Study weighs risks and benefits of phase I trials in pediatric cancer

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."

Waligora M, Bala MM, Koperny M, Wasylewski MT, Strzebonska K, Jaeschke RR, Wozniak A, Piasecki J, Sliwka A, Mitus JW, Polak M, Nowis D, Fergusson D, Kimmelman J.
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.

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