Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer (NORAD01)

Non Inferiority Multicenter Phase III Randomized Trial Comparing Preoperative Chemotherapy Only to Chemotherapy Followed by Chemoradiotherapy for Locally Advanced Resectable Rectal Cancer (Intergroup FRENCH-GRECCAR- PRODIGE)

This study is a non-inferiority phase III randomised trial comparing preoperative chemotherapy alone (modified FOLFIRINOX) to chemotherapy followed by chemoradiotherapy in patients with primary resectable locally advanced rectal cancer. The primary endpoint of the study is 3-year progression free survival. Expected 3 year PFS rate in the preoperative chemotherapy followed by chemoradiotherapy arm is 75%. This hazard rate, in an exponential survival model, corresponds to a decrease in the 3-year PFS rate on the preoperative chemotherapy arm to 67%. The study will randomize 540 patients (270 in the chemotherapy group and 270 in the chemoradiotherapy group) in 42 french academic centers.

This study is a national, multicenter, open-label randomized, 2-arm phase III non-inferiority trial. Patients with mid or low LARC (cT3N0 or cT1-T3N+ with CRM > 2 mm on pretreatment MRI) will be randomized to two arms of treatment: one experimental arm with systemic FOLFIRINOX chemotherapy for 3 months and one control arm with systemic FOLFIRINOX chemotherapy for 3 months followed by conventional standardized radiochemotherapy (intensified-modulated radiotherapy 50Gy + capecitabine). The choice of FOLFIRINOX for preoperative chemotherapy is based on recent data regarding its safety and efficacy rectal cancer with or without metastatic disease. Since the annual world meeting of ASCO 2020, a new standard of treatment has been adopted using the combination of chemotherapy followed by radiochemotherapy that has been show to improve disease free survival in phase III controlled randomized trial (Conroy et al, J Clin Oncol 38: 2020 (suppl; abstr 4007). All patients will have reassessment MRI after preoperative treatment and before surgery. Objectives and study endpoints - primary endpoint : 3-year progression-free survival (PFS) from the time to randomization. In this trial, a modified definition of PFS will be used for the primary endpoint. The rationale for using this modified definition of PFS is to better assess time to failure of the whole treatment strategy (preoperative treatment and surgery). Progression will be assessed as follows: progression during preoperative treatment and before surgery: circumferential resection margin ≤ 2mm at MRI reeassessemnt and diagnosis of any new distant lesion whatever the site (liver, lung, peritoneum, adrenal) are considered as progression events. progression after surgery: recurrence/progression after surgery or death, whatever comes first. Secondary endpoints: treatment related toxicity, treatment compliance, R0 resection rate, sphincter saving surgery rate, postoperative morbidity and mortality rates, loco-regional recurrence free survival, overall survival, bowel and sexual functions at diagnosis, quality of life, radiologic and pathologic response after preoperative treatment. Statistical analysis A sample size of 518 patients, based on an expected accrual duration of 36 months, 60 months follow-up, and an expected 3 year PFS rate in the preoperative chemotherapy followed by chemoradiotherapy arm of 75%, is expected to provide 239 PFS events required to provide 80% power to declare non-inferiority of the preoperative chemotherapy arm when the true hazard ratio between arms is 1.0 (H1). This design has a global type one-error rate of 0.05 if the true hazard ratio between arms is 1.39 (H0). This hazard rate, in an exponential survival model, corresponds to a decrease in the 3-year PFS rate on the preoperative chemotherapy arm to 67%. By considering a rate of 4% for not informative or lost to follow-up patients the total number of patients to be included in this trial was 518*100/96 = 540 patients. Ancillary studies Pronostic value of circulating cancer cells before and after preoperative treatment and after surgery in patients undergoing surgery for rectal cancer after chemotherapy or radiochemotherapy will be evaluated. After assessment of prognostic value of each rate on survival, recurrence and response to treatment, evaluation of prognostic impact of variation of the rate during differents phases of treatment will be carried out.

To demonstrate the non inferiority of preoperative modified FOLFIRINOX chemotherapy compared to radiochemotherapy in primary resectable locally advanced rectal cancer

Experimental : preoperative chemotherapy: Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively.

