The document discusses the long-term side effects of androgen deprivation therapy (ADT) for prostate cancer, including increased risks of osteoporosis, cardiovascular events, sarcopenic obesity, and bone loss. It provides evidence that ADT increases standard cardiovascular risk factors and cardiovascular events. While the effect on cardiovascular mortality is disputed, age and pre-existing conditions are the main risk factors. Exercise and drugs like SERMs may help mitigate side effects, but do not reduce cardiovascular events. Careful management of known risk factors is important when treating with ADT.

1. Best Supportive Care for Metastatic PCA treated by ADT Bertrand TOMBAL Cliniques universitaires Saint-Luc, Brussels, Belgium

2. Castration is the systemic treatment of choice for Advanced Prostate Cancer Charles HUGGINS 1901 – 1955 Winner of 1966 Nobel Prize Studies in prostate cancer : I. The effect of estrogens and androgen injection on serum phosphatases in metastatic carcinoma of the prostate Cancer Res., 1941 II. The effect of castration on advanced carcinoma of the prostate gland Arch. Surg., 1941

3. Skin Hair growth, balding, sebum production Liver Synthesis of serum proteins Male sexual organs Penile growth, spermatogenesis, prostate growth and function Brain Libido, Mood Muscle Increase in strength and volume Kidney Stimulation of erythropoietin production Bone marrow Stimulation of stem cells Bone Accelerated linear growth, closure of epiphyses But testosterone is also the major “male” hormone

4. Short-term side-effects… Loss of libido and sexual interest, erectile dysfunction, impotence Hot flushes Decline in intellectual capacity, emotional liability, depression Decline in physical activity and general vitality The castration syndrome

5. Cross sectional survey. N=96, SF-36 questionnaire Dacal et al., J AmGeriatr Soc 54:85–90, 2006. Impact of short-term side-effects on quality of life

6. Michael William Aucoin, Richard Joel Wassersug The sexuality and social performance of androgen-deprived (castrated) men throughout history: Implications for modern day cancer patients Social Science & Medicine 63 (2006) 3162–3173 We conclude that eunuch history contradicts the presumption that androgen deprivation necessarily leads to social and sexual impotence. The capabilities and accomplishments of eunuchs in the past gives patients on ADT grounds for viewing themselves in a positive light where they are neither socially impotent nor sexually chaste. Sexual side-effects and ADT

7. « ... perfect Don Juan in everyday life, in the salons and even in the intimacy of the bedrooms » Carlo Broschi (Farinelli) 1705- 1782 Sexual side-effects and ADT

8. Ginseng in the treatment of cancer induced fatigue. Barton DL et al., abstract 9001, ASCO 2007 282 randomized patients Placebo 69 pts 750 mg 70 pts 1 000 mg 72 pts 2 000 mg 71 pts 39 phase double aveugle évaluable 46 phase double aveugle évaluable 42 phase double aveugle évaluable 48 phase double aveugle évaluable 175 evaluable patients Eligibility : fatigue > 4 56 % chimiotherapy 18 % radiothérapy AUC 600 400 200 0 Activité Fatigue standard Placebo 750 mg 1 000 mg 2 000 mg Ginseng américain Placebo 750 mg 20 10 0 30 40 M oderate to important improvements Patients satisfied with treatment (%) 1 000 mg 2 000 mg Objective perception

