Prostate Cancer 2007 Screening, Diagnosis and Treatment of High

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					  Prostate Cancer 2007: Screening,
Diagnosis and Treatment of High Risk
             Populations

        William F. Santis, M.D.
        Concord Hospital Urology Group


             January 10, 2007
First…some
entirely
unrelated
history of
medicine…

The roots are
in urology…



  Physician/Uroscopy

  Walker, Anthony., Physick
     1763
The Village Doctor



                     • Uroscopy was the
                        practice of
                        diagnosing disease
                        by examination of
                        the urine
                     • A painting illustrating
                        the practice of
                        uroscopy in the 17th
                        century by David
                        Teniers the Younger
Panderen, Egbert van, 1581-1637? artist.Title[The Physician as God]
/Physical Desc.1 print : engraving ; 25 x 37 cm
Uroscopy Flask



                 free blown glass,
                 pontiled with a
                 woven basket,
                 probably from the
                 17-18th century
• Hold to light,
    angle
•   Color,
    consistentcy,
    smell, and
    sometimes
    taste to make
    a diagnosis
                 Uroscopy Wheel




The Fasciculus
Medicinae by
Johannes De
Ketham, 1491
 Who is at risk for prostate cancer?
  What is the scale of the problem?
 What are the issues with screening?
 What are the options for treatment?
What are the controversies with screening
           and treatment?

How can we decrease the risk of men dying of
   prostate cancer in New Hampshire?
                     ?
                     ?
                     ?
                     ?
                    ?
                    ?
                 Risk of Death for 40 year old U.S. Men,
                    to End of Life, by Leading Causes:
                               Note Smoking Related Disease
      Heart Disease                                                      341


      Lung Cancer                     80


            Stroke               62

Chronic Obstructive
Pulmonary Disease
                                55

      Pneumonia &
        Influenza         38


   Prostate Cancer        34

                      0          50        100    150    200     250   300     350
                                             Number of Men per 1,000
2006 Estimated US Cancer Deaths*
   Lung & bronchus             31%           Men
                                            291,270
                                                      Women
                                                      273,560
                                                                •26% Lung & bronchus
   Colon & rectum              10%                              •15%   Breast
   Prostate                     9%                              •10%   Colon & rectum
   Pancreas                      6%
                                                                • 6%   Pancreas
   Leukemia                      4%
                                                                • 6%   Ovary
   Liver & intrahepatic          4%
      bile duct                                                 • 4%   Leukemia
   Esophagus                     4%                             • 3%   Non-Hodgkin
   Non-Hodgkin                    3%                                     lymphoma
      lymphoma
                                                                • 3%   Uterine corpus
   Urinary bladder               3%
                                                                • 2%   Multiple myeloma
   Kidney                        3%
   All other sites               23%
                                                                • 2%   Brain/ONS
                                                                •23%    All other sites

   ONS=Other nervous system.
   Source: American Cancer Society, 2006.
Lifetime Probability of Developing Cancer, by Site, Men,
2000-2002*
                   Site                                                   Risk
                   All sites†                                               1 in 2
                   Prostate                                                 1 in 6
                   Lung and bronchus                                      1 in 13
                   Colon and rectum                                       1 in 17
                   Urinary bladder‡                                       1 in 28
                   Non-Hodgkin lymphoma                                   1 in 46
                   Melanoma                                               1 in 52
                   Kidney                                                 1 in 64
                   Leukemia                                               1 in 67
                   Oral Cavity                                            1 in 73
                   Stomach                                                1 in 82

      * For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2000 to 2002.

