Study Evaluating the Tailored Management of Locally-advanced Rectal Carcinoma

NCT04749108 | Recruiting Phase 2 DMC

• 2 other identifiers: PROICM 2021-01 GRE2021-000414-41
• Study Type: interventional
• Target: 1,075
• Locations: 1 country
• Sites: 30

Brief Summary

Locally advanced rectal carcinoma raise the issue of both the oncological control, local and general, and the therapeutic morbidity. Surgery alone can cure only one out of two patients, radiochemotherapy improves the local control but the metastatic risk remains about 30% with enhanced postoperative morbidity and poor functional results. The tumor response to preoperative treatment is the major prognostic factor which revealed the aggressiveness of the tumor. To this day, there are no biologic predictive markers for tumor response. 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).

Conditions

Locally Advanced Malignant Neoplasm; Rectal Carcinoma

Outcome Measures

Primary Outcomes (2)

• R0 resection rate (R0 is defined as Circumferential resection margin (CRM ≥ 1 mm) for Phase II

  The excision limits will be determined precisely on the part, after exhaustive sampling of the maximum tumor extension zones and containing the surface of the inked mesorectum.

  Within 15 days after surgery

• 3-year Disease free survival (DFS) for Phase III

  (DFS is defined as the time interval between randomization and the occurrence of the first event, such as local or metastatic recurrence, the development of a second cancer or death from any cause).Locoregional failure include locally progressive disease leading to an unresectable tumour, local R2 resection, or local recurrence after an R0-R1 resection. Patients without events at the time of analysis will be censored on the date of the last informative follow-up.

  3 years

Secondary Outcomes (25)

• Compliance rate with neoadjuvant treatment schedule

  Within 4.5 months after the start of treatment

• Pathological complete response rate

  Within 15 days after surgery

• Sphincter-saving surgery rate

  Up to 2 months after the end of the neoadjuvant treatment

• Quality of life by using the quality of life questionnaire score (QLQ-C30)

  For a 1-year follow-up

• Bowel function, Low anterior resection syndrome (LARS)

  For a 1-year follow-up

Study Arms (2)

Experimental: Arm A: immediate rectal surgery

EXPERIMENTAL

"Very good" responder patients will be randomly assigned to proctectomy performed within 4 to 6 weeks from randomization.

Drug: Induction chemotherapy - modified FOLFIRINOX regimen; Other: Early tumor response evaluation by MRI volumetry; Procedure: Radical proctectomy with total mesorectal excision

RCT Cap 50 and then rectal surgery

ACTIVE COMPARATOR

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.

Drug: Induction chemotherapy - modified FOLFIRINOX regimen; Other: Early tumor response evaluation by MRI volumetry; Radiation: Radiochemotherapy Cap 50; Procedure: Radical proctectomy with total mesorectal excision

Interventions

Induction chemotherapy - modified FOLFIRINOX regimen DRUG

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).

Experimental: Arm A: immediate rectal surgery; RCT Cap 50 and then rectal surgery

Early tumor response evaluation by MRI volumetry OTHER

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.

Experimental: Arm A: immediate rectal surgery; RCT Cap 50 and then rectal surgery

Radiochemotherapy Cap 50 RADIATION

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).

RCT Cap 50 and then rectal surgery

Radical proctectomy with total mesorectal excision PROCEDURE

The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.

Experimental: Arm A: immediate rectal surgery; RCT Cap 50 and then rectal surgery

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written consent,
• Patient who receive Folfirinox,
• Patient aged over 18 years old,
• World Health Organization (WHO) performance status ≥ 1,
• Histologically confirmed diagnosis of adenocarcinoma of the rectum,
• Distal part of the tumor from 1 to 12 cm from the upper part of the levator ani (dynamic rectal examination),
• No unequivocal evidence on CT-Scan of established metastatic disease,
• MRI evaluation of the locally advanced tumor before neoadjuvant chemotherapy:
• Predictive CRM \< 2 mm
• Or T3c-d (extending ≥ 5 mm beyond the muscularis propria) with extra mural venous invasion (EMVI)
• Or T4a-b (except bone and sphincteric invasion).
• 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).
• 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),
• 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.
• WHO performance status 0-1,

Sponsors & Collaborators

• Institut du Cancer de Montpellier - Val d'Aurelle: lead

Study Sites (30)