9. Non hormonal treatment of Hot Flushes 0 10 20 30 40 50 60 70 -70 -60 -50 -40 -30 -20 -10 Loprinzi, fluoxetine 20 mg/j Stearns, paroxetine 10 mg/j Stearns, paroxetine 20 mg/j Stearns, paroxetine CR 12,5 mg/j Stearns, paroxetine CR 25 mg/j Paroxetine total Gordon, sertraline 50 mg/j Kimmick, sertraline 50 mg/j Grady, sertraline 100 mg/j Sertraline total Loprinzi, venlafaxine 37,5 mg/j Loprinzi, venlafaxine 75 mg/j Loprinzi, venlafaxine 150 mg/j Venlafaxine total Total antidépresseurs Études HR (fixe) IC 95 Favour antidépresseurs Favour placebo 0 20 40 60 80 100 1 2 3 4 5 6 7 10 mg/j 20 mg/j 30 mg/j Placebo weeks Pourcentage 0 20 40 60 80 100 1 2 3 4 5 6 7 weeks percentage 0 10 20 30 40 50 60 70 -70 -60 -50 -40 -30 -20 -10 Favor gabapentine F avor placebo Pandya, 300 mg/j Études HR (fixe) IC 95 Pandya, 900 mg/j Guttuso, 900 mg/j Reddy, 2 400 mg/j Total ASCO 2008: C.L. Loprinzi et al., D.L. Barton et al, abstracts 9537 and 9538 actualized Citalopram Citalopram HF frequency 10 mg/j 20 mg/j 30 mg/j Placebo Gabapentin HF intensity

10. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking GnRH analogues for prostate cancer: a double-blind, randomised trial. Irani J et al. Lancet Oncol. 11(2):147-54, 2010 309 patients randomly assigned Venlafaxine 75 mg/d Cyproterone 100 mg/d Medroxyprogesterone acetate 20 mg/d

11. Anxiety and depression One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Almeida OP et al. Psychoneuroendocrinology. 2004 29(8):1071-81. testosterone ß-amyloid

12. Hemoglobin decrease and Anemia Immediate Versus Deferred Hormonal Treatment for Patients With Prostate Cancer Who Are Not Suitable for Curative Local Treatment: Results of the Randomized Trial SAKK 08/88 Studer et al, J Clin Oncol. 2004, 22 (20), 4109-18

13. Bone loss Sarcopenic obesity Long-term side-effects of ADT

14. Long-term side-effects of ADT Conditions Risk factors osteoporosis CV events Side-effects CV death F racture (SREs) Complications Bone loss Sarcopenic obesity

15. Sarcopenic obesity and ADT Prospective 12-wk study, 25 men with locally advanced or recurrent prostate cancer, LHRH agonists. Smith et al. J Clin Endocrinol Metab, 91(4):1305–1308, 2006

16. Sarcopenic obesity and ADT Prospective 12-wk study, 25 men with locally advanced or recurrent prostate cancer, LHRH agonists. Smith et al. J Clin Endocrinol Metab, 91(4):1305–1308, 2006

17. Observational study on 73196 Medicare enrollees age 66 years or older.P value for each < 0,001 Smith et al. J Clin Oncol 24:4448-4456. 2006 ADT and cardiovascular events

18. Cohort based study of 22,816 men with newly diagnosed PCa men Newly diagnosed prostate cancer patients who received ADT for at least 1 year were found to have a 20% higher risk of serious cardiovascular morbidity compared with similar men who did not receive ADT. Kaplan-Meier estimate of probability of cardiovascular events over time. Saigal et al. Cancer 2007;110:1493–500. ADT and cardiovascular events

19. Observational study of 37443 from 01/2001 to 12/2005 39% treated with ADT. Keating N et al. J Natl Cancer Inst 2010;102: 39 – 46 ADT and cardiovascular events

20. ADT and cardiovascular death RTOG 85-31 (RT + goserelin vs. RT alone). 945 men / 117 CV deaths treatment-related increase in cardiovascular mortality. At 9 years, CV mortality for men receiving adjuvant goserelin was 8.4% v 11.4% for men treated without adjuvant goserelin (Gray’s P .17). Efstathiou,J et al. Clin Oncol 27:92-99. 2008

21. ADT and cardiovascular risk. Summary Proven impact on standard CV risk factor Proven impact on CV events Disputable effect of CV death Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Levine et al. Circulation 2010;121;833-840;

22. ADT and cardiovascular risk. Summary Proven impact on standard CV risk factor Proven impact on CV events Disputable effect of CV death Age and cardiovascular co-morbordities are the most important risk factors ADT duration is a marginal effect, 6 months is enough to increase the risk

23. D’Amico et al. J Clin Oncol,2007, 25:2420-2425. ADT and cardiovascular death 1,372 men who were enrolled onto 3 RCTs between February 1995 and June 2001. Randomly assigned to receive radiation therapy with 0 versus 3 versus 6, 3 versus 8, or 0 versus 6 months of AST.

