The Weight of the Issue: Obesity and Cancer

1. The Weight of the Issue:Obesity and Cancer Blakely Kute, MD Hematology and Oncology Fellow February 3, 2011

2. Obesity and Cancer • Associated with wide range of cancer types • Varying mechanisms of inducing tumorigenesis • Hyperinsulinemia • Inflammation • Increased bioavailability of steroid hormones [1]

3. Obesity Trends* Among U.S. AdultsBRFSS,1990, 1999, 2009 (*BMI 30, or about 30 lbs. overweight for 5’4” person) 1999 1990 2009 No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30% http://www.cdc.gov/obesity/data/trends.html

4. Measuring Adiposity • Ideally include both subcutaneous and visceral • Methods: • Hydrodensitometry • Skin folds • Waist circumference • DEXA • CT • MRI

5. Measuring Adiposity • Body Mass Index • Most cost effective • Highly specific, but poor sensitivity • BMI > 30 failed to reveal 50% of people with excess body fat • Less sensitive in elderly – shift of peripheral fat to central • “Normal weight obesity” • Abdominal obesity • at risk for : • metabolic syndrome • hyperlipidemia • cardiovascular disease

6. Obesity and Cancer Connection • 1970s: adiposity contributes to increased incidence and/or death from: • Colon cancer • Gallbladder cancer • Liver cancer • Pancreatic cancer • Gastroesophageal cancer • Breast cancer (post menopausal) • Endometrial cancer • Kidney (renal cell) cancer

7. Overweight/Obesity Burden • Total health burden of obesity and overweight may exceed cigarette smoking • Past 15 years: • Smoking rates ↓ 20% • Obesity rates ↑ 48% • Life expectancy projected to continue to rise, but more slowly secondary to increasing obesity.

8. Obesity and Cancer Incidence • IARC estimates that obesity causes: • 11% of colon cancer cases • 9% of postmenopausal breast cancer cases • 39% of endometrial cancer cases • 25% of kidney cancer cases • 37% of esophageal cancer cases

9. Obesity and Cancer Incidence

11. Obesity and Cancer Mortality Connection • 1970s: • 15-20% of cancer deaths attributed to overweight and obesity • 2000s: • Still attributing 14-20% of cancer deaths to obesity and overweight • BMI > 40 associated with 52% (men) and 62 % (women) higher death rates from all cancers combined Callie EE. Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003; 348: 1625-1638.

12. Characterizing the association • Cancer Prevention Study II • Prospective mortality study begun by the ACS in 1982. • 1,184,617 participants • Volunteer enrollment • Completion of a confidential mailed questionnaire • Report of deaths before 1988 were from personal inquires. After 1988, reports were from the National Death Index. • Subset analysis used for weight association with increased risk of death from cancer

13. Applying the Data from Cancer Prevention Study • Baseline questionnaire – • asked current weight, weight one year previously, and height (without shoes) • Callie et al with ACS, 2003 • Subset analysis on the influence of excess body weight on the risk of death from cancer • Study Exclusions: • if you didn’t know your weight or had lost more than 10 lbs within the previous year • BMI <18.5 • previous cancer history, with the exception of non-melanoma skin cancer • if you excluded smoking or race history

14. Applying the Data from Cancer Prevention Study II • Subset analysis from Callie et al, 2003 studying weight on cancer mortality • 404,576 men • 495,477 women • Average age 57 • 16 year follow up: • 32,303 deaths from cancer in men • 24,842 cancer deaths in women • End points: deaths from all cancers and deaths from specific sites

15. Applying the Data from Cancer Prevention Study II • Callie et al also defined subset of non-smokers • 107,030 men • 276,564 women • Cancer deaths among non-smokers: • 5,314 deaths among men • 11,648 deaths among women • End points: deaths from all cancers and deaths from specific sites • Allowed the investigators to evaluate whether the association between BMI and mortality was subject to residual confounding by smoking status for smoking related cancers.

