Prostate Cancer- Epidemiology. Risk Factors for Prostate Cancer. Prostate Cancer- Epidemiology. Prostate Cancer and Genetics

Prostate Cancer

Gretchen Dickson, MD, MBA, FAAFP

ACTIVITY DISCLAIMER

The material presented here is being made available by the American Academy of Family Physicians for educational purposes only. This material is not intended to represent the only, nor necessarily best, methods or procedures appropriate for the medical situations discussed. Rather, it is intended to present an approach, view, statement, or opinion of the faculty, which may be helpful to others who face similar situations.

The AAFP disclaims any and all liability for injury or other damages resulting to any individual using this material and for all claims that might arise out of the use of the techniques demonstrated therein by such individuals, whether these claims shall be asserted by a physician or any other person. Every effort has been made to ensure the accuracy of the data presented here. Physicians may care to check specific details such as drug doses and contraindications, etc., in standard sources prior to clinical application. This material might contain recommendations/guidelines developed by other organizations. Please note that although these guidelines might be included, this does not necessarily imply the endorsement by the AAFP.

DISCLOSURE

It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflict of interest (COI), and if identified, conflicts are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or who agreed to an identified resolution process prior to their participation were involved in this CME activity.

All individuals in a position to control content for this activity have indicated they have no relevant financial relationships to disclose.

The content of my material/presentation in this CME activity will not include discussion of unapproved or investigational uses of products or devices.

Gretchen Dickson, MD, MBA, FAAFP

Program Director, Wesley Family Medicine Residency, Wichita, Kansas; Assistant Professor, Department of Family and Community Medicine, University of Kansas School Of Medicine–Wichita. Dr. Dickson earned her medical degree from the University of Pittsburgh School of Medicine, Pennsylvania, completing an area of concentration in women’s health. She completed her residency at the University of Missouri Kansas City Family Medicine Residency, where she served as chief resident. She also earned a Master of Business Administration degree from Rockhurst University, Kansas City, Missouri. Dr. Dickson completed fellowships in operative obstetrics and faculty development before serving as faculty at the Lancaster General Health Family Medicine Residency, Pennsylvania. In addition to serving as a family medicine residency program director, she maintains a full-spectrum clinical practice.

Learning Objectives

1. Counsel patients, using shared decision making resources, regarding the risks and benefits of prostate cancer screening.

2. Counsel patient with diagnosed localized prostate cancer about the risks and benefits of their treatments options, using a standardized clinical decision aid.

3. Collaborate with other health providers (e.g. urologists and oncologists) to construct a coordinated referral process for men requiring prostate cancer treatment.

4. Provide appropriate and current resources to survivors on the psychosocial effects of cancer.

Audience Engagement System

PROSTATE CANCER

Prostate Cancer- Epidemiology

• Worldwide incidence of 25.3/ 100,000 – Incidence peaked in 1992

– Falling incidence between 1992-1995 – 1% annual increase since 1995

• Second leading cause of cancer death in men – 32,050 deaths in 2010

– 11% of cancer deaths among men

Prostate Cancer- Epidemiology

• Cancer is detectable in – 50% of men at age 50 – 80% of men at age 80

• 16% of men will be diagnosed – 3% will die of prostate cancer

Risk Factors for Prostate Cancer

• Age

• Family History

– Father or Brother

• Race

– African American men have highest rates – Asian and Native American men have lowest rates

• Exposure to Agent Orange • Geographic Location

– Men who live north of 40 degrees latitude (north of Philadelphia) have highest risk of dying from prostate cancer of any men in US

• Vitamin D level effect?

Prostate Cancer and Nutrition

• Mediterranean diet pattern • High intake of folate • Cruciferous vegetables

(broccoli) • Fatty fish (salmon)

Risk Factors

• Heterocyclic amines from well-cooked red meat • High calorie diets • High saturated fat intake • Low fiber intake

• High dietary glycemic index

Prostate Cancer and Genetics

• Hereditary prostate cancer gene candidates – Single nucleotide polymorphisms

– Copy number variations – Ribonuclease L (RNASEL)

ASYMPTOMATIC SCREENING

USPSTF Recommendation

• The U.S. Preventive Services Task Force (USPSTF) recommends against prostate-specific antigen (PSA)-based screening for

prostate cancer (D recommendation).

