Prostate Cancer Screening and Treatment

1
Prostate Cancer Screening and Treatment

• David L. Maness, D.O., MSS, FAAFP
• Colonel, United States Army (Retired)
• Professor and Chairman
• UT Department of Family Medicine
• College of Medicine
• UT Health Science Center
• Memphis, Tennessee

2
Introduction

• Most common cancer in American men except for
  non-melanoma skin cancer
• 192,280 cases in 2009 with 27,360 deaths
• 1 in 6 chance of diagnosis
• 1 in 34 chance of dying
• 1/3 lt80 and 2/3 gt80 do not become clinically
  evident
• 5 year survival
• 100 if local or regional spread
• 31.9 if distant metastasis

3
Natural History

• Heterogeneous
• Some grow slow with no symptoms
• Some grow fast and metastasize
• Some grow at moderate rate
• Patients die of something else
• No strategies for prevention

4
Risk Factors

• Risk Factors
• Strongest risk predictor is age
• Ethnicity and family history are well established
  risks
• Medications, c0morbid conditions and dietary
  factors are less clear

5
Risk Factors-Genetic

• Heritable factors account for 42 of risk
• Increase two-fold with first degree relative
  (higher in twins)
• None associated with prognostic
  indicators-Gleason score, serum PSA level at Dx,
  or age
• MSR1 gene, RNAseL, genes related to
  androgen/estrogen metabolism
• BRCA1 and 2

6
Environment

• Chemical Compounds
• Occupation
• Dietary
• Medications
• Vitamins/supplements
• Comorbidities

• Agent orange
• Farming
• Lycopene
• Fish
• Dairy
• Meat
• Cruciferous vegetables
• Statins/Finasteride/ASA
• Vit E/Selenium/Multivitamin
• Diabetes/obesity

7
Chemicals

• Agent Orange (dioxin)
• Younger age
• More aggressive

8
Diet

• Animal fat-increased alpha-linoleic acid and low
  amounts of linoleic acid (combo in red meats and
  some dairy products)
• Vegetables-less than 14 servings weekly compared
  to more than 28 servings
• Tomato based products rich in lycopene (potent
  anti-oxidant) controversial-No evidence

9
Diet

• Soy intake
• Phytoestrogens (flavones, isoflavones,
  ligans)-naturally occurring plant compounds with
  estrogen-like activity
• Genistein and daidzein, predominate isoflavones
  derived mainly from soybeans and other legumes

10
Diet

• Multivitamins
• Does not appear to affect risk
• increased risk of advanced disease if taking more
  than seven times per week-Need further study
• Selenium-may be associated with decreased risk

11
Vitamins

• Vitamin E
• Alpha-tocopherol-potent anti-oxidant
• 36 decrease in Alpha-Tocopherol , Beta-Carotene
  Prevention Study (ATBC study)
• Other studies did not confirm

12
Exercise

• Physical activity
• Uncertain
• 47,620 Health Professions Follow-up study
  (1986-2000)
• Less likely to be diagnosed with high-grade
  prostate cancers
• Young lean men had more aggressive tumors

13
Sunlight

• Ultraviolet light exposure
• One case control study suggests protective effect
• Vitamin D related effect (?)

14
Medications

• Prostate Cancer Prevention Trial-finasteride to
  block the conversion of testosterone to more
  active derivative DHT
• Insulin and insulin-like growth factor
• increased risk with higher levels IGF-1
• most, but not all series, support relationship
  between high insulin levels, waist-hip ratio and
  prostate cancer risk

15
Medications

• NSAIDs (ASA)
• ACS Cancer Prevention Study II Nutrition Cohort
  (70,144 men)
• 30 or more pills per month for gt 5 years
• Decreased incidence (?)
• Case control or cohort studies (ASA-yes, NSAID ?)

16
Medications

• Statins
• 10-VAMC (443,805 men)-26,139 diagnosed with
  prostate cancer-statins provided a protective
  effect
• Portland Oregon VAMC-similar results
• Other studies (USHPFUS) and two meta-analysis
  studies no effect

17
Radiation Therapy

• EBRT for rectal cancer
• Decreased incidence for rectal cancer patients
  treated with EBRT
• Colon and rectal patients not treated with EBRT
  had same incidence of prostate cancer as general
  population

18
Comorbid conditions

• Diabetes
• Inverse relationship (16 lower risk)
• Chromosome 17q12 located within the TCF2 gene
• Alternate explanations
• Insulin and insulin-like growth factor
• Differential screening practices
• Competing mortality risks among diabetic patients