      ‡ Includes invasive and in situ cancer cases
      Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0 Statistical Research and
      Applications Branch, NCI, 2005. http://srab.cancer.gov/devcan
Prostate Cancer: 2006 Data US/NH
• 234,460 new cases
  – 1,200 in NH
• 27,350 deaths in US
  – 140 in NH



   Men do die from prostate cancer in this country and this
                             state
Do not forget to ask me questions during the talk!
Prostate Cancer Trends in Incidence and
Mortality, 1973–1999
Note Influence of PSA Assay

250
                Incidence   Mortality

200



150



100



 50



  0
      1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999
                                        Year
                    Prostate Cancer Incidence Rates by Stage
               120

               100
                                                                Localized
Rate per 100,000




                   80

                   60

                                                                     Regional
                   40
                                        Distant                                 Unstaged
                   20

                   0
                    1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995
                                            Year of Diagnosis
Prostate Cancer Risk factors:
    Increased risk                  Decreased risk
•   Family history              •   Low fat diet
    – 10% CaP genetic           •   Lycopene
    – Multiple DNA Loci being
      examined                  •   Vit E, Selenium
• High fat diet                 •   Finasteride (Proscar)
                                    – Decreased total
• African-American race               incidence
• Increasing age                    – Increased high grade
                                      disease
Multiple Risk Factors
 Amplify Risk
        Risk of Death From Prostate Cancer
           by Age and by Race/Ethnicity
                      Risk during the next 15 years
                            (per 1,000 men)
Race/Ethnicity         At age 50        At age 65
All                         2               16
African American            5               34
American Indian &           2               9
Alaska Native
Asian & Pacific             1                7
Islanders
Hispanic                    1               12
White                       2               14
      Disparity in Cancer Incidence:
      Rates* by Race and Ethnicity, 1998-2002
       Rate Per 100,000
800                                                                          Men             Women
700                          682.6


600    556.4

500
               429.3                                                                                420.7
                                       398.5         383.5
400
                                                              303.6                                          310.9
300                                                                         255.4
                                                                                      220.5
200

100

  0
           White             African American     Asian/Pacific Islander    American Indian/           Hispanic†
                                                                             Alaska Native


       *Age-adjusted to the 2000 US standard population.
       †Hispanic is not mutually exclusive from whites, African Americans, Asian/Pacific Islanders, and American Indians.

       Source: Surveillance, Epidemiology, and End Results Program, 1975-2002, Division of Cancer Control and
       Population Sciences, National Cancer Institute, 2005.
                                          ealthy People 2010 Objective Number: 03-07
                                            Reduce the prostate cancer death rate.
                                                     All Races, Male, All Ages                                Recent
                                                     Annual Sorted by Rate                                    Annual
                                   Met                                   Average                              Percent
                                                      Death
                                 Healthy                                  Deaths                             Change2
                                                       Rate
                                 People           over rate period       per Year                         in Death Rates
                                 Objectiv       deaths per 100,000       over rate                       (95% Confidence Interval)
                                    e          (95% Confidence Interval)   period                                                    Recent
            County                 of                                               Rate     Recent                                   Trend
                                 28.8? 1                                           Period    Trend 2                                 Period2

                                                                                   1997 -                                             1994 -
United States                       No      31.5 (31.3, 31.6)            31,723             falling    -4.1 (-4.3, -3.9)
                                                                                    2001                                               2001

                                                                                   1997 -                                             1991 -
New Hampshire (State)               No      30.0 (27.7, 32.6)              126              falling    -3.3 (-5.4, -1.2)
                                                                                    2001                                               2001

                                                                                   1997 -   stable                                    1977 -
Coos County                         No      41.5 (29.0, 58.7)                7                         0.6 (-1.3, 2.6)
                                                                                    2001                                               2001

                   Death Rates                                                     1997 -
Sullivan County                     No      41.0 (28.8, 57.2)                8                   **                 **                  **
                                                                                    2001


Cheshire County
                   Geographic Disparity
                                    No      34.1 (25.1, 45.5)               10
                                                                                   1997 -
                                                                                    2001
                                                                                            stable     0.9 (-0.9, 2.7)
                                                                                                                                      1977 -
                                                                                                                                       2001

                                                                                   1997 -   stable                                    1977 -
Grafton County                      No      33.4 (24.6, 44.4)               10                         -1.2 (-3.0, 0.7)
                                                                                    2001                                               2001

                                                                                   1997 -   stable                                    1977 -
Strafford County                    No      31.5 (23.7, 41.3)               11                         0.1 (-2.0, 2.3)
                                                                                    2001                                               2001

                                                                                   1997 -   stable                                    1977 -
Belknap County                      No      31.0 (22.0, 42.9)                8                         1.2 (-1.3, 3.7)
                                                                                    2001                                               2001

