MD Alexandre Challine

Jeremie Lefèvre

MD Ben Creavin

Olivier Benoit

MD Najim Chafai

MD Clotilde Debove

MD Thibault Voron

MD, PhD Yann Parc

MD, PhD Jeremie H Lefevre
email: jeremie.lefevre@aphp.fr

Jérémie H Pr

Lefèvre

Can a Local Drainage Salvage a Failed Colorectal or Coloanal Anastomosis? A Prospective Cohort of 54 Patients

Keywords: coloanal anastomosis, anastomotic leakage, anastomotic drainage, outcome

établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Indications for sphincter sparing rectal cancer resections have increased due to the reduction in the distal margin distance [START_REF] Moore | Adequacy of 1-cm distal margin after restorative rectal cancer resection with sharp mesorectal excision and preoperative combinedmodality therapy[END_REF][START_REF] Pahlman | Altering the therapeutic paradigm towards a distal bowel margin of < 1 cm in patients with low-lying rectal cancer: a systematic review and commentary[END_REF] and the downsizing effects of neoadjuvant therapy [START_REF] Appelt | Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy[END_REF] .

However, the rate of anastomotic leakage still ranges around 20% [START_REF] Denost | To Drain or Not to Drain Infraperitoneal Anastomosis After Rectal Excision for Cancer: The GRECCAR 5 Randomized Trial[END_REF][START_REF] Lefevre | Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6)[END_REF][START_REF] Hain | Persistent Asymptomatic Anastomotic Leakage After Laparoscopic Sphincter-Saving Surgery for Rectal Cancer: Can Diverting Stoma Be Reversed Safely at 6 Months?[END_REF] . Consequences of a leakage are severe and can lead to septic shock or death [START_REF] Peeters | Risk factors for anastomotic failure after total mesorectal excision of rectal cancer[END_REF] . The use of a diverting ileostomy does not prevent all anastomotic leakage; however, the severity of the sepsis related morbidity can be reduced [START_REF] Matthiessen | Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer: a randomized multicenter trial[END_REF][START_REF] Wong | A defunctioning ileostomy does not prevent clinical anastomotic leak after a low anterior resection: a prospective, comparative study[END_REF] . Leakages can be graded by the clinical outcomes of patients [START_REF] Rahbari | Definition and grading of anastomotic leakage following anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer[END_REF] . The most severe leakages (Grade C) are those who need a re-laparotomy for peritonitis. In such cases, the anastomosis is often taken down and an end stoma is created. For grade B leakage, medical treatment including antibiotics and local treatments are needed to treat a pelvic abscess. Finally, asymptomatic leakage can occur (A-grade) up to 6 months after bowel continuity [START_REF] Robert | Percutaneous transgluteal drainage of pelvic abscesses in interventional radiology: A safe alternative to surgery[END_REF] .

Recently, the endo-SPONGE ® has been used to treat leakage but currently there are few studies with small sample sizes describing this procedure [START_REF] Mussetto | Long-term efficacy of vacuum-assisted therapy (Endo-SPONGE((R))) in large anastomotic leakages following anterior rectal resection[END_REF][START_REF] Van Koperen | The Dutch multicenter experience of the endo-sponge treatment for anastomotic leakage after colorectal surgery[END_REF][START_REF] Arezzo | Long-term efficacy of endoscopic vacuum therapy for the treatment of colorectal anastomotic leaks[END_REF][START_REF] Jimenez-Rodriguez | A New Perspective on Vacuum-Assisted Closure for the Treatment of Anastomotic Leak Following Low Anterior Resection for Rectal Cancer, Is It Worthy?[END_REF][START_REF] Strangio | Endo-sponge therapy for management of anastomotic leakages after colorectal surgery: A case series and review of literature[END_REF][START_REF] Borstlap | Vacuum-assisted early transanal closure of leaking low colorectal anastomoses: the CLEAN study[END_REF][START_REF] Gardenbroek | Early reconstruction of the leaking ileal pouch-anal anastomosis: a novel solution to an old problem[END_REF][START_REF] Shalaby | Systematic review of endoluminal vacuum-assisted therapy as salvage treatment for rectal anastomotic leakage[END_REF] . Stoma reversal rates following this procedure vary between 37-90%. This technique requires several procedures in order to change the endo-SPONGE ® but can be performed in an outpatient setting and sometimes without sedation. The majority of grade B leakages are drained either by a surgical trans-anal approach or a radiological approach.

