Prostate Cancer

Julian Mander

RPH Urology

Histological Incidence at Autopsy

Histological cancer in autopsy studies

27% Third decade

20% Fourth decade

32% Fifth decade

55% Sixth decade

64% Seventh decade

Sakr et al: In Vivo 8:439,1994

Histological Incidence at Autopsy

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.

Incidental Prostate Cancer Found at Autopsy (Detroit, MI)

Causes of Death in Australia 2011

2.1 LEADING CAUSES OF DEATH , Australia - Selected years - 2002, 2006, 2011

Cause of death 2002 No. Rank 2006 No. Rank 2011 No. Rank

Ischaemic heart diseases 26 063 1 23 132 1 21 513 1

Cerebrovascular diseases 12 533 2 11 479 2 11 251 2

Dementia and Alzheimer disease 4 364 6 6 550 4 9 864 3

Trachea, bronchus and lung cancer 7 303 3 7 353 3 8 114 4

Chronic lower respiratory diseases 6 256 4 5 463 5 6 570 5

Diabetes 3 329 9 3 669 8 4 209 6

Colon, sigmoid, rectum and anus cancer 4 649 5 3 857 6 4 087 7

Blood and lymph cancer (including leukaemia) 3 791 7 3 700 7 3 978 8

Heart failure 3 367 8 2 902 11 3 488 9

Diseases of the urinary system 2 887 11 3 197 9 3 386 10

Prostate cancer 2 852 12 2 951 10 3 294 11

Breast cancer 2 716 13 2 643 13 2 937 12

Influenza and pneumonia 3 084 10 2 711 12 2 492 13

Pancreatic cancer 1 834 15 2 077 15 2 416 14

Intentional self-harm 2 320 14 2 118 14 2 272 15

Skin cancers 1 462 17 1 648 17 2 087 16

Accidental falls 629 38 1 288 20 1 845 17

Hypertensive diseases 1 353 20 1 500 18 1 802 18

Cardiac arrhythmias 1 226 21 1 280 21 1 612 19

Cirrhosis and other diseases of liver 1 354 19 1 416 19 1 589 20

Prostate cancer deaths per 100,000 male population 35.5 ~29 29.7

Australian Bureau of Statistics 2013 http://www.abs.gov.au/ausstats/abs@.nsf/Lookup/3303.0Chapter42011

Australian Mortality Data 1985 - 2002

Australian Bureau of Statistics Yearbook Australia 1301.0 - 2005 Health - Article - Cancer Trends

9.22 DEATH RATES(a) FROM SELECTED CANCERS

Males

Selected cancers 1985 1990 1995 2000 2002

Breast 0.2 0.3 0.4 0.2 0.2

Colorectal 37.9 35.2 33.9 30.5 27.7

Lung 77.2 68.5 63.9 54.7 53.3

Melanoma skin 6.8 7.6 8.1 7.4 8.0

Non-Hodgkin's lymphoma 8.0 10.0 9.9 10.4 9.5

Non-melanocytic skin 3.1 3.6 3.8 3.2 3.2

Prostate 35.7 39.9 41.4 35.9 35.5

All cancers 287.3 277.7 270.6 246.6 241.3

(a) Rate per 100,000 population, age standardised to the 2001 population (persons).

Source: AIHW 2003.

Prostate Cancer & Death in Australia

2011 Australia

3,294 deaths from prostate cancer

4,959 male deaths from lung cancer

62% of prostate cancer deaths >75 years

41% ‘’ ‘’ ‘’ >80 years

Australian Cancer Incidence and Mortality Books (ACIM)

http://www.aihw.gov.au/cancer/data/acim_books/index.cfm

~3% Male deaths are from prostate cancer

Prostate Cancer Deaths in Australia 2011

Australian figures 2011 Prostate cancer deaths: 3,294 Deaths (Male) from MVA: 921 Australian Govt Dept Transport and Infrastructure

http://statistics.infrastructure.gov.au/atsb/login.do?guest=guest&tableId=user/atsbguest/Road%20Deaths%20by%20State%20and%20Territory.txd

Suicide (Male) deaths: 1,726 ABS Yearbook 2013

http://www.abs.gov.au/ausstats/abs@.nsf/Lookup/F25E446E1BE6C931CA257B2E000D729C?opendocument

Western Australian Figures 2011 Mortality to incidence ratios (M/I): Males Females Prostate cancer 0.12 Breast cancer 0.17 Lung cancer 0.78 Overall cancer (2005) 0.36 0.30

