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Prostate Cancer Mr R Puri BSc, MBBS, MS, D Urol, FRCS(Urol) Consultant Urologist Bradford Royal Infirmary Relationship of the prostate to the urogenital tract Bladder Urethra Penis Testis Seminal vesicle Ejaculatory duct Prostate What does the prostate do? • The coagulum formed by the ejaculated semen liquefies within 20 minutes as a result of prostate proteolytic enzymes Best known is Prostate Specific Antigen PSA What does the prostate do? • Contributes to the seminal plasma – 60% seminal vesicles – 20% prostate • Prostate add – – – – PSA Zinc Phospholipids Spermine 200 180 160 140 120 100 80 60 40 20 0 Year USA 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 England and Wales Mortality rate per 100,000 males 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 Incidence rate per 100,000 males Age-adjusted incidence and mortality rates in the UK and the USA Yorkshire (England) 35 30 25 20 15 10 5 0 Year Oliver et al 2000 Prostate Cancer Facts • Commonest cancer in men after middle age • Second only to lung cancer as cause of death in men • Histological prostate cancer in 30% of population • Lifetime risk of developing clinical prostate cancer is 10% • Risk of death from prostate cancer is 3% NYCRIS Data 1998 Bradford HA pop. 483285 • Incidence - Europe • Mortality - Europe - 65.1/100,000 25.2/100,000 • Incidence - NYCRIS • Mortality - NYCRIS - 76.4 30.5 Bradford HA pop. 483285 Extent of problem • New cases per year - 183 • Deaths due to Ca P - 73 Only 94 out of the 183 will be offered potentially curative treatment Detection of Prostate Cancer • Digital Rectal examination • PSA testing • Trans rectal ultrasound and biopsy PSA production and action Epithelial cell Nucleus Testosterone 5a-R PSA (neutral serine protease) PSA secreted into gland lumen and blood stream Translation Transcription mRNA T, testosterone DHT, dihydrotestosterone 5a-R, 5a-reductase http://www.uronet.org/visual/mar97/image4.gif PSA values • Age specific 40 - 49 2.5 ng/ml (ug/L) 50 - 59 3.5 60 – 69 4.0 70 – 79 6.5 • ERSPC - any value above 3 is abnormal • Recent US guidelines - any value above 2.5 is abnormal PSA values-2 • PSA 2.5 – 4 4 - 10 > 10 • • • • Free / Total PSA Complexed PSA PSA density PSA velocity 12% CaP 36% CaP 50% CaP Presentation Localised Disease • • • • Local Disease Asymptomatic Raised PSA LUTS – Obstructive – Irritative UTI • • • • • • Locally Advanced Haematuria Impotence Suprapubic and perineal pain Haemospermia Anuria Renal failure Presentation Metastatic Disease • • • • • Low back pain Spinal cord compression Bone pain Anaemia Weight loss Presentation Why wait for symptoms ? Or Should we screen for prostate cancer ? Does screening decrease prostate cancer death? Study location and dates No. patients Effect of screening on mortality Canada 1986-1996 46,732 69%** Austria 1993-1998 21,079 42%* Europe 1998(ERSPC trial) 113,194 Data available after 2005 USA 1993(PLCO trial) 74,000 Data available after 2005 *p<0.05 **p<0.01 Bartsch et al 2000 Gohagan et al 1994 Labrie et al 1999 Schröder et al 1999 Benefits of PSA/DRE Screening: European Experience County Tyrol, Austria Population 630,000 Free PSA testing available 24hrs a day since 1993 • Decrease in mortality due to CaP by 32%,42% ,33% in 1997,98 &99 • Stage migration - Organ confined cancers increased from 28% in 93 to 82% in 98 Early Detection of Prostate Cancer Are There Any Benefits? • In non screened populations only 30% of CaP detected is organ confined • Only 22% of patients with PSA >10 have organ confined disease • Only 30% of patients with T3 disease are free of PSA recurrence 5 years after Radical Prostatectomy Early Detection of Prostate Cancer Are There Any Benefits? • In screened population 71-97% of