The influence of high body mass index on the prognosis of patients with esophageal cancer after...

The Influence of High Body Mass Index onthe Prognosis of Patients With EsophagealCancer After Surgery as Primary TherapyYuki Hayashi, MD, PhD1; Arlene M. Correa, PhD2; Wayne L. Hofstetter, MD2; Ara A. Vaporciyan, MD2; David C. Rice, MD2;

Garrett L. Walsh, MD2; Reza J. Mehran, MD2; Jeffrey H. Lee, MD3; Manoop S. Bhutani, MD3; Alexander Dekovich, MD3;

Stephen G. Swisher, MD2; and Jaffer A. Ajani, MD1

BACKGROUND: High body mass index (BMI), a prevalent condition in the United States, is associated with esopha-

geal adenocarcinoma (EAC). Its influence on a patient’s outcome remains unclear. In the current study, the authors

examined the impact of BMI on survival and complications in patients with esophageal cancer (EC) who underwent

surgery as their primary therapy. METHODS: The authors retrospectively reviewed 301 consecutive EC patients who

underwent surgery but received no adjunctive therapy. Patients were segregated into 2 subgroups based on their

baseline BMI: normal/low (<25 kg/m2) and high (�25 kg/m2). RESULTS: Seventy-six (25%) patients had a BMI <25

kg/m2 and 225 (75%) patients had a BMI �25 kg/m2. In the high BMI group, there were more men (P < .001), fewer

upper ECs (P ¼ .021), a lower baseline clinical stage (P ¼ .006), and frequent EAC (P < .001). Postoperative morbidity

was similar in both groups, with the exception of gastrointestinal complications (P ¼ .016). The 5-year overall survival

(OS) rates were 44% in the normal/low BMI group and 60% in the high BMI group (P ¼ .017). The 5-year disease-free

survival (DFS) rates were 41% in the normal/low BMI group and 60% in the high BMI group (P ¼ .005). On multivari-

able analysis, age, weight loss, peripheral vascular disease (PVD), and both clinical and pathological stage of disease

were found to be independent prognosticators for OS. Older age (hazard ratio [HR], 1.029; 95% confidence interval

[95% CI], 1.009-1.049 [P ¼ .004]), weight loss (HR, 1.525; 95% CI, 1.034-2.248 [P ¼ .033]), and PVD (HR, 2.325; 95%

CI, 1.039-5.204 [P ¼ .040]) were found to be associated with poor OS. CONCLUSIONS: High BMI is common in EC

patients and the better OS/DFS noted in patients with a high BMI is because of the diagnosis of a low baseline clini-

cal stage. Confirmation of these findings is warranted. Cancer 2010;116:5619–27. VC 2010 American Cancer Society.

KEYWORDS: body mass index, prognostic factors, esophageal cancer, surgery, stage..

High body mass index (BMI) is a serious health problem in the United States. According to the National Health andNutrition Examination Survey, approximately 65% of adults were overweight (defined as a BMI of 25 to 30 kg/m2) and30% were obese (defined as a BMI of�30 kg/m2).1 These numbers are increasing gradually. High BMI is associated withan increased risk of malignancies that are contributing to 14% to 20% of cancer-related deaths.2 The influence of highBMI on outcome in patients with cancer is an unsolved question. Recent studies demonstrated no significant correlationbetween BMI and survival rate in patients with ovarian, colon, and prostate cancer.3-6

In 2009, approximately 16,000 new cases and 14,000 deaths from esophageal cancer (EC) were estimated to haveoccurred in the United States.7 In the West, the incidence of esophageal adenocarcinoma (EAC) has been rising dramati-cally and that of squamous cell carcinoma (SCC) has been subsiding, with approximately 80% of new cases being diag-nosed as EAC.8 High BMI is a risk factor for gastroesophageal reflux disease (GERD) and, consequently, for EAC.9-11

Several studies have reported that high BMI was not associated with improved or reduced overall survival (OS) afteresophagectomy,12-14 although increased postoperative morbidity, such as respiratory complications, anastomotic leaks,and length of hospital stay, have been associated with high BMI in patients with gastroesophageal cancer who are

DOI: 10.1002/cncr.25745, Received: May 3, 2010; Revised: August 10, 2010; Accepted: August 18, 2010, Published online November 8, 2010 in Wiley Online

Library (wileyonlinelibrary.com)

Corresponding author: Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, Mail Stop 426, The University of Texas M. D. Anderson Cancer

Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: (713) 745-1163; [email protected]

1Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 2Department of Thoracic and Cardio-

vascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 3Department of Gastroenterology, Hepatology, and Nutrition, The Uni-

versity of Texas M. D. Anderson Cancer Center, Houston, Texas.

