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

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

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

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

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

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

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.

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

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

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

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.

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

52. Four steps to improve Talk about the disease

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

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

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