Risk Stratification of Cirrhotic Patients Undergoing Esophagectomy for Esophageal Cancer: A Single-Centre Experience

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Grass, Natalie Küsters, Marius Kemper, Jan Tintrup, Felix Piecha, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-725154/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Mar, 2022 Read the published version in PLOS ONE → Version 1 posted You are reading this latest preprint version Abstract Concomitant liver cirrhosis is a crucial risk factor for major surgeries. However, only few data are available concerning cirrhotic patients requiring esophagectomy for malignant disease. From a prospectively maintained database of esophageal cancer patients, who underwent curative esophagectomy between 01/2012 and 01/2016, patients with concomitant liver cirrhosis (LCP) were compared to non-cirrhotic patients (NLCP). Of 170 patients, 14 cirrhotic patients with predominately low MELD scores (≤ 9, 64.3%) were identified. Perioperative outcome was significantly worse for LCP, as proofed by 30-day (57.1% vs. 7.7, p<0.001) and 90-day mortality (64.3% vs. 9.6%, p<0.001), anastomotic leakage rate (64.3 vs. 22.3%, p=0.002) and sepsis (57.1 vs. 21.5%, p=0.006). Even after adjustment for age, gender, comorbidities, and surgical approach, LCP revealed higher odds for 30-day and 90-day mortality compared to NLCP. Moreover, 5-year survival analysis showed a significantly poorer long-term outcome of LCP (p=0.023). For risk stratification, none of the common cirrhosis scores proved prognostic impact, whereas components as Bilirubin (auROC 94.4%), INR (auROC=90.0%), and preoperative ascites (p=0.038) correlated significantly with the perioperative outcome. Curative esophagectomy for cirrhotic patients is associated with a dismal prognosis and should be evaluated critically. While MELD and Child score failed to predict perioperative mortality, Bilirubin and INR proofed excellent prognostic capacity in this cohort. Cardiothoracic Surgery Cancer Biology Risk stratification cirrhotic patients esophagectomy esophageal cancer single-centre experience crucial risk factor survival analysis Figures Figure 1 Figure 2 Introduction Ranking as the sixth leading cause of cancer-related mortality, esophageal cancer (EC) continues to be among the most aggressive tumours with limited prognosis 1 , which can be altered most favourably by surgical intervention. Esophagectomy with radical lymphadenectomy represents the mainstay of curative therapy for EC. By continuously refined diagnostics and multimodal treatment, 5-year survival increased to 20-45% for surgically treated patients 2-4 . However, esophagectomy is associated with high rates of perioperative morbidity and mortality, which are significantly increased with comorbidities and patients’ age and adversely impact long-term outcomes 5-7 . Due to rising incidence and optimized therapeutical strategies resulting in longer survival, liver cirrhosis represents a common cause of morbidity 8 . Accompanied with a higher incidence of extrahepatic malignancies compared to non-cirrhotic patients 9 , oncological therapy for cirrhotic patients (LCP) gains increasing relevance. As EC and cirrhosis share certain risk factors 10 , LCP are reported to be exposed to an eight-fold elevated risk for the development of EC 9 . Though, liver cirrhosis depicts a crucial risk factor for non-hepatic surgery 11-13 , with elevated morbidity and mortality following esophagectomy of 39.7-83.3% and 26.0-50.0%, respectively 14-18 . Although cirrhosis significantly compromises live expectancy 19 , long-term survival after esophagectomy for EC has been reported to be comparable between LCP and non-cirrhotic patients (NLCP) by several case series 14 , 16 , 18 . Limited evidence is available for treatment stratification of EC in LCP, in particular in terms of general health assessment and severity of liver cirrhosis, as stated by recent meta-analyses 20-22 . Thus, this study aims to evaluate, what factors might affect the perioperative and long-term outcome and whether radical esophagectomy represents a feasible option in the oncological treatment of cirrhotic patients. Methods Patients with concomitant liver cirrhosis were identified from a prospectively maintained database of EC patients, who underwent esophagectomy at the University of Hamburg Medical Institutions between January 2012 to May 2016. The study protocol was legitimated by the institutional review board of general medical chamber Hamburg and registered at clinicaltrial.gov (NCT04809870 on 18/03/2021). Informed consent was obtained from all patients included. The diagnosis of cirrhosis was confirmed by clinical signs, imaging, and histological proof, in particular in all cases of intraoperatively diagnosed cirrhosis. The severity of cirrhosis at the time of surgery was determined by preoperative laboratory data at hospital admission and preoperative imaging. Cirrhotic Patients with insufficient data for calculating preoperative model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) scores were excluded from further analysis. Studied variables for both, cirrhotic and non-cirrhotic patients included gender, age, coexisting medical conditions, the ASA classification, and CCI, tumor stage administered by America Joint Committee on Cancer Union, 7th edition, tumor localization, history of neoadjuvant therapy, laboratory data (creatinine, albumin, platelet count, bilirubin, and INR) and surgical approach. Moreover, for cirrhotic patients, etiology of cirrhosis, presence, and severity of preoperative ascites, portal hypertension, and esophageal varices were collected. Portal hypertension was defined by platelet count lower than 100 mrd/l and presence of ascites, splenomegaly, or esophageal varices. Surgeries were performed as thoracoabdominal esophagectomy with either two-field lymphadenectomy and intrathoracic anastomosis (Ivor-Lewis) or cervico-thoracoabdominal esophagectomy with three-field lymphadenectomy and cervical anastomosis (McKeown) depending on the tumor localization. Reconstruction was conducted by gastric conduit. Eligible approaches were conventionally open, hybrid (abdominal laparoscopically and thoracic open), and completely minimally invasive. The perioperative outcome was investigated by occurrence and severity of complications according to Clavien-Dindo classification, 30- and 90-day mortality as well as 5-year survival analysis. Pulmonary and cardiac complications are defined by any organ-related major complications (Clavien-Dindo ≥ 3). Anastomotic leakage was defined as any endoscopically proven