A Retrospective Analysis Comparing Outcomes Following Total Neoadjuvant Therapy and Following Neoadjuvant Chemoradiation Therapy in Patients with Locally Advanced Rectal Cancer

Abstract

To compare outcomes following Total Neoadjuvant Therapy (TNT) and following neoadjuvant chemoradiation therapy (nCRT) with or without adjuvant chemotherapy in patients with locally advanced rectal adenocarcinoma (LARC), defined as T3/4 or node positive disease, using the National Cancer Database. We identified LARC patients diagnosed between 2004 and 2015 who received chemotherapy and radiotherapy (RT) preoperatively and definitive surgery within one year of RT. Patients were considered to have received TNT if multiagent chemotherapy was given ≥2 months before RT and no adjuvant chemotherapy was given. Patients were considered to have received neoadjuvant chemoradiation therapy (nCRT) if preoperative RT and chemotherapy were started within 2 weeks from each other. A 2:1 propensity match was performed to account for selection bias, adjusting for age, gender, diagnosis year, race, comorbidity score, cT, cN, grade, facility type, urban status, insurance, and income. Kaplan-Meier survival analysis with log-rank test was used to compare overall survival (OS). Multivariable Cox regression modeling was performed to determine factors associated with OS. Multivariable logistic regression modeling was used to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM). After propensity matching, 372 patients receiving TNT were paired with 707 patients receiving nCRT. In the matched cohort, the median follow-up time was 31.0 months for TNT and 33.7 months for nCRT. Median time to surgery was 8.4 months (IQR: 7.2 to 9.2 months) for TNT compared to 4.4 months (IQR: 3.9 to 5.2 months) for nCRT. OS for TNT was similar to nCRT in both the matched (log-rank p=0.15) and the unmatched cohort (log-rank p=0.85). The 3- and 5-year OS rates for TNT vs. nCRT in the matched cohort were 88.5% vs. 88.9% and 73.6% vs. 78.5%, respectively (p>0.2 for both years). The multivariable analysis showed no significant difference in OS between TNT and nCRT (matched cohort: HR=1.21, 95%CI 0.87-1.69, p=0.25; unmatched cohort: HR=1.17, 95%CI: 0.90-1.51, p=0.24). Sensitivity analysis with 10:1 propensity matching for improved statistical power showed similar OS between TNT and nCRT (HR=1.16, 95% CI: 0.88-1.53, p=0.28). The pCR and negative CRM rates with TNT and nCRT were 16.9% vs. 13.1% (p=0.12) and 95.3% vs. 93.1% (p=0.30), respectively. TNT was not found to be significantly associated with pCR (OR=1.36, p=0.13) or negative CRM (OR=1.77, p=0.19) in multivariable logistic regression modeling. With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.