• Western Australia Figures 2011 Prostate cancer – number diagnosed: 2,086 vs number of deaths: 253 vs road toll: 126 (Male) Breast cancer (female) 1,423 238 Lung cancer (male) 595 462 Colorectal cancer (male) 774 224

Western Australian Cancer Registry

http://www.health.wa.gov.au/wacr/statistics/stats_full.cfm

Prostate Cancer Incidence and Mortality Trends USA

Prostate Cancer Incidence and Mortality Trends USA

* USA Govt Centre for Disease Control and Prevention http://www.cdc.gov/cancer/prostate/statistics/race.htm

Prostate Cancer Incidence Rates* by Race and Ethnicity, U.S., 1999–2009

Prostate Cancer Death Rates* by Race and Ethnicity, U.S., 1999–2009

Aetiology of Prostate Cancer

Testosterone

Promotes prostate cancer development

Prostate cancer does not develop in eunuchs

Testosterone supplements problematic in men with normal serum testosterone levels

• Genetics

Mutations in BRCA1 (on chromosome 17) and BRCA2 (on chromosome 13), important risk factors for ovarian

cancer 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 responsible

for 3% of prostate cancers.

• Dietary Factors

Little 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.

Pathology

Morphology Adenocarcinoma 99% cell of origin – basal cell most likely, not lumenal cell Ductal carcinoma 0.141% Mucinous adenocarcinoma 0.103% Small cell carcinoma 0.056% (neuroendocrine) Carcinosaroma 0.07% Embryonal carcinosarcoma 0.06%

Differentiation = Gleason score

Based on morphological appearance (grade 1 – 5) where two most common morphologies are added to give a sum score (2 – 10)

Gleason 3 + 4 = 7 where 3 is the most common morphological pattern and 4 is the second most common pattern

If three morphological patterns, first number is most common pattern and second number is the pattern with the highest grade

Higher score = poorer differentiation = worse prognosis

Gleason 3 Gleason 4 Gleason 4 Gleason 5

Gleason Score and Prognosis

Gleason score is an independent prognostic indicator:

Gleason 5 - 6 moderate grade cancer

Gleason 7 intermediate grade cancer

Gleason 8 - 10 high grade cancer

The 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 4-5 20 years

6 16 years

7 10 years

8-10 5 years

Gleason 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):538-42.

Clinical Management

Cancer screening and PSA

Diagnosis – TRUS biopsy and MRI

Prostate cancer prevention – “chemoprevention”

Expectant management “watchful waiting”.................

Curative therapy for Localized Disease (< T3 )

Surgery Perineal prostatectomy

Radical retropubic prostatectomy with dorsal vein ligation 1979 and neurovascular preservation 1982 by Patrick Walsh

Laparoscopic radical prostatectomy

Robotic laparoscopic radical prostatectomy

HIFU and Cryotherapy

Radiotherapy External External beam DXRT

Conformal external beam DXRT

IMRT Intensity Modulated Radiotherapy

IGRT Image Guided Radiotherapy

Internal LDR brachytherapy ( I125 seeds)

HDR brachytherapy

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.

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 2.2 - 3.2 days.

Immunoreactive PSA subgroup free PSA 1% - 30% of this group bound PSA bound to alpha 1 antichymotrypsin.

PSA Levels Affected By :

Prostatitis - levels up to 120 recorded, resolving with antibiotics.

Urine retention - up to 6 fold increase.

Ejaculation - 0.2 ng/ml increase 24 hours later.

Ambulation - decreases PSA up to 20%.

Prostate biopsy - 8 ng/ml increase 4 - 24 hours later.

TURP - 6 ng/ml increase with median return to baseline at 18 days

Klein et al, The effects of prostate manipulation on PSA levels.

Urologic Clinics of North America May 1998.

PSA as a screening test

PSA is a poor screening test with high sensitivity but very poor specificity

Advocated screening with yearly PSA and DRE for men between 50 and 70 years of age

Earlier commencement of screening advocated for those at risk of hereditary cancer between 40 and 70 years of age

Recommended 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.

PSA as a screening test

Australian Health Technology Advisory Committee (AHTAC) review 1996 - 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.”

Total PSA screening studies

PSA > 4ng/ml Overall cancer detection rate PPV

1.5% - 4.1% 33% mean

Incidence of cancer detection on prostate biopsy based on DRE findings and PSA.