anastomotic dehiscence and Chyle leak was defined by a concentration of triglycerides (TG) in drain fluids ≥ 3 times TGs in serum. Data management and statistical analysis were performed using IBM SPSS Statistics for Macintosh, Version 25.0. (Armonk, NY: IBM Corp.). For univariate analyses, the Student t test was applied for parametric continuous variables and the Man-Whitney-U test for nonparametric continuous variables. Categorical variables were tested using χ 2 -Test or the Fisher exact test as appropriate. A generalized linear model was used for adjusted outcome analysis, adjusting for age, gender, surgical approach, and comorbidity index. The sensitivity and specificity of available scores and parameters were calculated using receiver operating characteristics (ROC) curves. Survival rates were estimated using the log-rank test and described by Kaplan-Meyer curves. A two-sided p-value < 0.05 was considered as significant. The study was conformed to the standards of the Declaration of Helsinki. Results Clinicopathological Parameter From the prospective database of 170 patients, who underwent esophagectomy for esophageal cancer between 01/2012 and 04/2016, 14 patients with concomitant cirrhosis could be identified (Table 1). Both cohorts were of comparable age (64.4 ± 8.7 vs. 63.4 ± 10.8, p=0.826) while gender distribution differed, with significantly more female patients among the LCP (50.0% vs. 14.1%, p=0.003). Both, American Society of Anaesthesiology (ASA) and Charlson Comorbidity Index (CCI) demonstrated a significantly poorer general condition of LCP (p<0.001 and p=0.004, respectively). Nonetheless, NLCP also suffered from relevant comorbidities, reflected by 52.6% CCI of three or more points. Histology, grading, tumor size and location, nodal status, metastatic status, UICC stage, and proportion of neoadjuvant therapy were comparable between both groups. Surgical procedures were equally distributed with cervico-thoracoabdominal esophagectomies in 21.3% and 20.0%, respectively (p=0.953). Significantly more LCP were operated using minimally invasive techniques compared to NLCP (21.3% vs. 10.2%, p=0.017). Severity of liver cirrhosis 64.3% of LCP presented with a preoperative MELD score ≤ 9, 28.6% with MELD score 10-13, and 7.1% with a MELD score > 13, according to 28.6% CTP A and 71.4% CTP B patients (Table 2). Seven patients had a preoperatively diagnosed liver cirrhosis, 57.1% with a MELD score ≤ 9, three of these patients were prepared by a preoperative transjugular intrahepatic portosystemic shunt (TIPS). MELD (p=0.577) and CTG scores (p=1.000) were not significantly different between patients with a pre- and intraoperative diagnosis of cirrhosis. Portal hypertension was present in 35.7% of LCP. The most common etiology of cirrhosis was alcohol abuse (85.7%). Moreover, 64.3% of LPC suffered from severe hypalbuminaemia (< 25mg/dl), which did not significantly differ from the NLCP cohort (50.4%, p=0.385). Morbidity and mortality Postoperative outcome was drastically worse for LCP with significantly higher morbidity (p=0.035, Table 3) and 30-day and 90-day mortality rates (p<0.001). Renal failure (p=0.020), anastomotic leakages (p=0.002), and sepsis (p=0.006) were significantly more frequent in LCP, whereas pulmonary complications (p=0.854) and hepatic failure (p=0.095) were equally distributed in both groups. By subdividing LCP according to MELD score (Low-MELD ≤ 9, High-MELD > 9), both groups showed comparable results in contrast to NLCP, especially in terms of mortality. While sepsis and renal failure revealed only significant differences between NLCP and the High-MELD group, sepsis only differed significantly between NLCP and the Low-MELD group. Interestingly, postoperative outcomes of the Low-MELD and High-MELD groups were equal with no significant difference. After adjustment for gender, age, surgical approach and comorbidity index, LCP demonstrated 10.5 times higher odds for 30-day ([95%CI 2.704 - 40.763], p=0.001; Table 4) and 16.5 times higher odds for 90-day mortality ([95%CI 3.873 - 70.014], p<0.001) compared to NLCP. Moreover, increased risks for renal failure (p=0.010), anastomotic leakage (p=0.020), and sepsis (p=0.015) are shown for cirrhotic patients. Prediction of mortality The characteristics of LCP with and without mortality within 30 and 90 days after surgery are depicted in Table 5. Univariate analysis revealed significant differences for tumor stages (p=0.036), presence of preoperative ascites (p=0.031, p=0.038) and portal hypertension (p=0.031, p=0.038). MELD and Child Score just as their categories failed to predict 30-day or 90-day mortality. Hence, several components of these scores correlated significantly with mortality, such as bilirubin (p=0.018, p=0.001) and INR (p=0.009, p=0.002), and also platelet count (p=0.002, p=0.003) demonstrated statistical significance. Moreover, the occurrence of specific complications was not associated with mortality. In ROC analysis, MELD score, Child Score and CCI failed in predicting 30-day or 90-day mortality (auROC=0.644 – 0.688, Supplementary Figure S1 and S2). In contrast, bilirubin and INR proofed excellent prognostic capacity in predicting both, 30-day ad 90-day mortality (bilirubin: 30-d M auROC= 0.875 p=0.020, 90-d M auROC=0.944, p=0.008; INR: 30-d M auROC= 90.6% p=0.012, 90-d M auROC= 90.0 p=0.016, Figure 1 and Supplementary Figure S3). Long-term outcome Cirrhotic patients had a significantly poorer prognosis compared to NCLP. After exclusion of 19.2% of NLCP, who were lost to follow up, 1-, 3- and 5-year survival for NLCP were 71.8%, 44.4% and 32.3% compared to 21.4%, 7.1% and 0.0% for LCP, respectively (p<0.001, Figure 2). Considering only patients, who were discharged alive, NLCP also demonstrated significantly better long-term survival (p=0.023, Supplementary Figure S4). Discussion This study demonstrates enormous perioperative morbidity and mortality for cirrhotic patients undergoing radical esophagectomy for esophageal cancer. Moreover, the disastrous long-term outcome of perioperative survivors questions the justification of these risks. These findings are in line with previous meta-analysis demonstrating higher complication rates in LCP (39.7 – 83.3%) compared to non-cirrhotic patients 20 , 21 . As specific complications, anastomotic leakage rate, sepsis, and renal failure are significantly more frequent in this LCP cohort. Leakages rates of cirrhotic patients are reported to be more frequent 14 , 22 or more frequently associated with surgical death 14 , 15 compared to NLCP, while others describe comparable rates to the literature 20 or comparison group