The impact of obesity on esophagectomy: a meta-analysis

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1 Diseases of the Esophagus (2017) 31, 1 9 DOI: /dote/dox149 Original Article The impact of obesity on esophagectomy: a meta-analysis V. Mengardo, F. Pucetti, O. Mc Cormack, A. Chaudry, W. H. Allum Department of Upper Gastrointestinal Surgery, Royal Marsden Hospital, London, UK SUMMARY. The impact of body mass index (BMI) on postoperative outcomes after curative resection for esophageal cancer has been assessed in many studies worldwide with conflicting conclusions. The aim of this metaanalysis is to evaluate the influence of preoperative BMI on surgical and oncologic outcomes after radical surgery for esophageal cancer, in Western studies. A comprehensive electronic search was performed to identify Western publications reporting BMI and outcomes following surgery for esophageal cancer. Articles that did not report preoperative BMI, postoperative morbidity, and early mortality were excluded. Statistical analysis was performed using the OpenMetaAnalyst software (Version 10.10). One hundred and ninety records were examined and 8 studies were included with a total of 2838 patients. The study population was stratified into two groups: a nonobese group (BMI < 30 kg/m 2 ), containing 2199 patients, and an obese group (BMI 30 kg/m 2 ), with 639 patients. In the obese group, there was an increased risk (up to 35%) of anastomotic leak (P = 0.003; RR: 0.857, 95% CI: 0.497, 0.867). The obese group showed a significantly more favorable five-year overall survival (P = 0.011). Although there was a significant association between anastomotic leak and obesity, patients with obesity also have a better overall 5-year survival. This meta-analysis demonstrates that patients with obesity should be counseled regarding the specific risks of surgery but they can be reassured that despite these risks overall outcome is satisfactory. KEY WORDS: body mass index (BMI), esophageal cancer, esophagectomy, obesity. INTRODUCTION Several studies have shown that adiposity and high body mass index (BMI) are associated with increased morbidity and mortality following general and esophagogastric cancer surgery. 1,2 The BMI (the weight in kilograms divided by the square of the height in meters) is the World Health Organisation s 3 international index used to classify underweight (BMI < 18.5 kg/m 2 ), normal weight (BMI kg/m 2 ), overweight (BMI kg/m 2 ), and obese (BMI 30 kg/m 2 ) patients. Over the last 30 years, obesity rates have been steadily increasing among Western populations while its prevalence in Eastern regions has remained consistently low. Currently, Asia shows the lowest prevalence rate (3.2% in males, 6.8% in females) while USA records the highest (24% in males, 29.6% in females) and Europe presents an intermediate rate (21.5% in males, 24.5% in females). 4 6 Address correspondence to: Ms. Orla Mc Cormack, MD FRCSI, The Royal Marsden Hospital, 203 Fulham Road, Chelsea, London SW3 6JJ, UK. Orla.McCormack@rmh.nhs.uk Request for reprints should be addressed to corresponding author as above. Obesity is associated with a number of chronic conditions including diabetes mellitus, hypertension, ischemic heart disease, and cerebrovascular disease, all of which can increase anesthetic and surgical risk. 5,7,8 These comorbidities can contribute to postoperative complications such as wound infections, anastomotic leak, and respiratory disease. 9,10 Moreover, surgery in patients with obesity can result in increased blood loss and a longer operation time. 11 It is now well known that obesity plays a role in the etiology of esophagogastric junctional adenocarcinomas. 12 Studies on the impact of obesity on the surgical management of esophageal cancer are inconsistent with some reporting a higher incidence of postoperative complications. Outcomes such as operative time, postoperative bleeding, and lymph node harvest rate are variable between studies. Surprisingly, several studies confirm obesity is associated with better long-term overall survival Eastern studies often include patients with a BMI > 25 as obese and their study populations (early stage squamous cell carcinoma, SCC) are quite different to Western groups. 16 The aim of this meta-analysis is to evaluate the effect of preoperative BMI on outcome following C The Author(s) Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please journals.permissions@oup.com 1

