Prostate Cancer >95% adenocarcinoma Commonest male cancer in most Western countries First three commonest cancer death in many Western countries Latent cancer postmortem study of death after age of 50 in Western World found small volume and well differentiated cancer inside prostate in 30 – 40 % (15 – 20 % found in Eastern World) Clinical cancer West50 – 100 / 100,000 East10 – 20 / 100,000

Incidence & Mortality of Prostate Cancers

Life Time Probability of Prostate Cancer (USA) Scardino Urol Clin N Am %autopsy cancers 9.5%prostate cancers diagnosed 2.9%died of prostate cancer

Incidence of Latent Cancers Breslow Int J Cancer1977 Hong Kong15.8% Singapore13.2% Isreal22% Germany28.4% Sweden31.6% most were small in volume and well-differentiated Yatani Int J Cancer 1982 Japanese in Japan20.5% Japanese in Hawaii25.6% Colombians31.5% US Whites34.6% US Blacks36.9%

Aetiology Ageincidence increases with age Family History2-7x higher RaceBlack > White > Asian Dietfat, phyto-oestrogens Hormonesmale hormones Vasectomy1.2-2x higher Miscellaneouscadmium, Vit A, Vit D Chromosomal & genetic abnormalities

Phyto-oestrogens soya beans, peas weak oestrogenic effects Prostate 1997 Hong KongPortugalBritain enterolactone(ng/ml) prostatic fluid plasma daidzein(ng/ml) prostatic fluid plasma

Presentations Rarely cause symptoms until advanced Obstruction - slow stream, hesistancy, interrupted stream Irritation - frequency, nocturia, urgency Incidental finding from TURP for BPH Bone pain Anaemia Haematuria Renal impairment

PSA glycoprotein, liquefaction of semen in serum - free, bound to ACT, bound to alpha2-M normal serum value up to 4ng/ml 25% BPH > 4 20% significant cancer < 4 problems of sensitivity and specificity specific for prostate diseases, not cancer only controversial about the use in screening useful in monitoring the progress of the cancer

PSA & Cancer Detection

PSA PSA density0.15ng/ml/gm PSA velocity ng/ml or, <20% increase Free : total PSA< PSA age specific range No single method is more accurate Mettlon Cancer 1994 Woolf New Engl J Med 1995

PSA Screening to check PSA on asymptomatic normal people Early detection to check PSA on patients with LUTS age 50 to 70 (age 40 if strong familial history up to 75 if good medical health)

Cancer Detection DRE before PSA era >50% cancers picked up were advanced 25% cancers were organ confined asymmetry firmness / hardness nodules about 50% have cancers

Cancer Detection PSA after PSA era 65-75% cancers picked up were organ confined Catalona J Urol 1994 PSA < 41 cancer in 50 patients PSA > 41 cancer in 3 patients must do DRE, 25% cancers with PSA < 4 DRE alone missed 45% cancers

TRUS Prostate cancers echogenicity Shinohara J Urol % hypoechoeic 39% isoechoeic 1% hyperechoeic (15-50% hypoechoeic lesions have cancers)

TRUS in Cancer Detection McNeal Am J Surg Path radical prostatectomy 68% peripheral zone 24% transitional zone 8% central zone TRUS + sextant biopsy bilateral - upper, middle, lower transitional zone, seminal vesicles, hypoechoeic nodules

Cancer Screening DRE, PSA, TRUS biopsies/cancer detectedcancer detection rate North America/ North Europe3-53-5% Mediteranian6-81-3% Japan6--- Hong Kong6---

Staging of Prostate Cancer TNM 1997 T1nonpalpable tumour(Whitmore-Jewett) T1a<5% of prostate chips involvementA1 T1b>5% of prostate chips involvementA2 T1cpicked up by needle biopsies for elevation of PSAB0 T2tumour confined to prostate T2aone lobe or lessB1 T2bmore than one lobeB2 T3tumour beyond prostate T3aunilateral capsular involvementC1 T3bbilateral capsular involvementC1 T3cseminal vesicle involvementC1 T4involved adjacent structures T4abladder neck, external sphincter, rectumC2 T4blevator muscles, pelvic side wallC2 N+lymph nodes involvementD1 M+distant organs involvementD2

Grading of Prostate Cancer European well differentiated moderately well differentiated poorly differentiated American Gleason score (From 2 to 10) combination of 2 Gleason grades ( from 1 to 5) 1) commonest type 2) second commonest or worst differentiated

Staging Tests for Prostate Cancer DRE, PSA, TRUS (Prostatic acid phosphatase replaced by PSA) Chest X-ray Bone scan Computerised tomography of abdomen and pelvis Magnetic Resonance Imaging of prostate Staging lymphadenectomy

Controversies Screening of prostate cancers yes / no Treatment of localised cancers surveillance / hormonal / radiotherapy / radical prostatectomy Hormonal therapy for locally advanced / disseminated cancers early / delayed / intermittent monotherapy / maximal androgen blockade

Should Prostate Cancers Be Screened American Urological Association American Cancer Society advised DRE & PSA to screen prostate cancers US Preventive Health Task Force Canadian Task Force no screening yet because in the absence of proof of early detection reduces cancer mortality

