| Sponsor | CHU de Bordeaux |
| Coordinating Investigator | Pr Quentin DENOST Service de chirurgie digestive et endocrinienne Unité Colorectale Centre Médico-Chirurgical Magellan Hôpital Haut-Lévêque– CHU de Bordeaux 1, avenue Magellan 33600 PESSAC Courriel : quentin.denost@chu-bordeaux.fr |
| Acronym and title | GRECCAR 15 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) |
| Justification / context | 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 will be the first prospective randomized trial so far to evaluate the interest of pelvic reirradiation for LRRC, in previously irradiated patients. |
| Objectives | Primary objective 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. Secondary objectives To compare neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on: 3-year Disease Free Survival and 3-year Overall Survival;Surgical morbidity and mortality (Dindo classification) at 30 days;Compliance to the neoadjuvant treatment; Good tumor response; Quality of life at two years after surgery;To assess the toxicity of neoadjuvant treatment Ancillary study related-aims: To assess the prognostic impact of immune markers (blood and tumor) on 3-year disease-free survival and 3-year overall survivalTo assess the association between blood CMV infection at baseline, immune biomarkers and 3-year disease-free survival and 3-year overall survivalTo assess the effect modification of study strategy efficacy by baseline immune biomarkers.To compare induction chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on immune biomarkers changes during follow-up. We will focus on Bordeaux and others hospitals (n=39 patients), and immune biomarkers will be assessed longitudinally to evaluate their evolution and the influence of therapeutic strategies, at baseline, at the assessment of tumor response (6W (Arm A) et 4W (Arm B) at the end treatment), and at 12 months after surgery or in case of relapse. |
| Research strategy | This is a national, multicenter, open-label with blinded endpoint assessment, randomized, parallel-group phase III superiority clinical trial, comparing chemotherapy followed by pelvic reirradiation versus chemotherapy alone as neoadjuvant treatment before surgery in patients with local recurrent rectal cancer previously irradiated for the primary cancer. The randomization will be stratified according to the location of the recurrence (anterior and/or central vs. posterior and/or lateral). |
| Inclusion criteria | Signed and dated informed consent; Age ≥18 years; 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 ≥ 2000/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 ≥ 50 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 4 months 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 |
| Non-inclusion 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 (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); 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. |
| Treatments/Strategies/ Procedures of the research project | Before inclusion, centralized reassessment of pelvic MRI in order to insure the resectability of the tumor. Arm A (experimental): 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) * will be replaced by FOLFIRI (±EGFR inhibitor) in case of intolerance to the oxaliplatin, neurotoxicity or early LRRC (<6 months) 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. A quality control of reirradiation will be ensured by Société Française de Radiothérapie Oncologique (SFRO) and Société Française de Physique Médicale (SFPM). Arm B (Control): 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) * will be replaced by FOLFIRI (±EGFR inhibitor) in case of intolerance to the oxaliplatin, neurotoxicity or early LRRC (<6 months) Response assessment at 6 weeks (ARM A) and 4 weeks (ARM B) after the neoadjuvant treatment by pelvic MRI and TEP-scan. Surgery will be performed at : – Arm A: 8 weeks (±1) – Arm B: 6 weeks (±1) Pathological assessment will be performed in fresh, oriented and inked specimen according to a protocol. This examination will be performed blinded of group allocation. Follow-up (ARM A and ARM B) every 4 months until 2 years, and every 6 months until 3 years with chest, abdominal and pelvic CT-scan and tumor markers. |
| Evaluation criteria | Primary endpoint : Proportion of curative surgery (R0 resection) Secondary endpoints 3-year Disease Free and 3-year Overall Survival Surgical morbidity and mortality (Dindo classification) during first 30 days after the surgeryCompliance to treatment: proportion of patients receiving full allocated neoadjuvant treatmentProportion of good tumor response: LRRC with a decreasing size of 50% after preoperative treatment (defined as good MRI radiological responders according to previous data in the literature)Quality of life (QLQ-C30 and QLQ-CR29) before neoadjuvant treatment, before surgery, 4 months, one year and two years after surgeryProportion of treatment related toxicity using International Common Terminology Criteria for Adverse Events (CTCAE) grading system v5.0 Ancillary study: Analysis of the different subpopulations of lymphoid cells in circulating blood samples (Mature T cells, gdT cells and regulatory T cells)Analysis of serum levels of PD-L1 and of the cytokine profile (pro-inflammatory cytokines and growth factors)In tumour: biobanking of 2 surgical tissue samples for each patient, for cytomegalovirus (CMV) analysis (correlation between CMV tumour infection and evolution of colorectal cancer) and further analysis of immune markers within the tumourChange of immune markers during follow-up |
| Study size | We assume a 55% R0 rate in patients with previous pelvic irradiation. According to the literature, a +20% R0 rate increase to reach 75% with experimental intervention may be expected. In this setting, with a two-sided type 1 error of 5%, power of 80%, a failure of 5% (due to non-operated patients) in each group, the necessary sample size is 93 patients by arm, thus a total of 186 patients. |
| Duration of the research project | Duration of the inclusion period :3 years Duration of the involvement of each participant : 3 years Total duration of the research project : 6.5 years |
| Statistical analysis of the data | Proportion of curative surgery (R0 resection) will be compared between groups using the Chi-square test, the corrected Chi-square test, or the exact Fisher test according to the expected values under the hypothesis of independence. |
| Expected impacts | Surgical excision is the only chance of cure of LRRC and clinical algorithms for surgical management according to the location of the disease has been already reported. However, there is no data from prospective randomized studies regarding optimum preoperative treatments leading to a high variability of practices. The international consensus, based on retrospective data and experts‘point of view, highlights the low level of evidence regarding the neoadjuvant management of the LRRC. During the last 20 years, despite a high volume of publications with regards to LRRC and pelvic exenteration, the proportion of R0 resection and survival do not improve. This is likely due to the weak design of studies which are in the high majority of cases retrospective and without randomisation. Time is therefore to evaluate the efficacy of treatment intensification for LRRC in a randomized controlled trial in order to obtain a high level of evidence. Regarding the benefits for the patients, the intensification of the neoadjuvant treatment for LRRC in combination with the tumour response assessment would allow to improve the rate of curative surgery for LRRC and thus the survival for patients. Regarding the benefits for the public health care, GRECCAR 15 may improve the clinical pathway of patients with LRRC thanks to: the standardization of the preoperative management for LRRC proposed in this trial,the implementation of a quality protocol for pelvic reirradiation in case of LRRC,the standardization of the pathological assessment for LRRC specimen in a context of complex pelvic surgery, involving several organ in the high majority of cases,the implementation of this new strategy for patients with LRRC thanks to a real LRRC clinical and research network through both GRECCAR, PRODIGE and FRENCH groups. In this way, this implementation will be based on the clinician network (surgeon, oncologist and radiologist) and the highest scientific level of evidence as well. Moreover, the main investigator centre is currently working with the regional agency of the French health ministry in order to be recognized as a reference centre for LRRC with a national MDT (Multidisciplinary Team meeting) specifically dedicated in LRRC. All cases will be discussed in the Complex Pelvic Surgery Meeting in Bordeaux University Hospital before inclusion in order to insure the resectability of the LRRC and to centralize the surgical procedure for the more complex cases (lateral and posterior recurrences) in one of the 4 highest national volume centers. This MDT meeting has been built for one year and is specifically dedicated to LRRC surgery.The current bad oncological results of LRRC are associated with an expensive palliative management with poor quality of life. |
La recherche est enregistrée sur ClinicalTrials.gov : NCT03879109
