2 Histological Incidence at Autopsy Histological cancer in autopsy studies27% Third decade20% Fourth decade32% Fifth decade55% Sixth decade64% Seventh decadeSakr et al: In Vivo 8:439,1994
3 Histological Incidence at Autopsy Incidental Prostate Cancer Found at Autopsy (Detroit, MI)W.A. Sakr, et al. Eur.Urol. 30: 138, 1996.Removed the prostate glands from 525 consecutive male trauma victims dying in Detroit during the early 1990s.
4 Causes of Death in Australia 2011 2.1 LEADING CAUSES OF DEATH , Australia - Selected years , 2006, 2011Cause of death No Rank No Rank No RankIschaemic heart diseasesCerebrovascular diseasesDementia and Alzheimer diseaseTrachea, bronchus and lung cancerChronic lower respiratory diseasesDiabetesColon, sigmoid, rectum and anus cancerBlood and lymph cancer (including leukaemia)Heart failureDiseases of the urinary systemProstate cancerBreast cancerInfluenza and pneumoniaPancreatic cancerIntentional self-harmSkin cancersAccidental fallsHypertensive diseasesCardiac arrhythmiasCirrhosis and other diseases of liverProstate cancer deaths per 100,000 male population ~Australian Bureau of Statistics 2013
5 Australian Mortality Data 1985 - 2002 Australian Bureau of Statistics Yearbook Australia Health - Article - Cancer Trends
6 Prostate Cancer & Death in Australia 3,294 deaths from prostate cancer4,959 male deaths from lung cancer62% of prostate cancer deaths >75 years41% ‘’ ‘’ ‘’ >80 yearsAustralian Cancer Incidence and Mortality Books (ACIM)~3% Male deaths are from prostate cancer
7 Prostate Cancer Deaths in Australia 2011 Australian figures 2011Prostate cancer deaths: 3,294Deaths (Male) from MVA: Australian Govt Dept Transport and InfrastructureSuicide (Male) deaths: 1, ABS Yearbook 2013Western Australian Figures 2011Mortality to incidence ratios (M/I): Males FemalesProstate cancerBreast cancerLung cancerOverall cancer (2005)Western Australia Figures 2011Prostate cancer – number diagnosed: 2,086 vs number of deaths: 253 vs road toll: (Male)Breast cancer (female) ,Lung cancer (male)Colorectal cancer (male)Western Australian Cancer Registry
8 Prostate Cancer Incidence and Mortality Trends USA
9 Prostate Cancer Incidence and Mortality Trends USA Prostate Cancer Incidence Rates* by Race and Ethnicity, U.S., 1999–2009Prostate Cancer Death Rates* by Race and Ethnicity, U.S., 1999–2009* USA Govt Centre for Disease Control and Prevention
10 Aetiology of Prostate Cancer TestosteronePromotes prostate cancer developmentProstate cancer does not develop in eunuchsTestosterone supplements problematic in men with normal serum testosterone levelsGeneticsMutations in BRCA1 (on chromosome 17) and BRCA2 (on chromosome 13), important risk factors for ovariancancer and breast cancer in women, have also been implicated in prostate cancer.Other linked genes include the Hereditary Prostate Cancer Gene (HPC1) on chromosome 1, said to be responsiblefor 3% of prostate cancers.Dietary FactorsLittle scientific evidence for dietary factors involved in the development of prostate cancer.Relatively rare in South East Asian populations with diets high in phytoestrogens such as soy.
