Stacy Loeb, MD · • SUNLIGHT/VITAMIN D: associated with ↓ prostate cancer risk – Schwartz AnticaAg Med 2013; 13; 45 Possibly Beneficial • ASPIRIN: ↓ prostate cancer risk

Practice-Changing Publications in

Prostate Cancer:

“The Year in Review”

Stacy Loeb, MDDepartment of Urology

New York University (NY, USA)

Acknowledgement

AUA Prostate Cancer Update Course

William J Catalona, MD

Robert B Nadler, MD

Douglas M Dahl, MD

Stanley L Liauw, MD

Nature & Nurture

Genetic Factors

•Recent meta-analysis: 4X ↑ prostate cancer risk

(including both aggressive and non-aggressive disease)

•Shang et al. Eur Urol 2013 epub.

HOXB13 (Homeobox B13)- Chromosome 17

BRCA 1 & 2

•Present in 0.44 and 1.2% of prostate cancers , respectively

•↑ risk Gleason ≥8, stage T3/T4, lymph node involvement,

metastases, death

•Castro et al. JCO 2013; 31: 1748

• SUNLIGHT/VITAMIN D: associated with ↓ prostate cancer risk– Schwartz Antica Ag Med 2013; 13; 45

Possibly Beneficial

• ASPIRIN: ↓ prostate cancer risk in Finland registry (OR

0.90, 95% CI 0.84-0.96) and ↓ prostate cancer mortality

after treatment in CaPSURE (HR 0.43, 95% CI 0.21-0.87)•Veitonmäki et al. Eur J Cancer 2013, Choe et al. JCO October 2012

• STATINS: Meta-analysis showed↓ overall (RR 0.93,

95% CI 0.87-0.99, p=0.03) and significant prostate

cancer (RR 0.80, 95% CI 0.70-0.90, p<0.001) •Bansal et al. PLoS One October 2012

Possibly Harmful• DEEP FRIED FOOD: ↑ odds of prostate cancer with

increased intake of deep fried foods (french fries, donuts, etc)• Stott-Miller et al. Prostate 2013

• DAIRY: ↑ prostate cancer risk in Physician’s Health Study

• Whole milk associated with prostate cancer death• Song et al. J Nutrition 2013

• FISH OIL CONTROVERSY: ↑ single baseline serum level of

omega fatty acids associated with prostate cancer and high-

grade disease

• Did not assess dietary fish intake or supplements• Brasky et al. JNCI 2013 epub.

Nature & Nurture: Take Home Messages• Both genes and environment play a role in prostate

cancer

• BRCA: associated with more aggressive disease– Careful screening, not good candidates for active surveillance

• Eat a healthy diet, everything in moderation

• Aspirin and statins may have some benefit but also have

risks

– USPSTF recommended against aspirin for colorectal cancer

prevention due to bleeding risk

PSA Guidelines

ASCO “Provisional Opinion on Screening”

• Life expectancy >10 yr: Discuss that PSA testing may save

lives but is associated with harms, including

complications from unnecessary biopsy, surgery, or

radiation treatment

• Provide information on benefits and harms written in lay

language to facilitate the discussion

Basch et al. JCO August 2012; 30: 3020

American College of Physicians

• GUIDANCE STATEMENT 1: Clinicians inform men aged 50-69

about the limited potential benefits and substantial harms of

screening

– Decisions to screen should be based on risk factors, a

discussion of the benefits and harms, general health and life

expectancy, and patient preferences

• GUIDANCE STATEMENT 2: Do not screen average-risk men <50y,

>69y, or with a life expectancy <10-15y

Qaseem et al. Ann Int Med May 2013; 158: 761

American Urological Association Guideline

• Statement 1: Recommends against PSA in men <40 yr

• Statement 2: Does not recommend routine screening for average-risk men ages 40-54yr

• Statement 3: Shared decision-making for men ages 55-69 yr– Weigh the benefits of preventing prostate cancer mortality

in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment.

Carter et al. http://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm

American Urological Association Guideline

• Statement 4: To reduce harms, a routine

screening interval of ≥2yr may be preferred over

annual screening

• Statement 5: Does not recommend routine PSA

screening in men age 70+ years or life

expectancy <10-15yr

Carter et al. http://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm

EAU Guideline

• A baseline PSA should be obtained at age 40–45

– Use this level to determine screening intervals (~2-8y)

• PSA screening should be offered to men with a

life expectancy ≥10 yr

• Multivariable clinical risk-prediction tools should

be integrated into the decision-making process

Heidenreich et al. Eur Urol 2013 epub.

