Improving Outcomes in Laparoscopic Anterior Rectal Resection: The Benefits of REAL Score in Preoperative Risk Assessment for Anastomotic Leak

doi:10.21203/rs.3.rs-3301169/v1

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Improving Outcomes in Laparoscopic Anterior Rectal Resection: The Benefits of REAL Score in Preoperative Risk Assessment for Anastomotic Leak

https://doi.org/10.21203/rs.3.rs-3301169/v1

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PURPOSE To evaluate the effectiveness of a preoperative risk assessment tool called REctal Anastomotic Leak (REAL) score for predicting the risk of anastomotic leakage in patients undergoing laparoscopic anterior rectal resection with total mesorectal excision for rectal cancer.

METHODS This prospective study was conducted from May 1st ,2018, to May 1st, 2021 and included a consecutive unselected series of patients undergoing elective laparoscopic anterior rectal resection with total mesorectal excision for rectal cancer. We collected data on patients' medical histories, surgical procedures, length of hospital stay, and short-term outcomes. Operative steps, instrumentation, and postoperative cares were standardized to ensure patient consistency. We used the Charlson Comorbidity Index and the Clavien-Dindo classification system to assess comorbidities and complications respectively. We calculated the REAL score for each patient and statistically compared those who experienced an anastomotic leak to those who did not. Additionally, we conducted a univariate and multivariate analysis on other factors that may have influenced outcomes.

RESULTS The study included 57 patients with a mean age of 70 years and a Charlson Comorbidity Index of 6.1 ± 1.9. The tumor was located in the upper, mid, and lower rectum in 45.6%, 33.3%, and 21.1% of cases, respectively, and 57.9% of patients had a loop ileostomy fashioned. Indocyanine green angiography was used during surgery in 53.3% of cases. We had 3 cases (5.3%) of conversion to open laparotomy. Post-operative complications according to the Clavien-Dindo system showed rates of 21.0%, 8.8%, and 7.0% for grades 1, 2, and 3b, respectively. There were 6 cases of anastomotic leakage, with 4 treated surgically and 2 conservatively. Patients with anastomotic leak had a significantly higher REAL score than those without (71.3 ± 20.5 vs. 33.7 ± 21.3). The 30-day readmission and mortality rates were 5.3% and 0%, respectively. Low preoperative serum albumin levels, preoperative blood transfusions, and the absence of indocyanine green angiography during surgery were factors significantly associated with an increased risk of anastomotic leakage according to both univariate and multivariate analyses.

CONCLUSIONS The REAL score may be a helpful tool for evaluating the risk of anastomotic leak in patients undergoing laparoscopic anterior rectal resection with total mesorectal excision. Further investigation is needed to assess a potential improvement in the yield of the REAL score by incorporating the analysis of additional modifiable factors such as hypoalbuminemia, preoperative transfusion rate, and the use of indocyanine green fluorescence angiography during surgery.

anastomotic leak

anterior rectal resection

laparoscopy

risk factors

REAL score

Anterior rectal resection (ARR) with total mesorectal excision (TME) is the standard of care for rectal cancers eligible to surgery [1]. The prevalence of sphincter-preserving procedures has increased due to advancements in surgical techniques, dissection and transection devices, and anastomosis formation, as well as the widespread use of neoadjuvant therapeutic protocols. Minimally invasive procedures have reduced surgical trauma, resulting in more rapid and effective patient recovery. Level 1A evidence has suggested that a minimally invasive approach proved superior in terms of early outcomes and at least comparable oncological results to traditional surgery [2]. Despite this, the fashioning of colorectal anastomosis still represents a critical step during ARR. Colorectal anastomoses are, in fact, burdened by a high rate of dehiscence ranging from 1.8 to 19.2% [3], with a negative impact not only on post-operative morbidity and mortality but also on oncological outcomes [4]. Patients who developed AL showed a high reoperation rate, resulting in more extended post-operative hospital stays and delay in starting complementary therapies, also increasing the risk of 5-year local recurrences [5, 6]. AL is interpreted as the result of a complex and dynamic interaction between several factors, depending on the patient's performance status, characteristics of the tumor, and intraoperative findings. Identifying these factors early to stratify the risk of AL for each patient and consequently develop a predictive dehiscence model is today essential for orienting the surgical decision-making process. Meta-analysis on 26 studies involving a cohort of 9735 patients published in 2019 by Arezzo et al proposed a predictive score of anastomotic dehiscence after ARR, called REctal Anastomotic Leak - REAL – score [7]. It has a sensitivity of 79.1% and a specificity of 32.9% in identifying anastomotic leaks. The key advantage of the REAL score is that it can be used pre-operatively to influence surgical planning. In contrast, other predictive tools for anastomotic leakage rely on data that emerges in the days following surgery [8]. This study aimed to check the applicability of REAL score for the preoperative estimation of AL, focusing exclusively on laparoscopic ARR with TME. We hypothesized that this tool was helpful and that its integration with additional pre- and intra-operative evaluation elements could improve its effectiveness.

