The American Journal of Surgery (2015) 209, 969-973
Clinical Science
Increasing body mass index portends abbreviated survival following pancreatoduodenectomy for pancreatic adenocarcinoma Abhishek Mathur, M.D., Kenneth Luberice, B.S., Harold Paul, B.S., Co Franka, B.S., Alexander Rosemurgy, M.D.* Southeastern Center for Digestive Disorders and Pancreatic Cancer, Advanced Minimally Invasive and Robotic Surgery, Florida Hospital Tampa, Tampa, FL, USA
KEYWORDS: BMI; Pancreaticoduodenectomy; Pancreatic adenocarcinoma
Abstract BACKGROUND: Body mass index (BMI), a common surrogate marker for grading obesity, does not differentiate between metabolically active visceral fat and the relatively inert subcutaneous fat. We aim to determine the utility of BMI as a prognostic marker for the impact of obesity on outcomes and survival following pancreatoduodenectomy for pancreatic adenocarcinoma. METHODS: From a database of over 1,000 patients who had undergone pancreatoduodenectomy, 228 patients with a diagnosis of pancreatic adenocarcinoma were identified. Demographic data including BMI and perioperative parametersdoperative time, estimated blood loss, length of stay, survival, nodal status, and American Joint Committee on Cancer stagedwere obtained. Data are presented as median. RESULTS: One hundred ninety-two patients had a BMI less than or equal to 29 and 36 patients had a BMI greater than or equal to 30 (24 vs 34, P , .001). Median age was 70 and the majority of the patients (52%) were male and the 2 groups of patients did not differ in this regard. A significantly greater number of obese patients had positive nodes (69% vs 62%, P , .05) and this was associated with a worse survival (14 vs 18 months, P , .05). CONCLUSIONS: For patients with pancreatic adenocarcinoma undergoing pancreatoduodenectomy, obesity does not impact operative complexity or length of stay but results in a shortened survival. Therefore, we conclude that BMI is an important prognostic marker that portends an abbreviated survival following pancreatoduodenectomy for pancreatic adenocarcinoma. Ó 2015 Elsevier Inc. All rights reserved.
The authors declare no conflicts of interest. Presented in part at the Seventh Annual Academic Surgical Congress of the Society of University Surgeons and Association for Academic Surgeons, February 14–16, 2012, Las Vegas. * Corresponding author. Tel.: 11-813-615-7030; fax: 11-813-6158350. E-mail address: [email protected] Manuscript received September 4, 2014; revised manuscript November 19, 2014 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2014.12.037
Over 50,000,000 Americans have a body mass index (BMI) greater than 30.1,2 Obesity leads to multiple comorbidities including diabetes, hypertension, and hyperlipidemia (the metabolic syndrome). In addition, obesity causes fat infiltration of several organs including the heart, kidneys, liver, and pancreas. Epidemiologic evidence suggests an association between obesity and multiple cancers including pancreatic cancer.3,4 Under conditions of oxidative stress, fat-derived cytokines are
970 released locally and result in an inflammatory process and organ dysfunction. This process is believed to result in a proangiogenic/protumorogenic environment resulting in enhanced tumor growth and dissemination.5–9 Pancreatic cancer is one of the deadliest cancers with the shortest median survival time stage for stage of all cancer types.10,11 Increasing BMI has been shown to exponentially increase the relative risk of development of pancreatic cancer.10–14 Importantly, patterns of fat distribution resulting in central adiposity have been shown to be an independent risk factor in the development of pancreatic cancer.15 BMI, a common surrogate marker for grading obesity, does not differentiate between metabolically active visceral fat and the relatively inert subcutaneous fat. Moreover, there is no consensus on the utility of BMI in determining the correlation of obesity with perioperative outcomes and survival. Therefore, we aim to determine the utility of BMI as a prognostic marker for the impact of obesity on outcomes and survival following pancreatoduodenectomy for pancreatic adenocarcinoma. Our hypothesis in undertaking this study was that BMI is a surrogate marker for obesity and has an impact on outcomes and survival following pancreatoduodenectomy for pancreatic adenocarcinoma.
