The PSA Puzzle Claus G Roehrborn, MD

Professor and Chair

S.T. Harris Family Chair in Medical Science, in Honor of John D. McConnell, M.D.

E.E. Fogelson and Greer Garson Fogelson Distinguished Chair in Urology Department of Urology UT Southwestern Medical Center at Dallas

Cancer Statistics 2012

CA: A Cancer Journal for Clinicians

Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138

http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1

Cancer Statistics 2012

CA: A Cancer Journal for Clinicians

Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138

http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1

Cancer Statistics 2012

CA: A Cancer Journal for Clinicians

Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138

http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1

• • •

Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement DRAFT

The U.S. Preventive Services Task Force (USPSTF) recommends against prostate-specific antigen (PSA)-based screening for prostate cancer. This is a Grade D recommendation.

This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history. The Task Force did not evaluate the use of the PSA test as part of a diagnostic strategy in men with symptoms that are highly suspicious for prostate cancer. This recommendation also does not consider the use of the PSA test for surveillance after diagnosis and/or treatment of prostate cancer.

http://www.uspreventiveservicestaskforce.org/uspstf12/prostate/draftrecprostate.htm

The Prostate

PSA Fundamentals

• • • Prostate specific antigen (PSA) is an enzyme, produced in the glandular epithelial cells of the prostate, and only there (!) It is therefore specific to the prostate (and men) but not to specific prostate diseases Every men has a measurable level of PSA as long as he has a prostate – The only exception are men after total prostatectomy and those who are surgically or medically castrated

• • • • •

Common Disease States of the Prostate and PSA levels

Normal prostate in younger men – usually very low levels of PSA Benign prostatic hyperplasia (BPH): – PSA increases with age and with the size of the gland Inflammation/infection (prostatitis): – Relatively rare, can lead to a temporary increase Precancerous lesions in the prostate (HG PIN, atypia and dysplasia) – Slight elevation of PSA Prostate cancer – The higher the PSA, the greater the risk of cancer, but there is NO totally safe range

Prevalence of Prostate Cancer Among Men with a PSA of < 4.0 ng/ml in PCPT Thompson et al, NEJM 350 (22), 2004

Uses of PSA

• • • • To screen for prostate diseases in a distinct population (eg all men over 50, or all men with a family history) To diagnose or find diseases in men presenting to a health care provider with symptoms/problems To monitor diseases of the prostate during or after treatment To verify absence of disease (ie undetectable PSA after total prostatectomy)

PROSTATE CANCER MORTALITY AFTER INTRODUCTION OF PROSTATE-SPECIFIC ANTIGEN MASS SCREENING IN THE FEDERAL STATE OF TYROL, AUSTRIA

Bartsch et al, UROLOGY 58: 417–424, 2001

Mortality Results from a Randomized Prostate-Cancer Screening Trial Prostate, Lung, Colorectal, and Ovarian (PLCO) Andriole et al, N Engl J Med 2009;360:1310-9.

• From 1993 through 2001, 76,693 men at 10 U.S. study centers were randomized to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). • Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. • The subjects and health care providers received the results and decided on the type of follow-up evaluation. • Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained.

Number of Diagnoses of All Prostate Cancers (Panel A) and Number of Prostate-Cancer Deaths (Panel B) Conclusions After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups Andriole G et al. N Engl J Med 2009;10.1056/NEJMoa0810696

Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement DRAFT

• The U.S. Preventive Services Task Force (USPSTF) recommends against prostate-specific antigen (PSA)-based screening for prostate cancer. • This is a Grade D recommendation.

• This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history. The Task Force did not evaluate the use of the PSA test as part of a diagnostic strategy in men with symptoms that are highly suspicious for prostate cancer. This recommendation also does not consider the use of the PSA test for surveillance after diagnosis and/or treatment of prostate cancer.

http://www.uspreventiveservicestaskforce.org/uspstf12/prostate/draftrecprostate.htm

What is the current commotion all about?

• Screening studies: – Allocate one half of men to have annual PSA testing and biopsies if elevated, then treat – Allocate one half of men to NOT have annual PSA or PSA testing at all for the duration of the study, except if they have an abnormal examination, symptoms etc; then test, biopsy and treat • Endpoint: death from prostate cancer

PSA Screening Studies

• Hypothesis: – If PSA elevated prostate cancer is more likely – TRUS biopsy will find the cancer if it is there – If cancer is found, patient will have treatment – Treatment is effective in curing the cancer – Patients thus diagnosed with elevated PSA and cancer on biopsy will less likely die from prostate cancer over the course of the study

Better sleep leads to greater productivity

• Hypothesis: – Certain mattresses allow for a deeper sleep – A deeper sleep will cause a person to be better rested for the next day – A better rested person will be more productive at work – Greater productivity at work will increase efficiency and thus the financial bottom line of a factory

Better sleep leads to greater productivity

• Study design: – Allocate one half of the workers to sleep on a new mattress purchased for them – Allocate one half of workers to sleep on their old mattress, ask them not to buy any new mattress or change it during the study • Endpoint: productivity measures and financial bottom line comparing the two groups of workers

What did men in the PLCO study actually do in terms of PSA testing?