11 Pathology Morphology Differentiation = Gleason score Adenocarcinoma % cell of origin – basal cell most likely, not lumenal cellDuctal carcinoma %Mucinous adenocarcinoma %Small cell carcinoma % (neuroendocrine)Carcinosaroma %Embryonal carcinosarcoma %Differentiation = Gleason scoreBased on morphological appearance (grade 1 – 5) where two most common morphologies are added to give a sum score (2 – 10)Gleason = 7 where 3 is the most common morphological pattern and 4 is the second most common patternIf three morphological patterns, first number is most common pattern and second number is the pattern with the highest gradeHigher score = poorer differentiation = worse prognosisGleason Gleason Gleason Gleason 5
12 Gleason Score and Prognosis Gleason score is an independent prognostic indicator:Gleason moderate grade cancerGleason intermediate grade cancerGleason high grade cancerThe disease-specific mean survival (DSMS) in 305 men in Sweden diagnosed at TURP 1975 – 1990 who had no curative treatment (no staging information used)Gleason score yearsyearsyearsyearsGleason score and % cancer were independent predictors of DSMS (P < 0.001).Prognostic Value of Gleason Score in Prostate Cancer Egevad et al BJU Int 2002 Apr;89(6):
13 Clinical Management Cancer screening and PSA Diagnosis – TRUS biopsy and MRIProstate cancer prevention – “chemoprevention”Expectant management “watchful waiting”Curative therapy for Localized Disease (< T3 )Surgery Perineal prostatectomyRadical retropubic prostatectomy with dorsal vein ligation 1979 and neurovascular preservation 1982 by Patrick WalshLaparoscopic radical prostatectomyRobotic laparoscopic radical prostatectomyHIFU and CryotherapyRadiotherapy External External beam DXRTConformal external beam DXRTIMRT Intensity Modulated RadiotherapyIGRT Image Guided RadiotherapyInternal LDR brachytherapy ( I125 seeds)HDR brachytherapy
14 P.S.A. - Prostate Specific Antigen PSA is a Single chain glycoprotein.237 amino acids long translated as a 261 AA prepropeptide from chromosome 19 gene designated LKLK 3.Glycosylated PSA has MW 28,400 daltons.Functions as a serine protease, recognized as a member of the human kallikrein family.Functions to liquefy semen coagulum by breaking down gel forming proteins semenoglobulin I, semenoglobulin II and fibronectin, releasing spermatozoa.Originally identified in Japan in 1966 by Hara, who initially reported their findings on γ-seminoprotein in 1966 in Nippon Hoigaku Zasshi, the Japanese Journal of Legal Medicine, and in 1971 were able to characterize this protein. Although this antigen was later shown to be similar to PSA the original publications were in Japanese and consequently not available to the English - speaking scientific community. This was early work on a forensic science test for rape.
15 P.S.A. - Prostate Specific Antigen Synthesized in prostatic ductal epithelium and acini and secreted into prostatic ducts to become a component of semen.Detected in female and male periurethral glands, apocrine sweat glands, some breast cancers, some salivary gland cancers and breast milk.Thought to diffuse across cells and basement membrane to enter bloodstream, diffusion increased in inflammation and prostate cancer.Half life days.Immunoreactive PSA subgroupfree PSA 1% - 30% of this groupbound PSA bound to alpha 1 antichymotrypsin.
16 PSA Levels Affected By : Prostatitis - levels up to 120 recorded, resolving with antibiotics.Urine retention - up to 6 fold increase.Ejaculation ng/ml increase 24 hours later.Ambulation - decreases PSA up to 20%.Prostate biopsy - 8 ng/ml increase hours later.TURP - 6 ng/ml increase with median return to baseline at 18 daysKlein et al, The effects of prostate manipulation on PSA levels.Urologic Clinics of North America May 1998.
17 PSA as a screening testPSA is a poor screening test with high sensitivity but very poor specificityAdvocated screening with yearly PSA and DRE for men between 50 and 70 years of ageEarlier commencement of screening advocated for those at risk of hereditary cancer between 40 and 70 years of ageRecommended in some parts of the USA. A policy of the American Urological association.Prostate cancer screening is not currently recommended by Government health authorities in either Australia or the UK.
18 PSA as a screening testAustralian Health Technology Advisory Committee (AHTAC) review Australian Government Publishing Service 1996.“As a result of the evaluation of prostate cancer screening against established criteria, AHTAC recommends against the screening of asymptomatic men for prostate cancer.”“AHTAC recommends:that the use of PSA continue to be supported in the monitoring of men known to have prostate cancer and in patients selected for active treatment for BPH; and that men being offered, or requesting the PSA test must be fully informed of the limitations of the available tests and the possible further diagnostic and treatment choices with which they may be faced should they decide to proceed with the test.”