The American Journal of Surgery, Vol 209, No 6, June 2015
Statistical analysis Statistical analyses were undertaken using SigmaStat 3.5 (JandelCorp., San Jose, CA). Data are expressed as median or mean 6 standard deviation for illustrative purposes. Data were analyzed using Student t test or Mann–Whitney U test and Fisher’s exact test, where appropriate. Survival analyses were performed using Kaplan–Meyer methods. Significance was accepted with 95% confidence.
Results Patient population One hundred ninety-two patients had a BMI less than or equal to 29 and 36 patients had a BMI greater than or equal to 30 (BMI 24 6 3 vs 34 6 3, P ,.001). Average age (years) was no different for BMI less than or equal to 29 (67 6 3) versus for BMI greater than or equal to 30 (66 6 2). A histogram depicting the distribution of BMI in the entire cohort is depicted in Fig. 1. The patient population was predominantly male (52%) and no differences existed between nonobese and obese patients. Interestingly, our dataset did not have a statistical difference in diabetes between obese and nonobese patients (33% vs 26%).
Methods
Histologic parameters
Patient population
Histologic parameters are depicted in Table 1. No differences existed in tumor size (3.0 6 .5 vs 2.7 6 .2), perineural involvement (67% vs 71%), and angiovascular involvement (27% vs 29%) between nonobese and obese patients.
Approval to conduct this study was obtained from the University of South Florida Institutional Review Board. From a database of over 1,000 patients who had undergone pancreatoduodenectomy, 228 patients with a diagnosis of pancreatic adenocarcinoma were identified. Patients undergoing pancreaticoduodenectomy for duodenal cancers, ampullary cancers, cholangiocarcinomas, mucinous cystadenomas/adenocarcinomas, intraductal papillary mucinous neoplasms, uncommon pancreatic cancers, and pancreatitis were excluded from this study; only patients with proven adenocarcinoma of the pancreas undergoing pancreaticoduodenectomy were included. Preoperative evaluation included, as a minimum, a triple-phase oral and intravenous contrastenhanced computed tomography scan with thin slices through the pancreas. Only patients whose tumors were without evidence of unresectability underwent operative exploration. Unresectable tumors on computed tomography scans were denoted by the following criteria: (1) the presence of extrapancreatic disease beyond the extent of a pancreaticoduodenectomy, (2) celiac artery or superior mesenteric artery encasement, and (3) portal vein thrombosis or occlusion from tumor invasion. Demographic data, BMI, operative parameters (eg, time, estimated blood loss), length of stay (LOS), survival, tumor size, nodal status, and American Joint Committee on Cancer stage were recorded. Data are presented as median.
Perioperative outcomes Perioperative outcomes are depicted in Figs. 1 and 2. No differences existed in operative time (290 6 110 vs 325 6 80), blood loss (500 6 220 vs 475 6 280), and LOS (11 6 3 vs 10 6 4) between nonobese and obese patients. The clinically significant pancreatic fistulas that were recorded in our database suggested a fistula rate of
Figure 1 Histogram showing the distribution of BMI in the entire sample.
A. Mathur et al. Table 1
BMI effects survival after Whipple
971
Tumor parameters
Tumor size (cm) Perineural involvement Angiovascular involvement
N0
N1
3.0 6 .5 67% 27%
2.7 6 .2 71% 29%
1% in the nonobese patients and 3% in obese patients. This difference was not statistically significant.
Nodal disease and survival Nodal disease and survival are depicted in Figs. 3 and 4. Obese patients were more likely to have positive lymph nodes and this correlated with a statistically worse survival compared with nonobese patients. Calculation of number of positive nodes showed a statistically significant greater number of nodes ‘‘positive’’ in obese patients 1 (2 6 2.2) vs 2 (4 6 4.0) (P , .001).
Comments This study attempts to elucidate the role of BMI as a marker for the deleterious impact of obesity on outcomes for patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma. Patients undergoing resections for pancreatic head adenocarcinoma were identified from our prospectively maintained database. Patient demographics, including BMI, intraoperative parameters, LOS, mortality, and oncologic parametersdnodal status and survival, were recorded. Patients with elevated BMI demonstrated no differences in intraoperative parameters or LOS/morbidity. However, obesity was associated with
Figure 2 Operative time in minutes on the left and estimated blood loss in milliliter on the right.
