LAUSR

Assessing Metronomic Chemotherapy for Progressive Pediatric Solid Malignant Tumors To the Editor In the trial conducted by Pramanik and colleagues1 for treating progressive pediatric solid malignant tumors, the primary end point was progression-free survival (PFS). The jhazard 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. An alternative approach to handle this case is to use the mean PFS time to quantify the treatment benefit, which can be estimated by the area under the Kaplan-Meier curve.2-4 With reconstructed PFS data by scanning the Kaplan-Meier curves of Figure 2,5 the estimated mean PFS times for metronomic chemotherapy and BSC are 2.4 and 1.6 months, respectively. The difference in the mean PFS time is 0.8 months (95% CI, 0.14-1.5 months; P = .02). This quantification results in a statistically significant difference in favor of metronomic chemotherapy. Moreover, the difference of 0.8 months, coupled with the mean PFS time of 1.6 months for the control BSC arm, provides a more clinically meaningful interpretation of the treatment effect of metronomic chemotherapy than an HR of 0.65. The design and analysis of a future cancer clinical trial with overall survival/PFS outcome may be improved by adopting a robust, efficient statistical procedure that enables clinically meaningful interpretation of the treatment effect.