19 Total PSA screening studies PSA > 4ng/ml Overall cancer detection rate PPV1.5% - 4.1% % meanIncidence of cancer detection on prostate biopsy based on DRE findings and PSA.PSA ng/ml DRE negative DRE positive% %% %> % %Arcangeli et al Urologic Clinics of N. America, May 1998
20 PSA Density and Screening PSA density = Total PSA ng/ml / TRUS determined prostate volume in ml>0.15 with PSAreduces number of biopsies 50%misses 50% of cancersCatalona et al : J Urol 153:2031,1994
21 PSA Velocity and Screening This is shown to be higher in men with prostate cancer than in BPHPSA slope cut off 0.75 ng/ml per year with PSA <4 ng/mlsensitivity 79%specificity 66%Smith and Catalona: J Urol 152:1163, 1994Difficult because there is a 15% short term variation in PSA levelsStamey et al: J Urol 155: 1977,1996
22 Age Specific Reference Ranges in PSA Oesterling et al 471 men in Olmstead County, Minnesota had DRE, PSA and TRUS . Found to have increasing PSA with age at a rate of ng/ml per year.Oesterling et al: JAMA 270:860, 1993Catalona however found that 30% of organ confined histologically significant cancers in men older than 60 would be missed if age related reference ranges were used.Catalona et al: J Urol 152:2037, 1994Age related reference ranges improve specificity at the cost of sensitivity.
23 Free/Total PSA Ratio in Screening Note that there are over 50 commercially available PSA assays available and all should have different reference ranges, such is the complexity of the assay.Measurement of free PSA is difficult and F : T ratios should be validated for each individual test.Standardisation of these tests is difficult and not yet universal.%Free PSA falls as prostate cancer develops.Study PSA range F : T Ratio Sensitivity loss Specificity gainLuderer <20% % %Catalona > <20% % %
24 Free/Total PSA - Netherlands Schroder Study 9,600 men years old screened with PSA, DRE and TRUS4.3% cancer detection rate5.1 biopsy to cancer ratio64% of cancers specimen confined at radical prostatectomyBest sole predictor of prostate biopsy is total PSASpecificity of PSA in range is improved with F : T ratioF : T ratio < 20 in total PSA rangereduces biopsies by 38%misses 12% of cancersSchroder et al: Urologic Clinics of North America, May 1998
25 Years of Life Saved by Screening Sensitivity analysis of years of life saved by prostate cancer screening using various estimates of the natural history of prostate cancer.Grade of disease Years of life saved Years of life savedwithout QOLA with QOLAwell differentiatedmoderately ‘’poorly ‘’Chodak metanalysis: Urologic Clinics of North America May 1998The years of life saved using assumptions of the natural history of prostate cancer compare favorably to the years of life saved by other cancer screening programs.
26 Cost Effectiveness of Prostate CA Screening & Rx Estimates used because no randomized controlled studies of the effectiveness of prostate cancer screening have been done.Years of life lost because of prostate cancer age yearsGrade Years of life lostWell differentiatedModerately ‘’Poorly ‘’Cost per year of life saved by prostate cancer screening and RxAge range Saving $US DRE + PSA– 4627Benoit & Naslund: Urologic Clinics of North America, May 1998
27 Cost per Year of Life Saved By Various Interventions Intervention Cost per year of life saved $USSmoking cessation counseling , ,833Hypertension control ,600CABG ,900Renal dialysis , ,300Liver transplantation ,000Screening mammography , ,000Cervical cancer screening ,572Colon cancer screening , ,348For prostate cancer, cost per year of life saved through PSA and DRE screening programs compares extremely favorably with that for breast, cervix and colon cancer screening.Benoit & Naslund: Urologic Clinics of North America, May 1998
28 Conclusion on the socio - economic implications of PSA Screening Benoit and Naslund, Urologic Clinics of North America, May 1998“Although men aged years will potentially benefit the most from PSA screening, this benefit will not be realised until these men are in their seventh and eighth decade of life.”“Society must decide if the years of life saved in these men warrants the use of limited health care resources.”“This decision will be easier when randomised controlled trials are available to quantify the costs and benefits of PSA screening.”
29 PSA screening – large trial results Mortality Results From a Randomized Prostate-Cancer Screening TrialAndriole et al NEJM :Randomized trial on 76,693 men, annual PSA screening on 38,343 men vs no screening on 38,350 between 1993 – 2001.After 7 years, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group.The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and1.7 (44 deaths) in the screening group.Conclusion: After 7 to 10 years of follow up, the death rate from prostate cancer was very low and did not differ significantly between the two study groups.
30 PSA screening – large trial results Screening and Prostate Cancer Mortality in a Randomized European StudySchroder et al NEJM :182,000 men between ages 50 – 74 years in seven European countries randomized to two groups with one group receiving PSA screening and the other group not having PSA screening, recruited between 1991 and 2003.During a median follow up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group.The rate ratio for death from prostate cancer in the screening group as compared with the control group was 0.8.The absolute risk difference was 0.71 deaths per 1,000 men.This means that 1410 would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer.Conclusion: PSA based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis.