                                                                                   1997 -   stable                                    1977 -
Hillsborough County                 No      30.9 (26.4, 36.1)               34                         -0.4 (-1.6, 0.8)
                                                                                    2001                                               2001

                                                                                   1997 -   stable                                    1977 -
Rockingham County                  Yes      27.4 (22.4, 33.4)               22                         -1.5 (-3.2, 0.2)
                                                                                    2001                                               2001

                                                                                   1997 -   stable                                    1977 -
Carroll County                     Yes      24.7 (15.9, 37.8)                5                         -2.2 (-4.8, 0.5)
                                                                                    2001                                               2001
       Possible reasons for race related
      disparity with prostate cancer

      Incidence                   Mortality
• Genetic factors         •   Genetic factors
• Environmental/dietary   •   Choice of treatment
  factors
                          •   Stage at presentation
                          •   Economic
                          •   Cultural
                         Prostate Cancers Vary in Their Natural Histories

                                               Death From Prostate Cancer
                                                Patient 1
                         Symptomatic Phase




                                                       Patient 3            Patient 2
Progression of Disease




                          Detectable
                                    Death
                          Presymptomatic from Other Causes Death from Other Causes
                          Phase



                                                                      Patient 4
                          Disease Not
                          Detectable

                         Remaining Expected Lifetime
    Challenges of prostate cancer
      screening and treatment

• Goal: Find clinically significant cancer at a
  point when a cure is possible
• Goal: Avoid excessively aggressive
  treatment in clinically insignificant disease
• Examine prognostic factors of diagnosed
  disease to predict if it will be significant
• Consider patient medical issues, age,
  philosophy
6 weeks until spring training…..…
Back to the Pelvis: Where is the prostate, screening?
Prostate Cancer: Not to be confused with Benign
Prostatic Hypertropy (BPH)
• BPH is age related enlargement of benign tissue
• Enlarged tissue can cause urinary symptoms
• Treatment initiated if symptoms are
    bothersome, infections or incomplete bladder
    emptying
•   In contrast, Prostate cancer in early stages has
    no symptoms
Diagnostic triad for early detection of prostate cancer
 Traditional indication for Prostate
               Biopsy:
             Usually with LE >10yrs


• Abnormal DRE regardless of PSA
• Abnormal PSA velocity (.75 ng/dL/yr)
• PSA > 4.0 or age appropriate range
  – Consider decreasing in men in 40’s, 50’s or
    with risk factors (FH/AAmerican)

  Elevated PSA does not mean prostate cancer
       Screening Guidelines for the Early Detection of
                     Prostate Cancer
                 American Cancer Society

• The prostate-specific antigen (PSA) test and the digital rectal examination
    (DRE) should be offered annually, beginning at age 50, to men who have a
    life expectancy of at least 10 years.
•   Men at high risk (African-American men and men with a strong family history
    of one or more first-degree relatives diagnosed with prostate cancer at an
    early age) should begin testing at age 45. Starting at age 40 can be
    considered.
•   For men at average risk and high risk, information should be provided about
    what is known and what is uncertain about the benefits and limitations of
    early detection and treatment of prostate cancer so that they can make an
    informed decision about testing.
Average rate of rise in prostate-specific antigen
   levels with and without prostate cancer
           Age- and race-specific prostate-specific
                       antigen levels
"Normal" PSA Ranges (ng/mL) Among White and Black Men in the United States
                                                       *                               †
                         Based on 95% Specificity          Based on 95% Sensitivity


      Age Decade          White [9]       Black [10]       White [10]        Black [10]


           40               0–2.5           0–2.4             0–2.5            0–2.0
           50               0–3.5           0–6.5             0–3.5            0–4.0
           60               0–4.5           0–11.3            0–3.5            0–4.5
           70               0–6.5           0–12.5            0–3.5            0–5.5



*
Upper limit of normal PSA determined from 95% percentile of PSA among men without prostate cancer .