Studies on Screening

Baseline PSA Predicts Metastasis & Death

• Nested case control study in unscreened Swedish cohort (n=21,277)

• Baseline PSA at 45-49 predicted 25-yr risk of metastases and death

• Median PSA =0.7 ng/ml

• Highest 10th percentile (≥1.6 ng/ml) � 44% of prostate cancer deaths

Vickers et al. BMJ 2013;346:f2023

Quality of life in European Randomized Study

of Screening for Prostate Cancer

• Using modeling, predicted that annual screening of 1000

men would result in 73 life-years gained

– ↓to 56 quality-adjusted life years taking into account

downstream QOL effects (ex: impotence, incontinence)

• 23% of the gain in life years are potentially offset by the

loss in quality of life

– Wide range depending on men’s preferences

Heijnsdijk et al. NEJM 2012; 367: 595-605

Shared Decision-Making• 2010 National Health Interview Survey (n=3427 men ages 50-74)

– 55.8% ever had PSA test

• Examined 3 components of shared decision-making (advantages,

disadvantages, uncertainty)

– 65% reported none, only 8% reported all 3 elements

• Physician-uninformed non-screening >> physician-uninformed

screening

– Concern about non-uptake of screening without a shared

decision

Han et al. Annals of Family Medicine 2013; 11: 306

There’s More to Life Than Death

• USPSTF recommendation against PSA screening is largely based

on assessment that harms outweigh the mortality benefit

– Modeling studies also focus on trading off years of life

• Editorial discusses that death is not the only important endpoint:

dramatic reduction in metastatic disease with PSA screening

– Must weigh the sequellae of advanced disease (bone pain,

pathologic fractures, urinary obstruction) against the side

effects from treatment of early disease

Hartzband & Groopman NEJM 2012; 367: 987

PSA Screening Reduces Metastasis

• N=76,813 from European

Randomized Study of Screening

for Prostate Cancer (ERSPC)

• Intent-to-screen: 50% reduction

in metastases at diagnosis, 30%

reduction in metastases during 12

years follow-up

• Need to diagnose 12 to prevent 1

case of metastatic disease at 12yr

Schroder et al. Eur Urol 2012; 62: 745-52. Scosyrev et al Cancer 2012, 118:54

• 2008 US SEER data:

compared observed cases

of metastatic disease to

what would be expected

without screening (using

pre-PSA data)

• 8000 observed cases vs.

25,000 expected (3x higher

without screening)

• Baseline PSA in 40’s identifies high risk group

– Smarter screening: use level to guide screening

interval

• Patient preferences determine the ratio of

benefits and harms with screening

– Shared decision-making essential but underutilized

• There’s more to life than death!

– Screening reduces metastatic disease

Screening: Take-Home Messages

Biopsy & Staging

Prostate Biopsy Complications

Systematic Review• Bleeding complications: hematuria (10-84%),

hematospermia (1.1-93%), rectal bleeding (1.3-45%)

– Mostly minor, self-limited; rarely severe/requiring hospitalization

– Ok to perform biopsy on aspirin

• Infectious hospitalizations increasing � new strategies

• LUTS : transient dysuria in 6-25%, retention 0.2-1.7%

• Erectile dysfunction: controversial

Loeb et al. Eur Urol 2013 epub

Should Gleason 6 Be Called Cancer?

• Discussion about removing label of

cancer to reduce anxiety and

overtreatment

– Ex: use the term “IDLE” (indolent lesions

of epithelial origin) for low-risk cancers

• Problems:

– Morphologically and genetically, Gleason

6 is cancer with the ability to invade

tissues

– Biopsy Gleason score often

underestimates grade and extent

“What’s in a name? That which we call a rose by any other name would smell as sweet…”

• A modernized Gleason classification

ranging from 1-5 instead of 6-10

Gleason Score Prognostic Gleason

Grade Group

≤6 I/V

3+4=7 II/V

4+3=7 III/V

8 IV/V

9-10 V/V

Option 1: Not Cancer

Esserman et al. JAMA 2013 epub July 29

Option 2: Yes but rename

Carter JCO 2012; 30: 4294.

Prolaris Cell Cycle Progression Genes

• Expression of 31 cell cycle progression (CCP) genes,

normalized to 15 housekeeping genes = Prolaris

score (-1.3 to +4.7)

• CCP score sub-stratified patients with low clinical risk

as defined by CAPRA-S ≤ 2

• CCP score + CAPRA-S together risk stratification

– Potential role in active surveillance

Cooperberg et al, JCO 2013

Reducing Inappropriate Imaging

• US “Choosing Wisely” Campaign recently identified reducing imaging of low-risk prostate cancer as a target to decrease costs and improve quality of care

• Since 1990, nationwide Swedish effort to reduce inappropriate imaging through presentation of guidelines and provider feedback

– Successfully reduced imaging for low-risk prostate cancer from 45% to 3%

Makarov et al. JNCI 2013

Biopsy & Staging

• Biopsy risks increasingly recognized � new

strategies being explored

• Alternate nomenclature for low-grade disease

may reduce anxiety, but more accurate staging

needed

– New tissue tests may help improve staging

Treatment of Localized Disease

Dr. Walsh’s 30-Year Outcomes

• 1982: Dr Walsh’s 1st nerve sparing radical prostatectomy � examined his series at 30 year anniversary of this discovery

• N=4478 RRP from 1982-2011

• 25-year outcomes: PFS 68%, MFS 84%, CSS 86%

• Anatomic RRP remains gold standard to which alternate therapies should be compared

Mullins et al. J Urol 2012; 188: 2219

• PROTONS VS. IMRT

• Medicare data 2008-2009

(n=27,647)

• Protons had less GU toxicity at

6 months but no difference in

GU or GI toxicity by 12 months

• Cost : Protons $32,428 versus

IMRT $18,575

Yu et al. JNCI 2012; 105:25.

