's Hospital, Boston, Massachusetts. 4. Wayne State University, Detroit, Michigan. 5. City of Hope, Duarte, California. 6. University of Alabama at Birmingham, Birmingham, Alabama. 7. Golisano Children's Hospital, University of Rochester Medical Center, Rochester, New York. 8. Children's Hospital Los Angeles, University of Southern California, Los Angeles, California. 9. University of Arizona, Tucson, Arizona. 10. Children's Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin. 11. Oishei Children's Hospital, Roswell Park Comprehensive Center, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York.
Abstract
BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods. RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2 ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35). CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.
BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods. RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2 ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35). CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.
Authors: Steven E Lipshultz; M Jacob Adams; Steven D Colan; Louis S Constine; Eugene H Herman; Daphne T Hsu; Melissa M Hudson; Leontien C Kremer; David C Landy; Tracie L Miller; Kevin C Oeffinger; David N Rosenthal; Craig A Sable; Stephen E Sallan; Gautam K Singh; Julia Steinberger; Thomas R Cochran; James D Wilkinson Journal: Circulation Date: 2013-09-30 Impact factor: 29.690
Authors: Cindy L Schwartz; Leonard H Wexler; Mark D Krailo; Lisa A Teot; Meenakshi Devidas; Laurel J Steinherz; Allen M Goorin; Mark C Gebhardt; John H Healey; Judith K Sato; Paul A Meyers; Holcombe E Grier; Mark L Bernstein; Steven E Lipshultz Journal: Pediatr Blood Cancer Date: 2015-09-23 Impact factor: 3.167
Authors: Kelly D Getz; Lillian Sung; Todd A Alonzo; Kasey J Leger; Robert B Gerbing; Jessica A Pollard; Todd Cooper; E Anders Kolb; Alan S Gamis; Bonnie Ky; Richard Aplenc Journal: J Clin Oncol Date: 2020-04-28 Impact factor: 44.544
Authors: Yan Chen; Eric J Chow; Kevin C Oeffinger; William L Border; Wendy M Leisenring; Lillian R Meacham; Daniel A Mulrooney; Charles A Sklar; Marilyn Stovall; Leslie L Robison; Gregory T Armstrong; Yutaka Yasui Journal: J Natl Cancer Inst Date: 2020-03-01 Impact factor: 13.506
Authors: Saro H Armenian; Gregory T Armstrong; Gregory Aune; Eric J Chow; Matthew J Ehrhardt; Bonnie Ky; Javid Moslehi; Daniel A Mulrooney; Paul C Nathan; Thomas D Ryan; Helena J van der Pal; Elvira C van Dalen; Leontien C M Kremer Journal: J Clin Oncol Date: 2018-06-06 Impact factor: 44.544
Authors: Steven E Lipshultz; Rebecca E Scully; Stuart R Lipsitz; Stephen E Sallan; Lewis B Silverman; Tracie L Miller; Elly V Barry; Barbara L Asselin; Uma Athale; Luis A Clavell; Eric Larsen; Albert Moghrabi; Yvan Samson; Bruno Michon; Marshall A Schorin; Harvey J Cohen; Donna S Neuberg; E John Orav; Steven D Colan Journal: Lancet Oncol Date: 2010-09-16 Impact factor: 41.316
Authors: Barbara L Asselin; Meenakshi Devidas; Lu Chen; Vivian I Franco; Jeanette Pullen; Michael J Borowitz; Robert E Hutchison; Yaddanapudi Ravindranath; Saro H Armenian; Bruce M Camitta; Steven E Lipshultz Journal: J Clin Oncol Date: 2015-12-23 Impact factor: 44.544
Authors: Eric J Chow; Lena E Winestone; Philip J Lupo; Lisa R Diller; Tara O Henderson; Nina S Kadan-Lottick; Jennifer M Levine; Kirsten K Ness; Smita Bhatia; Saro H Armenian Journal: Cancer Epidemiol Biomarkers Prev Date: 2022-09-02 Impact factor: 4.090
Authors: Esmée C de Baat; Renée L Mulder; Saro Armenian; Elizabeth Am Feijen; Heynric Grotenhuis; Melissa M Hudson; Annelies Mc Mavinkurve-Groothuis; Leontien Cm Kremer; Elvira C van Dalen Journal: Cochrane Database Syst Rev Date: 2022-09-27
Authors: Rahela Aziz-Bose; Renee Margossian; Bethany L Ames; Kerry Moss; Matthew J Ehrhardt; Saro H Armenian; Torunn I Yock; Larissa Nekhlyudov; David Williams; Melissa Hudson; Anju Nohria; Lisa B Kenney Journal: JACC CardioOncol Date: 2022-08-16