†
    Upper limit of normal PSA required to maintain 95% sensitivity for cancer detection .
Free and total prostate-specific antigen:
  Only useful with PSA 4.0-10.0 ng/dl
Recent* Prostate-Specific Antigen (PSA) Test Prevalence (%),
by Educational Attainment and Health Insurance Status, Men 50
Years and Older, US, 2001-2004


                 70
                             58                                                      2001       2002        2004
                 60                  55
                                            52
                 50                                           46
Prevalence (%)




                                                                      42
                                                                             39
                 40
                                                                                                30     28
                 30                                                                                            25

                 20

                 10

                  0
                                   Total                 Less than a high school             No health insurance
                                                                education


                 *A prostate-specific antigen (PSA) test within the past year. Note: Data from participating states and the District of
                 Columbia were aggregated to represent the United States.
                 Source: Behavioral Risk Factor Surveillance System Public Use Data Tape (2001, 2002, 2004), National Center for
                 Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 2002, 2003, 2005.
Recent* Digital Rectal Examination (DRE)
Prevalence (%), by Educational Attainment and
Health Insurance Status, Men 50 Years and Older,
US, 2001-2004

                     60   57
                                53
                                       50                           2001        2002       2004
                     50
                                                    44
                                                           42
                     40                                           37
    Prevalence (%)




                                                                                  29
                     30                                                                  26
                                                                                                22
                     20

                     10

                      0
                               Total           Less than a high school         No health insurance
                                                      education


      *A digital rectal examination (DRE) within the past year. Note: Data from participating states and the District of
      Columbia were aggregated to represent the United States.
      Source: Behavioral Risk Factor Surveillance System Public Use Data Tape (2001, 2002, 2004), National Center for
      Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 2002, 2003, 2005.
                  Unsettled issue
      Potential                               Potential
      Benefits                                 Harms
• PSA screening detects
  cancers earlier.               • Screening is sensitive but
                                 not specific
• Treating PSA-detected
  cancers may be effective but   • Overdiagnosis is a problem
  we are uncertain which need      but we are uncertain about
  to be treated.                   the magnitude.

• PSA may contribute to the      • Treatment-related side
  declining death rate but we      effects are fairly common.
  are uncertain.
        In a high risk population this is more clear.
    There is little dispute that increasing awareness and
     screening in high risk populations is appropriate.
Smoking Stinks! Stay awake…we are
           getting there!
       Staging prostate cancer:
Treatment and outcomes of treatment
 are the same for high risk population
Gleason grading system:
Nomograms to predict pathologic stage

                                                Nomogram for Prediction of Final Pathologic Stage
             PSA 0.0–4.0 ng/mL Clinical         PSA 4.1–10.0 ng/mL Clinical       PSA 10.1–20.0 ng/mL Clinical           PSA > 20.0 ng/mL Clinical
                      Stage                               Stage                             Stage                                 Stage


  Gleason
          T1a T1b T1c T2a T2b T2c T3a T1a T1b T1c T2a T2b T2c T3a T1a T1b T1c T2a T2b T2c T3a T1a T1b T1c T2a T2b T2c T3a
  Score


  Organ-confined Disease


  2–4      90   80   89   81   72    77   —    84   70   83   71   61   66   43   76   58   75   60   48   53   —    —     38   58   41   29   —     —
   5       82   66   81   68   57    62   40   72   53   71   55   43   49   27   61   40   60   43   32   36   18   —     23   40   26   17   19     8
   6       78   61   78   64   52    57   35   67   47   67   51   38   43   23   —    33   55   38   26   31   14   —     17   35   22   13   15     6
   7       —    43   63   47   34    38   19   49   29   49   33   22   25   11   33   17   35   22   13   15    6   —     —    18   10    5    6     2
  8–10     —    31   52   36   24    27   —    35   18   37   23   14   15    6   —     9   23   14    7    8    3   —      3   10    5    3    3     1
  Established Capsular Penetration


