Total Neoadjuvant Therapy Treatment Sequence and its Impact on Pathologic Complete Response and Survival in Patients with Locally Advanced Rectal Cancer

Abstract

Several recent studies have suggested that total neoadjuvant therapy (TNT) provides improved pathologic response and disease-free survival over neoadjuvant chemoradiation. However, the timing of the radiation as a part of the total neoadjuvant paradigm is unclear. In some studies radiation has been used first and others it has been used after chemotherapy. This study compares pathologic complete response (pCR) and survival patterns with TNT using upfront chemotherapy followed by chemoradiation (C-CRT) versus upfront chemoradiation followed by chemotherapy (CRT-C) in patients with locally advanced rectal cancer using the National Cancer Database.Patients with cT3/4 or node positive rectal cancer, diagnosed between 2004-2017 were included. TNT with chemotherapy first was defined as chemotherapy given at least two months before concurrent chemoradiotherapy followed by definitive surgery. CRT-C was defined as chemotherapy and radiation starting within 14 days of each other, followed by chemotherapy, followed by definitive surgery four to six months later. Minimum follow up was 6 months, in order to account for immortal time bias. Multivariable logistic regression was performed to assess whether upfront chemotherapy followed by chemoradiation versus upfront chemoradiation followed by chemotherapy was significantly associated with pCR, defined as ypT0N0. Overall survival (OS) was analyzed via Kaplan-Meier method with the log-rank test. Multivariable Cox regression analysis was used to assess the impact of covariates on OS.There were 9,393 TNT cases identified. Of these, 1522(16.2%) received C-CRT and 7871(83.8%) received CRT-C. The pCR was 12.2% in both groups. On multivariable logistic regression analyses, there was no difference in pCR based on the timing of the radiation (OR 0.987, 95% CI 0.824-1.183, P = .89). Kaplan-Meier analysis revealed that the 5-year OS rates for TNT was superior for C-CRT over CRT-C, with 5-year OS of 66.5% vs. 65.9% (P = 0•020). However, on multivariable Cox regression, there was no significant difference in OS between C-CRT and CRT-C (HR = 0.981, 95% CI 0.864-1.115, P = 0•772).In this large hospital-based study, most patients receiving TNT received chemoradiation upfront. There were no differences in pCR or overall survival based on the timing of the radiation treatments.