Study Evaluating the Tailored Management of Locally-advanced Rectal Carcinoma

Study Overview
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Brief Summary
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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
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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.

Official Title
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Multicentric Phase II-III Study Evaluating the Tailored Management of Locally-advanced Rectal Carcinoma After a Favorable Response to Induction Chemotherapy

Conditions
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Locally Advanced Malignant Neoplasm, Rectal Carcinoma

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA FOR SCREENING 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). NON INCLUSION CRITERIA FOR SCREENING Non measurable rectal tumor or not assessed by MRI before inclusion, 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), 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)], 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. INCLUSION CRITERIA FOR EXPERIMENTAL TREATMENT WHO performance status 0-1, Patient with tumoral regression ≥ 60% and CRM ≥ 1mm, No unequivocal evidence on CT-Scan of established metastatic disease, General condition considered suitable for radical pelvic surgery and a systemic therapy with Capecitabine 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), 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), 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, No evidence of chronic or acute ischemic heart disease, Willing to participate to the study, and able to give informed consent and to comply with the treatment and follow-up schedules, Affiliation to the French Social Security System. NON-INCLUSION CRITERIA FOR EXPERIMENTAL TREATMENT Patient with a history of pelvic radiotherapy, Contraindication to chemotherapy and/or radiotherapy, Complete or partial Dihydropyrimidine deshydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL), Any infection that could jeopardize treatment administration, 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), History of inflammatory bowel disease, Patients with a history of pulmonary fibrosis or interstitial pneumonia, 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, Known hypersensitivity to Capecitabine drug, study drug classes, or any constituent of the products, Patient who received live attenuated vaccine within 10 days of inclusion, 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, Patient treated with an investigational drug within the last 30 days, Patient under curatorship or guardianship or safeguard justice, Inability to submit to medical monitoring of the trial for geographical, social or psychological reasons.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Arm A: immediate rectal surgery<br>Very good responder patients will be randomly assigned to proctectomy performed within 4 to 6 weeks from randomization. | Drug: Induction chemotherapy - modified FOLFIRINOX regimen<br>* 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).<br>Other: Early tumor response evaluation by MRI volumetry<br>* 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.<br>Procedure: Radical proctectomy with total mesorectal excision<br>* The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.<br>|
| Active Comparator: RCT Cap 50 and then rectal surgery<br>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<br>* 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).<br>Other: Early tumor response evaluation by MRI volumetry<br>* 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.<br>Radiation: Radiochemotherapy Cap 50<br>* 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).<br>Procedure: Radical proctectomy with total mesorectal excision<br>* The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance rate with neoadjuvant treatment schedule | To measure the compliance rate to the whole neoadjuvant schedule (induction CT + radiochemotherapy) | Within 4.5 months after the start of treatment | 
| Pathological complete response rate | To assess the pathological complete response rate (ypT0N0) | Within 15 days after surgery | 
| Sphincter-saving surgery rate | To assess the impact of the therapeutic strategy on the rate of sphincter-saving surgery. | Up to 2 months after the end of the neoadjuvant treatment | 
| Quality of life by using the quality of life questionnaire score (QLQ-C30) | 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. | For a 1-year follow-up | 
| Bowel function, Low anterior resection syndrome (LARS) | Assessed using LARS questionnaire (score 0-42, a high score indicates poor bowel function) | For a 1-year follow-up | 
| Quality of life by using the quality of life questionnaire score (QLQ-CR29) | Score 26-108, a high score indicates many symptoms of colorectal cancer. | For a 1-year follow-up | 
| 3-year local recurrence free survival rate (L-RFS) | 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 years | 
| 3-year metastasis recurrence free survival rate (M-RFS) | 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 years | 
| 3-year Overall survival (OS) | 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. | 3 years | 
| 5-year Overall survival (OS) | 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 years | 
| Local recurrence rate | 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. | For a 2-3-year follow-up | 
| Clavien-Dindo grade | 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. | Within 1 month after surgery | 
| Neoadjuvant rectal Score by Fokas | 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). | Within 15 days after surgery | 
| Rates of Total mesorectal excision (TME) grading according to Quirke | 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) | Within 15 days after surgery | 
| 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 | Histopathologic analysis of tumor. Grade 0 to grade 4 with (Grade 4 = sterilized tumor to grade 0 = no regression of tumor) | Approximately 6 weeks after randomization | 
| Metastasis recurrence rate | 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. | For a 2-3-year follow-up | 
| Disease Fee Survival rate (DFS) | 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. | For a 3-year follow-up | 
| Assessment of adverse events by using the NCI-CTCAE version 5 scale | From the signature of informed consent until 60 days after Surgery | Approximately 72 months for all patients | 
| Evaluation of urinary function by International Prostate Symptom Score (IPSS) questionnaire score | Score 0-35, a high score indicates an impaired urinary function. | For a 1-year follow-up | 
| Evaluation of sexual function in men by International Index of Erectile Function (IIEFS) questionnaire score | Score 1-25, a low score indicates an impaired sexual function in men. | For a 1-year follow-up | 
| Evaluation of sexual function in women by Female Sexual Function Index (FSFI) questionnaire score | Score 4-95, a low score indicates an impaired sexual function in women. | For a 1-year follow-up |