2 2 Diseases of the Esophagus radical surgery for esophageal cancer in a Western series. MATERIALS AND METHODS Search strategy and study selection A comprehensive electronic search from 2004 to December 2016 was performed to identify Western publications relating to preoperative BMI and outcomes after esophageal surgery for cancer. The search was performed using PubMed search engine and the following MeSH terms (Medical Subject Headings) were combined: Body mass index, Overweight, Obesity, Esophageal Neoplasm s, Esophageal Neoplasms/surgery, Esophagectomy, Surgical Procedures, Operative and Upper Gastrointestinal Tract Surgery. A further search of the reference lists of all relevant articles was also undertaken to identify any additional studies. In order to exclude overlapping publications or publications sharing the same population, the authors only included the most pertinent article in terms of clarity and completeness of information. Selected articles included all case-control and cohort studies according to the following criteria: (1) series from Western centers, (2) clear definition of overweight and obesity according to WHO classification, (3) homogeneous cohorts of patients with BMI as a lone variable between groups, (4) analysis of at least one of the outcomes of interest (surgical or oncological), (5) reporting on multimodal treatment details and (6) English language journals published since The exclusion criteria for the meta-analysis were as follows: reviews or case reports, studies sharing the same population, reports from Eastern countries, studies of the nutritional effect of esophagogastric surgery and those reporting or examining postoperative outcomes after esophagectomy for benign or traumatic conditions. Outcomes of interest and data extraction The following variables were used for comparison between the different BMI groups: anastomotic leak, perioperative bleeding, recurrent laryngeal nerve injury, chyle leak, abdominal and wound infection, cardiac complications, pulmonary complications, reoperation rate, in-hospital and 30 day mortality. Long-term survival was analyzed as an oncologic outcome. Data extraction included first author, publication date, study design, demographic characteristics (population size and inclusion period, and BMI cuts-off), multimodal treatment (neoadjuvant and adjuvant therapies, type of surgical procedures and whether a minimally invasive approach was used), and disease characteristics (histological subtype, pathological stage, and surgical margins). Groups identified According to the WHO definition, obesity is defined as a BMI 30 kg/m 2. This was used to stratify patients into two groups: nonobese (BMI < 30 kg/m 2 ) and obese (BMI 30 kg/m 2 ). The studies that were selected had constructed the groups according to the WHO definitions as per Table 1. Patients with BMI > 35 (7%; 187 patients) and BMI < 20 (10%; 295 patients) were included in these groups as they were not separated in the original studies. We have identified that this is a source of potential error in interpretation of the overall results. Quality assessment and statistical analysis Quality assessment and statistical methods were based on the Cochrane Handbook for Systematic Reviews of Interventions. 17 All retrieved articles were qualitatively evaluated in terms of patients selection, adequate reporting of outcomes and presence of clear variable definitions. Data from different studies reporting similar outcomes were combined and since only binary variables were examined the results were expressed as relative ratio (RR). Heterogeneity among selected articles was checked using χ 2 tests where admitted cuts-off were P-value < 0.05 for statistical significance and 95% as Confidence Interval (CI). After data extraction, forest plot analyses were conducted for all observed outcome variables. All statistical analyses were performed using Open Meta- Analyst software (Version 10.10) by the Center for Evidence-Based Medicine (CEBM) of Brown University. 