24. Nanda et al. JAMA. 2009;302(8):866-873 ADT and cardiovascular death

25. Long-term side-effects of ADT Conditions Risk factors How can we combat this? osteoporosis CV events Side-effects CV death F racture (SREs) Complications Bone loss Sarcopenic obesity

26. Randomized Controlled Trial of Resistance or Aerobic Exercise in Men Receiving Radiation Therapy for PCa Median adherence to prescribed exercise was 85.5%. Resistance (p.010) and aerobic exercise (p.004) mitigated. Resistance training improved QOL (p.015), aerobic fitness (p.041), upper- (p.001) and lower-body (p.001) strength, and triglycerides (p.036), while preventing an increase in body fat (p.049).

27. Randomized Controlled Trial of Resistance or Aerobic Exercise in Men Receiving Radiation Therapy for PCa Segal et al. J Clin Oncol. 20;27(3):344-51. 2009

28. Small estrogen receptor modulators (SERMS) are the next generation of drug to reduce side-effects of ADT

29. Toremifene Improves Lipid Profiles in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer: Interim Analysis of a Multicenter Phase III Study MR.Smith, et al. J ClinOncol 26:1824-1829. 2008 188/1389 men receiving ADT for prostate cancer randomly assigned to receive toremifene (80 mg/d) or placebo.

30. ADT and cardiovascular risk. Summary Proven impact on standard CV risk factor Proven impact on CV events Disputable effect of CV death Age and cardiovascular co-morbordities are the most important risk factors ADT duration is a marginal effect, 6 months is enough to increase the risk Primary control of known risk factors Supervised resistance training exercise SERMs No proven benefit on reducing CV events

31. Bone loss Sarcopenic obesity Long-term side-effects of ADT

32. Long-term side-effects of ADT Conditions Risk factors osteoporosis CV events Side-effects CV death F racture (SREs) Complications Bone loss Sarcopenic obesity

33. ADT is associated with rapid and clinically significant bone loss 0.5 1.0 2.0 2.6 4.6 7.4 7.7 0 2 4 6 8 10 Bone loss at 1 year (%) AI Therapy in postmenopausal women 2 ADT 3 AI Therapy + GnRH agonist in premenopausal women 4 Menopausal women <55 yrs 1 Postmenopausal women >55 yrs 1 Premature menopause secondary to chemotherapy 5 Naturally-occurring bone loss Cancer treatment induced bone loss Normal men 1 1. Higano. Nat Clin Pract Urol 2008;5:24–34; 2. Eastell et al. J Bone Miner Res 2006;21:1215–23; 3. Maillefert et al. J Urol 1999;161:1219–22; 4. Gnant et al. Lancet Oncol 2008;9:840–9; 5. Shapiro et al. J Clin Oncol 2001;19:3306–11.

34. Bone Turnover Increases During ADT ADT, androgen-deprivation therapy. Adapted from Mittan D, et al. J Clin Endocrinol Metab. 2002;87(8):3656-3661. Urine N-telopeptide (NTX) Bone-specific alkaline phosphatase (BALP) 6 months 12 months 6 months 12 months P < .05 P < .05 Control (n = 13) Prostate cancer patients on gonadotropin-releasing hormone (GnRH) agonist (n = 15)

35. 71 year old, metastatic prostate cancer, 3 years of ADT, excruciating back pain with a normal PSA + 3 yrs ADT

36. ADT Significantly Increases Fracture Risks Increased risk Hip fracture Relative risk Decreasing risk Increasing risk 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 1.76 1.21 Any fracture 76% 21% 1.18 18% Vertebral fracture 2.2 2.4 ADT, androgen-deprivation therapy; GnRH, gonadotropin-releasing hormone. Smith M, et al. J Urol . 2006;175:136-139. 3,779 patients treated with GnRH agonist 8,341 patients with no GnRH agonist

37. Cancer treatment induced bone loss Summary ADT induces rapid changes in bone remodelling Osteoporosis is frequent Fragility fractures are rare 5-10% maximum.

