Outcomes Based on Risk Assessment of Anastomotic Leakage after Rectal Cancer Surgery

It has been found that colorectal cancer (CRC) is the third commonest cancer in males and the second in females. In 2008, more over 1.2 million new CRC cases and 608.700 deaths were reckoned to be occurred (Ahmedin et al., 2011; Cho, 2013; Fathallah et al., 2013; Hwang et al., 2013). With the advent of stapling devices, surgical operation combining with preoperative chemoradiation therapy (PCRT) and by means of total preventive ileostomy rate of anal sphincter preservation in present days (Tjandra et al., 2005). Nevertheless, patients with rectal cancer undergoing anterior resection can develop various postoperative complications. It is quite obvious that AL is the severest and most morbid complication. AL is a severe complication after rectal surgery. Peritonitis and septicaemia lead to reoperations, admission


Introduction
It has been found that colorectal cancer (CRC) is the third commonest cancer in males and the second in females.In 2008, more over 1.2 million new CRC cases and 608.700 deaths were reckoned to be occurred (Ahmedin et al., 2011;Cho, 2013;Fathallah et al., 2013;Hwang et al., 2013).With the advent of stapling devices, surgical operation combining with preoperative chemoradiation therapy (PCRT) and by means of total preventive ileostomy rate of anal sphincter preservation in present days (Tjandra et al., 2005).Nevertheless, patients with rectal cancer undergoing anterior resection can develop various postoperative complications.It is quite obvious that AL is the severest and most morbid complication.
AL is a severe complication after rectal surgery.to the intensive care unit (ICU) and a profoundly increased mortality rate (Kube et al., 2010).Furthermore, AL is a risk factor for local recurrence of colorectal cancer, survival (Mirnezami et al., 2011).AL after rectal cancer surgery has been reported to range between 5% and 25% of patients (Mileski et al., 1988;Fazio et al., 2007;Veenhof et al., 2007).Not only, the instant clinical consequences, but also AL carries long-term outcome, such as intra pelvic infection, peritonitis, sepsis, longer hospital stay, considerable extra cost, increased in-hospital morbidity and mortality, impaired pelvic organ function (Eriksen et al., 2005;Law et al., 2007;Lee et al., 2008;Riss et al., 2011).Many studies on anterior resections regarding AL come from multi-center and different surgeons.A variety of factors predisposing to AL and survival analysis have been reported in the previous investigations.However, lack of data about the risk factors and outcomes associated with AL from a single-institute of one team of doctors.In addition, risk assessment and survival analysis in previous reports have been inconsistent because of the limited power of studies.The reduction of TSGF on POD 5 less than 10 U/ml and the pH value of pelvic drainage less than or equal to 6.978 on POD 3 were adopted in this series, in our previous studies [Yang et al., 2013 14 (7) & 14 (9)].The main objective of the current study was to analyze the incidence of AL, risk factors for AL and cancer-related survival.

Materials and Methods
Between January 2003 and December 2007, 460 randomly collected and routinely followed up patients with rectal cancer underwent anterior resection with double stapling anastomosis for primary rectal cancer at Hospital of Nanjing Medical University & Jiangsu Institute of Cancer Research, Nanjing, China.The medical notes of those patients were reviewed in detail.Eligibility stage, histologically proven adenocarcinoma, open and laparoscopic surgery with pelvic drainage, antibiotics using for 7 PODs, and cancer-related decease.Exclusion criteria were as follows: Hartmann's and Miles' procedure, anastomosis, or last observation and disease-free death.
the anal verge, as determined by rigid sigmoidoscopy.Total mesorectal excision was adopted as the standard surgical technique according to tumor location.Various independent clinical variables were analysed and detailed in Table 1 and 2. The Ethics Committee of Science approved data collection in the register.
Patients were followed up routinely by a protocol followed by visits every 6 months for the next 3 years.CEA, CA242, CA724 and CA199 levels were reviewed at each visit, and a CT scan of abdomen, pelvis, and thorax was performed at the 2-year follow-up.Colonoscopy was performed 1 year after surgery when the colon and rectum had previously been cleared of synchronous lesions, and repeated at 3-year intervals unless otherwise indicated in further detail as appropriate according to clinical The patient was placed in a modified lithotomy, right side down, Trendelenburg position.For patients undergoing laparoscopic surgery, an initial 12-mm port placement was carried out using the open technique, and pneumoperitoneum was accomplished using carbon    The AL in this study was determined by ICD-9 codes 997.4,567.22 (abdominopelvic abscess), and 569.81 All continuous variables were dichotomized.Chisquared or Fisher's exact test for categorical variables was used for statistical comparisons of those variables between the no leak and leak groups.Multivariate analysis to detect risk factors for AL was conducted with a logistic regression model.Difference in each variable has been analyzed using one-way analysis of variance (ANOVA) before multivariate analysis was performed.operation and death or last observation.Although 5-years follow-up was planned, median follow-up times were often less due to death.For example, the median followup time for the 460 patients with rectal cancer was 41.5 months due to death and the resultant decreased follow-up period.Disease-free survival time was calculated as the time between initial operation and recurrence or death.Survival analysis were analysed using the Cox regression p value < 0.05.Statistical analyses were performed using IBM SPSS statistics 19.0 for Windows (SPSS Inc; IBM, Chicago, IL).

