Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

Autor: Waligora M; Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Kraków, Poland., Bala MM; Department of Hygiene and Dietetics, Chair of Epidemiology and Preventive Medicine, Jagiellonian University Medical College, Kraków, Poland., Koperny M; Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Kraków, Poland.; Department of Public Health and Health Promotion, Regional Sanitary-Epidemiological Station in Kraków, Poland., Wasylewski MT; Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Kraków, Poland., Strzebonska K; Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Kraków, Poland., Jaeschke RR; Section of Affective Disorders, Department of Psychiatry, Jagiellonian University Medical College, Kraków, Poland., Wozniak A; Agency for Health Technology Assessment and Tariff System, Warsaw, Poland., Piasecki J; Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Kraków, Poland., Sliwka A; Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Kraków, Poland.; Department of Rehabilitation in Internal Diseases, Jagiellonian University Medical College, Kraków, Poland., Mitus JW; Department of Surgical Oncology, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Kraków, Poland.; Department of Anatomy, Jagiellonian University Medical College, Kraków, Poland., Polak M; Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Kraków, Poland.; Chair of Epidemiology and Population Studies, Jagiellonian University Medical College, Kraków, Poland., Nowis D; Department of Immunology, Medical University of Warsaw, Warsaw, Poland.; Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.; Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Warsaw, Poland., Fergusson D; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada., Kimmelman J; Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montreal, Canada.
Jazyk: angličtina
Zdroj: PLoS medicine [PLoS Med] 2018 Feb 20; Vol. 15 (2), pp. e1002505. Date of Electronic Publication: 2018 Feb 20 (Print Publication: 2018).
DOI: 10.1371/journal.pmed.1002505
Abstrakt: Background: Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials.
Methods and Findings: Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as "small sample size, non‑randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested." We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting.
Conclusions: Our meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje