Abstract
BackgroundPediatric 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 findingsOur 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.ConclusionsOur 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.
Highlights
Despite enormous strides in treating pediatric malignancies, childhood cancer remains the fourth leading cause of death in US children aged 1–18 years [1]
Our meta-analysis suggests that, on the whole, adverse event (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
Summary
Despite enormous strides in treating pediatric malignancies, childhood cancer remains the fourth leading cause of death in US children aged 1–18 years [1]. Phase I trials in children present risks of serious toxicity and limited prospect of benefit, and patients are potentially exposed to levels of drug that are inactive [2,11,23,24]. Several practices are designed to maximize the therapeutic prospect of Phase I pediatric cancer trials, including prior testing in adults and testing within a narrower dose range [2,4,25]. Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, 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
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