Results
by goup are detailed in Table 1.The overall AL rate was 7.6% (35/460 patients).A total of 460 patients [161 male patients (35.0%)] with a median age of 65 (49-72) years at the time of surgery were included.The majority of patients were ASA 1 or 2 (86.3%).Eighty six (18.7%) patients presented rectal cancer within 4 cm from the anal verge.Among all these patients, 47.2% (217) & 34.6% (159) of whom abused tobacco and alcohol, respectively.Two hundred and twelve (46.1.0%)sufferers were and postoperatively.The preoperative BMI was equal or greater than 35 (severe obesity) in 35 (7.6%) patients.
preoperatively.The correlations between demographic data and AL are summarized in Table 1.Univariate analysis demonstrated that AL was more common in patients with elder age (p<0.001),male gender (p<0.001),tobacco abuse (p=0.008),lower tumor site (p<0.001),high preoperative BMI (p<0.001),diabetes mellitus (p<0.001).Alcohol abuse, ASA score and TNM stage were not The medical and surgical characteristics are listed in Table 2. Nine (2.0%) patients received neoadjuvant chemoradiotherapy.The reduction of TSGF in 86 (18.7%), value of serum albumin in 15 (3.2%) and level of hemoglobin in 36 (7.8%) sufferers on POD 5 were less than 10U/ml, 30g/l and 70g/l; these value were selected as the criteria of grouping according to the references.Two (0.4%) patients undergoing surgery were equal or longer than 4 hours.Fifteen (3.3%) invalids were experiencing intraoperative hypotension.A preventive ileostomy was proceeded in 89 (19.3%) sicks, and a laparoscopic surgery was performed in 76 (16.5%) were administrated with NSAID and glucocorticoid in early PODs, respectively.The relationship of clinical characteristics to AL are epitomized in Table 2.The reduction of TSGF (p<0.001) on 5th POD and the pH value of pelvic dranage on 3rd POD (p<0.001) were the factors effect on preventing AL (p=0.01).Operation duration tended to be associated with the development of AL, with p values equal to 0.20.Surgical approach, neoadjuvant chemoradiotherapy, intraoperative hypotension, NSAID and glucocorticoid administration, operation duration, the value of serum albumin on 5th POD and the level of in univariate analysis.

