Neoadjuvant Chemotherapy for Obstructive Colon cancER First Treated by cOlostomy

Study Overview
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Brief Summary
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The aim of this study is to determine whether chemotherapy prior to tumor removal (neoadjuvant chemotherapy), in patients undergoing treatment for colon cancer in occlusion (CCO), would improve the rate of patients able to benefit from optimal treatment, i.e. complete treatment (including all neoadjuvant and adjuvant chemotherapy cures). This new strategy, which would combine chemotherapy before surgery and possibly post-operatively (depending on tumor analysis), could improve the prognosis of occluded colon cancers by treating circulating micrometastases and/or inducing a reduction in tumor size, thereby increasing the rate of complete resection.

Detailed Description
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In France, for patients admitted for an obstructive colon cancer, surgery is the preferred strategy. Primary diverting stoma is associated with low morbidity, and low 30-day mortality. Primary diverting stoma is not a major surgical undertaken, is effective to relief bowel obstruction, enables optimization of the patient's condition, allows adequate oncological staging and secondary elective colectomy. This strategy is actually recommended by the French and European Guidelines in patients with left-sided obstructive colon cancer and may be an option in patients with right-sided obstructive colon cancer, especially in those at high risk of postoperative complications Urgent surgery for obstructive colon cancer is associated with increased risk of postoperative morbidity, mortality and permanent stoma rates as it is generally performed in elderly patients with poor medical condition or in patients with severe comorbidities. Moreover, obstructive colon cancers are diagnosed at locally advanced (T4) or metastatic stage and, at equal tumour stage, obstruction itself negatively impacts oncological outcomes in colon cancer patients. Among the several factors that may explain poor oncological outcomes of OCC, the absence of adjuvant chemotherapy may play an important role. Adjuvant chemotherapy is the standard of care for patients undergoing curative resection for a stage III CC. For those with MSS high-risk stage II CC, adjuvant treatment is still a matter of debate. However, in the particular setting of MSS stage II obstructing CC, adjuvant chemotherapy may improve oncological outcomes. Because of high postoperative morbidity and patients' medical conditions, up to 37% of OCC patients for whom adjuvant systemic chemotherapy is considered appropriate do not receive this treatment. It is our hypothesis that the initiation of chemotherapy before resection of the primary tumour in a perioperative setting in patients with non-metastatic OLCC and for whom the obstruction has been relieved by a colostomy may allow to treat a higher proportion of patients with a full curative therapeutic sequence (including resection and chemotherapy if needed). Randomized phase II-III trials have demonstrated the feasibility (tolerance, postoperative morbidity) and the efficacy (tumor downstaging, tumor downsizing, histological regression, higher R0 resection rate) of neoadjuvant FOLFOX or CAPOX chemotherapy in uncomplicated colon cancer with a trend towards an improvement of DFS. Data of these studies led the French Oncological Authorities to accept neoadjuvant chemotherapy in a perioperative setting as a therapeutic option in patients with locally advanced colon cancer (TNCD 21/01/2019, chapter 3, Cancer du colon non métastatique (p10): Neo-adjuvant chemotherapy may be considered for locally advanced tumors deemed unresectable or at the limit of resectability (expert opinion); it is possible to perform an upstream stoma before starting chemotherapy (neo-adjuvant) and then a re-intervention aimed at exeresis (expert opinion). This treatment option should be discussed at the preoperative multidisciplinary consultation meeting if a T4 tumor is suspected during the preoperative workup. The authors concluded that neoadjuvant chemotherapy using FOLFOX was feasible and might be a treatment option for patients with obstructive colon cancer for whom the obstruction has been relieved by a definctioning stoma. Further large-scale studies are warranted to confirm the present findings. This is exactly what COnCERTO trial aims to determine. It is our hypothesis that the initiation of neoadjuvant chemotherapy in a perioperative setting in patients with non-metastatic MSS/pMMR Obstructive Colon Cancer (OCC) and for whom the obstruction has been relieved by a stoma may improve the compliance of the treatment and thus may allow to increase the rate of patients receiving the full curative therapeutic sequence according to the guidelines defined as following: Resection of the primary tumor WITH: Low-risk stage II: NO CHEMOTHERAPY High-risk stage II: CHEMOTHERAPY AT INVESTIGATOR'S DISCRETION Stage III pT1-T3N1: CAPOX (3 months) or FOLFOX (6 months) Stage III pT4 and/or N2: FOLFOX (6 months) MSS High-risk stage II are defined as following: No microsatellite instability and presence of vascular emboli, perinervous or lymphatic invasion, poor differentiation, <12 harvested lymph nodes, perforation). In addition, once OCC are known to have poor prognosis compared to their non-complicated counterparts, neoadjuvant chemotherapy (before resection of the primary) may improve prognosis of these patients by treating circulating micrometastases or by inducing tumor down-staging and thus improving the R0 resection rate. We thus designed a randomized phase III trial aiming to assess whether FOLFOX or CAPOX neoadjuvant chemotherapy in a perioperative setting may increase the rate of full curative therapeutic sequence in patients with MSS/pMMR OCC first treated by a defunctionning stoma (figure 5). Demonstrating the positive impact on complicance to the full curative therapic strategy of perioperative chemotherapy in patients with OCC treated by defunctioning stoma, may change medical practices at a national and international level and may lead to a new standard of care. OCC is a major public health issue with no improvement in prognosis during the past decade. By improving the compliance of treatment of patients with OCC, the present study will ensure public health and economic benefits

