Phase II trial of organ preservation program using short-course radiation and folfoxiri for rectal cancer (SHORT-FOX).
Authors: Pollom Erqi L. , Shelton Andrew , Fisher George A. , Bien Jeffrey , King Daniel , Johnson Tyler Paul , Chen Christopher , Shaheen Shagufta , Chong Curtis Robert , Vitzthum Lucas , Kirilcuk Natalie , Morris Arden M. , Kin Cindy , Dawes Aaron , Sheth Vipul , Sundaram Vandana , Brown Eleanor , Chang Daniel Tandel 
Published: January 2022

TPS218

Background: Locally advanced rectal cancer is treated with preoperative chemoradiotherapy followed by total mesorectal excision (TME). While this trimodal approach achieves low rates of local recurrences, distant metastasis rates can exceed 25%. Total neoadjuvant therapy (TNT) has been shown in OPRA, RAPIDO, and PRODIGE23 to reduce risk of distant metastasis and improve rates of pathological complete response compared to standard preoperative chemoradiotherapy. Thus, TNT not only addresses distant disease, but gives opportunity to reduce locoregional morbidity through organ preservation. We propose a treatment approach that incorporates TNT with FOLFOXIRI and up-front short-course radiation with the goal of increasing clinical complete response (cCR) rates and thereby eligibility for organ preservation. Currently, clinical response following neoadjuvant therapy is best assessed by a multidisciplinary team and includes flexible endoscopy and MRI. Circulating tumor DNA (ctDNA) analysis can be used as a noninvasive method for tumor monitoring. Biomarker development is essential to better select patients for treatment de-escalation and monitor for recurrence in order not to jeopardize the excellent cure rates following standard of care therapy. Methods: This is a single-arm, open-label, non-randomized study of an organ preservation approach using short-course radiation followed by FOLFOXIRI for patients with > T2N0 or low T2N0, M0 rectal adenocarcinoma (NCT04380337). Patients undergo radiation (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by 8 cycles of FOLFOXIRI. Patients are assessed for response at 8 weeks following chemotherapy completion using pelvic MRI (MRI Tumor Regression Grading), flexible sigmoidoscopy, and digital rectal exam. Those who achieve a cCR can defer TME and be surveilled. The primary objective is to assess cCR, with the hypothesis that this approach will achieve higher cCR rates than historical controls (40 versus 20%). Secondary objectives include assessing toxicity, local regrowth rate, disease-free survival, colostomy-free survival, overall survival, and longitudinal health-related quality of life. ctDNA will be collected throughout treatment and surveillance, and correlative studies will assess the association between ctDNA levels and cCR, local regrowth, and disease-free survival. A Simon 2-stage design addressed our primary objective. Assuming a one-sided type 1 error of 0.1, power of 0.9, a null cCR of 0.2 versus an alternate cCR of 0.4, we plan to enroll 37 patients. The null hypothesis will be rejected if > = 11 patients have cCR. Seventeen patients have been enrolled and the trial is currently on hold for planned interim analysis for futility and safety. If < = 3 patients have cCR or if > = 7 patients have non-hematologic grade 4+ toxicity, the study will be stopped. Otherwise, we will continue to enroll 20 more patients. Clinical trial information: NCT04380337.