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. 2022 Nov 14;51(4):646-663.
doi: 10.1080/02664763.2022.2145272. eCollection 2024.

The heterogeneity effect of surveillance intervals on progression free survival

Zihang Zhong  1 , Min Yang  1 , Senmiao Ni  1 , Lixin Cai  1 , Jingwei Wu  2 , Jianling Bai  1 , Hao Yu  1
Affiliations

The heterogeneity effect of surveillance intervals on progression free survival

Zihang Zhong et al. J Appl Stat. .

Abstract

Progression-free survival (PFS) is an increasingly important surrogate endpoint in cancer clinical trials. However, the true time of progression is typically unknown if the evaluation of progression status is only scheduled at given surveillance intervals. In addition, comparison between treatment arms under different surveillance schema is not uncommon. Our aim is to explore whether the heterogeneity of the surveillance intervals may interfere with the validity of the conclusion of efficacy based on PFS, and the extent to which the variation would bias the results. We conduct comprehensive simulation studies to explore the aforementioned goals in a two-arm randomized control trial. We introduce three steps to simulate survival data with predefined surveillance intervals under different censoring rate considerations. We report the estimated hazard ratios and examine false positive rate, power and bias under different surveillance intervals, given different baseline median PFS, hazard ratio and censoring rate settings. Results show that larger heterogeneous lengths of surveillance intervals lead to higher false positive rate and overestimate the power, and the effect of the heterogeneous surveillance intervals may depend upon both the life expectancy of the tumor prognoses and the censoring proportion of the survival data. We also demonstrate such heterogeneity effect of surveillance intervals on PFS in a phase III metastatic colorectal cancer trial. In our opinions, adherence to consistent surveillance intervals should be favored in designing the comparative trials. Otherwise, it needs to be appropriately taken into account when analyzing data.

Keywords: Progression-free survival; cancer clinical trial; false positive rate; power; surveillance interval.

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Conflict of interest statement

This publication is based on research using information obtained from https://data.ProjectDataSphere.org, which is maintained by Project Data Sphere. Neither Project Data Sphere nor the owner(s) of any information from the web site have contributed to, approved or are in any way responsible for the contents of this publication. No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
The false positive rate curves when the actual median survival time are the same between two treatment arms, under various censoring rates and heterogenous lengths of surveillance intervals. The black color curve represents the proportion of iterations that is rejecting the null hypothesis using the actual PFS data.
Figure 2.
Figure 2.
The estimated hazard ratio bias (EBIAS) curves based on surveillance-interval defined PFS.
Figure 3.
Figure 3.
The empirical power curves when the actual median survival time in treatment B is 1.1–2 times longer than that in treatment A, under various censoring rates and heterogenous lengths of surveillance intervals. The black curve represents the proportion of iterations that is rejecting the null hypothesis using the actual PFS data.
Figure 4.
Figure 4.
The estimated hazard ratio bias (EBIAS) curves based on surveillance-interval defined PFS.
Figure 5.
Figure 5.
Surveillance-interval defined Progression-Free survival by Wild-type KRAS with different surveillance intervals. (a) Panitumumab + FOLFIRI: 8-week surveillance interval vs. FOLFIRI: 8-week surveillance interval (set as reference); (b) Panitumumab + FOLFIRI: 10-week surveillance interval vs. FOLFIRI: 8-week surveillance interval; (c) Panitumumab + FOLFIRI: 12-week surveillance interval vs. FOLFIRI: 8-week surveillance interval.
Figure 6.
Figure 6.
Surveillance-interval defined Progression-Free survival by Mutant KRAS with different surveillance intervals. (a) Panitumumab + FOLFIRI: 8-week surveillance interval vs. FOLFIRI: 8-week surveillance interval (set as reference); (b) Panitumumab + FOLFIRI: 10-week surveillance interval vs. FOLFIRI: 8-week surveillance interval; (c) Panitumumab + FOLFIRI: 12-week surveillance interval vs. FOLFIRI: 8-week surveillance interval.
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