Weighing risks and benefits in paediatric cancer trials

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On average, 1 in 10 children who enrol in paediatric phase I cancer trials are improved after the trial, and 1 in 50 die from drug-related complications, according to a systematic review and meta-analysis by Jonathan Kimmelman from McGill University, Canada, and colleagues.

Paediatric 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 paediatric 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 tumours (3.17, 95% CI 2.62 to 3.72) compared to haematological 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.”

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.

Marcin Waligora, Malgorzata M Bala, Magdalena Koperny, Mateusz T Wasylewski, Karolina Strzebonska, Rafał R Jaeschke, Agnieszka Wozniak, Jan Piasecki, Agnieszka Sliwka, Jerzy W Mitus, Maciej Polak, Dominika Nowis, Dean Fergusson, Jonathan Kimmelman

PLOS Medicine abstract

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