• Compliance with the screening protocol in the screen

population overall was 85% for PSA testing and 86% for digital rectal examination.

• In the control group, the rate of PSA testing was 40%

in the first year and increased to 52% in the sixth year

• They did not really follow the rules of the study!

What might the factory workers do?

• Results: – Of the 38,000 workers who were given the new mattress 15% did not like it and did not use it – Of the 38,000 workers told to use their old mattress, 45% heard about the new mattress and bought it at some time during the two years to sleep on it – More workers who slept on the new mattress (in both group) said they felt they slept better – There was not demonstrable difference in productivity measures between the two groups

Better sleep leads to greater productivity

100% 80% 60% 40% 20% 0% 17000 21000 Old Mattress Group Bought new Used old 100% 80% 60% 40% 20% 0% 32000 6000 New Mattress Group Used new Used old

Better sleep leads to greater productivity

50000 40000 30000 20000 10000 0 6000 21000 Old Mattress Got new but used old Used old 50000 40000 30000 20000 10000 0 17000 32000 New Mattress Assigned to old but bought new Used new

How would the results be if we compare the workers actually using the new versus the old mattresses?

• This logical and seemingly legitimate question cannot be asked – it is called ‘per protocol’ analysis • The analysis has to be as intention to treat – Ie, you were told to sleep on the old mattress and – whatever you actually did – that is how we analyze you, as an old mattress user – You did not like the new mattress? Too bad, we will analyze you as though you used it anyway

Did we answer the question(s)

• What do you think now? Buy everybody a new mattress? No new mattresses for anybody?

• Did this long and large study answer your question regarding the connection from mattress to sleep to productivity?

• Did the PLCO study answer the question

regarding the connection between PSA testing and cancer diagnosis and mortality?

Mortality results from the Göteborg randomised population-based prostate-cancer screening trial Risk of prostate cancer In Sweden there is not much PSA screening outside the study, and thus, there is little contamination!

The results of a per protocol vs intention to treat are therefore quite similar!

Hugosson Lancet Oncol 2010; 11: 725–32

Mortality results from the Göteborg randomised population-based prostate-cancer screening trial Risk of death from prostate cancer The rate ratio of death from prostate cancer for attendees compared with the control group was 0·44 (95% CI 0·28–0·68; p=0·0002). Overall, 293 (95% CI 177–799) men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death.

Hugosson Lancet Oncol 2010; 11: 725–32

Screening and Prostate-Cancer Mortality in The European Randomized Study of Screening for Prostate Cancer Schr öder et al, N Engl J Med 2009;360:1320-8 .

Conclusions PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis Schroder F et al. N Engl J Med 2009;10.1056/NEJMoa0810084

Prostate Cancer Mortality Reduction by Prostate-Specific contamination or increased the risk reduction to 30% for Prostate Cancer (ERSPC)

Cumulative Hazard of Death from Prostate Cancer among Men 55 to 69 Years of Age.

• The European Randomized Study of Screening for Prostate Cancer continues to show a 21% reduction in prostate-cancer mortality in the screening group, after 11 years of follow-up.

• The number of cancers that would need to be detected to prevent one prostate-cancer death is 37.

Schröder FH et al. N Engl J Med 2012;366:981-990

Nothing about the evaluation process is inevitable, and all decisions are shared!

1. Decision to go to a physician or health provider 2. Whether to get a PSA test 3. How to interpret the results 4. Whether to do a biopsy 5. If the biopsy is positive, whether to treat, and if so how to treat the cancer

Cancer Statistics 2012

CA: A Cancer Journal for Clinicians

Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138

http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1

Original Article Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer

Anna Bill-Axelson, M.D., Ph.D., Lars Holmberg, M.D., Ph.D., Mirja Ruutu, M.D., Ph.D., Hans Garmo, Ph.D., Jennifer R. Stark, Sc.D., Christer Busch, M.D., Ph.D., Stig Nordling, M.D., Ph.D., Michael Häggman, M.D., Ph.D., Swen-Olof Andersson, M.D., Ph.D., Stefan Bratell, M.D., Ph.D., Anders Spångberg, M.D., Ph.D., Juni Palmgren, Ph.D., Gunnar Steineck, M.D., Ph.D., Hans-Olov Adami, M.D., Ph.D., Jan Erik Johansson, M.D., Ph.D., for the SPCG-4 Investigators N Engl J Med Volume 364(18):1708-1717 May 5, 2011

Cumulative Incidence of Death from Any Cause, Death from Prostate Cancer, and Development of Metastases.