32 Diagnosis – TRUS Biopsy Prostate biopsy is required for diagnosis, generally 11 biopsies takenTransperineal prostate biopsy using trans rectal U/S (TRUS) and 18F “Biopty” guns originally developed by Jim Anderson, interventional radiologist at RPH in 1989 using freehand technique.All TRUS biopsies done by Jim Anderson using this technique under local anaesthetic up to around 2000 with no antibiotic prophylaxis used. Rare septicaemia if patient had UTI/prostatitis at the time of biopsy (handful of cases over 10 years and around 18,000 TRUS biopsy episodes).TRUS biopsy largely taken over by urologists around 2000 using trans rectal approach under general anaesthetic. “Lists of TRUS biopsies”.3% Gram negative septicaemia rate with transrectal biopsy despite antibiotic prophylaxis.Now a move nationally by urologists over the last 12 months to move on to transperineal biopsy because of concerns over septicaemia and antibiotic prophylaxis.Many urologists have this technique from brachytherapy seed placement anyway but this is now being workshopped by urologists in the Eastern States.
33 Diagnosis - Prostate “Multiparametric” MRI New computer software enhancement of contrast MRI is providing more accurate assessment with “Multiparametric” MRI scanning:“Dynamic Contrast Enhanced” imaging DCE“Diffusion weighted imaging” DWI - Difference in Brownian motion of water molecules in cancervs normal tissue.Currently at RPH, 1.5 Tesla external MRI with multiparametric processing, DCE and DWI.1.5 Tesla vs 3.0 Tesla – possibly not as important as image processing and analysis.Endorectal coil 3.0 T claimed up to 98% specific and up to 86% PPV with DCE.MR Spectroscopy up to 93% PPVCurrent role seen as a localising test for targeted biopsy after negative biopsy with ongoing PSA rise.CURRENTLY SHOULD NOT BE USED AS A DIAGNOSTIC TEST WITH AN ABNORMAL PSA TOAVOID BIOPSY.
34 Lesion visible Hypoechoic Colour map graph Colour map PATIENT 76 YEAR OLD PSA ELEVATED FOR A NUMBER OF YEARS BIOPSY X4 INFLAMMATORY CHANGES TREATED WITHY CIPROFLOX PIN IDENTIFIED IN BIOPSY SPECIMEN PREVIOUSLYDiffusion Imaging(Brownian motion)T2 Axial SlightlyMore rostralDWIADCT2 Axial NADAxial UltrasoundLesion visible HypoechoicColour mapgraphColour map11 oc ext antTransperineal systematic cores (11 systematically) additional 2 cores from presumed index lesion at 11 oclock (13 cores in total) 8mm,13mm and 10 mm acinar Adenocarcinoma 11 oclock(Slide courtesy of Jim Anderson)
35 PreventionCastrate all adolescent males - prostate cancer unknown in eunuchs in China.Diets high in phytoestrogen - SE Asian populations and low cancer incidence.African americans - high testosterone and high incidence of prostate cancer.“Chemoprevention” – 5 alpha reductase inhibitors finasteride and dutasterideEffective but caution due to relative increase in high grade prostate cancer incidence FDA warns:The results of the PCPT trial showed that men on the finasteride arm had a 24.8% overall lower risk of being diagnosed with prostate cancer when compared to the placebo arm (p<0.0001). The reduction in risk of prostate cancer was limited to Gleason score (GS) 6 or lower prostate cancers. However, there was an increased incidence of GS 8-10 prostate cancers with finasteride versus placebo (1.8% versus 1.1%, respectively). The results of the REDUCE trial showed that men on dutasteride had a 23% overall lower risk of being diagnosed with biopsy detectable prostate cancer when compared to men on placebo (p<0.0001). This overall risk reduction was limited to a decrease in GS 6 or lower prostate cancers. In contrast, there was an increased incidence of GS 8-10 cancers with dutasteride versus placebo (1% versus 0.5%, respectively).
