A Prostate Cancer Update: Screening, Over Diagnosis, and Treatment

A Prostate Cancer Update: Screening, Over Diagnosis, and Treatment

Matthew D. Katz, M.D.Assistant ProfessorUrologic Oncology

Robotic and Laparoscopic SurgeryUniversity of Arkansas for Medical Sciences

Winthrop P. Rockefeller Cancer Center

Anatomy Genitourinary System

Campbell-Walsh UROLOGY, 9th edition

Prostate Cancer

• Most common non-skin cancer in men

• Second leading cause of cancer death in U.S. men

• About 25% of prostate cancers are thought to be clinically significant

Campbell-Walsh UROLOGY, 9th editionComprehensive Textbook of Genitourinary Oncology, 3rd edition

New Cases and Death Estimates

Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4.

Trends in Incidence Rates for Selected Cancers by Sex, United States, 1975 to 2010


Trends in Death Rates Overall and for Selected Sites by Sex, United States, 1930 to 2010

Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4

Lifetime Risk of Developing CaP


Probability of Developing Invasive Cancers Within Selected Age Intervals by Sex, United States, 2004–2006*

BIRTH TO 39 (%) 40 TO 59 (%) 60 TO 69 (%) 70 AND OLDER (%) BIRTH TO DEATH (%)

All sites†Male 1.43 (1 in 70) 8.42 (1 in 12) 15.61 (1 in 6) 37.84 (1 in 3) 44.05 (1 in 2)

Female 2.10 (1 in 48) 8.97 (1 in 11) 10.18 (1 in 10) 26.47 (1 in 4) 37.63 (1 in 3)

Urinary bladder‡Male 0.02 (1 in 4,741) 0.39 (1 in 257) 0.95 (1 in 106) 3.66 (1 in 27) 3.81 (1 in 26)

Female 0.01 (1 in 10,613) 0.12 (1 in 815) 0.26 (1 in 385) 1.01 (1 in 99) 1.18 (1 in 84)

Breast Female 0.49 (1 in 206) 3.75 (1 in 27) 3.40 (1 in 29) 6.50 (1 in 15) 12.08 (1 in 8)

ColorectumMale 0.08 (1 in 1,269) 0.91 (1 in 110) 1.48 (1 in 67) 4.50 (1 in 22) 5.39 (1 in 19)


LeukemiaMale 0.17 (1 in 603) 0.21 (1 in 475) 0.33 (1 in 299) 1.19 (1 in 84) 1.51 (1 in 66)


Lung & bronchus Male 0.03 (1 in 3,461) 0.95 (1 in 105) 2.35 (1 in 43) 6.71 (1 in 15) 7.73 (1 in 13)


Melanoma of the skin§ Male 0.16 (1 in 638) 0.64 (1 in 155) 0.72 (1 in 138) 1.77 (1 in 56) 2.67 (1 in 37)


Non-Hodgkin lymphona Male 0.13 (1 in 782) 0.44 (1 in 225) 0.59 (1 in 171) 1.71 (1 in 58) 2.28 (1 in 44)


Prostate Male 0.01 (1 in 9,422) 2.44 (1 in 41) 6.45 (1 in 16) 12.48 (1 in 8) 15.90 (1 in 6)

Uterine cervix Female 0.15 (1 in 648) 0.27 (1 in 374) 0.13 (1 in 755) 0.19 (1 in 552) 0.69 (1 in 145)

Uterine corpus Female 0.07 (1 in 1,453) 0.73 (1 in 136) 0.83 (1 in 121) 1.23 (1 in 81) 2.53 (1 in 40

Lifetime Risk of Dying from CaP

• Risk of dying from prostate cancer is ~3%• Once metastatic disease develops there is no

cure• Prior to PSA screening only 25% of CaP

presented confined to prostate vs. 91% since• 5 year CSS rates increased from ~70% to

100% (from 1980s to early 2000s)

Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4.Comprehensive Textbook of Genitourinary Oncology, 3rd editionCatalona et al. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270(8):948

Presentation• Most patients are asymptomatic• Diagnosed due to elevated PSA or

abnormal DRE• Advanced cancer may present with

bone pain, unintentional weight loss, hematuria, worsening LUTS, urinary retention, hydronephrosis, LE weakness/leg numbness/difficulty with ambulation


