Efficacy of Delayed Coloanal Anastomosis for Medium and Lower Rectum Cancer Treatment. Phase 2 Clinical Trial (CASCADOR)

Study Overview
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Brief Summary
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Hypothesis: In France, approximately 12,000 new rectal cancers are diagnosed each year. Frequency is one and a half times higher in men than in women. The average age of diagnosis is 65. Unlike colon cancer, technical management remains challenging with unresolved operating difficulties. Morbidity of surgical procedures remains high with a very large number of preventive or curative stoma derivations. Reference in surgical treatment is total excision of the rectum and its mesentery, followed by continuity restoration by immediate coloanal anastomosis (ACAI). In this procedure, rate of fistula that results is reported in the literature between 15 and 25%. An alternative to ACAI is delayed coloanal anastomosis without reservoir (ACAD). Based on retrospective experiences, we form the hypothesis that ACAD offers a much lower rate of fistula (<5%) and allows diminution of preventive stoma derivation practice. Morbidity and mortality are reduced, and patient's quality of life greatly improved. Direct costs (consumables intraoperative, hospitalization, stoma complications) and indirect (pocket-fitting stoma) are greatly reduced. This study is a multicentre, two arms, phase 2 clinical trial.

Official Title
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Efficacy of Delayed Coloanal Anastomosis for Medium and Lower Rectum Cancer Treatment. Phase 2 Clinical Trial.

Conditions
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Medium and Lower Rectal Cancer