but more severe manifestations 18 , 21 . Impaired conduit perfusion by aggravated venous outflow after the division of coronary veins has been discussed as a possible factor. Therefore, preoperative TIPS might have a positive impact on selected patients 23 . Moreover, protein metabolism disorder and immune dysfunction might further affect anastomotic closure 24 . Sepsis is also significantly more frequent among LCP, associated with 75% of 30-day mortality in our cohort. The main contributing factor might be an acquired immune dysfunction syndrome of cirrhotic patients 15 , 18 , 25 . Furthermore, renal failure is more common among LCP compared to NLCP, which affects in particular patients of the High-MELD group significantly (Table 3). Septical conditions might contribute to acute renal failure, but since Low-MELD patients are equally concerned by sepsis in contrast to kidney dysfunction, a hepato-renal component is to be assumed. In literature, only one publication reports postoperative renal failure, finding a highly significant distribution towards LCP with no association to postoperative deaths 15 . In contrast to recent publications 14-16 , 18 , 21 , 22 , postoperative ascites, pleural effusion, and postoperative liver failure are of unimportance in this LCP cohort. Potentially, the high proportion of intraoperatively diagnosed liver cirrhosis of 50%, which might be less affected by liver disease, as well as the high ratio of TIPS in preoperatively hydropic decompensated patients might contribute to this finding. Furthermore, although a higher rate of pulmonary complications was registered for LCP (25.0% vs. 42.9%, p=0.203, Table 3), no significant difference to NLCP could be found, also after adjustment for gender, age, surgical approach, and comorbidities (Table 4). The small sample size of this LCP cohort could prevent this difference from becoming significant. Potentially, a minimally-invasive rate twice of the NLCP cohort might also contribute to a reduction of pulmonary complications, as suggested by recent publications 15 , 20 . The 30-day and 90-day mortality rates, accounting for 57.1% and 64.3%, respectively, precisely describe the strongly increased perioperative risk of cirrhotic patients, which highly significantly differ from NLCP (p<0.001) before and after adjustment for confounders. In literature, perioperative mortality is reported to be lower, reporting 10.8-25.0%, for in-hospital mortality with a minor subset of studies referring to 30-day or 90-day mortality. Moreover, published meta-analyses indicated a potential publication bias 20 , 21 or low to moderate confidence in estimates 22 . Hence, it must be at least assumed that the underlying evidence could be biased by underreporting and quality of reported outcomes. This NLCP cohort demonstrates a high rate of 7.7% for 30-day mortality. Though, in contrast to the literature, this rate does not double after 90 days (9.6%) but normalizes to published rates for 90-day mortality (7.0 -13.3% 26-28 ). This finding might be addressed to an outstanding ratio of severe comorbidities in this NLCP cohort as indicated by CCI > 3 (52.6%). In comparison, recent publications included a minor subset of patients with severe comorbidities (CCI > 3: 1,4%, 30-d mortality 4.2% 26 ). Therefore, 30-day mortality, which is discussed as an indicator for hospital’s capability to provide perioperative care and is decisively influenced by patients’ age, and comorbidities, might be poorer, whereas 90-day mortality, reflecting surgical and cancer management decisions, is within recently published ranges 26-28 . The chance of cure is drastically poorer for LCP compared to NLCP: in 5-year survival analysis, 7.1% of cirrhotic patients are alive 3 years post-surgery. Even after the exclusion of postoperative deaths, survival of the LCP is still significantly worse (p=0.023). The limited available evidence of three studies reporting on this subject is summarized in two meta-analyses: while one analysis reports high heterogeneity (I 2 =74.8%) suggesting a random effect 22 , the other observes a tendency for unfavourable survival of LCP 21 . The risk assessment for LCP prior to esophagectomy remains elusive, as claimed by several studies 15 , 18 , 20 , 21 : MELD and CTP score are of no predictive value in this cohort, but components of both scores as preoperative ascites, bilirubin levels, and INR prove good prognostic capacity. Therefore, patients with completely normal bilirubin and INR levels and without any current or former sign of portal hypertension or hydropic decompensation could potentially be evaluated as candidates for curative esophagectomy. Not only the retrospective nature of this study– although the data are derived from a prospectively maintained database - restrains this research but also an inherent selection bias. Therefore, only CTP A and B patients were included, as recommended by the present evidence, and further unmeasurable factors may have led to the reluctance of responsible surgeons to operate on these fragile patients. Only a limited number of 14 LCP could be identified from the database, of which 64% were assigned to the Low- MELD group (≤ 9). Thus, reported observations need to be interpreted with caution. Further studies are needed to evaluate these findings. Overall, LC remains a crucial risk factor for major surgery, thus, for esophagectomy. A careful patient selection should be mandatory, which might approve patients for curative surgery with completely normal bilirubin and INR levels and without any current or former sign of portal hypertension or hydropic decompensation. Though, associated additionally with worse long-term survival, the justification for curative esophagectomy for cirrhotic patients remains questionable and needs further research. Declarations Authors Contribution J.K.G., J.R.I., M.R. conception and design, acquisition of data, analysis and interpretation of data, drafting of the article, and final approval of the version published. N.K., M.K., J.T., F.P., D.P., N.M., M.B. interpretation of data, drafting of the article and critical revision for important intellectual content. All authors reviewed the manuscript. Additional information The authors declare no competing interests. References 1. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians , doi:10.3322/caac.21660 (2021). 2. Kauppila, J. H., Mattsson, F., Brusselaers, N. & Lagergren, J. Prognosis of oesophageal adenocarcinoma and squamous cell carcinoma following surgery and no surgery in a nationwide Swedish cohort study. BMJ Open 8 , e021495, doi:10.1136/bmjopen-2018-021495 (2018). 