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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.

Chemotherapy

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.

Radiochemotherapy

Stéphane BENOIST, MD,PHD

Antoine BROUQUET, MD,PHD

Stephane BENOIST, PhD

Antoine BROUQUET, PhD

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

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

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)

Acute and late treatment related toxicity: the rates of treatment related toxicity grade II or more

Late treatment related toxicity: the rates of treatment related toxicity grade II or more

The rate of patients that receive full dose treatment

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

Rate of complete resection with safe \> 1mm circumferential and longitudinal margin

3-grades Quirke scoring system of the quality of mesorectal excision

A count of number of lymph nodes harvested

The rate of surgery with intestinal continuity and anal sphincter preservation

Postoperative morbidity: 30 day or in-hospital postoperative morbidity rates

Postoperative mortality: 30 day or in-hospital postoperative mortality rates

Pathologic response on Rodel Tumor Regression Grade

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

Loco-regional recurrence free survival: 3-year locoregional recurrence free survival rates

Uncontrolled local recurrence: 3-year uncontrolled local recurrence free survival rates

Overall survival: 3 year overall survival rates

Overall survival: 5 year overall survival rates

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)

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)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer	NCT03875781	Rectal Cancer Advanced Cancer	Chemotherapy Radiochemothera...	18 Years -	Assistance Publique - Hôpitaux de Paris
Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer	NCT03875781	Rectal Cancer Advanced Cancer	Chemotherapy Radiochemothera...	18 Years -	Assistance Publique - Hôpitaux de Paris
Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer	NCT03875781	Rectal Cancer Advanced Cancer	Chemotherapy Radiochemothera...	18 Years -	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for folfirinox,

Every month we try and update this database with for folfirinox, cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for folfirinox,

Every month we try and update this database with for folfirinox, cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for folfirinox, cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.