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

PLoS Med. 2018 Feb 20;15(2):e1002505. doi: 10.1371/journal.pmed.1002505. eCollection 2018 Feb.


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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Biomarkers / analysis*
  • Child
  • Clinical Trials, Phase I as Topic / methods*
  • Humans
  • Medical Oncology / methods*
  • Pediatrics / methods*
  • Risk Factors


  • Biomarkers

Grant support

This study was funded by the National Science Center, Poland, UMO-2011/03/D/HS1/01695 and UMO-2015/18/E/HS1/00354 (www.ncn.gov.pl). Authors received the funding: MW (PI), MK, JP, AS, MTW, KS, MP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.