Radiologic trans-gluteal drainage is a safe with rare complications reported as hemorrhage or creation of a fistula tract [START_REF] Harisinghani | Transgluteal approach for percutaneous drainage of deep pelvic abscesses: 154 cases[END_REF] and effective approach with successful management of abscess without recurrence being reported around 96% [START_REF] Robert | Percutaneous transgluteal drainage of pelvic abscesses in interventional radiology: A safe alternative to surgery[END_REF][START_REF] Harisinghani | Transgluteal approach for percutaneous drainage of deep pelvic abscesses: 154 cases[END_REF] . However, the functional outcomes of the anastomosis after radiological drainage is unknown. This too is true with regard to the trans-anal approach, with a lack of data currently in the literature. [START_REF] Okoshi | Efficacy of transanal drainage for anastomotic leakage after laparoscopic low anterior resection of the rectum[END_REF][START_REF] Sirois-Giguere | Transanal drainage to treat anastomotic leaks after low anterior resection for rectal cancer: a valuable option[END_REF] The need for a further drainage with this approach is reported to be 38% without abdominal surgery, however, stoma reversal rates are above 90% [START_REF] Sirois-Giguere | Transanal drainage to treat anastomotic leaks after low anterior resection for rectal cancer: a valuable option[END_REF] .

Definitive stoma rates following failed sphincter sparing surgery is close to 20% for all rectal cancer patients [START_REF] Den Dulk | A multivariate analysis of limiting factors for stoma reversal in patients with rectal cancer entered into the total mesorectal excision (TME) trial: a retrospective study[END_REF] . Maggiori et al. found the rate of definitive stoma increases after a nonconservative approach for grade C leakage [START_REF] Maggiori | Conservative management is associated with a decreased risk of definitive stoma after anastomotic leakage complicating sphincter-saving resection for rectal cancer[END_REF] . Redo surgery to create a new anastomosis is challenging, with a high morbidity and risk of injury to the genitourinary system [START_REF] Pitel | Redo coloanal anastomosis: a retrospective study of 66 patients[END_REF][START_REF] Lefevre | Redo surgery for failed colorectal or coloanal anastomosis: a valuable surgical challenge[END_REF] .

The aim of this study was to evaluate the efficacy of drainage procedures in maintaining a primary low anastomosis following anastomotic leakage

MATERIAL AND METHODS

Study design and settings

A retrospective observational study was performed on a prospectively maintained database of patients undergoing rectal resections with either a colorectal or coloanal anastomosis (CR-CAA) with diverting stoma between 2014-2017. Patients medical records were reviewed for patient characteristics, co-morbidities, surgical and histological characteristics, date of drain, duration of drain, the need for redo coloanal anastomosis and stoma closure rates.

Population and follow-up

Patients who had an anastomotic leakage diagnosed by imaging (CT scan) or local examination under general anesthesia and requiring a radiologic or trans anal surgical drainage during their post-operative courses were analyzed. Patients were excluded if they presented with peritonitis requiring emergency surgery by abdominal approach. Follow-up included clinical examination and C-Reactive Protein (CRP) levels at 1, 3 and 5 postoperative days [START_REF] Benoit | C-Reactive Protein Values After Colorectal Resection: Can We Discharge a Patient With a C-Reactive Protein Value >100? A Retrospective Cohort Study[END_REF] . In case of any deviation in the post-operative clinical course, a CT scan was performed. When a pelvic abscess occurred, 2 types of pelvic drainage were utilized: a radiologic drain (usually done under CT guidance) by a trans gluteal approach or by a trans anal approach under a general anesthetic. Drains were flushed with 10cc of sterile saline 3 times a day by a specialized nurse. Drains were removed when outputs remained low (<20cc a day) or when a repeat CT scan showed good resolution of the collection. When patients were discharged home with a drain, outpatient consultations occurred weekly. A consultation 1 month after discharge was performed to repeat a CT scan to assess resolution of the leakage and plan the stoma closure. Before stoma closure, integrity of anastomosis was tested with radiological assessment and clinical local exam. In case of persisting leakage with chronic sepsis or stricture, a redo surgery and new CAA was performed. The follow-up was stopped on October the first 2018.

