Medium and Lower Rectal Cancer
Conditions
Keywords
Rectal cancer, Coloanal anastomosis, Phase 2 clinical trial
Brief summary
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.
Interventions
PROCEDURE2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA)
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
PROCEDUREColo-anal anastomosis (CAA)
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
Sponsors
Institut Bergonié
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absence at Day 30 of a Symptomatic Anastomotic Leakage (AL) Among 2SCA | Delayed coloanal anastomosis effectiveness was evaluated in terms of symptomatic anastomotic fistula occurring during the 30 days post anastomosis and requiring stoma derivation. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-operative Morbidity | During the 30 first days after surgery (2SCA or CAA) | 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. |
| Postoperative Mortality | From the date of surgery to 30 days after surgery (2SCA or CAA) | Postoperative mortality was defined by the number of patients who deceased (all cause mortality) during the first 30 days after surgery (2SCA or CAA). |
| Progression-free Survival | 1 and 2 years after surgery (2SCA or CAA) | 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. |
| Stomata Bypass (Preventive or Therapeutic) | Presence of stomata bypass was evaluated at 30 days, 1 year and 2 years after surgery (2SCA or CAA) | 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. |
| Number of Participants With Anal Incontinence at 12 Months | At 12 months after surgery (2SCA or CAA) | 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. |
| Number of Participants With Anal Incontinence at 24 Months | At 24 months after surgery (2SCA or CAA) | 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. |
| Absence at Day 30 of a Symptomatic Anastomotic Leakage (AL) Among 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. | 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. |
| Number of Participants With Anal Incontinence at 6 Months | At 6 months after surgery (2SCA or CAA) | 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. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) Patients treated with 2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA) in centers who routinely performing this intervention.
2-stage pull-through colo-anal anastomosis without prophylactic derivation (2SCA): 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 | 48 |
| Colo-anal Anastomosis (CAA) Patients operated with colo-anal anastomosis (CAA) in centers who routinely performing this intervention.
Colo-anal anastomosis (CAA): 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 | 52 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No or other surgical intervention | 7 | 5 |
| Overall Study | Protocol Violation | 10 | 2 |
Baseline characteristics
| Characteristic | Colo-anal Anastomosis (CAA) | Total | 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) |
|---|---|---|---|
| Age, Continuous | 63 years | 62 years | 61 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment France | 52 participants | 100 participants | 48 participants |
| Sex: Female, Male Female | 24 Participants | 43 Participants | 19 Participants |
| Sex: Female, Male Male | 28 Participants | 57 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 48 | 0 / 52 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 30 / 48 | 24 / 52 |
Outcome results
Primary
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.
Time frame: Delayed coloanal anastomosis effectiveness was evaluated in terms of symptomatic anastomotic fistula occurring during the 30 days post anastomosis and requiring stoma derivation.
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Absence at Day 30 of a Symptomatic Anastomotic Leakage (AL) Among 2SCA | 1 Participants |
Secondary
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.
Time frame: Colo-anal anastomosis effectiveness will be evaluated in terms of symptomatic anastomotic fistula occurring during the 30 days post anastomosis and requiring stoma derivation.
Population: Eligible patient (without major protocol deviation) which was operated with complete CAA procedure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Absence at Day 30 of a Symptomatic Anastomotic Leakage (AL) Among CAA | 5 Participants |
Secondary
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.
Time frame: At 12 months after surgery (2SCA or CAA)
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure and CAA for 2SCA group and CAA group respectively and who responded to the questionnaire.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Number of Participants With Anal Incontinence at 12 Months | 15 Participants |
| Colo-anal Anastomosis (CAA) | Number of Participants With Anal Incontinence at 12 Months | 36 Participants |
Secondary
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.
Time frame: At 24 months after surgery (2SCA or CAA)
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure and CAA for 2SCA group and CAA group respectively and who responded to the questionnaire.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Number of Participants With Anal Incontinence at 24 Months | 11 Participants |
| Colo-anal Anastomosis (CAA) | Number of Participants With Anal Incontinence at 24 Months | 29 Participants |
Secondary
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.
Time frame: At 6 months after surgery (2SCA or CAA)
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure and CAA for 2SCA group and CAA group respectively and who responded to the questionnaire.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Number of Participants With Anal Incontinence at 6 Months | 25 Participants |
| Colo-anal Anastomosis (CAA) | Number of Participants With Anal Incontinence at 6 Months | 32 Participants |
Secondary
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.
Time frame: During the 30 first days after surgery (2SCA or CAA)
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure and CAA for 2SCA group and CAA group respectively.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Post-operative Morbidity | 13 Participants |
| Colo-anal Anastomosis (CAA) | Post-operative Morbidity | 10 Participants |
Secondary
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).
Time frame: From the date of surgery to 30 days after surgery (2SCA or CAA)
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure and CAA for 2SCA group and CAA group respectively.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Postoperative Mortality | 0 Participants |
| Colo-anal Anastomosis (CAA) | Postoperative Mortality | 0 Participants |
Secondary
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.
Time frame: 1 and 2 years after surgery (2SCA or CAA)
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure and CAA for 2SCA group and CAA group respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Progression-free Survival | 1-year PFS | 76.5 percentage or paticipants |
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Progression-free Survival | 2-years PFS | 63.3 percentage or paticipants |
| Colo-anal Anastomosis (CAA) | Progression-free Survival | 1-year PFS | 92.2 percentage or paticipants |
| Colo-anal Anastomosis (CAA) | Progression-free Survival | 2-years PFS | 81.3 percentage or paticipants |
Secondary
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.
Time frame: Presence of stomata bypass was evaluated at 30 days, 1 year and 2 years after surgery (2SCA or CAA)
Population: Eligible patient (without major protocol deviation) which was operated with complete 2SCA procedure and CAA for 2SCA group and CAA group respectively.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Stomata Bypass (Preventive or Therapeutic) | 30 days | 2 Participants |
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Stomata Bypass (Preventive or Therapeutic) | 1 year | 3 Participants |
| 2-stage Pull-through Colo-anal Anastomosis Without Prophylactic Derivation (2SCA) | Stomata Bypass (Preventive or Therapeutic) | 2 years | 6 Participants |
| Colo-anal Anastomosis (CAA) | Stomata Bypass (Preventive or Therapeutic) | 30 days | 49 Participants |
| Colo-anal Anastomosis (CAA) | Stomata Bypass (Preventive or Therapeutic) | 1 year | 3 Participants |
| Colo-anal Anastomosis (CAA) | Stomata Bypass (Preventive or Therapeutic) | 2 years | 8 Participants |