prostate cancer - king's college hospital - 006.1 - prostate cancer.pdf · coronary heart...
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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
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