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Prostate Cancer

Prostate Cancer. Mr R Puri BSc, MBBS, MS, D Urol, FRCS(Urol) Consultant Urologist Bradford Royal Infirmary. Bladder. Seminal vesicle. Urethra. Ejaculatory duct. Penis. Prostate. Testis. Relationship of the prostate to the urogenital tract. What does the prostate do?.

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Prostate Cancer

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  1. Prostate Cancer Mr R Puri BSc, MBBS, MS, D Urol, FRCS(Urol) Consultant Urologist Bradford Royal Infirmary

  2. Bladder Seminal vesicle Urethra Ejaculatoryduct Penis Prostate Testis Relationship of the prostate to the urogenital tract

  3. 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

  4. What does the prostate do? • Contributes to the seminal plasma • 60% seminal vesicles • 20% prostate • Prostate add • PSA • Zinc • Phospholipids • Spermine

  5. USA Yorkshire (England) England and Wales 200 35 180 30 160 140 25 120 20 Mortality rate per 100,000 males Incidence rate per 100,000 males 100 15 80 60 10 40 5 20 0 0 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 Year Year Age-adjusted incidence and mortality rates in the UK and the USA Oliver et al 2000

  6. Prostate CancerFacts • 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%

  7. Incidence - Europe Mortality - Europe Incidence - NYCRIS Mortality - NYCRIS - 65.1/100,000 - 25.2/100,000 - 76.4 - 30.5 NYCRIS Data 1998Bradford HA pop. 483285

  8. Bradford HA pop. 483285Extent 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

  9. Detection of Prostate Cancer • Digital Rectal examination • PSA testing • Trans rectal ultrasound and biopsy

  10. PSA production and action Epithelial cell Nucleus PSA secretedinto gland lumen and blood stream DHT PSA(neutral serine protease) Testosterone 5a-R Translation Transcription mRNA T, testosterone DHT, dihydrotestosterone 5a-R, 5a-reductase http://www.uronet.org/visual/mar97/image4.gif

  11. 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

  12. PSA values-2 • PSA 2.5 – 4 12% CaP 4 - 10 36% CaP > 10 50% CaP • Free / Total PSA • Complexed PSA • PSA density • PSA velocity

  13. Local Disease Asymptomatic Raised PSA LUTS Obstructive Irritative UTI Locally Advanced Haematuria Impotence Suprapubic and perineal pain Haemospermia Anuria Renal failure PresentationLocalised Disease

  14. PresentationMetastatic Disease • Low back pain • Spinal cord compression • Bone pain • Anaemia • Weight loss

  15. Presentation Why wait for symptoms ? Or Should we screen for prostate cancer ?

  16. Study location and dates Canada 1986-1996 Austria 1993-1998 Europe 1998- (ERSPC trial) USA 1993- (PLCO trial) No. patients 46,732 21,079 113,194 74,000 Effect of screeningon mortality 69%** 42%* Data availableafter 2005 Data availableafter 2005 ê ê *p<0.05 **p<0.01 Does screening decrease prostate cancer death? Bartsch et al 2000Gohagan et al 1994 Labrie et al 1999 Schröder et al 1999

  17. 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

  18. Early Detection of Prostate CancerAre 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

  19. Early Detection of Prostate CancerAre 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%

  20. 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

  21. Diagnosis:transrectal ultrasound (TRUS) http://www.uronet.org/visual/jan96/image6.jpg

  22. Biopsy technique

  23. Gleasongrade 1 2 3 4 5 Histological grading:Gleason system Kirby 1999

  24. Why the Debate About Treating Prostate Cancer? Prostate cancer is unique amongst solid tumours in that it exists in two form • Pussy cat • Tiger

  25. 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

  26. 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

  27. Treatment for prostate cancer Localisedprostatecancer Locallyadvanced Metastatic disease Hormone insensitive High-grade PIN TxN0M0 T3-4 D1.5 D2 D2.5 D3 Time (years) Treatment options: Radical prostatectomy Radiotherapy ‘Watchful waiting’ Hormonal therapy Chemotherapy Radiotherapy Hormonal therapy ‘Watchful waiting’ PIN, prostatic intraepithelial neoplasia