Prostate Cancer Related Deaths

• Analysis of cause of death for all men with prostate cancer in

– Swedish Cancer Registry (1061-2008, n=210,112) – US Surveillance Epidemiology and End Results

Program (1973-2008, n=490,341)

• Men diagnosed with prostate cancer less likely to die from prostate cancer than other cause

Prostate Specific Antigen Testing

• To prevent 1 prostate cancer death at 10 years – 1410 men need to be screened

– 48 men needed to be diagnosed with prostate cancer and receive early intervention

• Eliminating Swedish results in above study negates any mortality benefit

Prostate Specific Antigen Testing

• FDA approved in 1994

• No clear causal relationship between testing and decreased death

– Lead and lag time bias

• 30 million American men tested per year • Cost of 3 billion per year

Prostate Specific Antigen Testing

• Does not reduce prostate cancer specific mortality

– Even in subgroup analysis of men with positive family history or African American race

• Any benefit accrues only after 10-15 years, therefore limit screening by life expectancy

PLCO Cancer Screening Trial

• 76,693 men randomized to annual screening or usual care in the US

Screening/ Compliance 

Rates

Incidence Prostate Cancer per 

100,000 person years

Incidence of Death per 

100,000 person years Screening  Group 85% PSA 86% DRE 116 2.0 Usual Care  Group 40‐52% PSA 41‐46% DRE 95 1.7

European Randomized Study of Screening

for Prostate Cancer

• 182,000 men age 50-74, followed 9 years Screening protocol Cumulative Incidence_Cancer  Prostate  Rate_Cancer Ratio of _Death Prostate 

Screening 

Group PSA q 4 years 8.2% 0.8 Control Group No PSA testing 4.8% 1.0

Overdiagnosis Rate

• Overdiagnosis

– Detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient’s lifetime

Caucasian Men African American Men

Overdiagnosis rate among men with  prostate cancer detected  by PSA screening 29% 44% Lifetime probability of  prostate cancer  diagnosis prior to PSA 9% 9% Tumors detected by PSA  that would have  presented clinically 85% 63%

Notes from the USPSTF Recommendation

• Acknowledge that African American men have a 2x higher change of dying of prostate cancer

– Only 4% of enrolled men in studies

– Unclear if recommendations would change for this population– need more studies

– Risks currently outweigh known benefits • Men with known BRCA mutations also not

included in this recommendation

American Urologic Association

Recommendations

• Recommends against PSA screening in men under age 40 years. • Does not recommend routine screening in men between ages 40 to 54 years

at average risk.

– For men younger than age 55 years at higher risk decisions should be individualized.

• Strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA screening, and proceeding based on a man’s values and preferences.

• Routine screening interval of two years or more may be preferred over annual screening

• Does not recommend routine PSA screening in men age 70+ years or any man with less than a 10 to 15 year life expectancy.

Cost of Prostate Cancer Screening

Age Range of Patient Type of Screening Cost per year life saved

50‐69 (overall) PSA + DRE $3574‐4627

50‐59 PSA+ DRE $2339‐3005

60‐69 PSA+DRE $3905‐5070

Screening Recommendation Response

• 141 physicians and nurse practitioner in the Johns Hopkins Community Physicians group

– Response rate 89% (123) – Female 62% – 39% Family Medicine – 68% had 10+ years of practice

• 93% had heard about new USPSTF recommendations

– Agreement with recommendations

• 49% agreed or strongly agreed • 36% disagreed or strongly disagreed

– Planned change to practice

• 2% would no longer order routine PSA testing • 38% would not change screening practice

– Current practice (year prior to study)

• 17% ordered PSA without discussing it with patients • 36% recommended PSA after discussing risks/ benefits

SYMPTOMATIC TESTING

Presentation

• Urinary symptoms

– Dysuria, frequency, urgency or noctiuria • New-onset erectile dysfunction • Hematuria or hemaspermia

• Symptoms of metastatic disease (bone pain) • Abnormal digital rectal exam

Hematospermia

• Limited evidence in literature

• One study of 469 men with hematospermia found – 13 ultimately had prostate cancer (6%)

– All prostate cancer patients had PSA >3.0 ng/ml or abnormal DRE

• DRE and PSA indicated for men over 40 with hematospermia

Diagnosis

• Abnormal DRE warrants PSA testing • PSA > 10 ng/ml

– Proceed with biopsy

– Prostate cancer will be found in > 50% of patients • PSA 4-10ng/ml

– Proceed with biopsy

– 1 in 5 biopsies will show prostate cancer • PSA < 4ng/ml

– Unclear recommendations

Transrectal Prostate Biopsy

• Complications

– Asymptomatic bacteriuria – Urinary Tract Infection – Transitory Bacteremia – Fever – Sepsis • Antibiotic Prophylaxis – Effective at preventing above complications – No definitive data • 3 days vs. 1 day • Multiple dose vs. single

dose

• Route of administration • Choice of antibiotic

Gleason Score

• Within biopsy sample, most common pattern noted is assigned a Gleason grade

• Second most common pattern also assigned a Gleason grade

• Score is sum of two grades

• May see description of tertiary grade as well • 4+3 worse than 3+4

Gleason Grades

• 1= Small uniform glands

• 2= Increasing space between glands

• 3= Infiltration of cells from glands at the margin • 4= Irregular mass of cells with few glands • 5= Lack of glands