This study prospectively collected and analyzed data from a consecutive series of patients who underwent laparoscopic ARR with TME for rectal cancer at our division between May 1st, 2018, and May 1st, 2021. All patients diagnosed with rectal cancer who underwent elective laparoscopic ARR with TME as the initial treatment or following neoadjuvant therapy were included. In all cases, neoadjuvant treatment decisions were made after diagnostic workup and multidisciplinary discussion. Patients eligible for local excision, emergency procedures, Hartmann’s procedure, and abdominoperineal resection were excluded. Patients with a complete response after neoadjuvant therapy have been excluded as well. Preoperative diagnostic workup included a colonoscopy, contrast-enhanced CT scan of the thorax and abdomen, rectal endoscopic ultrasound, and pelvic MRI for all patients. Data were stored in prospectively updated institutional databases. Demographics, surgery- and postoperative-related data, and short-term outcomes were analyzed for each patient (Table 1). Comorbidity of each patient was assessed by Charlson comorbidity index [9]. Mechanical bowel preparation was performed using polyethylene glycol 70 + 70 g/2 L the day before surgery. All patients pre-operatively received short-term broad-spectrum intravenous antibiotics (ceftizoxime plus metronidazole) and antithrombotic prophylaxis with low molecular weight heparin according to body weight. A nasogastric tube and a urinary catheter were placed after induction of general anesthesia in all cases. All the procedures were performed by the same team, fully trained in both colorectal and minimally invasive surgery. Surgical instrumentation was standardized, and dissection was performed by harmonic scalpel (Harmonic ACE, Ethicon Endo-Surgery, OH, US). As regards surgical technique, all the procedures were performed using a standardized fully laparoscopic 4-port technique with a medial-to-lateral approach. Both inferior mesenteric artery and vein were highly ligated, as well as splenic flexure was routinely mobilized. Total mesorectal excision was performed according to the standard technique [10] and an end-to-end colorectal anastomosis fashioned using the Knight-Griffen technique. The level of visceral section was decided by NIR-near infrared fluorescence-guided angiographic evaluation after intravenous injection of 5-ml of solution containing ICG-indocyanine green (Verdye 25-mg, Diagnostic Green GmbH, DE) with a dilution of 2.5-mg/ ml. A loop ileostomy was fashioned in all cases of tumor located at the extraperitoneal rectum. Drains were not routinely used in our practice. Post-operative medical and nursing care followed a standardized protocol. The clinical course of each patient was documented. Early mobilization was encouraged, with removal of the urinary catheter. The nasogastric tube was removed after the first flatus. Criteria for the discharge included the absence of symptoms, tolerance of a minimum of 3 meals without restrictions and passage of stool. All adverse events occurring within 30 days post-surgery were considered complications and classified using the Clavien-Dindo classification system [11]. Anastomotic leakage was defined as any clinical or radiological evidence of anastomotic dehiscence, with or without the need for surgical revision, in accordance with the definition established by the ISREC-International Study Group of Rectal Cancer [12]. To evaluate the applicability of the REAL score in our laparoscopic series, patients were divided into two cohorts based on whether or not they developed AL. The REAL score percentage was calculated for all patients using a specific web-app (https://www.real-score.org) and the groups were compared using appropriate statistical methods. Univariate and multivariate analyses were conducted on both cohorts, focusing on integrative pre- and intraoperative elements not included in the predictive model under analysis. Short-term follow-up was conducted 30 days post-surgery.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation and analyzed using the T-Student test for normally distributed data and the Mann-Whitney U test for non-normally distributed data. Categorical variables were described as percentages and analyzed using the Chi-square test with Yates correction or Fisher’s exact test, as appropriate. A multivariate analysis of complication risk factors was also performed using binary logistic regression with a backward method. Results were reported as p-values, odds ratios, and 95% confidence intervals. A p-value of less than 0.05 was considered statistically significant. The statistical analysis was performed using XLSTAT version 2019.1 (Addinsoft Inc., NY, US).