PSA ng/ml DRE negative DRE positive

0 - 4 4 - 7% 10 - 13%

4 - 10 24 - 25% 41 - 62%

>10 31 - 42% 67 - 77%

Arcangeli et al Urologic Clinics of N. America, May 1998

PSA Density and Screening

PSA density = Total PSA ng/ml / TRUS determined prostate volume in ml

>0.15 with PSA 4 - 10

reduces number of biopsies 50%

misses 50% of cancers

Catalona et al : J Urol 153:2031,1994

PSA Velocity and Screening

This is shown to be higher in men with prostate cancer than in BPH

PSA slope cut off 0.75 ng/ml per year with PSA <4 ng/ml

sensitivity 79%

specificity 66%

Smith and Catalona: J Urol 152:1163, 1994

Difficult because there is a 15% short term variation in PSA levels Stamey et al: J Urol 155: 1977,1996

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 0.04 ng/ml per year.

Oesterling et al: JAMA 270:860, 1993

Catalona 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, 1994

Age related reference ranges improve specificity at the cost of sensitivity.

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 gain Luderer 4 - 10 <20% 5% 15% Catalona >4 <20% 10% 38%

Free/Total PSA - Netherlands Schroder Study

9,600 men 54 - 76 years old screened with PSA, DRE and TRUS

4.3% cancer detection rate

5.1 biopsy to cancer ratio

64% of cancers specimen confined at radical prostatectomy

Best sole predictor of prostate biopsy is total PSA

Specificity of PSA in range 4 - 10 is improved with F : T ratio

F : T ratio < 20 in total PSA range 4 - 10 reduces biopsies by 38% misses 12% of cancers Schroder et al: Urologic Clinics of North America, May 1998

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 saved

without QOLA with QOLA

well differentiated 1.35 1.01

moderately ‘’ 2.58 2.41

poorly ‘’ 2.78 2.68

Chodak metanalysis: Urologic Clinics of North America May 1998

The 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.

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 65 - 74 years

Grade Years of life lost

Well differentiated 2.2

Moderately ‘’ 4.9

Poorly ‘’ 7.1

Cost per year of life saved by prostate cancer screening and Rx

Age range Saving $US DRE + PSA

50 - 69 2339 - 3005

60 - 69 3905 - 5070

50 - 69 3574 – 4627

Benoit & Naslund: Urologic Clinics of North America, May 1998

Cost per Year of Life Saved By Various Interventions

Intervention Cost per year of life saved $US

Smoking cessation counseling 5,249 - 15,833

Hypertension control 32,600

CABG 62,900

Renal dialysis 42,000 - 80,300

Liver transplantation 225,000

Screening mammography 20,000 - 50,000

Cervical cancer screening 33,572

Colon cancer screening 28,848 - 113,348

For 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

Conclusion on the socio - economic implications of PSA Screening

Benoit and Naslund, Urologic Clinics of North America, May 1998

“Although men aged 50 - 75 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.”

PSA screening – large trial results

Mortality Results From a Randomized Prostate-Cancer Screening Trial

Andriole et al NEJM 2009 360:13 1310-19

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 and

1.7 (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.

PSA screening – large trial results

Screening and Prostate Cancer Mortality in a Randomized European Study Schroder et al NEJM 2009 360:13 1320-28

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.

End of the PSA Era?

Diagnosis – TRUS Biopsy

Prostate biopsy is required for diagnosis, generally 11 biopsies taken

Transperineal 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.

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 cancer

vs 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% PPV

Current 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 TO

AVOID BIOPSY.

PATIENT 76 YEAR OLD PSA ELEVATED FOR A NUMBER OF YEARS BIOPSY X4 INFLAMMATORY CHANGES TREATED WITHY CIPROFLOX PIN

IDENTIFIED IN BIOPSY SPECIMEN PREVIOUSLY

Transperineal 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)

11 oc ext ant

T2 Axial NADT2 Axial SlightlyMore rostral

DWI ADC

Colour mapColour map graph

Axial Ultrasound Lesion visible Hypoechoic

Diffusion Imaging (Brownian motion)

Prevention

Castrate 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 dutasteride

Effective 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).  

Prevention - Finasteride

USA Prostate cancer prevention trial 1993 – 2003

18,882 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 that the 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% to 1.8%raised (and more likely cause of early closure). Prompted FDA warning.

Subsequent analysis suggests finasteride “improved sensitivity of PSA for cancer overall, and especially for high grade cancer”.

The Influence of Finasteride on the Development of Prostate Cancer. Thompson et al NEJM 2003; 349: 215

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.