18 RESULTS Search results and included trials The search produced a total of 190 records matching all MeSH terms on the PubMed search engine (Fig. 1). After the initial selection, 58 articles were removed due to age of publication or overlapping data. One hundred and thirty-two studies were examined by comparing all of the abstracts to the inclusion criteria: 104 articles were excluded due to a lack of information on BMI, patients treatment, and if they were an Eastern series, reviews, or case reports. Twenty-eight papers were assessed for eligibility and 8 Western studies were included in the meta-analysis. All the main characteristics of the selected articles are summarized in Tables 1 and ,19-23 This amounted to a comprehensive population of 2838 patients who were stratified into two groups

3 Meta-analysis of obesity and esophagectomy 3 Table 1 Studies of esophageal resection: patient characteristics Study Country Study type Inclusion period Sample size BMI of patients Groups Scarpa et al. 13 Italy Prospective >30 61 BMI (22%) Cohort study vs BMI < (78%) < Blom et al. 19 The Netherlands Prospective >35 15 BMI (10%) Cohort study >30 61 vs BMI < (90%) < Melis et al. 14 USA, NY FL Retrospective >35 64 BMI (34%) Cohort study > vs BMI < (66%) Grotenhuis et al. 22 The Netherlands Prospective >30 58 BMI (10%) Cohort study vs BMI < (90%) < Madani et al. 15 Canada Prospective >30 56 BMI (39%) Cohort study vs < BMI < (61%) Kilic et al. 20 USA, PA Retrospective >30 84 BMI (30%) Cohort study vs BMI < (70%) Healy et al. 23 UK, Ireland Retrospective >35 6 BMI (24%) Cohort study >30 30 vs BMI < (76%) Scipione et al. 21 USA, CA Retrospective > BMI (50%) Case control study < vs BMI < (50%) Number of patients; Nonobese versus Obese, number of patients. Some underweight (BMI < kg/m 2 ) and Severely Obese (Obesity Class II-III, BMI > 35 kg/m 2 ) people were included in nonobese and obese groups respectively. according to WHO definition of obesity: 2199 (77%) patients were nonobese (BMI < 30 kg/m 2 ) and 639 (23%) were obese (BMI 30 kg/m 2 ). The results of the analyses on postoperative outcomes between the obese and nonobese groups are summarized in Table 3. Fig. 1 Selection process for articles chosen. Analysis of surgical outcomes Information on the type of operation performed was available for the majority of the studies (Table 2). There were 1131 (40%) transthoracic esophagectomies (including 2-stage, 3-stage, and thoracoabdominal approach), 1328 (47%) transhiatal esophagectomies, and 355 (13%) minimally invasive procedures. Information on the anastomotic type was incomplete but where available, there were 761 (30%) thoracic anastomoses compared to 1775 (70%) cervical anastomoses (Table 2). Histopathological stage was documented in 6 studies (1912 patients). For early stage disease (Stage 0 2) 55 (7%) patients were obese and 693 (93%) were nonobese. In late stage disease (Stage 3 4) 332 (29%) patients were obese, and 832 (71%) nonobese.

4 4 Diseases of the Esophagus Table 2 Studies of esophageal resection: treatment characteristics Early stage 0 2 Late stage 3 4 T stage 0 2 T stage 3 4 TT/TH/MI Type of anastomosis Follow-up Study Histopathology (obese vs nonobese) (obese vs nonobese) (obese vs nonobese) (obese vs nonobese) Chemotherapy Oesophagectomy (thoracic vs cervical) period Scarpa et al. 13 EAC (50%) 32 vs vs 102 NAC: /0/0 NS NS SCC (47%) AC: 50 Blom et al. 19 EAC (74%) 31 vs vs 374 NAC: 0 271/465/0 271 vs 465 NS SCC (22%) AC: NS Melis et al. 14 EAC (55%) 25 vs vs 205 NAC: /49/ vs SCC (45%) AC: 97 Grotenhuis et al. 22 EAC (85%) 23 vs vs 340 NAC: NS 15/541/0 0 vs 556 NS SCC (15%) AC: NS Madani et al. 15 EAC (100%) 14 vs vs 65 NAC: NS 77/65/0 0 vs (15 137) AC: NS Kilic et al. 20 EAC (81%) 65 vs vs 72 NAC: 139 0/0/282 0 vs 282 NS SCC (19%) AC: NS Healy et al. 23 EAC (100%) 27 vs 61 9 vs 52 NAC: /4/0 131 vs AC: NS Scipione et al. 21 EAC (91%) 75 vs vs 27 NAC: NS 0/204/0 0 vs 204 NS SCC (9%) AC: NS Total 55 vs vs vs vs vs 1775 Histopathology: EAC, esophageal adenocarcinoma; SCC, squamous cell carcinoma; Note: Staging information missing on 99 patients; Perioperative oncological treatments: AC, adjuvant chemotherapy; NAC, neoadjuvant chemotherapy; NS, not stated; TT, trans thoracic (including 2-stage, 3-stage and thoraco-abdominal approaches); MI, minimally invasive; TH, transhiatal; Follow-up: Median in months, (Range if possible); Data not available on 24 patients.

