Management of locally advanced rectal cancer: Clinical outcomes and use of ctDNA in a single-institution study

Introduction Improved rates of complete clinical response (cCR) after total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) have resulted in widespread utilization. However, regrowth occurs, requiring strict surveillance, which may be improved with circulating tumor DNA (ctDNA). This study aimed to describe a single institution's oncologic outcomes and experience using ctDNA in LARC patients. Methods Patients diagnosed with LARC from 2021-2024 were recommended TNT if they had cT2/3N+ or cT4Nany, threatened circumferential resection margin and adequate functional status. TNT included induction or consolidation chemotherapy with FOLFOX or CAPOX with short- or long-course chemoradiation. Outcomes included clinical response, recurrence-free survival (RFS), duration of ctDNA negativity, and recurrence lead time. Patient demographics, tumor characteristics, and laboratory results including ctDNA were analyzed. Results Of 226 patients, 127 received TNT. Mean age was 59.4 years; 59.3% were male, and 74.8% of patients were white. 17.3% had stage 2 disease, 60.6% stage 3, and 7.1% stage 4. Among the patients who completed TNT (n=123), 43.9% demonstrated a complete clinical response (cCR) or near complete clinical response (nCR), and 49.6% incomplete response (IR). RFS did not differ significantly between the TNT (watch and wait) group and patients who received neoadjuvant therapy and surgery (p = 0.46; median follow-up > 17 months). Post-operative ctDNA was negative in 96.2% (50/52) of surgical patients. Among 19 TNT watch-and-wait patients with available ctDNA and without recurrence, 100% of their ctDNA testing has remained negative. Four patients were noted to convert from ctDNA negative to positive after definitive treatment; 3 experienced distant recurrence and 1 local regrowth. Discussion TNT enables organ preservation without compromising oncologic outcomes. These data demonstrate feasibility of incorporating ctDNA into surveillance, although prospective data are needed.