A Man, a Glove and a Gland: Finding Prostate Cancer

A Man, a Glove and a Gland: Finding Prostate Cancer

Mike Thom, MD

Primary Care Conference

March 30, 2005

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A Man, a Glove and a Gland: Objectives

• Appreciate the incidence of prostate cancer in one (i.e. this) general internist’s practice

• Appreciate the controversy that abounds in applying screening modalities in the diagnosis of prostate cancer

• Learn to trust your finger (more on that later)• Agree that we need improved methods to

determine how to differentiate who will die with their disease from who will die from it.

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Case Outlines

• Patient S.F.

• Age: 41

• PSA: 1.0

• PSA Velocity: NA

• Exam: L Sided Nodule

• Gleason Score: 3+3=6

• Therapy: RRP 3/04

• Comments: F/U PSA <0.1

• Continence: Dry

• Erections: Fully Potent

• Patient D.K.• Age = 47• PSA = 0.6• PSA Velocity = NA• Exam: Nodule R apex• Gleason Score: 3+6=6• Therapy: XRT 9/04• Comments: Pos bx next to

nodule• Continence: Dry• Erections: ??

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Case Outlines

• Patient R.F.• Age: 57• PSA: 2.4• PSA Velocity: 0.5ng/yr• Exam: Nodule L base• Gleason Score: 3+3=6• Therapy: RRP 6/04• Comments: Nodule 7/02;

+FH• Continence: Dry• Erections: Adequate

• Patient J.F.• Age: 62• PSA: 2.8• PSA Velocity: -0.9ng/yr• Exam: Nodule R apex• Gleason Score: 3+3=6• Therapy: RRP 7/04• Comments: PSA 3.4

11/03; Nodule present in 2001

• Continence: Dry• Erections: Partial

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Case Outlines

• Patient: C.S• Age: 63• PSA: 6.9• PSA Velocity: 1.0 ng/yr• Exam: L lobe>R lobe BPH• Gleason Score: 3+3=6,

10% • Therapy: Pending• Comments: PSA 7.3,

2001; 5.6, 2003• Continence: NA• Erections: Partial

• Patient J.D.• Age: 65• PSA: 7.0• PSA Velocity: 4.1 ng/yr• Exam: Nodule R lobe• Gleason Score: 3+3=6, 1%• Therapy: XRT 1/04• Comments: • Continence: Dry• Erections: ??

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Case Outlines

• Patient: D.R.• Age: 67• PSA: 5.7• PSA Velocity: 2.2 ng/yr• Exam: BPH, no nodules• Gleason Score: 3+3=6• Therapy: RRP 2/04• Comments: PSA 2.8 to 5.7

in 16 months• Continence: Dry• Erections: “80%”

• Patient T.B.• Age: 67• PSA: 6.8• PSA Velocity: 1.7 ng/yr• Exam: BPH me, nodule

urology• Gleason Score: 3+4=7• Therapy: RRP 1/04• Comments: Androgen rx

for hypogonadism 2003 • Continence: Dry• Erections: ??

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Case Outlines

• Patient: L.P.• Age: 69• PSA: 7.7• PSA Velocity: 1.2 ng/yr• Exam: BPH, no nodules• Gleason Score: 3+4=6,

50%• Therapy: RRP 8/04• Comments: • Continence: SUI, mild• Erections: on awakening

• Patient C.P.• Age: 70• PSA: 2.4• PSA Velocity: 0.05 ng/yr• Exam: Nodule, R base• Gleason Score: 3+3=6• Therapy: RRP 5/04• Comments: Nodule R base

2002 • Continence: Dry• Erections: Impotent pre-op

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Case Outlines

• Patient: L.K.

• Age: 76

• PSA: 4.0

• PSA Velocity: 0.27 ng/yr

• Exam: Nodule R apex

• Gleason Score: 4+3=7, 60% involved

• Therapy: Observation

• Comments: Nodule in 2003, hx CAD, COPD

• Continent: NA

• Erections: Minimal

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A Man, a Glove and a Gland: Finding Prostate Cancer

• Financial Conflicts• Dr. Hedican sent me a Christmas card• Golden (or brown?) Glove Award nomination?