• Grades range 1-5, Score ranges 2-10

Mid Presentation Question and Answer

TREATMENT FOR PROSTATE CANCER

Prostate Cancer Treatment

• Should be individualized

• Consider risk factors and comorbidities as well as potential side effects

Prostate Cancer- Treatment

• Early Stage

– Radical Prostatectomy – External beam radiation – Interstitial Radiation therapy – Active surveillance

• Advanced Stage

Adverse Effects

• Bowel dysfunction

• Urinary dysfunction including incontinence • Sexual dysfunction

– Impotence – Loss of libido

– Ejaculatory dysfunction

Active Surveillance

• Postponing curative intent treatment until evidence of disease progression

• Indicated for

– Men with very low risk prostate cancer and life expectancy of less than 20 years

– Men with low risk disease and life expectancy of less than 10 years

• No RCT comparing immediate definitive treatment and active surveillance

• Complications

– Anxiety

• Significant move to definitive treatment within 1-2 years despite absence of progression

Radiation Therapy

• Inadequate evidence

– Increased survival with radiation vs. no therapy – External beam radiation vs. interstitial radiation • If external beam radiation chosen

– Higher dose better for long term survival than low dose

External Beam RT

– Acute radiation proctitis (~ 20% of men affected) – Radiation enteritis

• More common if pelvic lymph nodes are treated • Symptoms: cramping, urgency and frequent defecation • Treatment: Antidiarrheal agents or topical anti-inflammatory • Expected resolution: 3-8 weeks following end of treatment – Cystitis/ Urethritis

• ~ 50% of men affected

• Symptoms: dysuria, frequency, urgency

• Expected resolution: 3-5 weeks following end of treatment – Erectile Dysfunction

• 60-70% of men affected

• Expected resolution: Often permanent requiring treatment

Brachytherapy

• Implantable radioactive source to limit damage to normal tissue

– Low dose

• Implantable iodine-125 or palladium-103 seeds • Requires one 90 minute procedure

– High dose

• Implantable Iridium-192 • Requires 48 hour hospitalization • Complications

– Urinary symptoms

• Transient frequency, urgency, dysuria • Occurs days after implantation

• Late complications are incontinence, urethral stricture, urinary retention

– Erectile dysfunction

• Usually permanent • Occurs in 50% of men

– Gastrointestinal

• Less common than with external beam RT

Radical Prostatectomy

• RCT of 731 men who received either observation or radical prostatectomy

– Mean age = 67 years – Median PSA= 7.2ng/ml Radical Prostatectomy  (n=364) Observation (n=367) Death 47% (171) 50% (183) Death from prostate  cancer or treatment 6% (21) 8% (31)

Radical Prostatectomy

– Symptoms in up to 25% of men beyond 1 year – Treatment options

• Waiting- gradual return to function expected • Biofeedback and pelvic floor training • Urethral sling

• Artificial urinary sphincter

• Erectile dysfunction

– Nearly universal if nerve sparing procedure not performed – Treatment

• Watchful waiting- some centers have had up to 80% of men regain function • PDE-5 Inhibitor

• Penile injection therapy • Vacuum erection devices • Implantable prosthesis

Androgen Suppression

• Intermittent vs. continuous therapy

– Data limited to RCTs with small sample size and short duration

– No data for overall survival or disease progression – Intermittent may reduce adverse events

Androgen Deprivation Therapy

• Sexual dysfunction – Expected with treatment

– Can try alternative dosing to allow for intermittent regain of function

– Counseling often helpful for couples • Osteoporosis

– Screen for with DEXA

– Calcium and Vitamin D recommended at start of therapy – Bisphosphonates may be helpful

– SERMs may also be helpful

Calcium and Vitamin D for ADT

• Does calcium and Vitamin D really help with bone loss?

