Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer

Study Overview
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Brief Summary
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GRECCAR 15 is focused on Locally Recurrent Rectal Cancer (LRRC) for patients with previous pelvic radiotherapy for the primary rectal cancer. This situation leads to a 20% higher risk of non-curative resection for the LRRC management (R1 status) impacting significantly the overall survival. The widespread use of neoadjuvant radiotherapy for primary rectal cancer introduces this new problem: the treatment of LRRC in previously irradiated area. The objective of GRECCAR 15 is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC.

Detailed Description
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The incidence of rectal cancer in the European Union is 15-25/100 000 per year. There is a 5-10% rate of locally recurrent rectal cancer (LRRC), with an overall survival rate of 40% at 5 years after complete resection. Curative surgery of LRRC requires multi-visceral resections which are associated with significant post-operative morbidity of 60%. Despite the combination of a potential curability and the high post-operative morbidity, there are currently neither good data from prospective randomized studies regarding optimum preoperative treatments for LRRC nor is there data assessing the efﬁcacy of response to any such treatments. Moreover, the widespread use of neoadjuvant radiotherapy for primary cancer introduced a new problem: the treatment of LRRC in previously irradiated area. Some studies investigated various modalities of reirradiation and showed acceptable late toxicity and encouraging outcome. GRECCAR 15 would be the first prospective randomized trial so far to evaluate the interest of pelvic reirradiation for LRRC, in previously irradiated patients. The objective is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC. Patients will be followed every 4 months during 2 years, and every 6 months the last year with chest, abdominal and pelvic scan and tumour markers.

Official Title
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A Phase III Randomized Trial Evaluating Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer (GRECCAR - PRODIGE - FRENCH)

