Obesity does not appear to affect the morbidity of treatments for esophageal cancer. Samuel Bak. BK1464 Added Perspective I. Oil on canvas, 12ʺ 16ʺ. The Impact of Body Mass Index on Esophageal Cancer Joyce Y. Wong, MD, Ravi Shridhar, MD, PhD, Khaldoun Almhanna, MD, MPH, Sarah E. Hoffe, MD, Richard C. Karl, MD, FACS, and Kenneth L. Meredith, MD, FACS Background: Surgeons are increasingly operating on patients who are overweight or obese. The influence of obesity on surgical and oncologic outcomes has only recently been addressed. We focus this review on obesity and its impact on esophageal cancer. Methods: Recent literature and our own institutional experience were reviewed to determine the impact of body mass index on the perioperative and long-term outcomes of patients with esophageal cancer. Results: With few exceptions, no significant differences were seen in perioperative outcomes or survival in patients treated for esophageal cancer when stratified by body mass index. Conclusions: Although obesity poses increased operative challenges to the surgeon, surgical and oncologic outcomes remain unchanged in obese patients compared with patients who are not obese. Introduction With the rising global incidence of obesity, particularly in the United States, the effects of obesity on multiple aspects of health care have been tremendous. Diabetes, orthopedic problems, and various cancers have been linked to the increasing prevalence of obesity. Body mass index (BMI) traditionally has been used as a way of categorizing obesity. Current guidelines from the US Centers for Disease Control and Prevention and from the World Health Organization define a From the Surgical Oncology Fellowship Program (JYW), the Radiation Oncology Program (RS, SEH), and the Gastrointestinal Tumor Program (KA, RCK, KLM) at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted July 5, 2012; accepted October 10, 2012. Address correspondence to Kenneth L. Meredith, MD, FACS, Gastrointestinal Tumor Program, Moffitt Cancer Center, 12902 Magnolia Drive, FOB-2 GI PROG, Tampa, FL 33612. E-mail: Kenneth. Meredith@Moffitt.org No significant relationship exists between the authors and the companies/organizations whose products or services may be referenced in this article. normal BMI range as 18.5 to 24.9 kg/m 2. Overweight is defined as a BMI range of 25.0 to 29.9 kg/m 2, and obesity is defined as a BMI of 30 kg/m 2 and above. 1 The incidence of esophageal cancer has also recently risen dramatically in North America. In 2009, more than 16,000 new cases were diagnosed and more than 14,000 deaths in the United States were related to esophageal cancer. 2 Epidemiologic factors such as increasing BMI as an etiologic factor have been proposed, but no clear link has yet been elucidated. In this article, we review the impact of BMI and its relation to esophageal cancer. Methods We performed a review of existing literature analyzing the impact of elevated BMI on esophageal cancer. Specifically, we investigated the impact of BMI on operative factors (length of operation, estimated blood loss, and intraoperative considerations), postoperative complications, and oncologic outcomes (survival, disease-free survival [DFS], nodal harvest, and disease 138 Cancer Control April 2013, Vol. 20, No. 2
recurrence). We also investigated our own institutional outcomes from a comprehensive esophageal cancer database. Statistical analyses were performed utilizing the Kaplan-Meier method, with differences between survival curves analyzed using the log rank test. Clinical and pathological data were compared using Fisher exact test, chi-squared test, and analysis of variance when appropriate. Statistical analyses were performed with STATA IC (STATA Statistical Software, release 10.0; Strata Corp, College Station, TX, USA). All statistical tests performed were two-sided and were considered significant at the 5% level (P.05). Results Preoperative Factors In a cohort of more than 500,000 individuals from the United States who were prospectively followed, at least a two-fold increased risk of esophageal adenocarcinoma was observed in patients with a BMI 30 kg/m 2 or above. 3 In similar studies from Norway and the Netherlands, patients who were obese had a relative risk of developing esophageal carcinoma 2 to 4 times greater than patients who were not obese, with men having a slightly higher relative risk than women. 