Official Title
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Neoadjuvant Chemotherapy for Obstructive Colon cancER First Treated by cOlostomy : A Randomized Phase III Trial - COnCERTO (French 01-18)

Conditions
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Colon Cancer

Intervention / Treatment
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* Drug: Neoadjuvant chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years ECOG performance status 0 or 1 Patients with obstructive colon cancer treated by defunctioning stoma Pathologically confirmed adenocarcinoma (≥10 cm from the anal verge- left transverse colon) - MSS/pMMR (microsatellites stable primary tumor) status Patient requiring colectomy Laboratory data including : White blood cell count ≥ 3.109 /L with Neutrophils ≥ 1,5.109 / L, Platelet count ≥ 100.109 / L, Hemoglobin ≥ 9 g/dL (5,6 mmol/L), Total bilirubin ≤ 1,5 x ULN (upper limit of normal), ASAT and ALAT ≤ 2,5 x ULN, Alkaline phosphatase ≤ 1,5 x ULN, Serum creatinine ≤ 1,5 x ULN (performed 10-15 days prior to randomization). Non metastatic colon cancer (lung, liver, peritoneal) on thoracic-abdomino-pelvis CT scan Absence of synchronous colorectal cancer No prior chemotherapy or abdominal or pelvic irradiation No history of colorectal cancer No serious medical co-morbidity : uncontrolled inflammatory bowel disease, uncontrolled angina, recent [within the past 6 months] myocardial infarction, or another serious medical condition, judged to compromise ability to tolerate chemotherapy and/or surgery Women of childbearing potential with effective contraception will be required during chemotherapy treatment and for 6 months after cessation of chemotherapy treatment and a negative blood pregnancy test by beta-HCG at inclusion. Women surgically sterile (absence of ovaries and/or uterus) Postmenopausal women: confirmation diagnostic (non-medically induced amenorrhea for at least 12 months prior to the inclusion visit) For men participating in the study, contraception is required during the trial and for 6 months after stopping chemotherapy treatment. Patient able to comply with the study protocol, in the investigator's judgment Patient affiliated with, or beneficiary of a social security (national health insurance) category Person informed and having signed his consent Exclusion Criteria: Contraindication to colectomy and/or anesthesia Rectal cancer located within 10 cm of the anal verge by endoscopy or under the peritoneal reflection at surgery Patient having received radiation therapy prior to surgery Metastatic spread at baseline assessment (lung, liver, peritoneal) History or current evidence on physical examination of central nervous system disease or; Peripheral neuropathy ≥ grade 1 Contraindication to study neoadjuvant chemotherapy treatments Presence of inflammatory bowel disease, HNPCC syndrome or polyposis Clinically relevant coronary artery disease or history of myocardial infarction in the last 6 months, or high risk of uncontrolled arrhythmia Uracilemia ≥ 150 ng/ml (suggestive of complete DPD deficiency) Medical, geographical, sociological, psychological or legal conditions that would not permit the patient to complete the study or sign informed consent Any significant disease, which, in the investigator's opinion, would exclude the patient from the study. Patient is a pregnant (positive blood pregnancy test) or breastfeeding (lactating) woman or intending to become pregnant during the study and for at least 6 months after the treatment termination Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision) Simultaneous participation in another interventional research

