Prostate cancer

Metastatic disease

• 80% will die of prostate cancer

• 5 year survival only 25%• No major advances in cure since 1942

Impact of early prostate cancer from Iversen et al

0

2

4

6

8

10

12

70-80years

60-70years

50-60years

40-50years

Life Years Lost

NNT for all tumours: 19-41

PSA Isoforms etc• Free/Total PSA, Complex PSA

– Improves 2nd Bx yield– Not assessed versus PSA TZ density

• UPM-3– Urine test, high specificity for cancer– No validation for

• Prostatitis• PSAD• Race

Rebiopsy

• Suspicious focal area• Atypia / AAH• High Grade PIN• ?Atrophy

– Rebiopsy with targeted bx

• Normal, persistently raised PSA– Template Bx under GA

Early Treatment Options

Surgery

Surveillance

Radiotherapy

Racial Elements• PROstate Cancer in Ethnic SubgroupsS

– Black men in UK have RR of 3.2

– Equal in Carribean and African men– Younger age of onset

New and controversial• Radical Treatment

– Screening

– Prostatectomy techniques– Brachytherapy

– Conformal radiotherapy

• Early hormone therapy• Treatment of bone metastases• Focal Therapy

Screening• PSA screening is best model• Cut off arguable: probably 2.5ug/l• Screening reduces Ca specific mortality in all

studies reported• But NNT not agreed

Radical Treatment• Radical Prostatectomy• External Beam Radiotherapy• Brachytherapy

– Little difference in good risk at 7 years– RP ? better in longer term– RP ? better in high risk– No good RCT’s

Prostatectomy techniques• Nerve sparing• Continence Preserving• Laparoscopic/ “robotic”

Brachytherapy• Radioactive seeds under US control• Good PSA data in good risk patients at 7

years• ED higher than thought (30-70%)• Unsuitable for

– High risk– Obstruction

Conformal radiotherapy• Major advance in EBRT• Allows doses up to 77Gy• Reduced toxicity• Now IMRT

Cryotherapy• Day case general anaesthesia• Urethral warming

• Percutaneous cryoneedles• Rectal protection• Continuous monitoring

• Double freeze/thaw cycle (-40°C)

• Catheter for 1 week

Technique

Technique• Freezing controlled by TRUS and thermocouples

ED after PC Treatment• High straight after surgery & Cryo• High later after radiation• Equal 5 years after surgery or WW

• “Penile Rehabilitation”

“Penile Rehabilitation”• Benefit for injections, pumps & PDE5’s

after surgery• Now standard practice in SE Thames

Early or Late Hormone Therapy?• Definite benefits of early treatment in

breast cancer• Original VACURG data showed less

prostate cancer mortality but high CVS mortality

• All recent studies favour Early treatment

Early Treatment?AGAINST• Expense• Trials Flawed

• Side effects– Cognition– Osteoporosis

• Possibility of HRPC developing earlier

FOR� Reduce

complications

� Reduce progression� Reduce PSA

Reduce anxiety� ?? Extend Life

Chemotherapy• Mitoxantrone

– 40% reduction in PSA

– Improvement in wellbeing– Mucositis and lassitude

0

50

100

150

200

250

Mito+

Pred

Pred

Kantoff et al, JCO; 17,1999.

�Taxanes�50% reduction in PSA

�? Survival benefit

�Significant toxicity

�Possible synergy with Estracyt

�Other agents show negligible benefit over corticoids

• Osteoclast inhibitors: – may be toxic to prostate cancer cells

• Pamidronate, Clodronate, Zoledronate– Oral or IV

• Rapid relief of bone pain in 40-75%• Reduction in development of new sites• Possible reduction in bony progression

in high risk patients

Biphosphonates

Focal Therapy• Many prostate ca unilateral• Focal therapy has low side effects

– Cryotherapy

– HIFU– PDT

The Metabolic Syndrome

The Metabolic Syndrome: Constellation of CHD Risk Factors

• Abdominal obesity*• Atherogenic dyslipidemia• Elevated blood pressure

• Insulin resistance ±±±± glucose intolerance

• Prothrombotic state: increased fibrinogen, and PAI-1• Proinflammatory state: increased CRP

NCEP ATP III. Circulation. 2002;106:3143-3421.

Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G.

*Abdominal obesity: men >>>> 102 cm; women >>>> 88 cm

The Metabolic Syndrome

• Incidence is rapidly increasing in the US and other countries; related to increasing obesity

• The metabolic syndrome enhances the risk for CHD at any given LDL-cholesterol level

• Has been compared to cigarette smoking as an equal partner to premature CHD

NCEP ATP III. Circulation. 2002;106:3143-3421.

Coronary Heart Disease Mortality

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 3.77 (1.74-8.17)

Follow-up, Y

Cu

mu

lati

ve H

azar

d (

%)

Yes

No

866

288

852

279

834

234

292

100

Unadjusted Kaplan-Meier Curve

No. at Risk

Metabolic Syndrome

YesMetabolic Syndrome:

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 3.55 (1.96-6.43)

Follow-up, Y

866

288

852

279

834

234

292

100

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 2.43 (1.64-3.61)

Follow-up, Y

866

288

852

279

834

234

292

100

Cardiovascular Disease

MortalityAll Cause Mortality

Lakka H-M, et al. JAMA. 2002;288:2709-2716.

