Valeria Tonini,Manuel Zanni

Valeria Tonini,Manuel Zanni,Department of Medical and Surgical Sciences,University of Bologna,Bologna 40138,Bologna,Italy

Abstract Colorectal cancer(CRC)is one of the most common malignancies in the world.Despite significant improvements in surgical technique,postoperative complications still occur in a fair percentage of patients undergoing colorectal surgery.The most feared complication is anastomotic leakage.It negatively affects shortterm prognosis,with increased post-operative morbidity and mortality,higher hospitalization time and costs.Moreover,it may require further surgery with the creation of a permanent or temporary stoma.While there is no doubt about the negative impact of anastomotic dehiscence on the short-term prognosis of patients operated on for CRC,still under discussion is its impact on the long-term prognosis.Some authors have described an association between leakage and reduced overall survival,disease-free survival,and increased recurrence,while other Authors have found no real impact of dehiscence on long term prognosis.The purpose of this paper is to review all the literature about the impact of anastomotic dehiscence on long-term prognosis after CRC surgery.The main risk factors of leakage and early detection markers are also summarized.

Key Words:Anastomotic leakage;Colorectal surgery;Colon cancer;Rectal cancer;Long term prognosis;Long term survival

lNTRODUCTlON

Definition,incidence and classification

Anastomotic leakage(AL)is a major cause of postoperative morbidity and mortality after colorectal cancer(CRC)surgery.AL is a defect of the intestinal wall integrity at the colorectal or colo-anal anastomosis site(including suture and staple lines of neorectal reservoirs)leading to a communication between the intra-and extraluminal compartments[1].However,there are several definitions of AL in literature and most studies define it using clinical signs(pain,fever,tachycardia,peritonitis,purulent or fecal drainage),radiographic findings(fluid and/or gas-containing collections),and/or intraoperative features(peritoneal effusion and ruptured anastomosis)[1,2].The use of different definitions in clinical studies can partly explain the considerable variations in AL reported rates.The incidence of AL reported in different studies is highly variable(2%-19%)and certainly influenced first of all by the surgeon's experience and the emergency or elective surgical setting.It is also influenced by the site of the anastomosis:It is lowest for ileocolic anastomoses(1%-3%)and highest for coloanal anastomoses(10%-20%)[3-5].

AL has been divided into "early" and "late" depending on whether AL is diagnosed within or after 30 d after surgery[6].In general,early AL manifests with severe peritonitis and it is mainly related to a technical error in performing the anastomosis,usually due to mal vascularization of the intestinal stumps or tension at the anastomotic site[7].In contrast,late AL is often associated with long-standing pelvic abscess[8]and is due to preexisting conditions in patients,such as local sepsis,poor nutrition,immunosuppression,morbid obesity,and radiation exposure[9].

AL is also classified according to severity into grade A,B and C.Grade A is represented by AL that does not require active therapeutic intervention,grade B by AL that requires active therapeutic intervention but manageable without re-laparotomy,and grade C by AL that requires re-laparotomy[1].

RlSK FACTORS

Several risk factors for anastomotic dehiscence following colorectal surgery have been identified over the years.They can be classified for convenience into preoperative,intraoperative,and postoperative[10].

Preoperative risk factors commonly reported in the literature include male sex[7],obesity[11],tobacco habit,alcohol consumption,an American Society of Anaesthesiologistscore of 3 or higher[6],and prolonged corticosteroid intake[12].Tumor location,size and stage must be considered among the risk factors.Akiyoshiet al[13]reported that tumor localization in the rectum,rather than the colon,was independently predictive of AL development on multivariate analysis.

The AL rate was 10 times higher(20.6%vs2.3%)when the anastomotic region was located within 5 cm of the anal verge[14].