3. Jung, H. K. et al. 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Tables Due to technical limitations, table 1-5 is only available as a download in the Supplemental Files section. Additional Declarations No competing interests reported. Supplementary Files SupplemataryFiguresLCSciRep.pptx Supplementary Figure S1-S4 Tables.pdf Table 1-5 Cite Share Download PDF Status: Published Journal Publication published 09 Mar, 2022 Read the published version in PLOS ONE → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Grass","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACxgYILcfAAyR5SNFiTLwWGEhsIFoLcwP7tQ8//tSlbzhz+ADDmwqiHMZTPLO37XDuhrNtCYxzzhCnJZmBt+FA7obzPAbMvG1EamH8A3SYwXn+D8y8/4jSwn6YmYeNOcHgbA8DM28DMVqaeZiZZdsOG848c8zg4JxjRGgxbG9/zPjmT50835nkhw/e1BCjpZnHAM45QIQGBgZ5BvYHRCkcBaNgFIyCEQwATjo10cwSq78AAAAASUVORK5CYII=","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Julia","middleName":"K.","lastName":"Grass","suffix":""},{"id":40837951,"identity":"c3fa1efc-3c36-4673-8f9e-b328a67d1853","order_by":1,"name":"Natalie Küsters","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Natalie","middleName":"","lastName":"Küsters","suffix":""},{"id":40837952,"identity":"bbfc42dd-0693-4c17-a2a2-753e71cc0791","order_by":2,"name":"Marius Kemper","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marius","middleName":"","lastName":"Kemper","suffix":""},{"id":40837955,"identity":"45284833-14b6-4924-95fb-9ed274317699","order_by":3,"name":"Jan Tintrup","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Tintrup","suffix":""},{"id":40837956,"identity":"e908c817-33e8-46dd-9728-7e44ccea345c","order_by":4,"name":"Felix Piecha","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Felix","middleName":"","lastName":"Piecha","suffix":""},{"id":40837958,"identity":"cd0a45d6-54a9-4b34-995a-c4e9190f9a0e","order_by":5,"name":"Jakob R. Izbicki","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jakob","middleName":"R.","lastName":"Izbicki","suffix":""},{"id":40837960,"identity":"7e43c32d-b597-48e3-866e-7a8a140ce469","order_by":6,"name":"Daniel Perez","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Perez","suffix":""},{"id":40837962,"identity":"eef49cff-1021-45c4-8967-17b6a19e85b4","order_by":7,"name":"Nathaniel Melling","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nathaniel","middleName":"","lastName":"Melling","suffix":""},{"id":40837963,"identity":"5cfd4497-fa21-482c-aac3-04c4bdfaa8db","order_by":8,"name":"Maximilian Bockhorn","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maximilian","middleName":"","lastName":"Bockhorn","suffix":""},{"id":40837964,"identity":"c285d251-ec46-4b23-9010-da0badd37f9f","order_by":9,"name":"Matthias Reeh","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Reeh","suffix":""}],"badges":[],"createdAt":"2021-07-16 12:29:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-725154/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-725154/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1371/journal.pone.0265093","type":"published","date":"2022-03-09T19:24:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":11721527,"identity":"48aa0ea3-688c-404b-b77c-f5ab92946d69","added_by":"auto","created_at":"2021-07-22 18:55:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29530,"visible":true,"origin":"","legend":"Comparison of receiver operating characteristic (ROC) curves for prediction of 90-day mortality in cirrhotic patients by Bilirubin, INR and platelet count. \nBilirubin and platelet count providing an excellent diagnostic capacity.\np-values in bold indicate statistical significance. AUC: area under the curve, CI: confidence interval, INR: international normalized ratio.","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-725154/v1/680f37b39ce3fce2db3fc1ad.png"},{"id":11721528,"identity":"20e59327-e5f5-4b58-bb60-fdc877f9510d","added_by":"auto","created_at":"2021-07-22 18:55:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26463,"visible":true,"origin":"","legend":"Cumulative Survival curves after esophagectomy of cirrhotic (LCP) and non-cirrhotic patients (NLCP). \n1-, 3- and 5-year survival were 79.1%, 44.40% and 32.3% in the NLCP cohort and 21.4%, 7.1% and 0.0% in the LCP group. 19.2% of NLCP were lost to follow-up and excluded from analysis. ","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-725154/v1/a3e12e79f535b626380ef500.png"},{"id":19040056,"identity":"ab7096a4-763b-4463-86c5-1ab0452770cb","added_by":"auto","created_at":"2022-03-09 19:24:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":314543,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-725154/v1/fc40f9f1-7dae-46a8-ade3-0d120f2d714a.pdf"},{"id":11721530,"identity":"68b01764-2612-4ae6-ab4f-e1a59c834df6","added_by":"auto","created_at":"2021-07-22 18:55:45","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":6935104,"visible":true,"origin":"","legend":"Supplementary Figure S1-S4","description":"","filename":"SupplemataryFiguresLCSciRep.pptx","url":"https://assets-eu.researchsquare.com/files/rs-725154/v1/be6625d2f36508397216ce44.pptx"},{"id":11721645,"identity":"fcf0f6a8-c6ea-45eb-8401-22626e364be5","added_by":"auto","created_at":"2021-07-22 18:58:45","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":123858,"visible":true,"origin":"","legend":"Table 1-5","description":"","filename":"Tables.pdf","url":"https://assets-eu.researchsquare.com/files/rs-725154/v1/11d4ca09ee1a4c16205f9c1c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRisk Stratification of Cirrhotic Patients Undergoing Esophagectomy for Esophageal Cancer: A Single-Centre Experience\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRanking as the sixth leading cause of cancer-related mortality, esophageal cancer (EC) continues to be among the most aggressive tumours with limited prognosis\u0026nbsp;\u003csup\u003e1\u003c/sup\u003e, which can be altered most favourably by surgical intervention. Esophagectomy with radical lymphadenectomy represents the mainstay of curative therapy for EC. By continuously refined diagnostics and multimodal treatment, 5-year survival increased to 20-45% for surgically treated patients\u0026nbsp;\u003csup\u003e2-4\u003c/sup\u003e. However, esophagectomy is associated with high rates of perioperative morbidity and mortality, which are significantly increased with comorbidities and patients\u0026rsquo; age and adversely impact long-term outcomes\u0026nbsp;\u003csup\u003e5-7\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDue to rising incidence and optimized therapeutical strategies resulting in longer survival, liver cirrhosis represents a common cause of