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Prostate Cancer: To screen or not to screen; that is the question

• Prostate cancer is the most commonly diagnosed

visceral cancer in the US.• Second leading cause of cancer death in males

• 17% risk of being diagnosed with prostate cancer• 3% risk of death from prostate cancer

• Autopsy series reveal prostate cancer present in 1/3

men age 65- 80 and 2/3 men > age 80– Dorr VJ; Williamson SK; Stephens RL. Arch Intern Med 1993 Nov

22;153(22):2529-37

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Prostate Cancer: To screen or not to screen; that is the question

• The controversy …• No studies as of yet have shown clear cut benefit

from screening but …• There is considerable potential harm from

aggressive treatments• “Is cure possible in those for whom it is necessary,

and is cure necessary in those for whom it is possible?– Whitmore WF Jr. Urol Clin North Am 1990

Nov;17(4):689-9

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Screening for Prostate Cancer: Measurement of Prostate Specific Antigen (PSA)

• PSA: Glycoprotein expressed by normal and

neoplastic prostate tissue

• Expression per cell is less in neoplastic tissue than

normal tissue

• PSA normally produced as a prohormone

(proPSA) secreted into the prostate ductal lumen

• ProPSA acted on to generate active PSA

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• Active PSA undergoes proteolysis to form inactive PSA

• Inactive PSA enters bloodstream and circulates unbound (free PSA)

• Small amounts of active PSA enters bloodstream and become bound by protease inhibitors

• Prostate cancer cells generate less PSA per cell• Cancer disrupts basement membrane and normal

lumen architecture

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• In prostate CA, proPSA enters circulation and a larger fraction of cancer cell generated PSA escapes proteolysis.

• More PSA therefore is bound by serum protease inhibitors, resulting in a lower percentage of free or unbound PSA in the serum of men with prostate cancer

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Screening for Prostate Cancer: Measurement of PSA: Age specific references

• 40 to 49 years-old … 0 to 2.5 ng/ml




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Screening for Prostate Cancer: Measurement of PSA: Causes of elevated serum PSA

• BPH

• Prostate cancer

• Prostate inflammation

• Perineal trauma

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Measurement of PSA: Causes of elevated serum PSA: BPH

• Most common reason for elevated PSA is BPH

• BPH tissue produces more PSA per gram than

normal prostate tissue

• Considerable overlap between men with BPH and

prostate cancer

• Medical treatment of BPH with finasteride reduces

PSA by nearly 50% during the first 3 months of

therapy

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Measurement of PSA: Causes of elevated serum PSA: Prostate inflammation

• Prostatitis an important cause of elevated PSA

• One approach in elevated PSA with normal exam

is to treat with antibiotics and then repeat PSA

after six to eight weeks

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Measurement of PSA: Causes of elevated serum PSA: Perineal trauma

• DRE may cause minor, insignificant elevations of

PSA in the 0.2 to 0.4 ng/ml range• PSA may be measured immediately after DRE• Ejaculation may increase levels up to 0.8 ng/ml,

returning to normal within 48 hrs.• Vigorous biking may elevate the value

inconsistently• TURP or prostate biopsy elevates values for six

weeks

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Measurement of PSA: Test Performance

• Determining accuracy difficult• Most men with normal PSA do not undergo

biopsy unless DRE abnormal• False negative rate of transrectal biopsies may

range from 10 to 20 %– Levine MA; Ittman M; Melamed J; Lepor. J Urol 1998

Feb;159(2):471-5

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Measurement of PSA: Test Performance

• In one protocol using large numbers of samples doing biopsies, it is estimated that upwards of 25% of cancers detected by PSA screening were too small to have accounted for the PSA rise that prompted the biopsy– McNaughton Collins M; Ransohoff DF; Barry M.