Low anterior resection(LAR)involves surgery in an anatomically confined space and when tumor size and/or stage increases,intrapelvic manipulation becomes limited and rectal dissection more challenging.In a series of 154 patients with rectal carcinoma,tumor size ≥ 5 cm in diameter was associated with a 4-fold increased risk of leakage[15].Zhuet al[16]found that tumors greater than 3 cm in diameter,as well as TNM stage,were independently associated with leakage.

Intraoperative risk factors include:The surgeon experience(and hospital size)[7],the number of linear stapler firings[7],left colic artery ligation[17],emergency surgery(patients with peritonitis and/or bowel obstruction are at higher risk of postoperative adverse events)[18],operative time[19]and blood loss during surgery.Intra-operatively,it is also important to ensure good vascularization of the anastomosed bowel segments.Indocyanine green(ICG)fluorescence angiography may help in this evaluation.In a recent meta-analysis,an incidence of anastomotic dehiscence was observed in 3.8% of cases in the ICG group and 7.8% in the control group in which ICG was not used[20].

Postoperative risk factors are anemia,hypoalbuminemia,and late initiation of enteral nutrition[21].

EARLY DETECTlON AND MARKERS

Early detection of AL is crucial to treat patients limiting negative effects.Baeza-Murciaet al[22]analyzed the accuracy of C-reactive protein(CRP)and procalcitonin(PCT)for early detection of AL and have found that CRP is more accurate than PCT on both postoperative day(POD)3 and 5.According to this study CRP measured on POD 5 is the most useful test for early diagnosis of AL and that values above 9.1 mg/dL are indicative of anastomotic dehiscence.

In a recent meta-analysis by Yeunget al[23]a CRP cutoff level of 14.8 mg/dL at POD 3 had a sensitivity and specificity of 95%,while CRP cut-off levels of 12.3 mg/dL at day 4,11.5 mg/dL at day 5,10.5 mg/dL at day 6,and 9.6 mg/dL at day 7 had a sensitivity and specificity of 100% for anastomotic dehiscence.

According to Garcia-Graneroet al[24]and El Zaheret al[25],PCT is also a very good predictor of anastomotic dehiscence,particularly from POD 5 or higher.The predictive power of PCT may also be enhanced in combination with CRP or white blood cell,or both(area under the curve 0.92,0.92,0.93,respectively)[25].A recent meta-analysis by Xuet al[26]shows that PCT at POD 3 has potential clinical value in the early diagnosis of AL and has better diagnostic accuracy in patients undergoing laparoscopic surgery.Cut-off values are recommended in the range of 0.7-1.3 ng/mL to ensure accurate diagnosis and safe discharge.However,PCT is a valid predictor only for patients with major clinical losses confirmed by radiology and presenting with severe clinical signs and symptoms that require a change in therapeutic management and in most cases a reintervention.Cousinet al[27]conducted a meta-analysis and concluded that PCT does not add value to CRP in the diagnosis of AL.

It can be said that CRP and PCT at POD 5 have a high negative predictive value,which would allow early and safe discharge.

Tavernieret al[28]considered 5 criteria for safe early discharge after laparoscopic colorectal surgery:A CRP level of less than 15 mg/dL,absence of fever during the entire hospital stay(temperature＜38 °C),return of bowel function(flatus with or without stool),adequate pain control with oral analgesics(pain less than 5 out of 10 on a 10-point visual analog scale)and tolerance of a solid diet.The negative predictive value in ruling out an anastomotic leak was 98.4% for all 5 criteria combined.The falsenegative rate was 13.3%.

