Survival-Inferred Fragility Index in Phase III Colorectal Cancer Trials: A Systematic Review
4 affiliations
- 1Department of Clinical Research Management, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou 450008, China
- 2Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou 450001, China
- 3Clinical Trials Center, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, 17 South Panjiayuan Lane, Beijing 100021, China
- 4IRB Office, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 113, Baohe Avenue, Shenzhen 518116, China
Abstract
Background: Conventional measures such as p-values and hazard ratios (HRs) do not directly quantify the sensitivity of time-to-event outcomes to small changes in individual outcomes. The Survival-Inferred Fragility Index (SIFI) evaluates the minimum number of survival-outcome changes required to reverse trial conclusions and provides complementary information on result robustness. Methods: This systematic review (PROSPERO: CRD420251182325) identified phase III colorectal cancer randomized controlled trials (RCTs) published from 2015 to 2025 via PubMed, Embase, and Cochrane. SIFI was calculated using Bomze’s framework with the “flip best” strategy. The fragility quotient (FQ) and the relationship between SIFI and withdrawals or losses to follow-up (WCLFU) were assessed. Analyses used R version 4.5.1. Results: SIFI was calculated for 50 phase III colorectal cancer RCTs, including 9 three-arm trials, resulting in 59 pairwise comparisons. Among positive results, median SIFI values for colorectal, colon, and rectal cancer were 6.0 (interquartile range [IQR]: 2.0 to 11.0), 19.0 (IQR: 15.5 to 22.5), and 4.0 (IQR: 4.0 to 4.0). Higher SIFI was observed in trials with HR < 0.75 than in those with HR 0.75–0.94 (median SIFI: 9.0 vs. 1.0; p = 0.035) and in trials with power > 85% than in those with power ≤ 85% (median SIFI: 8.5 vs. 2.0; p = 0.028). For negative results, median SIFI values were −4.5 (IQR: −7.2 to −3.0), −30.5 (IQR: −43.5 to −18.0), and −10.5 (IQR: −11.0 to −5.5). Greater absolute SIFI values were associated with adjuvant therapy, sample size ≥ 500, disease-free survival as the primary endpoint, and HR ≥ 0.95 (all p ≤ 0.005). Overall, 44.07% of pairwise comparisons had an absolute SIFI < 5. Conclusions: SIFI shows some phase III colorectal cancer RCT conclusions were sensitive to small outcome changes. It complements conventional statistics by illuminating result robustness.
Related
- Iron homeostasis landscape informs patient survival and neoadjuvant chemotherapy response in cancer.
- Complete Cancer Prevalence Predictions via LASSO Regularization and Flexible Parametric Survival Cure Models
- Sex difference in survival benefits of immune checkpoint inhibitors in advanced non-small cell lung cancer: A meta-analysis
- The Fragile Coupon Collector: Random Deadlines, Critical Fragility, and Optimal Sampling
- Finding Icebergs in Language-Model Workflow: Diagnosing Latent Structural Fragility with Stochastic Semantic Evidence Graphs
BibTeX
@article{guo2026survivalinferred,
title = {{Survival-Inferred Fragility Index in Phase III Colorectal Cancer Trials: A Systematic Review}},
author = {Lanwei Guo and Jiani Yuan and Xuejing Zhang and Lin Cai and Xinxin Yan and Huamei Luan and Chenxin Zhu and Yan Zheng and Yanyan Liu and Huiyao Huang},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203394},
url = {https://www.mdpi.com/2072-6694/18/20/3394},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Survival-Inferred Fragility Index in Phase III Colorectal Cancer Trials: A Systematic Review
AU - Lanwei Guo
AU - Jiani Yuan
AU - Xuejing Zhang
AU - Lin Cai
AU - Xinxin Yan
AU - Huamei Luan
AU - Chenxin Zhu
AU - Yan Zheng
AU - Yanyan Liu
AU - Huiyao Huang
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203394
UR - https://www.mdpi.com/2072-6694/18/20/3394
AB - Background: Conventional measures such as p-values and hazard ratios (HRs) do not directly quantify the sensitivity of time-to-event outcomes to small changes in individual outcomes. The Survival-Inferred Fragility Index (SIFI) evaluates the minimum number of survival-outcome changes required to reverse trial conclusions and provides complementary information on result robustness. Methods: This systematic review (PROSPERO: CRD420251182325) identified phase III colorectal cancer randomized controlled trials (RCTs) published from 2015 to 2025 via PubMed, Embase, and Cochrane. SIFI was calculated using Bomze’s framework with the “flip best” strategy. The fragility quotient (FQ) and the relationship between SIFI and withdrawals or losses to follow-up (WCLFU) were assessed. Analyses used R version 4.5.1. Results: SIFI was calculated for 50 phase III colorectal cancer RCTs, including 9 three-arm trials, resulting in 59 pairwise comparisons. Among positive results, median SIFI values for colorectal, colon, and rectal cancer were 6.0 (interquartile range [IQR]: 2.0 to 11.0), 19.0 (IQR: 15.5 to 22.5), and 4.0 (IQR: 4.0 to 4.0). Higher SIFI was observed in trials with HR < 0.75 than in those with HR 0.75–0.94 (median SIFI: 9.0 vs. 1.0; p = 0.035) and in trials with power > 85% than in those with power ≤ 85% (median SIFI: 8.5 vs. 2.0; p = 0.028). For negative results, median SIFI values were −4.5 (IQR: −7.2 to −3.0), −30.5 (IQR: −43.5 to −18.0), and −10.5 (IQR: −11.0 to −5.5). Greater absolute SIFI values were associated with adjuvant therapy, sample size ≥ 500, disease-free survival as the primary endpoint, and HR ≥ 0.95 (all p ≤ 0.005). Overall, 44.07% of pairwise comparisons had an absolute SIFI < 5. Conclusions: SIFI shows some phase III colorectal cancer RCT conclusions were sensitive to small outcome changes. It complements conventional statistics by illuminating result robustness.
SN - 2072-6694
ER -