Ethics

This study obtained Institutional Review Board approval. Patients provided informed consent for surgery or other procedures. The study followed the ethical guidelines contained in the ‘‘World Medical Association Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects’’ adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, more recently revised by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013 [13].

Table 1: Data Analyzed
Data	Item
Demographics/ pathology	Age, y
	Sex
	BMI, kg/m2
	ASA score
	Charlson Comorbidity Index
	History of previous abdominal surgery
	Preoperative hemoglobin value
	Preoperative transfusion
	Preoperative serum albumin value
	Preoperative TNM staging^a
	Preoperative CEA
	Rate of neoadjuvant therapy
Surgery-related	Conversion to open
	Operative time
	Estimated blood loss, mL
	ICG-NIR fluorescence using
	Stapler firings number
	Loop ileostomy rate
Outcomes	Time of first stool, d
	Early postoperative complications^b
	Anastomotic leak
	Reoperation rate
	Length of hospital stay, d
Short-term follow up	Late postoperative complications
	30-days readmission rate
Abbreviations:
	ASA, American Society of Anesthesiology
	BMI, Body Mass Index
	CEA, carcinoembryonic antigen
	ICG-NIR, indocyanine green - near-infrared
^a American Joint Cancer Committee/ Union Internationale Contre le Cancer - AJCC/ UICC
^b Clavien-Dindo classification system

Demographics and disease-related data are summarized in Table 2. Table 3 collects data related to surgery and short-term outcomes of the patients. We used ICG-NIR fluorescence technology for 54.4% of the patients since we adopted it in mid-2019. We converted three cases (5.3%) to open laparotomy due to anatomical difficulties that prevented safe laparoscopy. Postoperative complications, classified according to the Clavien-Dindo system, are summarized in Table 4. Six cases (10.5%) had AL, which required surgery in four cases (Clavien-Dindo grade IIIb) and conservative treatment in two cases (Clavien-Dindo grade II). The 30-days readmission rate at 30 was 5.3%. All three readmitted cases had adhesive small bowel obstruction, one of which showed resolution after conservative therapy while two underwent surgery with synchronous closure of the ileostomy. Figure 1 shows that the REAL score values were significantly higher in the AL group (71.3 ± 20.5) than in the non-AL group (33.7 ± 21.3). Table 5 shows the univariate and multivariate analysis results of other risk factors for AL not included in the REAL score. Low preoperative albumin levels, preoperative blood transfusions and the application of ICG-NIR angiography during surgery were statistically significant risk factors.

