Screening for Prostate CancerShould we still test for PSA?

Peter T. Scardino, M.D. and Andrew Vickers, Ph.D.

Memorial Sloan-Kettering Cancer Center

New York

U.S. Preventive Services Task Force (USPSTF)Screening for Prostate Cancer

Grade: D

Definition: The USPSTF recommends against screening for prostate cancer with PSA. There is moderate or high certainty that there is no net benefit or that the harms outweigh the benefits.

Suggestions for Practice: Discourage the use of PSA screening.

Why the recommendation against screening for prostate cancer?

Screening and consequent treatment, as currently practiced, are often harmful:

• Too much screening of elderly men with a short life expectancy• Too liberal criteria for biopsy • Too aggressive treatment of low risk cancers• Inadequate treatment of high risk cancers• Treatment largely administered by low volume providers

(higher risks of side effects and lower risks of cure)

Vickers AJ, Lilja H. Time for another rethink on prostate cancer screening. Nat Rev Clin Oncol. 2011; 9:7-8.

Estimated Prevalence of PSA screening by Year and Agein the U.S.

Drazer MW, Huo D, Schonberg MA, et al. Population-based patterns and predictors of PSA screening among older men in the United States. J Clin Oncol 2011; 29: 1736-1743.

PSA Variability: In a given individual levels vary over time by ±30%

Eastham et al. JAMA 2003; 289:2695.

Serial annual

0123456789

1 2 3 4 5

Measurement

PSA

Patient A Patient B Patient C Patient D Patient E

PSA Variability (annual test)Percent of men with abnormal PSA during 5 year period (n=972 men)

and probability that PSA would later return to normal and remain normal

Definition of % ever Probability that PSA would abnormal PSA abnormal return to normal remain normal

>4.0 ng/ml 21% 44 % 80 %

>2.5 ng/ml 37% 40 % 65 %

Age specific 20% 55 % 83 %

%FPSA (PSA 4-10) 15% 53 % 74 %

Any 37%

Modified from Eastham JA et al. JAMA 2003; 289:2695.

Complications Following Prostate Biopsy

Study population30-day hospitalization

rate (%) Infection BleedingUrinary

obstruction30-day mortality

rate (%)5% random sample of Medicare participants, 1991-2007 (n = 17,472)

6.9 0.38 Not reported

Not reported

0.31

All men receiving an initial prostate biopsy not resulting in diagnosis of cancer in Ontario, Canada, 1996-2005 (n=41,682)

1.9 1.36 0.37 0.17 0.11

Consecutive patients at a single academic medical center, 2001-2010 (n = 1,000)

2.5 1.2 0.4 0.8 —

Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011;186:1830-1834.

Nam RK, Saskin R, Lee Y, Liu Y, Law C, Klotz LH, Loblaw DA, Trachtenberg J, Stanimirovic A, Simor AE, Seth A, Urbach DR, Narod SA. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010;183:963-968.

Pinkhasov GI, Lin YK, Palmerola R, Smith P, Mahon F, Kaag MG, Dagen JE, Harpster LE, Reese CT, Raman JD. Complications following prostate needle biopsy requiring hospital admission or emergency department visits - experience from 1000 consecutive cases. BJU Int 2012;110:369-374.

OVER DETECTION

Of all screen-detected cancers, an estimated 10-56% would not have become apparent or caused symptoms in the patients’ lifetimes, and the lead time for diagnosis is estimated at 5-12 years.

Use of Watchful Waiting among U.S. Patients with Localized Prostate Cancer by Risk Category (1990-2006)

Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010; 28: 11117-1123.

Low HighIntermediate

What is wrong with the USPSTF recommendation?

• European randomized trial has not reached its primary endpoint• Inappropriate inclusion of very different trials in meta-analysis• Lack of appreciation for the strong relationship between PSA

and prostate cancer mortality • Inadequate consideration of time-to-event (long delay between

elevated PSA and death from prostate cancer)• Overall mortality is not an appropriate endpoint• Mortality risk of surgery exaggerated (0.5%)

Vickers AJ, Lilja H. Time for another rethink on prostate cancer screening. Nat Rev Clin Oncol. 2011; 9:7-8.

Does PSA Screening Reduce Prostate Cancer Mortality?

Over 9 years, PSA screening reduced deaths from prostate cancer by 20% but was associated with a high risk of over diagnosis: 1410 men would need to be screened and 48 additional cases would need to be diagnosed or treated to prevent one death from prostate cancer.

