Original Article
Endoscopic Esophageal Tumor Length A Prognostic Factor for Patients With Esophageal Cancer Puja Gaur, MD1; Boris Sepesi, MD2; Wayne L. Hofstetter, MD3; Arlene M. Correa, PhD3; Manoop S. Bhutani, MD4; Thomas J. Watson, MD5; Stephen G. Swisher, MD3; and Members of the M. D. Anderson Esophageal Cancer Group and the University of Rochester School of Medicine and Dentistry Foregut Group
BACKGROUND: Pathologic esophageal tumor length (pL) is an independent predictor of long-term survival. However, whether patients with longer (high-risk) tumors can be identified by endoscopy before surgery has not been established. The objective of the current study was to determine the value of endoscopically measured tumor length (cL) in predicting overall survival in patients with esophageal adenocarcinoma. METHODS: All patients with esophageal adenocarcinoma who had undergone resection without neoadjuvant therapy and who had documented preoperative endoscopy findings were identified retrospectively by using prospectively collected databases at 2 institutions: The University of Texas M. D. Anderson Cancer Center (n ¼ 164; training set) and University of Rochester Medical Center (n ¼ 109; validation set). Esophageal tumors were assessed preoperatively by endoscopy for cL, depth (cT), and lymph node involvement (cN). Univariate and multivariate analyses of cL and other standard prognostic factors were performed. RESULTS: In the training set, cL was correlated directly with pL (Pearson correlation [r] ¼ 0.683; P < .001). Regression tree analyses suggested an optimum cutoff point of cL >2 cm to identify patients with decreased long-term survival (5-year survival rate: cL >2 cm, 29%; cL 2 cm, 78%; P < .001). Multivariate Cox regression analysis demonstrated that cL >2 cm was an independent risk factor for long-term survival (hazard ratio, 2.3; 95% confidence interval, 1.1-4.4; P ¼ .02) even after controlling for age, cT, and cN. Validation with the validation dataset confirmed that cL was correlated directly with pL (r ¼ 0.657; P < .001) and predicted long-term survival using a cL cutoff point of >2 cm (hazard ratio, 2.8; 95% confidence interval, 1.4-5.8; P ¼ .004; univariate analysis). CONCLUSIONS: Endoscopic esophageal tumor length was identified as an independent predictor of long-term survival and may help to C 2010 American Cancer identify high-risk patients before they receive cancer-directed therapy. Cancer 2011;117:63–9. V Society. KEYWORDS: esophageal cancer, endoscopy, esophageal tumor length, long-term survival, TNM staging.
The incidence of esophageal cancer in the United States has continued to rise over the past 2 decades.1-3 With the advent of neoadjuvant therapy, we have started to make significant progress in terms of response rates and overall prognosis in patients with esophageal cancer.4,5 However, the selection of patients to receive neoadjuvant treatment is based strictly on TNM staging, which does not take tumor length into account. In the current American Joint Committee on Cancer (AJCC) staging system for esophageal tumors, stage depends on the depth of the tumor (T classification), lymph node involvement (N classification), and distant metastasis (M classification). Before 1987, the AJCC staging system used tumor length (T1, 5 cm; and T3, evidence of extraesophageal spread) and circumferential involvement to
Corresponding author: Stephen G. Swisher, MD, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 445, Houston, TX 77030; Fax: (713) 794-4901;
[email protected] 1 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 2Department of Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York; 3Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 4Department of Gastrointestinal Hepatology and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 5Department of Thoracic and Foregut Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York
Members of University of Rochester School of Medicine and Dentistry Foregut Group: Jaffer A. Ajani, MD (Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas); Jeremy Erasmus, Jr., MD (Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas); Ritsuko Komaki, MD (Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas); Jeffrey H. Lee, MD (Gastrointestinal Hepatology and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas); Dipen Maru, MD (Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas); Reza Mehran, MD, David C. Rice, MD, Jack A. Roth, MD, Ara A. Vaporciyan, MD, and Garrett L. Walsh, MD (Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas); and Jeffrey H. Peters, MD (Department of Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York). DOI: 10.1002/cncr.25373, Received: November 11, 2009; Revised: February 17, 2010; Accepted: March 8, 2010, Published online August 27, 2010 in Wiley Online Library (wileyonlinelibrary.com)
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Original Article
predict patient prognosis. However, at the 1987 AJCC annual meeting, the current TNM staging system was adopted, in which tumor length is not a staging criterion. We previously demonstrated that pathologic tumor length determined after surgical resection is an independent predictor of survival in patients with esophageal cancer, even after controlling for other standard prognostic factors, such as pathologic tumor depth, pathologic lymph node involvement, and tumor grade.6,7 However, to our knowledge, whether patients with longer tumors can be identified by endoscopy before surgical resection has not been fully evaluated. In the current study, we sought to determine the value of endoscopically measured tumor length in predicting overall patient survival and, thus, identifying those high-risk patients with esophageal cancer who may benefit from neoadjuvant therapy.
