Evaluation of the robustness of randomized controlled trials for the treatment modalities of esophageal cancer using the fragility index – a systematic review

Background: Esophageal cancer remains a significant global health challenge. Several treatment modalities were explored in randomized controlled trials (RCTs) in recent decades. This study evaluates the robustness of RCTs focusing on esophageal cancer treatment using the fragility index (FI) and reverse fragility index (RFI). Methods: A systematic review of RCTs studying different treatment modalities for esophageal cancer from 2000 to 2023 was conducted. The FI and RFI were utilized to gauge the robustness of statistically significant and non-significant outcomes, respectively. The FI represents the minimal number of patient outcomes that would need to alter to overturn a trial’s statistical significance, while RFI indicates the minimal changes required to achieve significance in non-significant results. Results: Out of 4028 studies retrieved, 21 RCTs were included for final analysis. The studies spanned 2001 to 2023 with a mean followup of 66 months (range, 29–108 months) and median number of patients of 194 (range, 45–802). The most common treatment modalities examined in these studies were neoadjuvant chemoradiotherapy (n= 7, 33.3%), neoadjuvant chemotherapy (n= 4, 19.0%), and neoadjuvant immunotherapy (n= 2, 9.5%). Only 5 studies (23.8%) had a statistically significant primary outcome result with a median FI of 6 (IQR, 2.5–8.5). Non-significant primary outcomes were seen in 16 studies (76.2%) with a median RFI of 4 (IQR 1–11) and lost to followup of 0 (IQR 0–4). In the study with the highest FI (10), the FI was lower than the number of patients lost to followup (13). Conclusion: Our findings demonstrate that most RCTs on esophageal cancer treatments did not report significant primary outcomes. The few studies that reported significant results had a low fragility index, suggesting a vulnerability in their findings.