Fragility Index analysis for robustness of evidence in Randomized Controlled Trials in National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer.

Abstract

Robustness of evidence from randomized controlled trials (RCTs) is crucial for guiding clinical decisions in rectal cancer. We evaluated the reliability of RCTs cited by the National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer using the Fragility Index (FI) that quantifies the stability of trial outcomes. RCTs referenced in the latest NCCN guidelines for rectal cancer were reviewed. Data from eligible trials were extracted. FI was calculated to assess the robustness of evidence across different treatment modalities. Sixty-seven RCTs (published: 1987-2022) involving 16,990 patients were analyzed. Most studies (58.2%) were conducted in Europe. Common treatment areas included metastatic liver disease (28.9%) and neoadjuvant chemotherapy (14.9%). Primary outcomes were disease-free survival and overall survival (OS) in 15 studies each (22.4%), local recurrence rates in 6 (9%), and tumor response in 5 (7.5%). The median FI was 9 (interquartile range [IQR] 2-20). Studies on surgical interventions had the highest median FI (21 [IQR 7-27]) followed by studies on neoadjuvant radiotherapy (19 [IQR 14-25]). Neoadjuvant immunotherapy studies had the lowest median FI of 0, indicating less robust evidence. Notably, surgical intervention studies showed the largest gap between FI and patients lost to follow-up (21 vs. 13.5), while neoadjuvant immunotherapy studies showed more patients lost to follow-up than the median FI (0 vs. 5), highlighting the need for stronger evidence. In conclusion, evidence supporting most treatments for rectal cancer in the NCCN guidelines is robust, although neoadjuvant immunotherapy requires further scrutiny due to its low FI. FI offers a nuanced perspective on the reliability of trial outcomes.