the detected cancers were organ confined at staging • 70% of these cancers are organ confined after radical prostatectomy • 10 year PSA non progression rate is 80% • Disease specific survival rate at 15 years is 84-97% Screening for prostate cancer: conclusions • Ongoing debate: would increased detection decrease disease-specific mortality? • Screening costs need to be balanced against higher costs of treating patients with advanced disease • Costs could be considerably reduced by increased sensitivity of screening assay Diagnosis: transrectal ultrasound (TRUS) http://www.uronet.org/visual/jan96/image6.jpg Biopsy technique Histological grading: Gleason system Gleason grade 1 2 3 4 5 Kirby 1999 Why the Debate About Treating Prostate Cancer? Prostate cancer is unique amongst solid tumours in that it exists in two form • Pussy cat • Tiger Why the Debate About Treating Prostate Cancer? Latent Cancer (Pussy Cats) • Prevalence 20-48%, increases with age 60 -70% of men over 80 years have latent carcinoma prostate • Well to moderately differentiated, localised, CaP in older men is often not clinically significant Why the Debate About Treating Prostate Cancer? The Tigers • A patient below 65yrs diagnosed to have a CaP has a75% chance of developing metastasis and 52% chance of dying from CaP if he lives 15 years • Screening does not detect latent cancer • Majority of cancers detected on screening are localised cancers • Localised CaP is curable Treatment for prostate cancer High-grade PIN Localised prostate Locally cancer advanced TxN0M0 T3-4 Metastatic Hormone disease insensitive D1.5 D2 D2.5 D3 Time (years) Treatment options: Radical prostatectomy Radiotherapy ‘Watchful waiting’ Hormonal therapy Radiotherapy Hormonal therapy ‘Watchful waiting’ PIN, prostatic intraepithelial neoplasia Chemotherapy Clinical staging TNM 1997 T1a/b T3a T1c T1a T3b T2a T1b T3c T1c T2b T4 Clinical staging (4) N+ Nx = loco-regional lymph nodes cannot be evaluated N0 = no lymph node involvement N1-N3 = regional lymph metastasis M+ Mx = no metastasis can be evaluated M0 = no distant metastasis M1 = distant metastasis present a = lymph nodes other than regional nodes b = skeletal c = other sites D1-D1.5 D2-D2.5 D3 refractory to hormonal therapy D3S hormone sensitive D3I hormone insensitive N1 = solitary <2 cm N2 = solitary >2 cm and <5 cm N3 = >5 cm No TNM equivalent The use of nomograms for predicting disease recurrence • • • Preoperative PSA level Preoperative Gleason score TNM clinical stage Preoperative and postoperative nomograms Kattan et al 1998 Kattan et al 1999 Partin et al 1997 Partin’s Normograms T1c (inpalpable) Gleason sum score 7 PSA <4 OC 63% PSA 4-10 OC 49% PSA 10 – 20 OC 35% T2a OC 22% Treatment Localised Prostate Cancer • Radical Prostatectomy – – – – Retropubic Perineal Laproscopic Robotic • Radiotherapy – External beam – CT guided Conformal – Brachytherapy • Experimental – Cryotherapy Radical Prostatectomy Disadvantages of Radical Prostatectomy • • • • Mortality 0.5% Incontinence rate 10% Impotence >50% ? Effect on survival Majority of patients would be happy to go through the procedure again inspite of the side effects Radiotherapy External Beam RT Brachtherapy •Standard •Iodine •Conformal CT guided planning •Palladium *TRUS planning *MRI planning Adjuvant Hormone Treatment Neoadjuvant Hormone Treatment Brachytherapy Transperineal seed implant Belldegrun et al 2000 Brachytherapy vs radical prostatectomy: 7-year progression-free survival Brachytherapy Radical prostatectomy No. patients Ramos et al 1999 79% 84% 299 Polascik et al 1998 Ragde et al 1997 79% 98% 198 Radiotherapy plus hormonal therapy for locally advanced prostate cancer Neoadjuvant Pilepich et al 1995 RTOG 86-10 Significant improvement in progressionfree survival