Study Evaluating the Tailored Management of Locally-advanced Rectal Carcinoma
- Conditions
- Rectal CarcinomaLocally Advanced Malignant Neoplasm
- Interventions
- Drug: Induction chemotherapy - modified FOLFIRINOX regimenOther: Early tumor response evaluation by MRI volumetryProcedure: Radical proctectomy with total mesorectal excisionRadiation: Radiochemotherapy Cap 50
- Registration Number
- NCT04749108
- Lead Sponsor
- Institut du Cancer de Montpellier - Val d'Aurelle
- 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).
- Detailed Description
Cancer of the rectum is a common disease. It affects nearly 15,000 new people each year, with more men (53%) than women (47%).
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1075
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Experimental: Arm A: immediate rectal surgery Induction chemotherapy - modified FOLFIRINOX regimen "Very good" responder patients will be randomly assigned to proctectomy performed within 4 to 6 weeks from randomization. Experimental: Arm A: immediate rectal surgery Early tumor response evaluation by MRI volumetry "Very good" responder patients will be randomly assigned to proctectomy performed within 4 to 6 weeks from randomization. Experimental: Arm A: immediate rectal surgery Radical proctectomy with total mesorectal excision "Very good" responder patients will be randomly assigned to proctectomy performed within 4 to 6 weeks from randomization. RCT Cap 50 and then rectal surgery Radiochemotherapy Cap 50 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. RCT Cap 50 and then rectal surgery Induction chemotherapy - modified FOLFIRINOX regimen 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. RCT Cap 50 and then rectal surgery Early tumor response evaluation by MRI volumetry 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. RCT Cap 50 and then rectal surgery Radical proctectomy with total mesorectal excision 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.
- Primary Outcome Measures
Name Time Method R0 resection rate (R0 is defined as Circumferential resection margin (CRM ≥ 1 mm) for Phase II Within 15 days after surgery 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.
3-year Disease free survival (DFS) for Phase III 3 years (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.
- Secondary Outcome Measures
Name Time Method Compliance rate with neoadjuvant treatment schedule Within 4.5 months after the start of treatment To measure the compliance rate to the whole neoadjuvant schedule (induction CT + radiochemotherapy)
Pathological complete response rate Within 15 days after surgery To assess the pathological complete response rate (ypT0N0)
Sphincter-saving surgery rate 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.
Quality of life by using the quality of life questionnaire score (QLQ-C30) For a 1-year follow-up The EORTC QLQ-C30 uses for the questions 1 to 28 a 4-point scale. The scale scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit") and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome.
The EORTC QLQ-C30 uses for the questions 29 and 30 a 7-points scale. The scale scores from 1 to 7: 1 ("very poor") to 7 ("excellent"). Half points are not allowed. The range is 6. First of all, raw score has to be calculated with mean values. Afterwards linear transformation is performed to be comparable. More points are considered to have a better outcome.Bowel function, Low anterior resection syndrome (LARS) For a 1-year follow-up Assessed using LARS questionnaire (score 0-42, a high score indicates poor bowel function)
Quality of life by using the quality of life questionnaire score (QLQ-CR29) For a 1-year follow-up Score 26-108, a high score indicates many symptoms of colorectal cancer.
3-year local recurrence free survival rate (L-RFS) 3 years The time interval from the date of randomization to the date of local recurrence or death from any cause).Patients alive without local recurrence will be censored at the date of last follow-up.
3-year metastasis recurrence free survival rate (M-RFS) 3 years The time interval from the date of randomization to the date of metastatic recurrence or death from any cause).Patients alive without metastasis will be censored at the date of last follow-up.
3-year Overall survival (OS) 3 years The time interval from the date of randomization to the date of death from any cause. Patients alive will be censored at the date of last follow-up.
5-year Overall survival (OS) 5 years The time interval from the date of randomization to the date of death from any cause. Patients alive will be censored at the date of last follow-up.