morbidity\u0026nbsp;\u003csup\u003e8\u003c/sup\u003e. Accompanied with a higher incidence of extrahepatic malignancies compared to non-cirrhotic patients\u0026nbsp;\u003csup\u003e9\u003c/sup\u003e, oncological therapy for cirrhotic patients (LCP) gains increasing relevance. As EC and cirrhosis share certain risk factors\u0026nbsp;\u003csup\u003e10\u003c/sup\u003e, LCP are reported to be exposed to an eight-fold elevated risk for the development of EC\u0026nbsp;\u003csup\u003e9\u003c/sup\u003e. Though, liver cirrhosis depicts a crucial risk factor for non-hepatic surgery\u0026nbsp;\u003csup\u003e11-13\u003c/sup\u003e, with elevated morbidity and mortality following esophagectomy of 39.7-83.3% and 26.0-50.0%, respectively\u0026nbsp;\u003csup\u003e14-18\u003c/sup\u003e. Although cirrhosis significantly compromises live expectancy\u0026nbsp;\u003csup\u003e19\u003c/sup\u003e, long-term survival after esophagectomy for EC has been reported to be comparable between LCP and non-cirrhotic patients (NLCP) by several case series\u0026nbsp;\u003csup\u003e14\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e16\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLimited evidence is available for treatment stratification of EC in LCP, in particular in terms of general health assessment and severity of liver cirrhosis, as stated by recent meta-analyses\u0026nbsp;\u003csup\u003e20-22\u003c/sup\u003e. Thus, this study aims to evaluate, what factors might affect the perioperative and long-term outcome and whether radical esophagectomy represents a feasible option in the oncological treatment of cirrhotic patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePatients with concomitant liver cirrhosis were identified from a prospectively maintained database of EC patients, who underwent esophagectomy at the University of Hamburg Medical Institutions between January 2012 to May 2016. The study protocol was legitimated by the institutional review board of general medical chamber Hamburg and registered at clinicaltrial.gov (NCT04809870 on 18/03/2021). Informed consent was obtained from all patients included. The diagnosis of cirrhosis was confirmed by clinical signs, imaging, and histological proof, in particular in all cases of intraoperatively diagnosed cirrhosis. The severity of cirrhosis at the time of surgery was determined by preoperative laboratory data at hospital admission and preoperative imaging. Cirrhotic Patients with insufficient data for calculating preoperative model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) scores were excluded from further analysis. Studied variables for both, cirrhotic and non-cirrhotic patients included gender, age, coexisting medical conditions, the ASA classification, and CCI, tumor stage administered by America Joint Committee on Cancer Union, 7th edition, tumor localization, history of neoadjuvant therapy, laboratory data (creatinine, albumin, platelet count, bilirubin, and INR) and surgical approach. Moreover, for cirrhotic patients, etiology of cirrhosis, presence, and severity of preoperative ascites, portal hypertension, and esophageal varices were collected. Portal hypertension was defined by platelet count lower than 100 mrd/l and presence of ascites, splenomegaly, or esophageal varices.\u003c/p\u003e \u003cp\u003eSurgeries were performed as thoracoabdominal esophagectomy with either two-field lymphadenectomy and intrathoracic anastomosis (Ivor-Lewis) or cervico-thoracoabdominal esophagectomy with three-field lymphadenectomy and cervical anastomosis (McKeown) depending on the tumor localization. Reconstruction was conducted by gastric conduit. Eligible approaches were conventionally open, hybrid (abdominal laparoscopically and thoracic open), and completely minimally invasive. The perioperative outcome was investigated by occurrence and severity of complications according to Clavien-Dindo classification, 30- and 90-day mortality as well as 5-year survival analysis. Pulmonary and cardiac complications are defined by any organ-related major complications (Clavien-Dindo\u0026thinsp;\u0026ge;\u0026thinsp;3). Anastomotic leakage was defined as any endoscopically proven anastomotic dehiscence and Chyle leak was defined by a concentration of triglycerides (TG) in drain fluids\u0026thinsp;\u0026ge;\u0026thinsp;3 times TGs in serum.\u003c/p\u003e \u003cp\u003eData management and statistical analysis were performed using IBM SPSS Statistics for Macintosh, Version 25.0. (Armonk, NY: IBM Corp.). For univariate analyses, the Student \u003cem\u003et\u003c/em\u003e test was applied for parametric continuous variables and the Man-Whitney-U test for nonparametric continuous variables. Categorical variables were tested using χ\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e-Test or the Fisher exact test as appropriate. A generalized linear model was used for adjusted outcome analysis, adjusting for age, gender, surgical approach, and comorbidity index. The sensitivity and specificity of available scores and parameters were calculated using receiver operating characteristics (ROC) curves. Survival rates were estimated using the log-rank test and described by Kaplan-Meyer curves. A two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as significant. The study was conformed to the standards of the Declaration of Helsinki.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinicopathological Parameter\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom the prospective database of 170 patients, who underwent esophagectomy for esophageal cancer between 01/2012 and 04/2016, 14 patients with concomitant cirrhosis could be identified (Table 1). Both cohorts were of comparable age (64.4 \u0026plusmn; 8.7 vs. 63.4 \u0026plusmn; 10.8, p=0.826) while gender distribution differed, with significantly more female patients among the LCP (50.0% vs. 14.1%, p=0.003). Both, American Society of Anaesthesiology (ASA) and Charlson Comorbidity Index (CCI) demonstrated a significantly poorer general condition of LCP (p\u0026lt;0.001 and p=0.004, respectively). Nonetheless, NLCP also suffered from relevant comorbidities, reflected by 52.6% CCI of three or more points. Histology, grading, tumor size and location, nodal status, metastatic status, UICC stage, and proportion of neoadjuvant therapy were comparable between both groups. Surgical procedures were equally distributed with cervico-thoracoabdominal esophagectomies in 21.3% and 20.0%, respectively (p=0.953). Significantly more LCP were operated using minimally invasive techniques compared to NLCP (21.3% vs. 10.2%, p=0.017).