19
Comorbid Conditions

• Obesity
• Doubled in last 20 years
• Conflicting data
• High-grade and advanced-fatal disease
• Increased recurrence and mortality
• Might be risk factor for tumor progression rather
  than initiation
• Lower PSA levels
• Decreased production
• Hemodilution

20
Disease

• Prostatitis
• Several case-control and cohort studies and two
  meta-analysis suggest modest increased risk
• PSA increased in prostatitis-more biopsies
• Ascertainment bias

21
Hormones

• Hormone levels
• 18 prospective trials (3886 men with prostate
  cancer and 6438 controls)
• Testosterone, dihydrotestosterone and other
  active androgen derivatives were not associated
  with increased risk
• Testosterone supplementation not a risk
• No association with pre-diagnosis serum levels of
  estrogens

22
Surgery and Sex

• Vasectomy-absence of relationship (recall bias)
• Ejaculatory frequency (two case control studies)
  gt5 ejaculations per week while in their 20s had
  a lower risk
• Heath Professionals Follow-up Study
• gt20 monthly ejaculations during their 40s,
  within the past year, or averaged over a lifetime
  had a lower risk

23
Clinical Presentation

• Pre-PSA-first detected by DRE or urinary symptoms
• Post-PSA-usually asymptomatic at presentation
  detected by PSA
• Symmetric enlargement and firmness is usually BPH
• asymmetric areas of induration or nodules are
  usually cancer

24
Symptoms

• Urinary Symptoms-urgency, nocturia, frequency,
  hesitancy (BPHgtCA)
• New onset erectile dysfunction-enlargement of
  prostate encroaches on neurovascular bundle
  involved in erectile function
• Hematuria and hematospermia rare but in older
  male consider evaluation
• Bone pain or spinal cord compression-small number

25
DRE

• 2-3 of men have abnormal DRE (induration, marked
  asymmetry or nodularity)
• Clinically or pathologic-advanced disease
• Detect tumors in posterior and lateral aspects
• Do not detect T1 or 30 from other part of
  prostate
• PSA can be drawn after rectal exam
• 59 sensitive and 94 specific
• PPV 5-30

26
PSA

• Tumor marker to identify disease progression or
  recurrence, can precede clinical disease by 5-10y
  
• Cancer screening in 90s
• Peak in 92
• Majority localized
• Levels
• lt4
• 4-10
• gt10

27
Other PSA tests

• Goal-improve test specificity and decrease
  unnecessary biopsies
• PSA velocity, PSA density, serial PSA testing,
  age-specific reference ranges, free vs bound PSA,
  complexed PSA
• not much effect yet
• Rise in PSA greater than 0.75 ng/ml/year (based
  on 3 measurements over 12-24 months) should be
  referred for biopsy (Grade 2c)

28
Can I draw PSA now?

• DRE-increase by .26-.4ng/ml, okay to measure
• Ejaculation-increase by 0.8 (48 hours)
• Bacterial prostatitis-returns to baseline in 6-8
  weeks
• Prostate biopsy-increase by 7.9ng/ml in 4-24
  hours, returns to baseline 2-4 weeks
• TURP-increase by 5.9ng/ml (3 weeks)

29
Recommendation based on PSA

• PSA lt4ng/ml
• 70-80 sensitive, 60-70 specificity
• Positive predictive value
• gt4ng/ml-30 (1 in 3 prostate cancer)
• Majority will have negative biopsies
• 3 separate studies of men gt50, 136 of 319
• 21 of cancer between 2.6 and 3.9ng/ml
• Higher likelihood of finding contained cancers

30
What is the optimal PSA Level?

• What if you reduce the cutoff to 2.5?
• Normal PSA/DRE-449 of 2950 (15.2 had prostate
  cancer)
• Of these, 67 (2.3) had high grade prostate
  cancer (Gleason gt7)
• Number doubles-however, many would not become
  clinically evident
• Over diagnosis and overtreatment

31
PSA Level

• PSA level between 2.1 and 4ng/ml
• 24.7 had prostate cancer
• 5.2 Gleason score gt7
• 2.5ng/ml
• number doubles-many would not become clinically
  evident
• overdiagnosis and overtreatment
• 1.1ng/ml-miss 17 of cancers

32
Recommendation based on PSA

• PSA 4-10ng/ml
• PPV4-10ng/ml-25
• Biopsy to increase chance to find disease limited
  to prostate
• Specificity is lower (false positive higher)
• For every cancer detected four men will have an
  unnecessary biopsy (1 in 5 have cancer)
• Overlap between BPH and cancer
• Tends to be higher in cancer