Risk Factors

• Age• + Family history• African American


Prevention• PCPT (Prostate Cancer Prevention Trial)

– 18,000 men randomized to placebo vs. Proscar 5mg qDay

– 7 year follow-up– Decreased risk of prostate cancer by 25%– Found small increase in high-grade cancer

development– Further subset analysis did NOT show this

to be trueThomson IM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med, 349, 2003Kaplan SA et al. PCPT- Evidence that finasteride reduces the risk of most frequently detected intermediate and grade (Gleason score 6 and 7) cancer. Urology, 73, 2009

Prevention• REDUCE trial (Reduction by Dutasteride of

Prostate Cancer Events)– 8,000 men >50 yrs old were randomized to

placebo vs. Dutasteride 0.5mg qDay– Follow-up 4 years– Decreased risk of developing Gleason score 5-

6 cancer by 27%– Did not reduce risk of Gleason 7-10 cancer– Did not increase risk of developing high grade

cancer– Enhanced ability of PSA to detect high grade

cancers Andriole GL et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 362, 2010

Screening

American Urological Association 2009, National Comprehensive Cancer Network 2010, European Association of Urology 2009, American Cancer Society 2010

Guideline Age to start CaP screening Suggested Screening Tests

AUA 2009 40 PSA and DRE

NCCN 2010 40 PSA and DRE

EAU 45 PSA and DRE

ACS 2010 40-50 (depends on risk) PSA with or without DRE

Screening • Should you screen at all?• What age should you stop screening?• Some advocate men >75 should not be

screened* • AUA and NCCN guidelines state that

screening should be individualized based on overall health (life expectancy >10yrs, FH of longevity, minimal competing medical comorbidities)

American Urological Association 2009, National Comprehensive Cancer Network 2010, European Association of Urology 2009, American Cancer Society 2010*U.S. Preventative Service Task Force Guidelines, 2008

Screening• Controversial • Does PSA-based screening lead to decrease in

risk of death from prostate cancer?• Advantages

– May prolong survival and save lives– Save men from long painful death with little

effective treatments available (costs?)• Disadvantages

– Overdiagnosis which leads to Overtreatment– Potential decrease in QOL from treatment (costs?)


USPSTF To Downgrade PSA ScreeningFrom "I" to "D" — As In "Don't Do It"

• U.S. Preventative Service Task Force recommended NOT to use PSA to screen for prostate cancer

• Based on meta-analysis of available literature

The Cancer Letter, Oct. 7, 2011

Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force

ABSTRACT Background: Prostate specific antigen-based screening can detect prostate cancer in earlier, asymptomatic stages, when treatments might be more effective. Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer. Data Sources: MEDLINE (2002 to July 2011), the Cochrane Library Database (through the 2nd quarter of 2011) and reference lists. Study Selection: Randomized trials of PSA-based screening; randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting for localized prostate cancer; and large (n>1000), uncontrolled observational studies of perioperative harms. Data Extraction: Investigators abstracted details about the patient population, study design, data analysis, and results and assessed quality using predefined criteria.

Conclusions: After about 10 years, PSA-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.

The Cancer Letter, Oct. 7, 2011

Screening• Two large trials done recently

looking at survival benefit from screening:• PLCO screening trial (U.S.) and ERSPC

screening trial (European)• These two RCT were largely basis for

USPSTF recommendations

Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

PLCO (US trial)• Prostate, lung, colorectal, ovarian Cancer

screening trial (U.S.)– 76,693 men randomized – Ages 55-74 included – After 7 years risk of death same– Significant flaws in study makes

conclusions questionable• Found no survival benefit for PSA based

screening

Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009

PLCO trial flaws• Significant rates of screening in “control”

arm – 52% contamination (men were screened prior

to study)• Relatively low rate of biopsy in men who

had “abnormal” screening results in screen arm – Less than 50% of men in screened arm with

indication had biopsy done• Short follow-up (less than 10 yrs)

Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009

ERSPC screening trial (European)

