Neoadjuvant Radiotherapy Improves OS With Trade-Off in Rectal Cancer

Neoadjuvant radiotherapy prior to surgery was associated with a 3-year OS rate of 88.5% in patients with locally advanced rectal cancer.

Neoadjuvant radiotherapy followed by surgery improved oncological outcomes, although it also excessively diverted stoma nonreversal, in patients with locally advanced rectal cancer, according to results from a Taiwanese cohort study of nationwide registries published in JAMA Network.

The 3-year overall survival (OS) rate was 88.5% with neoadjuvant radiotherapy compared with 85.2% with up-front surgery (HR, 0.74; 95% CI, 0.59-0.92); the local recurrence rates were 5.7% vs 6.6%, respectively, which was deemed not to be a significant difference (HR, 0.78; 95% CI, 0.55-1.11).

Approximately half of all patients who received surgery (49.4%; n = 1875) underwent diverting stoma creation. A total of 65.5% of patients who received neoadjuvant radiotherapy followed by surgery had diverting stoma creation compared with 41.0% of patients who received up-front surgery (risk ratio, 1.60; 95% CI, 1.46-1.75).

Furthermore, 71.6% of stomas were closed within 1 year, although the higher risk for unreversed stomas after neoadjuvant radiotherapy before surgery remained. Stomas were unreversed at 3 years in 26.6% of patients, and 13.1% of all patients had a permanent diverting stoma. More permanent diverting stomas were observed with neoadjuvant radiotherapy (20.6%) vs up-front surgery (11.1%; risk ratio, 1.91; 95% CI, 1.62-2.25).

Pathological analysis showed that neoadjuvant radiotherapy was associated with the downstaging of locally advanced rectal cancer, and that the involved surgical margin rate difference between neoadjuvant radiotherapy (3.1%) and up-front surgery (4.9%) was not significant (standardized mean difference, 0.09). Deep vein thrombosis was more frequent in patients who received neoadjuvant radiotherapy; the incidences of other complications were comparable between the groups.

A subgroup analysis based on tumor height indicated that neoadjuvant radiotherapy was not associated with significantly increased OS vs up-front surgery in middle rectal cancer (HR, 0.70; 95% CI, 0.48-1.02), was associated with significantly increased OS (HR, 0.66; 95% CI, 0.46-0.96) and reduced local recurrence (HR, 0.53; 95% CI, 0.30-0.95) in lower rectal cancer, and was not associated with improved OS (HR, 1.54; 95% CI, 0.82-2.90) or local recurrence (HR, 1.08; 95% CI, 0.23-5.00) in upper rectal cancer.

Across the varying tumor heights, neoadjuvant radiotherapy before surgery was associated with higher rates of diverting stomas created; however, in both groups, stomas were more likely to be created for lower-lying tumors. The risk of diverting stoma creation with neoadjuvant radiotherapy vs up-front surgery was highest in upper rectal cancer (risk ratio, 3.61; 95% CI, 2.03-6.43) and lowest in lower rectal cancer (risk ratio, 1.31; 95% CI, 1.17-1.47). The risk of permanent diverting stomas at 3 years was highest in upper rectal cancer (risk ratio, 3.54; 95% CI, 1.44-8.69) and lowest in lower rectal cancer (risk ratio, 1.62; 95% CI, 1.33-1.98).

“In this cohort study of nationwide registries in Taiwan, [neoadjuvant radiotherapy] prior to surgery was associated with improved outcomes for patients with resectable [locally advanced rectal cancer] overall compared with up-front surgery,” wrote lead study author Po-Chuan Chen, MD, of the Department of Surgery at National Cheng Kung University Hospital in the College of Medicine at National Cheng Kung University in Tainan, Taiwan, with coauthors. “However, these benefits came at the cost of increased risk of diverting stoma creation and nonreversal. Possibly reflecting quality improvement in surgery in recent years, the oncological benefits of [neoadjuvant radiotherapy] were observed only for middle or lower rectal cancer. Thus, for upper rectal cancer, the trade-off between using [neoadjuvant radiotherapy] to pursue better oncological outcomes and creating diverting stomas to lower the risk of symptomatic leak may not be justified.”

A total of 3792 patients were included in this emulated target trial, of whom 1308 patients received neoadjuvant radiotherapy prior to surgery, and 2484 patients received up-front surgery. Long-course radiotherapy was given to 82.3% of those who received neoadjuvant radiotherapy, and concurrent 5-fluouracil-based chemotherapy was received by 78.6%. Notably, patients who received neoadjuvant radiotherapy were more likely to receive 5-fluouracil-based adjuvant chemotherapy and less likely to receive adjuvant radiotherapy.

Before propensity score fine stratification, the median age of patients was 62.0 years (IQR, 53.0-71.0) in the neoadjuvant radiotherapy group vs 65.0 years (IQR, 56.0-74.0) in the up-front surgery group. Those in the neoadjuvant radiotherapy group were more likely to be male (72.1% vs 61.1%), have advanced N-stage disease (cN2; 38.3% vs 18.9%), have lower rectal cancer (56.3% vs 22.0%), receive treatment at tertiary referral centers (52.9% vs 31.5%), and undergo laparoscopic/robotic surgery (57.6% vs 48.9%).

Data were collected from the Taiwan Cancer Registry Database and the Taiwan National Health Insurance Database. Included patients were 20 years or older and had clinically resectable locally advanced rectal cancer between January 1, 2014, and December 31, 2017.

Excluded patients included those who had nonadenocarcinoma pathologies, lacked information about surgery, had treatment initiated more than 6 weeks after diagnosis, did not undergo curative resection, or underwent stoma creation before treatment initiation.

The primary end points of interest were OS and local recurrence; the secondary end point was intraoperative diverting stoma outcomes.

Reference

Chen PC, Yang AS, Fichera A, et al. Neoadjuvant radiotherapy vs up-front surgery for resectable locally advanced rectal cancer. JAMA Netw Open. 2025;8(5):e259049. doi:10.1001/jamanetworkopen.2025.9049