Rectal CancerPhase 3NORAD01NCT03875781
Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer
A Phase 3 study testing Chemotherapy and Radiochemotherapy in people with Rectal Cancer and Advanced Cancer, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rectal Cancer, Advanced Cancer
- What is being tested?
- Chemotherapy and Radiochemotherapy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 540 participants
- Where
- 1 siteFrance
- Study dates
- 5 Jun 2019to 5 Dec 2026
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 23Show fewer
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
France1 site, 1 recruiting
- Recruiting
BENOIST
Le Kremlin-Bicêtre, Île-de-France Region, 94275
Stephane BENOIST, PhD, +33 1 45 21 34 72, stephane.benoist@aphp.fr
Antoine BROUQUET, PhD, +33 1 45 21 34 70, antoine.brouquet@aphp.fr
About this study
Official title: 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.
Read the detailed description
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.
- Conditions
- Rectal Cancer, Advanced Cancer
- Being tested
- Chemotherapy, Radiochemotherapy
- Keywords
- Rectal cancer, FOLFIRINOX,, chemotherapy, radiochemotherapy, surgery
- Medical subject headings
- Rectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ChemotherapyDrug
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.
RadiochemotherapyDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| A: Modified Folfirinox | Experimental | 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. Receives: Drug: Chemotherapy |
| B: Modified Folfirinox followed by Radiochemotherapy | Active comparator | 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 Receives: Drug: Radiochemotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Survival
3-year progression-free survival
Measured: 3 years
Secondary outcomes (30)
Acute treatment toxicity
Acute and late treatment related toxicity: the rates of treatment related toxicity grade II or more
Measured: Up to 1 month after the end of preoperative treatment
Late toxicity related to treatment
Late treatment related toxicity: the rates of treatment related toxicity grade II or more
Measured: 3 years after surgery
Compliance to treatment
The rate of patients that receive full dose treatment
Measured: Up to 1 month after the end of preoperative treatment
Radiological response
Radiologic response on post-treatment MRI based on tumor size reduction and tumor regression grade (ymrTRG)
Measured: 28±5 days after the end of preoperative treatment
The rate of R0 resection
Rate of complete resection with safe > 1mm circumferential and longitudinal margin
Measured: 4 weeks after surgery
Quality of mesorectal excision: 3-grades Quirke scoring system
3-grades Quirke scoring system of the quality of mesorectal excision
Measured: 4 weeks after surgery
Number of lymph nodes harvested
A count of number of lymph nodes harvested
Measured: 4 weeks after surgery
Size of circumferential margin
Mesurement of circumferential margin
Measured: 4 weeks after surgery
Size of longitudinal margin
Mesurement of longitudinal margin
Measured: 4 weeks after surgery
Sphincter saving surgery rate
The rate of surgery with intestinal continuity and anal sphincter preservation
Measured: 4 weeks after surgery
Postoperative morbidity
Postoperative morbidity: 30 day or in-hospital postoperative morbidity rates
Measured: 30 days after resection
Postoperative mortality
Postoperative mortality: 30 day or in-hospital postoperative mortality rates
Measured: 30 days after resection
Pathologic response after chemotherapy
Pathologic response on Rodel Tumor Regression Grade
Measured: 4 weeks after surgery
Pathologic response after chemoradiotherapy
Pathologic response after chemoradiotherapy: rate of major pathologic response base on Rodel Tumor Regression Grade
Measured: 4 weeks after surgery
Loco-regional recurrence free survival
Loco-regional recurrence free survival: 3-year locoregional recurrence free survival rates
Measured: At 3 years
Uncontrolled local recurrence
Uncontrolled local recurrence: 3-year uncontrolled local recurrence free survival rates
Measured: At 3 years
Overall survival
Overall survival: 3 year overall survival rates
Measured: At 3 years
Overall survival
Overall survival: 5 year overall survival rates
Measured: At 5 years
EORTC QLQ-CR29
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)