Outcome and variables

The primary outcome was maintenance of the primary CR-CAA after a local drainage and the closure of the diverting stoma. The secondary outcome was the rate of definitive stoma.

Statistical analysis

The R software was used (R Development Core Team (2005). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL: http://www.R-project.org). Descriptive analysis was performed using percentages, means, medians and proportion, with standard deviation and interquartile ranges reported. Univariate analysis was performed on the primary binary outcomes with general linear models with the univariateTable function of the R-Package Publish. A p-value lower than 0.05 was considered as significant. (software version 9.3; SAS Institute Inc., Cary, NC, USA). .

RESULTS

Participants and incidence of leakage

The flowchart of the study is presented in the figure 1. A total of 326 patients underwent a low anastomosis with diverting stoma for rectal cancer in the present study, of which, 77 (23.6%) anastomotic leakages occurred. 11 (3.4%) anastomotic leakages needed an emergency abdominal surgery (Grade C). Among the remaining 66 B-grade leakages, 17 (5.2%) were treated medically with antibiotics alone and 49 (15.0%) were managed by drainage. The evolution of our practice is illustrated in figure 2. There was no difference in the rate of leakage per year (p=0.41), or number requiring drainage (p=0.30), however, abdominal re-intervention for new coloanal anastomosis rates were lower (p<0.001).

Characteristics of drained patients

49 patients underwent pelvic drainage, with the majority diagnosed by fever in the postoperative course. 43 patients (96%) had a CRP at post-operative day (POD) 3 or 5 >100. Patient characteristics are detailed in table 1. The mean age was 62±13 years, of which, 29 (59.2%) were male. A total of 34 patients (69%) underwent neoadjuvant therapy. 47 (96%) patients had resections for low or mid rectal tumors. All patients had a diverting ileostomy. A laparoscopic approach was the most frequent approach used (n=40, 82%). The majority of patients had a J-pouch or side to end anastomosis (n=40, 82%).

Drainage description

Characteristics of drain management are described in table 2. A surgical trans-anal approach under general anesthetic was performed for 18 (37%) patients while 31 (63%) patients underwent a radiological transgluteal approach. Surgical trans-anal drainage was more likely used for purulent flowing and radiological drainage for fever (p=0.01). The median interval between surgery and drainage was 15 days [9-24]. Escherichia coli was found in 19 (73%) available cases while 2 (10%) had extended spectrum Beta Lactamase. Drainage duration more than 10 days was more frequent for surgical drainage (p<0.001). 14 (28%) patients needed a second drainage to treat a recurrent abscess (median time interval between drainages of 44 days [22-66]). The length of stay (LOS) for surgery and drain management was 24±10 days. LOS was lower for radiologic drainage (22±10 vs. 28±10, p=0.02). 12 (26%) patients were discharged with a drain.

Follow-up

Maintenance of the anastomosis was achieved in 24 (49%) patients, with stoma reversals after a mean interval of 5.0 ± 2.7 months. 20 (41%) patients needed a new procedure to treat a chronic leakage (n=18, 90%) or a stenosis (n=2, 10%). Among those 20, 14 (70%) patients required a new coloanal or ileoanal anastomosis, 4 (20%) required a new delayed coloanal anastomosis, and 2 (10%) had an endstoma performed. 39 on the 49 patients (80%) had no stoma at the end of follow up (22 ± 14 months) with stoma closure interval of 7 ± 4 months and 15 ± 12 months of follow-up after stoma reversal.