Table 2: Demographics and disease-related data (median ± SD - N, %)
Age, y		70 ± 10.8
Male/ Female		43/14, 75.4/24.6
ASA score	I	29, 50.9
	II	21, 36.8
	III	7, 12.3
	IV	0, 0
BMI, kg/m2		26.2 ± 4.5
Charlson Comorbidity Index		6.1 ± 1.9
Diabetes		9, 15.8
Smoke		14, 24.5
Previous abdominal surgery		13, 22.8
Mean preoperative hemoglobin value, mg/mL		13.3 ± 2.9
Preoperative blood transfusions		7, 12.3
Mean preoperative albumin value, g/dL		3.7 ± 0.6
Carcinoembryonic antigen value, ng/mL		5.4 ± 12.1
Tumor location§, cm	11–15	26, 45.6
	6–10	19, 33.3
	< 5	12, 21.1
Neoadjuvant therapy		16, 28.1
T stagingç	Tx	2, 3.5
	T1	8, 14.0
	T2	16, 28.1
	T3	25, 43.9
	T4	6, 10.5
N staging	N0	39, 68.4
	N1	9 (15.8)
	N2	9 (15.8)
M staging	M0	55, 96.5
	M1	2, 3.5
§ from anal verge
ç UICC - Union for International Cancer Control

Table 3: surgery-related data and short-term outcomes (median ± SD - N, %)
Operative time, min	308 ± 70.7
Estimated blood loss, mL	60.6 ± 8.1
Loop ileostomy rate	33, 57.9
ICG-NIR fluorescence*	31, 54.4
Number of stapler firings for rectal division	1.5 ± 0.6
Conversion rate	3, 5.3
Anastomotic leak	6, 10.5
Reoperation	4, 7.0
Hospital stay, dd	13.6 ± 9.9
Number of lymph nodes harvested	24.5 ± 12.2
Positive lymph nodes	1.3 ± 2.7
30-day readmission rate	3, 5.3
* IndoCyanine Green-Near InfraRed

Table 4: Complications according to Clavien-Dindo classification system
Grade		N, %
I	Postoperative ileus	3, 5.3
	Acute retention of urine	3, 5.3
	Wound infection	2, 3.5
	Pneumonia	2, 3.5
	Proctorrhagia	1, 1.7
	Partial ileostomy detachment	1, 1.7
	Total	12, 21.0
II	Blood transfusion	3, 5.3
	Anastomotic leak	2, 3.5
	Total	5, 8.8
III a	Total	//
III b	Anastomotic leak	4, 7.0
	Total	4, 7.0
IV a	Total	//
IV b	Total	//
V	Total	//

	N 57 (%)	ReAL score (% ± SD)	p value
no-AL	51 (89.5)	33.684 ± 21.283
AL	6 (10.5)	71.257 ± 20.484	0.0001

Table 5: Additional risk factors for AL (median ± SD - N, %)

	Univariate analysis			Multivariate analysis
	AL	no-AL	p value	Chi-square Wald	p value
n	6, 10.5	51, 89.5
Operative time, min	290.0 ± 65.57	315.88 ± 76.78	0.496
Estimated blood loss, mL	62.0 ± 8.36	60.33 ± 8.04	0.438
Charlson comorbidity index	6.00 ± 1.41	6.176 ± 1.925	0.829
ICG-NIR fluorescence*	0, 0	31, 54.4	0.005	0.0001	0.005
Number of stapler firings for rectal division	2 ± 0.7	1.43 ± 0.55	0.036	19.561	0.148
Preoperative albumin level, mg/dL	3.038 ± 0.30	3.837 ± 0.562	0.001	33.743	0.004
Preoperative blood transfusions	3, 50	2, 3.9	0.001	0	0.035
* IndoCyanine Green-Near InfraRed