• European Randomized Study of Screening for Prostate Cancer– 182,000 men randomized– Ages 50-74 included– Median f/up of 9 years there was 20%

reduction in CaP deaths in screened group

– 41 % reduction in metastases at presentation

Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

ERSPC screening trial (European) flaws

• Numerous sites of trial entry (7 countries)

• Mortality reduction of 20% came with large investment• To prevent one cancer death, need over

1400 men to be screened over decade and 48 men would require treatment

Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

Screening• Problems with both studies

– Short follow-up <10 years (mortality from CaP is very low in first 10 years)

– Subset analysis not done for high risk men (i.e. those with +FH, AA)

Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

Göteborg Screening Trial• Göteborg randomized population-based

prostate screening trial– 20,000 men randomized– Ages 50-64 included (median 56)– Median follow-up 14 years– Found 44% risk reduction in CaP specific

death in screened group– NNT analysis revealed that 293 men needed to

be screened and 12 men need to be diagnosed in order to prevent 1 death

Hugosson et al. Mortality results from the Göteborg randomised Population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725-32.

Diagnosis• PSA can be elevated secondary to BPH,

prostatitis, recent ejaculation, prostate trauma (massage, biopsy, urethral instrumentation, cycling, etc…)

• Use of age and ethnicity adjusted PSA values


Age Caucasian African-American Asian-American

40-49 0-2.5 0-2.0 0-2.0

50-59 0-3.5 0-4.0 0-3.0

60-69 0-4.5 0-4.5 0-4.0

70-79 0-6.5 0-5.5 0-5.0

Diagnosis• PSA not perfect and can only be used

to define risk of prostate cancer NOT diagnosis

• No universally accepted threshold value

• Decision to biopsy based on many different criteria (age, overall health, PSA velocity, PSADT, FH, race, etc…)


Indications for Prostate Biopsy

• Suspicious DRE• Age, ethnicity, +FH• Abnormal total PSA


When to Perform Imaging to Evaluate for Metastatic Disease

• Bone scan– Indicated: PSA>20, Gleason score ≥8,

Bone pain• Pelvic CT/MRI

– Indicated: PSA>20, Gleason score ≥8 • Newer data suggests fused PET/CT with 11C-

Acetate may be much better at detecting microscopic +LN

Campbell-Walsh UROLOGY, 9th editionOyama et al. 11C-Acetate PET imaging of prostateCancer: detection of recurrent disease at PSA relapse. 2003. J Nuc Med. 44; 549

When to Perform Imaging to Evaluate for Metastatic Disease (bone scan)


Total PSA Probability of +Bone Scan

<10 2.3%

10-20 5.3%

20-50 16%

>50 >35%

Biopsy Gleason

Score

Probability of +Bone Scan

≤7 5.5%

≥8 28%

Pet Imaging in Prostate Cancer

Example of Positive LN

Prostate Cancer—Indolent vs. Aggressive?

• Risk based on individual results– PSA– DRE – Gleason Score: major score + minor score

= sum score• (1-5) + (1-5) = (2-10)

– Number of + biopsies


Prostate Cancer—Indolent vs. Aggressive?

• Low Risk– PSA < 10 – Gleason score ≤6

• Intermediate Risk– PSA 10-20, Gleason 7 or Gleason 6 with PSA

>10• High Risk

– PSA > 20, Gleason 8-10


Treatment options for Localized Prostate Cancer

• Active Surveillance• Surgery• Radiation• Cryoablation


Active Surveillance

• Not discussed enough in this country• Strict selection criteria

• Low risk: cT1-2a, PSA<10, life expectancy <10yrs, Gleason 6 or less

• Very low risk: cT1-2a, PSA<10, life expectancy up to 20yrs, Gleason 6 or less, <3 cores +, <50% of each core involved


Cryoablation (freezing of prostate)

• Cancer-specific outcomes not as mature as surgery or radiation– Almost all men will have significant ED after Tx– Not good option for locally advanced or high risk

patients– Useful for men with previous pelvic radiation,

rectal disorders, or inflammatory bowel disease• Good salvage therapy option for men with recurrent

disease after radiation, brachytherapy or cryoablation


Radiation• Various delivery methods

– XRT (external beam radiotherapy)• Whole pelvis, 3-D conformal, IMRT

(intensity modulated radiation therapy)– Brachytherapy (radioactive seeds)