On those 10 patients who had a definitive stoma (20%), 5 had a redo-procedure, with 2 patients who had an end stoma during the redosurgery, 3 presented a recurrence of leakage after their redo coloanal anastomosis. 5 patients had not redosurgery and no stoma reversal (1 lost of follow-up, 2 for chronic leakages, 2 for patient's refusal).

Risk factor of failure to maintain the anastomosis

In univariate analysis (table 3), a surgical drainage (p=0.05), a drainage duration> 10 days (p=0.005), the interval between surgery and drainage> 15 days (0.03), side to end or Jpouch anastomosis (p=0.02) and year of surgery were associated with failure to maintain the CR-CA anastomosis.

DISCUSSION

This study reports a single centers experience of drainage procedures following anastomotic leakage for low colorectal/coloanal anastomosis for rectal cancer. Maintenance of the anastomosis was achieved in 50% of the cohort undergoing local drainage, however, the rate of definitive end stoma was 20%. The present study found that a short drainage duration was associated with maintenance of the primary anastomosis in univariate and multivariate analysis. Furthermore, the implementation of a more conservative management (drainage) over the years, decreased the rate of redo-surgery, increasing the likelihood of maintaining the anastomosis.

Local drainage

Only 5 patients, excluded from the analysis, needed an emergency abdominal surgery after a local drainage for peritonitis. The choice of the drainage procedure is not clear in the literature.

In our study, we found a benefit to maintain for the radiological drainage in univariate analysis.

A recent review reported quite the same rate of definitive stoma of 25% after vacuum-assisted therapy. [START_REF] Shalaby | Systematic review of endoluminal vacuum-assisted therapy as salvage treatment for rectal anastomotic leakage[END_REF] Bortslap et al. found also the same efficacity to heal leakage at 6 months with only the half of anastomosis healed. [START_REF] Borstlap | Vacuum-assisted early transanal closure of leaking low colorectal anastomoses: the CLEAN study[END_REF] However, utilizing a local drainage as a first approach in the management of grade B leakages is feasible based on the results reported in the present study.

Definitive stoma rate and leakage rate

The end-stoma rate in this study is in line with previous reported literature (>20%) [START_REF] Denost | To Drain or Not to Drain Infraperitoneal Anastomosis After Rectal Excision for Cancer: The GRECCAR 5 Randomized Trial[END_REF][START_REF] Den Dulk | A multivariate analysis of limiting factors for stoma reversal in patients with rectal cancer entered into the total mesorectal excision (TME) trial: a retrospective study[END_REF] although, the results in the present study are based on grade B leakages with longer follow up.

Overall symptomatic leakage rate was 24% with 3% classified as grade C leakage and 20% as grade B. These rates are in accordance with previous reported studies, with rates varying between 8-28% [START_REF] Denost | To Drain or Not to Drain Infraperitoneal Anastomosis After Rectal Excision for Cancer: The GRECCAR 5 Randomized Trial[END_REF][START_REF] Lefevre | Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6)[END_REF][START_REF] Detering | Three-Year Nationwide Experience with Transanal Total Mesorectal Excision for Rectal Cancer in the Netherlands: A Propensity Score Matched Comparison with Conventional Laparoscopic Total Mesorectal Excision[END_REF] . Our rate of leakage is high, but the inclusion of patient is highly selective with 96% of patients had a low or a mid tumors and consequently had a total mesorectal excision. [START_REF] Matthiessen | Risk factors for anastomotic leakage after anterior resection of the rectum[END_REF] Near 70% of patients had neoadjuvant therapy. Even if neoadjuvant irradiation did not seem increase the rate of leakage, literature is not clear about the outcome of a leakage occurring after radiotherapy. [START_REF] Chang | Preoperative chemoradiotherapy effects on anastomotic leakage after rectal cancer resection: a propensity score matching analysis[END_REF][START_REF] Hu | Does neoadjuvant therapy increase the incidence of anastomotic leakage after anterior resection for mid and low rectal cancer? A systematic review and meta-analysis[END_REF] It could increase the rate of definitive stoma. At least, rate of leakage varies based on definition of leakage [START_REF] Olsen | Rate of anastomotic leakage after rectal anastomosis depends on the definition: Pelvic abscesses are significant[END_REF] , and our definition of leakage included all pelvic collection and peritonitis.