Cancer December 15, 2010 5619

Original Article

undergoing surgery.14,15 Many of these studies includedsmall number of patients, in whom adjunctive therapy(preoperative chemotherapy and/or radiotherapy) wasused.

The goal of the current analysis was to learn aboutthe impact of high or low BMI on long-term outcome aswell as surgical complications in 301 patients with ECwho underwent surgery as their primary therapy at TheUniversity of Texas M. D. Anderson Cancer Center(MDACC) but did not receive any adjunctive therapy.

MATERIALS AND METHODS

Patients

We searched the EC database in the Department of Tho-racic and Cardiovascular Surgery at MDACC to find 301consecutive patients who were fully staged and had under-gone surgery as their primary therapy and received no ad-junctive therapy. Patients who did not undergo surgery atMDACCwere not included in this database.

Patients were included if they had histologic docu-mentation of EAC or SCC histology and computed to-mography scans of the chest and abdomen. All eligiblepatients were aged �18 years. Staging was determinedbased on the American Joint Committee on CancerTNM staging system.16 No other selection criteria wereimplemented. Stored information regarding alcohol con-sumption, smoking (ever smoker), surgical complications,and other parameters such as length of hospital stay andmortality were captured and analyzed. The InstitutionalReview Board of MDACC approved this analysis.

Surgery

Types of esophagectomy included Ivor-Lewis, transhiatal,total esophagectomy, and minimally invasiveesophagectomy.

Follow-Up and Survival

Patients were followed periodically for at least 5 years oruntil death. Additional follow-up data were obtainedfrom review of the MDACC tumor registry and the hos-pital records or Social Security database. Follow-up timewas calculated from the date of surgery to the event ordate of the last contact.

Statistical Analysis

The data in the EC database were collected in a prospec-tive manner with a standardized approved protocol. Allstatistical analyses were performed using the SPSS Statisti-

cal Software Package (version SPSS 15.0; SPSS Inc, Chi-cago, Ill). The differences between groups were tested forsignificance using the Student t test for continuous varia-bles and the Fisher exact test or chi-square test for categor-ical variables. Univariable Cox regression analyses wereperformed using death and disease recurrence or death asthe outcomes with a significance level of P � .05. Covari-ates that were significant at P � .25 were included in themultivariable Cox regression analyses. Backward stepwiseWald elimination at P ¼ .10 was used to find a finalmodel. Death and disease recurrence or death functionswere calculated according to the Kaplan-Meier methodand differences were assessed using the log-rank test.

RESULTS

Patient Characteristics

A total of 301 consecutive EC patients who underwentsurgery as their primary therapy (and received no adjunc-tive therapy) were analyzed. Among these, 266 (88%)patients had EAC and 35 (12%) patients had SCC.Patient characteristics are summarized in Table 1. Menpredominated the group as expected (P � .001) and ade-nocarcinoma histology was common (P� .001).

Patient Characteristics by BMI

Patients were divided into 2 groups according the tradi-tional BMI cutpoints (<25 kg/m2 or �25 kg/m2). Therewere 76 patients (25.2%) with a pretreatment BMI <25kg/m2 and 225 patients (74.8%) with a pretreatmentBMI�25 kg/m2. As shown in Table 1, the 2 groups werewell matched with regard to age, Zubrod performance sta-tus, past medical history except for sex, diabetes, and his-tological type. However, in the high BMI group, male sex,a primary tumor in the lower esophagus (with or withoutgastroesophageal junction [GEJ] involvement), EAC, andlower baseline clinical stage were represented at a statisti-cally significantly higher rate than in patients in the lowBMI group (P� .001, P¼ .021, P� .001, and P¼ .006,respectively). Patients who lost weight during the preced-ing 3 months from the date of surgery or who smokedtobacco were more likely to be in the normal/low BMIgroup compared with the high BMI group (P� .001 andP¼ .031, respectively).

Surgical Outcomes

Ivor-Lewis esophagectomy was performed in 132patients, transhiatal esophagectomy was performed in125 patients, total esophagectomy was performed in 24

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5620 Cancer December 15, 2010

patients, and minimally invasive esophagectomy was per-formed in 17 patients. Outcomes of surgery are shown inTable 2. The 30-day surgical mortality rate was 2.6% (2patients) in the normal/low BMI group and 1.8% (4patients) in the high BMI group (P ¼ .473). Althoughgastrointestinal complications (diarrhea, dumping syn-drome, gastric outlet/conduit obstruction, ileus, and smallbowel obstruction) were more frequent in the high BMIgroup, there was no significant difference noted with

regard to other postoperative complications, such aspulmonary (P ¼ .796), cardiovascular (P ¼ .271), andwound-related/infectious complications (P ¼ .509) andanastomotic leak (P ¼ .786). The median postoperativehospital stay was 11 days in the normal/low BMI groupand 12 days in the high BMI group.

