Mistry Hitesh B
Division of Pharmacy, University of Manchester, Manchester, United Kingdom.
PeerJ. 2017 Nov 29;5:e4111. doi: 10.7717/peerj.4111. eCollection 2017.
A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence, it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. I found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial I found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.
肿瘤药物研发中反复出现的一个问题是，利用早期临床数据预测新疗法的III期试验结果。解决这个问题的一种方法是从描述肿瘤大小动态变化的数学模型中得出指标，即再生长率和肿瘤再生长时间。在众多研究中，它们已被证明是总生存期的有力预测指标，但对于这些指标是如何得出的，以及它们是否比经验性终点更具预测性，仍存在争议。这项工作探讨了将模型衍生指标用作生存分析预测指标时出现的问题。通过正向和反向比对，计算了三项大型临床研究的再生长率和肿瘤再生长时间。后者涉及将患者重新比对至其疾病进展时间。因此，它既考虑了估计再生长率和肿瘤再生长时间所花费的时间，也评估了这些预测指标与疾病进展后生存期的相关性。我发现，使用反向比对时，再生长率和肿瘤再生长时间均与生存期无关。这表明，直至疾病进展的肿瘤动态变化与进展后生存期无关。对于III期试验的预测，我发现这些指标的表现并不优于经验性终点。这些结果凸显出，在将肿瘤成像动态变化与生存期关联时必须谨慎，并且将新方法与现有方法进行基准对比至关重要。