4,5 Surgeons are operating on an increasing number of patients who fall into the overweight and obese categories. Of 541 patients treated for esophageal cancer at our center, 510 were included in an analysis in which perioperative and postoperative outcomes were analyzed according to BMI. 6 Patients with a BMI 30 kg/m 2 or above tended to be younger and male, and they also tended to have diabetes or hiatal hernia. 6 However, there were no differences across BMI groups (normal weight, overweight, and obese) with respect to cardiac comorbidities, cerebrovascular disease, chronic pulmonary disease, renal disease, or liver disease (P >.05 across all groups). 6 There were also no differences in the smoking or alcohol status of patients between BMI groups (P >.05; Table 1). 6 Table 1. Demographics, Medical Comorbidities, and Surgery Performed Stratifi ed by BMI in Patients Undergoing Esophagectomy (N = 510) Characteristic Normal Weight, N (%) a Overweight, N (%) b Obese, N (%) c P Demographics (N = 510) Male sex 118 (79.7) 159 (90.3) 143 (86.1).02 Age (yrs mean ± SD) 65.3 ± 10.3 66.2 ± 9.7 62.4 ± 10.7.002 Medical comorbidities Coronary artery disease/myocardial infarction 29 (19.6) 48 (27.3) 44 (26.5).2 Cerebrovascular disease 13 (8.8) 15 (8.5) 11 (6.6).7 Chronic obstructive pulmonary disease 58 (39.2) 68 (38.6) 67 (40.4).9 Diabetes 15 (10.1) 20 (11.4) 39 (23.5).001 Renal disease 5 (3.4) 5 (2.8) 3 (1.8).6 Liver disease 1 (0.7) 3 (1.7) 1 (0.6).6 Hiatal hernia 30 (20.3) 26 (14.8) 47 (28.3).01 Gastroesophageal reflux disease 63 (42.6) 84 (47.7) 89 (53.6).2 Alcohol history 92 (62.2) 93 (52.8) 93 (56.0).2 Smoking history 120 (81.1) 141 (80.1) 134 (80.7).7 Type of operation Transthoracic 100 (72.5) 127 (75.6) 117 (73.1).3 Transhiatal 17 (12.3) 19 (11.3) 13 (8.1) Minimally invasive transthoracic 6 (4.3) 6 (3.6) 3 (1.9) Minimally invasive transhiatal 15 (10.9) 16 (9.5) 27 (16.8) a BMI = 20-24 kg/m 2. b BMI = 25-29 kg/m 2. c BMI 30 kg/m 2. BMI = body mass index. Adapted from Table 1 in Melis M, Weber JM, McLoughlin JM, et al. An elevated body mass index does not reduce survival after esophagectomy for cancer. Ann Surg Oncol. 2011;18(3):824-831. With kind permission from Springer Science + Business Media. April 2013, Vol. 20, No. 2 Cancer Control 139
Operative Factors Patients with a BMI 30 kg/m 2 or above who underwent esophagectomy for adenocarcinoma or squamous cell carcinoma were less likely to receive neoadjuvant chemotherapy; however, no significant difference in preoperative stage, as determined by the American Joint Committee on Cancer staging system was observed. 6 When separately analyzing preoperative stage by tumor size or nodal status, no differences were seen between normal weight, overweight, or obese BMI groups. 6 There was also no difference in type of surgery (transthoracic vs transhiatal, open vs minimally invasive) performed across BMI groups (Table 1). 6 With respect to intraoperative factors, patients who were obese required longer operative times (291 minutes for obese vs 266 minutes for overweight vs 271 minutes for normal weight patients), but estimated blood loss did not significantly differ across groups. An analysis of 282 patients undergoing minimally invasive esophagectomy demonstrated similar findings. 7 Patients who were obese required longer operative times than patients who were not obese, but no significant differences were seen in blood loss, intensive care unit stay, or overall hospital stay. 7 Postoperative Complications Considering postoperative complications, several studies have observed that patients who are obese (BMI 30 kg/m 2 ) have an increased anastomotic leak rate (14% vs 2%, P =.009) and respiratory complications (58% vs 38%, P =.038) but no increased mortality. 8,9 At our institution we have not observed significant differences in frequency of any postoperative complication, including respiratory failure, pneumonia, intraoperative cardiac complications, anastomotic leak, anastomotic stricture, venous thrombosis, pulmonary embolism, reoperation, or 30-day mortality across BMI groups (P >.05; Table 2). 6,10 Even after considering patients who are severely Table 2. Complications in the Institutional Cohort and in Patients Receiving Neoadjuvant Chemoradiation Therapy Followed by Resection Postoperative Complication Normal Weight, N (%) a Overweight, N (%) b Obese, N (%) c P Institutional cohort, 1994 2008 (N = 510)* Pneumonia 24 (16.2) 26 (14.8) 29 (17.5).8 Respiratory failure 11 (7.4) 10 (5.7) 13 (7.8).7 Anastomotic leak 11 (7.4) 7 (4.0) 9 (5.4).4 Anastomotic stricture 21 (14.2) 23 (13.1) 25 (15.1).9 Deep venous thrombosis 3 (2.0) 2 (1.1) 3 (1.8).8 Pulmonary embolism 1 (0.7) 4 (2.3) 5 (3.0).3 Reoperation 4 (2.7) 7 (4.0) 3 (1.8).6 30-day mortality 4 (2.7) 3 (1.7) 6 (3.6).5 Cohort who received neoadjuvant chemoradiation, 1994 2012 (N = 303)** Pneumonia 19 (19.0) 13 (12.1) 12 (20.3).4 Respiratory failure 9 (6.0) 8 (7.4) 6 (10.3).8 Anastomotic leak 5 (5.0) 4 (3.7) 7 (11.9).2 Anastomotic stricture 8 (8.1) 10 (9.3) 8 (13.8).4 Deep venous thrombosis 3 (3.0) 1 (1.0) 2 (3.4).5 Pulmonary embolism 1 (1.0) 2 (1.9) 3 (5.0).2 Reoperation 4 (3.9) 4 (3.7) 5 (8.5).5 30-day mortality 1 (1.0) 2 (1.8) 2 (3.4).6 a BMI = 20-24 kg/m 2. b BMI = 25-29 kg/m 2. c BMI 30 kg/m 2. BMI = body mass index. *Adapted from Table 1 in Melis M, Weber JM, McLoughlin JM, et al. An elevated body mass index does not reduce survival after esophagectomy for cancer. Ann Surg Oncol. 