  2–4       9   19   10   18   25    21   —    14   27   15   26   35   29   44   20   36   22   35   43   37   —    —     47   34   48   52   —     —
   5       17   32   18   30   40    34   51   25   42   27   41   50   43   57   33   50   35   50   57   51   59   —     57   48   60   61   55    54
   6       19   35   21   34   43    37   53   27   44   30   44   52   46   57   —    49   38   52   57   50   54   —     51   49   60   57   51    46
   7       —    44   31   45   51    45   52   36   48   40   52   54   48   48   38   46   45   55   51   45   40   —     —    46   51   43   37     2
  8–10     —    43   34   47   48    42   —    34   42   40   49   46   40   34   —    33   40   46   38   33   26   —     24   34   37   28   23    17
  Seminal Vesicle Involvement


  2–4       0    1    1    1    2     2   —     1    2    1    2    4    5   10    2    4    2    4    7    8   —    —      9    7   10   14   —     —
   5        1    2    1    2    3     3    7    2    3    2    3    5    6   12    3    5    3    5    8    9   15   —     10    9   11   15   19    26
   6        1    2    1    2    3     4    7    2    3    2    3    5    6   11   —     4    4    5    7    9   14   —      8    8   10   13   17    21
   7       —     6    4    6   10    12   19    6    9    8   10   15   18   26    8   11   12   14   18   22   28   —     —    22   24   27   32    36
  8–10     —    11    9   12   17    21   —    10   15   15   19   24   28   35   —    15   20   22   25   30   34   —     20   31   33   33   38    40
  Lymph Node Involvement


  2–4       0    0    0    0    0     0   —     0    1    0    0    1    1    1    0    2    0    1    1    1   —    —      4    1    1    3   —     —
   5        0    1    0    0    1     1    2    1    2    0    1    2    2    3    3    5    1    2    4    4    7   —     10    3    3    7    7    11
   6        1    2    0    1    2     2    5    3    5    1    2    4    4    9   —    13    3    4   10   10   18   —     23    7    8   16   17    26
   7       —     6    1    2    5     5    9    8   12    3    4    9    9   15   18   24    8    9   17   18   26   —     —    14   14   25   25    32
  8–10     —    14    4    5   10    10   —    18   23    8    9   16   17   24   —    40   16   17   29   29   37   —     51   24   24   36   35    42
Prognostic indicators
•   PSA
•   Stage
•   Grade
•   #positive biopsy cores
•   %biopsy core positive

       This helps us predict what cancer may be
                significant vs. insignificant

    When stratified by these indicators, patients in high risk
           groups have the same treatment outcome
 D’Amico et al risk stratification for clinically
         localized prostate cancer

       Low risk Diagnostic PSA < 10.0 ng/mL and
         Highest biopsy Gleason score < 6 and
               Clinical stage T1c or T2a

Intermediate risk Diagnostic PSA > 10 but < 20 ng/mL or
         Highest biopsy Gleason score = 7 or
                   Clinical stage T2b

        High risk Diagnostic PSA > 20 ng/mL or
          Highest biopsy Gleason score > 8 or
                 Clinical stage T2c/T3
            PSA = prostate-specific antigen
African American Men with Prostate Cancer

• Usually present with more advanced disease
• Often present with higher risk disease
• When stratified by risk group have the same
  outcome from each type of prostate cancer
  treatment

Goal: Improve screening rate
Goal: Earlier detection of disease
Goal: Appropriate treatment depending on
     prognostic factors
 Treating Prostate Cancer
Early Disease: Success depends on prognostic
    factors
    • Surgery
    • External Beam Radiation
                –    With or without Androgen Deprivation (hormonal
                     therapy)
    •   Brachytherapy (Low risk disease)
    •   Cryotherapy
    •   Watchful Waiting (Low risk disease)
    •   Risks, Pros and Cons of each
Advanced Disease
    • Hormone Therapy
    • Chemotherapy
    • Pain Management

                     PSA will indicate status of disease
Traditional Treatment Suggestions:
• Age 30 – 60 radical prostatectomy (RP),
  WWaiting if appropriate candidate
• Age 60 – 70 XRT, seeds, RP, wwaiting if
  appropriate candidate
• Age >70 if LE>10yrs XRT, seeds,
  wwaiting if appropriate, delayed androgen
  deprivation
• LE<10yrs: WWaiting, delayed androgen
  deprivation
RRP: The Surgical Approach
                                  Surgical
3-4 hours, general               Approach
anesthesia.
                         Pelvic
                                        Bladder
Incision: 8cm           Bone
Begins just below       (Pubis)                   Rectum
navel and extends to
pubic bone.