Disease recurrence after surgery developed in 25patients (32.9%) in the normal/low BMI group and 53patients (23.6%) in the high BMI group. The type of

Table 1. Patient Characteristics

BMI <25 kg/m2

N576BMI ‡25 kg/m2

N5225P

Patient demographicsGender (M:F) 53:23 204:21 <.001

Age, y .098

£60 24 (31.6%) 95 (42.2%)

61-70 25 (32.9%) 77 (34.2%)

>70 27 (35.5%) 53 (23.6%)

Weight loss in last 3 mo 34 (44.7%) 50 (22.2%) <.001

Social historyAlcohol intake ‡4 oz/d 24 (31.6%) 62 (27.6%) .502

Smoker 46 (60.5%) 104 (46.2%) .031

ASA score 3-4 57 (75.0%) 171 (76.0%) .860

Past medical historyCongestive heart failure 1 (1.3%) 2 (0.9%) .584

COPD 6 (7.9%) 22 (9.8%) .625

Coronary artery disease 10 (13.2%) 45 (20.0%) .182

PVD 3 (3.9%) 6 (2.7%) .406

Diabetes 5 (6.6%) 35 (15.6%) .046

Tumor informationClinical stage .006

0 4 (5.3%) 24 (10.7%)

I 23 (30.3%) 104 (46.2%)

II 40 (52.6%) 79 (35.1%)

III 7 (9.2%) 18 (8.0%)

IV 1 (1.3%) 0

Pathological stage .006

0 2 (2.6%) 23 (10.2%)

I 25 (32.9%) 110 (48.9%)

II 27 (35.5%) 46 (20.4%)

III 18 (23.7%) 36 (16.0%)

IV 4 (5.3%) 8 (3.6%)

Location .021

Cervical/upper/middle 16 (21.1%) 24 (10.7%)

Lower/GEJ/gastric 60 (78.9%) 201 (89.3%)

Histology <.001

Adenocarcinoma 55 (72.4%) 211 (93.8%)

Squamous cell carcinoma 21 (27.6%) 14 (6.2%)

Histological grade .458

Well 3 (4.1%) 17 (8.5%)

Moderately 41 (56.2%) 96 (48.0%)

Poorly 28 (38.4%) 85 (42.5%)

Undifferentiated 1 (1.4%) 2 (1.0%)

BMI indicates body mass index; M:F, male:female; ASA, American Society of Anesthesiologists; COPD, chronic obstruc-

tive pulmonary disease; PVD, peripheral vascular disease; GEJ, gastroesophageal junction.

Weight and Esophageal Cancer Outcome/Hayashi et al


recurrence in the 2 groups was similar (P ¼ .144 and P¼.164, respectively).

OS and Disease-Free Survival

The 5-year OS rates were 43.9% for patients with nor-mal/low BMI and 60.2% for patients with high BMI (P¼ .017) (Fig. 1). The 5-year disease-free survival (DFS)rates were 41.0% for patients with normal/low BMI and59.9% for patients with high BMI (P ¼ .005) (Fig. 2). Inthe univariable analysis, the factors that were found to be

significantly associated with OS are shown in Table 3.High BMI and a lower esophageal/gastric/GEJ tumorlocation were associated with longer OS. Patients withweight loss before surgery, a history of alcohol and/smok-ing, peripheral vascular disease (PVD), a tumor diameter>3 cm, SCC histology, poor histologic differentiation, alarger number of cancer-positive lymph nodes, and stageII to IV disease were found to have a significantly shorterOS.

Multivariable Analysis

BMI was eliminated (P ¼ .40) after Step 1 of the 9-stepmultivariable analysis. Age, weight loss before surgery,PVD, and both baseline clinical and pathological stage ofdisease were recognized as independent prognostic factorson the multivariable Cox regression analysis (P ¼ .004,P¼ .033, P¼ .040, P¼ .043, and P� .001, respectively)(Table 4). Hazard ratios (HRs) for factors associated withpoor OS were as follows: older age (HR, 1.029), weightloss before surgery (HR, 1.525), and PVD (HR, 2.325).