38. Fracture Risk Increases With Duration of ADT Shahinian VB, et al. N Engl J Med. 2005;352(2):154-164 Longitudinal study of 50,613 patients with PC from 1992-1997

39. Cancer treatment induced bone loss Summary ADT induces rapid changes in bone remodelling Osteoporosis is frequent Fragility fractures are rare 5-10% maximum. Pre-existing low BMD Endocrine disease, corticoids, alcohol,… ADT duration

40. Bisphosphonates in the prevention of ADT induced bone-loss Zoledronate 4mg once 1 year Zoledronate 4mg q.3mths 1 year Michaelson et al., JCO 15, 1038-42, 2007 Smith et al. , J.Urol 169, 2008-12,2003

41. Denosumab in men receiving ADT for prostate cancer Supplemental calcium and vitamin D Baseline 36 months R A N D O M I S E Men with non metastatic prostate cancer receiving continuous ADT (n=1468) Stratified by Age (<70 years vs  70 years) Prior ADT duration (  6 months vs >6 months) Denosumab 60 mg SC Q6M (  6 doses) (n=734) Placebo SC Q6M (  6 doses) (n=734) Smith, et al. N Engl J Med 2009;361:745–55. Study Endpoints Primary Percentage change from baseline at month 24 in lumbar spine BMD Secondary Incidence of new vertebral fractures over 36 months Fracture at any site (morphometric/clinical vertebral or nonvertebral) Time to first clinical fracture Percentage change from baseline at 24 and 36 months in BMD at: lumbar spine (36 months only), total hip and femoral neck Safety events

42. Denosumab significantly reduces incidence of new vertebral fractures compared with placebo 0 2 4 6 P=0.004 P=0.004 P=0.006 Incidence Percentage of subjects Relative risk Denosumab (n=679) Placebo (n=673) Month 12 Month 24 Month 36 − 85% − 69% − 62% 13 2 22 7 26 10 1.9% 0.3% 3.3% 1.0% 3.9% 1.5% 8 Smith, et al. N Engl J Med 2009;361:745–55.

43. Clinical Risk stratification Who needs treatment ? EAU guidelines: Based on DEXA scan, to be done at initiation Treat osteoporosis NCCN Guidelines Use FRAX (secondary osteoporosis): treat if 10 yrs. risk of Hip fracture is > 3% or > 10% of osteoporotic fracture EAU guidelines 2010, Available online at http://www.uroweb.org NCCN practice guidelines v.3.2010, available online at http://www.nccn.org

44. Clinical Risk stratification Confirmed on X-Rays ADT or other risk fracture DEXA Hip Radius Lumbar Spine T-score <-2.5 (osteoporosis) T-score -1.0 to -2.5 (osteopenia) T-score > -1.0 Treatment Repeat DEXA after 1 year Repeat DEXA after 2 year Modified from Diamonds et al., Cancer 2004, 100, 892-899 Calcium Vitamine D supplements Any fracture after minimal trauma Suspected vertebral fracture

45. Clinical Risk stratification Kanis et al, Osteoporos Int (2008) 19:385–397 Ebeling P N Engl J Med 2008;358:1474-82.

46. The importance of supporting patients through ADT

47. Which side effects are reported to the patient? What level of information do we provide to patients? Telephone interviews: 40 urologists and 10 radiation oncologists 24% academic centre, 20% with academic affiliation, 56% private institutions Hot flushes 96% Loss of libido and erectile dysfunction 58% Fatigue, loss of vitality, asthenia 35% Osteoporosis 31% Weight gain 21% Gynaecomastia / feminization 19% Muscular weakness and atrophy 10% Emotional concerns, bad mood, depressions 6%

