Timing of Surgery and Pathologic Complete Response (pCR) after Completing Total Neoadjuvant Therapy for Rectal Adenocarcinoma: A Retrospective Study of the National Cancer Database

Abstract

Total neoadjuvant therapy (TNT) is a treatment strategy for rectal cancer that includes a course of multiagent chemotherapy and a separate course of radiation +/- concurrent chemotherapy before definitive surgery. The use of TNT has increased in recent years and carries the potential for improved sphincter preservation and a significant risk reduction of locoregional recurrence. However, the influence of rest period from end of radiation to surgery after TNT is unclear. The objective of this study was to evaluate the relationship between rest period and pCR using data from the National Cancer Database. We hypothesized that longer duration of rest period before surgery will be positively associated with pCR. Patients aged 18 years and older diagnosed with primary rectal cancer between 2016 and 2020, who underwent an NCCN-recommended TNT regimen followed by definitive surgery at a Commission on Cancer-accredited facility were retrospectively analyzed in the current study. We included 5,997 patients who met the following inclusion criteria: clinical stage T2 and above, any N stage, M0, adenocarcinoma histology, and not receiving any adjuvant therapy. Logistic regression methods were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between duration of rest period and pCR. Restricted cubic splines were used to evaluate potential non-linear relationship between duration of rest period and pCR. The median age of the study sample was 57 years old (interquartile range: 49 - 65), with majority of them being males (62.3%) and reporting Non-Hispanic White race and ethnicity (75.5%). The overall pCR rate was 18.6%. The majority received long-course radiation (76.7%) and induction chemotherapy (86.3%). In multivariable adjusted models, there was a non-linear relationship between duration of rest period and pCR (p = 0.036). Rest periods of 8-24 weeks were significantly associated with elevated odds of pCR with the odds highest at 14 weeks (OR = 2.86, 95% CI: 1.20 - 6.84) when compared to rest periods of less than a week. There was no difference in pCR between long-course vs. short course radiation and no difference between those who received induction chemotherapy vs. consolidative chemotherapy. Although the rest period is inherently longer when radiation therapy precedes consolidative chemotherapy, the order of chemotherapy to radiation itself did not impact pCR but rather the duration of rest period. These data demonstrate an ideal window for surgery to achieve pCR in rectal cancer in the TNT era and the need for further prospective investigations of optimal rest period before surgery to achieve maximal pCR with homogenous TNT treatment regimens.