Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 35 Landsdowne Street, Cambridge, MA 02139, USA.
Fractal Therapeutics, 955 Massachusetts Ave Ste 199, Cambridge, MA 02139, USA.
Eur J Cancer. 2019 Mar;109:196-203. doi: 10.1016/j.ejca.2018.11.008. Epub 2019 Feb 7.
We seek to characterize how faster tumour shrinkage rate (k) can lead to paradoxically shorter Response Evaluation Criteria in Solid Tumors (RECIST) time to progression ('TTP20' - tumour size exceeding its minimum by 5 mm and 20%) [1] and, therefore, progression-free survival (PFS). Specifically, we investigate under what conditions this paradoxical behaviour occurs, what fraction of patients satisfy these conditions, whether this phenomenon can invert population-level PFS hazard ratio, and consistency of an alternative time-to-event benefit metric with k.
We use a mathematical model treating tumour burden as decreasing drug-sensitive and increasing drug-resistant cell subpopulations. We fit this model to data from several clinical trials with different indications [2]. We simulated a more effective treatment and recorded whether patients' TTP20 increased or decreased. We performed a study-level analysis to compare the relationship of speed and depth of response with TTP20 for both the administered 'control' and simulated 'more effective' drug. We propose and test an alternative benefit metric: the model-projected time that tumour size reaches 120% of baseline (TTB120).
Depending on indication, 3-27% of patients are estimated to have a paradoxically inverse relationship between k and TTP20. Simulated head-to-head studies show that TTP20-based PFS can favour the less effective drug. In contrast, TTB120 always favours the more effective drug.
We demonstrate the paradoxical behaviour of RECIST TTP20 - as an exemplar of percent-change-from-nadir based cancer progression criterion - both in theory and in observed patient data at the individual and trial level. We propose an alternative tumour size-based criterion (TTB120) that is directionally consistent with tumour shrinkage rate.
我们旨在描述更快的肿瘤退缩率（k）如何导致实体瘤反应评估标准（RECIST）进展时间（“TTP20”-肿瘤大小比最小尺寸增加 5mm 和 20%[1]）的悖论性缩短，从而导致无进展生存期（PFS）的缩短。具体来说，我们研究了这种悖论行为发生的条件、满足这些条件的患者比例、这种现象是否会反转人群水平的 PFS 风险比，以及替代时间事件获益指标与 k 的一致性。
我们使用一种将肿瘤负担视为减少药物敏感和增加药物抵抗细胞亚群的数学模型。我们将该模型拟合到来自具有不同适应症的几个临床试验的数据[2]。我们模拟了一种更有效的治疗方法，并记录了患者的 TTP20 是否增加或减少。我们进行了一项研究水平的分析，以比较两种给药“对照”和模拟“更有效”药物的速度和反应深度与 TTP20 的关系。我们提出并测试了一种替代获益指标：肿瘤大小达到基线 120%的模型预测时间（TTB120）。
根据适应症的不同，估计有 3-27%的患者的 k 和 TTP20 之间存在悖论性的反比关系。模拟的头对头研究表明，基于 TTP20 的 PFS 可以有利于疗效较低的药物。相比之下，TTB120 总是有利于更有效的药物。
我们在理论和个体及试验水平的观察性患者数据中证明了 RECIST TTP20 的悖论性行为-作为基于最低点百分比变化的癌症进展标准的范例。我们提出了一种替代的基于肿瘤大小的标准（TTB120），与肿瘤退缩率在方向上是一致的。