5 Meta-analysis of obesity and esophagectomy 5 Table 3 Summary of outcomes after esophagectomy (includes overall survival) Outcomes Number of studies included Association with RR (C.I.) P-value Any complications 6 None (0.879, 1.074) Anastomotic leak 7 Higher BMI (0.497, 0.867) Wound infections 5 None (0.672, 1.632) Chyle leak 4 None (0.363, 7.957) Vocal cord paresis 4 None (0.746, 2.650) Cardiac complications 5 None (0.604, 1.716) Pulmonary complications 8 None (0.775, 1.330) Bleeding 3 None (0.528, 1.090) Reoperation 4 None (0.874, 2.266) Early mortality 8 None (0.501, 1.433) Surgical radicality 5 None (0.745, 1.399) Five year overall survival 3 Higher BMI (1.038, 1.323) Significant results; Values were calculated with Fixed Effects MH. Both postoperative surgical and medical complications were analyzed. Most articles did not follow a standardized classification of complications. Only one study classified complications 19 according to Clavien- Dindo. 24 There was no significant association between all complications and BMI (Supplementary Fig. S1) (P = 0.578). The obese group was found to have a significantly increased incidence of anastomotic leak (RR = [0.497, 0.867], P = 0.003) (Fig. 2). All other postoperative complications such as postoperative bleeding, early mortality, chyle leak, recurrent laryngeal nerve injury, re-operation, wound infection, cardiac, or respiratory complications did not show any significant association with obesity (Supplementary Figs S2 S9). Analysis of oncological outcomes The rate of surgical margin positivity after esophagectomy was compared in 5 studies and this was not significantly associated with BMI (RR = [0.745, 1.399], P = 0.899) (Supplementary Fig. S10). Only three of the studies reported results on long-term survival. According to the data, the higher BMI group was significantly associated with a better 5 year overall survival (RR = [1.038, 1.323], P = 0.011) (Fig. 3). DISCUSSION This meta-analysis, of 2838 patients undergoing esophagectomy, has evaluated perioperative morbidity and mortality in obese patients (BMI 30). Obesity was strongly associated with an anastomotic leak. The severity of anastomotic leak (ranging from subclinical, found on imaging to gastric necrosis requiring reoperation) is unclear from the 8 studies. A transhiatal esophagectomy with a cervical anastomosis was often performed in patients with SCC, whereas an Ivor Lewis esophagogastrectomy with a thoracic anastomosis was the operation of choice for junctional adenocarcinomas. The operation type may be the reason for this significant effect on anastomotic integrity. This study also demonstrates that the obese group had a better 5-year overall survival rate after esophageal resection for cancer. This result is not as easy to interpret and may reflect staging differences or less cachexia in the obese group. The study did not reveal any relationship between obesity and wound infection, cardiac complications, postoperative bleeding, or respiratory complications, which have been associated with obesity in other studies Preoperative optimization and prophylactic measures such as prehabilitation, optimization of cardiac function and perioperative antibiotics in this group may explain this result. In the last 20 years, many authors have focused on obesity and its effect on surgical procedures It is well established that patients with obesity have a higher incidence of comorbidities such as diabetes, cardiac and pulmonary conditions, as well as increased girth, which leads to technical difficulty during surgery, worse postoperative recovery and, therefore, an impact on health care expenditure. Studies pertaining to obesity and esophageal cancer resections have shown conflicting results. Some have described an association between obesity and severe complications including anastomotic leak, 22 others have described no difference in complications between obese and nonobese in the postoperative period. 21 Some have documented that patients with obesity show better disease free and overall survival, others discount this and show the same outcome for both groups Eastern studies analyzing the influence of high BMI on patients undergoing esophagectomy use different classifications than the WHO definition, for example, Zogg et al. included patients with abmi> 27.5 as obese. 28 Indeed a WHO expert consultation has published recommendations on BMI in Asian populations indicating that a BMI > 23 represented increased risk and a BMI > 27.5 represented high risk. 29 Eastern study populations can be quite different to Western series. Zhang et al. reported a series of 2031 patients, which consisted mainly of

6 6 Diseases of the Esophagus Fig. 2 Anastomotic leak: There was a significant association between anastomotic leak and BMI 30 Subgroup 1 comprised studies with mixed histopathology (SCC and EAC). Subgroup 2 contained studies with EAC only. As subgroup 2 were small in number, this separate analysis was not significant. The total group is referred to in the results section. patients with SCC (87.4%) with an early pathological stage (mostly stage II). 16 Our study sought to clarify the risk of obesity (BMI > 30) in Western studies. Our study population had a higher number of cervical anastomoses (1775) than thoracic (762). We found that obesity is a risk factor for a postoperative anastomotic leak. This could be explained by impaired vascularity of the gastric conduit, by microvascular disease and diabetes, which are more common in patients with obesity. 19 Pierie et al. demonstrated, in 1994, that assessment of blood perfusion of the gastric tube is a significant predictor of anastomotic stricture rates and impaired healing in cervical anastomoses. 30 A more recent paper has shown that BMI > 25 kg/m 2 was significantly associated with development of a cervical stricture on univariate analysis. 31 Increased tension on the conduit due to a cervical anastomosis may also contribute to this result. Neck dissection itself can be more challenging in a patient with obesity with a short neck Long-term survival is an interesting outcome of this meta-analysis. Several studies previously reported no