Risk factors

The present study reported that an early and short duration drainage was associated with maintenance of the anastomosis. However, this should be interpreted with caution and could be influenced by leakage and drainage characteristics. For example, a leakage with high output is associated with worse outcomes and may require a longer drainage period especially if there is a longer interval between surgery and drainage. Previous studies report similar result with improved stoma reversal rates after an early drainage [START_REF] Van Koperen | The Dutch multicenter experience of the endo-sponge treatment for anastomotic leakage after colorectal surgery[END_REF][START_REF] Jimenez-Rodriguez | A New Perspective on Vacuum-Assisted Closure for the Treatment of Anastomotic Leak Following Low Anterior Resection for Rectal Cancer, Is It Worthy?[END_REF] . As showed in several studies on the vacuum therapy, leakages with an early drainage have a better prognostic than others. [START_REF] Van Koperen | The Dutch multicenter experience of the endo-sponge treatment for anastomotic leakage after colorectal surgery[END_REF][START_REF] Borstlap | Vacuum-assisted early transanal closure of leaking low colorectal anastomoses: the CLEAN study[END_REF] It is probably explained by the fibrosis which is more frequent after a chronic leakage found during the redo-surgery. Influenced by previous reports in the literature, the management of anastomotic leakage in our center has evolved, which has resulted in a reduction in the number of re-do surgeries [START_REF] Hain | Persistent Asymptomatic Anastomotic Leakage After Laparoscopic Sphincter-Saving Surgery for Rectal Cancer: Can Diverting Stoma Be Reversed Safely at 6 Months?[END_REF][START_REF] Maggiori | Conservative management is associated with a decreased risk of definitive stoma after anastomotic leakage complicating sphincter-saving resection for rectal cancer[END_REF][START_REF] Fong | Chronic anastomotic sinus after low anterior resection: when can the defunctioning stoma be reversed?[END_REF] . This evolution was significantly associated with maintaining the anastomosis on univariate and multivariate analysis. Furthermore, and end-to-end anastomosis was associated with maintenance of the anastomosis compared to a side-to-end or J-pouch anastomosis. We did not have the details of the leakage location in patients with side-to end of J pouch. Interestingly, Hain et al. found no difference in terms of definitive stoma rates based on the location of leakage in side to end or J-pouch anastomosis [START_REF] Hain | Anastomotic leakage after side-toend anastomosis for rectal cancer: does leakage location matter?[END_REF] . The functional outcome is significantly better when an alternative anastomosis to an end to end is used. We believe that an end-to-end should be not systematically performed in regards of our results to improve the functional results and quality of life. However, it may be of interest in high-risk patient as recent randomized control trials have questioned this finding [START_REF] Marti | Clinical Outcome After Rectal Replacement With Side-to-End, Colon-J-Pouch, or Straight Colorectal Anastomosis Following Total Mesorectal Excision: A Swiss Prospective, Randomized, Multicenter Trial[END_REF] . Finally, after comparison of type of local drainage, radiological drainage was associated with the success to maintain the primary anastomosis.

Limitations

Firstly, the retrospective design of the present study does not allow the authors to standardize the indication for drainage. The majority of drainages in this study were performed for sepsis, however, some drainages were performed for asymptomatic leakage, elevated CRP levels and following radiological assessment. Surgical trans-anal drainage was commonly utilized for purulent leakage. There was no significant difference regarding the maintenance of anastomosis, but all 6 patients drained for purulent flowing did not kept their initial anastomosis. Characteristics of each drainage influenced the length of stay and the feasibility of outpatient management for the drain. The use of CT scans to diagnose anastomotic leakage has increased over the years, mainly due to the improved access to scanners and imaging quality. Bias in this study was minimized by adjusting for time on multivariate analysis.