Subgroup Analysis

Patients in the high BMI group were more likely to have aclinical stage of disease that was 0 to I than those in thenormal/low BMI group, in whom clinical stage was morelikely to be II to IV (P � .001). Therefore, we performedsubgroup analysis in patients with EAC (because thesepatients were preponderant) who had a clinical T classifi-cation of�T2. In this subgroup of 115 patients (Table 5),

Table 2. Postoperative Complications and Outcome

BMI<25 kg/m2

n 5 76

BMI‡25 kg/m2

n 5 225

P

ComplicationPulmonary 31 (40.8%) 88 (39.1%) .796

Cardiovascular 13 (17.1%) 52 (23.1%) .271

GI events 10 (13.2%) 60 (26.7%) .016

Anastomotic leak 10 (13.2%) 32 (14.4%) .786

Wound/infection 18 (23.7%) 62 (27.6%) .509

Blood transfusion 11 (15.4%) 31 (13.8%) .880

Outcome30-d mortality 2 (2.6%) 4 (1.8%) .473

Recurrence 25 (32.9%) 53 (23.6%) .108

Local/regional

recurrence

15 (19.7%) 29 (12.9%) .144

Distant recurrence 21 (26.9%) 45 (15.3%) .164

BMI indicates body mass index; GI, gastrointestinal.

Figure 1. Kaplan-Meier estimated overall survival probabilityis shown by a body mass index (BMI) �25 kg/m2 versus aBMI <25 kg/m2. Results of the log-rank test indicated thatoverall survival was significantly higher in the overweight(BMI �25 kg/m2) group (P ¼ .017).

Figure 2. Kaplan-Meier estimated disease-free survival proba-bility is shown by a body mass index (BMI) �25 kg/m2 versusa BMI <25 kg/m2. Results of the log-rank test indicated thatdisease-free survival was significantly higher in the over-weight (BMI �25 kg/m2) group (P ¼ .005).

Original Article


there were 32 patients (27.8%) with normal/low BMI and83 patients (72.2%) with high BMI. There was no differ-ence in patient baseline characteristics noted between the2 groups, including for the factors that were significant inthe entire cohort. There were no differences noted withregard to the postoperative complications in the 2 groups(Table 6). The BMI of the patients in this subgroup,whether <25 kg/m2 or �25 kg/m2, did not appear tohave any relation to OS on either the log-rank test or uni-

variable Cox regression analysis (P ¼ .882 for both) (Fig.3) (Table 7). Pathological stage of disease and number ofdissected and cancer-positive lymph nodes were recog-nized as independent prognostic factors on the multivari-able Cox regression analysis (P� .001, P¼ .003, and P¼.029, respectively) (Table 8). This finding suggests norelation between BMI and the aggressiveness of EC, butBMI certainly appears to be associated with the diagnosisof early stage EC that leads to an improved OS in thegroup with high BMI, as discussed earlier.

DISCUSSIONThe literature is not clear regarding the impact of BMI onthe outcome of patients with EC. Intuitively, one wouldimagine that high BMI would be associated with a higherrate of postoperative complications, but there may not besubstantive influence on OS or DFS. A few reports thatspecifically focused on BMI suggested that pretreatmentBMI was not associated with differential outcome withregard to OS or DFS.12-14 However, the largest study todate is by Trivers et al17 and included 1142 EAC patientswho were segregated in 3 groups: those with a BMI <25kg/m2, those with a BMI of 25 to29.9 kg/m2, and thosewith a BMI �30 kg/m2. Patients with a BMI �30 kg/m2

did not appear to have a survival advantage or disadvant-age but<18% of patients had a BMI�30 kg/m2. Patientswith a BMI between 25 and 29.9 kg/m2 survived longerthan those with a BMI<25 kg/m2. Precise stage of disease

Table 3. Univariable Analysis of Factors Related to Survival(Cox Regression Analysis)

P HazardRatio

95% CI

Patient demographicsFemale gender .828 1.054 0.653-1.701

Age .056 1.017 1.000-1.035

BMI ‡25 kg/m2 .018 0.640 0.442-0.928

Weight loss in last 3 mo <.001 3.161 2.216-4.507

Social historyAlcohol intake ‡ 4 oz/d .029 1.488 1.041-2.126

Smoker <.001 2.562 1.712-3.825

ASA score 3-4 .087 1.467 0.946-2.277

Past medical historyCongenital heart failure .049 3.159 1.003-9.949

COPD .110 1.535 0.908-2.597

PVD .001 3.513 1.709-7.222

Tumor informationClinical stage <.001

0 1.000

I .366 1.792 0.505-6.353

II <.001 10.342 3.088-34.639

III <.001 17.139 4.866-60.365

IV .002 40.697 4.044-409.530

Type of surgery .002

Ivor-Lewis esophagectomy 1.000

Transhiatal esophagectomy .144 0.752 0.513-1.102

Total esophagectomy .005 2.101 1.250-3.530

Minimally invasive

esophagectomy

.077 0.168 0.023-1.213

Tumor diameter >3 cm <.001 6.211 4.226-9.128

Pathological stage <.001

0 1.000

I .310 0.598 0.221-1.616

II .020 3.074 1.194-7.913

III <.001 9.135 3.556-23.462

IV .004 5.066 1.670-15.368

Tumor location

(lower/GEJ/gastric)