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Arm I (Adjuvant chemotherapy) / Control arm<br>Diverting stoma - colectomy - +/- adjuvant chemotherapy The colectomy (open or laparoscopic) should be performed within 1 to 20 days after the randomization and with respect of the oncological quality criteria of resection. After completion of surgery, adjuvant chemotherapy will be discussed as follow: Low-risk stage II: No adjuvant treatment High-risk MSS stage II (vascular emboli, lymphatic or perinervous invasion, poor differentiation, <12 harvested lymph nodes, perforation): Investigator's discretion pT1-T3N1: CAPOX (3 months) or FOLFOX (6 months) pT4 and/or N2: FOLFOX (6 months) | |
| Experimental: Arm II (Neoadjuvant Chemotherapy) / Experimental arm<br>Patients receive systemic CAPOX or FOLFOX chemotherapy (3 months) within 21 days after the randomization. After completion of neoadjuvant chemotherapy and within 3 to 5 weeks, the colectomy (open or laparoscopic) will be performed with respect of the oncological quality criteria. Adjuvant chemotherapy will be discussed as follow: Low-risk stage II: No adjuvant treatment High-risk MSS stage II (vascular emboli, perinervous or lymphatic invasion, poor differentiation, <12 harvested lymph nodes, perforation): Investigator's discretion Stage III: CAPOX or FOLFOX (3 months) | Drug: Neoadjuvant chemotherapy<br>* Diverting stoma- neoadjuvant chemotherapy - colectomy - +/- adjuvant chemotherapy<br>* Other names: Arm II;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the success of a full curative therapeutic | The treatment is complete if all the chemotherapy treatments (adjuvant for arm I / neoadjuvant and adjuvant for arm II) is done. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neoadjuvant chemotherapy Adverse events | Adverse events (grade 3,4 and 5 toxicity) related to neoadjuvant chemotherapy including those related to the primary tumor | 36 months | 
| adjuvant chemotherapy adverse events | Adverse events (grade 3, 4 and 5 toxicity) related to adjuvant chemotherapy including those related to the primary tumor | 36 months | 
| Number of cycles administered of neoadjuvant chemotherapy | Number of cycles administered of neoadjuvant chemotherapy | 36 months | 
| Rate of primary tumour resection | Rate of primary tumour resection | 36 months | 
| Quality and completeness of the surgical excision | number of lymph nodes examined, completeness of the mesocolon, margins | 36 months | 
| Overall morbidity according to the Dindo classification | according to the Dindo classification | at 90 days postoperatively. | 
| Overall mortality | mortality without relapse | at 3 years and mortality without stoma at 3 years. | 
| Quality of life evaluated using EORTC QLQ-C30 and QLQ-CR29 dedicated to CRC | using EORTC QLQ-C30 and QLQ-CR29 dedicated to CRC | at J0, week5 (FOLFOX)/week7 (CAPOX), week9 (FOLFOX) and every 6 months a year |