Should Prostate Cancers Be Screened Stewart-Brown BMJ 1997 screening could seriously damage your health morbidities of screening tests psychological disturbances complications of radical treatment

Complications of Radical Treatment Woolf New Engl J Med 1995 Radical prostatectomy impotence20-85% incontinence1-27% urethral stricture10-18% rectal injury1-3% thromboembolism2-30% death0.3-2% Radiotherapy acute GI/GU Cx3-67% chronic Cx requiring surgery or prolonged hospitalisation1-2% anorectal Cx2-23% impotence 40-67% urethral/bladder Cx3-17% incontinence1-3% death %

Should Prostate Cancers Be Screened Cost & morbidities Latent Cancers Effective treatment for cancers Rapid rise of prostate cancers in USA 86,000 (1985) to 244,000 (1995) >150,000 radical prostatectomy done in 1996 commonest Urological operations in USA

Treatment of Early Prostate Cancer Surveillance Radical prostatectomy 10 years or more life expectancy for better benefits Radical radiotherapy external RT, brachytherapy Cryotherapy (Hormonal therapy not curative) (No effective chemotherapy)

Surveillance for Localised Prostate Cancers Chodak New Engl J Med 1994 grade 1grade 2grade 3 n=492n=265n=62 10 years10 years10 years dx specific survival death from cancers death from other causes censored still at risk metastases free survival metastases death from other causes censored still at risk93376

Localised Prostate Cancer Surveillance small number of patients died of cancer elderly patients not randomised No randomised studies to compare surgery to radiotherapy 25 – 35% of patients had cancer detected in prostate biopsies after radiotherapy Cryotherapy new treatment and no long term results

Treatment of Advanced / Metastatic Cancer Hormonal therapy main treatment Huggins was awarded the Nobel Prize in 1966 for his work in the treatment of prostate cancer with hormonal therapy (thought even curative in those days) Chemotherapy with limited use Radiotherapy for palliation

Hormonal Therapy 70-80% response rates Not curative become hormonal independent in months 1) orchidectomy 2) oestrogens 3) LHRH agonists (medical castration) 4) anti-androgens (steroidal, non-steroidal) *** similar efficacy *** Peeling Urol 1989 Catalona New Engl J Med 1994

Early / Delayed Hormonal Treatment 1950’s immediate treatment VACURG Surg Gyn Obst patients with stage C & D cancers placebo 5 mg DES orchidectomy orchidectomy + 5 mg DES delayed treatment did not compromise overall survival

Early / Delayed Hormonal Therapy VACURG Cancer stage C / D prostate cancers cancer deathCV deathtotal death placebo n= DES n= orchidectomy n= orchidectomy + DES n=

Early / Delayed Hormonal Therapy MRC Study Br J Urol 1997 immediatedeferred n=469n=465 all death p<0.01 death from cancer p<0.001 pathological #1121NS cord compression9232p<0.025 ureteric obstruction33552p<0.025 yearly follow up 29 patients did not have hormone up to death many patients had no bone scan

Early / Delayed Hormonal Therapy Complications of prolonged androgen deprivation osteoporosis and fracture anaemia muscle wasting potency Biochemical progression elevated PSA could be years ahead of imaging in picking up cancer recurrence much longer hormonal treatment

Monotherapy / Maximal Androgen Blockade Crawford & Eisenberger New Engl J Med 1989 median progressionmedian overall free survival (months)survival (months) leuprolide + placebo n= leuprolide + flutamide n= p=0.039p=0.035 (minimal disease + good performance status) leuprolide + placebo n= leuprolide + flutamide n=414261

Monotherapy / Maximal Androgen Blockade Prostate Cancer Trialists’ Collaborative Group Lancet 1995 meta-analysis study 22/25 randomised studies initiated before December years survival surgical / medical castration22.8% n=2817 maximal androgen blockade26.2% n=2832 NS

Monotherapy / Maximal Androgen Blockade Eisenberger & Crawford New Engl J Med 1998 orchidectomy + placebo (n=685)flutamide (n=697) median survival29.9m33.5m (minimal disease)51.0m52.1m median progression free18.6m20.4m (minimal disease)46.2m48.1m all NS

Neoadjuvant Hormonal Therapy for Localised Cancers Solomon Clin Invest Med 1993 surgery + neoadj.surgery n=156n=119 positive margin7.8%33.8% downstaging21.1%-33.8% organ confined77.8%49.3%

Neoadjuvant Hormonal Therapy Goldenberg J Urol 1997 surgery + neoadj.surgery n=112n=101 positive margin29%65% organ confined42%20% 2 yeras failure23%19%

Radiotherapy +/- Adjuvant LHRH Agonist Bolla New Engl J Med 1997 RTRT + LHRH n=198n=203 5 years overall survival62%79%p=0.001 surviving 5 years & free of disease48%85%p<0.001

Radiotherapy +/- Adjuvant LHRH Agonist Pilepich J Clin Oncol 1997 RTRT + LHRH n=468n=477 5 years survival71%75%NS local recurrence29%16%p<0.001 metastases30%17%p<0.001