Active comparator: preoperative chemotherapy : Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively FOLLOWED BY Preoperative radiochemotherapy with concurrent capecitabine 825 mg/m2/12h 5 days/week and intensity modulated radiation therapy using a simultaneous integrated boost technique with 45 Gy in 25 fractions in pelvic volume and 50 Gy in 25 fractions to the tumor

Arm A : Experimental Intervention Type : Drug Intervention Name : Modified FOLFIRINOX (experimental arm) Intervention Description : preoperative chemotherapy: Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively.

Arm B: Active comparator Intervention Name : modified FOLFIRINOX followed by preoperative standardized radiochemotherapy (control arm) Intervention Description : preoperative chemotherapy: Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively.followed by preoperative radiochemotherapy with concurrent capecitabine 825 mg/m2/12h 5 days/week and intensity modulated radiation therapy using a simultaneous integrated boost technique with 45 Gy in 25 fractions in pelvic volume and 50 Gy in 25 fractions to the tumor.

Radiologic response on post-treatment MRI based on tumor size reduction and tumor regression grade (ymrTRG)

Pathologic response after chemoradiotherapy: rate of major pathologic response base on Rodel Tumor Regression Grade

Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)

Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)

Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)

Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)

Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)

Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)

Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)

Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)

Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)

Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)

Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)

Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)

Inclusion Criteria: Histologically proven middle or low rectal carcinoma, ≤ 10 cm from the anal verge on MRI (sagittal slide) cT3N0 and/or cT1-T3N+ on pretreatment imaging work up (pelvic contrast enhanced MRI and/or endorectal ultrasound), Pretreatment predictive circumferential margin > 2mm on pretreatment imaging work up (pelvic contrast enhanced MRI) Patients must be 18 years old or older A World Health Organization (WHO/ECOG) performance status of 0 or 1 Informed consent signed Patients of childbearing / reproductive potential should use adequate birth control measures during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Exclusion Criteria: Rectal tumor > 10 cm from the anal verge on MRI (sagittal slide) cT4 tumor on pretreatment imaging work up (pelvic contrast enhanced MRI and/or endorectal ultrasound) or involvement of external sphincter Circumferential margin ≤ 2 mm on pretreatment imaging work up (pelvic contrast enhanced MRI) Metastatic disease Prior pelvic irradiation or any contraindication to pelvic irradiation Contraindication to oxaliplatin or irinotecan or 5FU based chemotherapy Concomitant treatment with warfarin is contraindicated and warafarin must be replaced whenever possible to allow for inclusion. Recent or concomitant treatment with brivudine is contraindicated contraindications to 5-FU: complete and permanent insufficiency in dihydropyrimidine dehydrogenase, bone marrow insufficiency, chronic and severe infection contraindication to irinotecan : inflammatory bowel disease, bilirubin serum level > 3 times the upper limit of the normal rate, severe bone marrow insufficiency, WHO/ECOG performence status > 2, Concomitant treatment with millepertuis. contraindication to oxaliplatin : *bone marrow insufficiency before treatment initiation (neutrophil count <2x109/L and/or platelet count <100x109/L), peripheral neuropathy with permanent invalidity before treatment initiation severe renal insufficiency (Creatinin clearance <30 ml/min) contraindications to folinic acid : Biermer anemia and other anemia related to B12 vitamin insufficiency contraindications to capecitabin : severe renal insufficiency (Creatinin clearance <30 ml/min), complete and permanent insufficiency in dihydropyrimidine dehydrogenase live attenuated vaccine should not be used during and 6 months after preoperative treatment. Previous colorectal cancer Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial protected adults Pregnancy or breastfeeding Patient with no national health or universal plan affiliation coverage.

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Brouquet A, Bachet JB, Huguet F, Karoui M, Artru P, Sabbagh C, Lefevre JH, Vernerey D, Mariette C, Vicaut E, Benoist S; on behalf the FRENCH , GRECCAR, PRODIGE study groups. NORAD01-GRECCAR16 multicenter phase III non-inferiority randomized trial comparing preoperative modified FOLFIRINOX without irradiation to radiochemotherapy for resectable locally advanced rectal cancer (intergroup FRENCH-GRECCAR- PRODIGE trial). BMC Cancer. 2020 May 29;20(1):485. doi: 10.1186/s12885-020-06968-1.