PLCO: No ERSPC: Yes, but at high cost

Lancet Oncology, published online July 1, 2010

Over 14 years PSA testing increased the number of cancers detected by 50% but reduced the risk of dying of prostate cancer by 44% in all men and 56% in screened men. The number needed to screen to prevent one death was 293, and number needed to diagnose or treat was 12.

• 5 treated tp prevent one death

Clinical cancerAUC 0.74

Prostate cancer deathAUC 0.89

at age 60

Proportion of population withPSA level within each range,median is 1.0.

Vickers A, Cronin A, Björk T, Manjer J, Dahlin A, Bjartell A, Scardino P, Ulmert D and Lilja H. BMJ 2010; Sep 14;341:c4521. . 

Probability of eventually developing or dying of prostate cancer by PSA at age 60

Mid-life PSA levels strongly predict long-term risk of prostate cancer morbidity.

Cancer Incidence and Mortality Ratesage-adjusted, standardized over time

http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012

Screening Smarter:How to Increase the Benefits and Reduce the Risks

of Screening for Prostate Cancer

• Risk-adjust screening by age and PSA (reduce false positives)• Reduce false positive PSA results by repeating (verifing)

positives and by adding additional markers (4 kallikrein panel or -2(pro)PSA) (reduce indications for biopsy)

• Active surveillance for low-risk cancers (reduce harms of unnecessary therapy)

• Refer patients who need treatment to high-volume physicians or centers (reduce harm of necessary therapy)

Vickers A, Roobol M, Lilja H. Annu. Rev. Med. 2012. 63:161–70.

Memorial Sloan-Kettering Cancer Center 2010 Guidelines Risk-adjusted Screening for Prostate Cancer

• Begin PSA testing at age 45

• For men age 45 - 59• PSA ≥ 3 ng/ml : consider biopsy• PSA > 1 but < 3 ng/ml : return for PSA every 2-4 years• PSA <1 ng/ml : return for PSA in 5 years or at age 50 or 60,

whichever comes first

• For men age 60 – 70 • PSA ≥ 3 ng/ml : consider biopsy• PSA > 1 but < 3 ng/ml : return for PSA every two years• PSA < 1 ng/ml : no further screening

• For men age 71 or higher • No further screening

How to Increase the Benefits and Reduce the Risks of Screening for Prostate Cancer

• Risk adjust screening by age and PSA (reduce false positives)• Reduce false positive PSA results by adding additional markers

(4 kallikrein panel or -2(pro)PSA) (reduce indications for biopsy)

• Active surveillance for low risk cancers (reduce harms of unnecessary therapy)

• Refer patients who need treatment to high volume physicians or centers (reduce harm of necessary therapy)

Vickers A, Roobol M, Lilja H. Annu. Rev. Med. 2012. 63:161–70.

New PSA Markers

• tPSA = total PSA, the standard measure• fPSA = free PSA (unattached)• % fPSA = ratio of free to total PSA• hK2 = human kallikrein 2• iPSA = intact PSA• 4K panel = tPSA, fPSA, iPSA, hK2• [-2] proPSA = a precursor (proenzyme) of PSA• %p2PSA = [-2] proPSA/fPSA × 100• PHI = ([-2] proPSA/fPSA × √tPSA)

Reduce false positive PSA tests with use of a 4 kallikrein panel* of biomarkers

for screening or early detection of prostate cancer(PSA, free PSA, intact PSA, hK2)Biopsies Cancers High grade ≥7

cancers

Total Reduced Total Missed Total MissedBiopsy allif PSA >3 753 - 192 - 40 -

Four panel model (bx if risk ≥20%)

317 436 (58%) 162 30 (16%) 38 2 (5%)

*PSA, free PSA, intact PSA, hK2

Gupta A, Roobol MJ, Savage CJ, Peltola M, Pettersson K, Scardino PT, Vickers AJ, Schröder FH, Lilja H. Br J Cancer. 2010;103:708-14

Four-kallikrein panel (PSA, fPSA, intact PSA, hK2) Four-kallikrein panel (PSA, fPSA, intact PSA, hK2) is as sensitive as PSA but much more specific and can reduce biopsies by ~50%is as sensitive as PSA but much more specific and can reduce biopsies by ~50%

