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 SymposiumInaugural Meeting
New York CityOctober 6, 2009
ARS
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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 see What you don’t see What you feel
ARS
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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 rehabilitation1
– Intimacy and communication
1. Canada Cancer 2005
Approaches to ED
“Penile rehab”
Drug therapy– Phosphodiesterase type 5 (PDE-5) inhibitors– Vasoactive agents
Vacuum erection device (VED)
Combinations
Penile prosthesis
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
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ARS
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Exercise helps!
What kind?– Aerobic– Resistance– Stretching
How to accomplish?– With help and support– Make it a part of your schedule– Start out slowly
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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
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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
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 enlargement
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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!
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Additional Slides
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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
16The History of Hormonal Therapy
for Prostate Cancer
orchiectomy
LHRH analogs
symptomatic bone mets
PSA
biochemical relapse
1940’s 1980’s 1990’s 2000’s
asymptomaticbone mets
localized PCa
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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
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
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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
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Treatment Options for Hot FlashesHormonal
Progestational agents– Megestrol acetate (Megace)1
– Depot medroxyprogesterone acetate2
– Cyproterone acetate3
Estrogens– Diethylstilbestrol (DES)4
– Estradiol patches5,6
– 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.
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Treatment Options for Hot FlashesNon-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
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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 strength5
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 stopped2
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
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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
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Benefits of Resistance ExerciseNon-cancer setting
Increases lean body mass, reduces body fat1,2
– Muscles burn more calories than fat
– Maintain or lose weight
Lowers resting blood pressure1
Improves glycemic control in diabetics2
Increases HDL (good cholesterol)3
Improves physical endurance and aerobic capacity4
1. Kelley Circulation 2000 2. Casteneda Diabetes Care 2002 3. Hurley Med Sci Sports Exer 1988 4. Vincent Arch Int Med 2002
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What you see: Hair Changes
Thinning or loss of body hair– Unexpected– Distressing
Beard softer
Educate the patient
Reversible
26What you don’t see:
Loss of Bone Mineral Density
A significant proportion of men with PCa have low BMD before ADT1
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
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BMD Evaluation and Treatment
Monitor DEXA or Q-CT scan before, during ADT1
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
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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…
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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
30What 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
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Diabetes and Cardiovascular Disease During ADT:Observational Study of 73,196 Men
1.00
1.10
1.20
1.30
1.40
1.50
Adjusted Hazard
Ratio
Diabetes CHD MI SuddenDeath
Keating, J Clin Oncol 2006.
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ADT Effects on Cardiovascular Risk Factors
Alteration in lipids1
Increase in body weight1
Increase in BMI1
Increase in body fat, decrease in lean body mass1,2
Increase in fasting insulin levels3
Increase in hemoglobin A1C3
Decrease in arterial compliance4
Prolongation of QT interval5
1Smith M, J Clin Endocrinol Metab 2002. 2Lee H, Cancer. 2005. 3Smith M, J Clin Endocrinol Metab. 2006. 4Dockery F, Clin Sci (London). 2003.5 Keating N, J Clin Oncol. 2006.
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Recommendations
Monitor
– Serum glucose
– Lipids
– Blood pressure
– Weight
Exercise
Diet
Treat hyperlipidemia, hypertension, diabetes
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What you feel:Fatigue, Lack of Energy or Initiative
Probably underestimated
“Severe” fatigue in 14% after 3 months ADT1
Appears to be independent of psychological
issues or anemia 2
1. Stone P Eur J Cancer 2000 2. Choo R Can J Urol 2005
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Baseline versus 12 weeks ADT
Exercise Control P-value
FACT-Fatigue 0.8 -2.2 0.002
FACT-P 2.0 -3.3 0.001
Muscle Fitness
Upper body 13.1 -2.6 0.009
Lower body 11.8 -1.6 <0.001
Segal J Clin Oncol 2004
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What you feel: Depression
Major depressive disorders seen in 13% of men on ADT1
– 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 depression2
1. Pirl Psycho-Oncology 2002. 2. Passik J Clin Oncol 1998
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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 fatigue1
Exercise
1. Fava J Clin Psychiat 2005
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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
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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
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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
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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?
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Multidisciplinary effort Urologist, medical oncologist, radiation oncologist
Internist
Dietician
Physical therapist, trainer
Nurses
Social worker
Psychologist, psychiatrist
Sex therapist
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Evidence for IRS after 12 months ADT
Basaria Cancer 2006
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Metabolic FactorsPercent Change from Baseline After ADT
Investigator N ADTDuration ADT, wks Weight BMI
Fat Mass
Lean Mass
Fasting Insulin HbA1C
Fasting Glucose
Smith J 1
(2001)22 M 12 0 - 8 -2.6 63.5 - 0
Smith M 2 (2002)
40 M 48 2.4 2.4 9.4 - - - -
Dockery 3 (2003)
16 M 12 - 0 - - 64 - 0
Smith M 4 (2004)
26 M 52 3.2 - 11.2 -3.6 - - -
Lee 5 (2005)
65 M? 52 - - 6.6 -2.0 - - -
Yannucci 6 (2006)
1102 M, C 12, 24 “small” - - - -Stat. Sig.
2 (NS)
Smith M 7
(2006)25 M, C 12 - - 4.3 - 25.9 2.9 2 (NS)
1Smith J, J Clin Endocrinol Metab 2001. 2Smith M, J Clin Endocrinol Metab 2002. 3Dockery F, Clin Sci (London) 2003. 4Smith M , J Clin Oncol 2004 . 5Lee H, Cancer 2005. 6Yannucci J, J Urol 2006 . 7Smith M, J Clin Endocrinol Metab 2006.
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Before ADT
After ADT
Smith JC, J Clin Endocrinol Metab 2001.
Peripheral and Central Arterial Wave Forms
Potential ADT Effects on HTN, CVD
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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.
LipidsPercent Change from Baseline after ADT
Investigator N ADTDuration,
wksTotal
CholesterolHDL LDL Triglycerides
Eri 1 (1995) 26 M 24 10.6 8.2 0 26.9
Smith J2 (2001) 22 M 12 3 42 -2 13
Smith M 3 (2002) 40 M 48 9 11.3 7.3 26.5
Dockery 4 (2003) 16 M 12 7 20 0 0
Yannucci 5 (2006) 1102 M, C 12, 24 12-37 1-19 2-20 11-75
Smith M.5 (2006) 25 M, C 12 9.4 9.9 8.7 23
47Role of ADT in Primary Therapy of
Prostate Cancer
Kawasaki and Carroll CaP SURE Database 2005
ADT
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Diabetes CHD MI SuddenDeath
No ADTADT
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Keating, J Clin Oncol 2006.
Diabetes and Cardiovascular Disease During ADT: Observational Study of 73,196 Men