.021 0.592 0.379-0.925

Histology: SCC .010 1.835 1.157-2.911

Histological grade: poorly <.001 2.711 1.887-3.897

No. of positive lymph nodes <.001 1.115 1.085-1.145

95% CI indicates 95% confidence interval; BMI, body mass index; ASA,

American Society of Anesthesiologists; COPD, chronic obstructive pulmo-

nary disease; PVD, peripheral vascular disease; GEJ, gastroesophageal

junction; SCC, squamous cell carcinoma.

Table 4. Multivariable Analysis of Factors Related to Survival(Cox Regression Analysis)a

P HazardRatio

95% CI

Age .004 1.029 1.009-1.049

Weight loss in last 3 mo .033 1.525 1.034-2.248

PVD history .040 2.325 1.039-5.204

Clinical stage .043

0 1.000

I .298 2.065 0.527-8.090

II .050 4.189 0.998-17.579

III .094 3.618 0.803-16.309

IV .485 2.514 0.189-33.433


0 1.000

I .052 0.343 0.116-1.010

II .798 1.161 0.371-3.637

III .048 3.320 1.012-10.891

IV 0.408 1.754 0.463-6.640

95% CI indicates 95% confidence interval; PVD, peripheral vascular

disease.a Body mass index was eliminated in the first step of this analysis with a P

value of .40.



at diagnosis was not reported in this analysis and theauthors, unfortunately, did not analyze the relationbetween ‘‘stage’’ at diagnosis and BMI. In a much smallerstudy, Di Fiore et al18 demonstrated that a BMI of >18kg/m2was one of the independent prognostic factors in105 patients treated with definitive chemoradiotherapy (P¼ .003). However, in this study, the cutpoint for BMIwas nontraditional and the sample size was small.

In the current study, 74.8% of EC patients had highBMI and had better OS and DFS compared with thosewith normal/low BMI. However, high BMI, per se, wasnot found to be an independent prognosticator. Further

analyses of our data revealed a finding that has not yetbeen reported in the literature, namely that high BMI wasassociated with early baseline stage EC. Thus, the betterOS and DFS reported in the high BMI group is attributedto lower EC stage and high BMI does not appear to influ-ence the aggressiveness of established EC. Why wouldhigh BMI be associated with a diagnosis of early stage EC?An answer to this intriguing finding remains unclear. Wespeculate that because patients with high BMI are diag-nosed with GERD more often than those with low

Table 5. Patient Characteristics for Patients With �T2Adenocarcinoma

BMI<25 kg/m2

n532

BMI‡25 kg/m2

n583

P

Patient demographicsGender (M:F) 27:5 73:10 .758

Age, y .038

£60 8 (25.0%) 34 (41.0%)

61-70 9 (28.1%) 30 (36.1%)

>70 15 (46.9%) 19 (22.9%)

Weight loss in last 3 mo 17 (53.1%) 34 (41.0%) .239

Social historyAlcohol intake ‡4 oz/d 11 (34.4%) 27 (32.5%) .850

Smoker 23 (71.9%) 53 (63.9%) .416

ASA score 3-4 26 (81.3%) 67 (80.7%) .949

Past medical historyCongestive heart failure 1 (3.1%) 2 (2.4%) .628

COPD 3 (9.4%) 6 (7.2%) .481

Coronary artery disease 5 (15.6%) 17 (20.5%) .553

PVD 2 (6.3%) 5 (6.0%) .630

Diabetes 5 (15.6%) 14 (16.9%) .872


II 26 (81.3%) 67 (80.7%)

III 5 (15.6%) 16 (19.3%)

IV 1 (3.1%) 0

Pathological stage .762

I 5 (15.6%) 16 (19.3%)

II 14 (43.8%) 28 (33.7%)

III 10 (31.3%) 32 (38.6%)

IV 3 (9.4%) 7 (8.4%)

Location .519

Cervical/upper/middle 2 (6.3%) 7 (8.4%)

Lower/GEJ/gastric 30 (93.8%) 76 (91.6%)

Histological grade .148

Well 1 (3.1%) 4 (4.9%)

Moderately 17 (53.1%) 25 (30.5%)

Poorly 14 (43.8%) 51 (62.2%)

Undifferentiated 0 2 (2.4%)

BMI indicates body mass index; M:F, male:female; ASA, American Society

of Anesthesiologists; COPD, chronic obstructive pulmonary disease; PVD,

peripheral vascular disease; GEJ, gastroesophageal junction.