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSeverity of liver cirrhosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e64.3% of LCP presented with a preoperative MELD score \u0026le; 9, 28.6% with MELD score 10-13, and 7.1% with a MELD score \u0026gt; 13, according to 28.6% CTP A and 71.4% CTP B patients (Table 2). Seven patients had a preoperatively diagnosed liver cirrhosis, 57.1% with a MELD score \u0026le; 9, three of these patients were prepared by a preoperative transjugular intrahepatic portosystemic shunt (TIPS). MELD (p=0.577) and CTG scores (p=1.000) were not significantly different between patients with a pre- and intraoperative diagnosis of cirrhosis. Portal hypertension was present in 35.7% of LCP. The most common etiology of cirrhosis was alcohol abuse (85.7%). Moreover, 64.3% of LPC suffered from severe hypalbuminaemia (\u0026lt; 25mg/dl), which did not significantly differ from the NLCP cohort (50.4%, p=0.385).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMorbidity and mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostoperative outcome was drastically worse for LCP with significantly higher morbidity (p=0.035, Table 3) and 30-day and 90-day mortality rates (p\u0026lt;0.001). Renal failure (p=0.020), anastomotic leakages (p=0.002), and sepsis (p=0.006) were significantly more frequent in LCP, whereas pulmonary complications (p=0.854) and hepatic failure (p=0.095) were equally distributed in both groups. By subdividing LCP according to MELD score (Low-MELD \u0026le; 9, High-MELD \u0026gt; 9), both groups showed comparable results in contrast to NLCP, especially in terms of mortality. While sepsis and renal failure revealed only significant differences between NLCP and the High-MELD group, sepsis only differed significantly between NLCP and the Low-MELD group. Interestingly, postoperative outcomes of the Low-MELD and High-MELD groups were equal with no significant difference. After adjustment for gender, age, surgical approach and comorbidity index, LCP demonstrated 10.5 times higher odds for 30-day ([95%CI 2.704 - 40.763], p=0.001; Table 4) and 16.5 times higher odds for 90-day mortality ([95%CI 3.873 - 70.014], p\u0026lt;0.001) compared to NLCP. Moreover, increased risks for renal failure (p=0.010), anastomotic leakage (p=0.020), and sepsis (p=0.015) are shown for cirrhotic patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrediction of mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe characteristics of LCP with and without mortality within 30 and 90 days after surgery are depicted in Table 5. Univariate analysis revealed significant differences for tumor stages (p=0.036), presence of preoperative ascites (p=0.031, p=0.038) and portal hypertension (p=0.031, p=0.038). MELD and Child Score just as their categories failed to predict 30-day or 90-day mortality. Hence, several components of these scores correlated significantly with mortality, such as bilirubin (p=0.018, p=0.001) and INR (p=0.009, p=0.002), and also platelet count (p=0.002, p=0.003) demonstrated statistical significance. Moreover, the occurrence of specific complications was not associated with mortality.\u003c/p\u003e\n\u003cp\u003eIn ROC analysis, MELD score, Child Score and CCI failed in predicting 30-day or 90-day mortality (auROC=0.644 \u0026ndash; 0.688, Supplementary Figure S1 and S2). In contrast, bilirubin and INR proofed excellent prognostic capacity in predicting both, 30-day ad 90-day mortality (bilirubin: 30-d M auROC= 0.875 p=0.020, 90-d M auROC=0.944, p=0.008; INR: 30-d M auROC= 90.6% p=0.012, 90-d M auROC= 90.0 p=0.016, Figure 1 and Supplementary Figure S3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLong-term outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCirrhotic patients had a significantly poorer prognosis compared to NCLP. After exclusion of 19.2% of NLCP, who were lost to follow up, 1-, 3- and 5-year survival for NLCP were 71.8%, 44.4% and 32.3% compared to 21.4%, 7.1% and 0.0% for LCP, respectively (p\u0026lt;0.001, Figure 2). Considering only patients, who were discharged alive, NLCP also demonstrated significantly better long-term survival (p=0.023, Supplementary Figure S4).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrates enormous perioperative morbidity and mortality for cirrhotic patients undergoing radical esophagectomy for esophageal cancer. Moreover, the disastrous long-term outcome of perioperative survivors questions the justification of these risks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese findings are in line with previous meta-analysis demonstrating higher complication rates in LCP (39.7 \u0026ndash; 83.3%) compared to non-cirrhotic patients\u0026nbsp;\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e. \u0026nbsp;As specific complications, anastomotic leakage rate, sepsis, and renal failure are significantly more frequent in this LCP cohort. Leakages rates of cirrhotic patients are reported to be more frequent\u0026nbsp;\u003csup\u003e14\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e or more frequently associated with surgical death\u0026nbsp;\u003csup\u003e14\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e compared to NLCP, while others describe comparable rates to the literature\u0026nbsp;\u003csup\u003e20\u003c/sup\u003e or comparison group but more severe manifestations\u0026nbsp;\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e. Impaired conduit perfusion by aggravated venous outflow after the division of coronary veins has been discussed as a possible factor. Therefore, preoperative TIPS might have a positive impact on selected patients\u0026nbsp;\u003csup\u003e23\u003c/sup\u003e. Moreover, protein metabolism disorder and immune dysfunction might further affect anastomotic closure\u0026nbsp;\u003csup\u003e24\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSepsis is also significantly more frequent among LCP, associated with 75% of 30-day mortality in our cohort. The main contributing factor might be an acquired immune dysfunction syndrome of cirrhotic patients\u0026nbsp;\u003csup\u003e15\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e25\u003c/sup\u003e. Furthermore, renal failure is more common among LCP compared to NLCP, which affects in particular patients of the High-MELD group significantly (Table 3). Septical conditions might contribute to acute renal failure, but since Low-MELD patients are equally concerned by sepsis in contrast to kidney dysfunction, a hepato-renal component is to be assumed. In literature, only one publication reports postoperative renal failure, finding a highly significant distribution towards LCP with no association to postoperative