2011;18(3):824-831. With kind permission from Springer Science + Business Media. **Adapted from Table 2 in Shridhar R, Hayman T, Hoffe SE, et al. Body mass index and survival in esophageal adenocarcinoma treated with chemoradiotherapy followed by esophagectomy. J Gastrointest Surg. 2012;16(7):1296-1302. With kind permission from Springer Science + Business Media. 140 Cancer Control April 2013, Vol. 20, No. 2
obese (BMI > 35 kg/m 2 ), we saw no increased risk of morbidity or mortality in these patients compared with patients who had normal BMI. 10 Long-term Survival In analyzing our institutional experience, we have observed that patients who were obese did not receive neoadjuvant chemotherapy to the same degree as patients who were of a normal weight. However, 5-year overall survival (OS) and DFS did not significantly differ between obese and normal weight patients. Melis et al 6 reported improved 5-year OS and DFS rates in patients who were obese compared with overweight and normal weight patients (48%, 41%, and 34% [P =.05] and 48%, 44%, and 34% [P =.01], respectively; Table 3 6,10 ), corroborating smaller studies that also reported improved 5-year OS and DFS rates in patients who are obese. 9,11 Similar findings were observed in patients treated at our institution with neoadjuvant chemoradiotherapy followed by surgical resection. In a cohort of 303 patients treated between 1994 and 2012 with neoadjuvant therapy, there was no statistically significant difference in 5-year OS or DFS rates across BMI groups. 10 Discussion The association between obesity and the increased incidence of esophageal adenocarcinoma has been demonstrated in multiple studies from North America and Europe. Overweight and obese patients have a higher incidence of gastroesophageal reflux disease (GERD), a finding initially thought to contribute to the increased incidence of esophageal cancer. 12 No study to date has definitively shown a clear association between reflux symptoms and incidence of cancer; however, GERD is more prevalent in patients who are obese and may contribute to Barrett s esophagus (BE), a precursor to adenocarcinoma. 13 Several groups have theorized that central abdominal adiposity, rather than BMI, is more indicative of increased risk for developing BE, with a waist-to-hip ratio being a potentially more useful parameter to predict BE. 14,15 This may contribute toward the increased incidence of esophageal cancer seen in men because they tend to have greater central obesity irrespective of BMI. 14,16 Central obesity is also associated with higher levels of serum adipocytokines, interleukin-6, and tumor necrosis factor, which may be relevant in the development of BE. 17,18 Leptin, which is secreted by adipocytes, is also elevated in obesity and may have stimulatory properties in the setting of BE. 18 An Australian study 19 demonstrated elevated serum levels of leptin was associated with a three-fold increased risk of developing BE in men; this increased risk in men persisted despite adjustment for BMI. However, the risk of BE decreased with increasing leptin levels in women, suggesting that multiple pathways for carcinogenesis in obesity may exist and potentially vary between men and women. 19 Insulin resistance, which is also prevalent in people who are obese, may also Table 3. OS, DFS, and Median Survival in Normal, Overweight, and Obese Patients 5-yr Endpoint Normal Weight a Overweight b Obese c P Institutional cohort, 1994 2008 (N = 510)* OS (%) 34 41 48.05 Median OS (mos) 24 43 58 <.01 DFS (%) 34 44 48.01 Median DFS (mos) 21 38 58 <.01 Cohort who received neoadjuvant chemoradiation, 1994 2012 (N = 303)** OS (%) 33 38 38.3 Median OS (mos) 28 40 30.3 DFS (%) 36 35 37.6 Median DFS (mos) 22 24 23.6 a BMI = 20-24 kg/m 2. b BMI = 25-29 kg/m 2. c BMI 30 kg/m 2. BMI = body mass index, DFS = disease-free survival, OS = overall survival. *Data from Melis M, Weber JM, McLoughlin JM, et al. An elevated body mass index does not reduce survival after esophagectomy for cancer. Ann Surg Oncol. 2011;18(3):824-831. **Data from Shridhar R, Hayman T, Hoffe SE, et al. Body mass index and survival in esophageal adenocarcinoma treated with chemoradiotherapy followed by esophagectomy. J Gastrointest Surg. 2012;16(7):1296-1302. April 2013, Vol. 20, No. 2 Cancer Control 141