48. What proportion of doctors provide recommendations for the management of side effects? What level of information do we provide to patients? Telephone interviews: 40 urologists and 10 radiation oncologists 24% academic centre, 20% with academic affiliation, 56% private institutions Hot flushes 96% 48% Loss of libido and erectile dysfunction 58% 32% Fatigue, loss of vitality, asthenia 35% 29% Osteoporosis 31% 67% Weight gain 21% 55% Gynaecomastia / feminization 19% 56% Muscular weakness and atrophy 10% 80% Emotional concerns, bad mood, depressions 6% 67%

52. Four steps to improve Talk about the disease

53. 263 prostate cancer patients and spouses randomized to either standard care or standard care plus a 5-session family intervention The intervention targeted couples’ communication, hopes, coping, uncertainty, and symptom management At 4-month follow-up, intervention patients reported less uncertainty and better communication with spouses Intervention spouses reported higher quality of life, more self-efficacy, better communication, and less negative appraisal of caregiving Randomized clinical trial of a family intervention for prostate cancer patients and their spouses Northouse et al. Cancer 2007;110: 2809–18

54. Four steps to improve Talk about the disease Pro-actively managed side effects

55. We conclude that eunuch history contradicts the presumption that androgen deprivation necessarily leads to social and sexual impotence The capabilities and accomplishments of eunuchs in the past gives patients on ADT grounds for viewing themselves in a positive light where they are neither socially impotent nor sexually chaste The sexuality and social performance of androgen-deprived (castrated) men throughout history: Implications for modern day cancer patients Aucoin & Wassesug, Soc Sci Med 2006; 63: 3162–73

56. Four steps to improve Talk about the disease Pro-actively managed side effects Eat healthily Move your body

57. Randomized Controlled Trial of Resistance or Aerobic Exercise in Men Receiving RT for prostate cancer Median adherence to prescribed exercise was 85.5% Resistance (p=0.010) and aerobic exercise (p=0.004) mitigated Resistance training improved QoL (p=0.015), aerobic fitness (p=0.041), upper- (p=0.001) and lower-body (p=0.001) strength, and triglycerides (p=0.036), while preventing an increase in body fat (p=0.049) Segal et al. J Clin Oncol 2009; 27: 344 – 51

58. Segal et al. J Clin Oncol 2009; 27: 344 – 51 Randomized Controlled Trial of Resistance or Aerobic Exercise in Men Receiving RT for prostate cancer

60. Distribution of a tool kit to patients Component Description Information brochure Explains the effects of ADT on the body and ways of lessening treatment-related side effects Practical guidance Everyday dietary advice (extracted from the information brochure), physical exercises (walking, aerobic and resistance exercises) to be pursued or started, in order to adopt a new lifestyle Lifestyle diary Instrument to evaluate progress: diet, walking times, number of exercises, indicators (hot flashes, waist circumference, weight) Recipe booklet Principles of an ADT-adapted diet, advice on preparing and cooking food, suitable tasty recipes Educational tool-kit on diet and exercise: Survey of prostate cancer patients about to receive androgen deprivation therapy Lebret, Coloby, Descotes, Droupy, Geraud & Tombal. Urology, in press

61. Completely agree More or less agree Do not really agree Totally disagree No response I have a healthier diet 30 51 8 2 9 I feel an active participant in the fight against disease 30 51 10 0 9 I feel in better physical shape 18 58 13 3 8 I feel in better mental health 20 54 13 3 10 I sleep better 15 46 24 6 9 Educational tool-kit on diet and exercise: Survey of prostate cancer patients about to receive androgen deprivation therapy Lebret, Coloby, Descotes, Droupy, Geraud & Tombal. Urology, in press

62. Conclusion “ The whole is more than the sum of its parts” Aristotle, 384 – 322 BC “Metaphysics” Treat the patient, not only the disease…. The three steps for a holistic approach of ADT Improve the compliance to guidelines and prescribe hormonal therapy only to those patients who need it Promote alternative strategies to reduce side effects Implement counselling programme for patients so that they (try to) minimize the metabolic impact of hormonal therapy