deaths\u0026nbsp;\u003csup\u003e15\u003c/sup\u003e. In contrast to recent publications\u0026nbsp;\u003csup\u003e14-16\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e, postoperative ascites, pleural effusion, and postoperative liver failure are of unimportance in this LCP cohort. Potentially, the high proportion of intraoperatively diagnosed liver cirrhosis of 50%, which might be less affected by liver disease, as well as the high ratio of TIPS in preoperatively hydropic decompensated patients might contribute to this finding. Furthermore, although a higher rate of pulmonary complications was registered for LCP (25.0% vs. 42.9%, p=0.203, Table 3), no significant difference to NLCP could be found, also after adjustment for gender, age, surgical approach, and comorbidities (Table 4). The small sample size of this LCP cohort could prevent this difference from becoming significant. Potentially, a minimally-invasive rate twice of the NLCP cohort might also contribute to a reduction of pulmonary complications, as suggested by recent publications\u0026nbsp;\u003csup\u003e15\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e. The 30-day and 90-day mortality rates, accounting for 57.1% and 64.3%, respectively, precisely describe the strongly increased perioperative risk of cirrhotic patients, which highly significantly differ from NLCP (p\u0026lt;0.001) before and after adjustment for confounders. In literature, perioperative mortality is reported to be lower, reporting 10.8-25.0%, for in-hospital mortality with a minor subset of studies referring to 30-day or 90-day mortality. Moreover, published meta-analyses indicated a potential publication bias\u0026nbsp;\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e or low to moderate confidence in estimates\u0026nbsp;\u003csup\u003e22\u003c/sup\u003e. Hence, it must be at least assumed that the underlying evidence could be biased by underreporting and quality of reported outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis NLCP cohort demonstrates a high rate of 7.7% for 30-day mortality. Though, in contrast to the literature, this rate does not double after 90 days (9.6%) but normalizes to published rates for 90-day mortality (7.0 -13.3%\u0026nbsp;\u003csup\u003e26-28\u003c/sup\u003e). This finding might be addressed to an outstanding ratio of severe comorbidities in this NLCP cohort as indicated by CCI \u003cu\u003e\u0026gt;\u003c/u\u003e 3 (52.6%). In comparison, recent publications included a minor subset of patients with severe comorbidities (CCI \u003cu\u003e\u0026gt;\u003c/u\u003e 3: 1,4%, 30-d mortality 4.2%\u0026nbsp;\u003csup\u003e26\u003c/sup\u003e). Therefore, 30-day mortality, which is discussed as an indicator for hospital\u0026rsquo;s capability to provide perioperative care and is decisively influenced by patients\u0026rsquo; age, and comorbidities, might be poorer, whereas 90-day mortality, reflecting surgical and cancer management decisions, is within recently published ranges\u0026nbsp;\u003csup\u003e26-28\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe chance of cure is drastically poorer for LCP compared to NLCP: in 5-year survival analysis, 7.1% of cirrhotic patients are alive 3 years post-surgery. Even after the exclusion of postoperative deaths, survival of the LCP is still significantly worse (p=0.023). The limited available evidence of three studies reporting on this subject is summarized in two meta-analyses: while one analysis reports high heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=74.8%) suggesting a random effect\u0026nbsp;\u003csup\u003e22\u003c/sup\u003e, the other observes a tendency for unfavourable survival of LCP\u0026nbsp;\u003csup\u003e21\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe risk assessment for LCP prior to esophagectomy remains elusive, as claimed by several studies\u0026nbsp;\u003csup\u003e15\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e: MELD and CTP score are of no predictive value in this cohort, but components of both scores as preoperative ascites, bilirubin levels, and INR prove good prognostic capacity. Therefore, patients with completely normal bilirubin and INR levels and without any current or former sign of portal hypertension or hydropic decompensation could potentially be evaluated as candidates for curative esophagectomy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot only the retrospective nature of this study\u0026ndash; although the data are derived from a prospectively maintained database - restrains this research but also an inherent selection bias. Therefore, only CTP A and B patients were included, as recommended by the present evidence, and further unmeasurable factors may have led to the reluctance of responsible surgeons to operate on these fragile patients. Only a limited number of 14 LCP could be identified from the database, of which 64% were assigned to the Low- MELD group (\u0026le; 9). Thus, reported observations need to be interpreted with caution. Further studies are needed to evaluate these findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOverall, LC remains a crucial risk factor for major surgery, thus, for esophagectomy. A careful patient selection should be mandatory, which might approve patients for curative surgery with completely normal bilirubin and INR levels and without any current or former sign of portal hypertension or hydropic decompensation. Though, associated additionally with worse long-term survival, the justification for curative esophagectomy for cirrhotic patients remains questionable and needs further research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.K.G., J.R.I., M.R. conception and design, acquisition of data, analysis and interpretation of data, drafting of the article, and final approval of the version published. N.K., M.K., J.T., F.P., D.P., N.M., M.B. interpretation of data, drafting of the article and critical revision for important intellectual content. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. Sung, H.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA: a cancer journal for clinicians\u003c/em\u003e, doi:10.3322/caac.21660 (2021).\u003c/p\u003e\n\u003cp\u003e2. Kauppila, J. H., Mattsson, F., Brusselaers, N. \u0026amp; Lagergren, J. 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Sozzi, M., Siboni, S., Asti, E., Bonitta, G. \u0026amp; Bonavina, L. Short-Term Outcomes of Minimally Invasive Esophagectomy for Carcinoma In Patients with Liver Cirrhosis. \u003cem\u003eJournal of laparoendoscopic \u0026amp; advanced surgical techniques. Part A\u003c/em\u003e\u003cstrong\u003e27\u003c/strong\u003e, 592-596, doi:10.1089/lap.2017.0115 (2017).