36 Prevention - Finasteride USA Prostate cancer prevention trial 1993 – 200318,882 men with PSA < 3 and normal DRE enrolled.5 mg of Finasteride per day or placebo.Study closed 15 months before planned closure because overwhelming evidence thatthe primary end point (prostate cancer prevalence) had been met.24.8 % reduction in prostate cancer risk.Increased proportion of high grade prostate cancers diagnosed from 1.1% to1.8%raised (and more likely cause of early closure). Prompted FDA warning.Subsequent analysis suggests finasteride “improved sensitivity of PSA for canceroverall, and especially for high grade cancer”.The Influence of Finasteride on the Development of Prostate Cancer Thompson et al NEJM 2003; 349: 215
37 Expectant Management“Watchful waiting” PSA between 4-10, do repeat PSA at regular intervals, 3 to 6 monthly, act when certain parameters breached.Pre biopsy - lower chance of cure with higher PSA due to interval progression, significant drop in cure rates once PSA>10.Post biopsy - little rational basis, chance of successful curative therapy must drop over time (albeit slowly in many cancers).However, ~50% chance of death from prostate cancer over 10 years without treatment in stage T1c prostate cancer Gleason 7, few +ve biopsies.Patients should have management options discussed and have a clear course of action in their minds prior to having PSA test.Ask “what if ?” prior to PSA testing.
38 Expectant ManagementAlbertsen et al Competing Risk Analysis for Men Aged 55 to 74 Years at Diagnosis Managed Conservatively for Clinically Localised Prostate CancerJAMA 280(11),
39 Radical Prostatectomy Cure 80% PSA 4-10, Gleason < 7, Stage T1c (Positive margin rate average30% in Perth)This group of patients have % mortality from prostate cancer without any treatment over 10 year time frame, depending on age (see previous).Cure 50% PSA 10-15, generally higher stage.Morbidity 10% incontinence80% impotence0.5% deathblood transfusion, rectal injury, lymphocoele“PSA recurrence” = not curedRx radiotherapy (? 1/3 cured)hormonal manipulation? Better local control ? Better survival in this group
44 Radical Prostatectomy Open radical retropubic prostatectomyNow 4 – 5” midline incision3 – 4 days hospital stay2 – 3 weeks indwelling catheterLaparoscopic radical retropubic prostatectomy2” incision + port sites2 – 3 days in hospital1 – 2 weeks indwelling catheterMore rapid return to workCancer outcomes the same for open vs laparoscopic radical prostatectomySlightly lower impotence rate for laparoscopic radical prostatectomySlightly higher complication rate for laparoscopic radical prostatectomy, including rectal injuryRobotic radical prostatectomy
45 Robotic Radical Prostatectomy Da Vinci robot developed through the 1990’s and given approval by US FDA in Installed SJOG Subiaco in 2008.Purchase cost $3 million in Australia with $300,000 yearly maintenance fees.Cost $4,000 per case in disposable instruments.Patient out of pocket costs $7,000 - $8,000 per procedure in Perth.Four interactive robotic arms controlled from the console.Endoscopic camera with two lenses gives the surgeon full stereoscopic vision from the console.
47 Robotic Radical Prostatectomy 2012 in USA 367,000 robotic operations performed (all, including prostate).1,400 hospitals in USA have at least one Da Vinci robot.Cancer outcomes no different.Complication rate the same as manual laparoscopic radical prostatectomy.Incontinence % vs 2% open radical prostatectomy Lepor et al Reviews in Urology 2005 Summer; 7(3): 115–127Impotence % vs 30% “ “ “ “ “Rectorethral fistula % overall with no good comparison laparoscopic/robotic/openHospital stay the same as manual laparoscopic radical prostatectomy, all lapararoscopic prostatectomy 1 – 2 days shorter hospital stay than open radical prostatectomy.
48 Radiotherapy – External Beam Results suggest efficacy equal to radical prostatectomy, but staging difficulties and poor data.Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy Kupelian et al Cleveland Clinic J Clin Oncol 2002 Aug 15;20(16):CONCLUSION: Eight-year biochemical failure rates were identical between radiotherapy and surgery in any subgroup. Outcome isdetermined mainly by pretreatment PSA levels, bGS, clinical T stage, and, for RT patients, radiation dose.MD Anderson data shows external beam DXRT much better outcomes with higher doses, around 76 Gray, hence newer image guided radiotherapy should be more effectiveSix week treatmentMorbidity % radiation proctitis2% radiation cystitis- 50% impotence within first year, increasing thereafter- insignificant incontinencePretreatment hormonal manipulation 6 months appears to improve cure rate.Bladder cancer in 0.58% of 342,937 men treated for CA prostate, twice as likely in DXRT vsradical prostatectomy Secondary Bladder Cancer After Radiotherapy For Localized Prostate CancerAbern et al Chicago, IL (AUA presentation) J Urology 185, No. 4S, Supplement May 2011
49 Image Guided Radiotherapy IGRT and IMRT Image guided linear accelerators used to target the prostate.IMRT Intensity modulated therapy advanced 3DCRT is now further refined.Gold seed fiducial markers placed trans perineally using trans rectal U/S.CT scan imaging data used for planning.Cone beam flat panel CT used for targeting.Allowing dose escalation to 78 – 86 Gy (? Use of hydrogel spacer for rectal separation).Reduced risk of significant complication to 1- 2%.Long term outcome data not available but early biochemical control (PSA) improved.