20. More results • Proportion of cancer deaths attributable to overweight and obesity: • Men: 4.2 to 14.2 percent • Women: 14.3 to 19.8 percent • Lower risks based on entire population studied • Higher risks based on nonsmoking population • Potentially, more than 90,000 US deaths from cancer might be avoided if adults could maintain BMI under 25.0 throughout life

21. Abdominal Obesity • Definition: • ≥ 88 cm in women and ≥ 102 cm in mne • Incidence: • ≥ 70% of women and ≥ 50% of men aged 50-79 years • Importance • Visceral adipocytes: • more metabolically active • high lipolytic activity • release large amounts fatty acids • Increases incidence of (independent of BMI): • Pancreatic, endometrial and postmenopausal breast cancer

22. Abdominal Obesity • Weight circumference subset of Cancer Prevention Study II • Correlated independently of BMI with: • elevated inflammatory markers • type 2 diabetes and insulin resistance • Dyslipidemia • Increasing waist circumference associated with progressively higher risk of all cause mortality in men and women (after adjustment for BMI)

23. Proposed mechanisms • Adipose tissue constitutes an active endocrine and metabolic organ resulting in: • Chronic hyperinsulinemia • Elevated endogenous sex steroids • Chronic inflammation • Non-alcoholic fatty liver disease • Increased incidence of GERD • ?? Vit D deficiency

24. Proposed mechanisms

25. Chronic Hyperinsulinemia • Associated with colon, breast, pancreatic, and endometrial cancers • Tumorigenic effects: • Directly mediated from receptors on (pre)neoplastic cells • Indirectly via changes in hormone metabolism • Androgens, estrogens, progesterone, IGF-1 and its binding proteins

26. Increased Endogenous Steroids • Associated with endometrial and post-menopausal breast cancer

27. Endometrial cancer • Most closely linked cancer with obesity and overweight

28. Chronic Inflammation • Associated with: • Multiple Myeloma • Non-Hodgkin’s lymphoma • Liver • Increased TNF-alpha, IL-6 and STAT3

29. Colon cancer • Obese men more likely than obese females to develop colon cancer • Theories: • Abdominal obesity, more prevalent in men, is a greater risk factor than peripheral fat • Offsetting beneficial effect of obesity from elevated endogenous hormones • Theory based on decreased rates of CRC in women on postmenopausal hormone therapy • Highly associated with increased insulin levels

30. Post-menopausal Breast Cancer • Obesity may increase rates 30-50% • Adult weight gain associated with ↑ risk • Obesity associated with increased likelihood of recurrence, regardless of menopausal status, after adjustment for stage/treatment • “Very obese” (BMI > 40) have death rates 3X higher than “very lean” (BMI <20.5) • Some theories regarding delayed diagnosis in obese patients

31. Specific cancers • Endometrial cancer • 1st cancer to be found to be related to obesity • Direct relationship • 2-3.5-fold increase in risk of incidence • Renal Cell carcinoma • Association of obesity seems to be independent of hypertension

32. Specific cancers • Esophageal, adenocarcinoma • Indirectly via increased reflux • Proposed direct mechanism too • Hepatocellular cancer • Likely related to the spectrum of NASH -> cirrhosis-> HCC • Gallbladder • Not shown to be consistently related, but related to increased risk of gallstones -> chronic inflammation

33. Specific cancers • Lung cancer • Inversely associated • Theory: Smoking is primary cause of lung cancer and smoking is inversely related to BMI • Prostate cancer • No firm relationship, but suggestion • Likely related to hyperinsulinemia • More likely to have aggressive disease that recurs

34. Specific cancers • Ovarian cancer • No firmly established link • May be some increased link to certain pathologies (endometrioid) • Cervical cancer • Not enough data to confirm link • Several studies showing decreased compliance with PAP smears with increasing body weight