Remaining Urethra is
sewn to bladder neck                              Prostate
over a catheter.                    Urethra
Emerging Therapy:
Laparoscopic Radical
Prostatectomy
 Eliminates the need for a
  incision by using a telescopic
  instruments called a
  laparoscopes.
 Small camera attached to the
  laparoscope allows the surgeon
  to view inside the abdomen.
 More rapid recovery
 Unclear if any benefit for
  cancer cancer control, urinary
  or sexual function.
 The Da Vinci Robot:
 Laparoscopic approach
Surgeon operates from a
console with a 3-D screen.
Grasp controls to
manipulate surgical tools
within the patient.
Robotic arms translate
finger, hand, and wrist
movements.
Shortens learning curve of
surgeons
Very High-Precision
Cost, Benefit unclear
Radiation Therapy (RT)
 High-Powered X-Rays that damage DNA
   and kill prostate cancer cells.

1. External Beam Radiation Therapy
   (EBRT): X-rays aimed at prostate.

2. Brachytherapy: Radioactive seed
   implants into prostate.
External Beam Radiation
 Goal: Maximize damage to the prostate
  and minimize damage to surrounding
    tissues (i.e. bladder and rectum)


                                Seminal
                                Vesicles



                            Prostate
Image of Prostate With
Radioactive Bead Implants
Watchful Waiting
A.K.A. observation, with an eye towards
 curative therapy or palliative therapy.
Diagnosis of an early-stage (T1-T2), low-
 grade tumor. Low risk disease.
No medical treatment is provided.
PSA quarterly, Rebiopsy yearly
Consider treatment if PSA changes or
 Biopsy differs significantly
Removing Androgens
1. Orchiectomy (castration): surgical removal of
     the testicles.
2.   Oral drug which has the same effect as
     castration. Blocks testosterone
     production. Include LHRH agonists and
     antagonists and oral estrogens.
3.   Anti-androgens which block the effects of
     testosterone.
4.   Combination therapies.
Results of Androgen Removal
Impotence
Loss of sexual desire (libido)
Hot flashes
Weight gain
Fatigue
Reduced brain function
Loss of muscle and bone mass
Some cardiovascular risks
Prostate Cancer is an
 Endocrine Disorder
     Know the
Hormonal Pathways
Cases:
• 65 yo with PSA 12 on first evaluation
• PE: Bilateral firmness
• Biopsy: 7/12 biopsies positive for Gleason
  7 and 8 adenocarcinoma in 30-50% of
  each core
• High risk disease
• Surgical resection vs. XRT with androgen
  deprivation
Cases:

• 71 yo with PSA 5.6, normal DRE
• Biopsy 1/12 cores positive for Gleason 6
  adenocarcinoma in 4% of solitary core
• May be ideal candidate for watchful
  waiting, numerous options if one treats
• If wwaiting, Q3mos PSA
• Rebiopsy if PSA increase
Cases:

• 61 yo with PSA 7.1, normal DRE
• 3/12 biopsies positive for Gleason 6
  adenocarcinoma in 15-80% of each biopsy
  core
• Appropriate for surgery, seeds, XRT,
  consider wwaiting
Cases:
• 61 yo with PSA 2.5 to 3.7 in one year
  (abnormal PSA velocity). Dominant
  nodule on DRE
• Biopsy 5/12 biopsies positive for 10-60%
  of each core, Gleason 7 adenocarcinoma
• Staging negative
• Not a good watchful waiting candidate
  (number of biopsies +, Gleason 7)
• XRT or RP
        nhprostatecancer.org

       National Cancer Institute
           www.cancer.gov

       American Cancer Society
          www.cancer.org

National Comprehensive Cancer Network
            www.nccn.org

      American Urological Assn.
         www.auanet.org
      Conclusions:
• We can improve education
    and screening for high risk
    goups
•   Assure appropriate treatment
    options are available for all
    patients
•   Our ability to determine who
    should be treated is impoving
    with ongoing research
•   Questions????


     Thank You!