JAMA 1997 Nov 12;278(18):1516-9

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Measurement of PSA: Test Performance: Sensitivity and Specificity

• Using traditional cutoff of 4.0 ng/ml;– Sensitivity estimated at 70%

– Specificity estimated at 60-70%

• Aggressive high grade cancers produce less PSA

per unit volume, hence reduced sensitivity of PSA

• Lower sensitivity in men with symptomatic BPH

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• Physicians’ Health Study (early 1980s), before

PSA availability– Gann PH; Hennekens CH; Stampfer MJ. JAMA 1995

Jan 25;273(4):289-94

• 366 men with prostate cancer detected clinically

• 1098 age matched controls

• PSA later measured from stored serum

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• Physicians’ Health Study (early 1980s), before PSA availability– Gann PH; Hennekens CH; Stampfer MJ. JAMA 1995 Jan

25;273(4):289-94

• PSA cutoff of 4.0 was 73% sensitive in detecting cancer

within four years of entering study (87% in detecting

aggressive cancers)

• PSA specificity 91%

• PSA over 4.0 preceded clinical detection by 5 yrs

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Measurement of PSA: Test Performance: Positive predictive value (PPV)

• Positive predictive value = the proportion of men with an abnormal value who have prostate cancer

• Overall PPV for PSA > 4.0 ng/ml approx. 30%• PSA 4.0 to 10.0 ng/ml is 25%• PSA > 10 ng/ml equates with PPV from 42 to 64%• 75% cancers found in 4.0 to 10.0 ng/ml zone are

organ confined and potentially curable• 50% organ confined if PSA > 10 ng/ml

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Measurement of PSA: Effect of lowering PSA cutoffs

• Prostate Cancer Prevention Trial

– Prevalence of prostate cancer among men with a prostate specific

antigen level < or = 4.0 ng/ml. N Engl J Med 2004. May 27; 350

(22):2239-46. Thompson IM et al

• 18,882 men

• 9459 randomly assigned to placebo had annual PSA and DRE

• 2950 of 9459 never had PSA > 4.0 or abnormal DRE

• After 7 years, all 2950 (ages 62 to 91 yrs) underwent prostate biopsy

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• Prostate Cancer Prevention Trial:

– Prevalence of prostate cancer among men with a prostate specific

antigen level < or = 4.0 ng/ml

• Prostate cancer found in 449/2950 (15.2%)

• 67/449 (14.9%) = Gleason score 7 or higher

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• 6.6% prevalence with PSA < 0.5

• 10.1% prevalence with PSA 0.6 to 1.0




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• Nevertheless, a study of 875 men undergoing radical prostatectomy found limited association between pre op PSA of 2 to 9 and cure rates

• Survival curves did not diverge until PSA > 7• Most PSA elevations below 7.0 attributed to BPH

• Stamey TA; Johnstone IM; McNeal JE; Lu AY; Yemoto

CMSO - J Urol 2002 Jan;167(1):103-11.

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Measurement of PSA: Improving the accuracy

• PSA velocity• PSA density• Free PSA• Complexed PSA• Age-specific reference ranges• Race-specific reference ranges• None of above reduce the number of unnecessary

biopsies or improve clinical outcomes

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Screening for prostate cancer: Digital Rectal Exam (DRE)

• Abnormal findings include– Nodules– Asymmetry– Induration

• DRE can detect findings in the posterior and lateral aspect of the gland …

• 85% of cancers arise peripherally where they can be detected

• The majority of cancers detected by DRE alone are clinically or pathologically advanced

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Screening for prostate cancer: Digital Rectal Exam (DRE)

• No controlled studies have shown a reduction in morbidity or mortality when detected by DRE at any age

• Urologists have relatively low interrater agreement for detecting prostate abnormalities. (84% concordance in recommending findings for biopsy)– Interexaminer variability of digital rectal examination in

detecting prostate cancer. Smith DS, Catalona WJ; Urology 1995 Jan;45(1):70-4.

• Positive predictive value of DRE … 5 to 30%

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Screening for prostate cancer: Combining PSA and DRE

• Combined use can increase the overall rate of cancer detection

• Multicenter screening study• 6630 men• 15% PSA > 4.0; 15% DRE abnl; 26% either/or

both• 1,167 biopsies• 264 cancers• PSA found 82% (216 of 264) and DRE 55% (146

of 264)

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Screening for prostate cancer: Combining PSA and DRE

• 45% cancers detected by PSA alone; 18% detected by DRE alone

• 160 (of the 264 pts with cancer) underwent radical prostatectomy

• 114/160 (71%) had organ confined disease

• PSA detected 85/114 (75%) organ confined disease

• DRE detected 64/114 (56%) organ confined disease

• Both DRE and PSA positive detected 50 of 64 (78%) over DRE alone– Catalona, WJ; J Urol 1994 May;151(5): 1283-90

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Screening for prostate cancer: Effectiveness: Evidence from randomized trials

• There are no convincing data from randomized, controlled clinical trials of screening that show benefits on morbidity and mortality.

