Pathologic Complete Response and Survival in Rectal Cancer: A Systematic Review and Meta-Analysis

Area of Science:

• Gastrointestinal Oncology
• Clinical Trial Methodology
• Biostatistics

Background:

• Pathologic complete response (pCR) is increasingly utilized as a surrogate endpoint in gastrointestinal oncology randomized clinical trials (RCTs).
• The US Food and Drug Administration has endorsed this approach, but its validity as a predictor of survival remains under investigation.
• This study addresses the need for further verification of pCR's surrogate status in rectal cancer.

Purpose of the Study:

• To evaluate the association between pathologic complete response (pCR) and survival outcomes (overall survival and disease-free survival) at the trial level.
• To analyze data from randomized clinical trials (RCTs) investigating neoadjuvant therapy for rectal cancer.
• To determine if pCR can reliably predict survival in this patient population.

Main Methods:

• A systematic review and meta-analysis of RCTs identified through PubMed, EMBASE, and Cochrane databases up to January 2024.
• Inclusion criteria focused on rectal cancer RCTs with neoadjuvant therapy, surgical resection, and reported data on pCR, overall survival (OS), and disease-free survival (DFS).
• Weighted linear regression was employed to assess the correlation between pCR and survival metrics, with risk of bias and certainty of evidence evaluated.

Main Results:

• Twenty-five RCTs comprising 11,882 patients were included in the meta-analysis.
• No significant trial-level correlation was found between pCR and overall survival (OS) (β = 0.37; P = .57).
• Similarly, pCR was not correlated with disease-free survival (DFS) (β = -0.84; P = .32), even after sensitivity analyses excluding high-risk studies.

Conclusions:

• This systematic review and meta-analysis found no trial-level association between pathologic complete response (pCR) and survival in rectal cancer patients treated with neoadjuvant therapy.
• The findings challenge the established use of pCR as a surrogate endpoint for survival in this context.
• Clinicians and researchers should exercise greater caution when interpreting and applying pCR as a surrogate for survival outcomes in rectal cancer clinical trials.