Local recurrence rate For a 2-3-year follow-up The time interval from the date of randomization to the date of local recurrence. Patients without local recurrence will be censored at the date of last follow-up or death.
Clavien-Dindo grade Within 1 month after surgery Grade 1 (light) to Grade 5 = Death of patient . It is widely used throughout surgery for grading adverse events (i.e. complications) which occur as a result of surgical procedures.
Neoadjuvant rectal Score by Fokas Within 15 days after surgery The score uses the variables of clinical tumor stage, pathologic tumor stage, and pathologic nodal stage which are commonly available, furthering its utility in the clinical setting. The final scores range from 0 (good prognostic) to 100 (poor prognostic).
Rates of Total mesorectal excision (TME) grading according to Quirke Within 15 days after surgery This grade is given by the pathologist on the appearance of the mesorectum on fresh specimen (complete grade = good resection), incomplete and near incomplete grade (between good and poor resection), incomplete grade = poor resection)
Distal margin to the tumor Within 15 days after surgery Definitive stoma rate 36 MONTHS Second surgery rate 36 MONTHS Rehospitalization rate Within 1 month after surgery Dworak Classification Approximately 6 weeks after randomization Histopathologic analysis of tumor. Grade 0 to grade 4 with (Grade 4 = sterilized tumor to grade 0 = no regression of tumor)
Metastasis recurrence rate For a 2-3-year follow-up the time to metastasis defined as the time interval from the date of randomization to the date of metastasis. Patients without metastasis will be censored at the date of last follow-up or death.
Disease Fee Survival rate (DFS) For a 3-year follow-up the time interval from the date of randomization until the date of the first cancer-related event, or death from any cause). Patients alive without event will be censored at the date of last follow-up.
Assessment of adverse events by using the NCI-CTCAE version 5 scale Approximately 72 months for all patients From the signature of informed consent until 60 days after Surgery
Evaluation of urinary function by International Prostate Symptom Score (IPSS) questionnaire score For a 1-year follow-up Score 0-35, a high score indicates an impaired urinary function.
Evaluation of sexual function in men by International Index of Erectile Function (IIEFS) questionnaire score For a 1-year follow-up Score 1-25, a low score indicates an impaired sexual function in men.
Evaluation of sexual function in women by Female Sexual Function Index (FSFI) questionnaire score For a 1-year follow-up Score 4-95, a low score indicates an impaired sexual function in women.
Trial Locations
- Locations (29)
Hôpital Européen de MARSEILLE
🇫🇷Marseille, Bouches-du-rhône, France
CH PAU
🇫🇷Pau, Pyrénées-atlantiques, France
Hôpital Nord 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
Hôpital Bicêtre
🇫🇷Le Kremlin-Bicêtre, Val De Marne, France
Centre Georges-François Leclerc
🇫🇷Dijon, France
Chu Lille
🇫🇷Lille, France
CHU de Lyon
🇫🇷Lyon, Rhône, France
Ch Annecy
🇫🇷Annecy, Savoie, France
Hôpital La Timone
🇫🇷Marseille, France
CHU Rouen
🇫🇷Rouen, Seine-Maritime, France
Chu Grenoble
🇫🇷Grenoble, France
CHU de Nîmes
🇫🇷Nîmes, France
Hôpital Diaconesses
🇫🇷Paris, France
Institut de Cancérologie de l'Ouest
🇫🇷Saint-Herblain, France
CHU de Toulouse
🇫🇷Toulouse, France
Bordeaux Colorectal Institute
🇫🇷Bordeaux, France
CAC Léon Bérard
🇫🇷Lyon, France
Centre Antoine Lacassagne
🇫🇷Nice, France
Hôpital Saint-Louis
🇫🇷Paris, France
Hôpital Saint-Antoine
🇫🇷Paris, France
Hôpital Européen Georges-Pompidou
🇫🇷Paris, France