Table 6. Postoperative Complications and Outcome forPatients With �T2 Adenocarcinoma

BMI<25 kg/m2

n532

BMI‡25 kg/m2

n583

P

ComplicationPulmonary 15 (46.9%) 28 (33.7%) .192

Cardiovascular 7 (21.9%) 15 (18.1%) .642

GI events 1 (3.1%) 22 (26.5%) .005

Anastomotic leak 3 (9.4%) 9 (10.8%) .559

Wound/infection 6 (18.8%) 20 (24.1%) .539

Blood transfusion 6 (18.8%) 12 (14.5%) .570

Outcome30-d mortality 1 (3.1%) 2 (2.4%) .628

Recurrence 13 (40.6%) 44 (53.0%) .234

Local/regional recurrence 6 (18.8%) 25 (30.1%) .218

Distant recurrence 12 (37.5%) 39 (47.0%) .359

BMI indicates body mass index; GI, gastrointestinal.

Figure 3. Kaplan-Meier estimated overall survival probabilityis shown by a body mass index (BMI) �25 kg/m2 versus aBMI <25 kg/m2 in patients with clinical T2 and higher adeno-carcinoma. Results of the log-rank test indicated that therewas no significant difference in overall survival between the 2groups (P ¼ .882).

Original Article


BMI,19-23 patients with high BMI are more likely toundergo endoscopic surveillance and this could result inthe diagnosis of early EC. Lagergren et al11 reported anodds ratio of 7.7 for EAC among patients with GERDsymptoms compared with individuals without GERDsymptoms. The hypothesis that high BMI patients tend tohave GERD, which is associated with EAC, is compatiblewith our results. In our cohort of patients with high BMI,EAC and lower esophageal localization were significantlymore frequent than for patients with low BMI, who had alower frequency of EAC and tended not have to primary

tumors in the lower esophagus (P < .001 and P ¼ .021,respectively).

We found that the patients with normal/low BMIwere more likely to have an advanced stage (stage II-IV) ofEC (P¼ .001). Greater than half of the patients with highBMI (56.9%) were diagnosed with clinical stage 0 or I dis-ease, whereas 35.6% of patients with normal/low BMIhad an early clinical stage of disease at diagnosis. One ex-planation for this trend could be that the patients withadvanced disease have low appetite and/or significant dys-phagia (and weight loss). In the current study cohort,44.7% of patients with normal/low BMI had lost weightin the 3 months before surgery whereas only 22.2% ofpatients with high BMI lost weight (P< .001). Our otherfinding with regard to weight loss, which correlates with ahigher tumor burden, as a poor prognosticator is consist-ent with previously published literature.

High BMI was considered to be a risk factor for sur-gical complications such as cardiac insufficiency, respira-tory failure, anastomotic leak, and wound dehiscence.However, we were not able to confirm these findings andour findings are similar to more recent reports.24,25 Wedid observe more gastrointestinal complications inpatients with high BMI (P ¼ .016) compared with thosewith low BMI. These findings need confirmation and thereason for this observation is not clear.

The current study included patients with both EACand SCC but EAC was diagnosed in approximately93.8% of patients with high BMI and 72.4% of patientswith normal/low BMI (P< .001). Our study could be bi-ased because patients with EAC have been reported tohave a better prognosis than those with SCC.26,27

Holscher et al26 and Meltzer27 have reported that SCCinvades the submucosa and lymph nodes at an early stage

Table 7. Univariable Analysis of Factors Related to Survivalfor Patients With �T2 Adenocarcinoma (Cox RegressionAnalysis)