Figure 3 the right.
Length of stay in days on the left and % morbidity on
increased incidence of node positive patients and a decreased survival. Obesity has become a pandemic in the last decade. In addition to its well-documented effects on the cardiovascular system, there is now a growing body of evidence incriminating it in an increased incidence of cancers. Epidemiologic evidence suggests that the relative risk of pancreatic cancer increases by 1.12 for every 5-point increase in BMI.16 Furthermore, patients with a BMI greater than 35 have a 45% greater risk of development of pancreatic cancer.13 Additionally, Mathur et al have demonstrated that obesity is associated with a worse prognosis from hepato-pancreatico-biliary cancers.17–20 BMI is commonly used as a marker for obesity. However, it does not distinguish between the distributions of adiposity in the body. It is now known that visceral adiposity may be responsible for the majority of the ills of obesity. We, therefore, devised this study to evaluate the utility, if any, of BMI in predicting outcomes for our patients who underwent pancreatoduodenectomy. Clinical experience would suggest that the presence of obesity results in a greater difficulty in obtaining operative exposures from increased visceral fat results in obscuring operative planes. This would intuitively translate into longer operative times and more blood loss. However, our study suggests that neither of these parameters are significantly affected by an elevated BMI. Our findings are echoed by Fleming et al21 who have also shown that the surrogate measures of surgical complexity such as estimated blood loss and operative time are not affected by an increasing BMI. The logical conclusion would be that elevated BMI is not a deterrence to performing a safe pancreatoduodenectomy. However, previous data from our group have suggested that BMI does not correlate well with intra-abdominal fat.16 Given that it is this visceral fat that would likely be the culprit in operative difficulty,
972
Figure 4 % Node positive patients on the left and survival in months on the right. *Significant difference (P 5 .05) between the groups in regard to: Node Positive and Survival.
these findings should be taken with caution. Additionally, our group is a tertiary referral center for pancreatic adenocarcinoma and has high surgeon volumes for pancreatoduodenectomy; therefore, it is possible that greater surgeon experience and skill could nullify the effects of fat and its related operative difficulty. The impact of an increasing BMI on morbidity following pancreatoduodenctomy is contentious. Weber et al22 have suggested that BMI greater than 27 is associated with an increased risk of major complications with an odds ratio of 3.3. However, this has been refuted by 2 large center studies showing no association of BMI with major complications.23,24 Our data suggest that morbidity and therefore LOS are no different in the setting of an elevated BMI. House et al have demonstrated that elevated measurements of visceral fat on cross-sectional imaging are associated with increased total complications. Importantly, their study also noted that BMI was not associated with an increased incidence of elevated morbidity. Furthermore, pancreatic fistula development was related to visceral fat increase and not a rise in BMI. Mathur et al25 have shown that a fatty pancreas from increased visceral fat infiltration is associated with an increased incidence of pancreatic fistula. Significantly, they also did not note a difference in BMI in their cohort of patients with and without visceral fat infiltration. These findings again suggest that BMI may be an inconsistent surrogate for obesity. Adipose tissue is believed to influence oncologic outcomes as a result of an altered proinflammatory protumorogenic milieu. Experimental models evaluating the outcome of pancreatic adenocarcinoma in strains of obese versus lean mice have shown that obese mice developed larger tumors, and a significantly greater number of mice developed metastases; mortality was also greater in obese mice. Furthermore, the intratumoral adipocyte mass in tumors from both obese strains was significantly greater than that in