However, data collection on drain output, microbiology and length of drainage was limited due to the retrospective nature of the study.

Furthermore, the small size of patients undergoing drainage was small, limiting the results of the study and the strength of the association interpretation. However, to the authors knowledge, this is the first and largest study to assess risk factor for failing to maintain a colorectal anastomosis.

Conclusion

Local drainage avoided re-do anastomosis in 50% of patients who had a grade B leakage for low colorectal/coloanal anastomosis for rectal cancer. An end-to-end anastomosis, a shorter length of drainage and radiological drainage were associated with maintenance of the primary anastomosis. End stoma (n=10)

Figure 1 .Figure 2 .

 12 Figure 1. Flow chart of the study

Figure 2 .

 2 Figure 2. Representation of the evolution of the rates of conservation, leakage, drainage and new anastomosis by years.

Figure 2 Introduction Background/rationale 2 3 3 4 Methods Study design 4 4 5 5 4 7 5 Data sources/ measurement 8 * 5 9 Describe any efforts to address potential sources of bias page 5 5 ( 5 Continued on next page Results Participants 13 * 5 ( 6 data 15 * 7 Discussion 7 Limitations 19 9 Interpretation 20 8 Generalisability 21 1 *

 22334445547585955513561577199208211 Figure 2

Table 1 .

 1 Characteristics of patient treated by local drainage.

	Type

Table

Table 2 .

 2 Characteristics of drainage

	Total (n=49)

Table 3 .

 3 univariate analysis: risk factors of a failure to maintain the CR-ACA anastomosis

	Variable		Success (n=24)	Failure (n=25)	p value
	Age		59.1 ± 13.4	65.0 ± 12.5	0.11
	BMI		25.1 ± 4.4	24.8 ± 3.8	0.82
	% of male		17 (70.8)	12 (48.0)	0.18
		1	10 (41.7)	9 (36.0)
	ASA score	2	13 (54.2)	15 (60.0)	0.92
		3	1 (4.2)	1 (4.0)
	Local resection before LARS		3 (12.5)	2 (8.0)	0.96
	Neoadjuvant Teatment		14 (58.3)	20 (80.0)	0.18
	Length between anal sphincter and tumor	1-3 cm 3-8 cm 8-13 cm	13 (54.2) 9 (37.5) 2 (8.3)	11 (44.0) 14 (56.0) 0 (0.0)	0.2
	Laparoscopy		20 (83.3)	20 (80.0)	1
	Mechanical anastomosis		13 (56.5)	10 (40.0)	0.39
	Type of anastomosis	End to end Others	8 (33.3) 16 (66.7)	1 (4.0) 24 (96.0)	0.02
	Pelvic drainage		12 (50.0)	20 (80.0)	0.06
	T	0-2 3-4	11 (45.8) 13 (54.2)	8 (32.0) 17 (68.0)	0.48
	N	0 +	17 (70.8) 7 (29.2)	12 (48.0) 13 (52.0)	0.18
	M	1	1 (4.2)	2 (8.0)	1
	R	1	1 (4.2)	4 (16.0)	0.37
	Adjuvant treatment		6 (25.0)	13 (54.2)	0.08
	Septic leakage		16 (66.7)	12 (48.0)	0.3
	Type of drain	Surgical Radiological	5 (20.8) 19 (79.2)	13 (52.0) 12 (48.0)	0.05
	Time between surgery and drainage > 15 days	8 (33.3)	17 (68.0)	0.03
	Duration of drainage > 10 days	4 (16.7)	15 (60.0)	0.005
	Need for 2 nd drainage		4 (16.7)	10 (40.0)	0.14
	Year of surgery	2014-2015 2016-2017	7 (29.2) 17 (70.8)	19 (76.0) 6 (24.0)	0.003