Multicenter Phase 2 Trial: a Tailored Strategy for Locally Advanced Rectal Carcinoma - Full Text View

Purpose

The purpose of this study is to determine whether the tailored management of locally advanced rectal carcinoma can improve the oncologic and functional outcome.

Condition	Intervention	Phase
Locally Advanced Malignant Neoplasm Rectal Carcinoma	Drug: Induction trichemotherapy - FOLFIRINOX regimen Other: Early tumor response evaluation by MRI volumetry Radiation: Radiochemotherapy Cap 50 Radiation: Radiochemotherapy Cap 60 Procedure: Radical proctectomy with total mesorectal excision	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Randomized Multicenter Phase 2 Study: a Tailored Strategy for Locally Advanced Rectal Carcinoma

Further study details as provided by Institut du Cancer de Montpellier - Val d'Aurelle:

Primary Outcome Measures:

Ro resection rate [ Time Frame: Within 15 days after surgery ]
To confirm the feasibility of a tailored management with a 90% R0 resection rate achieved for all arms.

Secondary Outcome Measures:

Efficiency of MRI for prognosis [ Time Frame: Within 15 days after the surgery ]
To specify the efficiency of MRI for prognosis in terms of volumetry, downstaging, downsizing and CRM measurement after completion of the induction trichemotherapy.
Compliance rate with neoadjuvant treatment schedule [ Time Frame: Within 4 months after the start of treatment ]
To measure the compliance rate to the whole neoadjuvant schedule (induction CT + radiochemotherapy)
Acute and late toxicity of neoadjuvant treatments [ Time Frame: For the duration of treatment, as expexcted to be up to 4 months and within the 5-year follow-up ]
To evaluate overall toxicity of neoadjuvant treatments (induction trichemotherapy + radiochemotherapy) according to the Common Terminology Criteria for Adverse Events v4.0 (NCI CTC v4.0).
Pathological complete response rate [ Time Frame: Within 15 days after surgery ]
To assess the pathological complete response rate (ypT0N0)
Tumor regression grade (TRG) [ Time Frame: Within 15 days after surgery ]
To assess at pathologic examination the tumor regression grade (TRG) according to the Dworak classification.
Perioperative and postoperative morbidity [ Time Frame: Within 6 weeks after surgery and during the 5-year follow-up ]
To assess the impact of the therapeutic strategy on perioperative and postoperative morbidity.
Sphincter-saving surgery rate [ Time Frame: Up to 2 months after the end of the neoadjuvant treatment ]
To assess the impact of the therapeutic strategy on the rate of sphincter-saving surgery.
Functional outcome [ Time Frame: For a 5-year follow-up ]
To assess the long-term digestive,urinary and sexual functional results of tailored strategy
Quality of life [ Time Frame: For a 5-year follow-up ]
To assess the impact of treatments on quality of life according to the EORTC QLQ-C30.
Local recurrence rate [ Time Frame: For a 5-year follow-up ]
To measure the local recurrence rate in each treatment arm.
Incidence of metastases [ Time Frame: For a 5-year follow-up ]
To measure the incidence of distant metastases (liver, pulmonary, peritoneal, ganglionnary or any others) in each treatment arm.


Enrollment:	150
Study Start Date:	May 2011
Study Completion Date:	September 2014
Primary Completion Date:	September 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm A: immediate rectal surgery "Very good" responder patients will be randomly assigned to proctectomy within 2-4 weeks after the end of the induction chemotherapy.	Drug: Induction trichemotherapy - FOLFIRINOX regimen A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15). Other: 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. Procedure: Radical proctectomy with total mesorectal excision The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Arm B: 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).	Drug: Induction trichemotherapy - FOLFIRINOX regimen A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15). Other: 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. Radiation: Radiochemotherapy Cap 50 RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or 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 RT treatment (2 daily intake). Procedure: Radical proctectomy with total mesorectal excision The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Arm C: RCT Cap 50 and then rectal surgery "Good or poor" 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).	Drug: Induction trichemotherapy - FOLFIRINOX regimen A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15). Other: 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. Radiation: Radiochemotherapy Cap 50 RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or 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 RT treatment (2 daily intake). Procedure: Radical proctectomy with total mesorectal excision The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Experimental: Bras D: RCT Cap 60 and then rectal surgery "Good or poor" 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 60 grays (2Gy/day, 5 days a week, 6 weeks, boost 14 Gy).	Drug: Induction trichemotherapy - FOLFIRINOX regimen A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15). Other: 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. Radiation: Radiochemotherapy Cap 60 RCT Cap 60 will combine radiotherapy at a dose of 60 Gy by either conventional 3D or IMRT (2 Gy per fraction, 5 fractions per week during 6 weeks / 44 Gy in mini pelvis, and boost 16 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of RT treatment (2 daily intake) Procedure: Radical proctectomy with total mesorectal excision The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.