35. Additional complications of obesity • Dosing chemotherapy • Actual verses adjusted BSA • Potential for difficulty with radiation dosimetry and higher rate of complications • Increased surgical complications: • Increased OR time, impaired respirations, difficult intubations, poor exposure to operative field, increased blood loss • Postoperative complications: increased risk for DVT, poor wound healing, and pulmonary complications

36. Can weight loss help? • Bariatric surgery population studied • Varying results • Mean weight loss 14-27%in US and Swedish group showed up to 38% lower cancer death rates • Decrease in post-menopausal breast ca rates • Other studies do not demonstrate such effects • Weight loss after menopause significantly decreases breast cancer risk

37. Is extra weight ever helpful • Surgical studies • Protective in premenopausal breast cancer • BMI >28

38. Implications on Kentucky 1. Mississippi 33.8% 2. Alabama 31.6%3. Tennessee 31.6%4. West Virginia 31.3% 5. Louisiana 31.2%6. Oklahoma 30.6%7. Kentucky 30.5% 8. Arkansas 30.1%9. South Carolina 29.9%10. North Carolina 29.4% 10. Michigan 29.4% 12. Missouri 29.3% 13. Ohio 29.0% 13. Texas 29.0% 15. South Dakota 28.5% 16. Kansas 28.2% 17. Pennsylvania 28.1% 17. Georgia 28.1% 17. Indiana 28.1% 2010 Obesity Rates

39. 2009 Obesity Data No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

40. Implications on Kentucky • Education and Prevention are key • 2009 KY started school nutrition programs • Do not have mandate regarding school physical activity • Louisville had Health Promotion Schools of Excellence • Better BMI documentation and obesity discussions • UK study showed only 61% of patients in a large primary health care group had BMI documented • Those with high BMIs had poorer control of HTN, HLD, and glucose than did their normal BMI counterparts

41. References • Calle EE and R Kaaks. Overweight, Obesity and Cancer: Epidemiological Evidence and Proposed Mechanisms. Nat Rev Cancer 2004. 4(8). • http://www.cdc.gov/obesity/data/trends.html • Okorodudu DO, Jumean MF, Montori VM, Romero-Corral A, Somers VK, Erwin PJ, Lopez-Jimenez F. Diagnostic performance of body mass index to identify obesity as defined by body adiposity: a systematic review and meta-analysis. Int J Obes 2001; 34(5):791-799. • Romero-Corral A, Somers VK, Sierra-Johnson J, Korenfeld Y, Boarin S, Korinek J, Jensen MD, Parati G, Lopez-Jimenez F. Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality. Eur Heart J. 2010; 31(6):737-746. • Callie EE. Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003; 348: 1625-1638. • Wolin KY, Carson K, Colditz GA. Obesity and Cancer. The Oncologist 2010; 15:556-565. • Stewart ST, Cutler DM, Rosen AB. Forecasting the effects of obestiy and smoking on U.S. life expectancy. N Engl J Med 2009; 361:2252-2260. • International Agency for Research on Cancer. Weight Control and Physical Activity, Volume 6, Lyon: International Agency for Research on Cancer, 2002:1-315. • Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569-578. • Jacobs EJ, Newton CC, Wang Y, Patel AV, McCullough ML, Campbell PI, Thun MJ, Gapstar SM. Waist Circumference and All-Cause Mortality in a Large US Cohort. Arch Intern Med 2010; 170:1293-1301. • Langunova Z, Porojnicu AC. Grant WB, Bruland O, Moan JE. Obesity and increased risk of cancer: Does decrease of serum 25-hydroxyvitamin D level with increasing body mass explain some of the association? Mol. Nutr. Food Res. 2010;54:1127-1133. • Modesitt SC and vanNagell JR. The Impact of Obesity on the Incidence and Treatment of Gynecologic Cancers: A Review. Obstetrical and Gynelogical Survey 2005; 60(10):683-692. • Msnbc.com • http://www.statehealthfacts.org/profileind.jsp?ind=52&cat=2&rgn=19 • http://www.ket.org/commonhealth/models/healthpromo.htm