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 12 10 8 6 4 2 0 70-80 years 60-70 years from Iversen et al 50-60 years Life Years Lost 40-50 years NNT for all tumours: 19-41
PSA Isoforms etc Free/Total PSA, Complex PSA Improves 2 nd 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
Freezing controlled by TRUS and thermocouples Technique
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? FOR Reduce complications Reduce progression Reduce PSA Reduce anxiety?? Extend Life AGAINST Expense Trials Flawed Side effects Cognition Osteoporosis Possibility of HRPC developing earlier
Chemotherapy Mitoxantrone 40% reduction in PSA Improvement in wellbeing Mucositis and lassitude Taxanes 50% reduction in PSA? Survival benefit Significant toxicity Possible synergy with Estracyt 250 200 150 100 50 0 Mito + Pred Pred Kantoff et al, JCO; 17,1999. Other agents show negligible benefit over corticoids
Biphosphonates 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
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 *Abdominal obesity: men > 102 cm; women > 88 cm NCEP ATP III. Circulation. 2002;106:3143-3421. Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G.
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.
Unadjusted Kaplan-Meier Curve 20 Coronary Heart Disease Mortality 20 Cardiovascular Disease Mortality 20 All Cause Mortality Cumulative Hazard (%) 15 10 5 RR (95% CI), 3.77 (1.74-8.17) 15 10 5 RR (95% CI), 3.55 (1.96-6.43) 15 10 5 RR (95% CI), 2.43 (1.64-3.61) 0 No. at Risk Metabolic Syndrome 0 2 4 6 8 10 12 Follow-up, Y 0 0 2 4 6 8 10 12 Follow-up, Y 0 0 2 4 6 8 10 12 Follow-up, Y Yes No 866 288 852 279 834 234 292 100 866 288 852 279 834 234 292 100 866 288 852 279 834 234 292 100 Metabolic Syndrome: Yes No Lakka H-M, et al. JAMA. 2002;288:2709-2716.
Increasing Obesity in the US NHANES (1999) data on overweight and obesity (BMI 25 kg/m ² ) reported 61% of adults (aged 20 74 years) are overweight or obese 34% are overweight (BMI 25 29.9 kg/m ² ) 27% are obese (BMI 30 kg/m ² ) 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 3 of the following are needed for diagnosis: Risk Factor Defining Level Abdominal obesity Waist circumference Men Women Triglycerides HDL cholesterol Men Women Blood pressure Fasting glucose > 102 cm (> 40 in) > 88 cm (> 35 in) 150 mg/dl < 40 mg/dl < 50 mg/dl 130/85 mm Hg 110 mg/dl 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.
Benefit of Treating The Metabolic Syndrome: Finnish Diabetes Prevention Study 25% After 4 years, risk of diabetes reduced by 58% 20% 15% 10% 5% 0% Intervention With Diabetes (%) Control Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.
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 ED Bhasin, S et al. J Clin Endocrinol Metab 2007; 91(6):1195-2010
Testosterone and Bone Mineral Density
Testosterone and Bone Mineral Density Snyder, P. J. et al. J Clin Endocrinol Metab 1999;84:1966-1972 Copyright 1999 The Endocrine Society
Testosterone and lean body fat Snyder, P. J. et al. J Clin Endocrinol Metab 1999;84:2647-2653 Copyright 1999 The Endocrine Society
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 Metab 1999;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 yes 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;91:199
Treatment Usually therapeutic trial of Testosterone over 3 month period Testosterone testing correlating with effect Options: Gel or patches Short acting injections Depot injections