Prevention and Screening Controversies in Prostate Cancer

Prevention and Screening Controversies in Prostate Cancer E. David Crawford, MD Professor of Surgery (Urology) and Radiation Oncology Head, Urologic O...
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Prevention and Screening Controversies in Prostate Cancer E. David Crawford, MD Professor of Surgery (Urology) and Radiation Oncology Head, Urologic Oncology E. David Crawford Endowed Chair in Urologic Oncology University of Colorado Health Sciences Center Denver, Colorado

Outline Overview Prevention Screening

Prostate Cancer: Incidence Rates 39.55 14.06 8.51 49.70 1.08 5.13 31.03 92.39

Incidence = number of cases per 100,000 population. Parkin DM et al. CA Cancer J Clin. 1999;49:33-64.


Number/100,000 Men

Death Rates From Prostate Cancer 60 50 40

African American

30 20 10 0

White Hispanic

American Indian

Asian or Pacific Islander

1990 1991 1992 1993 1994 1995 1996 1997 1998

Year MMWR Morb Mortal Wkly Rep. 2002;51:49-53.


Projected Prostate Cancer Incidence in the United States Factors   2% annual increase historically   Aging male population   Comorbidities decline

Chan JM, et al. J Urol. 2004;172:S13-S17.


Prostate-Specific Antigen The most important tumor marker in solid tumor oncology, widespread use of PSA began in the mid-1980s Stage migration resulting from the use of PSA –  Most cancers in the United States today are nonpalpable, PSA-detected, and organ confined Difficulties with widespread use of PSA –  Organ specific, not cancer specific –  Level elevated by cancer, inflammation, trauma, or hyperplasia –  Correlates poorly with cancer volume


Trends in Stage With the Use of PSA Screening 140

Clinical Stage* (1983-1995)

Rate per 100,000

120 100 80

Localized Regional Distant Unstaged

60 40 20 0 83 84 85 86 87 88 89

90 91 92

93 94 95

Year of Diagnosis

*Prostatectomy cases with regional stage disease recoded to localized stage.


Chemoprevention Prostate Cancer

Expenditures Prostate- 8 billion 11.2% Lung- 9.6 billion 13.3% Breast 8.1 billion 11.2&

Average Annual Cost per Patient Patients with prostate cancer cost $28,847 in the 1 year following diagnosis. Those who received any treatment were more costly.

$40,873 $28,847 $12,329


Costs were calculated from diagnosis through 1 year WW – Watchful Waiting




Why Prostate Cancer Prevention? Significant public health risk –  186,000 new cases and 26,000 deaths yearly (2008) Risk factors (age, race, genes) are not modifiable Benefit of screening on mortality is unproven Therapy is associated with morbidity

That Leaves Prevention

Relationship of Dietary Fat Intake and Death Rate from Prostatic Cancer

Carroll KK and Khor HT. Prog Biochem Pharmacol. 1975;10:308.

Prostate Cancer Diet & Exercise Risk Factors May Increase Risk •  Fat / Red Meat •  Cooking methods

May Decrease Risk •  Plant-based Foods/ Vegetables

•  Dairy/Calcium

•  Tomatoes •  Cruciferous

•  Smoking

•  Soy/Legumes

•  Total Calories, Body size

•  Specific Nutrients •  Selenium •  Vitamin E •  Carotenoids/Lycopene •  Total Antioxidants

•  Fish / Marine Omega 3 Fatty acids •  Moderate to Vigorous Exercise

SELECT Schema Pre-Randomization Period Calendar Year 2001 – 2004 (Planned 2001 – 2006)

Calendar Year 2001 - 2013


Vitamin E +

Vitamin E +

Placebo +

Placebo +





Follow - up Prostate cancer, other cancer, death

Lippman, Klein , Crawford, E D, et al JAMA




Placebo F/U q3mo x 7yr Annual DRE & PSA Biopsy for cause

End of Study Biopsy

End of Study Biopsy

Total Number of Cancers by Gleason Score

25% Risk Reduction

Thompson et al, NEJM 349:215, 2003

Delaying cancer = preventing it ! † Death M+ Advanced Palpable

T1 PSA  PIN normal 20-------------30-------------40--------------50-------------60-------------70--------------80-------------90

Eric Klein,.

Statins and Prostate Cancer Risk Risk Group

Risk Ratio

Any Px Cancer


Advanced Px Cancer Any use Use < 5 yrs Use > 5 yrs

0.51 0.60 0.26

Health Professionals Follow-up Study, N = 34,989 Platz et al, JNCI 98:1819-25, 2006

Effect of Statins on PSA Longitudinal study, Durham VA N = 1214 –  No hx Px Ca New rx with statin for dyslipidemia

Hamilton et al, JNCI 100:1511, 2


1989 •  Prostate cancer became the most common cancer in American Males •  And the second leading cause of death •  Options: –  Do nothing –  Prevention –  Early detection –  Improve outcome for advanced disease

1989-Fast forward, what happened? Prevention: PCPT 25% reduction

Largely ignored

REDUCE Schema Randomization

month: -7

Entry biopsy


Placebo run-in

2 year biopsy

4 year biopsy



For-cause biopsies may occur here

Andriole et al, J Urol 172:1314, 2004

Optimism that Screening Is Associated with a Fall in Mortality •  Fall in mortality now seen –  SEER –  Olmsted County –  Canada/Quebec –  DoD (US) –  Tyrol, Austria

Evidence is conflicting, not strong enough to support public policy

•  Mortality fall not seen where PSA screening not performed –  Mexico—where little to no PSA screening is performed


Flying High


PCA3 score

prostate tumor DRE marker release from tumor cell shedding

blood sample

Measure PSA protein in serum

urine sample

Measure PCA3 and PSA mRNA from cells

PCA3 Score = PCA3/ d from Marks LS Rev Urol. 2008 Summer; 175–181. PSA10(3): mRNA x10-3

Renal and Urology News June 2005, April 2008

PROSTATE SCREENING 2009 Organization American Urological Association (AUA)

Recommendation Men who are in good health: annual PSA testing starting at age 50, or 40 if high-risk (AA, or with a father, brother or son with prostate cancer.)

