Prostate Cancer

Prostate Cancer Screening and Treatment C G French MD FRCSC Dept of Surgery Memorial University

Prostate Cancer Incidence increases with age:  Between the ages of 40-59, 1 in 55 men will develop prostate cancer  Between the ages of 60-79, 1 in 7 men will develop clinically significant disease. 

Treatment Options        

Radical prostatectomy (open or robotic) External beam radiation (IMRT) Seeds implantation (brachytherapy) Combination beam and seed implant Cryotherapy (total or focal) Hormone therapy Chemotherapy HIFU

Optimal Outcomes after RP      

Statistical analysis to predict probability of “optimal outcome” (Trifecta) after RP based on MSK data base 647 patients evaluable, July 1998 – July 2003. Mean age 58 Stage: T1c or T2a : 78.8% Optimal Outcome = PSA at 0.2 , Dry without pads, Potent: normal erections with or without PDE5 Population: mean age 58, nerve sparing RP (Bilateral in 93.4%) Trifecta probability: 1 year: 30%, 2 years: 42%, 3 years: 47% , 4 years : 53% Saranchuk, Kattan, Elkin, Touijer, Scardino. Achieving Optimal Outcomes after Radical Prostatectomy J Clinical Oncology 23: No 18, 4146-4151.

The Perfect Prostate Cancer Treatment 

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Cancer (PSA) Control: patient does not die from prostate cancer Continent with normal urinary function Potent with preservation of erectile function

PSA Screening 

Not recommended by:  

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National cancer institute 

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Under investigation

Canadian Urological Association 

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US Peventative Health Care Canadian Task force on preventative health

Patients need to decide

American Urological Association 

Yearly DRE and PSA after 50

PSA Screening 

Need to balance risks with benefits.    

Risk of overtreatment Psychological risk of high PSA without cancer Benefit of early curative treatment Benefit of preventing disabling cancer spread

PSA Screening  

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Statistical data is mixed regarding survival advantage to screening. Radical prostatectomy data now decisively shows survival benefit over conservative treatment.( 5% survival advantage) Numerical years is not as important as the quality of those years. Physicians who treat Prostate cancer feel very strongly that the statistics will prove PSA helpful in the long run. New tests will be used in conjunction with PSA

182000 men randomized to Screening every 4 years QuickTimeª and a decompressor are needed to see this picture.

Compared to control. Age 55=69 Mean follow up 9 yrs Incidence

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Conclusion: PSA based screening reduced the death rate of prostate cancer by 20% but resulted in a high risk of overdiagnosis

screened 8.2% control 4.8%

PLCO Dataset 76693 men screened QuickTimeª and a decompressor are needed to see this picture.

Yearly DRE and PSA Vs “Usual Care” 116 per 10000 screened

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Conclusion: At 7-10 years follow-up The death rate of prostate cancer was low And did not differ significantly.

95 per 10000 usual care

Single elevated PSA, what now? 

How do we as urologists decide upon biopsy?   

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Age adjusted PSA velocity Symptoms that suggest inflammation (any symptoms really) Free PSA (less often) DRE findings (large gland vs firm nodule) Associated Comorbidities – (life expectancy) Family History

Population studies. 

Mean PSA according to age:     

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<50 --0.8 50-59 –1.5 60-69 –2.3 70-79 –2.8 >80 –4.4

If PSA elevated:  

25 -35% of patients with a return visit and a single repeat PSA will be normal 40 – 50% of patients eventually return to normal

JAMA, May2003:V289,No.20 Variation of Serum PSA Levels

Population studies. PSA 4-10

25% Biopsy positive 75% negative

If we include all the previous information our goal is to decrease unnecessary biopsies. 40 – 50% Biopsy positive Decreased biopsies

PSA during Prostate Cancer Surveilance Klotz, J Urol Oct 2006, U of T     

231 Patients, Prospective cohort Mean age 70 Gleason 3+3 or less Mean PSA 10 PSA doubling times  

High risk 2.97 years (40%) Low risk 6.54

PSA Patterns    

Spike rise and fall Slow rising Fast rising Persistantly elevated plateau

PSA Patterns  

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Spike rise and fall 54 yo lawyer with PSA 14. First level. Mild irritative urinary symptoms. No family history. DRE normal, 25gms. PSA repeated 1 month –8.1 Then 3monthly 7.1, 5.4, 3.6. Inflammatory rise and fall, no biopsy needed. Follow PSA until Nadir. Aim for age adjusted normal level <2.5.

PSA Patterns    

Slow Persistant Rise 64 yo with PSA 6.4, last two years 4.5 and 4.1. Mild obstructive symptoms, DRE 60 gms, no nodules. No family history, excellent health. PSA repeated 5.2

PSA Patterns 

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Pattern is doubling slow, suggestive of BPH. PSA is elevated when age adjusted Biopsy –negative PSA then yearly 5.6, 6.1, 5.9

PSA Patterns    

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Rapid Persistant Rise 58 yo with PSA 4.5 Last 2 years 3.1, 1.9 His brother had Radiation for prostate cancer at age 65. Repeat PSA monthly for 3 months 

4.7, 4.9, 5.1

PSA Patterns   

Biopsy Gleason 3+4=7 3/8 cores positive Treatment 

Radical prostatectomy

PSA Patterns  

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Persistant High PSA 64 yo with PSA 16.1 No symptoms. Previous biopsies times 2 showed inflammatory infiltrate. No family history. DRE benign PSA is surrogate of inflamation and not a useful screen in this patient. PSA yearly 12.1, 14.2, 16.5, 12.1

How I do it: Factors to support observation and repeat PSA  

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Any symptoms of inflammation of BPH Spike in PSA, or history of rapid rise and normalize Risk of UTI Normal DRE, or large by volume No Family History Age >65 Life expectancy <10yrs

How I do it: Factors to support Biopsy       

Strong Family History Step wise slow rise in PSA over 1-2 yrs Age adjusted cutoff No symptoms Firm Nodule Healthy fit < age 60 Patient is very worried

Prostatic Intraepithelial Neoplasia: What is the clinical significance?