Expectant Management

Albertsen et al Competing Risk Analysis for Men Aged 55 to 74 Years at Diagnosis Managed Conservatively for Clinically Localised Prostate Cancer

JAMA 280(11), 975 1998

Radical Prostatectomy

Cure 80% PSA 4-10, Gleason < 7, Stage T1c (Positive margin rate average 30% in Perth)

This group of patients have 10 - 20 % 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% incontinence 80% impotence 0.5% death blood transfusion, rectal injury, lymphocoele

“PSA recurrence” = not cured Rx radiotherapy (? 1/3 cured) hormonal manipulation ? Better local control ? Better survival in this group

Puboprostatic Ligaments and Endopelvic Fascia

Dorsal Vein Ligation

Neurovascular Bundles

Neurovascular Bundle preservation

Radical Prostatectomy

Open radical retropubic prostatectomy

Now 4 – 5” midline incision

3 – 4 days hospital stay

2 – 3 weeks indwelling catheter

• Laparoscopic radical retropubic prostatectomy

2” incision + port sites

2 – 3 days in hospital

1 – 2 weeks indwelling catheter

More rapid return to work

• Cancer outcomes the same for open vs laparoscopic radical prostatectomy

• Slightly lower impotence rate for laparoscopic radical prostatectomy

• Slightly higher complication rate for laparoscopic radical prostatectomy, including rectal injury

• Robotic radical prostatectomy

Robotic Radical Prostatectomy

Da Vinci robot developed through the 1990’s and given approval by US FDA in 2000. 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.

Da Vinci Robot

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 7% vs 2% open radical prostatectomy Lepor et al Reviews in Urology 2005 Summer; 7(3): 115–127

Impotence 25% vs 30% “ “ “ “ “

Rectorethral fistula 0.53% overall with no good comparison laparoscopic/robotic/open

Hospital stay the same as manual laparoscopic radical prostatectomy, all lapararoscopic prostatectomy 1 – 2 days shorter hospital stay than open radical prostatectomy.

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):3376-85.

CONCLUSION: Eight-year biochemical failure rates were identical between radiotherapy and surgery in any subgroup. Outcome is

determined 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 effective

Six week treatment

Morbidity 2% radiation proctitis 2% radiation cystitis - 50% impotence within first year, increasing thereafter - insignificant incontinence

Pretreatment 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 vs radical prostatectomy Secondary Bladder Cancer After Radiotherapy For Localized Prostate Cancer

Abern et al Chicago, IL (AUA presentation) J Urology 185, No. 4S, Supplement May 2011

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.

IGRT

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 Urology

187, Issue 4, April 2012,1259-1265

The adjusted 10-year prostate cancer specific mortality was ;

1.8% (95% CI 1.6–2.1) Radical prostatectomy 6, 485 patients

2.9% (95% CI 2.6–3.3) External beam DXRT 2,264 “

2.3% (95% CI 2.0–2.6) LDR Brachytherapy 1,680 “

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).

Brachytherapy - HDR

Control rod needles positioned under GA with TRUS day before

Stabilizing template sutured to perineum, dosimetry figured by physicists/radiotherapist, needles connected to HDR machine

Iridium 192 radioactive wire source inserted via established needles, with dwell time and location governed by pre programmed HDR machine

Time on machine relatively short – minutes

Template and needles removed at the end of procedure

High doses of radiotherapy delivered with low morbidity

Generally 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 Cancer Deger et al European Urology Volume 47, 4, April 2005, Pages 441–448

Five-year progression free survival: 81% in the low risk group, 65% in the intermediate risk group 59% in the high risk group

HIFU

High 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 ultrasound

in localized prostate cancer. Ganzer et al BJUI August 2013 112,3 322–329

538 patients mean follow up 8.1 years mean age 67.7 years 490 ≤ Gleason 7 221 stage T1 296 stage T2

TURP performed 4 -6 weeks prior to HIFU if prostate > 30 gm

Actuarial BDFS 5 years: 81% Biochemical disease free survival Phoenix criteria (PSA nadir+2 ng/mL)

10 years: 61% Mean PSA nadir 0.4

297 patients biopsied 25.6% biopsies showed cancer

Cancer specific deaths 3.3%

Complications: rectorethral fistula 0.7% 4 patients

bladder outflow obstruction 28%

urine incontinence 2.8%

impotence @ 12 months 75% Not as yet available in WA but available in Melbourne and Sydney

HIFU

2 machines available: Sonotherm and Ablatherm

HIFU

Clinical Management

Palliative therapy for metastatic disease

Hormonal manipulation Castration

Estrogens

LHRH analogues

Antiandrogens

Intermittent hormone manipulation

Abiraterone

Ketoconazole

Chemotherapy Mitoxantrone

Docetaxel

Carbazetaxel

Immunotherapy Sipileucel T

Injectable radiotherapy Strontium

Radium

Targeted therapy ?