Anastomotic leakage (AL) is one of the most insidious and potentially fatal sequela of colorectal surgery, negatively impacting on morbidity and quality of life as well as on both disease-free and overall survival [14, 15]. AL after rectal surgery is globally higher than that recorded after resective surgery of both right and left colon. As a result, ARR with TME represents the colorectal surgical procedure with the greatest risk of developing postoperative AL [16]. AL was also shown to be independently associated with major low anterior resection syndrome, resulting in a decreased quality of life [17]. The ISREC-International Study Group of Rectal Cancer has defined AL as a defect in intestinal wall integrity localized at the colorectal or colo-anal anastomotic site - including manual, mechanical or neorectal reservoir suture lines - responsible for the formation of a communication between the intraluminal and the extraluminal spaces. A pelvic abscess located near the anastomosis was also to be considered as an expression of AL [12]. The etiopathogenesis of AL is multifactorial and includes various risk factors, such as patient-related factors, disease-related factors, and surgery-related factors. Furthermore, host genetics, gut microbiota, inflammation, and the immune system may play roles in AL [18, 19]. Identifying risk factors and developing predictive tools to stratify the risk of AL for each patient have become essential in colorectal surgery. The REAL score is a predictive model designed to quantify the factors associated with the risk of AL pre-operatively. The AL rate from the original paper on 9735 patients was 9.7%, ranging from 0.0 to 36.3% [7]. Compared to other tools such as the Dutch Leakage - DULK - score or the C-reactive protein and procalcitonin dosage which have emerged as effective predictors of AL starting from the 2–3 postoperative day [20–21], the main feature of REAL score is to calculate the risk of AL pre-operatively, and identified five major risk factors responsible for its occurrence, namely male gender, preoperative short-course radiotherapy, stage of disease, distance of the colorectal anastomosis from the anal verge, and the need for preoperative blood transfusions. Of these factors, only preoperative blood management is modifiable. Male gender was associated with a higher incidence of AL, as male individuals are anatomically characterized by a narrower and deeper pelvis, making the surgical approach to the middle and lower rectum more challenging [22]. Several experiences have underlined the association between neoadjuvant therapy and the occurrence of AL, however, the evidence is still controversial. Kobayashi et al. reported an AL rate of 6.3%, emphasizing preoperative radiotherapy as an independent risk factor [23]. Marijnen et al. analyzed the results from the randomization of 1861 patients to short-course radiotherapy plus TME versus TME alone, demonstrating no statistically significant differences, with an AL rate of 11% and 12% in the radiotherapy plus surgery and surgery alone cohorts, respectively [24]. A more advanced disease stage has been correlated with a higher risk of AL, due to the increasing levels of both local and systemic inflammation, as well as because of the surgical complexity. These conditions showed an increased local recurrence rate due to the micro implantation of tumor cells [25], and an amplified systemic pro-inflammatory response, which sustained disease progression [26]. Several Authors have focused on the relationship between the incidence of AL and the distance of the tumor from the anal verge, which appears to be inversely proportional. Rullier et al. reported an overall leak rate of 13% on a series of 272 patients who underwent ARR, and a 6.5 higher incidence of AL in the subgroup with anastomosis at less than 5 cm from the anal verge. Vignali et al. presented similar results in a study on 1014 patients with an AL rate of 7.7% after mechanical resection performed 7 cm or less from the anal margin compared with a 1% rate for resections of the upper rectum. Protective ostomy creation has been traditionally identified as an effective strategy to reduce the risk of AL [27, 28]. However, the evidence has been contradictory, and the presence of an ostomy may also lead to underestimating the real rate of subclinical AL [29]. In our study, a loop ileostomy was performed in 33 of 57 patients (57.89%), precisely reflecting the tumor's location (19 patients with tumors 6–10 cm from the anal verge, 12 patients with tumors less than 5 cm from the anal verge). Of the patients complicated by AL, 3 (50%) had a protective ileostomy. Various factors, including obesity, high ASA scores, and high Charlson Comorbidity Index scores, influence the risk of anastomotic leak (AL) in patients undergoing surgery [30]. The Charlson score considers a range of factors, such as physiological, anamnestic, metabolic, and oncological ones. In this study, the average Charlson score was 6.1 ± 1.9. Out of 57 patients, 6 experienced post-operative AL, indicating an incidence rate of 10.5%. The diagnosis of AL was made, on average, 5.5 ± 2.25 days after surgery. Among the 6 patients, 4 