P HazardRatio

95% CI

Patient demographicsFemale gender .734 1.116 0.592-2.104

Age .916 0.999 0.978-1.020

BMI ‡25 kg/m2 .882 0.965 0.606-1.538

Weight loss in last 3 mo .001 2.109 1.364-3.260

Social historyAlcohol intake ‡4 oz/d .337 0.803 0.513-1.257

Smoker .388 1.228 0.770-1.958

ASA score 3-4 .960 1.014 0.588-1.747

Past medical historyCongenital heart failure .434 1.585 0.500-5.026

COPD .642 1.189 0.573-2.466

PVD .363 1.472 0.640-3.387


II 1.000

III .048 1.683 1.006-2.817

IV .242 3.286 0.447-24.151

Type of surgery .508

Ivor-Lewis esophagectomy 1.000

Transhiatal esophagectomy .654 1.109 0.705-1.747

Total esophagectomy .120 1.741 0.865-3.506

Minimally invasive

esophagectomy

.409 0.433 0.059-3.159

Tumor diameter >3 cm <.001 3.663 2.151-6.237


I 1.000

II .071 2.003 0.943-4.257

III <.001 7.561 3.526-16.214

IV .007 3.699 1.425-9.605

Tumor location

(lower/GEJ/gastric)

.116 0.555 0.267-1.155

Histological grade: poorly .007 1.869 1.190-2.935

No. of dissected lymph nodes .082 0.980 0.958-1.003

No. of positive lymph nodes <.001 1.069 1.033-1.106

95% CI indicates 95% confidence interval; BMI, body mass index; ASA,

American Society of Anesthesiologists; COPD, chronic obstructive pulmo-

nary disease; PVD, peripheral vascular disease; GEJ, gastroesophageal

junction.

Table 8. Multivariable Analysis of Factors Related toSurvival for Patients With �T2 Adenocarcinoma(Cox Regression Analysis)

P HazardRatio

95% CI


I 1.000

II .055 2.132 0.984-4.617

III <.001 5.480 2.415-12.433

IV .105 2.429 0.831-7.100

Tumor location (lower/GEJ/gastric) .062 0.466 0.209-1.041

Histological grade: poorly .094 1.525 0.931-2.499

No. of dissected lymph nodes .003 0.955 0.927-0.984

No. of positive lymph nodes .029 1.072 1.007-1.141

95% CI indicates 95% confidence interval; GEJ, gastroesophageal

junction.



and the 5-year OS rate of patients with stage I disease whoundergo surgery was 82.5% in patients with EAC and59.2% in patients with SCC. However, this finding is notgeneralizable and further studies are warranted.

There are weaknesses to the current study: 1) it is aretrospective review; 2) we included a relatively smallnumber of patients; 3) we cannot explain why patientswith high BMI had earlier stage EC at diagnosis; and 4)some of our findings are not consistent with the literature.The strengths of the current study are 1) a homogeneousstudy population (surgery only as therapy and no adjunc-tive therapy received); 2) detailed analysis is provided; 3)many findings are consistent with the literature; and 4) ithas novel findings.

BMI was not an found to be an independent prog-nostic factor, but it was associated with a lower baselinestage of EAC. It appears that BMI itself has no influenceon the clinical aggressiveness of EC and in the currentanalyses; it was found to have no adverse influence withregard to surgical complications as a whole. The incidenceof GERD and EAC is high in patients with high BMI andour novel findings present an opportunity for detectingEAC at an early stage if patients with high BMI can be sur-veyed more aggressively.

In conclusion, high BMI is common in patientswith EC and patients with high BMI are diagnosed withearly stage EC and therefore tend to have better survivalthan those with low/normal BMI.

CONFLICT OF INTEREST DISCLOSURESSupported in part by grants from The University of Texas M.D. Anderson Cancer Center; the Dallas, Park, Cantu, Smith,and Myers families; and the River Creek Foundation. Alsosupported by National Cancer Institute (NCI) GrantsRO1CA138671, R21CA127672, and R21CA129906. Tissuesfrom some patients presented in this article were used to gener-ate preliminary data for the above NCI grants.

REFERENCES

1. Ogden CL, Carroll MD, Curtin LR, McDowell MA, TabakCJ, Flegal KM. Prevalence of overweight and obesity in theUnited States, 1999-2004. JAMA. 2006;295:1549-1555.

2. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ.Overweight, obesity, and mortality from cancer in a pro-spectively studied cohort of U.S. adults. N Engl J Med.2003;348:1625-1638.

3. Barrett SV, Paul J, Hay A, Vasey PA, Kaye SB, GlasspoolRM. Does body mass index affect progression-free or overallsurvival in patients with ovarian cancer? Results from SCO-TROC I trial. Ann Oncol. 2008;19:898-902.

4. Matthews KS, Straughn JM Jr, Kemper MK, Hoskins KE,Wang W, Rocconi RP. The effect of obesity on survival in

patients with ovarian cancer. Gynecol Oncol. 2009;112:389-393.

5. Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Impact ofbody mass index and weight change after treatment on can-cer recurrence and survival in patients with stage III coloncancer: findings from Cancer and Leukemia Group B89803. J Clin Oncol. 2008;26:4109-4115.

