Meta-Analysis on Pediatric Cancer Clinical Trials

Overview of Pediatric Cancer Mortality

A recent meta-analysis published in PLOS Medicine has examined the overall risk versus benefit in pediatric cancer clinical trials. According to the Canadian Cancer Society, cancer is responsible for more deaths in children than asthma, diabetes, cystic fibrosis, and AIDS combined. To combat this, pharmaceutical companies and the global scientific community are dedicated to reducing mortality rates associated with pediatric cancer through optimized clinical trial designs.

Challenges in Clinical Trial Design

Traditionally, pediatric cancer clinical trials have involved adjusting the dosages of anti-cancer drugs that have demonstrated efficacy in adults. However, the acceptable risk levels for children, combined with the rarity of pediatric cancers compared to adult cases, complicate the determination of appropriate dosages for potential pediatric anti-cancer drugs. Additionally, the limited capacity for informed consent among pediatric patients often leads to trial designs that prioritize minimizing risk, potentially sacrificing therapeutic benefits.

Study Insights from McGill University

A study led by researchers from McGill University analyzed existing literature, encompassing data from 170 studies and 4,604 pediatric patients. This review focused exclusively on phase I clinical trials, which are the initial stage of safety and efficacy testing in humans. These trials typically involve small sample sizes and lack randomization in treatment allocation. The analysis evaluated benefits by measuring the overall objective response rate (ORR), defined by the FDA as the reduction in tumor size for a sustained period. Risks were assessed by evaluating the occurrence of severe side effects, known as adverse events, which are classified into grades, with grades 3 and 4 being particularly severe and grade 5 classified as fatal.

Findings on Objective Response and Adverse Events

The overall objective response rate among patients was found to be 10.29%. When analyzed by type of cancer, hematological malignancies exhibited a significantly higher response rate of 27.9%, compared to a mere 3.17% in solid tumors. The overall risk, as measured by grade 5 adverse events, was 2.09%, while the frequency of grade 3 and 4 adverse events was notably high, averaging 1.32 per patient. In summary, the study suggests that one in ten patients enrolled in pediatric phase I trials experienced benefits, whereas one in fifty faced potentially fatal drug-induced side effects.

Comparison of Risks and Benefits in Pediatric and Adult Trials

The authors concluded that the risk versus benefit ratios for phase I clinical trials in pediatric cancer are not significantly different from those observed in adult trials. For instance, the overall objective response rate for solid tumors differed only slightly between adults (3.8%) and children (3.17%). Furthermore, the authors noted that in subsequent phase II trials, 39% of pediatric cancer patients received drugs at lower concentrations than those recommended based on phase I results.

Study Limitations and Implications

The authors acknowledged several limitations in their study, including the inherent variability among clinical studies, reliance solely on published data, and insufficient details regarding adverse events, all of which could introduce bias. Nevertheless, this analysis encourages policymakers and clinicians to reconsider the safety guidelines governing phase I clinical trials in pediatric oncology.

Reference

Waligora, M., Bala, M. M., Koperny, M., Wasylewski, M. T., Strzebonska, K., Jaeschke, R. R., … Kimmelman, J. (2018). Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis. PLoS Med, 15(2), e1002505. doi:10.1371/journal.pmed.1002505