51 LDR Brachytherapy - Seeds I125 seeds implanted in prostate with transperineal needle application.Survival Among Men With Clinically Localized Prostate CancerTreated With Radical Prostatectomy or Radiation Therapy in the Prostate Specific Antigen Era Kibel et al J Urology187, Issue 4, April 2012,The adjusted 10-year prostate cancer specific mortality was ;1.8% (95% CI 1.6–2.1) Radical prostatectomy 6, patients2.9% (95% CI 2.6–3.3) External beam DXRT , “2.3% (95% CI 2.0–2.6) LDR Brachytherapy , “10,429 consecutive patients with localized prostate cancer in 2 centres,Cleveland Clinic and Barnes-Jewish Hospital (St Louis)~ 70% Stage T1C, 25% T2~ 75% Gleason 6, 25% Gleason 7(External beam DXRT generally higher stage and grade)$18,000 cost currently in Perth (SCGH).
52 Brachytherapy - HDRControl rod needles positioned under GA with TRUS day beforeStabilizing template sutured to perineum, dosimetry figured by physicists/radiotherapist, needles connected to HDR machineIridium 192 radioactive wire source inserted via established needles, with dwell time and location governed by pre programmed HDR machineTime on machine relatively short – minutesTemplate and needles removed at the end of procedureHigh doses of radiotherapy delivered with low morbidityGenerally given an external beam “boost”Treatment at SCGH, generally reserved for high grade, poor prognosis localized disease (high risk)High Dose Rate (HDR) Brachytherapy with Conformal Radiation Therapy for Localized Prostate CancerDeger et al European Urology Volume 47, 4, April 2005, Pages 441–448Five-year progression free survival: % in the low risk group,65% in the intermediate risk group59% in the high risk group
53 HIFUHigh Intensity focused ultrasound with TRUS targeting.Acoustic energy converted to heat in tissue with thermal tissue injury.Outpatient procedure lasting 1 – 3 hours.Cancer outcomes:Fourteen-year oncological and functional outcomes of high-intensity focused ultrasoundin localized prostate cancer. Ganzer et al BJUI August ,3 322–329538 patients mean follow up 8.1 years mean age 67.7 years ≤ Gleason stage T stage T2TURP performed 4 -6 weeks prior to HIFU if prostate > 30 gmActuarial BDFS 5 years: 81% Biochemical disease free survival Phoenix criteria (PSA nadir+2 ng/mL)10 years: 61% Mean PSA nadir 0.4297 patients biopsied % biopsies showed cancerCancer specific deaths 3.3%Complications: rectorethral fistula % patientsbladder outflow obstruction %urine incontinence %12 months %Not as yet available in WA but available in Melbourne and Sydney
54 HIFU2 machines available: Sonotherm and Ablatherm
57 Palliative Hormonal Manipulation - Castration Studies on Prostatic Cancer I.The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases inMetastatic Carcinoma of the Prostate*Charles Huggins, M.D., and Clarence V. Hodges,M.D. Chicago, Illinois Cancer Res 1941;1:“3. In prostatic cancer with marked elevation of acid phosphatase, castration or injection of large amounts of estrogen caused a sharp reduction of this enzyme to or towards the normal range. Alkaline phosphatase values rose following castration and then decreased, but more slowly than acid phosphatase. In certain cases, these values reached and were maintained in a normal range during the period of observation, 180 days, while in other patients the values were slightly above normal.”Huggins awarded Nobel Prize in Medicine in 1966 for his work on prostate cancerResponse rate: 80% respond with biochemical and clinical remission Catalona and Scott J Urol 119,Response duration: Most patients with metastatic disease demonstrate hormone manipulation resistance within 18 – 24 monthsAverage survival 3 – 5 years on hormone manipulation when presenting with metastatic diseaseEarly vs delayed hormonal manipulation: VACURG study 1967 showed no survival difference with early vs delayed therapy
58 Palliative Hormonal Manipulation - Estrogens Estrogen therapy shown to be effective in Huggins and Hodges 1941 study with stilbestrol 1 mg I/V or estradiol 1.66 to 3.32 mg I/V Cancer Res 1941;1:Estradiol (given I/M and orally) shown to be more effective palliation than castration in palliation of metastatic prostate cancer with ~ 25% better survival at 2 years in high grade cancer, but with higher cardiovascular mortality in the estrogen treated group Haapiainen et al BJU (1986) 58,Thromboembolism risksStibestrol used as an alternative to castration up until the arrival of LHRH analogues (1993 PBS Aus)dosage 1mg – 3mg per daySome resurgence in the 1990’s as second line hormonal manipulation