Endoscopic esophageal tumor length was determined on the basis of a review of each patient’s preoperative esophagogastroduodenoscopy or endoscopic ultrasonography report. Endoscopic tumor length was determined by the longest craniocaudal axial length. If multiple nodules were identified, then the longest nodule length was recorded as the endoscopic tumor length. If the endoscopist did not identify a tumor, mass, lesion, or nodule, then the length of the polyp (the long axis of the greatest dimension of the polyp), ulcerated area, mucosal defect, nodular mucosa, or focal thickening of the esophageal wall/stricture was used. Pathologic tumor length was determined from each patient’s pathology report. The pathologic esophageal tumor length was determined by a team of trained pathologists on examination of the resected esophageal specimen as described previously.6,7 If adenocarcinoma was noted in 1 or more foci but no clear mass was identified, then a pathologic tumor length of 0.1 cm was assumed.
MATERIALS AND METHODS Acquisition of Clinical Data All patients who underwent esophagectomy for adenocarcinoma of the esophagus or gastroesophageal junction at The University of Texas M. D. Anderson Cancer Center (M. D. Anderson) between January 1995 and December 2007 were reviewed. Patients who had received neoadjuvant therapy in the past were excluded, as were those who underwent an emergent, salvage, or redo operation. Patients who did not undergo a curative resection and patients with incomplete data or perioperative mortality also were excluded. In total, 164 patients from M. D. Anderson ultimately were included, and these patients were used as a training set. By using the same inclusion and exclusion criteria, a second group of patients treated at the University of Rochester School of Medicine and Dentistry was identified; these 109 patients were used as a validation set. This review was approved by the institutional review boards of both institutions. Before resection, all patients were staged clinically with esophagogastroduodenoscopy or endoscopic ultrasonography, computed tomography of the chest and abdomen, positron emission tomography, or fine-needle aspirations when available. Medical records were reviewed for demographic factors (age, sex, race, and functional status as determined by the American Society of Anesthesiologists scale8), tumor-related factors (histology, location, grade, endoscopically determined tumor length, and clinical T and N classification), type of resection, and other prognostic factors.
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Statistical Analysis The Pearson chi-square test was used to assess correlation between endoscopically measured tumor length and pathologically measured tumor length. A regression tree survival analysis was used to determine the optimum cutoff point for endoscopic tumor length, which was 2 cm. Then, patients were divided into 2 groups—patients with tumors 2 cm in length and patients with tumors >2 cm in length—for survival analyses. Further analysis was performed using a univariate Cox proportional hazards regression model to examine the association between each potential predictor and survival.9 Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to quantify the strength of the association between predictors and survival. Preoperative predictors with P values .25 in univariate analysis were entered into a multivariate Cox proportional hazards regression model.9 By using Wald stepwise selection with P ¼ .10 as entry and removal probability, the final model for the dataset was obtained. Overall survival was estimated by the Kaplan-Meier method using the date of esophageal resection as the starting point and the date of death or last follow-up as the endpoint.10 Kaplan-Meier survival curves were compared using the log-rank test. All statistical calculations were performed using S-PLUS 8.0 (rpart library; TIBCO Software Inc., Palo Alto, Calif), SPSS 15.0 (SPSS Inc., Chicago, Ill), and GraphPad Prism 5.0 (GraphPad Software, San Diego, Calif). Statistical significance was defined as P < .05.
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Endoscopic Esophageal Tumor Length/Gaur et al
Table 1. Characteristics of Patients in the Training and Validation Sets
Characteristic
Patients Median age [range], y
P
No. of Patients (%) Training Set
Validation Set
164 (100) 65 [26-84]
109 (100) 65 [36-85[
.484
Sex Men Women
140 (85) 24 (15)
95 (87) 14 (13)
.676
148 (90) 16 (10)
100 (92) 9 (8)
.674
8 (5) 156 (95)
3 (3) 106 (96)
.534
46 (28) 108 (66) 10 (6)
NA
Race Caucasian Other
Tumor location Cervical/upper/middle esophagus Lower/gastric/gastroesophageal junction
ASA score 1: No functional limitation 2: Definite functional limitation 3: Constant threat to life
2 cm
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Table 2. Characteristics of Tumors in the Training and Validation Sets
Characteristic
No. of Patients (%) Training Set
P
Validation Set
Clinical tumor length, cm 0-1 >1-2 >2-3 >3
69 37 16 42
(42) (22) (9) (26)
12 13 17 67
(11) (12) (16) (61)