Shearer et al 1992 Significant reduction in tumour volume (downsizing) Adjuvant Bolla et al 1997, 1999 EORTC 22863 Significant improvement in overall survival & disease-free survival Pilepich et al 1997 Lawton et al 1999 RTOG 85-31 Significant improvement in overall 5-year survival (for poor prognosis patients) Granfors et al 1998 Significant improvement in progressionfree survival & overall survival Management of locally advanced/ metastatic prostate cancer • LHRH agonists • Orchiectomy • Antiandrogen monotherapy • Maximal androgen blockade Early treatment of locally advanced disease/metastatic/poorly differentiated cancer Treatment of T3NXM0 MRC study Feb 1997 BJU • Deferred treatment resulted in • • • • • Higher incidence of local progression Higher incidence of painful metastasis Higher incidence of ureteric obstruction Twice the number of serious complications Disadvantage in terms of survival Prostate cancer is hormone-dependent Testosterone Hypothalamus Pituitary LHRH Testes Prostate Prolactin Adrenal Cortisol LHRH, luteinising hormone-releasing hormone LH, luteinising hormone ACTH, adrenocorticotrophin Adrenal androgens LHRH Agonists Zoladex Prostap Mechanism of action of ‘Zoladex’ (goserelin) 2. Hypersecretion of LH 1. Normal LH release P LH P LH 3. Hyposecretion of LH P LH Furr and Hutchinson 1992 Administration of ‘Zoladex’ (goserelin) Antiandrogens: chemical structures NH O OH C C CH3 CH2 SO2 F NHCOCOH NO2 CH3 CH3 CF3 CF3 Hydroxyflutamide CN ‘Casodex’ (bicalutamide) CH3 CH3 O C NH C C CH2 CH3 C=O OAc N NO2 CF3 O CH3 Nilutamide (RU 23908) CH3 O CI Cyproterone acetate Mechanism of action of Flutamide &‘Casodex’ (bicalutamide) Androgens ACTH Prostate cell Adrenal gland Nucleus DHT LHRH Hypothalamus Pituitary gland X Other target tissues DHT Androgen receptor Testis LH -ve feedback control Circulating testosterone ‘Casodex’ (bicalutamide) Overall survival in M0 patients: median 6.3 years’ follow-up % patients 100 surviving 80 60 40 20 ‘Casodex’ (bicalutamide) 150 mg Castration 0 Time (days) HR 1.05; 95% CI 0.81, 1.31; p=0.70 Iversen et al 2000 Hormone insensitive prostate cancer: Options • Antiandrogen withdrawal • Second-line hormonal therapy • Chemotherapy Role of androgen ablation in hormone sensitive/insensitive prostate cancer • Not all of the cancer will be unresponsive and discontinuation of androgen suppression could allow tumour regrowth • Continued androgen suppression may provide survival benefits in hormone-refractory prostate cancer • Androgen ablation should be continued indefinitely based on minimal risk versus potential benefits The role of antiandrogens in hormone ‘insensitive’ prostate cancer • Progressing prostate cancer may respond to switching the antiandrogen therapy – ‘Casodex’ (bicalutamide) is effective in some patients previously treated with flutamide – flutamide is effective in some patients in whom first-line hormonal therapy has been highly effective • There are treatment options if patients progress on antiandrogens Stilboesterol Honvan Chemotherapy In patients with hormone-refractory prostate cancer • • • • prednisone mitoxantrone docetaxel estramustine • ZD1389 ZD1839: mechanism of action Potent and selective inhibitor of the epidermal growth factor receptor (EGFR) Cancer cell X Kinase Proliferation X Apoptosis X Angiogenesis X Metastasis X Membrane Nucleus ZD1839 HOLISTIC APPROACH It is the recognition that the patient must be educated so that he can, understand how to live, and sometimes die with his disease, but without anxiety. Case 1 • 62 year civil servant presents with nocturnal voiding frequency of times for last 6 months Case 2 • 72 years old farmer presents with haemospermia. PSA 17 clinically T2b neoplastic prostate Case 3 • 79 years old with acute retention