59 Palliative Hormonal Manipulation – LHRH Analogues Goserelin (Zoladex) was the first LHRH analogue licensed for use FDA 1989 TGA 1991initially 3.6 mg monthly S/C pellet injection, later 10.8 mg 3 monthly S/C pellet injectionSynthetic analogue of LHRH, now also Leuprorelin (Lucrin) and Triptorelin (Diphereline available as 6 months dose)Works by binding to the LHRH receptor cells in the pituitary gland leading to an initial increase in production of luteinizing hormone which gives an initial increase in the production of testosterone, with potential tumour flare.Initial flare may be treated by co-prescribing/co-administering antiandrogen (CPA, Bicalutamide etc).After a period of about 14–21 days, production of LH is greatly reduced due to receptor downregulation, and testosterone is reduced to castrate levels.Same efficacy as castration in management of metastatic prostate cancerSide effects: impotence, hot flushes, weight gain, depression, osteoporosis (same as for castration)Cost is $ for a 10.8 mg injection to the government ($4, per year), on PBS either $5.90 ( for concession holders) or $36.10 to the patient.
60 Palliative Hormonal Manipulation - Antiandrogens Steroidal antiandrogens directly affect gene expression due to their fat-soluble nature that allows them to diffuse through the plasma membrane’s phospholipid bilayer and prevent the binding of testosterone and dihydrotestosterone (DHT) to androgen receptors inside the cancer cell.Cyproterone acetete 100 mg bd as monotherapy may preserve sexual function whilst controlling prostate cancer, but mainly used to prevent “flare” on initiation of LHRH analogues or as second line hormonal manipulation with “hormone resistance” (failure of LHRH analogue or castration) –Non-steroidal antiandrogens counter androgens and have no steroidal effects. Antiandrogens act by blocking androgen receptors on the cancer cell surfaceFlutamide, Nilutamide and CosudexSecond line hormonal manipulation (adding to LHRH analogue or castration) can lead to a PSA response of 50% or greater in 4%–50% of patients. The median duration of response is between 4.0 and 11.0 months.Rotation through steroidal and non steroidal antiandrogens can give prolonged remission in some
61 Palliative Hormonal Manipulation – Intermittent Hormonal Manipulation Bruchovsky from Vancouver first published on this in 1990Large multicenter trial of intermittent hormonal manipulation (IADT) vs continuous hormonal manipulation (CADT) in 383 patients published in 2012 showed no statistical difference in either overall survival or progression free survival between intermittent or continuous therapy and no difference in quality of life scores. Poor study with some randomized and some non randomized.Intermittent hormonal therapy in the treatment of metastatic prostate cancer: a randomized trialMottet et al BJUInternational | 110, 1262–1269One small trial in 2002 suggested benefit but subsequently several large trials showing no real benefit. Some subjective improvement in quality of life thought to occur.Anecdotally useful in low bulk disease, i.e. failure of curative therapy for localized diseaseProblematic in advanced symptomatic diseaseIn high bulk disease, treat until PSA nadir achieved (average ~ 7 months) then observed without treatment until predetermined PSA rise reached – predetermined PSA rise different in different centres (PSA 10 in the above study)
62 Chemotherapy - Docetaxel Randomized trial of Docetaxel vs Mitoxantrone (both with prednisolone) published in NEJM 2004The median survival was 16.5 months in the mitoxantrone group vs 18.9 months in the group given docetaxel every 3 weeks.Among these two groups, 32 percent vs 45 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone)22 percent vs 35 percent (P = 0.01) had predefined reductions in pain13 percent vs 22 percent (P = 0.009) had improvements in the quality of lifeAdverse events were also more common in the groups that received docetaxelDocetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate CancerTannock et al NEJM 351;15 October 7, 2004
