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

NCT ID: NCT03879109

Last Updated: 2024-08-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 58 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-08
• Study Completion Date: 2027-12-31

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.

Conditions

Rectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: Induction Chemotherapy followed by Pelvic reirradiation

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.

Group Type: EXPERIMENTAL

Chemotherapy FOLFIRINOX, 6 cycles

Intervention Type: DRUG

• oxaliplatin: 85 mg/m2
• irinotecan: 180 mg/m²
• folinic acid: 400 mg/m2
• 5FU : 400 mg/m2 (bolus)
• 5FU : 2400 mg/m2 (continuous infusion)

Radiochemotherapy

Intervention Type: RADIATION

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.

Surgery

Intervention Type: PROCEDURE

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)

Arm B: Chemotherapy alone

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)

Group Type: ACTIVE_COMPARATOR

Chemotherapy FOLFIRINOX, 6 cycles

Intervention Type: DRUG

• oxaliplatin: 85 mg/m2
• irinotecan: 180 mg/m²
• folinic acid: 400 mg/m2
• 5FU : 400 mg/m2 (bolus)
• 5FU : 2400 mg/m2 (continuous infusion)

Surgery

Intervention Type: PROCEDURE

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)

Interventions

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

Radiochemotherapy

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: RADIATION

Surgery

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)

Intervention Type: PROCEDURE

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christophe LAURENT

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux

Locations

Institut Sainte Catherine

Avignon, , France

CHU Bordeaux

Bordeaux, , France

CHU Grenoble

Grenoble, , France

Centre Oscar Lambret

Lille, , France

Hospices Civils de Lyon, HCL

Lyon, , France

Institut Paoli Calmette

Marseille, , France

Institut du Cancer de Montpellier

Montpellier, , France

CHRU Nancy

Nancy, , France

Groupe Hospitalier Paris Saint-Joseph

Paris, , France

CHU Rennes

Rennes, , France

CHU Rouen

Rouen, , France

Institut de Cancérologie de l'Ouest

Saint-Herblain, , France

CHU Toulouse

Toulouse, , France

Countries

France

References

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.

Reference Type: DERIVED

PMID: 33843133 (View on PubMed)

Other Identifiers

CHUBX 2017/52

Identifier Type: -

Identifier Source: org_study_id