1. Managing the Side Effects of Androgen Deprivation Therapy Celestia (Tia) Higano, MD, FACP Professor Departments of Medicine and Urology University of Washington Member, Fred Hutchinson Cancer Research Center Prostate Cancer Symposium Inaugural Meeting New York City October 6, 2009

2. ARS ?

3. 3 Side-Effects of ADT Loss of libido Erectile dysfunction Hot flashes Weight gain Gynecomastia Loss muscle mass, strength Decr size penis and testes Hair changes Loss of BMD Anemia Onset/worsening of lipids, HTN, CVD, diabetes Depression Emotional lability Cognitive function Aches and pains Fatigue, Lack of energy, Lack of initiative “Big Three” What you seeWhat you don’t see What you feel

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5. 5 Loss of Libido and Erectile Dysfunction  Sexual function and couple’s relationship before cancer diagnosis and treatment  Loss of libido – Difficult to overcome on ADT  Erectile dysfunction – Many causes  Consider counselor or sex therapist referral – Sexual rehabilitation 1 – Intimacy and communication 1. Canada Cancer 2005

6. Approaches to ED  “Penile rehab”  Drug therapy – Phosphodiesterase type 5 (PDE-5) inhibitors – Vasoactive agents  Vacuum erection device (VED)  Combinations  Penile prosthesis

7. What do these have in common?  Hot flashes  Loss of bone density  Depression  High blood pressure, diabetes, increased lipids  Decreased muscle mass  Weight gain  Change in cognitive function  Fatigue, loss of initiative 7

8. ARS ?

9. Exercise helps!  What kind? – Aerobic – Resistance – Stretching  How to accomplish? – With help and support – Make it a part of your schedule – Start out slowly 9

10. 10 What you see: Gynecomastia  Often associated with breast tenderness  Generally not totally reversible – Made worse by weight gain  An ounce of prevention – Electron beam radiation of breast tissue  Treatment – Subcutaneous mastectomy

11. 11 What you see: Decrease in Penile and Testicular Size  Up to 68% have penile shortening after RP 1  Penile rehab – Post operative – During ADT  Shrinkage of testicles physiologic related to testosterone levels 1. Savoie J Urol 2003

12. Intermittent ADT  Lower testosterone for a given period and then stop ADT and allow testosterone to rise  Many ADT toxicities are reversible – Fatigue – Hair changes – Testicular shrinkage  Some are not so reversible – Weight gain – Breast enlargement12

13. Take Home Messages  Understand what to expect  Be proactive – Don’t wait to see if you have side effects – Meet with a nutritionist, physical therapist – Have appropriate tests DEXA, lipid panel, glucose, CBC, weight, blood pressure  Exercise!13

14. Additional Slides14

15. 15 Overview  Androgen deprivation (ADT) – “Hormonal therapy” – Testosterone lowering drugs  History of ADT in treatment of prostate cancer  Define the side effects of ADT  Monitoring and intervention strategies

16. 16 The History of Hormonal Therapy for Prostate Cancer orchiectomy LHRH analogs symptomatic bone mets PSA biochemical relapse 1940’s 1980’s 1990’s2000’s asymptomatic bone mets localized PCa

17. 17 Disease States and Natural History Localized 40-60% 5 - 15 yrs 3.5 yrs Biochemical HRPC Met HRPC Biochemical relapse Death 1.5 yrs 2 - 5 yrs Metastatic

18. 18 Populations of Men with Prostate Cancer Treated with ADT  Newly diagnosed localized – As primary therapy (not standard of care) – In combination with radiation therapy – High risk adjuvant therapy  Non-metastatic – 50,000 new cases per year – Now the largest percentage of PCa patients – Long natural history  Metastatic – Bone, nodal, other sites – Median survival 3-5 years

19. 19 The “Big Three” 3. Hot Flashes  75% have them but how bothersome? – 11% “severely distressed” 1 – Emotional, physical symptoms – Can disturb sleep – Do not abate over time  Few well done prospective trials – Hot flash scales 2,3 1. Spetz J Urol 2001 2. Quella Urol Nurs 1994 3. Moyad Urol Oncol 2005

20. 20 Treatment Options for Hot Flashes Hormonal  Progestational agents – Megestrol acetate (Megace) 1 – Depot medroxyprogesterone acetate 2 – Cyproterone acetate 3  Estrogens – Diethylstilbestrol (DES) 4 – Estradiol patches 5,6 – Estrogen gel 1. Loprinzi N Engl J Med 1994. 2. Charig Urology 1989 3. Cervenakov Int Urol Nephrol 2000 4. Atala A Urology 1992. 5. Gerber GS Urology 2000. 6. Spetz J Urol 2001.

