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NY Prostate Cancer Conference - M.R. Smith - Session 7: Predicting toxicity after androgen deprivation: cardiovascular events
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NY Prostate Cancer Conference - M.R. Smith - Session 7: Predicting toxicity after androgen deprivation: cardiovascular events

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  • The primary efficacy endpoint was the difference between zoledronic acid and placebo in the mean change from baseline in bone mineral density (BMD of the lumbar spine at one year, shown as the All intent-to-treat (ITT) group. Men treated with zoledronic acid had an increase of more than 5% in LS-BMD, compared with a decrease in the placebo group (p<0.001) Also shown are results for the subgroups of patients who took only an LHRH agonist (LHRH), or who took both an LHRH agonist and an antiandrogen (LHRH/AA). Regardless of which type of ADT was given, treatment with zoledronic acid resulted in an increase in BMD while placebo patients experienced a decrease in BMD of the spine. Interestingly, patients receiving both LHRH and an antiandrogen had a greater increase with zoledronic acid and a greater decrease on placebo. Differences in both subgroups were significant at the p<0.001 level.
  • Consistent with these adverse METABOLIC effects, ADT is associated with greater risk for diabetes and cardiovascular disease. In a large population-based study from OUR group, ADT was associated with greater risk for new diabetes mellitus, coronary heart disease, and myocardial infarction. Notably, theses increased risks are apparent with short-term treatment and persist with longer-term therapy.
  • Consistent with these adverse METABOLIC effects, ADT is associated with greater risk for diabetes and cardiovascular disease. In a large population-based study from OUR group, ADT was associated with greater risk for new diabetes mellitus, coronary heart disease, and myocardial infarction. Notably, theses increased risks are apparent with short-term treatment and persist with longer-term therapy.
  • Consistent with these adverse METABOLIC effects, ADT is associated with greater risk for diabetes and cardiovascular disease. In a large population-based study from OUR group, ADT was associated with greater risk for new diabetes mellitus, coronary heart disease, and myocardial infarction. Notably, theses increased risks are apparent with short-term treatment and persist with longer-term therapy.
  • Consistent with these adverse METABOLIC effects, ADT is associated with greater risk for diabetes and cardiovascular disease. In a large population-based study from OUR group, ADT was associated with greater risk for new diabetes mellitus, coronary heart disease, and myocardial infarction. Notably, theses increased risks are apparent with short-term treatment and persist with longer-term therapy.
  • Consistent with these adverse METABOLIC effects, ADT is associated with greater risk for diabetes and cardiovascular disease. In a large population-based study from OUR group, ADT was associated with greater risk for new diabetes mellitus, coronary heart disease, and myocardial infarction. Notably, theses increased risks are apparent with short-term treatment and persist with longer-term therapy.
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    • 1. Predicting Toxicity after Androgen Deprivation: Cardiovascular Events Matthew R. Smith, M.D., Ph.D. Professor of Medicine Harvard Medical School Director, Genitourinary Oncology Program Massachusetts General Hospital
    • 2. May 3, 2010 US Food and Drug Administration announces investigation into link between androgen deprivation therapy for and risk for diabetes and heart disease in men with prostate cancer
    • 3. What are the putative mechanism(s) for treatment-related diabetes and CVD?
    • 4. GnRH Agonists Decrease Muscle Mass and Increase Fat Mass Weight Muscle Mass Fat Mass Smith MR et al (2002) J Clin Endocrinol Metab 87:599-603 12-month changes P<0.001 for each comparison
    • 5. Abdominal Obesity and Sarcopenia during ADT Eugonadal young man Older man on ADT Smith MR et al (2002) J Clin Endocrinol Metab 87:599-603 Saylor PJ and Smith MR et al (2009) J Urol Figure 2: GnRH agonist-associated sarcopenic obesity. GnRH agonists increase abdominal cross sectional area primarily through the accumulation of subcutaneous fat. Cross sectional images of a young healthy man (A) and of an obese man receiving long term GnRH agonist therapy (B). Note the relative paucity of abdominal and paraspinal musculature and the accumulation of subcutaneous fat. (A) (B)
    • 6. Smith MR et al (2006) J Clin Endocrinol Metab 91:1305-8 Shift in insulin response c/w insulin resistance Insulin Sensitivity During GnRH Agonist Therapy
    • 7. GnRH Agonists Increase Serum Lipids Smith et al (2002) J Clin Endocrinol Metab 87(2): 599-603
    • 8. Risk for Coronary Heart Disease by Triglyceride, HDL Cholesterol, and LDL Cholesterol Levels Emerging Risk Factors Collaboration (2009) JAMA 302:1993-2000 Triglycerides LDL Cholesterol HDL Cholesterol
    • 9. GnRH Agonists and C-Reactive Protein Smith et al (2008) Cancer 112: 2118 P=0.75
    • 10. Metabolic Effects of ADT and Predicted CVD Risk Decreased Risk No effect Increased Risk ↑ HDL cholesterol -> Blood pressure ↑ LDL cholesterol -> CRP ↓ Insulin sensitivity
    • 11. Unadjusted Rates for Diabetes, CHD, and MI SEER-Medicare Analyses Unadjusted incidence Events/1,000 patient-years Keating, O’Malley, and Smith (2006) J Clin Oncol 24(27): 4448-56
    • 12. Strength and Consistency of Association SEER-Medicare Analyses 0.5 1.0 2.0 0.5 1.0 2.0 Diabetes Adjusted HR, 95% CI GnRH agonist Orchiectomy ADT Better ADT Worse ADT Better ADT Worse MI Adjusted HR, 95% CI Keating, O’Malley, and Smith (2006) J Clin Oncol 24(27): 4448-56 P=0.03 P=0.44 P<0.001 P=0.005
    • 13. Dose-Response Relationship SEER-Medicare – Outcomes by Treatment Duration 0.5 1.0 2.0 0.5 1.0 2.0 Diabetes Adjusted HR, 95% CI GnRH agonist duration 1-4 months ADT Better ADT Worse ADT Better ADT Worse MI Adjusted HR, 95% CI 5-12 months 13-24 months ≥ 25 months P<0.001 P<0.001 P<0.001 P<0.001 P=0.19 P=0.21 P=0.42 P=0.24 Keating, O’Malley, and Smith (2006) J Clin Oncol 24(27): 4448-56
    • 14. References: Keating et al (2006) JCO; Alibhai et al (2009) JCO; Keating et al (2010) JNCI Consistency of Association Comparison of Large Population-Based Studies 0.5 1.0 2.0 0.5 1.0 2.0 Diabetes Adjusted HR, 95% CI SEER-Medicare (n= 73,196) Ontario registry (n= 39,418) Veterans Administration (n= 37,433) ADT Better ADT Worse ADT Better ADT Worse MI Adjusted HR, 95% CI 3917 events 4967 events 2573 events 7055 events 2034 events 847 events
    • 15. Ontario Registry – Multivariate Analyses Alibhai et al. J Clin Oncol 2009
    • 16. RTOG 85-31 Cardiovascular Mortality Efstathiou et al J Clin Oncol 2009
    • 17. RTOG 85-31 – Univariate Analyses Efstathiou et al. J Clin Oncol 2009
    • 18. Conclusions
        • Unclear whether relationship between ADT and CVD is causal or casual
        • Metabolic effects of ADT have mixed effects on predicted CVD risk
        • Association between ADT and CVD is not consistent across different studies and forms of ADT
        • Traditional CVD risk factors are associated with CVD events during ADT

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