33
Recommendation based on PSA

• PSA gt10ng/ml
• PPVgt10ng/ml-42-64
• Prostate biopsy recommended
• Chance of finding cancer is gt50
• Increases likelihood of extraprostatic
  involvement 24 to 50 fold

34
Diagnosis

• Gold standard-prostate biopsy
• Complications
• hematospermia
• hematuria
• rectal bleeding
• urinary retention

35
Prostate Cancer Trends in Incidence and
Mortality, 19731999 (Courtesy CDC)
36
Prostate Cancer Incidence Rates by
Stage, 19731995 (Courtesy CDC)
37
Tumor Rates by Grade (Courtesy CDC)
Moderate
Well
Poor
Unknown
38
Cellular Classification

• 95 Adenocarcinomas
• Bioptic gun with US guidance (2 complication
  rate, 4 hospitalizations out of 670 men)
• Gleason grade
• Five grades
• 1 is most well-differentiated and 5 is most
  poorly differentiated
• Primary and secondary score

39
TNM Staging System

• T1-microscopic and neither palpable nor visible
  on TRUS
• T2-palpable and appear confined to gland
• T3-protrude through capsule or into seminal
  vesicles
• T4-fixed and have extended beyond the prostate
• N-Regional lymph nodes
• M-Distant metastasis
• G-Histopathologic grade

40
TNM Staging

• Clinical staging-determine prognosis and guide
  therapy
• Underestimates extent of tumor found at surgery
• Upstaging directly related to Gleason score
• Endorectal coil MRI-better images and thinner
  slices

41
Treatment-Early Disease

• No good studies comparing therapies
• American Prostate Cancer Intervention versus
  Observational trial (PIVOT)
• Small Italian study
• Prostate Testing for Cancer and Treatment
  (ProtecT) in United Kingdom

42
Treatment-Early Disease

• Active surveillance (watchful waiting) and
  treatment provide similar results for early stage
  disease
• Radical prostatectomy
• Erectile dysfunction-20-70
• Urinary incontinence-15-50
• External beam radiation therapy (EBRT)
• Erectile dysfunction-20-45
• Urinary incontinence-2-16
• Brachytherapy

43
Treatment-Advanced Disease

• Between 1984 and 1991
• 30-40 presented with advanced disease
• Now only 5 have distant metastasis
• 10-12 have local or distant metastasis at time
  of diagnosis

44
Locally Advanced Disease

• External beam radiation therapy
• Radical prostatectomy-select cases
• Hormone therapy alone
• RT but much debate
• Nonsteroidal antiandrogens
• Androgen Deprivation Therapy (ADT)
• Bilateral orchiectomy
• Hormonal therapy

45
Treatment-Advanced Disease

• Management of side effects
• Metabolic and cardiovascular effects-greater
  incidence of DM and CVD
• Sexual dysfunction-20-70
• Osteoporosis and bone fractures-increases bone
  turnover and decreases BMD (20 have fractures
  within 5 years of therapy)
• Hot flashes-50-60
• Gynecomastia

46
Treatment-Chemotherapy

• Docetaxel plus prednisone in hormone refractory
  prostate cancer
• Palliative therapy for bone metastasis
• NSAIDS/tylenol for mild pain
• Opioids for moderate to severe pain
• External beam radiation therapy
• Radiopharmaceuticals
• Radiofrequency ablation

47
Rising PSA After Treatment

• Increased PSA with no signs/symptoms
• Use pretreatment clinicopathologic factors (T
  stage, PSA, Gleason score, margin and code
  status)
• Radiation therapy
• Salvage prostatectomy
• Cryotherapy
• Hormone therapy (ADT)

48
Prognosis

• Confined to prostate-usually greater than 5 years
• Locally advanced cancer (usually not curable)
• Substantial fraction will die of tumor
• Median survival may be as long as 5 years
• Advanced cancer with distal metastasis
• Current therapy will not cure it
• Median survival 1-3 years
• Most will die of prostate cancer

49
Risk of Death From Prostate Cancer by Age and by
Race/Ethnicity (Courtesy CDC)
50
What Happened to U.S. Prostate Cancer Mortality
Rates as Screening Rates Increased? (Courtesy
CDC)
51
UK Data

• US vs UK
• UK does not do mass screening
• Mortality similar

52
What Happens to Prostate Cancer (Courtesy
CDC)Mortality Rates in the U.K., where PSA
Screening Is Rare?
53
PLCO

• 55-74
• No difference in survival between screened and
  nonscreened arms at 7-10 years
• No reduction in primary outcome of prostate
  cancer mortality
• Cancer detection in screening group much higher
• Many flaws in study design
• High rate of contamination in control group