No

Increasing Obesity in the US• NHANES (1999) data on overweight and

obesity (BMI ≥≥≥≥ 25 kg/m²) reported

– 61% of adults (aged 20–74 years) are overweight or obese� 34% are overweight (BMI 25–29.9 kg/m²)

� 27% are obese (BMI ≥≥≥≥ 30 kg/m²)

National Health and Nutrition Examination Survey. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf. Accessed January 9,

2003.

Causes of The Metabolic Syndrome

• Overweight/obesity• Physical inactivity• Genetics• Closely associated with insulin resistance

− Underlying cause of diabetes− Reduced HDL-C− Elevated triglycerides− Hypertension− Abdominal obesity

NCEP ATP III. Circulation. 2002;106:3143-3421.

Diagnosis of The Metabolic Syndrome

≥≥≥≥ 110 mg/dLFasting glucose

≥≥≥≥ 130/85 mm HgBlood pressure

<<<< 50 mg/dL– Women

<<<< 40 mg/dL– Men

≥≥≥≥ 150 mg/dL

HDL cholesterol

Waist circumference

>>>> 102 cm (>>>> 40 in)

>>>> 88 cm (>>>> 35 in)

Abdominal obesity

– Men

– Women

Defining Level

3 of the following are needed for diagnosis:

NCEP ATP III did not find adequate evidence to recommend routine measurement of insulin

resistance (eg, plasma insulin), proinflammatory state, or prothrombotic state in the diagnosis of the metabolic syndrome.

NCEP ATP III. Circulation. 2002;106:3143-3421.

Triglycerides

Risk Factor

Benefit of Treating The Metabolic Syndrome:Finnish Diabetes Prevention Study

• After 4 years, risk of diabetes reduced by 58%

Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.

Intervention ControlWith Diabetes (%)

0%

5%

10%

15%

20%

25%

Treatment of The Metabolic Syndrome

• Correct insulin resistance– Weight reduction

– Increased physical activity– Drugs which decrease insulin resistance

have not been proven to reduce CHD risk

• Control diabetes mellitus, if present

NCEP ATP III. Circulation. 2002;106:3143-3421.

Andropause

Andropause: Questions• Does it exist?• If yes, physiologic or pathologic?• Does treatment help?• Harms associated with treatment?• Whom to test?• How to test?• How to treat?

Testosterone and Sexual Function• Sexual dysfunction common in men with

hypogonadism• Non-controlled studies using variety of

Testosterone formulations– Improved sexual activity/satisfaction

– Increased spontaneous erections/duration– Improved sexual performance

Darby E, Anawalt,BD. Treat Endocrinol 2005;4(5):293-309

Testosterone and Libido• Systematic review of randomized control

trials (5 trials)• pts with total testosterone < 300 ng/dl

(longest trial only 6 months)– Inconsistent but overall large improvement in

libido

• Pts with total testosterone > 300 ng/dl– No significant benefit in libido

Bhasin, S et al. J Clin Endocrinol Metab 2007; 91(6):1195-2010

Testosterone and ED• Systematic review of placebo-controlled

trials in pts with total testosterone < 300 ng/dl– Results were inconsistent

– Pooled estimate was not significant

• Pts with total testosterone > 300 ng/dl– Inconsistent results with no significant benefit

on EDBhasin, S et al. J Clin Endocrinol Metab 2007; 91(6):1195-2010

Testosterone and Bone Mineral Density

Copyright ©1999 The Endocrine Society

Snyder, P. J. et al. J Clin Endocrinol Metab 1999;84:1 966-1972

Testosterone and Bone Mineral Density

Copyright ©1999 The Endocrine Society

Snyder, P. J. et al. J Clin Endocrinol Metab 1999;84:2 647-2653

Testosterone and lean body fat

Testosterone and muscle strength

• Muscle strength (knee extension)– No improvement with treatment

– No inverse relation with pretreatment testosterone level

• Physical function – No improvement with treatment– No inverse relation with pretreatment T levels

Snyder, P. J. et al. J Clin Endocrinol Metab1999;84:2647-2653

ADAM Questionnaire

1. Do you have a decrease in libido (sex drive)?2. Do you have a lack of energy?3. Do you have a decrease in strength and/or endurance?4. Have you lost height?5. Have you noticed a decreased “enjoyment of life”?6. Are you sad and/or grumpy?7. Are your erections less strong?8. Have you noted a recent deterioration in your ability to play

sports?9. Are you falling asleep after dinner?10. Has there been a recent deterioration in your work

performance?

A positive Questionnaire result is defined as a “ye s” to questions 1 or 7 or any 3 other questions

Metabolism, Vol 9, No. 9, Sept 2000. 1239-42

Diagnostic Testing for Androgen Deficiency

• When/How to test?– Morning (before 10 am) total testosterone

level should be initial test

– Low results should be confirmed with at least 1 more morning test

Bhasin, S. et al. J Clin Endocrinol Metab 2006;91:1995

Treatment• Usually therapeutic trial of Testosterone over 3

month period

• Testosterone testing correlating with effect• Options:

– Gel or patches– Short acting injections– Depot injections