6. Siddiqui SA, Inman BA, Sengupta S, et al. Obesity and sur-vival after radical prostatectomy: a 10-year prospectivecohort study. Cancer. 2006;107:521-529.

7. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancerstatistics, 2009. CA Cancer J Clin. 2009;59:225-249.

8. Brown LM, Devesa SS, Chow WH. Incidence of adenocar-cinoma of the esophagus among white Americans by sex,stage, and age. J Natl Cancer Inst. 2008;100:1184-1187.

9. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obe-sity and the risk for gastroesophageal reflux disease and itscomplications. Ann Intern Med. 2005;143:199-211.

10. MacDonald WC, MacDonald JB. Adenocarcinoma of theesophagus and/or gastric cardia. Cancer. 1987;60:1094-1098.

11. Lagergren J, Bergstrom R, Nyren O. Association betweenbody mass and adenocarcinoma of the esophagus and gastriccardia. Ann Intern Med. 1999;130:883-890.

12. Morgan MA, Lewis WG, Hopper AN, et al. Prognostic sig-nificance of body mass indices for patients undergoingesophagectomy for cancer. Dis Esophagus. 2007;20:29-35.

13. Skipworth J, Foster J, Raptis D, Hughes F. The effect ofpreoperative weight loss and body mass index on postopera-tive outcome in patients with esophagogastric carcinoma.Dis Esophagus. 2009;22:559-563.

14. Healy LA, Ryan AM, Gopinath B, Rowley S, Byrne PJ,Reynolds JV. Impact of obesity on outcomes in the manage-ment of localized adenocarcinoma of the esophagus andesophagogastric junction. J Thorac Cardiovasc Surg.2007;134:1284-1291.

15. Fujitani K, Ajani JA, Crane CH, et al. Impact of inductionchemotherapy and preoperative chemoradiotherapy on oper-ative morbidity and mortality in patients with locoregionaladenocarcinoma of the stomach or gastroesophageal junc-tion. Ann Surg Oncol. 2007;14:2010-2017.

16. Greene FL, ed. AJCC Cancer Staging Atlas/American JointCommittee on Cancer. New York, NY: Springer; 2006.

17. Trivers KF, De Roos AJ, Gammon MD, et al. Demo-graphic and lifestyle predictors of survival in patients withesophageal or gastric cancers. Clin Gastroenterol Hepatol.2005;3:225-230.

18. Di Fiore F, Lecleire S, Pop D, et al. Baseline nutritional sta-tus is predictive of response to treatment and survival inpatients treated by definitive chemoradiotherapy for a locallyadvanced esophageal cancer. Am J Gastroenterol.2007;102:2557-2563.

19. Ayazi S, Hagen JA, Chan LS, et al. Obesity and gastro-esophageal reflux: quantifying the association between bodymass index, esophageal acid exposure, and lower esophagealsphincter status in a large series of patients with refluxsymptoms. J Gastrointest Surg. 2009;13:1440-1447.

20. Friedenberg FK, Xanthopoulos M, Foster GD, Richter JE.The association between gastroesophageal reflux disease andobesity. Am J Gastroenterol. 2008;103:2111-2122.

21. Bytzer P, Christensen PB, Damkier P, Vinding K, Seer-sholm N. Adenocarcinoma of the esophagus and Barrett’sesophagus: a population-based study. Am J Gastroenterol.1999;94:86-91.

Original Article


22. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Sympto-matic gastroesophageal reflux as a risk factor for esophagealadenocarcinoma. N Engl J Med. 1999;340:825-831.

23. Ye W, Chow WH, Lagergren J, Yin L, Nyren O. Risk ofadenocarcinomas of the esophagus and gastric cardia inpatients with gastroesophageal reflux diseases and after anti-reflux surgery. Gastroenterology. 2001;121:1286-1293.

24. Kilic A, Schuchert MJ, Pennathur A, et al. Impact of obe-sity on perioperative outcomes of minimally invasive esopha-gectomy. Ann Thorac Surg. 2009;87:412-415.

25. Mullen JT, Davenport DL, Hutter MM, et al. Impact ofbody mass index on perioperative outcomes in patientsundergoing major intra-abdominal cancer surgery. Ann SurgOncol. 2008;15:2164-2172.

26. Holscher AH, Bollschweiler E, Schneider PM, Siewert JR.Prognosis of early esophageal cancer. Comparison betweenadeno- and squamous cell carcinoma. Cancer. 1995;76:178-186.

27. Meltzer SJ. The molecular biology of esophageal carcinoma.Recent Results Cancer Res. 1996;142:1-8.



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