21. 21 Treatment Options for Hot Flashes Non-Hormonal  5-Hydroxytryptamine reuptake inhibitors – Venalfaxine (Effexor) 1 – Sertraline (Zoloft) 2  Gabapentin (Neurontin) 3  Acupuncture 4  Soy products?  Not effective or no longer recommended – Clonidine 5 – Vitamin E 6, 7 1. Quella J Urol 1999 2. Roth J Urol 1998 3. Guttso Neurology 2000. 4. Hammar J Urol 1999. 5. Loprinzi J Urol 1994 6. Lonn JAMA 2005 7. Miller Ann Int Med 2005

22. 22 What you see: Weight Gain and Associated Changes  Median of 3-6 kg gain over 9-12 months ADT 1,2  Decrease in lean body mass, 2-3% 1,3,4  Decrease in muscle strength 5  Increase in total body fat, 10-20% 1,3,4  Changes occur early (<18 mo) and do not continue 4  Difficult to loose weight even if ADT stopped 2 1. Smith MR J Clin Endocrinol Metab 2002 2. Higano CS Urology 1996 3. Berruti A J Urology 2002 4. Lee Cancer 2005 5. Segal J Clin Oncol 2004

23. 23 Preventive Approach  Early consultation with nutritionist – Discuss healthy diet to maintain or lose weight – Snacking strategies – Recommend daily calcium and vit D intake  Physical therapist or licensed trainer – Aerobic exercise routines – Resistance exercises

24. 24 Benefits of Resistance Exercise Non-cancer setting  Increases lean body mass, reduces body fat 1,2 – Muscles burn more calories than fat – Maintain or lose weight  Lowers resting blood pressure 1  Improves glycemic control in diabetics 2  Increases HDL (good cholesterol) 3  Improves physical endurance and aerobic capacity 4 1. Kelley Circulation 2000 2. Casteneda Diabetes Care 2002 3. Hurley Med Sci Sports Exer 1988 4. Vincent Arch Int Med 2002

25. 25 What you see: Hair Changes  Thinning or loss of body hair – Unexpected – Distressing  Beard softer  Educate the patient  Reversible

26. 26 What you don’t see: Loss of Bone Mineral Density  A significant proportion of men with PCa have low BMD before ADT 1  Many prostate cancer patients have low vit D levels  Men tend to have a low dietary intake of calcium  BMD loss occurs at greater rate than seen in women 2, 3  Risk of fracture is increased 4, 5  Unlike weight gain, BMD loss continues over time 6 1. Smith MJ Cancer 2001 2. Higano Urology 2004 3. Smith MR NEJM 2001 4. Shahinian NEJM 2005 5. Smith J Clin Oncol 2005 6. Lee Cancer 2005

27. 27 BMD Evaluation and Treatment  Monitor DEXA or Q-CT scan before, during ADT 1  Treat osteoporosis – Bisphosphonate plus calcium and vit D Alendronate (Fosamax) Risedronate (Actonel)* Zoledronic acid (Zometa)* 2 – Estrogens 1. Higano Urol Clin North Amer 2004 2. Smith J Urol 2003 *not approved for treatment of male osteoporosis

28. 28 Minimize Loss of BMD  Weight bearing (resistance) exercise  Adequate calcium and vitamin D intake  Lifestyle changes – Smoking, alcohol and caffeine intake  Prophylactic therapy with zoledronic acid--not yet  Not proven to prevent fracture in setting of ADT, but…

29. 29 What you don’t see: Anemia  Incidence up to 90% 1, 2  Usually mild to moderate  Normochromic, normocytic  Does not correlate with fatigue symptoms  Responds well to erythropoietin 3,4  Reversible 1. Crawford Cancer 1990 2. Strum J Urol 1997 3. Strum Br J Urol 1997 4. Beshara Prostate 1997

30. 30 What you don’t see: ADT Induces Insulin Resistance-Like Syndrome  Hyperlipidemia 1, 2  Glucose intolerance 3, 4, 5  Hypertension 3, 4  Increased cardiovascular risk 3, 4, 6 1. Arrer J Clin Endocrin Metab 1996 2. Smith MR J Clin Endocrin Metab 2002 3.Higano Urology 1996 4. Inaba Metabolism 2005 5. Basaira Cancer 2006 6. Keating J Clin Oncol 2006

31. 31 Diabetes and Cardiovascular Disease During ADT: Observational Study of 73,196 Men Keating, J Clin Oncol 2006.

32. 32 ADT Effects on Cardiovascular Risk Factors  Alteration in lipids 1  Increase in body weight 1  Increase in BMI 1  Increase in body fat, decrease in lean body mass 1,2  Increase in fasting insulin levels 3  Increase in hemoglobin A1C 3  Decrease in arterial compliance 4  Prolongation of QT interval 5 1 Smith M, J Clin Endocrinol Metab 2002. 2 Lee H, Cancer. 2005. 3 Smith M, J Clin Endocrinol Metab. 2006. 4 Dockery F, Clin Sci (London). 2003. 5 Keating N, J Clin Oncol. 2006.