7 Meta-analysis of obesity and esophagectomy 7 Fig. 3 5 Year Overall Survival: There was a significant association between 5-year overall survival and BMI 30. influence of obesity on overall survival 32 while some considered obesity as a negative prognostic factor and others reported that a higher BMI could be a protective factor after surgery. 14 In this study, the obese group had a significantly better 5-year overall survival even though the two groups were comparable in terms of surgical radicality. A number of factors may account for this apparent benefit. Obesity may confer a protective nutritional effect. Multiple hormonal, endocrine, or nutritional factors could contribute to the benefit of obesity in this situation. 14,15 Grotenhuis et al. reportedareducedrateofcircumferential margin involvement reflecting a greater volume of fat around the esophagus; this study however, did not show an overall difference in survival. 22 A number of studies have reported an association of raised BMI with earlier stage disease. 15,20,22,23,36 This may reflect higher rates of endoscopic surveillance in view of the higher rates of gastro-esophageal reflux symptoms in obese patients. 37 This however was not borne out in this analysis as the patients with early stage disease comprised 292 (25%) obese and 872 (75%) nonobese. In the group with late stage disease the proportions were similar (409 (25%) were obese and 1237 (75%) were nonobese). The improved survival in obese patients may be a relative difference reflecting the poorer outcome with normal or low BMI in whom weight loss may have a greater effect. 14,36 We excluded eastern studies to minimize heterogeneity between articles, specifically, regarding patient characteristics, and differences in terms of diagnostic and multimodal approach. The number of available western series that fit the inclusion criteria has limited this meta-analysis. Despite this, significant differences in operative technique (ranging from totally minimally invasive to open approach with cervical anastomosis) and histological characteristics (SCC and esophageal adenocarcinoma, EAC) persisted (Table 2). Another limitation, that previous meta-analyses have mentioned, is the influence of a phenomenon named obesity paradox : an intrinsic selection bias against the obese group due to multiple comorbidities leading to better mean performance status by more careful selection for surgery. 38 As standardized classifications and definitions of all variables of interest were not used in these studies, data extraction was limited due to inconsistency in variables such as specific patient characteristics (comorbidities, ASA score or tumor location), other treatment data and oncological features (type of lymphadenectomy and surgical radicality).

8 8 Diseases of the Esophagus As some studies did not independently define underweight patients (BMI < 25) or super obese patients, these were included in the nonobese and obese group, respectively, and may have confounded the results. Many studies do not undertake to separate out these diverse groups. As both extremes can equally contribute to significant morbidity in their own right there is an inaccurate portrayal of the extent of the problem when groups are combined. Only one of the eight studies reported complications according to the Clavien-Dindo grade. 24 This greatly impacts the quality of the studies and as a result the quality of the meta-analysis. The findings of this study have highlighted further areas to assess to improve outcome for this group of patients. The higher rate of anastomotic leak with a cervical anastomosis is well known but does seem to be a particular problem in the obese population. There is good evidence to support prehabilitation in terms of postoperative morbidity, length of stay, nutritional and physical status. 39 A trial examining a prehabilitation program (PREHAB) in patients undergoing esophagogastric surgery is underway 40 and it will be interesting to see if such an approach would be beneficial to the obese group. In summary, this meta-analysis demonstrates that in Western series of patients with esophageal cancer 23% of patients had obesity. This is associated with an increase in morbidity, specifically anastomotic leak but this did not translate into early mortality or a reduction in long term survival. While a raised BMI should not preclude multimodal treatment including surgical resection in Western patients, we would suggest it is important to mitigate risk by careful preoperative planning, optimization and a higher index of suspicion for anastomotic leak postoperatively. SUPPLEMENTARY DATA Supplementary data are available at DOTESO online. 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