Discussion
The AL rate after colorectal surgery varies between on the type of resection performed, being higher in extraperitoneal anastomosis (Bellows et al., 2009).The rate of 7.6% in this study falls within the range of previously published series.This rate is, however, lower than the average leak rate of 10% reported in a systematic review by (Paun et al., 2010).It is also lower than the leak rate reported in a similar study from Denmark looking at this complication using a population database (Bertelsen et al., 2009).It is not different from comparable reports that the low leak rate in the present study could be explained to perform high ligation of the inferior mesenteric artery to ensure the collateral blood supply, and success to test the integrity of the anastomosis can contribute to the low leak rate.Furthermore, our outcomes are similar to some others that AL is associated with a poor survival and a higher tumor recurrence rate after curative resection of colorectal cancer (Law, et al., 2007;Harris, et al., 2010).
The advantages of a single register include the based on a truly unselected study population and without biasis or confounding factor.According to this research, positionally lower tumour site, elder age, male gender, preventive BMI, the reduction of TSGF on POD 5 and the pH value of pelvic drainage on POD3.It seemed that the AL incidence of rectal cancer was unrelated to the rest of the factors in this study.
As in previous studies, advanced age, greater than 60 years, is the principal significant risk factor for anastomotic leaks on both univariate and multivariate analysis (Kumar et al., 2011;Peeters et al., 2005).observation that the risk of AL increased in parallel with the value of BMI is potentially of considerable clinical importance.The results of this study is akin to those of others reporting no association between obesity and risk of AL (Yamamoto et al., 2012), but the present register recorded no information on analysis of perioperative BMI shifting was therefore performed.The association between BMI and AL could be that obesity causes bad injury, ischemia of resection margin and leak.In addition to be a risk factor for AL, BMI was also a risk factor for long-term survival.Studies assessing obesity and CRC outcomes have yielded concordant results.Meyerhardt and colleagues initially showed obesity was associated women with stage II-III colon cancer.A cohort study of 4288 patients with Dukes B and C colon cancer showed increased recurrence or metachronous tumours (HR=1.38,1.10 to 1.73), overall mortality (HR=1.28,1.04 to 1.57) ).According to this series, the Cancer Prevention Study II Nutrition Cohort suggested that pre diagnosis, but not post diagnosis, BMI was associated with an increased risk, cancer-related mortality (RR=1.35,1.01 to 1.80).To sum up, it is suggested, although inconsistently, that obesity might be associated with a decrease in cancer-related survival in patients with CRC (Meyerhardt et al., 2003;Dignam et al., 2006;Campbell et al., 2012).
The substitution of the anastomotic level for the distance of tumor from the anal verge has been commonly reported (Peeters et al., 2009) , in spite of the actual distance from the anal verge to the anastomosis (Eriksen et al., 2005).The two modus are not quite comparable, because the introduction of TME has resulted in very low anastomoses in patients with a tumour below 10 cm (ultra low tumor is below 4 cm) from the anal verge (wang er al., 2010).In the present register, the tumour position was recorded, our results were similar to those of others showing a higher risk of leak for low tumours (Gastinger et al., 2005;Wong et al., 2005).
In the light of other studies (Marusch et al., 2002;Eriksen et al., 2005;Lipska et al., 2006;Bennis et al., 2012), we found a higher rate of AL in males.This might be due to the special anatomy of narrow male pelvis making consideration of this leads to the possibility that there is a disparate cellular pathway for collagen metabolism, tissue recovery and healing in the two genders.The strong connection of a colorectal anastomoses with the concentration of collagen in the anastomotic area had al., 2006).Researches of collagen formation during tissue healing indicated that aged males deposited less collagen surgery.Obviously more collagen than men accumulated by premenopausal women implied that a young lady has a high level collagen formation capacity while the postmenopausal hasn't.These come outs manifest that the female hormones are related to collagen deposition, and the estrogen is a protected factor of AL presumably and mediately (Markiewicz et al., 2007;Aznal et al., 2012;Gormsen et al., 2012).
the growth of tumour vessels, and has been shown greatly to correlate hyperplasia of tumour tissue to surrounding capillary vessels.Plenty of studies have demonstrated that TSGF has high sensitivity for the detection of malignant tumours (Yang et al., 2007;Bünger et al., 2011;Deng et al., 2011;Zhou et al., 2012), especially in colorectal cancers.The postoperative reduction of TSGF at 10 U/ ml in day 5 was proposed as observationally diagnostic and prognostic indicator of colorectal cancer in previous research (Yang et al., 2009), and in present study, it was adopted for a risk factor that had been never reported.Less than 10 U/ml of the reduction in 5th POD was deemed to be a risk factor of AL in this study.It is interesting to note that the less decrease of TSGF after surgery, the more increase of AL, and vice versa.It is possible that less declining TSGF is a active promotion of AL, however, this remains to be confirmed by further study about molecular mechanism.Further study is also warranted intrinsic association between the postoperative reduction likely indicates that the reduction of TSGF in early PODs is an inchoately predictive mark of AL for a patient who undergoes a anastomosis of colon-rectum or colon-anal.A postoperative continuous monitoring of the reductive TSGF for identifying AL could be a recommendatory step in early PODs, and also it is to be a guidelines for preventing of AL in someday when intensive studies are adequate.
Many risk factors for AL have been reported in the literature, and the majority has been analyzed in this study.Data from previous study demonstrated that baccy had been shown to impair tissue healing and increase the risk of wound complications and AL after gastrointestinal surgery (Kasperk et al., 2000;Sorensen et al., 2005).However, the current study provide evidence that smoking is not a independent factor of AL after the multivariate difference of the serum albumin POD 5 and DM was found in multivariate analysis between the groups with and without leak.As in previous studies (Kasperk et al., 2000;Peeters et al., 2009), no association between AL and preoperative therapy was found, although the proportion of patients in this study receiving neoadjuvant therapy was small.
It was known to all that the 5-year survival rate of it was believed that the good physical status would be a factor for improving long-term outcomes (Speed-Andrews et al., 2012), which was the explanation why the High-ASA score patients had a worse outcomes.
In conclusion, being male, advanced age and severe obesity are all independent risk factors for AL.Our study also offers strong evidence that ultra low rectal cancer (lower than 4cm from anal verge) is an independent risk factor for anastomotic leak after anterior resection with a double stapling technique.Our data suggest that a reduction of TSGF on POD 5 and the pH value of pelvic drainage, the two newly found independent risk factors in our previous studies, were the omens of early AL after anastomosis with a double stapling technique.We also believe that the safety of ultra low colorectal (coloanal) anastomosis will be improved with technical advances in the near future.In addition to their high risk of immediate postoperative morbidity and mortality, AL, worse physical status, severe obesity and advanced TNM stage had similarly negative impacts on survival.Efforts should be undertaken to avoid these complication to improve the long-term outcome.
Peritonitis and septicaemia lead to reoperations, admission