Study Evaluating the Tailored Management of Locally-advanced Rectal Carcinoma
NCT ID: NCT04749108
Last Updated: 2025-11-17
Study Results
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Basic Information
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RECRUITING
PHASE2/PHASE3
1075 participants
INTERVENTIONAL
2021-11-26
2026-08-31
Brief Summary
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The purpose of this trial is to tailor the management according to the early tumoral response after short and intensive induction chemotherapy. MRI volumetric tumor response will be used to distinguish between good responders and bad responders.
"Very good" responders will be randomized to either immediate surgery or radiochemotherapy followed by surgery (Standard arm: Cap 50).
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Detailed Description
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In more than 9 out of 10 cases, it occurs after 50 years. Three types of treatments are used to treat rectal cancer: surgery, radiotherapy and drug treatments.
The standard treatment for Locally Advanced Rectal Cancers (LARC) is multidisciplinary, combining chemotherapy, radiotherapy and surgery. The usual treatment in this situation is called induction chemotherapy administrated before radiochemotherapy. This phase of treatment taking place before surgery is called neoadjuvant therapy.
However, treating all cancers of the locally advanced rectum with the same neoadjuvant treatment exposes patients who are good responders to neoadjuvant chemotherapy with possible toxicity to radiotherapy and patients who are poor responders to ineffectiveness of conventional radiotherapy with surgery and so to a mutilating ineffective treatment.
The short- and long-term toxicity of pelvic radiation may be the most compelling reason to reconsider reflexive neoadjuvant radiochemotherapy (NA-RCT) and to move toward a more individualized approach.
A large North American trial is currently evaluating the suppression of preoperative radiation therapy in patients selected as a good responder to induction chemotherapy.
A first trial called GRECCAR-4 (Surgical Research Group on Rectum CAncer) with induction chemotherapy by 5 Fluorouracil + Irinotecan + Oxaliplatin and personalized radiochemotherapy reported the following results:
* High-dose induction chemotherapy is well tolerated and reproducible
* Early assessment after neo-adjuvant chemotherapy makes it possible to discriminate between good and bad responders without a negative impact on surgery.
* Personalized management of LARC according to the early tumor response to chemotherapy is possible.
* In good responder patients, a resection rate of 100% was achieved (even in the arm without radiotherapy), but due to poor recruitment, it is not possible to draw a formal conclusion regarding these promising results.
* The oncological results at 5 years show a local recurrence rate of 0% for the good responders and 4.8% for the poor responders. The 5-year overall survival was 86.7% with a 5-year progression-free survival of 75.0%.
GRECCAR 14 is the only French trial to question the feasibility of appropriate management of non-metastatic LARC. Its main objective is to evaluate, in good responder patients, personalized management after preoperative CT treatment.
GRECCAR-14 will try to confirm this strategy taking into account the 1st results of GRECCAR 4.
The study will initially focus on 200 patients to assess the surgical quality of this therapeutic strategy and then on 230 additional patients to assess the effectiveness of this personalized treatment on survival without recurrence.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Experimental: Arm A: immediate rectal surgery
"Very good" responder patients will be randomly assigned to proctectomy performed within 4 to 6 weeks from randomization.
Induction chemotherapy - modified FOLFIRINOX regimen
An induction chemotherapy (6 cycles) combining irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2 followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered every 15 days (D1=D15).
Early tumor response evaluation by MRI volumetry
Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.
Radical proctectomy with total mesorectal excision
The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
RCT Cap 50 and then rectal surgery
Very good" responder patients will be randomly assigned to receive chemoradiotherapy combining the administration of oral capecitabine (1600 mg/m2/day, BID) and radiotherapy at a total dose of 50 grays (2Gy/day, 5 days a week, 5 weeks, boost 6 Gy) followed after 7 weeks by a proctectomy.
Induction chemotherapy - modified FOLFIRINOX regimen
An induction chemotherapy (6 cycles) combining irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2 followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered every 15 days (D1=D15).
Early tumor response evaluation by MRI volumetry
Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.
Radiochemotherapy Cap 50
RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or Intensity-Modulated RadioTherapy (IMRT) (2 Gy per fraction, 5 fractions per week during 5 weeks / 44 Gy in mini pelvis, and boost 6 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of radiotherapy treatment (2 daily intake).
Radical proctectomy with total mesorectal excision
The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Interventions
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Induction chemotherapy - modified FOLFIRINOX regimen
An induction chemotherapy (6 cycles) combining irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2 followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered every 15 days (D1=D15).
Early tumor response evaluation by MRI volumetry
Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.
Radiochemotherapy Cap 50
RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or Intensity-Modulated RadioTherapy (IMRT) (2 Gy per fraction, 5 fractions per week during 5 weeks / 44 Gy in mini pelvis, and boost 6 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of radiotherapy treatment (2 daily intake).