54
ERSPC

• 55-69
• Less contamination in control arm
• PSA of 3 ng/ml as screening cutoff
• No predefined treatment protocols
• In certain age groups in regions with relatively
  high cancer death rates-led to 20 relative risk
  reduction in mortality
• Lack of overall survival benefit
• Morbidity, costs and QOL required to capture a
  small benefit is unknown

55
ERSPC

• 1410 men screened, 48 treated to prevent 1
  mortality from prostate cancer
• False positive PSA account for 75.9 of biopsies

56
Quality of Life

• QOL measured by
• Sexual function
• Urinary incontinence
• Urinary irritation or obstruction
• Bowel or rectal function
• Vitality
• 50-83 of men after RP
• 31-78 after RT
• 30-78 after brachytherapy

57
Quality of Life (spouse)

• Partners or spouses
• RP-44-69
• RT-22-48
• Brachytherapy-13-41

58
Screening

• Does early detection extend life?
• Does screening cause significant morbidity?
• Do benefits outweigh harms?
• Does early detection reduce mortality?
• Is there an optimal screening method for prostate
  cancer?

59
Screening

• Screening is controversial
• DRE use for prostate screening has not been
  definitively shown to be effective
• PSA use for prostate cancer screening has not
  been definitively shown to be effective

60
Screening

• PSA detects cancer earlier
• Treatment of cancer might be effective but not
  certain/may contribute to declining death rate
  but not certain
• False positives common
• Significant side effects of treatment (QOL)
• Overdiagnosis a problem
• 29 whites
• 44 blacks
• Treatment related side effects common

61
Harms False Positives (Courtesy CDC)
Of 100 unscreened men in each group
Age (in years) With PSA gt4.0 With Cancer False Positives
50s 5 12 34
60s 15 35 1012
70s 27 9 18
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Current Recommendations

• American Cancer Society and American Urological
  Society recommend informed consent regarding the
  risks and benefits of screening
• DRE and PSA annually for men gt50 yo with life
  expectancy of 10 years (Grade 2C)

63
Current Recommendations

• Canadian TF-recommends against screening for
  prostate cancer with PSA or TRUS and states there
  is insufficient evidence to recommend for or
  against screening with DRE

64
Current Recommendations

• Begin screening at age 45 yo for high risk men
  (black males and first degree relatives with
  prostate cancer diagnosed at a young age) (Grade
  2C)
• Abnormal DRE or PSAgt7 should be referred for
  transrectal biopsy (Grade 2C)
• PSA between 4 and 7 undergo repeat PSA testing in
  several weeks (Grade 2C)

65
Current Recommendations

• USPSTF Recommendation
• The combination of DRE/PSA for prostate cancer
  screening has not been definitively shown to be
  effective
• There is no good RCT study regarding prostate
  cancer screening

66
Current Recommendations

• The USPSTF concludes that for men younger than
  age 75 years, the benefits of screening for
  prostate cancer are uncertain and the balance of
  benefits and harms cannot be determined.
• For men 75 years or older, there is moderate
  certainty that the harms of screening for
  prostate cancer outweigh the benefits.

67
Shared Decision Making

• Provide patient information
• Discuss QA
• Discuss past experience
• Listen, answer questions and make joint decision

68
Is PSA level reliable?

• Fluctuation in individuals and assays
• 972 unscreened men in polyp prevention trial
• 44 with PSA gt4ng/ml had normal PSA at one or
  more visits over next four years

69
Summary

• Conflicting recommendations
• May reduce morbidity and mortality, yet best
  method of screening is undetermined
• Treatment may adversely affect patient without
  benefit
• Cost-benefit remains unknown
• Treatment trials for early stage prostate cancer
  have not been conducted with predominately screen
  detected cancers

70
Summary

• Screening for prostate cancer remains a very
  contentious issue. The meta-analysis from two
  large randomized controlled studies (55,512
  patients) indicate no statistically significant
  difference in prostate cancer mortality between
  men randomized for screening and control (RR
  1.01, 95CI 0.80-1.29). Based on these studies,
  there is insufficient evidence to either support
  or refute the routine mass screening, or no
  screening, to reduce prostate cancer mortality.
  One must keep in mind that these studies were
  flawed.

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Summary
Potential Benefits
Potential Harms

• PSA screening detects cancers earlier.
• Treating PSA-detected cancers may be effective
  but we are uncertain.
• PSA may contribute to the declining death rate
  but we are uncertain.

Bottom line Uncertainty about benefits and magnitude of harms (Courtesy CDC)
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Questions????