Prostate Cancer. Julian Mander RPH Urology. Histological Incidence at Autopsy. Histological cancer in autopsy studies 27% Third decade
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
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.
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 Bureau of Statistics Yearbook Australia 1301.0 - 2005 Health - Article - Cancer Trends
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)
Prostate cancer deaths: 3,294
Deaths (Male) from MVA: 921 Australian Govt Dept Transport and Infrastructure
Suicide (Male) deaths: 1,726 ABS Yearbook 2013
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
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
Prostate Cancer Incidence Rates* by Race and Ethnicity, U.S., 1999–2009
Prostate Cancer Death Rates* by Race and Ethnicity, U.S., 1999–2009
* USA Govt Centre for Disease Control and Prevention http://www.cdc.gov/cancer/prostate/statistics/race.htm
Promotes prostate cancer development
Prostate cancer does not develop in eunuchs
Testosterone supplements problematic in men with normal serum testosterone levels
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.
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.
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 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 Int2002 Apr;89(6):538-42.
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)
free PSA 1% - 30% of this group
bound PSA bound to alpha 1 antichymotrypsin.
Klein et al, The effects of prostate manipulation on PSA levels.
Urologic Clinics of North America May 1998.
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.”
1.5% - 4.1% 33% mean
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
reduces number of biopsies 50%
misses 50% of cancers
Catalona et al : J Urol 153:2031,1994
Smith and Catalona: J Urol 152:1163, 1994
Stamey et al: J Urol 155: 1977,1996
Oesterling et al: JAMA 270:860, 1993
Catalona et al: J Urol 152:2037, 1994
Luderer 4 - 10 <20% 5% 15%
Catalona >4 <20% 10% 38%
reduces biopsies by 38%
misses 12% of cancers
Schroder et al: Urologic Clinics of North America, May 1998
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
Chodakmetanalysis: Urologic Clinics of North America May 1998
Grade Years of life lost
Well differentiated 2.2
Moderately ‘’ 4.9
Poorly ‘’ 7.1
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
Intervention Cost per year of life saved $US
Smoking cessation counseling 5,249 - 15,833
Hypertension control 32,600
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
Benoit & 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.”
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.
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.
“Dynamic Contrast Enhanced” imaging DCE
“Diffusion weighted imaging” DWI - Difference in Brownian motion of water molecules in cancer
vs normal tissue.
PATIENT 76 YEAR OLD PSA ELEVATED FOR A NUMBER OF YEARS BIOPSY X4 INFLAMMATORY CHANGES TREATED WITHY CIPROFLOX PIN IDENTIFIED IN BIOPSY SPECIMEN PREVIOUSLY
T2 Axial Slightly
T2 Axial NAD
Lesion visible Hypoechoic
11 oc ext ant
Transperineal systematic cores (11 systematically) additional 2 cores from presumed index lesion at 11 oclock (13 cores in total) 8mm,13mm and 10 mm acinarAdenocarcinoma 11 oclock
(Slide courtesy of Jim Anderson)
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).
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
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
30% in Perth)
blood transfusion, rectal injury, lymphocoele
Rx radiotherapy (? 1/3 cured)
? Better local control ? Better survival in this group
Now 4 – 5” midline incision
3 – 4 days hospital stay
2 – 3 weeks indwelling catheter
2” incision + port sites
2 – 3 days in hospital
1 – 2 weeks indwelling catheter
More rapid return to work
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
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 ClinOncol 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
2% radiation cystitis
- 50% impotence within first year, increasing thereafter
- insignificant incontinence
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
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)
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
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 survivalPhoenix 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%
2 machines available: Sonotherm and Ablatherm
Hormonal manipulation Castration
Intermittent hormone manipulation
Immunotherapy Sipileucel T
Injectable radiotherapy Strontium
Targeted therapy ?
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 remissionCatalona 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
dosage 1mg – 3mg per day
initially 3.6 mg monthly S/C pellet injection, later 10.8 mg 3 monthly S/C pellet injection
Cyproteroneacetete 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) –
Flutamide, Nilutamide and Cosudex
Intermittent hormonal therapy in the treatment of metastatic prostate cancer: a randomized trial
Mottet et al BJUInternational2012 | 110, 1262–1269
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
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
elevation of ALT and AST
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.
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
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.
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).
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.