Conflicting recommendations Updates expected

American Cancer Society (ACS)

Offer to men > 50 who expect to live another 10 years, and high risk if they're age 45 and older.

Centers for Disease Control and Prevention (CDC)

Considers evidence “insufficient to determine whether the benefits outweigh the harms”.

U.S. Preventive Services Task Force (USPSTF)

Do not screen > 75 and older, or in men who will probably live 10 years or fewer. For men under 75, the evidence insufficient to determine whether the benefits outweigh the harms. (Am J Prev Med 2008;34(2):164)

American College of Preventive Medicine (ACPM)

Discuss risks/benefits. The need for screening questionable in elderly men with other chronic illnesses and men with life expectancies of less than 10 years.

PLCO Cancer Screening Trial •  Multi-center randomized screening trial for: –  –  –  – 

•  •  •  • 

Prostate Lung Colo-rectal Ovarian

155,000 men and women aged 55-74 Recruitment: 1993-2001 Screening: 1993-2006 Follow-up until 2015 by annual survey and mortality search

PLCO Screening Centers

Screening Interventions in PLCO Trial •  Prostate – Annual DRE x 4 and PSA x 6 •  Lung – Annual Chest Xray x 4 –  Spiral CT for smokers •  Colon – FSG at years 1 and 6 •  Ovary – TVU x 4 and CA125 x 6

PLCO Screening Follow-up •  Intervention Arm: –  Screening results reported to patient and PCP –  “Community standard of care” applied to biopsy and treatment decisions

•  Comparison Arm: –  “Community standard of care”

PLCO Study Endpoints •  Cause-specific mortality •  Outcomes of screening exams •  Incident and prevalent cancers

Original Article

Mortality Results from a Randomized ProstateCancer Screening Trial Gerald L. Andriole, M.D., E. David Crawford, M.D., Robert L. Grubb, III, M.D., Saundra S. Buys, M.D., David Chia, Ph.D., Timothy R. Church, Ph.D., Mona N. Fouad, M.D., Edward P. Gelmann, M.D., Paul A. Kvale, M.D., Douglas J. Reding, M.D., Joel L. Weissfeld, M.D., Lance A. Yokochi, M.D., Barbara O'Brien, M.P.H., Jonathan D. Clapp, B.S., Joshua M. Rathmell, M.S., Thomas L. Riley, B.S., Richard B. Hayes, Ph.D., Barnett S. Kramer, M.D., Grant Izmirlian, Ph.D., Anthony B. Miller, M.B., Paul F. Pinsky, Ph.D., Philip C. Prorok, Ph.D., John K. Gohagan, Ph.D., Christine D. Berg, M.D., for the PLCO Project Team

N Engl J Med Volume 360(13):1310-1319 March 26, 2009

Characteristics of the Subjects at Baseline

Andriole GL et al. N Engl J Med 2009;360:1310-1319

Number of Diagnoses of All Prostate Cancers (Panel A) and Number of Prostate-Cancer Deaths (Panel B)

Andriole GL et al. N Engl J Med 2009;360:1310-1319

Tumor Stage, Histopathological Type, and Gleason Score for All Prostate Cancers at 10 Years, According to Method of Detection and Time of Diagnosis

Andriole GL et al. N Engl J Med 2009;360:1310-1319

Death Rates from Prostate Cancer per 10,000 Person-Years at 10 Years

Andriole GL et al. N Engl J Med 2009;360:1310-1319

Causes of Death at 10-Year Follow-up

Andriole GL et al. N Engl J Med 2009;360:1310-1319

PLCO Trial Conclusions: •  7-10 years, no difference in mortality •  Few CaP related deaths in either group- 92 screening and 82 control at 10 years •  Balance of benefits and harms unfavorable and does not support routine screening, at this time •  Even if mortality is shown to decrease, still significant harm to many men

PLCO Trial Conclusions: •  First report-planned follow for at least 13 years, more to come •  Contamination-as high as 50%, could be a contributing factor, improved therapy could also be a contributing factor•  PSA not the best test, far from it •  Need a better test and marker of progression

Thoughts • 

Screening doesn’t work for all cancers: Lung, neuroblastoma, and not all breast cancers •  Need to separate diagnosis from treatment, clearly over treating men •  But, need to remember that 28,000 men died in 2008 of CaP •  We need to figure out who needs to be diagnosed and effectively treated.

There are a lot of exciting things happening in the PLCO Trial Biorepository: More than 2.7 million specimens Exam Cycle Baseline Year 1 Year 2 Year 3 Year 4 Year 5 2004-2013

Risk Usual Factors Diet X


Serum Plasma RBC Intervention Arm X X X X X X

Viable Tumor DNA Cells Sample








X x

Comparison Arm X




AUA and ASCO 2009

PLCO Prostate Subcommittee Thanks to participants Urologists G. Andriole, Chair C. Amling D. Crawford, V. Chair R. Grubb Westat D. Carrick B. O’Brien L. Ragard T. Riley IMS J. Ciapp B. Lake J. Mabie

NCI C. Berg R. Hayes G. Izmerlian B. Kramer D. Levin A. Miller P. Pinksy P. Prorok

Others D. Chia T. Church D. Reding B. Wilcox

A special thanks to Barry Kramer and Phil Prorok for their leadership and guidance during the past 15 years

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