Institut Paoli Calmettes

Marseille, Bouches Du Rhône, 13009, France

RECRUITING

Hôpital Nord de Marseille

Marseille, Bouches Du Rhône, 13015, France

NOT YET RECRUITING

Hôpital Européen de MARSEILLE

Marseille, Bouches-du-rhône, 13003, France

RECRUITING

CHU Besançon

Besançon, Doubs, 25030, France

RECRUITING

CHU de Bordeaux

Bordeaux, Gironde, 33600, France

RECRUITING

Insitut Régional du Cancer de Montpellier

Montpellier, Hérault, 34298, France

RECRUITING

CHU de Nancy

Vandœuvre-lès-Nancy, Lorraine, 54511, France

RECRUITING

Centre Alexis Vautrin

Nancy, Meurthe Et Moselle, 54519, France

RECRUITING

Centre Oscart Lambret

Lille, Nord, 59000, France

RECRUITING

CHU Amiens

Amiens, Picardie, 80054, France

RECRUITING

CHU Clermont-Ferrand

Clermont-Ferrand, Puy De Dôme, 63000, France

RECRUITING

CH PAU

Pau, Pyrénées-atlantiques, 64000, France

RECRUITING

CHU de Lyon

Lyon, Rhône, 69310, France

RECRUITING

CH Annecy

Annecy, Savoie, 74330, France

NOT YET RECRUITING

CHU Rouen

Rouen, Seine-Maritime, 76031, France

RECRUITING

Hôpital Bicêtre

Le Kremlin-Bicêtre, Val De Marne, 94270, France

RECRUITING

Bordeaux Colorectal Institute

Bordeaux, 33300, France

RECRUITING

Centre Georges-François Leclerc

Dijon, 21079, France

NOT YET RECRUITING

Chu Grenoble

Grenoble, France

RECRUITING

Chu Lille

Lille, 59037, France

RECRUITING

CAC Léon Bérard

Lyon, France

RECRUITING

Hôpital La Timone

Marseille, 13005, France

RECRUITING

Centre Antoine Lacassagne

Nice, France

RECRUITING

CHU de Nîmes

Nîmes, 30029, France

RECRUITING

Hôpital Saint-Louis

Paris, 75010, France

RECRUITING

Hôpital Saint-Antoine

Paris, 75012, France

RECRUITING

Hôpital Européen Georges-Pompidou

Paris, 75015, France

RECRUITING

Hôpital Diaconesses

Paris, 75020, France

RECRUITING

Institut de Cancérologie de l'Ouest

Saint-Herblain, 44800, France

RECRUITING

CHU de Toulouse

Toulouse, 31059, France

RECRUITING

Related Publications (13)

• 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.

  PMID: 22529255 BACKGROUND

• 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.

  PMID: 26189067 BACKGROUND

• 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.

  PMID: 22362002 BACKGROUND

• 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.

  PMID: 23581977 BACKGROUND

• 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.

  PMID: 25677122 BACKGROUND

• 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.

  PMID: 24419115 BACKGROUND

• 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.

  PMID: 25939207 BACKGROUND

• 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.

  PMID: 28594714 BACKGROUND

• 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.

  PMID: 19647949 BACKGROUND

• 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.

  PMID: 29219925 BACKGROUND

• 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.

  PMID: 31436325 BACKGROUND

• 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.

  PMID: 32359501 BACKGROUND

• Rouanet P, Castan F, Mazard T, Lemanski C, Nougaret S, Deshayes E, Chalbos P, Gourgou S, Taoum C; GRECCAR, PRODIGE study group. GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol. Colorectal Dis. 2023 Oct;25(10):2078-2086. doi: 10.1111/codi.16740. Epub 2023 Sep 11.

  PMID: 37697712 BACKGROUND

MeSH Terms

Conditions

Rectal Neoplasms

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Philippe Rouanet, MD

  Philippe.Rouanet@icm.unicancer.fr

  STUDY CHAIR

Central Study Contacts

Philippe Rouanet, MD

CONTACT

4 67 61 30 71; Philippe.Rouanet@icm.unicancer.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Drug: Induction chemotherapy - modified FOLFIRINOX regimen Other: Early tumor response evaluation by MRI volumetry Radiation: Radiochemotherapy Cap 50 Procedure: Radical proctectomy with total mesorectal excision

Study Record Dates

• First Submitted: February 5, 2021
• First Posted: February 11, 2021
• Study Start: November 26, 2021
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: February 5, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Access to study data upon written detailed request sent to ICM, following publication and until 5 years after publication of summary data.
• Access Criteria: The data shared will be limited to that required for independent mandated verification of the published results, the applicant will need authorization from ICM for personal access, and data will only be transferred after signing of a data access agreement.

Locations

FR (30)