Cardiovascular effects of Androgen Deprivation Therapy

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Cardiovascular effects of Androgen Deprivation
Therapy

• Malcolm Mason

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For Consideration

• Effects of hypogonadism (other than in prostate
  cancer)
• Studies on prostate cancer patients
• Imperial College
• Cardiff University/MRC
• HOT OFF THE PRESS!!!!...........

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Or

• Why the idea was brilliant
• Why the pilot studies were worth publishing
• The story of a dogs dinner.
• Why it didnt mater after all, because the
  message is EXTREMELY IMPORTANT!!!!

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PCTCG Meta-analysis, 2002
Prostate Cancer-Specific Mortality
Non-prostate cancer mortality
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(No Transcript)
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Measuring Arterial Compliance
Augmentation Index
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Hypogonadism
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Effects of Hypogonadism

• Central obesity
• Insulin resistance
• Low levels of LDL
• High levels of HDL, Cholesterol
• High levels of triglycerides, fibrinogen,
  plasminogen activator-1

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Effects of testosterone replacement in
hypogonadal men

• Improves insulin sensitivity
• Improves central obesity
• Reduces cholesterol and LDL
• May reduce HDL as well

Shabsigh et al, Am J Cardiology, 2005 9667M-72M
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UK Studies in Prostate Cancer Patients
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Hammersmith study

• 16 men beginning LHRH for prostate cancer
• 15 controls
• Measured arterial compliance, pulse wave
  velocities
• Fasting lipids and glucose tolerance tests
• Before therapy, and 3 months after

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Hammersmith study
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Hammersmith Study
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Hammersmith study

• Significant fall in arterial compliance, and
  increase in central pulse wave velocity.
• Increase in fasting insulin, total cholestserol
  and HDL
• No change in BMI, serum glucose, LDL

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Cardiff Pilot Study

• 14 patients on STAD
• 8 patients on LTAD
• Measured arterial compliance, lipids, insulin at
  baseline, 1,3 and 6 months

J Clin Endocrinol Metab. 2000 86 4261-4267.
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Cardiff Pilot Study
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Cardiff Pilot Study
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Cardiff Pilot Study

• Reduced arterial compliance
• Increased pulse wave velocity
• Increase in fat mass, decrease in lean body mass
• Rise in fasting serum insulin
• No change in glucose or lipids
• Improvement in arterial compliance in STAD
  patients after 6 months

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Cardiff Follow-on Study
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Baseline characteristics of patients
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Results (Fasting Insulin)

• None of the four t-tests significant at 0.05 level

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Results (Fasting Glucose)

• None of the four t-tests significant at 0.05 level

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Results (Cholesterol)

• Change from baseline to month 1 significant at
  0.001 level, other t-tests not significant at
  0.05 level

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Results (HDL Cholesterol)

• Change from baseline to month 1 significant at
  0.001 level, other t-tests not significant at
  0.05 level

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Results (LDL Cholesterol)

• None of the four t-tests significant at 0.05 level

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Results (Triglycerides)

• Change from baseline to month 1 significant at
  0.05 level, other t-tests not significant at 0.05
  level

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Results (Augmentation 1)

• None of the four t-tests significant at 0.05
  level, for either of these augmentation measures

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Results (Bone Density)

• None of the four t-tests significant at 0.05
  level, for either of the bone density measures

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Conclusions of Cardiff Follow-on Study

• Inconsistent evidence of adverse effects of AD
• Cholesterol, HDL, LDL, triglycerides, fat mass
  and augmentation levels all dropped in the first
  month and regained pre-randomisation levels by
  month three.
• These changes were coincident with the use of CPA
• Further work is needed to explain this and
  determine whether it is clinically relevant

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Might we have done better to study younger
patients (e.g. age lt 55)? Should we have
screened for and selected out patients with CV
disease of any sort (e.g. hypertension)?
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And something else funny.Excess CV death
from stilboestrol seems to occur EARLY (e.g. 1st
2 months)
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From the US

• Cross-sectional study
• 18 men CaP for at least 12 months prior to study
• 17 age-matched men CaP treated with RT or RP, but
  NO ADT
• Basaria S et al, Cancer, 2006, 106581-8

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Cross-sectional study - results
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Hot off the Press

• SEER database
• 73, 196 men with loco-regional prostate cancer
• Cox regression analysis for effects of LHRH or
  orchidectomy on
• Diabetes
• Coronary heart disease
• Sudden cardiac death

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Events of the order of 3,000 to 18,000.!
Keating NL, et al, JCO 24 (27) 4448-56 20th
September 2006
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SEER Effects even with short duration of therapy
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Conclusion

• ADT is bad for you
• We need to find a way of delivering it safely

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Acknowledgements

• Howard Kynaston
• Sarah Bennett
• Theresa Morley
• Jamie Smith
• Steve Davies
• Max Parmar
• Matt Sydes
• Rachel Morgan