RELATlONSHlP BETWEEN AL AND SHORT-TERM PROGNOSlS

AL affects the outcome of surgery,worsening the short-term outcomes and increasing the time and cost of hospitalization[29,30].The mortality related was reported to be between 0.8% and 27%[31].Mortality was higher after leak from a colonic anastomosis than after leak from a rectal anastomosis(43.8%vs7.1%)[31].Bertelsenet al[32]found in a multicenter study a 4-fold increase in 30-d mortality in patients with AL[32].According to a Cochrane review,AL is associated with a perioperative mortality rate of 2% to 24% and high morbidity,with the risk of a definitive ostomy exceeding 25%[33].Warpset al[34]found an overall AL rate of 4.8%,ranging from 4.0%(right hemicolectomy)to 15.4%(subtotal colectomy).AL was predominantly managed with reintervention,ranging from 81.2% of cases after transversectomy to 92.4% after sigmoid resection.After reintervention,the highest mortality rates were observed for transversectomy(15.4%)and right hemicolectomy(14.4%)and the lowest for sigmoid resection(5.6%)and subtotal colectomy(5.9%).The intensive care unit admission rate was 62.6% overall(range 56.7%-69.2%)and the stoma rate ranged from 65.5%(right hemicolectomy)to 93.0%(sigmoid resection).

RELATlONSHlP BETWEEN AL AND LONG-TERM PROGNOSlS

While the short-term consequences of AL are well known,its impact on long-term prognosis in CRC patients is still debated.

In the literature,the first authors to concern themselves with outcomes related to anastomotic dehiscence after resective surgery for CRC were Phillipset al[35]and Sauvenet al[36].In both cases,the parameter evaluated was local recurrence(LR).In the first study,AL did not appear among the significant risk factors for recurrence,while in the second,anastomotic dehiscence was associated with an increased rate of LR.In the same years,Amatoet al[37]evaluated the association between CRC and AL by focusing exclusively on patients with rectal tumors operated with an anterior resection.In this study,AL did not influence the recurrence rate.

In 1991,Akyolet al[38]performed a study on patients operated for left colon or rectal cancer and demonstrated an important influence of AL on recurrence and cancer-specific survival(CSS)at 24 mo.The independence of the impact of dehiscence on outcomes from tumor stage was highlighted.This was the first study that analyzed local and distant recurrence separately and used multivariate Cox regression.

Two years later,a study published by Fujitaet al[39]showed the impact of AL on LR and disease-free survival(DFS).DFS is significantly lower in the AL group for patients with Duke stage A and B cancers but not for C and D.The importance of this work also lies in the separate evaluation of subjects with colon and rectal cancer.

Petersenet al[40]studied the influence of leakage on LR,CSS,overall survival(OS)and postoperative mortality.AL influence only LR and CSS,confirming the previous findings of Akyolet al[38].Branaganet al[41]reached similar conclusions in 2005.Further studies[42-44]showed a correlation between AL and higher 30-d mortality,lower OS and CSS.

Lawet al[45]in 2007 found a significant association between AL and 5-year CSS,30-d mortality and recurrence(local and systemic).

According to the study by Eberhardtet al[46],AL does not change the risk of recurrence and mortality for colon cancer,whereas it does for rectal cancer.The article also offers an assessment of OS,CSS,LR and overall recurrence for each stage,as well as an analysis of these outcomes at both 1 and 5 years after surgery.

Krarupet al[59-60]identified in patients with AL an increase in distant recurrence(DR)and in mortality.However,there was no significant association with LR.Nordholm-Carstensenet al[61]and Nget al[62]evaluated the impact of AL in patients with stage IV CRC.The 3-year survival rate is affected by dehiscence for both colon(18.7%vs44.6%)and rectum(53.7%vs73.3%).

The first meta-analysis on this topic was performed by Mirnezamiet al[63]on 22 studies.It reported an association between AL and LR,DR and cancer-specific mortality.

The subsequent meta-analysis by Haet al[64]evaluated 34 studies and divided the results into two categories.In the first group rectal anastomosis data were analyzed,and AL was associated with increased LR and reduced OS,CSS,and DFS.There were no significant effect on distant recurrence.In the second group colic anastomoses were analyzed and AL was associated with reduced OS and DFS and there was no correlation with local or distant recurrence.