contribute to the onset of esophageal carcinogenesis by promoting cell proliferation, inhibiting apoptosis, and enhancing angiogenesis by promoting the metabolic syndrome. 17 Clearly, there may be complex associations between central obesity and the development of esophageal carcinoma that require further study to fully elucidate. It is often assumed that patients who are obese have a higher risk of surgical complications compared with patients who are within the normal weight range. However, data assessing the effect of obesity on outcomes of various surgical procedures have provided inconsistent results with the exception of a consistent increased risk for minor surgical site infections among the obese. 5 Scipione et al 20 evaluated a cohort of patients who were profoundly obese (BMI 35 kg/ m 2 ) and underwent transhiatal esophagectomy. The authors reported higher intraoperative blood loss and a greater need for partial sternotomy in the patients who were profoundly obese compared with controls (BMI = 18.5 30 kg/m 2 ), but there was no difference in overall hospital stay. A prospective single-institution trial (N = 6,336; n = 808 obese patients) studied patients undergoing various elective general surgical procedures. 21 Despite higher rates of diabetes, hypertension, and coronary disease in the patients who were obese, the morbidity rates among patients with BMI lower than 30 kg/m 2 and patients with BMI 30 kg/m 2 or above were similar (16.3% vs 15.1%; P =.26), with the exception of an increased incidence of surgical site infection after open surgery in patients who were obese (4% vs 3%; P =.03). Furthermore, in multivariate regression analyses, obesity was not a risk factor for the development of postoperative complications. However, this study had several limitations, including the exclusion of patients undergoing thoracic procedures, a significantly higher number of laparoscopic procedures conducted among patients who were not obese, and a lack of data about the outcomes according to the specific operations. Therefore, it was difficult to draw conclusions regarding the association between obesity and outcomes after gastrointestinal oncologic surgery. There may be concern that obesity may adversely impact an effective oncologic outcome for esophageal cancer. In our experience, as well as that of others, no difference in R0 resection was seen in patients with higher BMIs compared with patients with normal BMIs. 6,9 Although several studies reported that fewer lymph nodes were retrieved in patients who were obese, this is not reflected in all studies, although the range of number of retrieved lymph nodes is typically smaller with increasing BMI. 22 Several studies compared disease recurrence between patient groups with BMIs above 25 kg/m 2 compared with patients with BMIs lower than 25 kg/m 2 and found no significant difference. This also held true when considering local recurrence or the development of distant metastatic disease. 23,24 Conclusions Although patients who are obese and present for surgical evaluation for esophageal carcinoma tend to have more comorbidities than normal-weight patients, their perioperative outcomes and overall survival are comparable with non-obese patients. Despite longer operative times, postoperative complications and hospital length of stay are not increased. Overall and disease-free survival rates remain similar to patients with a normal weight. Although obesity may pose operative challenges, carefully selected patients with high body mass index may undergo esophagectomy without compromising oncologic outcome and have similar perioperative morbidity. References 1. US Department of Health & Human Services. NIH study identifies ideal body mass index. NIH News National Institutes of Health. December 2, 2010. http://www.nih.gov/news/health/dec2010/nci-01.htm. Accessed December 20, 2012. 2. Petrelli NJ, Winer EP, Brahmer J, et al. Clinical Cancer Advances 2009: major research advances in cancer treatment, prevention, and screening a report from the American Society of Clinical Oncology. J Clin Oncol. 2009;27(35):6052-6069. 3. Abnet CC, Freedman ND, Hollenbeck AR, et al. 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