Measured: Diagnosis time
EORTC QLQ-CR29
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)
Measured: 28±5 days after the end of preoperative treatment
EORTC QLQ-CR29
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)
Measured: At 6 months after surgery
EORTC QLQ-CR29
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)
Measured: 1 year after surgery
LARS Scores
Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
Measured: Diagnosis time
LARS Scores
Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
Measured: 28±5 days after the end of preoperative treatment
LARS Scores
Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
Measured: 6 months after surgery
LARS Scores
Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
Measured: 1 year after surgery
Quality of life - physical functioning: QLQ-C30
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)
Measured: At diagnosis
Quality of life - physical functioning: QLQ-C30
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)
Measured: 28±5 days after the end of preoperative treatment
Quality of life - physical functioning: QLQ-C30
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)
Measured: 6 months after surgery
Quality of life - physical functioning: QLQ-C30
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)
Measured: 1 year after surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Mar 2019
- Study start5 Jun 2019
- Primary completion5 Dec 2026 (estimated)
- Study completion5 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Rectal CancerStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- To demonstrate the non inferiority of preoperative modified FOLFIRINOX chemotherapy compared to radiochemotherapy in primary resectable locally advanced rectal cancer
- Masking
- None (open label)
- Enrolment
- 540 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Stéphane BENOIST, MD,PHD, Study chair, Service de chirurgie digestive et oncologique Hôpital Bicêtre - 94275 LE KREMLIN BICETRE
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03875781
- Sponsor's protocol ID
- P170920J
- Acronym
- NORAD01
- Status last verified
- Jan 2026
- First submitted
- 18 Feb 2019
- Last updated
- 15 Jan 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. doi: 10.1056/NEJMoa060829.
PubMed 16971718Wiltink LM, Chen TY, Nout RA, Kranenbarg EM, Fiocco M, Laurberg S, van de Velde CJ, Marijnen CA. Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomised trial. Eur J Cancer. 2014 Sep;50(14):2390-8. doi: 10.1016/j.ejca.2014.06.020. Epub 2014 Jul 21.
PubMed 25060825Schrag D, Weiser MR, Goodman KA, Gonen M, Hollywood E, Cercek A, Reidy-Lagunes DL, Gollub MJ, Shia J, Guillem JG, Temple LK, Paty PB, Saltz LB. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014 Feb 20;32(6):513-8. doi: 10.1200/JCO.2013.51.7904. Epub 2014 Jan 13.
PubMed 24419115Bensignor T, Brouquet A, Dariane C, Thirot-Bidault A, Lazure T, Julie C, Nordlinger B, Penna C, Benoist S. Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation. Colorectal Dis. 2015 Jun;17(6):491-8. doi: 10.1111/codi.12879.
PubMed 25524450Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial. J Clin Oncol. 2016 Sep 20;34(27):3300-7. doi: 10.1200/JCO.2016.66.6198. Epub 2016 Aug 1.
PubMed 27480145Brouquet 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.
PubMed 32471382
Study at a glance
From the registry record, last updated by the sponsor on 15 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT03875781
- Acronym / sponsor ID
- NORAD01 / P170920J
- Conditions
- Rectal Cancer, Advanced Cancer
- Keywords
- Rectal cancer, FOLFIRINOX,, chemotherapy, radiochemotherapy, surgery
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 540 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 5 Jun 2019 (actual)
- Primary completion
- 5 Dec 2026 (estimated)
- Study completion
- 5 Dec 2026 (estimated)
- First posted
- 15 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- To demonstrate the non inferiority of preoperative modified FOLFIRINOX chemotherapy compared to radiochemotherapy in primary resectable locally advanced rectal cancer
| Arm | Type | Receives |
|---|---|---|
| A: Modified Folfirinox | Experimental | Drug: ChemotherapyExperimental : 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. |
