Smoking Status and Response to Total Neoadjuvant Therapy for Rectal Cancer: A National Cohort Study

Tobacco smoking is prevalent among patients with rectal cancer, yet its effect on pathologic response to total neoadjuvant therapy (TNT) remains unknown. This study evaluated the association between smoking status and pathologic response to TNT in locally advanced rectal cancer, using the neoadjuvant rectal (NAR) score and pathologic complete response (pCR) rate.

This retrospective cohort study used the National Cancer Database to identify adults diagnosed in 2023 with clinical stage Ⅱ-Ⅲ rectal adenocarcinoma who received TNT followed by proctectomy. Smoking status at diagnosis was categorized as never, current, or former. Primary outcomes were favorable NAR score (< 8) and pCR (ypT0N0).

Among 1767 patients, 49.7% were never smokers, 30.5% former, and 19.8% current smokers. Rates of favorable NAR score and pCR were highest among never smokers (33.4 and 21.7%), intermediate among former smokers (28.8 and 19.9%), and lowest among current smokers (25.5 and 16.3%). On multivariable analysis, current smoking was associated with lower odds of favorable NAR score than was never smoking (odds ratio 0.59; 95% confidence interval 0.40-0.86). A similar trend was seen for pCR, though this did not reach statistical significance (odds ratio 0.58; 95% confidence interval 0.34-1.00). Former smoking was not significantly different from never smoking in terms of a favorable NAR score or pCR.

Current smoking status was independently associated with lower rates of response to TNT in locally advanced rectal cancer, whereas former smoking was not when compared with never smoking. These findings identify active tobacco exposure as a potential modifiable risk factor.