The American Journal of Surgery, Vol 209, No 6, June 2015 tumors of lean mice.19,20 This along with the increased baseline levels of pancreatic tissue proinflammatory cytokines including tumor necrosis factor and interleukin-6 in the setting of obesity changes the tumor–stroma interaction, which undoubtedly plays a critical role in tumor proliferation and metastases.26 Additionally, recent data have shown that visceral fat-derived stem cells from obese patients promote the migration of pancreatic cancer cells.27 Thereby establishing a mechanistic link to elevated visceral fat stores and enhanced tumor metastases, which would result in inferior oncologic outcomes. Clinical studies looking at oncologic outcomes using BMI as a surrogate measure have been mixed. Our study demonstrates that an elevated BMI is associated with increased nodal metastases and decreased survival. Fleming et al21 have corroborated these findings showing that a BMI greater than 30 was associated with decreased survival and increased incidence of lymph node metastases. However, Benns et al, Khan et al, and Dandona et al have independently in large single institution studies shown that elevated BMI is not associated with lymph node status or survival.28–30 The answer to this controversy could once again lie in the degree of visceral fat infiltration. Our group has previously demonstrated that visceral fat infiltration as measured by high-resolution computed tomography predicts increased nodal metastases and decreased survival.16 To further elucidate the impact of the type of obesity, we measured both visceral fat and subcutaneous fat. Visceral fat pad was increased by 38% in patients with nodal metastases. In stark contrast, no difference was noted in the subcutaneous fat pad.16 Balentine et al31 confirmed are findings showing that visceral fat and not BMI was associated with a worse overall survival. In summary, with resected pancreatic adenocarcinoma, our study suggests that increased BMI is associated with lymphatic metastases and worse survival. However, there are clearly substantial differences in the impact of BMI on perioperative and oncologic outcomes in the literature. These are likely because of the lack of accuracy of BMI in differentiating the metabolically active visceral fat and the relatively inert subcutaneous fat. As described in our discussion, there is now a critical mass in the literature elucidating the mechanistic effects of visceral fat preferentially promoting the growth and dissemination of hepatopancreatico-biliary-related cancers. Therefore, further studies evaluating the oncologic impact of obesity need to focus on developing and using quantification of visceral fat rather than BMI as a surrogate measure of obesity.
References 1. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288:1723–7. 2. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000;894: 1–253.
A. Mathur et al.
BMI effects survival after Whipple
3. International Agency for Research on Cancer Working Group on Evaluation of Cancer-Preventive Strategies. Weight Control and Physical Activity. Lyon, France: IARC Press; 2002. 4. Joint World Health Organization/Food and Agriculture Organization Expert Consultation. Diet, Nutrition and the Prevention of Chronic Diseases. WHO Technical Report Series No. 916; 2003. 5. Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol 2006;207: 12–22. 6. Somasundar P, Yu AK, Vona-Davis L, et al. Differential effects of leptin on cancer in vitro. J Surg Res 2003;113:50–5. 7. Fantuzzi G. Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol 2008;121:326–30. 8. Dalamaga M, Migdalis I, Fargnoli JL, et al. Pancreatic cancer expresses adiponectin receptors and is associated with hypoleptinemia and hyperadiponectinemia: a case-control study. Cancer Causes Control 2009;20:625–33. 9. Kelesidis I, Kelesidis T, Mantzoros CS. Adiponectin and cancer: a systematic review. Br J Cancer 2006;94:1221–5. 10. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 2003;348:1625–38. 11. Michaud DS. Epidemiology of pancreatic cancer. Minerva Chir 2004; 59:99–111. 12. Silverman DT, Swanson CA, Gridley G, et al. Dietary and nutritional factors and pancreatic cancer: a case-control study based on direct interviews. J Natl Cancer Inst 1998;90:1710–9. 13. Stolzenberg-Solomon RZ, Adams K, Leitzmann M, et al. Adiposity, physical activity, and pancreatic cancer in the National Institutes of HealthAARP Diet and Health Cohort. Am J Epidemiol 2007;167:586–97. 14. Larsson SC, Orsini N, Wolk A. Body mass index and pancreatic cancer risk: a meta-analysis of prospective studies. Int J Cancer 2007;120: 1993–8. 15. Patel AV, Rodriguez C, Bernstein L, et al. Obesity, recreational physical activity, and risk of pancreatic cancer in a large US cohort. Cancer Epidemiol Biomarkers Prev 2005;14:459–66. 16. Mathur A, Hernandez J, Shaheen F, et al. Preoperative computed tomography measurements of pancreatic steatosis and visceral fat: prognostic markers for dissemination and lethality of pancreatic adenocarcinoma. HPB (Oxford) 2011;13:404–10. 17. Mathur A, Zyromski NJ, Pitt HA, et al. Pancreatic steatosis promotes dissemination and lethality of pancreatic cancer. J Am Coll Surg 2009; 208:989–94; discussion 994–6.