63 New Palliative Therapies For Advanced Disease ABIRATERONEDeveloped at the Institute for Cancer Research (starting with ketoconazole), Royal Marsden and patented in 1993.Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1)CYP17 catalyzes two sequential reactions:(a) the conversion of pregnenolone and progesterone to their 17-α-hydroxy derivatives by its 17 α-hydroxylase activity(b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione respectively, by its C17,20 lyase activityCurrent intracrine and paracrine theory for failure of hormonal manipulation.2010 interim results of phase III clinical trial in previously treated docetaxel overall survival was increased by 3.9 months (14.8 monthsversus 10.9 months for placebo).70% show significant PSA reduction.Works better in men with ERG proto-oncogene = ETS (erythroblast transformation- specific) related geneERG protein is a transcription regulatorApproved by the FDA in April 2011Placed on PBS Australia August 2013 for failed hormone manipulation followed by failed chemotherapy with DocetaxelAnnual cost ? $40,000Single daily tablet 1gm (on empty stomach) administered with prednisolone 5mg b.d.Side effects: hypertension, fluid retention, CCF and hypokalemiaadrenal insufficiencyelevation of ALT and AST
64 New Palliative Therapies For Advanced Disease CABAZITAXELA semi-synthetic derivative of a natural taxoid.It was developed by Sanofi-AventisApproved by the U.S. Food and Drug Administration (FDA) for the treatment ofhormone-refractory prostate cancer in June 2010.It is a microtubule inhibitor.Phase III trial with 755 men for the treatment of hormone-refractory prostate cancermedian survival was 15.1 months for patients receiving cabazitaxel versus 12.7months for patients receiving mitoxantrone.Used with prednisolone.Approved by TGA but rejected PBS listing in 2011 for patients with metastatichormone refractory prostate cancer having failed docetaxel as well.
65 New Palliative Therapies For Advanced Disease SIPULEUCEL-TImmunostimulant therapy.A course of Sipuleucel-T treatment consists of three basic steps:1. A patient's own white blood cells, primarily antigen-presenting cells (APCs), also called dendritic cells, areextracted in a leukapheresis procedure.2. The blood product is sent to the factory and incubated with a fusion protein (PA2024) consisting of two parts,a) The antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells, andb) An immune signalling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps theAPCs to mature.The activated blood product (APC8015) is returned from the factory to the infusion center and re-infused into thepatient to cause an immune response against cancer cells carrying the PAP antigen.A complete Sipuleucel-T treatment repeats three courses over the span of a month, with two weeks betweensuccessive courses.IMPACT trial served as the basis for licensing approval of Sipuleucel-T by the FDA in This trial enrolled 512 patients with asymptomatic or minimally symptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for Sipuleucel-T patients was 25.8 months comparing to 21.7 months for placebo-treated patients. Overall survival was statistically significant The longer survival without tumour shrinkage of change in progression may suggest the effect of an unmeasured variable.A course of treatment in Australia apparently $120,000.
66 New Palliative Therapies For Advanced Disease RADIUM-223 CHLORIDEPhase III clinical trials showed a 2.8 months increase in median overall survival due to the drug as compared to placebo (the increase was from 11.2 months to 14.0 months) in 922 patients.May 2013 FDA approval as a treatment for failed hormonal manipulation with symptomatic bone metastases and without known visceral disease.Alpha radiation from radium-223 decay to kills prostate cancer cells. Radium-223 targets to bone tissue by virtue of its chemical similarity to calcium. Alpha radiation has an effect over a range of 2-10 cells, which is short-range when compared to current intravenous radiation therapy which is based on beta or gamma radiation, and, therefore, causes less damage to surrounding healthy tissues. Radium-223 has a half life of 11.4 days, making it suitable for cancer treatment.(Strontium 89 (Metastron) has been in use since 1992 for the same circumstances but 50 day half life – Beta radiation).Side effectsNausea, diaorrhea, vomiting and swelling of the leg, ankle or foot. The most common abnormalities detected during blood testing were anaemia, lymphocytopenia, leukopenia, thrombocytopenia and neutropenia. Excreted by the gut.In clinical trials, radium-223 chloride was administered by intravenous injection once a month for 4 or 6 months.