• Predicts locally advanced and recurrent cancer (Steuber T, et al. Clin Chem 2007;53:233)

• Reduces unnecessary biopsies in screening population(Vickers AJ, et al. BMC Med 2008;6:19)

• Predicts outcomes of biopsy after clinical work-up(Benchikh A, et al. BMC Cancer 2010;10:635)

• Predicts result of repeat biopsy (Gupta A, et al. Brit J Ca 2010;103:708)• Reduces unnecessary biopsies

(Kirk R. Nature Reviews Clinical Oncology 2010;7:424)• Predicts cancer in men already screened once or more

(Vickers AJ, et al. Clin Ca Res 2010;16:3232)• Predicts cancer in unscreened men

(Vickers AJ, et al. Cancer Epi Bio Prev 2010;20:255)• Validates accuracy in reducing biopsy during screening

(Vickers A, et al. JCO 2010;28:2493)

New PSA Markers

A Multicenter Study of [-2]Pro-Prostate Specific Antigen Combined With Prostate Specific Antigen and Free Prostate Specific Antigen for Prostate Cancer Detection in the 2.0 to

10.0 ng/ml Prostate Specific Antigen Range

William J. Catalona, Alan W. Partin, Martin G. Sanda, John T. Wei, George G. Klee, Chris H. Bangma, Kevin M. Slawin, Leonard S. Marks, Stacy Loeb, Dennis L. Broyles, Sanghyuk S. Shin, Amabelle B. Cruz, Daniel W. Chan, Lori J. Sokoll, William L.

Roberts, Ron H.N. van Schaik, Isaac A. Mizrahi. J Urol 2011;185:1650-1655.

New PSA Markers

In the 2 to 10 ng/ml PSA range at 80% to 95% sensitivity, the specificity and AUC (0.703) of phi exceeded those of PSA and %f PSA

How to Increase the Benefits and Reduce the Risks of Screening for Prostate Cancer

• Risk adjust screening by age and PSA (reduce false positives)• Reduce false positive PSA results by adding additional markers

(4 kallikrein panel or -2(pro)PSA) (reduce indications for biopsy)

• Active surveillance for low risk cancers (reduce harms of unnecessary therapy)

• Refer patients who need treatment to high volume physicians or centers (reduce harm of necessary therapy)

Vickers A, Roobol M, Lilja H. Annu. Rev. Med. 2012. 63:161–70.

All-cause mortality for men with conservatively managed prostate cancerCharlson Comorbidity index 0

J Rider et al. Long-term outcomes according to risk category of prostate cancer. Nation-wide, population-based cohort. Eur Urol 2012.

PIVOT: RP v. ObservationOverall results: all-cause and prostate cancer-specific mortality

N=731

Wilt et al. N Engl J Med 2012; 367:203

PIVOT: RP v. ObservationPatients with high risk cancers

Wilt et al. N Engl J Med 2012; 367:203-213

All cause mortality in patients (n=251) with PSA > 10 ng/mL (HR 0.36, p<0.02).

Prostate cancer mortality in patients (n=157) with high-risk cancer (HR 0.40, p=0.05)

PSA > 10

AUA High risk

Randomized trial of RP v. WW Radical prostatectomy significantly reduced the risk of death from any cause (HR 0.75),

death from prostate cancer (HR 0.62) and metastases (HR 0.59) compared to WW.

The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age.

RP also dramatically reduced the risk of clinical local progression (HR 0.34) and the need for hormone therapy.

From: Bill-Axelson, A. et al. for the SPCG-4 Investigators. Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer. NEJM, 2011, 364:1708-1717.

Klotz L et al. J Clin Onc 2010; 28:126

Pathologic Organ Confined

Biopsy Gleason 6

Number of new patients enrolled in active surveillance by year

0

200

400

600

800

1000

0.000.100.200.300.400.500.600.700.80

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Intermediate and High Risk

Low Risk

Is PSA Screening for Prostate Cancer Dead?Is there anything better?

PSA screening, the way it has been done, should stop. We can screen more effectively, keeping the mortality rate from prostate cancer low without harming large numbers of men, by screening smarter:

•Risk-adjusting the frequency of testing and repeating the test of an elevated level after 6-12 weeks•Using more specific panels of markers to reduce unnecessary biopsies •Expanding Active Surveillance for low-risk cancers and in older men•Referring patients to high-volume centers for treatment