• Two large randomized trials underway … American Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer.

• Results will be pooled, not available for a few years

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Screening for prostate cancer: Effectiveness: Evidence from observational studies

• Surveillance Epidemiology and End Results (SEER) tumor registry data have shown a significant decline in the incidence of advanced stage disease, potentially consistent with effective screening– Eisner, MP; Kosary, CL, et al. SEER Cancer Statistics

Review, 1973-1999. National Cancer Institute, Bethesda, MD, 2002.

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Prostate cancer mortality rates, which initially increased following the advent of PSA testing, have

now declined to pre-PSA levels

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Evidence from observational studies:

• Center for Prostate Disease Research Database at Walter Reed Army Medical Center– Paquette EL - Urology - 01-NOV-2002; 60(5): 756-9

• 2042 patients with prostate cancer were registered between 1988 and 1998

• The 5-year disease-specific survival rate was 86.9% for year groups 1988 to 1991 and 93.7% for patients diagnosed from 1992 to 1994

• Prostate cancer was the cause of death for 37.5% of the patients in 1988 to 1989 versus 15.4% in 1999 to 2000.

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• Marked stage migration has occurred; from 1988 to 1998, the percentage of patients presenting with metastatic disease decreased from 14.1% to 3.3%

• Conclusion: A statistically significant improved 5-year disease-specific survival and a decreased chance of dying from prostate cancer has occurred after the widespread implementation of PSA.

• The authors suspected that PSA testing has resulted in fewer patients presenting with metastatic disease and more patients presenting with localized disease amenable to curative treatment

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• The authors felt this portends well for the use of PSA screening to improve outcomes for prostate cancer.

• However, randomized trials (currently underway) are needed to confirm the improvements in survival and mortality.

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Screening for prostate cancer: Harm from screening

• Psychological effects of a suspicious prostate cancer screening test followed by a benign biopsy result. McNaughton-Collins M; Fowler FJ Jr; Caubet JF; Bates DW; Lee JM; Hauser A; Barry MJ- Am J Med 2004 Nov 15;117(10):719-25.

• 167 men having undergone prostate biopsy with benign results and 233 men with a normal PSA responded to a questionaire

• Questions concerned demographic characteristics, medical history, psychological effects, biopsy experience, and prostate cancer knowledge

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• Forty-nine percent (81/167) of men in the biopsy group reported having thought about prostate cancer either "a lot" or "some of the time", compared with 18% (42/230) in the control group (P < 0.001).

• 40% (67/167) in the biopsy group reported having worried "a lot" or "some of the time" that they may develop prostate cancer, compared with 8% (18/231) in the control group (P < 0.001).

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• Men who underwent prostate biopsy more often

reported having thought and worried about prostate

cancer, despite having received a benign result.

• This under-recognized human cost of screening

should be considered in the debate about the

benefits and harms of prostate cancer screening.

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• Risk from prostate biopsy – < 1% risk of hospitalization following procedure

– Pain common and most of my patients tell me they would really have preferred some sedation

• Over-diagnosis: Refers to the detection of cancers that would not have become clinically significant

• This is of particular concern since most men with screening-detected prostate cancer have early stage disease and will be offered aggressive treatment

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• 17% risk of being diagnosed with prostate cancer• 3% risk of death from prostate cancer

• Autopsy series reveal prostate cancer present in 1/3

men age 65- 80 and 2/3 men > age 80• “Is cure possible in those for whom it is necessary,

and is cure necessary in those for whom it is possible?– Whitmore WF Jr. Urol Clin North Am 1990

Nov;17(4):689-9

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Screening for prostate cancer: Harm from screening: Risk of therapy