Intervention / Treatment
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* Procedure: 2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA)
* Procedure: Colo-anal anastomosis (CAA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven rectal adenocarcinoma. Medium or lower rectum tumour requiring removal of the entire rectum and its mesorectum. T1 N+ or T2 N+ or T3 N+ or T3 N0 and M0 tumour. Age between 18 and 75 years . ASA ≤ 2. Sphincter continence compatible with coloanal anastomosis. Patients who received preoperative radiotherapy alone or chemotherapy and radiotherapy. Patient affiliated to social security. For patients of childbearing age, use of contraception. Patient information and consent for study participation Exclusion Criteria: Other histology of rectal cancer. T1 N0 or T2 N0 or T4 tumour. Metastatic disease M1. History of cancer except cervix in situ carcinoma or skin basal cell carcinoma. Patient with psychological, social, family or geographical reasons who couldn't be treated or monitored regularly by the criteria of the study Patients deprived of liberty or under guardianship. Pregnant or nursing women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two multicenter parallel single-arm phase II trials. One trial assessing 2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA) in centers who routinely performing this intervention. One trial assessing colo-anal anastomosis (CAA) in centers who routinely performing this intervention.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA)<br>Patients treated with 2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA) in centers who routinely performing this intervention. | Procedure: 2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA)<br>* 2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA) Whatever the mode of continuity restoration used, resection is the same in the two groups. It consists of total excision of the rectum and its mesorectum, that intervention should be performed by laparotomy or laparoscopy. After surgical resection, the colon is exteriorized through the anus and attached to the buttock. By day 6, exteriorized colon is resected and coloanal anastomosis is performed without preventive stoma derivation<br>|
| Experimental: Colo-anal anastomosis (CAA)<br>Patients operated with colo-anal anastomosis (CAA) in centers who routinely performing this intervention. | Procedure: Colo-anal anastomosis (CAA)<br>* After the surgical resection, coloanal anastomosis is performed usually after completion of a reservoir J when it is possible. Preventive ostomy is performed most often. In the absence of fistula, the patient will reoperation for stoma closure of its branch<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absence at Day 30 of a Symptomatic Anastomotic Leakage (AL) Among 2SCA | Efficacy of the intervention was defined as the absence at day 30 of a symptomatic AL (either with entero-cutaneous fistula or perianastomotic abscess with infectious conditions and/or transit impairment) requiring diverting stoma (curatively for 2-stage CA or prophylactic-based for CA). AL was defined as fecal matter in the drainage system when a drainage system was present. Clinical signs included fever and subocclusion requiring a pelvic scan and collection of liquid and gas in the peri-anastomotic region. Non-symptomatic ALs which did not require any investigation nor treatment, in particular no diverting stoma, were not considered failures. Assuming an efficacy rates of 85% (null hypothesis) and 95% (alternative hypothesis), and relied on a superiority test at the 5% significance level (one-sided) with 80% power, 53 eligible and assessable patients were required. Efficacy of the intervention was concluded if at least 49 patients had no symptomatic AL at day 30. | Delayed coloanal anastomosis effectiveness was evaluated in terms of symptomatic anastomotic fistula occurring during the 30 days post anastomosis and requiring stoma derivation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stomata Bypass (Preventive or Therapeutic) | Number of patients with stomata bypass (preventive or therapeutic) at each time of follow-up after surgery (2SCA or CAA). A stomata bypass is the result of a surgical operation in which a damaged part is removed from the ileum (ileostomy) or colon (colostomy) and the cut end diverted to an artificial opening in the abdominal wall. | Presence of stomata bypass was evaluated at 30 days, 1 year and 2 years after surgery (2SCA or CAA) | 
| Post-operative Morbidity | Post-operative morbidity was assessed in terms number of patients with at least one surgical complications related to treatment and related to a serious adverse event. | During the 30 first days after surgery (2SCA or CAA) | 
| Postoperative Mortality | Postoperative mortality was defined by the number of patients who deceased (all cause mortality) during the first 30 days after surgery (2SCA or CAA). | From the date of surgery to 30 days after surgery (2SCA or CAA) | 
| Progression-free Survival | Progression-free survival (PFS) was defined as the time from the date of surgery and the date of the earliest of the following events: The patient's death, whatever the cause, Local progression or remotely. Progression was defined as clinical or radioglogical progression. Radiological progression was defined Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions 1-year and 2-year progression-free rates were estimated. | 1 and 2 years after surgery (2SCA or CAA) | 
| Number of Participants With Anal Incontinence at 6 Months | The digestive functions, especially anal incontinence was evaluated according to the scale of 5 items Jorge and Wexner (score from 0 to 20). The rate of patients with anal incontinence (score >=5) at 6 months was reported. | At 6 months after surgery (2SCA or CAA) | 
| Number of Participants With Anal Incontinence at 12 Months | The digestive functions, especially anal incontinence was evaluated according to the scale of 5 items Jorge and Wexner (score from 0 to 20). The rate of patients with anal incontinence (score >=5) at 12 months was reported. | At 12 months after surgery (2SCA or CAA) | 
| Number of Participants With Anal Incontinence at 24 Months | The digestive functions, especially anal incontinence was evaluated according to the scale of 5 items Jorge and Wexner (score from 0 to 20). The rate of patients with anal incontinence (score >=5) at 24 months was reported. | At 24 months after surgery (2SCA or CAA) | 
| Absence at Day 30 of a Symptomatic Anastomotic Leakage (AL) Among CAA | Efficacy of the intervention was defined as the absence at day 30 of a symptomatic AL (either with entero-cutaneous fistula or perianastomotic abscess with infectious conditions and/or transit impairment) requiring diverting stoma. AL was defined as fecal matter in the drainage system when a drainage system was present. Clinical signs included fever and subocclusion requiring a pelvic scan and collection of liquid and gas in the peri-anastomotic region. Non-symptomatic ALs which did not require any investigation nor treatment, in particular no diverting stoma, were not considered failures. The effectiveness of the CAA surgery will be evaluated in terms of absence of fistula requiring stoma diversion. Similarly to 2SCA group, 53 CAA eligible and evaluable patients will be required. If 49 or more patients (out of 53) have no fistula requiring stoma diversion, then we conclude that the CAA is effective. To anticipate any non evaluable patients, we plan to recruit 58 patients CAA. | Colo-anal anastomosis effectiveness will be evaluated in terms of symptomatic anastomotic fistula occurring during the 30 days post anastomosis and requiring stoma derivation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal cancer, Coloanal anastomosis, Phase 2 clinical trial