\u003c/p\u003e\n\u003cp\u003e16. Wang, Z. Q.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Can oesophagectomy be performed for patients with oesophageal carcinoma and concomitant liver cirrhosis? A retrospective study based on a propensity-matched cohort. \u003cem\u003eInteractive cardiovascular and thoracic surgery\u003c/em\u003e\u003cstrong\u003e25\u003c/strong\u003e, 442-447, doi:10.1093/icvts/ivx132 (2017).\u003c/p\u003e\n\u003cp\u003e17. Lu, M. S.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Is it safe to perform esophagectomy in esophageal cancer patients combined with liver cirrhosis? \u003cem\u003eInteractive cardiovascular and thoracic surgery\u003c/em\u003e\u003cstrong\u003e4\u003c/strong\u003e, 423-425, doi:10.1510/icvts.2005.110387 (2005).\u003c/p\u003e\n\u003cp\u003e18. Valmasoni, M.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Esophageal Cancer Surgery for Patients with Concomitant Liver Cirrhosis: A Single-Center Matched-Cohort Study. \u003cem\u003eAnnals of surgical oncology\u003c/em\u003e\u003cstrong\u003e24\u003c/strong\u003e, 763-769, doi:10.1245/s10434-016-5610-8 (2017).\u003c/p\u003e\n\u003cp\u003e19. D'Amico, G., Garcia-Tsao, G. \u0026amp; Pagliaro, L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. \u003cem\u003eJournal of hepatology\u003c/em\u003e\u003cstrong\u003e44\u003c/strong\u003e, 217-231, doi:10.1016/j.jhep.2005.10.013 (2006).\u003c/p\u003e\n\u003cp\u003e20. Asti, E., Sozzi, M., Bonitta, G., Bernardi, D. \u0026amp; Bonavina, L. Esophagectomy in patients with liver cirrhosis: a systematic review and Bayesian meta-analysis. \u003cem\u003eJournal of visceral surgery\u003c/em\u003e\u003cstrong\u003e155\u003c/strong\u003e, 453-464, doi:10.1016/j.jviscsurg.2018.03.014 (2018).\u003c/p\u003e\n\u003cp\u003e21. Deng, H. Y.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Can we perform esophagectomy for esophageal cancer patients with concomitant liver cirrhosis? A comprehensive systematic review and meta-analysis. \u003cem\u003eDis Esophagus\u003c/em\u003e\u003cstrong\u003e32\u003c/strong\u003e, doi:10.1093/dote/doz003 (2019).\u003c/p\u003e\n\u003cp\u003e22. 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T. \u0026amp; Manoria, P. Immune Dysfunction in Cirrhosis. \u003cem\u003eJournal of clinical and translational hepatology\u003c/em\u003e\u003cstrong\u003e5\u003c/strong\u003e, 50-58, doi:10.14218/JCTH.2016.00056 (2017).\u003c/p\u003e\n\u003cp\u003e26. In, H.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Doubling of 30-Day Mortality by 90 Days After Esophagectomy: A Critical Measure of Outcomes for Quality Improvement. \u003cem\u003eAnnals of surgery\u003c/em\u003e\u003cstrong\u003e263\u003c/strong\u003e, 286-291, doi:10.1097/SLA.0000000000001215 (2016).\u003c/p\u003e\n\u003cp\u003e27. Talsma, A. K., Lingsma, H. F., Steyerberg, E. W., Wijnhoven, B. P. \u0026amp; Van Lanschot, J. J. The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care. \u003cem\u003eAnnals of surgery\u003c/em\u003e\u003cstrong\u003e260\u003c/strong\u003e, 267-273, doi:10.1097/SLA.0000000000000482 (2014).\u003c/p\u003e\n\u003cp\u003e28. Walters, D. M., McMurry, T. L., Isbell, J. M., Stukenborg, G. J. \u0026amp; Kozower, B. D. Understanding mortality as a quality indicator after esophagectomy. \u003cem\u003eAnn Thorac Surg\u003c/em\u003e\u003cstrong\u003e98\u003c/strong\u003e, 506-511; discussion 511-502, doi:10.1016/j.athoracsur.2014.03.041 (2014).\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations, table 1-5 is only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Risk stratification, cirrhotic patients, esophagectomy, esophageal cancer, single-centre experience, crucial risk factor, survival analysis","lastPublishedDoi":"10.21203/rs.3.rs-725154/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-725154/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eConcomitant liver cirrhosis is a crucial risk factor for major surgeries. However, only few data are available concerning cirrhotic patients requiring esophagectomy for malignant disease. \u003c/p\u003e\u003cp\u003eFrom a prospectively maintained database of esophageal cancer patients, who underwent curative esophagectomy between 01/2012 and 01/2016, patients with concomitant liver cirrhosis (LCP) were compared to non-cirrhotic patients (NLCP).\u003c/p\u003e\u003cp\u003eOf 170 patients, 14 cirrhotic patients with predominately low MELD scores (≤ 9, 64.3%) were identified. Perioperative outcome was significantly worse for LCP, as proofed by 30-day (57.1% vs. 7.7, p\u0026lt;0.001) and 90-day mortality (64.3% vs. 9.6%, p\u0026lt;0.001), anastomotic leakage rate (64.3 vs. 22.3%, p=0.002) and sepsis (57.1 vs. 21.5%, p=0.006). Even after adjustment for age, gender, comorbidities, and surgical approach, LCP revealed higher odds for 30-day and 90-day mortality compared to NLCP. Moreover, 5-year survival analysis showed a significantly poorer long-term outcome of LCP (p=0.023). For risk stratification, none of the common cirrhosis scores proved prognostic impact, whereas components as Bilirubin (auROC 94.4%), INR (auROC=90.0%), and preoperative ascites (p=0.038) correlated significantly with the perioperative outcome. Curative esophagectomy for cirrhotic patients is associated with a dismal prognosis and should be evaluated critically. While MELD and Child score failed to predict perioperative mortality, Bilirubin and INR proofed excellent prognostic capacity in this cohort.\u003c/p\u003e","manuscriptTitle":"Risk Stratification of Cirrhotic Patients Undergoing Esophagectomy for Esophageal Cancer: A Single-Centre Experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-22 18:55:43","doi":"10.21203/rs.3.rs-725154/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f931eb80-8800-4f42-8c7b-349886ccb789","owner":[],"postedDate":"July 22nd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":5906798,"name":"Cardiothoracic Surgery"},{"id":5906799,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2022-03-09T19:24:47+00:00","versionOfRecord":{"articleIdentity":"rs-725154","link":"https://doi.org/10.1371/journal.pone.0265093","journal":{"identity":"plos-one","isVorOnly":true,"title":"PLOS ONE"},"publishedOn":"2022-03-09 19:24:47","publishedOnDateReadable":"March 9th, 2022"},"versionCreatedAt":"2021-07-22 18:55:43","video":"","vorDoi":"10.1371/journal.pone.0265093","vorDoiUrl":"https://doi.org/10.1371/journal.pone.0265093","workflowStages":[]},"version":"v1","identity":"rs-725154","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-725154","identity":"rs-725154","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}