• In absence of therapy, most men found with prostate cancer from screening will have a lengthy period of time without clinical problems

• Operative mortality about 0.5% under age 75, approaches 1% over age 75

• Radical prostatectomy leads to sexual dysfunction in upwards of 70% of men and urinary problems in 15 to 50% of men

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• External beam radiation may cause …– erectile dysfunction in 20 to 45% of men with

previously normal erectile function

– urinary incontinence in 2-16% of previously continent men

– bowel dysfunction in 6 to 25% of men with previously

• Brachytherapy may cause all of above and may also lead to significant bladder outlet symptoms– Not indicated in men with very large prostates

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• Given the lack of data on whether screening improves disease-free survival …

• Quality of life issues related to treatment selection become increasingly important decision-making factors.

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Approach to screening: Informed consent: ACP summary of discussion points

• Prostate cancer is an important health problem. • The benefits of one-time or repeated screening and

aggressive treatment of prostate cancer have not yet been proven.

• Digital rectal examinations and PSA measurements can have both false-positive and false-negative results.

• The probability that further invasive evaluation will be required as a result of testing is relatively high.

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Approach to screening: Informed consent: ACP summary of discussion points

• Aggressive therapy is necessary to realize any benefit from the discovery of a tumor.

• A small but finite risk for early death and a significant risk for chronic illness, particularly with regard to sexual and urinary function, are associated with these treatments.

• Early detection may save lives.• Early detection and treatment may avert future

cancer-related illness.

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Approach to screening: Age, frequency and method of screening

• Age 50 for men with life expectancy greater than 10 years

• Black men and men with a family history of prostate cancer … discuss screening at age 40-45

• PSA and DRE• While annual testing is recommended, screening

studies have shown that cancer detection rates and the positive predictive value of PSA substantially decrease after the initial screening

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Approach to screening: Referral to urology

• Men with abnormal prostate exams … – Nodule– Induration– Marked asymmetry

• Abnormal PSA– PSA > 7.0– Value consistently between 4.0 and 7.0 on repeat

several weeks apart (refrain from sexual activity or biking for 48 hours, if prostatitis, treat it)

– PSA velocity over 0.75 ng/ml/year (3 serial tests/12 mo)

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Approach to screening: When to stop

• Actuarial tables suggest only men 75 and younger have a 10-year life expectancy

• Observational study of Swedish men diagnosed with localized prostate cancer at median age of 72

• Men choosing watchful waiting had an 11 percent chance of dying from prostate cancer during 15 years of follow-up, compared with 10 percent among men who received initial treatment

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Approach to screening: When to stop

• However, when follow-up of the men choosing watchful

waiting was extended to 21 years, the mortality rate from

prostate cancer increased approximately threefold for men

who survived beyond 15 years.

• The authors concluded that aggressive treatment might be

warranted for men with a life expectancy exceeding 15

years, corresponding to an age at diagnosis of 70 years.– Natural history of early, localized prostate cancer. Johansson JE;

Andren O; Andersson SO; Dickman PW; Holmberg L; Magnuson A; Adami H - JAMA 2004 Jun 9;291(22):2713-9.

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Screening for prostate cancer: Conclusions

• It is unclear whether screening for prostate cancer reduces morbidity or mortality, and whether even if it does so, the benefits of screening outweigh potential harms to quality of life.

• Given the lack of conclusive evidence of benefits of screening from randomized trials, some suggestive evidence of benefits from observational trials, and the potential harms associated with screening, we feel that individual patient preferences are usually the deciding factor in determining whether or not screening for prostate cancer is appropriate in that patient

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Screening for prostate cancer: Conclusions

• Discussions of screening for prostate cancer should present patients with information on the risks and benefits of screening– (See attachment at end of handout)

• For appropriate patients who desire screening, DRE and PSA should be done every 1-2 years

• See guidelines discussed above for reasons for referral to a urologist

• Hopefully we’ll have more definitive data soon concerning morbidity and mortality benefits from screening

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December 26, 2004: Oil and acrylic on canvas, 48” x 24”

A Man, a Glove and a Gland: Finding Prostate Cancer

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