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Chemotherapy FOLFIRINOX, 6 cycles
* Radiation: Radiochemotherapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent Age ≥18 years LRRC (histologically proven) ≤ 15 cm from the anal verge First or second LRRC (histologically proven) ≤ 15 cm from the anal verge Previous pelvic irradiation for the primary rectal cancer or primary recurrence (25-50.4Gy) No distant metastasis Resectable locally recurrent rectal cancer (according to the International consensus, absolute contraindications for resectabililty are bilateral sciatic nerve involvement, circumferential bone involvement, high sacral involvement requiring total sacrectomy; relative contraindications for resectabilty are sciatic notch involvement and encasement external iliac vessels) Adequate hematologic function : Hemoglobin ≥ 9 g/dL, leukocytes ≥ 4000/mm3, neutrophil count ≥ 1500/mm3, blood platelets ≥ 100 000/mm3 Adequate hepatic function : total bilirubin ≤ 1,5 x ULN, ASAT et ALAT ≤ 3 x ULN, alkalin phosphatases ≤ 3 x ULN Adequate renal function : creatinine clearance ≥ 30 ml/min ECOG performance status < 2 Women not sterilized by the first treatment (ovarian transposition) and males (and their female partners) patients agree to use two methods of effective contraception (one of them being a barrier method) during the study, for at least 6 months for men and for women after the last administration of study treatment Patient affiliated to a social security system or beneficiary of the same Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Exclusion Criteria: Recurrent rectal cancer after local excision Concomitant cancer or medical history of cancer within 5 years other than cancers treated in situ (cervical carcinoma or basocellular carcinoma or spinocellular carcinoma) Contraindication for chemotherapy Contraindication for chemotherapy (refer to Summary of characteristics of the products of the study drugs available at http://base-donnees-publique.medicaments.gouv.fr) or radiotherapy or surgery Symptomatic cardiac or coronary insufficiency Personal or family history of long QT syndrome congenital ECG at screening or baseline (predose) with QT/QTc > 450 msec (male) or QT/QTc > 470 msec (female) Chronic inflammatory bowel disease and/or bowel obstruction Patients with hypocalcemia, hypokalemia, hypomagnesemia. Progressive active infection (HIV or chronic hepatitis B or C) or any other severe medical condition that may preclude the delivery of treatment Complete or partial Dihydropyrimidine deshydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL) If contraindication to FOLFIRINOX, possibility to administred FOLFOX or FOLFIRI +/-EGFR (Contraindication to oxaliplatin: peripheral neuropathy > grade 1 (CTCAE grading system v5.0) Peripheral neuropathy > grade 1 (CTCAE grading system v5.0) Concomitant treatment with millepertuis, yellow fever vaccine, live attenuated vaccine, phenytoin, warfarin or sorivudine (or chemically equivalent) Pregnant or breast-feeding woman Persons deprived of liberty or under guardianship or incapable of giving consent Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule, as assessed by investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Induction Chemotherapy followed by Pelvic reirradiation<br>Protocol of chemotherapy FOLFIRINOX*, 6 cycles : oxaliplatin: 85 mg/m2 irinotecan: 180 mg/m² folinic acid: 400 mg/m2 5FU : 400 mg/m2 (bolus) 5FU : 2400 mg/m2 (continuous infusion) Protocol of reirradiation consists in conformational intensity modulated external irradiation, delivering a 30.6 Gy dose (1.8 Gy/day), with concomitant chemotherapy including Capecitabine 1600 mg/m²/day, five days a week. | Drug: Chemotherapy FOLFIRINOX, 6 cycles<br>* oxaliplatin: 85 mg/m2 irinotecan: 180 mg/m² folinic acid: 400 mg/m2 5FU : 400 mg/m2 (bolus) 5FU : 2400 mg/m2 (continuous infusion)<br>Radiation: Radiochemotherapy<br>* Reirradiation consists in conformational intensity modulated external irradiation (Intensity-modulated radiotherapy Volumetric Modulated Arc Therapy or tomotherapy) delivering a 30.6 Gy dose with high-energy photons in fractions of 1.8 Gy per day (17 fractions) 5 days a week With Concomitant chemotherapy including Capecitabine 1600 mg/m²/day, five days a week.<br>Procedure: Surgery<br>* Surgery will be performed at: Arm A: 8 weeks (±1) after the end of treatment Arm B: 6 weeks (±1) after the end of treatment Surgical procedures are defined into three categories: Total mesorectal excision (TME) Extended-TEM (e-TME) Pelvic exenteration (PE)<br>|
| Active Comparator: Arm B: Chemotherapy alone<br>Protocol of chemotherapy FOLFIRINOX*, 6 cycles : oxaliplatin: 85 mg/m2 irinotecan: 180 mg/m² folinic acid: 400 mg/m2 5FU : 400 mg/m2 (bolus) 5FU : 2400 mg/m2 (continuous infusion) | Drug: Chemotherapy FOLFIRINOX, 6 cycles<br>* oxaliplatin: 85 mg/m2 irinotecan: 180 mg/m² folinic acid: 400 mg/m2 5FU : 400 mg/m2 (bolus) 5FU : 2400 mg/m2 (continuous infusion)<br>Procedure: Surgery<br>* Surgery will be performed at: Arm A: 8 weeks (±1) after the end of treatment Arm B: 6 weeks (±1) after the end of treatment Surgical procedures are defined into three categories: Total mesorectal excision (TME) Extended-TEM (e-TME) Pelvic exenteration (PE)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of curative surgery | To determine the rate of R0 resection | At surgery, expected average 6 to 8 weeks after neoadjuvant treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Rate of disease-free survival at 3 years | From surgery until 3 years of follow-up | 
| Overall Survival | Rate of overall survival at 3 years | From surgery until 3 years of follow-up | 
| Surgical morbidity | To analyse surgical morbidity (Dindo classification) during first 30 days after the surgery | From surgery until 30 days after surgery | 
| Surgical mortality | To analyse surgical mortality (Dindo classification) during first 30 days after the surgery | From surgery until 30 days after surgery | 
| Compliance to treatment | Proportion of patients receiving full allocated neoadjuvant treatment | From beginning of neoadjuvant treatment until surgery, expected average 20 weeks after neoadjuvant treatment | 
| Proportion of good tumor response | Rate of tumor with a decreasing size of 50% at least after preoperative treatment at MRI | At 6 weeks (Arm A) and 4 weeks (Arm B) after neoadjuvant treatment | 
| Quality of life (QLQ CR-30) | The scores of questionnaire QLQ C-30 will be examined The EORTC QLQ-C30 is a patients self-rating questionnaire that measures physical, role, social, emotional, and cognitive functions as well as overall QoL. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales. | Before neoadjuvant treatment, before surgery, 4 months, one year and two years after surgery | 
| Quality of life (QLQ CR-29) | The scores of questionnaire QLQ CR-29 will be examined. The EORTC QLQ-CR29 has five functional and 18 symptom scales. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales. | Before neoadjuvant treatment, before surgery, 4 months, one year and two years after surgery | 
| Tolerance to treatment | Number of patients with adverse events | From beginning of neoadjuvant treatment until 1 year after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally recurrent rectal cancer, Pelvic reirradiation, Oncological surgery