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

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.

Ethical issues in the care of adolescent and young adult oncology patients

“…Brown and Slutzky recently published a systematic review on the refusal of treatment in pediatric oncology, and Sisk et al provide a framework for the clinician's role in disagreements between adolescents and parents. 16 36,37 Single-agent phase I trials have objective response rates of approximately 10%, 38 although participants may derive other benefits, such as disease stabilization, improvement in symptoms, and improved quality of life, as well as psychosocial and emotional benefits, from continuing to pursue therapeutic alternatives. Most participants in early-phase trials cite hope for treatment benefit as their primary motive for enrollment, and many maintain overly optimistic expectations of benefit.…”

A Systematic Review of Pediatric Phase I Trials in Oncology: Toxicity and Outcomes in the Era of Targeted Therapies

“…Overall, phase I leukemia trials accounted for a large proportion of the trials with these higher response rates and were associated with significantly higher ORRs per trial with a median (25th percentile to 75th percentile) of 42% (22%–58%), compared with 3% (0%–11%) for all other trials ( p < .0001). In a recent systematic review and meta‐analysis approach, a significantly higher overall response rate in hematological malignancies than in solid tumors was similarly reported . Of note in this study, the higher trial response rates among the leukemia trial population did not correspond to a higher rate of DLT per trial in this trial subgroup ( p = .35).…”

Reprioritizing Risk and Benefit: The Future of Study Design in Early‐Phase Cancer Research

“…Phase I trials have historically resulted in objective response rates (ORR) of 4% to 6%, but more recent reviews have shown ORRs of 9% to 11%, with another 19% of subjects having stable disease for more than four months 4 . A recent review of pediatric phase I trials found an ORR of 27.9% specific to hematologic malignancies 5 . Additionally, biologically targeted agents tend to have fewer acute toxicities‐adverse events compared to cytotoxic agents, with approximately 10% of subjects experiencing grade 3 or 4 toxicities, and a 0.4% to 0.5% toxic death rate 6 .…”

“…4 A recent review of pediatric phase I trials found an ORR of 27.9% specific to hematologic malignancies. 5 Additionally, biologically targeted agents tend to have fewer acute toxicitiesadverse events compared to cytotoxic agents, with approximately 10% of subjects experiencing grade 3 or 4 toxicities, and a 0.4% to 0.5% toxic death rate. 6 For some diseases, such as leukemia, chances of benefiting from a phase I trial have increased over time; for others, such as solid tumors, this progress has been slower.…”