• Maybe

– 12 clinical trials demonstrated that bone loss persisted at doses of

• 500-1000mg Calcium daily • 200-500 IU Vitamin D daily

– Trials with higher dose calcium/ vitamin D ongoing – Risk may outweigh benefit

Androgen Deprivation Therapy

• Vasomotor symptoms – Not well studied

– Consider same treatments used for menopausal women – Treatments studied in men include:

• SSRI • Gabapentin • Soy • Acupuncture • Cyproterone

Androgen Deprivation Therapy

• Body Image Issues – Gynecomastia – Decreased genital size – Thinning of body hair – Decreased muscle mass – Increase fat deposition

Androgen Deprivation Therapy

• Increased risk for – Cardiovascular disease – Diabetes

– Colon cancer – Fatigue – Anemia

• Risk stratify at outset of ADT and modify risk factors

Androgen Suppression

• Should have q 6 month follow-up with PCP to optimize cardiovascular risk factors

Beta Blocker Therapy and ADT

• Study of men receiving beta blocker and who were diagnosed with prostate cancer in Norway • Beta blocker use

– Reduced prostate cancer specific mortality (HR=0.14, CI0.02-0.85, p=0.032)

– No effect on overall mortality (HR=0.88, CI=0.56-1.38, p=0.57)

Sipuleucel-T Vaccine

• Therapeutic autologous vaccine

– Infusion of antigen presenting cells, obtained from leukapheresis, exposed to chimeric protein

• Indicated for men with asymptomatic or minimally symptomatic castrate resistant metastatic prostate cancer • Benefit

– 4.1 month increase in mediate survival – 23% reduction in risk of death

• Side effects

– Flu like illness

Localized Prostate Cancer Follow-up

• No RCT to define optimal surveillance strategy

History and Physical Examination

• May be reassuring to patient, but unlikely to detect local recurrence

• Digital Rectal Examination – Inexpensive and low risk

– Unclear use following prostatectomy • Retrospective analysis of 501 men

– 72 had risking PSA – 4 had abnormal DRE

– Clinical significance of change in DRE unknown

PSA Monitoring

• Indicated for follow-up surveillance • No trials define optimal monitoring interval • National Comprehensive Cancer Institute

– Measure serum PSA every 6-12 months for 5 years, then annually

PSA Recurrence

• Depends on initial treatment

• Elevation alone does not mean therapy is required • Radical Prostatectomy

– Any detectable PSA indicates remaining prostate – Presumed to be recurrent disease

• Radiation Therapy

– PSA levels bounce following radiation therapy complicating monitoring at 12- 18 months

ASTRO and PHOENIX

• ASTRO criteria – Written in 1997

– Biochemical recurrence after RT is 3 consecutive PSA rises following a nadir

• Phoenix criteria – Written in 2005

– PSA rise by 2ng/ml or more above nadir PSA is biochemical failure

Imaging Studies

• Not used routinely to detect recurrence • Bone scan

– Useful for detecting skeletal metastases

– PSA will be more effective at detecting recurrence than bone scan

• Trans-rectal ultrasound

– Not indicated

• Pelvic CT

– Limited sensitivity to detect recurrent disease. Not indicated

• Immunoscintography

METASTATIC PROSTATE CANCER

Metastatic Follow-up

• PSA testing does not prolong life expectantly, but may signal treatment failure

• Focus is on managing adverse effects of treatment, particularly ADT

PREVENTION

BPH treatment & prostate cancer

• Prostate Cancer Prevention Trial (PCPT) – 26% reduction in prostate cancer with 5mg

finasteride

• Reduction by Dutasteride of Prostate Cancer Events (REDUCE)

– 23% reduction in prostate cancer with 0.5mg dutasteride

BPH treatment & prostate cancer

• Decreased incidence of GS 6 or lower prostate cancer

• Increased incidence of GS 8 or greater prostate cancer

• FDA warning issued that treatment for BPH may increase high risk prostate cancer risk

Prevention Strategies

• Limit fat from red meat and dairy products

• Limit calcium to recommended daily allowance (1500mg/day) • Omega-3 fatty acids might be protective– eat more fish

• Increase lycopene by eating cooked tomatoes or cruciferous vegetables • Avoid smoking

• Seek medical treatment for chronic disease– if you do develop prostate cancer, you’re more likely to survive if chronic diseases are controlled • Avoid over-supplementation– A healthy diet is probably all you really need • Relax. Stress reduction improves survivorship.

Q & A

Practice Recommendations

• Do not screen for prostate cancer using PSA • If you do screen using PSA, then use shared

decision making to inform patient of risks/ benefits

• Remember to treat the long term sequelae of prostate cancer treatment to improve quality of life

Contact Information

• Gretchen M Dickson, MD, MBA, FAAFP