Detailed Description:

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 trichemotherapy. 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). "Good or bad" responders will be randomized between two arms: intensive radiochemotherapy (Cap 60) or the standard arm (Cap 50).

This tailored management should result in a better oncologic prognosis with a lower rate of post therapeutic functional disorders.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically confirmed rectal carcinoma
Primary tumor evaluated by pelvic MR Imaging:

i) iT3 ≥c tumors, with MRI showing a predictive CRM ≤ 2 mm or a EMS (Extra Mural Spread) ≥ 5 mm

ii) Resectable iT4 tumors (only randomized within the "poor responders" group)

iii) Any T tumors with MRI showing a predictive CRM ≤ 1 mm

No detectable metastases: Thorax-abdomen-pelvic CT-scan
Patient ≥ 18 years
ECOG Performance Status 0-1-2
Patient information and written informed consent form signed
Patient who can receive radiotherapy and chemotherapy
Negative pregnancy test in women of childbearing potential
Patient covered by a Social Security system
Hematology : Haemoglobin ≥ 9 g/dL, WBC ≥ 4000/mm3, neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
Hepatic function : total bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 3 x ULN, Alkaline phosphatases ≤ 3 x ULN
Renal function : creatinine ≤ 1.25 x ULN or creatinine clearance ≥ 60 ml/min

Exclusion Criteria:

Indication for immediate surgery
Primary tumor not measured at the MRI before inclusion
Previous pelvic radiotherapy
Contraindication to radiotherapy and/or chemotherapy
Severe renal or liver impairment
Cardiac and/or coronary disease which could contraindicate 5-Fu administration
Active infectious disease
Peripheral sensitive neuropathy
History of prior cancer (except if it was cured more than 5 years ago, and if complete remission)
Patient (male or female) of reproductive potential not using an effective contraceptive method during the whole treatment and up to 6 months after the completion of treatment
Concurrent participation in any other clinical trial likely to interfere with the therapeutic schedule
Fertile female patient not using adequate contraception, or breast-feeding woman

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01333709

Locations


France
CRLC Val d'Aurelle-Paul Lamarque
Montpellier, France, 34298

Sponsors and Collaborators

Institut du Cancer de Montpellier - Val d'Aurelle

Investigators


Principal Investigator:	Philippe ROUANET, MD, Ph D	CRLC Val d'Aurelle-Paul Lamarque

More Information


Responsible Party:	Institut du Cancer de Montpellier - Val d'Aurelle
ClinicalTrials.gov Identifier:	NCT01333709 History of Changes
Other Study ID Numbers:	GRECCAR 4 2010-023546-73 ( EudraCT Number )
Study First Received:	April 8, 2011
Last Updated:	March 2, 2015

Keywords provided by Institut du Cancer de Montpellier - Val d'Aurelle:


locally advanced rectal carcinoma Tailored treatment strategy MRI volumetry Early tumor response

Additional relevant MeSH terms:


Carcinoma Neoplasms Rectal Neoplasms Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site	Digestive System Diseases Gastrointestinal Diseases Intestinal Diseases Rectal Diseases Capecitabine Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents

ClinicalTrials.gov processed this record on July 07, 2017

Multicenter Phase 2 Trial: a Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR4)