33. 33 Recommendations  Monitor – Serum glucose – Lipids – Blood pressure – Weight  Exercise  Diet  Treat hyperlipidemia, hypertension, diabetes

34. 34 What you feel: Fatigue, Lack of Energy or Initiative  Probably underestimated  “Severe” fatigue in 14% after 3 months ADT 1  Appears to be independent of psychological issues or anemia 2 1. Stone P Eur J Cancer 2000 2. Choo R Can J Urol 2005

35. 35 Baseline versus 12 weeks ADT ExerciseControlP-value FACT-Fatigue0.8-2.20.002 FACT-P2.0-3.30.001 Muscle Fitness Upper body13.1-2.60.009 Lower body11.8-1.6<0.001 Segal J Clin Oncol 2004

36. 36 What you feel: Depression  Major depressive disorders seen in 13% of men on ADT 1 – 8 times higher than general male population – Prior history of depression is a risk factor  Men may not exhibit depression in the usual manner  Oncologists are bad at recognizing depression 2 1. Pirl Psycho-Oncology 2002. 2. Passik J Clin Oncol 1998

37. 37 Managing emotional side effects  Assess for pre-existing depression history  Treat or refer for anti-depressant therapy  Use of Provigil as an adjunct to anti-depressant therapy to help treat fatigue 1  Exercise 1. Fava J Clin Psychiat 2005

38. 38 What you feel: Cognitive Function  Anecdotal evidence  Prospective trials, 9-12 months ADT suggest impact on – Spatial abilities 1,2,3 – No other significant group differences but individual patients deteriorated 3  Long term data lacking 1. Cherrier J Urol 2003 2. Salminen Br J Cancer 2003 3. Salminen Cancer 2005

39. 39 Patient Perspective on Changes Due to ADT “ My mental and physical vigor had deserted me…I started developing breasts and gaining weight, particularly in the backside, like a woman. My penis has shrunk; it’s dead, in fact. It’s been lost between my thighs, which have grown enormous…I find it hard to look at my body” Navon Qual Health Res 2003

40. 40 Strategies to Address Side-Effects  Lifestyle changes 1 – Diet – Exercise  Calcium and vitamin D  Monitor and treat co-morbidities  Sexual rehabilitation, couples counseling  Intermittent ADT 1. Chan Proc 2006 Prostate Cancer Symposium abstract #20

41. 41 Conclusions  ADT can cause significant physical, emotional and cognitive changes  Consider co-morbidities of patient in light of many potential complications  Patients must be educated as to what to expect  Counseling patients on proactive strategies – Minimize side-effects – Give patients a greater sense of control – Modulate disease progression?

42. 42 Multidisciplinary effort  Urologist, medical oncologist, radiation oncologist  Internist  Dietician  Physical therapist, trainer  Nurses  Social worker  Psychologist, psychiatrist  Sex therapist

43. 43 Evidence for IRS after 12 months ADT Basaria Cancer 2006

44. 44 Metabolic Factors Percent Change from Baseline After ADT InvestigatorNADT Duration ADT, wksWeightBMI Fat Mass Lean Mass Fasting InsulinHbA1C Fasting Glucose Smith J 1 (2001) 22M120-8-2.663.5-0 Smith M 2 (2002) 40M482.4 9.4---- Dockery 3 (2003) 16M12-0--64-0 Smith M 4 (2004) 26M523.2-11.2-3.6--- Lee 5 (2005) 65M?52--6.6-2.0--- Yannucci 6 (2006) 1102M, C12, 24“small”---- Stat. Sig. 2 (NS) Smith M 7 (2006) 25M, C12--4.3-25.92.92 (NS) 1 Smith J, J Clin Endocrinol Metab 2001. 2 Smith M, J Clin Endocrinol Metab 2002. 3 Dockery F, Clin Sci (London) 2003. 4 Smith M, J Clin Oncol 2004. 5 Lee H, Cancer 2005. 6 Yannucci J, J Urol 2006. 7 Smith M, J Clin Endocrinol Metab 2006.

45. 45 Before ADT After ADT Smith JC, J Clin Endocrinol Metab 2001. Peripheral and Central Arterial Wave Forms Potential ADT Effects on HTN, CVD

46. 46 C, Combined GnRH analog plus antiandrogen, M, Monotherapy with GnRH analog 1 Eri L, J Urol. 1995. 2 Smith J, J Clin Endocrinol Metab. 2001. 3 Smith M, J Clin Endocrinol Metab. 2002. 4 Dockery F, Clin Sci (London). 2003. 5 Yannucci J, J Urol. 2006. 6 Smith M, J Clin Endocrinol Metab. 2006. Lipids Percent Change from Baseline after ADT InvestigatorNADT Duration, wks Total Cholesterol HDLLDLTriglycerides Eri 1 (1995)26M2410.68.2026.9 Smith J 2 (2001)22M12342-213 Smith M 3 (2002)40M48911.37.326.5 Dockery 4 (2003)16M1272000 Yannucci 5 (2006)1102M, C12, 2412-371-192-2011-75 Smith M. 5 (2006)25M, C129.49.98.723

47. 47 Role of ADT in Primary Therapy of Prostate Cancer Kawasaki and Carroll CaP SURE Database 2005 ADT

48. 48 0 10 20 30 40 50 60 70 80 DiabetesCHDMISudden Death No ADT ADT Events per 1000 person years Keating, J Clin Oncol 2006. Diabetes and Cardiovascular Disease During ADT: Observational Study of 73,196 Men