History 

Atypical epithelial proliferations of the prostate have long been recognized    

Oertel Andrews McNeal Bostwick

1926 1949 1965 1987

History 

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A correlation between atypical epithelium and carcinoma lead to further characterization Prostatic Epithelial Neoplasia  

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Bostwick and Brawer 1987 Further graded I,II,III by Bostwick and McNeal

Atypical Adenomatous Hyperplasia

History 

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The diagnosis of grades I,II,III PIN varied among individual pathologists Thus the grading system of low and high grade PIN was adopted International Consultation on PIN and Pathologic Staging of Prostate cancer 

Dec 1995 at Mayo Clinic (Bostwick)

Histologic PIN 

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Hyperchromatic acini with crowding and irregular spacing of inner secretory cells Low Grade 

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Crowded hyperplastic epithelium with marked variation of nuclear size and only few nucleoli Difficult to differentiate between reactive

High Grade 

More pronounced crowding and less variation in nuclear size (all large) with prominent nucleoli

High Grade PIN as a precursor for Cancer 

High grade PIN is associated with prostate cancer, low grade is NOT 

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50% of re-biopsies for high grade PIN show carcinoma

Similar chromosomal abnormalities to cancer Increasing grades of PIN show progressive change in expression of biologic markers 

P53, bcl-2, e-cadherin

High Grade PIN as a precursor for Cancer 

Autopsy and prostatectomy data 

Whole prostatectomy specimens   

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With Cancer 80% associated PIN Without cancer 50% associated PIN These include high and low grades

Like prostate cancer, more common in the apical portion and peripheral zone of the gland It is estimated that PIN may preclude cancer by 10 years

Does Therapy cause regression of PIN?   

After radiotherapy PIN is nearly impossible to diagnose Antiandrogen therapy causes apoptosis of PIN, normal epithelium and carcinoma. Finasteride therapy causes glands to shrink and changed the gland appearance: This is likely the effect noted in the Prostate Cancer prevention Trial

PSA and PIN 

Does PIN increase serum PSA levels?

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What is the pathophysiology of increased serum PSA?

Elevated PSA   

Persistent increased serum PSA leads to prostatic biopsy. When High grade PIN is found does this histologic diagnosis explain the PSA? Some authors suggest there is a correlation but close scrutiny of the data suggest a confounding incidence of cancer volume

Elevated PSA 

Alexander et al. Urology 1996  

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PIN volume did not correlate with PSA When adjusted for cancer volume, prostate volume or BPH there was no correlation to serum PSA

Davidson et al. J. Urol 1995 

Hazards model PSA >4  Initial Biopsy High PIN 

3.64 RR 15 RR

Free/Total PSA 

The ratio of free PSA is lower in cancer but not in PIN %Fpsa 27.7 20.1 20.8 14.9

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Normal BPH PIN Cancer

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Ramos et al. J Urol 1999

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psa 1.2 4.2 4.4 4.9

age 61 67 67 65

Volume(cc’s) 39.3 36.3 37.6

Biopsy technique and PIN   

Repeat biopsy for PIN reveal cancer in 3575% This variation is due to the technique of biopsy employed Lower number and targeted biopsies are more likely to reveal cancer on second biopsy when compared to sextant U/S guided

Biopsy technique and PIN 

13 radical prostatectomy specimens where only PIN was diagnosed preoperatively.  

Prostate cancer was diagnosed in all The volume of cancer correlated to the biopsy technique Less sampling = Higher volume of cancer  Alexander et al., Ronnett et al. 

Clinical Relevance Of PIN      

Only significant if it’s HIGH GRADE Is the patient a candidate for radical therapy? If No then likely not relevant. How well was the prostate sampled? If not well then the RR for cancer is higher Radical therapy is not indicated for a diagnosis of PIN alone

Clinical Significance Of PIN 

Current recommendations are to Rebiopsy in 6 months and if PIN is still found continue every 6 months for 2 years then yearly.

Clinical Significance Of PIN   

What about Chemoprevention? Trials are underway The presence of PIN could be used as a marker of failure.

Conclusions PSA screening is the best tool we have but is still controversial A single high level is a flag, needs to be repeated and reviewed by a physician skilled in identifying patterns PIN on a biopsy usually requires a repeat biopsy to rule out cancer PSA slowly rises with BPH, but can be correlated to prostate volume and the rising trend is slower than that of prostate cancer.

Conclusions PSA slowly rises with BPH, but can be correlated to prostate volume and the rising trend is slower than that of prostate cancer. Finasteride can reduce progression of BPH and reduce urinary retention and the need for prostate surgery. PSA levels drop then stabilize on finasteride, if PSA rises despite treatment non BPH causes should be considered.