required laparotomic surgical revision, while 2 were treated conservatively. The mean hospital stay for patients with AL was 34 ± 20.33 days. Comparing the REAL tool scores between the patients with AL and those without AL showed a statistically significant difference (71.257 ± 20.484 vs. 33.684 ± 21.283; p = 0.0001). The REAL score was calculated based on rectal resections that did not differentiate between conventional and minimally invasive surgery. However, the latter combined with the total mesorectal excision (TME), has been found to have better early outcomes and comparable or better oncological results compared to traditional surgery [31]. Therefore, this study aimed to determine the REAL score's effectiveness on a laparoscopic case series. Laparoscopic surgery is technically challenging but has shown non-inferiority compared to open surgery. It reduces additional surgery-related risk factors such as prolonged operative times and the number of stapled-firings for the rectal section [32]. Kim and colleagues studied the risk factors associated with anastomotic leak (AL) in 270 patients who underwent laparoscopic rectal resection (ARR) using the Knight-Griffen technique. Their AL rate was 6.3%, and they found that tumor location in the medium and low rectum, operative time greater than 200 minutes, number of linear stapler firings greater than 3, and a diameter of the circular stapler greater than 31 mm were negative prognostic factors [33]. In our study, we found that the number of stapler firings for the rectal division was a statistically significant factor at the univariate but not at the multivariate level. At the same time, operative time did not emerge as a directing factor toward AL. We conducted a multivariate analysis to identify additional conditions that predispose patients to AL. We found that both hypoalbuminemia levels and the need for preoperative blood transfusions were statistically significant. Hypoalbuminemia and malnutrition, which may result from cancer or neoadjuvant therapy, increase the risk of complications and mortality [34–36]. Similarly, according to Kang et coworkers, malnutrition was an independent factor in multivariate analysis for the development of AL in a series of 72,055 patients who underwent ARR [37]. An analysis performed by Xu et al on 382 patients undergoing resective surgery for rectal cancer underlined that hypoalbuminemia and perioperative blood transfusions were independent risk factors for the development of AL [38]. In addition, preoperative blood transfusions can cause an immunosuppressed state and increase the risk of developing post-operative complications and poor long-term oncological outcomes. Both hypoalbuminemia and low blood counts affect perfusion and oxygenation of the anastomosis, predisposing to an eventual dehiscence [39–42]. We found that the use of indocyanine green (ICG)-near-infrared (NIR) angiography was statistically relevant for AL. This tool allows for real-time evaluation of the pre- and post-anastomotic visceral perfusion status, effectively minimizing some of the factors predisposing to a leak. We used ICG-NIR angiography to evaluate pre- and post-anastomotic visceral perfusion in 31 patients and found no cases of AL in this subcohort of patients. The progressive diffusion of the intraoperative evaluation of anastomotic perfusion by immunofluorescence with ICG-NIR has contributed to reducing the rate of AL, especially in high-risk patients. Furthermore, as the era of artificial intelligence (AI) applied to surgery has started, the REAL score may integrate previous anastomotic leak prediction scores and help refine AI models over time, making them more accurate in predicting anastomotic leak risk in future patients. This could lead to better decision-making during surgical planning and reduce the incidence of anastomotic leaks after colorectal surgery.

The REAL score may be a valuable instrument in evaluating the likelihood of anastomotic leak in patients undergoing laparoscopic ARR with TME. This predictive model's efficacy can be further amplified by incorporating additional preoperative modifiable factors such as hypoalbuminemia and preoperative blood transfusion rate. Moreover, combined with applying fluorescence-guided surgery principles, it could help the surgeon effectively reduce the anastomotic leakage rate.

Contributions Francesco Roscio conceived the study; Francesco Roscio, Francesco Maria Carrano and Eleonora Monti wrote the manuscript; Francesco Roscio, Eleonora Monti, Federico Clerici, Francesco Maria Carrano and Ildo Scandroglio collected the data; Federico Clerici performed the statistical analysis. All authors read and approved the final version of the manuscript.

Conflict of interest The authors declare no competing interests.

Funding No funding was obtained for this study.

Data Availability Statement The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at ASST Valle Olona

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Improving Outcomes in Laparoscopic Anterior Rectal Resection: The Benefits of REAL Score in Preoperative Risk Assessment for Anastomotic Leak

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