| B: Modified Folfirinox followed by Radiochemotherapy | Active comparator | Drug: RadiochemotherapyActive 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (23 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ChemotherapyArm 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. | Drug | A: Modified Folfirinox |
| RadiochemotherapyArm 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. | Drug | B: Modified Folfirinox followed by Radiochemotherapy |
Primary outcome
Survival
Time frame: 3 years
3-year progression-free survival
30 secondary outcomes
Acute treatment toxicity
Time frame: Up to 1 month after the end of preoperative treatment
Late toxicity related to treatment
Time frame: 3 years after surgery
Compliance to treatment
Time frame: Up to 1 month after the end of preoperative treatment
Radiological response
Time frame: 28±5 days after the end of preoperative treatment
The rate of R0 resection
Time frame: 4 weeks after surgery
Quality of mesorectal excision: 3-grades Quirke scoring system
Time frame: 4 weeks after surgery
Number of lymph nodes harvested
Time frame: 4 weeks after surgery
Size of circumferential margin
Time frame: 4 weeks after surgery
Size of longitudinal margin
Time frame: 4 weeks after surgery
Sphincter saving surgery rate
Time frame: 4 weeks after surgery
Postoperative morbidity
Time frame: 30 days after resection
Postoperative mortality
Time frame: 30 days after resection
Pathologic response after chemotherapy
Time frame: 4 weeks after surgery
Pathologic response after chemoradiotherapy
Time frame: 4 weeks after surgery
Loco-regional recurrence free survival
Time frame: At 3 years
Uncontrolled local recurrence
Time frame: At 3 years
Overall survival
Time frame: At 3 years
Overall survival
Time frame: At 5 years
EORTC QLQ-CR29
Time frame: Diagnosis time
EORTC QLQ-CR29
Time frame: 28±5 days after the end of preoperative treatment
EORTC QLQ-CR29
Time frame: At 6 months after surgery
EORTC QLQ-CR29
Time frame: 1 year after surgery
LARS Scores
Time frame: Diagnosis time
LARS Scores
Time frame: 28±5 days after the end of preoperative treatment
LARS Scores
Time frame: 6 months after surgery
LARS Scores
Time frame: 1 year after surgery
Quality of life - physical functioning: QLQ-C30
Time frame: At diagnosis
Quality of life - physical functioning: QLQ-C30
Time frame: 28±5 days after the end of preoperative treatment
Quality of life - physical functioning: QLQ-C30
Time frame: 6 months after surgery
Quality of life - physical functioning: QLQ-C30
Time frame: 1 year after surgery
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jan 2026.
- Background: PubMed 16971718Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. doi: 10.1056/NEJMoa060829.
- Background: PubMed 25060825Wiltink LM, Chen TY, Nout RA, Kranenbarg EM, Fiocco M, Laurberg S, van de Velde CJ, Marijnen CA. Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomised trial. Eur J Cancer. 2014 Sep;50(14):2390-8. doi: 10.1016/j.ejca.2014.06.020. Epub 2014 Jul 21.
- Background: PubMed 24419115Schrag D, Weiser MR, Goodman KA, Gonen M, Hollywood E, Cercek A, Reidy-Lagunes DL, Gollub MJ, Shia J, Guillem JG, Temple LK, Paty PB, Saltz LB. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014 Feb 20;32(6):513-8. doi: 10.1200/JCO.2013.51.7904. Epub 2014 Jan 13.
- Background: PubMed 25524450Bensignor T, Brouquet A, Dariane C, Thirot-Bidault A, Lazure T, Julie C, Nordlinger B, Penna C, Benoist S. Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation. Colorectal Dis. 2015 Jun;17(6):491-8. doi: 10.1111/codi.12879.
- Background: PubMed 27480145Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial. J Clin Oncol. 2016 Sep 20;34(27):3300-7. doi: 10.1200/JCO.2016.66.6198. Epub 2016 Aug 1.
- Derived from this study: PubMed 32471382Brouquet 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Stéphane BENOIST, MD,PHD study chair
Service de chirurgie digestive et oncologique Hôpital Bicêtre - 94275 LE KREMLIN BICETRE
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Chemotherapy and Radiochemotherapy in people with Rectal Cancer and Advanced Cancer, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 15 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Stéphane BENOIST, MD,PHD (+ 33 1 45 21 34 72, stephane.benoist@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Survival (time frame: 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03875781, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jan 2026.