Clinical trial NCT03875781: Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Rectal Cancer
Advanced Cancer
Keywords: Rectal cancer
FOLFIRINOX,
chemotherapy
radiochemotherapy
surgery
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-03-15
Enrollment: 540
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: To demonstrate the non inferiority of preoperative modified FOLFIRINOX chemotherapy compared to radiochemotherapy in primary resectable locally advanced rectal cancer
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Survival
timeFrame: 3 years
Secondary outcomes:
measure: Acute treatment toxicity
timeFrame: Up to 1 month after the end of preoperative treatment
measure: Late toxicity related to treatment
timeFrame: 3 years after surgery
measure: Compliance to treatment
timeFrame: Up to 1 month after the end of preoperative treatment
measure: Radiological response
timeFrame: 28±5 days after the end of preoperative treatment
measure: The rate of R0 resection
timeFrame: 4 weeks after surgery
measure: Quality of mesorectal excision: 3-grades Quirke scoring system
timeFrame: 4 weeks after surgery
measure: Number of lymph nodes harvested
timeFrame: 4 weeks after surgery
measure: Size of circumferential margin
timeFrame: 4 weeks after surgery
measure: Size of longitudinal margin
timeFrame: 4 weeks after surgery
measure: Sphincter saving surgery rate
timeFrame: 4 weeks after surgery
measure: Postoperative morbidity
timeFrame: 30 days after resection
measure: Postoperative mortality
timeFrame: 30 days after resection
measure: Pathologic response after chemotherapy
timeFrame: 4 weeks after surgery
measure: Pathologic response after chemoradiotherapy
timeFrame: 4 weeks after surgery
measure: Loco-regional recurrence free survival
timeFrame: At 3 years
measure: Uncontrolled local recurrence
timeFrame: At 3 years
measure: Overall survival
timeFrame: At 3 years
measure: Overall survival
timeFrame: At 5 years
measure: EORTC QLQ-CR29
timeFrame: Diagnosis time
measure: EORTC QLQ-CR29
timeFrame: 28±5 days after the end of preoperative treatment
measure: EORTC QLQ-CR29
timeFrame: At 6 months after surgery
measure: EORTC QLQ-CR29
timeFrame: 1 year after surgery
measure: LARS Scores
timeFrame: Diagnosis time
measure: LARS Scores
timeFrame: 28±5 days after the end of preoperative treatment
measure: LARS Scores
timeFrame: 6 months after surgery
measure: LARS Scores
timeFrame: 1 year after surgery
measure: Quality of life - physical functioning: QLQ-C30
timeFrame: At diagnosis
measure: Quality of life - physical functioning: QLQ-C30
timeFrame: 28±5 days after the end of preoperative treatment
measure: Quality of life - physical functioning: QLQ-C30
timeFrame: 6 months after surgery
measure: Quality of life - physical functioning: QLQ-C30
timeFrame: 1 year after surgery
Other outcomes:
Locations:
city: Le Kremlin-Bicêtre
country: France
facility: BENOIST
state: Ile de France
Study officials:
affiliation: Service de chirurgie digestive et oncologique Hôpital Bicêtre - 94275 LE KREMLIN BICETRE
name: Stéphane BENOIST, MD,PHD
role: STUDY_CHAIR
References:
citation: 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.
citation: Wiltink 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.
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citation: Bensignor 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.
citation: Deng 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.
citation: 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.