973 18. Mathur A, Franco ES, Leone JP, et al. Obesity portends an increased morbidity, and early recurrence following liver transplantation for hepatocellular carcinoma. HPB (Oxford) 2013;15: 504–10. 19. Zyromski NJ, Mathur A, Pitt HA, et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery 2009;146: 258–63. 20. Kausch W. Das Carcinom der papilla duodeni und seine radikale Entfernung. Beitr Z Clin Chir 1912;78:439–86. 21. Fleming JB, Gonzalez RJ, Petzel MQ, et al. Influence of obesity on cancer-related outcomes after pancreatectomy to treat pancreatic adenocarcinoma. Arch Surg 2009;144:216–21. 22. Weber SM, Cho CS, Merchant N, et al. Laparoscopic left pancreatectomy: complication risk score correlates with morbidity and risk for pancreatic fistula. Ann Surg Oncol 2009;16:2825–33. 23. Williams TK, Rosato EL, Kennedy EP, et al. Impact of obesity on perioperative morbidity and mortality after pancreaticoduodenectomy. J Am Coll Surg 2009;208:210–7. 24. House MG, Fong Y, Arnaoutakis DJ, et al. Preoperative predictors for complications after pancreaticoduodenectomy: impact of BMI and body fat distribution. J Gastrointest Surg 2008;12:270–8. 25. Mathur A, Pitt HA, Marine M, et al. Fatty pancreas: a factor in postoperative pancreatic fistula. Ann Surg 2007;246:1058–64. 26. Mathur A, Marine M, Lu D, et al. Nonalcoholic fatty pancreas disease. HPB (Oxford) 2007;9:312–8. 27. Mathur A, Murr M, Watson J, et al. Adipose-derived stem cells contribute to obesity-induced inferior oncologic outcomes of pancreatic cancer. HPB 2012;14(Supplement). 28. Benns M, Woodall C, Scoggins C, et al. The impact of obesity on outcomes following pancreatectomy for malignancy. Ann Surg Oncol 2009;16:2565–9. 29. Khan S, Sclabas G, Reid-Lombardo K, et al. Does body mass index/ morbid obesity influence outcome in patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma? J Gastrointest Surg 2010;14:1820–5. 30. Dandona M, Linehan D, Hawkins W, et al. Influence of obesity and other risk factors on survival outcomes in patients undergoing pancreaticoduodenectomy for pancreatic cancer. Pancreas 2011;40:931–7. 31. Balentine CJ, Enriquez J, Fisher W, et al. Intra-abdominal fat predicts survival in pancreatic cancer. J Gastrointest Surg 2010;14: 1832–7.
©2015 Elsevier
Clinical Science
Increasing body mass index portends abbreviated survival following pancreatoduodenectomy for pancreatic adenocarcinoma Abhishek Mathur, M.D., Kenneth Luberice, B.S., Harold Paul, B.S., Co Franka, B.S., Alexander Rosemurgy, M.D.* Southeastern Center for Digestive Disorders and Pancreatic Cancer, Advanced Minimally Invasive and Robotic Surgery, Florida Hospital Tampa, Tampa, FL, USA
KEYWORDS: BMI; Pancreaticoduodenectomy; Pancreatic adenocarcinoma
Abstract BACKGROUND: Body mass index (BMI), a common surrogate marker for grading obesity, does not differentiate between metabolically active visceral fat and the relatively inert subcutaneous fat. We aim to determine the utility of BMI as a prognostic marker for the impact of obesity on outcomes and survival following pancreatoduodenectomy for pancreatic adenocarcinoma. METHODS: From a database of over 1,000 patients who had undergone pancreatoduodenectomy, 228 patients with a diagnosis of pancreatic adenocarcinoma were identified. Demographic data including BMI and perioperative parametersdoperative time, estimated blood loss, length of stay, survival, nodal status, and American Joint Committee on Cancer stagedwere obtained. Data are presented as median. RESULTS: One hundred ninety-two patients had a BMI less than or equal to 29 and 36 patients had a BMI greater than or equal to 30 (24 vs 34, P , .001). Median age was 70 and the majority of the patients (52%) were male and the 2 groups of patients did not differ in this regard. A significantly greater number of obese patients had positive nodes (69% vs 62%, P , .05) and this was associated with a worse survival (14 vs 18 months, P , .05). CONCLUSIONS: For patients with pancreatic adenocarcinoma undergoing pancreatoduodenectomy, obesity does not impact operative complexity or length of stay but results in a shortened survival. Therefore, we conclude that BMI is an important prognostic marker that portends an abbreviated survival following pancreatoduodenectomy for pancreatic adenocarcinoma. Ó 2015 Elsevier Inc. All rights reserved.