  28. Clinical staging TNM 1997 T1a/b T1c T2a T2b T3a T3b T3c T4 T1a T1b T1c

  29. D3 refractory tohormonal therapy Clinical staging (4) N+ Nx = loco-regional lymph nodes cannot be evaluatedN0 = no lymph node involvementN1-N3 = regional lymph metastasis N1 = solitary <2 cm N2 = solitary >2 cm and <5 cm N3 = >5 cm D1-D1.5 M+ Mx = no metastasis can be evaluatedM0 = no distant metastasisM1 = distant metastasis present a = lymph nodes other than regional nodes b = skeletal c = other sites D2-D2.5 D3S hormone sensitive D3I hormone insensitive No TNM equivalent

  30. 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

  31. PSA <4 OC 63% PSA 4-10 OC 49% PSA 10 – 20 OC 35% T2a OC 22% Partin’s NormogramsT1c (inpalpable) Gleason sum score 7

  32. TreatmentLocalised Prostate Cancer • Radical Prostatectomy • Retropubic • Perineal • Laproscopic • Robotic • Radiotherapy • External beam – CT guided Conformal • Brachytherapy • Experimental • Cryotherapy

  33. Radical Prostatectomy

  34. 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

  35. Radiotherapy Brachtherapy External Beam RT • Standard • Conformal CT guided planning • Iodine • Palladium *TRUS planning *MRI planning Adjuvant Hormone Treatment Neoadjuvant Hormone Treatment

  36. BrachytherapyTransperineal seed implant Belldegrun et al 2000

  37. Brachytherapy vs radical prostatectomy:7-year progression-free survival Ramos et al 1999 Polascik et al 1998Ragde et al 1997 Brachytherapy 79% 79% Radical prostatectomy 84% 98% No. patients 299 198

  38. Radiotherapy plus hormonal therapy for locally advanced prostate cancer Neoadjuvant Pilepich et al 1995RTOG 86-10 Shearer et al 1992 Adjuvant Bolla et al 1997, 1999EORTC 22863 Pilepich et al 1997Lawton et al 1999RTOG 85-31 Granfors et al 1998 Significant improvement in progression-free survival Significant reduction in tumour volume (downsizing) Significant improvement in overall survival & disease-free survival Significant improvement in overall 5-year survival (for poor prognosis patients) Significant improvement in progression-free survival & overall survival

  39. Management of locally advanced/ metastatic prostate cancer • LHRH agonists • Orchiectomy • Antiandrogen monotherapy • Maximal androgen blockade

  40. 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

  41. Prostate cancer is hormone-dependent Testosterone Testes Pituitary Hypothalamus Prostate Oestrogen LH Prolactin LHRH ACTH Adrenal Cortisol Adrenalandrogens LHRH, luteinising hormone-releasing hormone LH, luteinising hormoneACTH, adrenocorticotrophin

  42. LHRH Agonists Zoladex Prostap

  43. 2. Hypersecretion of LH 1. Normal LH release LH P P LH 3. Hyposecretion of LH P LH Mechanism of action of ‘Zoladex’ (goserelin) Furr and Hutchinson 1992

  44. Administration of ‘Zoladex’ (goserelin)

  45. O OH CH2 SO2 C NH C F CH3 CF3 CN O OAc NH C N NO2 CH3 C C CF3 O CH3 Antiandrogens: chemical structures CH3 NHCOCOH NO2 CH3 CF3 Hydroxyflutamide ‘Casodex’ (bicalutamide) CH3 C = O CH3 CH3 CH2 O CI Nilutamide (RU 23908) Cyproterone acetate

  46. Mechanism of action of Flutamide &‘Casodex’ (bicalutamide) Androgens ACTH Prostate cell Adrenal gland Nucleus DHT LHRH X Hypothalamus Other target tissues Pituitary gland ‘Casodex’ (bicalutamide) DHT Androgen receptor Testis LH Circulating testosterone -ve feedback control

  47. Overall survival in M0 patients:median 6.3 years’ follow-up % patients surviving 100 80 60 40 ‘Casodex’ (bicalutamide) 150 mg 20 Castration 0 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 Time (days) Iversen et al 2000 HR 1.05; 95% CI 0.81, 1.31; p=0.70

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