The Association of Time Interval between Surgery and Neoadjuvant Chemoradiation Therapy with pCR and Overall Survival for Locally Advanced Rectal Adenocarcinoma

Abstract

To determine the best time interval between neoadjuvant radiation therapy (RT) and surgery that is associated with the highest rate of complete pathological response (pCR) and evaluate its impact on overall survival (OS) for locally advanced rectal adenocarcinoma. We hypothesize that the longer interval the higher pCR and a higher pCR is associated with a higher OS. The National Cancer Database (NCDB) was used to extract data on patients diagnosed with stage II and III adenocarcinoma of the anus, rectum, or rectosigmoid between 2004-2019 and who had ≤ 24 weeks' time interval between neoadjuvant RT and surgery. Multivariable logistic regression analysis was used to determine factors associated with achieving pCR and odds ratios (OR) were reported as a measure of association between the covariates of interest and the outcome of achieving pCR. Multivariable Cox regression analysis was conducted to estimate hazard ratios (HR) and their associated 95% confidence intervals. The multivariable analyses were adjusted for age at diagnosis, sex, race, income, education, facility type, insurance status, comorbidity score, place of living, chemotherapy's sequence with surgery and RT, and year of diagnosis. Among 28,656 patients, 4,455 (15.6%) achieved pCR. In the multivariable logistic regression analysis, patients who received surgery between 5-8 weeks, 9-12 weeks, 13-16 weeks, 17-20 weeks, or 21-24 weeks after the completion of RT were more likely to achieve pCR compared to < = 4 weeks (ORs: 1.63, 2.16, 1.82, 1.73, 1.75, respectively, p<0.001 for all) with OR being the highest for the 9-12 weeks interval. In the multivariable Cox regression analysis, patients who achieved pCR had comparable OS regardless of when the surgery took place between < = 4 to 24 weeks after completing RT compared to < = 4 weeks after RT. Among patients who did not achieve pCR, OS was only similar if surgery was received between 5-8 weeks or 9-12 weeks after RT compared to < = 4 weeks after RT (HR: 0.90, p = 0.19 and HR: 1.02, p = 0.78 respectively). However, surgery between 13-16 weeks after RT, 71-20 weeks or 21-24 weeks after RT was associated with worse OS compared to < = 4 weeks after RT (HRs: 1.30, 1.67, 1.79, respectively, p<0.01). In the current study, we found that among patients who achieve pCR, OS does not depend on the time interval between the completion of RT and receipt of surgery, while among patients who do not achieve pCR, delaying surgery >12 weeks is associated with reduced OS. An interval of 9-12 weeks was the best optimal time as it was associated with the highest OR of achieving pCR and better OS compared to other interval times.