Radical proctectomy with total mesorectal excision
The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Eligibility Criteria
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Inclusion Criteria
2. Patient who receive Folfirinox,
3. Patient aged over 18 years old,
4. World Health Organization (WHO) performance status ≥ 1,
5. Histologically confirmed diagnosis of adenocarcinoma of the rectum,
6. Distal part of the tumor from 1 to 12 cm from the upper part of the levator ani (dynamic rectal examination),
7. No unequivocal evidence on CT-Scan of established metastatic disease,
8. MRI evaluation of the locally advanced tumor before neoadjuvant chemotherapy:
1. Predictive CRM \< 2 mm
2. Or T3c-d (extending ≥ 5 mm beyond the muscularis propria) with extra mural venous invasion (EMVI)
3. Or T4a-b (except bone and sphincteric invasion).
1. Non measurable rectal tumor or not assessed by MRI before inclusion,
2. Ultra-low rectal tumor at diagnosis which imposes radiotherapy administration (inferior tumor pole less than 1 cm from the upper part of the levator ani).
3. Active cardiac disease including any of the following: a. Congestive heart failure ≥ New York Heart Association (NYHA) class 2 (appendix 4), b. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), c. Myocardial infarction less than 6 months before first dose of treatment, d. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted),
4. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to study inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors \[Ta (non invasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)\],
5. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before start of treatment.
1. WHO performance status 0-1,
2. Patient with tumoral regression ≥ 60% and CRM ≥ 1mm,
3. No unequivocal evidence on CT-Scan of established metastatic disease,
4. General condition considered suitable for radical pelvic surgery and a systemic therapy with Capecitabine
5. Adequate hematologic, hepatic, renal and ionogram function assessed within 7 days prior to study treatment a. Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3 b. Total bilirubin ≤ 1.5 x Upper Limit Normal (ULN), Alkaline phosphatases ≤ 3 x ULN and ASpartate aminoTransferase (AST) and ALanine aminoTransferase (ALT) ≤ 3 x ULN, c. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min according to Modification of Diet in Renal Disease (MDRD),
6. For women of reproductive potential, negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study treatment. Women not of reproductive potential are female patients who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy),
7. For women of childbearing potential and men, agreement to use an adequate contraception for the duration of study participation and up to 6 months following completion of therapy. Females of childbearing potential who are sexually active with a non-sterilized male partner must use 2 methods, of effective contraception. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care,
8. No evidence of chronic or acute ischemic heart disease,
9. Willing to participate to the study, and able to give informed consent and to comply with the treatment and follow-up schedules,
10. Affiliation to the French Social Security System.
1. Patient with a history of pelvic radiotherapy,
2. Contraindication to chemotherapy and/or radiotherapy,
3. Complete or partial Dihydropyrimidine deshydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL),
4. Any infection that could jeopardize treatment administration,
5. Any other serious concomitant disease or disorder that may interfere with the patient's participation in the study and safety during the study (e.g., severe liver, heart, kidney, lung, metabolic, or psychiatric disorders),
6. History of inflammatory bowel disease,
7. Patients with a history of pulmonary fibrosis or interstitial pneumonia,
8. Patients using antivitamin K (Coumadin etc…) but it's possible to substitute the antivitamin K treatment with low molecular weight heparins (LMWHs) before starting chemotherapy,
9. Known hypersensitivity to Capecitabine drug, study drug classes, or any constituent of the products,
10. Patient who received live attenuated vaccine within 10 days of inclusion,
11. Pregnant or breastfeeding woman. If a patient is of childbearing age, she must have a negative pregnancy test (serum β-hCG) documented 72 hours prior to inclusion,
