Metronomic Therapy for Progressive Pediatric Solid Malignant Tumors

To the Editor In the trial conducted by Pramanik and colleagues for treating progressive pediatric solid malignant tumors, the primary end point was progression-free survival (PFS). The hazard ratio (HR) for metronomic chemotherapy vs best supportive care (BSC) was 0.69 (95% CI, 0.47-1.03; P = .07). Numerically, this HR value is impressive, but it is not statistically significant. Therefore, the authors concluded that metronomic chemotherapy would not improve PFS, compared with placebo, among pediatric patients with extracranial progressive solid malignant tumors. The profile of the difference of the 2 Kaplan-Meier PFS curves in Figure 2 of the article for metronomic chemotherapy and BSC suggests that the proportional hazards model assumption is not plausible. That is, the HR is not constant over the entire study follow-up time. This implies that the observed HR is difficult to interpret clinically and, furthermore, it is likely that the test based on HR might not have enough statistical power to detect a real metronomic treatment effect. The authors also reported that the median PFS times between the 2 arms were similar. On the other hand, visually the Kaplan-Meier curves suggested that metronomic chemotherapy appeared to prolong the patients' PFS after 2 months of follow-up. For this situation, the median is not sensitive enough to capture the relatively long-term survival profile from metronomic chemotherapy. It is also known that generally the estimate of the median survival time is notoriously unstable and results in an inconclusive claim about the treatment difference.

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