The authors declare no conflicts of interest. Presented in part at the Seventh Annual Academic Surgical Congress of the Society of University Surgeons and Association for Academic Surgeons, February 14–16, 2012, Las Vegas. * Corresponding author. Tel.: 11-813-615-7030; fax: 11-813-6158350. E-mail address: [email protected] Manuscript received September 4, 2014; revised manuscript November 19, 2014 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2014.12.037
Over 50,000,000 Americans have a body mass index (BMI) greater than 30.1,2 Obesity leads to multiple comorbidities including diabetes, hypertension, and hyperlipidemia (the metabolic syndrome). In addition, obesity causes fat infiltration of several organs including the heart, kidneys, liver, and pancreas. Epidemiologic evidence suggests an association between obesity and multiple cancers including pancreatic cancer.3,4 Under conditions of oxidative stress, fat-derived cytokines are
970 released locally and result in an inflammatory process and organ dysfunction. This process is believed to result in a proangiogenic/protumorogenic environment resulting in enhanced tumor growth and dissemination.5–9 Pancreatic cancer is one of the deadliest cancers with the shortest median survival time stage for stage of all cancer types.10,11 Increasing BMI has been shown to exponentially increase the relative risk of development of pancreatic cancer.10–14 Importantly, patterns of fat distribution resulting in central adiposity have been shown to be an independent risk factor in the development of pancreatic cancer.15 BMI, a common surrogate marker for grading obesity, does not differentiate between metabolically active visceral fat and the relatively inert subcutaneous fat. Moreover, there is no consensus on the utility of BMI in determining the correlation of obesity with perioperative outcomes and survival. Therefore, we aim to determine the utility of BMI as a prognostic marker for the impact of obesity on outcomes and survival following pancreatoduodenectomy for pancreatic adenocarcinoma. Our hypothesis in undertaking this study was that BMI is a surrogate marker for obesity and has an impact on outcomes and survival following pancreatoduodenectomy for pancreatic adenocarcinoma.
The American Journal of Surgery, Vol 209, No 6, June 2015
Statistical analysis Statistical analyses were undertaken using SigmaStat 3.5 (JandelCorp., San Jose, CA). Data are expressed as median or mean 6 standard deviation for illustrative purposes. Data were analyzed using Student t test or Mann–Whitney U test and Fisher’s exact test, where appropriate. Survival analyses were performed using Kaplan–Meyer methods. Significance was accepted with 95% confidence.
Results Patient population One hundred ninety-two patients had a BMI less than or equal to 29 and 36 patients had a BMI greater than or equal to 30 (BMI 24 6 3 vs 34 6 3, P ,.001). Average age (years) was no different for BMI less than or equal to 29 (67 6 3) versus for BMI greater than or equal to 30 (66 6 2). A histogram depicting the distribution of BMI in the entire cohort is depicted in Fig. 1. The patient population was predominantly male (52%) and no differences existed between nonobese and obese patients. Interestingly, our dataset did not have a statistical difference in diabetes between obese and nonobese patients (33% vs 26%).
Methods
Histologic parameters
Patient population
Histologic parameters are depicted in Table 1. No differences existed in tumor size (3.0 6 .5 vs 2.7 6 .2), perineural involvement (67% vs 71%), and angiovascular involvement (27% vs 29%) between nonobese and obese patients.
