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

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1 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 Gretchen Dickson, MD, MBA, FAAFP 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. 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. Audience Engagement System Step 1 Step 2 Step 3 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. 1

2 Prostate Cancer- Epidemiology PROSTATE CANCER Worldwide incidence of 25.3/ 100,000 Incidence peaked in 1992 Falling incidence between % annual increase since 1995 Second leading cause of cancer death in men 32,050 deaths in % 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 Prostate Cancer and Genetics Protective Factors 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 Hereditary prostate cancer gene candidates Single nucleotide polymorphisms Copy number variations Ribonuclease L (RNASEL) 2

3 USPSTF Recommendation The U.S. Preventive Services Task Force (USPSTF) recommends against prostatespecific antigen (PSA)-based screening for prostate cancer (D recommendation). ASYMPTOMATIC SCREENING Prostate Cancer Related Deaths Analysis of cause of death for all men with prostate cancer in Swedish Cancer Registry ( , n=210,112) US Surveillance Epidemiology and End Results Program ( , 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 years, therefore limit screening by life expectancy 3

4 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 European Randomized Study of Screening for Prostate Cancer 182,000 men age 50-74, followed 9 years Screening protocol Cumulative Incidence Prostate Cancer Rate Ratio of Prostate Cancer Death Screening Group Usual Care Group 85% PSA 86% DRE 40 52% PSA 41 46% DRE Screening Group PSA q 4 years 8.2% 0.8 Control Group No PSA testing 4.8% 1.0 Overdiagnosis Rate Caucasian Men African American Men Overdiagnosis rate among men with Detection of prostate cancer 29% through PSA 44% testing prostate cancer detected by that PSA screening otherwise would not have been diagnosed within the patient s lifetime Lifetime probability of prostate cancer diagnosis prior to PSA Tumors detected by PSA that would have presented clinically 9% 9% 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 (overall) PSA + DRE $ PSA+ DRE $ PSA+DRE $ PSA only $

5 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 Transrectal Prostate Biopsy 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 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 5

6 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 Androgen Suppression Therapy 6

7 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 Indicated for low risk clinically localized prostate cancer Complications 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) 7

8 Radical Prostatectomy Urinary Incontinence 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 mg Calcium daily 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 8

9 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 Increases risk of Central obesity Diabetes Metabolic syndrome CV related death Hyperlipidemia Osteoporosis 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, CI , p=0.032) No effect on overall mortality (HR=0.88, CI= , 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 FOLLOW-UP SURVEILLANCE LOCALIZED PROSTATE CANCER 9

10 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 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 Helpful in determining site of recurrence, but not detecting recurrence 10

11 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 METASTATIC PROSTATE CANCER BPH treatment & prostate cancer PREVENTION 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 Maintain a healthy weight 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. 11

12 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 Gretchen.dickson@wesleymc.com 12