12. Patient treated with an investigational drug within the last 30 days,
13. Patient under curatorship or guardianship or safeguard justice,
14. Inability to submit to medical monitoring of the trial for geographical, social or psychological reasons.
18 Years
ALL
No
Sponsors
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Institut du Cancer de Montpellier - Val d'Aurelle
OTHER
Responsible Party
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Principal Investigators
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Locations
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Institut Paoli Calmettes
Marseille, Bouches Du Rhône, France
Hôpital Nord de Marseille
Marseille, Bouches Du Rhône, France
Hôpital Européen de MARSEILLE
Marseille, Bouches-du-rhône, France
CHU Besançon
Besançon, Doubs, France
CHU de Bordeaux
Bordeaux, Gironde, France
Insitut Régional du Cancer de Montpellier
Montpellier, Hérault, France
CHU de Nancy
Vandœuvre-lès-Nancy, Lorraine, France
Centre Alexis Vautrin
Nancy, Meurthe Et Moselle, France
Centre Oscart Lambret
Lille, Nord, France
CHU Amiens
Amiens, Picardie, France
CHU Clermont-Ferrand
Clermont-Ferrand, Puy De Dôme, France
CH PAU
Pau, Pyrénées-atlantiques, France
CHU de Lyon
Lyon, Rhône, France
CH Annecy
Annecy, Savoie, France
CHU Rouen
Rouen, Seine-Maritime, France
Hôpital Bicêtre
Le Kremlin-Bicêtre, Val De Marne, France
Bordeaux Colorectal Institute
Bordeaux, , France
Centre Georges-François Leclerc
Dijon, , France
Chu Grenoble
Grenoble, , France
Chu Lille
Lille, , France
CAC Léon Bérard
Lyon, , France
Hôpital La Timone
Marseille, , France
Centre Antoine Lacassagne
Nice, , France
CHU de Nîmes
Nîmes, , France
Hôpital Saint-Louis
Paris, , France
Hôpital Saint-Antoine
Paris, , France
Hôpital Européen Georges-Pompidou
Paris, , France
Hôpital Diaconesses
Paris, , France
Institut de Cancérologie de l'Ouest
Saint-Herblain, , France
CHU de Toulouse
Toulouse, , France
Countries
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Central Contacts
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Facility Contacts
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Michel Rivoire, MD
Role: primary
References
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Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012 Jun 1;30(16):1926-33. doi: 10.1200/JCO.2011.40.1836. Epub 2012 Apr 23.
Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Strobel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. doi: 10.1016/S1470-2045(15)00159-X. Epub 2015 Jul 15.
Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012 Jul;99(7):918-28. doi: 10.1002/bjs.8702. Epub 2012 Feb 23.
Bregendahl S, Emmertsen KJ, Lous J, Laurberg S. Bowel dysfunction after low anterior resection with and without neoadjuvant therapy for rectal cancer: a population-based cross-sectional study. Colorectal Dis. 2013 Sep;15(9):1130-9. doi: 10.1111/codi.12244.
Chen TY, Wiltink LM, Nout RA, Meershoek-Klein Kranenbarg E, Laurberg S, Marijnen CA, van de Velde CJ. Bowel function 14 years after preoperative short-course radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomized trial. Clin Colorectal Cancer. 2015 Jun;14(2):106-14. doi: 10.1016/j.clcc.2014.12.007. Epub 2014 Dec 31.
Schrag D, Weiser MR, Goodman KA, Gonen M, Hollywood E, Cercek A, Reidy-Lagunes DL, Gollub MJ, Shia J, Guillem JG, Temple LK, Paty PB, Saltz LB. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014 Feb 20;32(6):513-8. doi: 10.1200/JCO.2013.51.7904. Epub 2014 Jan 13.
Weiser MR, Fichera A, Schrag D, Boughey JC, You YN. Progress in the PROSPECT trial: precision treatment for rectal cancer? Bull Am Coll Surg. 2015 Apr;100(4):51-2. No abstract available.
Rouanet P, Rullier E, Lelong B, Maingon P, Tuech JJ, Pezet D, Castan F, Nougaret S; and the GRECCAR Study Group. Tailored Treatment Strategy for Locally Advanced Rectal Carcinoma Based on the Tumor Response to Induction Chemotherapy: Preliminary Results of the French Phase II Multicenter GRECCAR4 Trial. Dis Colon Rectum. 2017 Jul;60(7):653-663. doi: 10.1097/DCR.0000000000000849.
Kang JH, Kim YC, Kim H, Kim YW, Hur H, Kim JS, Min BS, Kim H, Lim JS, Seong J, Keum KC, Kim NK. Tumor volume changes assessed by three-dimensional magnetic resonance volumetry in rectal cancer patients after preoperative chemoradiation: the impact of the volume reduction ratio on the prediction of pathologic complete response. Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):1018-25. doi: 10.1016/j.ijrobp.2009.03.066. Epub 2009 Aug 3.
Rouanet P. Which Trial to Demonstrate the Truthfulness of a Tailored Strategy in Rectal Carcinoma? Dis Colon Rectum. 2018 Jan;61(1):e1-e2. doi: 10.1097/DCR.0000000000000977. No abstract available.
Nougaret S, Castan F, de Forges H, Vargas HA, Gallix B, Gourgou S, Rouanet P; GRECCAR Study Group. Early MRI predictors of disease-free survival in locally advanced rectal cancer from the GRECCAR 4 trial. Br J Surg. 2019 Oct;106(11):1530-1541. doi: 10.1002/bjs.11233. Epub 2019 Aug 22.
Fokas E, Glynne-Jones R, Appelt A, Beets-Tan R, Beets G, Haustermans K, Marijnen C, Minsky BD, Ludmir E, Quirke P, Sebag-Montefiore D, Garcia-Aguilar J, Gambacorta MA, Valentini V, Buyse M, Rodel C. Outcome measures in multimodal rectal cancer trials. Lancet Oncol. 2020 May;21(5):e252-e264. doi: 10.1016/S1470-2045(20)30024-3.
Other Identifiers
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2021-000414-41
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
PROICM 2021-01 GRE
Identifier Type: -
Identifier Source: org_study_id
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