On average, 1 in 10 children who enroll in pediatric phase I cancer trials are improved after the trial, and 1 in 50 die from drug-related complications, according to a new systematic review and meta-analysis published this week in PLOS Medicine by Jonathan Kimmelman from McGill University, Canada, and colleagues.
Pediatric phase I trials are critical for establishing the safety and dosing of anti-cancer drugs in children. National and international regulations, however, establish limits on allowable risk for research involving minors. In the new study, researchers systematically searched for pediatric phase I cancer studies published between 2004 and 2015. They identified 170 studies involving 4,604 patients, and pooled the objective response rates and the occurrence of grade 3, 4, or 5 (fatal) drug-related adverse events.
Overall, the response rate among all trials was 10.29% (95% CI 8.33 to 12.25) but the rate was significantly different for solid tumors (3.17, 95% CI 2.62 to 3.72) compared to hematological malignancies (27.90, 95% CI 20.53 to 35.27). The overall rate of fatal grade 5 adverse events was 2.09% (95% CI 1.45 to 2.72) and there was an average of 1.32 grade 3 and 4 drug-related adverse events per person. On the whole, adverse event and response rates were similar to those seen in adult phase I cancer trials.
The authors note several limitations to their study, including heterogeneity in the types of cancer and treatment in the included trials, reliance on published data only, and low-quality or incomplete reporting of some trial outcomes.
"Our data, coupled with careful ethical analysis, provide an empirical basis for further discussions about the therapeutic status of phase I trials in children," the authors say. "In particular, they provide evidence for refining risk/benefit in phase I trials and identifying those studies that present greater challenges for meeting standards of acceptable risk in children."
This study was funded by the National Science Center, Poland, UMO-2011/03/D/HS1/01695 and UMO-2015/18/E/HS1/00354 (http://www.
The authors have declared that no competing interests exist.
Waligora M, Bala MM, Koperny M, Wasylewski MT, Strzebonska K, Jaeschke RR, et al. (2018) Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis. PLoS Med 15(2): e1002505. https:/
Research Ethics in Medicine Study Group (REMEDY), Department of Philosophy and Bioethics, Jagiellonian University Medical College, Krakow, Poland
Department of Hygiene and Dietetics, Chair of Epidemiology and Preventive Medicine, Jagiellonian University Medical College, Krakow, Poland
Department of Public Health and Health Promotion, Regional Sanitary-Epidemiological Station in Krakow, Poland
Section of Affective Disorders, Department of Psychiatry, Jagiellonian University Medical College, Krakow, Poland
Agency for Health Technology Assessment and Tariff System, Warsaw, Poland
Department of Rehabilitation in Internal Diseases, Jagiellonian University Medical College, Krakow, Poland
Department of Surgical Oncology, Maria Sk?odowska-Curie Memorial Cancer Centre and Institute of Oncology, Krakow, Poland
Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland
Chair of Epidemiology and Population Studies, Jagiellonian University Medical College, Krakow, Poland
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
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montreal, Canada
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