The studies by Sammouret al[65]and Gotoet al[66]also analyzed CSS.They showed a significant reduction in 5-year OS for patients with AL,without finding differences in LR,CSS and postoperative mortality(in rectal carcinoma,leakage affects only the latter).The second one documented instead a reduction in OS(80.8%vs90.3%)and CSS(89.6%vs95.1%),an increase in LR and no correlation with distant recurrence.

A subsequent meta-analysis conducted in 2020 by Bashir Mohamedet al[67]demonstrated a lack of significant effect of AL on recurrences,however it reduced OS,DFS and CSS.

Recent articles on this topic were written by Stormarket al[68]and Kryzauskaset al[69].The former concluded that leakage only after surgery for stage III CRC is able to reduce survival,whereas the latter demonstrated that AL impaired disease-free and OS in patients undergoing sigmoid and rectal surgery.

Regarding rectal cancer alone,the first data of the new millennium showed an increase in LR and a decrease in CSS[70,71].Subsequent studies can be divided into 3 categories.In the first group,there are studies that supported the absence of an impact of AL on cancer outcomes such as OS,CSS,DFS,LR and DR[72-79].The second group covers studies defining AL as an independent prognostic factor for reduced OS,CSS,DFS and increased recurrence[80-83].In the third group,we can place studies[84-88]midway between the first two categories,as the study of Nohet al[88],demonstrating that AL is associated with increased LR and reduced DFS,whereas its relationship with OS and distant recurrence is not significant.These findings were confirmed in a recent study by Peltriniet al[89].

To the above groups,we must also add studies evaluating also perioperative mortality.Ptoket al[90]and Hainet al[91]found an impact of dehiscence on 30-d mortality,DFS,and LR,whereas Eriksenet al[92]and Bertelsenet al[32]found an increase in 30-d mortality,but without a significant increase in LR.Bertelsenet al[32]also noted the lack of reduction in OS and impact on distant recurrence[32].

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Limet al[93]in 2015 classified ALs into 3 categories based on the consequences:(1)Generalized peritonitis;(2)Localized peritonitis with or without abscess;and(3)Fistula.Oncologic outcomes were evaluated separately for each type and reduced OS and LRFS(LR-free survival)were identified.According to Bostr?met al[94],leaks only impact OS if they require intervention.

In 2022,Dulskaset al[95]evaluated AL in patients undergoing right colectomy for CRC and concluded that AL is a factor that negatively affects long term prognosis.In contrast,a Dutch retrospective study found that disease recurrence is not associated with AL after CRC resection[96].

Koedamet al[97],analyzing data from the COLOR and COLOR II studies,show that ALs after rectal cancer surgery are associated with an increased rate of LR and a decreased DFS at 5-year follow-up.DR and OS are not significantly affected.Regarding colon cancer surgery,no significant effect of AL on long-term oncologic outcomes was observed,presumably because of a relatively low leakage rate.Strengths of this study include the randomized,multicenter design of the two included studies[98,99]and uniform study protocol for perioperative care and follow-up to limit practice variability.

All studies on this topic are summarized in Table 1.

Table 1 Summary table of all studies reporting on anastomotic leakage and outcomes after colorectal cancer surgery

CONCLUSlON

AL appears to be an independent risk factor influencing long-term oncologic outcomes after rectal cancer surgery.On the other hand,regarding colon cancer,the results are still extremely heterogeneous and unclear.Further studies on patients undergoing resection for CRC are needed to confirm the oncological impact of AL.

Based on these data,we would recommend more frequent follow-up for patients with AL after CRC cancer surgery.

FOOTNOTES

Author contributions:Tonini V and Zanni M contributed equally to this work,performing the research,analizing the data and writing the manuscript All authors have read and approve the final manuscript.

Conflict-of-interest statement:All the authors report no relevant conflicts of interest for this article.

Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See:https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin:Italy

ORClD number:Valeria Tonini 0000-0003-3130-2928;Manuel Zanni 0000-0001-7732-7739.

S-Editor:Li L

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P-Editor:Wu RR