Palliative Hormonal Manipulation - Castration

Studies on Prostatic Cancer I.

The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in

Metastatic Carcinoma of the Prostate*

Charles Huggins, M.D., and Clarence V. Hodges,M.D. Chicago, Illinois Cancer Res 1941;1:293-297

“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 cancer

Response rate: 80% respond with biochemical and clinical remission Catalona and Scott J Urol 119, 1-8 1978

Response duration: Most patients with metastatic disease demonstrate hormone manipulation resistance within 18 – 24 months

Average survival 3 – 5 years on hormone manipulation when presenting with metastatic disease

Early vs delayed hormonal manipulation: VACURG study 1967 showed no survival difference with early vs delayed therapy

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;1:293-297

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, 528 - 533

Thromboembolism risks

Stibestrol used as an alternative to castration up until the arrival of LHRH analogues (1993 PBS Aus)

dosage 1mg – 3mg per day

• Some resurgence in the 1990’s as second line hormonal manipulation

Palliative Hormonal Manipulation – LHRH Analogues

Goserelin (Zoladex) was the first LHRH analogue licensed for use FDA 1989 TGA 1991

initially 3.6 mg monthly S/C pellet injection, later 10.8 mg 3 monthly S/C pellet injection

• Synthetic 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 cancer

• Side effects: impotence, hot flushes, weight gain, depression, osteoporosis (same as for castration)

• Cost is $1108.97 for a 10.8 mg injection to the government ($4,435.88 per year), on PBS either $5.90 ( for concession holders) or $36.10 to the patient.

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 surface

Flutamide, Nilutamide and Cosudex

Second 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

Palliative Hormonal Manipulation – Intermittent Hormonal Manipulation

• Bruchovsky from Vancouver first published on this in 1990

Large 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 trial

Mottet et al BJUInternational 2012 | 110, 1262–1269

• One 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 disease

• Problematic in advanced symptomatic disease

• In 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)

Chemotherapy - Docetaxel

Randomized trial of Docetaxel vs Mitoxantrone (both with prednisolone) published in NEJM 2004

The 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 pain

13 percent vs 22 percent (P = 0.009) had improvements in the quality of life

Adverse events were also more common in the groups that received docetaxel

Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer

Tannock et al NEJM 351;15 October 7, 2004

New Palliative Therapies For Advanced Disease

ABIRATERONE

Developed 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 activity

Current 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 months

versus 10.9 months for placebo).

70% show significant PSA reduction.

Works better in men with ERG proto-oncogene = ETS (erythroblast transformation- specific) related gene

ERG protein is a transcription regulator

Approved by the FDA in April 2011

Placed on PBS Australia August 2013 for failed hormone manipulation followed by failed chemotherapy with Docetaxel

Annual cost ? $40,000

Single daily tablet 1gm (on empty stomach) administered with prednisolone 5mg b.d.

Side effects: hypertension, fluid retention, CCF and hypokalemia

adrenal insufficiency

elevation of ALT and AST

New Palliative Therapies For Advanced Disease

CABAZITAXEL

A semi-synthetic derivative of a natural taxoid.

It was developed by Sanofi-Aventis

Approved by the U.S. Food and Drug Administration (FDA) for the treatment of

hormone-refractory prostate cancer in June 2010.

It is a microtubule inhibitor.

Phase III trial with 755 men for the treatment of hormone-refractory prostate cancer

median survival was 15.1 months for patients receiving cabazitaxel versus 12.7

months for patients receiving mitoxantrone.

Used with prednisolone.

Approved by TGA but rejected PBS listing in 2011 for patients with metastatic

hormone refractory prostate cancer having failed docetaxel as well.

New Palliative Therapies For Advanced Disease

SIPULEUCEL-T

Immunostimulant 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, are

extracted 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, and

b) An immune signalling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the

APCs to mature.

The activated blood product (APC8015) is returned from the factory to the infusion center and re-infused into the

patient 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 between

successive courses.

IMPACT trial served as the basis for licensing approval of Sipuleucel-T by the FDA in 2010. 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.

New Palliative Therapies For Advanced Disease

RADIUM-223 CHLORIDE

Phase 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 effects

Nausea, 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.