Approval to conduct this study was obtained from the University of South Florida Institutional Review Board. From a database of over 1,000 patients who had undergone pancreatoduodenectomy, 228 patients with a diagnosis of pancreatic adenocarcinoma were identified. Patients undergoing pancreaticoduodenectomy for duodenal cancers, ampullary cancers, cholangiocarcinomas, mucinous cystadenomas/adenocarcinomas, intraductal papillary mucinous neoplasms, uncommon pancreatic cancers, and pancreatitis were excluded from this study; only patients with proven adenocarcinoma of the pancreas undergoing pancreaticoduodenectomy were included. Preoperative evaluation included, as a minimum, a triple-phase oral and intravenous contrastenhanced computed tomography scan with thin slices through the pancreas. Only patients whose tumors were without evidence of unresectability underwent operative exploration. Unresectable tumors on computed tomography scans were denoted by the following criteria: (1) the presence of extrapancreatic disease beyond the extent of a pancreaticoduodenectomy, (2) celiac artery or superior mesenteric artery encasement, and (3) portal vein thrombosis or occlusion from tumor invasion. Demographic data, BMI, operative parameters (eg, time, estimated blood loss), length of stay (LOS), survival, tumor size, nodal status, and American Joint Committee on Cancer stage were recorded. Data are presented as median.
Perioperative outcomes Perioperative outcomes are depicted in Figs. 1 and 2. No differences existed in operative time (290 6 110 vs 325 6 80), blood loss (500 6 220 vs 475 6 280), and LOS (11 6 3 vs 10 6 4) between nonobese and obese patients. The clinically significant pancreatic fistulas that were recorded in our database suggested a fistula rate of
Figure 1 Histogram showing the distribution of BMI in the entire sample.
A. Mathur et al. Table 1
BMI effects survival after Whipple
971
Tumor parameters
Tumor size (cm) Perineural involvement Angiovascular involvement
N0
N1
3.0 6 .5 67% 27%
2.7 6 .2 71% 29%
1% in the nonobese patients and 3% in obese patients. This difference was not statistically significant.
Nodal disease and survival Nodal disease and survival are depicted in Figs. 3 and 4. Obese patients were more likely to have positive lymph nodes and this correlated with a statistically worse survival compared with nonobese patients. Calculation of number of positive nodes showed a statistically significant greater number of nodes ‘‘positive’’ in obese patients 1 (2 6 2.2) vs 2 (4 6 4.0) (P , .001).
Comments This study attempts to elucidate the role of BMI as a marker for the deleterious impact of obesity on outcomes for patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma. Patients undergoing resections for pancreatic head adenocarcinoma were identified from our prospectively maintained database. Patient demographics, including BMI, intraoperative parameters, LOS, mortality, and oncologic parametersdnodal status and survival, were recorded. Patients with elevated BMI demonstrated no differences in intraoperative parameters or LOS/morbidity. However, obesity was associated with
Figure 2 Operative time in minutes on the left and estimated blood loss in milliliter on the right.
Figure 3 the right.
Length of stay in days on the left and % morbidity on
increased incidence of node positive patients and a decreased survival. Obesity has become a pandemic in the last decade. In addition to its well-documented effects on the cardiovascular system, there is now a growing body of evidence incriminating it in an increased incidence of cancers. Epidemiologic evidence suggests that the relative risk of pancreatic cancer increases by 1.12 for every 5-point increase in BMI.16 Furthermore, patients with a BMI greater than 35 have a 45% greater risk of development of pancreatic cancer.13 Additionally, Mathur et al have demonstrated that obesity is associated with a worse prognosis from hepato-pancreatico-biliary cancers.17–20 BMI is commonly used as a marker for obesity. However, it does not distinguish between the distributions of adiposity in the body. It is now known that visceral adiposity may be responsible for the majority of the ills of obesity. We, therefore, devised this study to evaluate the utility, if any, of BMI in predicting outcomes for our patients who underwent pancreatoduodenectomy. Clinical experience would suggest that the presence of obesity results in a greater difficulty in obtaining operative exposures from increased visceral fat results in obscuring operative planes. This would intuitively translate into longer operative times and more blood loss. However, our study suggests that neither of these parameters are significantly affected by an elevated BMI. Our findings are echoed by Fleming et al21 who have also shown that the surrogate measures of surgical complexity such as estimated blood loss and operative time are not affected by an increasing BMI. The logical conclusion would be that elevated BMI is not a deterrence to performing a safe pancreatoduodenectomy. However, previous data from our group have suggested that BMI does not correlate well with intra-abdominal fat.16 Given that it is this visceral fat that would likely be the culprit in operative difficulty,
972
Figure 4 % Node positive patients on the left and survival in months on the right. *Significant difference (P 5 .05) between the groups in regard to: Node Positive and Survival.