Bill-Axelson A et al. N Engl J Med 2011;364:1708-1717

Cumulative Incidence of Death from Prostate Cancer and Development of Metastases among Men with Low-Risk Prostate Cancer.

Bill-Axelson A et al. N Engl J Med 2011;364:1708-1717

Survival Among Men With Clinically Localized Prostate Cancer Treated With Radical Prostatectomy or Radiation Therapy in the Prostate Specific Antigen Era

Source: Journal of Urology, The 2012; 187:1259-1265 (DOI:10.1016/j.juro.2011.11.084 ) Copyright © 2012 American Urological Association Education and Research, Inc. Terms and Conditions

Learning curve for cancer control after radical prostatectomy stratified by preoperative risk group Low Intermediate High Klein et al J Urol 2008 Jun;179(6):2212-6

Effects of surgeon experience on outcome by preoperative risk group and in 5,038 patients treated after 1995 Klein et al J Urol 2008 Jun;179(6):2212-6

80 70 60 20 10 0 50 40 30

2006 period life table for the Social Security area population

20,7 17,0 13,6 10,5 7,8 5,6 http://www.ssa.gov/OACT/STATS/table4c6.html

Use of PSA in men with voiding symptoms and benign prostatic growth or BPH

• I use PSA in men with voiding symptoms and BPH to – – Estimate prostate size Determine the risk of worsening of symptoms – Determine the risk of requiring surgery in the future – Determine the risk of not being able to urinate at all – Monitor disease activity over time – Monitor response to certain types of drugs (5 alpha reductase inhibitors [Avodart, Jalyn, Proscar])

0.8

0.6

1 0.4

0.2

-0.2

-0.4

0 -0.6

-0.8

-1 0.5

< 30 3.0

AGE VERSUS LOG SERUM PSA AND LOG VOLUME Means ± 95% CI for age categories and linear regression lines 3.8

50 3.7

30 - 39 40 - 49 50 - 59 Age, years 60 - 69 70 + 3.6

3.5

3.4

3.3

3.2

3.1

3 20 < 30 30 - 39 40 - 49 50 - 59 Age, years 60 - 69 70 +

SERUM PSA VERSUS PROSTATE VOLUME CONFIDENCE BANDS FOR DIFFERENT AGE GROUPS 40 35 30 25 0 55 50 45 85 80 65 60 75 70 1 2 3 50-59 4 5 PSA (ng/ml) 6 7 8 35 30 9 25 10 0 45 40 55 50 70 65 60 85 80 75 1 60-69 2 3 4 5 PSA (ng/ml) 6 7 8 75 70 85 80 35 30 45 40 55 50 65 60 9 25 0 10 1 2 70+ 3 4 5 PSA (ng/ml) 6 7 8 9 10

CUMULATIVE INCIDENCE OF AUR, SURGERY AND EITHER ONE FOR PLACEBO TREATED PTS IN 4-YR PLESS STUDY BY INCREASING PSA 30 25 20 15 10 Either Surgery AUR 5 0 >0 .0

>0 .5

>1 .0

>1 .5

>2 .0

>2 .5

>3 .0

>3 .5

>4 .0

>4 .5

>5 .0

>5 .5

>6 .0

>6 .5

>7 .0

>7 .5

>8 .0

47

Monitor PSA in men after treatment

• • After radiation therapy the PSA decreases usually to a level of < 1.0. – Monitoring is important – If the PSA increases from the lowest measured level , and that increase is confirmed by a second measurement, the cancer has recurred and additional treatment is needed During hormone therapy the PSA usually drops, and an increase is indicative of the cancer not responding to the treatment any longer

Monitor PSA in men after prostatectomy

• • After total prostatectomy the PSA should be undetectable (<0.05) Monitoring over time is important: – If PSA becomes detectable it indicates persistent or recurrent cancer – The rate of increase over time indicates how aggressive the recurrent cancer is – Additional treatments such as radiation and/or hormone therapies can be monitored by a subsequent decrease in PSA levels

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