Managing the Side Effects of Androgen Deprivation Therapy Celestia (Tia) Higano, MD, FACP Professor Departments of Medicine and Urology University of Washington.

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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3

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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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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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

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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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50

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70

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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