• Temporary high dose rate (usually combined with XRT boost)

• permanent low dose rate


Radiation• For low risk disease IMRT or

Brachytherapy good treatment choices– No need to add ADT

• For intermediate risk disease should add ADT– 2 months before, during, and for 6 months

after XRT• For high risk disease should add longer

course of ADT– Just before, during, and for 3 years after XRT

• No randomized prospective trials comparing surgery to radiation

D’Amico et al. Androgen suppression and radiation vs. radiation alone for prostate cancer. JAMA, 299, 2008Bolla et al. Three years of adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy. N Engl J Med, 337, 1997

Surgery

• Different approaches to remove prostate–Open–Laparoscopic (use straight

instruments)–Robotic (use wristed instruments

with 7 degrees of freedom)Campbell-Walsh UROLOGY, 9th editionComprehensive Textbook of Genitourinary Oncology, 3rd edition

Surgery

• Only form of treatment with randomized trial revealing CSS and OS advantage when compared to surveillance

• Survival benefit was seen for men <65 yrs of age

Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian Prostate Cancer Group 4 randomized trial. J Natl Cancer Inst, 100, 2008

Surgery

• Authors of that study recently published updated 15 year follow-up data

• Again found CSS and OS benefit for men undergoing RP vs. surveillance in <65 yrs of age

Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

Original Article Radical Prostatectomy or Watchful Waiting in Early

Prostate Cancer

Anna Bill-Axelson, M.D., Ph.D., Lars Holmberg, M.D., Ph.D., Hans Garmo, Ph.D., Jennifer R. Rider, Sc.D., Kimmo Taari, M.D., Ph.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., Anders Spångberg, M.D., Ph.D., Ove Andrén, M.D., Ph.D., Juni Palmgren,

Ph.D., Gunnar Steineck, M.D., Ph.D., Hans-Olov Adami, M.D., Ph.D., and Jan-Erik Johansson, M.D., Ph.D.

Volume 370(10):932-942 March 6, 2014, N Engl J Med

Original Article Radical Prostatectomy or Watchful Waiting in Early

Prostate Cancer

• This randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy.

• The number of men younger than 65 needed to treat to prevent one death is now four.

• Follow-up of 18 years Volume 370(10):932-942 March 6, 2014, N Engl J Med

Prevalence of Metastases and Use of Palliative Treatment in Men Alive at Various Time Points since Randomization

Bill-Axelson A et al. N Engl J Med 2014;370:932-942

Volume 370(10):932-942 March 6, 2014, N Engl J Med

PIVOT (Prostate cancer Intervention Versus Observation Trial)

• Randomized men ≤75yrs old to radical prostatectomy vs. expectant management with all-cause mortality as primary end-point

• 731 men studied• Median f/up 10 years• Different than Scandinavian trial

– looked at same thing, but now in PSA screening era

Wilt et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med, 367, 2012Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

PIVOT (Prostate cancer Intervention Versus Observation Trial)

• Found 47% (171/364) men died who had surgery vs. 49.9% (183/367) in observation arm

• 5.8% (21) men who had surgery died from CaP or treatment vs. 8.4% (31) in observation arm

• Essentially NO Difference between groups– Surgery associated with ↓ all-cause mortality

in men with PSA>10 and possibly in intermediate or high-risk tumors

Wilt et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med, 367, 2012Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

ProtecT (Prostate testing for cancer and Treatment)

• RCT of treatment effectiveness in UK• Opened 2001 and closed 2008• 111,000 men randomly assigned to

surveillance, radiation, or surgery• Primary end-point will be CSS at 10yrs• With numerous secondary end-points

including QOL analyses

Donovan et al. Prostate testing for cancer and treatment (ProtecT) feasibility study. Health Technol Assess 2003; 7:14

Conclusions• Prostate cancer very common problem• Need to know which men to offer

screening, when to begin and end, and how often to offer screening

• Currently we overdiagnose, which leads to overtreatment of prostate cancer in U.S.

• Desperately need to find better ways to delineate aggressive forms of prostate cancer from indolent disease in order to offer treatment to men who will benefit and spare those who will not

Documents

A Prostate Cancer Update: Screening, Over Diagnosis, and Treatment