these findings should be taken with caution. Additionally, our group is a tertiary referral center for pancreatic adenocarcinoma and has high surgeon volumes for pancreatoduodenectomy; therefore, it is possible that greater surgeon experience and skill could nullify the effects of fat and its related operative difficulty. The impact of an increasing BMI on morbidity following pancreatoduodenctomy is contentious. Weber et al22 have suggested that BMI greater than 27 is associated with an increased risk of major complications with an odds ratio of 3.3. However, this has been refuted by 2 large center studies showing no association of BMI with major complications.23,24 Our data suggest that morbidity and therefore LOS are no different in the setting of an elevated BMI. House et al have demonstrated that elevated measurements of visceral fat on cross-sectional imaging are associated with increased total complications. Importantly, their study also noted that BMI was not associated with an increased incidence of elevated morbidity. Furthermore, pancreatic fistula development was related to visceral fat increase and not a rise in BMI. Mathur et al25 have shown that a fatty pancreas from increased visceral fat infiltration is associated with an increased incidence of pancreatic fistula. Significantly, they also did not note a difference in BMI in their cohort of patients with and without visceral fat infiltration. These findings again suggest that BMI may be an inconsistent surrogate for obesity. Adipose tissue is believed to influence oncologic outcomes as a result of an altered proinflammatory protumorogenic milieu. Experimental models evaluating the outcome of pancreatic adenocarcinoma in strains of obese versus lean mice have shown that obese mice developed larger tumors, and a significantly greater number of mice developed metastases; mortality was also greater in obese mice. Furthermore, the intratumoral adipocyte mass in tumors from both obese strains was significantly greater than that in
The American Journal of Surgery, Vol 209, No 6, June 2015 tumors of lean mice.19,20 This along with the increased baseline levels of pancreatic tissue proinflammatory cytokines including tumor necrosis factor and interleukin-6 in the setting of obesity changes the tumor–stroma interaction, which undoubtedly plays a critical role in tumor proliferation and metastases.26 Additionally, recent data have shown that visceral fat-derived stem cells from obese patients promote the migration of pancreatic cancer cells.27 Thereby establishing a mechanistic link to elevated visceral fat stores and enhanced tumor metastases, which would result in inferior oncologic outcomes. Clinical studies looking at oncologic outcomes using BMI as a surrogate measure have been mixed. Our study demonstrates that an elevated BMI is associated with increased nodal metastases and decreased survival. Fleming et al21 have corroborated these findings showing that a BMI greater than 30 was associated with decreased survival and increased incidence of lymph node metastases. However, Benns et al, Khan et al, and Dandona et al have independently in large single institution studies shown that elevated BMI is not associated with lymph node status or survival.28–30 The answer to this controversy could once again lie in the degree of visceral fat infiltration. Our group has previously demonstrated that visceral fat infiltration as measured by high-resolution computed tomography predicts increased nodal metastases and decreased survival.16 To further elucidate the impact of the type of obesity, we measured both visceral fat and subcutaneous fat. Visceral fat pad was increased by 38% in patients with nodal metastases. In stark contrast, no difference was noted in the subcutaneous fat pad.16 Balentine et al31 confirmed are findings showing that visceral fat and not BMI was associated with a worse overall survival. In summary, with resected pancreatic adenocarcinoma, our study suggests that increased BMI is associated with lymphatic metastases and worse survival. However, there are clearly substantial differences in the impact of BMI on perioperative and oncologic outcomes in the literature. These are likely because of the lack of accuracy of BMI in differentiating the metabolically active visceral fat and the relatively inert subcutaneous fat. As described in our discussion, there is now a critical mass in the literature elucidating the mechanistic effects of visceral fat preferentially promoting the growth and dissemination of hepatopancreatico-biliary-related cancers. Therefore, further studies evaluating the oncologic impact of obesity need to focus on developing and using quantification of visceral fat rather than BMI as a surrogate measure of obesity.
References 1. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288:1723–7. 2. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000;894: 1–253.
A. Mathur et al.
BMI effects survival after Whipple
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