Organ preservation and total neoadjuvant therapy for rectal cancer: Investigating long course chemoradiation versus short course radiation therapy.
Authors: Romesser Paul Bernard , Park Byung Kwan , Pappou Emmanouil , Nemirovsky David , Alvarez Janet , Omer Dana Mohamed Rashid , Sarkar Reith , Verheij Floris S , Reyngold Marsha , Wu Abraham Jing-Ching , Hajj Carla , Weiser Martin R. , Roth O'Brien Diana A , Paty Philip , Cercek Andrea , Saltz Leonard B. , Crane Christopher H. , Gonen Mithat , Garcia-Aguilar Julio , Smith Jesse Joshua 
Published: June 2023

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Background: The efficacy of long course chemoradiation (LCRT) vs. short course radiation therapy (SCRT) relative to organ preservation (OP) in rectal cancer (RC) is unknown. We compared OP rates between SCRT and LCRT total neoadjuvant therapy (TNT) strategies. Methods: During the COVID-19 pandemic we established an institutional SCRT mandate with no exceptions. For comparison, we identified RC patients treated with LCRT immediately before and after the mandate period. After completion of TNT, patients were restaged by clinical exam, endoscopy, and MRI. A watch and wait (WW) approach was recommended for patients with a clinical complete response (cCR), defined by the MSK regression schema. Total mesorectal excision (TME) was recommended for non-cCR patients. OP was defined as remaining TME-free with no evidence of disease in the pelvis. We performed survival analysis for: local regrowth rate, OP, disease-free survival (DFS), and overall survival (OS). The validated low anterior resection syndrome (LARS) questionnaire (LARS-Q) was used to determine percentage of patients with major LARS. Results: We identified 332 consecutive patients with non-metastatic rectal adenocarcinoma treated with TNT (Jan. 2018-Jan. 2021). Patient and tumor characteristics were similar in the LCRT (n = 256) and SCRT (n = 76) cohorts. No significant differences in high-risk features were noted. Most patients had clinical stage III disease (82% in LCRT vs. 83% in SCRT). Induction chemotherapy followed by consolidative radiation was the most common treatment order (78% (LCRT) vs. 70% (SCRT)). The median interval from end of TNT to clinical restaging was 8 weeks (LCRT) and 9 weeks (SCRT). The cCR rate was 46% in both cohorts. Among patients with a cCR, the likelihood of WW management was similar (98% (LCRT) vs. 94% (SCRT)). From start of TNT, the median follow-up was 32 and 28 months respectively for LCRT and SCRT. The 2-year OS (95% vs. 92%), DFS (78% vs 70%), and distant recurrence (20% vs. 21%) rates were similar. Among all patients, the 2-year OP rate was 40% (95% CI 35-47%) for LCRT and 29% (95% CI 20-42%) with SCRT. In those patients managed by WW, the 2-year local regrowth rate was 20% (95% CI 12-27%) with LCRT vs. 36% (95% CI 16-52%) with SCRT. Percentage of patients reporting major LARS symptoms were similar among WW patients post TNT: baseline (23% (LCRT) vs. 18% (SCRT)), 6-months (41% (LCRT) vs. 42% (SCRT)), and 12-months (25% (LCRT) vs. 15% (SCRT)). Conclusions: In this nonrandomized comparison, while cCR rates were similar, we observed a numerically higher local regrowth rate with SCRT-TNT than with LCRT-TNT. Rate of major-LARS symptoms were similar with LCRT-TNT than with SCRT-TNT. The ongoing ACO/ARO/AIO-18.1 trial, hypothesizing that LCRT-TNT will increase OP rates relative to SCRT-TNT, will definitively address this question.