Use of Expensive Technology

Jacobs et al. JAMA 2013 epub

• US SEER-Medicare (2004-2009)

examined rates of IMRT, EBRT,

robotic, open and observation

• Advanced technology increased

from 25% to 34% for men with

low-risk disease and a high risk

of noncancer mortality

15-year Functional Outcomes After Treatment

• Prostate Cancer Outcomes

Study: n=1655 men treated in

1994-1995

• Prospensity score adjustment

• Continued decline in both groups

• Early differences minimized by 15y

• No control group

Resnick et al. NEJM 368:436, 2013

RP

5/15 y

RT

5/15 y

Incontinence 13/18 5/9

Bowel

urgency

16/22 31/36

Poor

erections

76/87 72/94

Symptoms over time

Active Surveillance Outcomes

• PRIAS: n=2494 on AS

• Median f/u 1.6 years

• Estimated 4-year therapy-free survival=67.7

• 2 cases of metastatic disease, 0 deaths

Bul et al. Eur Urol 2012 epub

• Model of CaPSURE and Johns

Hopkins to estimate difference

in immediate surgery versus

active surveillance

• 2/3 will eventually need

treatment (at average of 6.4 yr)

• No significant difference in

overall survival

Xia et al. Clin Cancer Res 2012; 18:5471

Phase 1 Trial of Focal Laser Therapy

• N=9 patients with a focal suspicious lesion on MRI in same location as positive biopsy

• Patient in MRI machine � laser target lesion via brachytherapy template– 2.5-4 hours OR time, no immediate complications

• Mean PSA 5.5 before treatment, also 5.5 at 6mos postop (p=0.8)

• 3 patients with ≥5 point decrease in SHIM at 6 mos

• 2/9 patients had Gleason 6 cancer on biopsy at 6 mos

Oto et al. Radiology 2013 epub.

Localized: Take-Home Messages

• Open prostatectomy excellent long-term

oncologic outcomes

• Increased use of expensive treatment alternatives

• Active surveillance safe in short-term

• Focal therapy modalities expanding

– Need more data on cost-effectiveness

Recurrent & Advanced

Disease

Long term update of EORTC 22911: Adjuvant RT

• Phase III study of men with pT3 or positive

margins, given RT vs observation (n=1005)

• Median f/u 10.6 yr: improvement in biochemical

progression-free survival (61% vs. 41%)

• No difference in overall survival, unlike SWOG

Bolla et al. Lancet 380:93, 2012

Intermittent vs Continuous Androgen Deprivation

• 765 continuous vs. 770 intermittent androgen deprivation

• Median survival = 5.8y continuous vs. 5.1y intermittent

• Hazard ratio for death with intermittent therapy, 1.10; 90% CI

0.99 to 1.23)

– Cannot rule out a 20% greater risk of death with

intermittent therapy than with continuous therapy

• Intermittent therapy was associated with better erectile

function and mental health at month 3 but not thereafter

Hussain et al. N Engl J Med 2013; 368: 1314.

First-Line Abiraterone• N=1088 with mCRPC (no prior chemo)

• Abiraterone + prednisone improved median progression free survival of 16.5 vs. 8.3 mo (HR 0.53 p<0.001), delayed time to pain and chemo

• Improved OS (HR 0.75 p<0.01) endpoint not reached at cessation of study

• FDA approved for pre- and post-chemo use

Ryan et al. NEJM 2013; 368:138-48

AFFIRM: Enzalutamide (MDV 3100)

• Does not require prednisone

• Phase 3 trial N=1199 with metastatic castrate-resistant prostate cancer

• Study stopped because of prolonged survival

• Time to progression: 8.3 vs 2.9 months

• Time to skeletal event: 16.7 vs 13.3 months

• Side effects: fatigue, diarrhea, 0.6% seizures

Scher et al for AFFIRM. NEJM 2012; 367:1187

Radium-223 (Alpharadin)• First ever radiopharmaceutical

– Bone metastasis-targeting agent (binds to areas of increased bone turnover and emits high energy alpha particles of short-range)

• ALSYMPCA trial: Radium-223 vs. placebo injection for bone metastatic CRPC– Improved overall survival (median 14.9 vs. 11.3 mos)

– Reduced skeletal-related events, improved QOL

– Minimal myelotoxicity, few adverse events

Parker et al. NEJM 2013; 369: 213

Advanced Disease: Take Home Message

• Conflicting data on benefit of adjuvant radiation after prostatectomy

– Consider early salvage strategy

• Intermittent ADT not non-inferior

• Explosion of new drugs for CRPC

– Timely given projected resurgence of metastatic disease with less screening