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Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer (GRECCAR15)

Primary Purpose

Rectal Cancer

Status
Active
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Chemotherapy FOLFIRINOX, 6 cycles
Radiochemotherapy
Surgery
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring Locally recurrent rectal cancer, Pelvic reirradiation, Oncological surgery

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Institut Sainte Catherine
  • CHU Bordeaux
  • CHU Grenoble
  • Centre Oscar Lambret
  • Hospices Civils de Lyon, HCL
  • Institut Paoli Calmette
  • Institut du Cancer de Montpellier
  • CHRU Nancy
  • Groupe Hospitalier Paris Saint-Joseph
  • CHU Rennes
  • CHU Rouen
  • Institut de Cancérologie de l'Ouest
  • CHU Toulouse

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm A: Induction Chemotherapy followed by Pelvic reirradiation

Arm B: Chemotherapy alone

Arm Description

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.

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)

Outcomes

Primary Outcome Measures

Proportion of curative surgery
To determine the rate of R0 resection

Secondary Outcome Measures

Disease Free Survival
Rate of disease-free survival at 3 years
Overall Survival
Rate of overall survival at 3 years
Surgical morbidity
To analyse surgical morbidity (Dindo classification) during first 30 days after the surgery
Surgical mortality
To analyse surgical mortality (Dindo classification) during first 30 days after the surgery
Compliance to treatment
Proportion of patients receiving full allocated neoadjuvant treatment
Proportion of good tumor response
Rate of tumor with a decreasing size of 50% at least after preoperative treatment at MRI
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.
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.
Tolerance to treatment
Number of patients with adverse events

Full Information

First Posted
March 13, 2019
Last Updated
January 24, 2023
Sponsor
University Hospital, Bordeaux
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1. Study Identification

Unique Protocol Identification Number
NCT03879109
Brief Title
Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer
Acronym
GRECCAR15
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 8, 2019 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
December 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Bordeaux

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rectal Cancer
Keywords
Locally recurrent rectal cancer, Pelvic reirradiation, Oncological surgery

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A: Induction Chemotherapy followed by Pelvic reirradiation
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm B: Chemotherapy alone
Arm Type
Active Comparator
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Chemotherapy FOLFIRINOX, 6 cycles
Intervention Description
oxaliplatin: 85 mg/m2 irinotecan: 180 mg/m² folinic acid: 400 mg/m2 5FU : 400 mg/m2 (bolus) 5FU : 2400 mg/m2 (continuous infusion)
Intervention Type
Radiation
Intervention Name(s)
Radiochemotherapy
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Surgery
Intervention Description
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)
Primary Outcome Measure Information:
Title
Proportion of curative surgery
Description
To determine the rate of R0 resection
Time Frame
At surgery, expected average 6 to 8 weeks after neoadjuvant treatment
Secondary Outcome Measure Information:
Title
Disease Free Survival
Description
Rate of disease-free survival at 3 years
Time Frame
From surgery until 3 years of follow-up
Title
Overall Survival
Description
Rate of overall survival at 3 years
Time Frame
From surgery until 3 years of follow-up
Title
Surgical morbidity
Description
To analyse surgical morbidity (Dindo classification) during first 30 days after the surgery
Time Frame
From surgery until 30 days after surgery
Title
Surgical mortality
Description
To analyse surgical mortality (Dindo classification) during first 30 days after the surgery
Time Frame
From surgery until 30 days after surgery
Title
Compliance to treatment
Description
Proportion of patients receiving full allocated neoadjuvant treatment
Time Frame
From beginning of neoadjuvant treatment until surgery, expected average 20 weeks after neoadjuvant treatment
Title
Proportion of good tumor response
Description
Rate of tumor with a decreasing size of 50% at least after preoperative treatment at MRI
Time Frame
At 6 weeks (Arm A) and 4 weeks (Arm B) after neoadjuvant treatment
Title
Quality of life (QLQ CR-30)
Description
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.
Time Frame
Before neoadjuvant treatment, before surgery, 4 months, one year and two years after surgery
Title
Quality of life (QLQ CR-29)
Description
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.
Time Frame
Before neoadjuvant treatment, before surgery, 4 months, one year and two years after surgery
Title
Tolerance to treatment
Description
Number of patients with adverse events
Time Frame
From beginning of neoadjuvant treatment until 1 year after surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christophe LAURENT
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institut Sainte Catherine
City
Avignon
Country
France
Facility Name
CHU Bordeaux
City
Bordeaux
Country
France
Facility Name
CHU Grenoble
City
Grenoble
Country
France
Facility Name
Centre Oscar Lambret
City
Lille
Country
France
Facility Name
Hospices Civils de Lyon, HCL
City
Lyon
Country
France
Facility Name
Institut Paoli Calmette
City
Marseille
Country
France
Facility Name
Institut du Cancer de Montpellier
City
Montpellier
Country
France
Facility Name
CHRU Nancy
City
Nancy
Country
France
Facility Name
Groupe Hospitalier Paris Saint-Joseph
City
Paris
Country
France
Facility Name
CHU Rennes
City
Rennes
Country
France
Facility Name
CHU Rouen
City
Rouen
Country
France
Facility Name
Institut de Cancérologie de l'Ouest
City
Saint-Herblain
Country
France
Facility Name
CHU Toulouse
City
Toulouse
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33843133
Citation
Denost Q, Frison E, Salut C, Sitta R, Rullier A, Harji D, Maillou-Martinaud H, Rullier E, Smith D, Vendrely V; on behalf the GRECCAR Group. A phase III randomized trial evaluating chemotherapy followed by pelvic reirradiation versus chemotherapy alone as preoperative treatment for locally recurrent rectal cancer - GRECCAR 15 trial protocol. Colorectal Dis. 2021 Jul;23(7):1909-1918. doi: 10.1111/codi.15670. Epub 2021 Jun 10.
Results Reference
derived

Learn more about this trial

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

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