Curative chemoradiation for low rectal cancer: Primary clinical outcomes from a multicenter phase II trial.
Authors: Jensen Lars Henrik , Risum Signe , Nielsen Jesper Dan , Mynster Tommie , Ploeen John , Rahr Hans B. , Havelund Birgitte Mayland , Appelt Ane L , Lindebjerg Jan , Rafaelsen Soeren Rafael , Jakobsen Anders , Poulsen Laurids 
Published: June 2022

LBA3514 Background: Organ preserving treatment strategies based on chemoradiotherapy may spare rectal cancer patients of major surgery and stoma. We suggest substantially improved tumor control by increasing the radiotherapy dose, without significant increase in the rate of late effects. We designed a prospective phase II trial to test high-dose radiotherapy of low rectal cancer for organ preservation in a multicenter setting. Methods: We enrolled patients with localized T1-3 N0-1 M0 rectal cancer within 6 cm from the anal verge and in performance status 0-2. Any N1-nodes had to be at the level of the tumor and included in the primary tumor-volume. Radiotherapy consisted of 62 Gy to the tumor and 50.4 Gy to the regional lymph nodes, delivered in 28 fractions using intensity modulated radiation therapy and daily image guidance. Capecitabine 825 mg/m2 BID. Patients with clinical complete response (cCR) 6–12 weeks after end of treatment were allocated to follow-up. Surgery was offered only in case of residual cancer or later re-growth. The primary endpoint was the proportion of patients with locoregional tumor control after two years by chemoradiation alone. Secondary endpoints included long-term side effects (CTCAE grading), cCR, rate of distant metastases, and overall survival. Results: Three Danish centers enrolled 107 patients between 2015 and 2019. Baseline classifications were T1/T2/T3 and N1 in 15%/54%/31% and 29%, respectively. The median age was 71 years and 64% were male. 92 (86.0%) had cCR and were allocated to observation. Four patients drew consent or died leaving 103 observed for at least 2 years. 23 had regrowth after cCR, five of whom had organ preserving transanal endoscopic microsurgery, 15 other curative surgery, and three palliation. 63 had no locoregional regrowth. Thus 61% (63/103) of patients with 2 years of follow-up had locoregional tumor control with chemoradiation alone. The actuarial estimate of locoregional control at 2 years from start of observation was 73.8% (95%CI 63.2-81.8). Calculated from time of enrollment, metastasis-free and overall survival at 30 months was 85.4% (95%CI 76.5-91.1) and 94.8% (95%CI 87.8-97.8). In the 63 patients with complete response at 2 years, ‘Low Anterior Resection Syndrome-score’ was None=37%, Minor=28%, and Major=35%. The most severe toxicity was erectile dysfunction grade 3 (n=3), grade 2 (n=4), grade 1 (n=6), and grade 0 (n=26). Grade 2 diarrhea, constipation, fecal incontinence, rectal bleeding and decreased libido were each reported in one case, while urinary frequency grade 2 was seen in four patients. Conclusions: The vast majority of patients with low rectal cancer can be cured by modern radiotherapy 62 Gy in 28 fractions with excellent patient-reported outcomes, toxicity, tumor control, and survival. The treatment is feasible in a multicenter setting. We suggest this approach as a standard of care option. Clinical trial information: NCT02438839.