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					 Update on Prostate
 Cancer Treatment

     Jamal Khader, MD
   Cons. Radiation Oncologist
Radiation Oncology Department
 King Hussein Cancer Center
        Amman - Jordan
             Aim of this talk

1. What is incidence in Jordan and West (USA) ?

2. Has Prostate Cancer screening been successful ?

3. Is there any change in the treatment CONCEPT ?
         4. What is the best treatment?
           ( Frequently asked Question )




Wait &   Active    Sx    XRT    Brachy     HT   CTX
Watch surveillance
5. Is active surveillance in low risk pts is a valid
  option?
6. Do we now understand better the S/E of
  hormonal therapy?
7. CTX ? What is the current standard of
  treatment ?
8. Any new Directions?
9. What have we achieved in the last 15 yrs ?
  Multidisciplinary Approach

Uro-surgeon
Medical Oncologist
Radiation Oncologist
Sexual Rehabilitation Service
Incidence in Jordan
                                                                50
                                                                     100
                                                                                 150
                                                                                                           250




                                                            0
                                                                                                200 185
                                                Lung

                                           b la d d e r




                                                                                          168 158
                                       L e u k e m ia




                                                                               123
                                       C o l o r e c ta l




                                1996
                                                                           109
                                                 S kin




                                                                      89
                                           p r o s ta te

                                           B la d d e r




National Cancer Registry Data
                                                                                               178 176




                                                Lung
                                                                                         153




                                       L e u k e m ia

                                       C o l o r e c ta l




                                1997
                                                                               130 124




                                           p r o s ta te
                                                                           112




                                                  NHL
                                                                                                     196




                                                Lung
                                                                                                 184




                                       C o l o r e c ta l
                                                                                         151




                                           B la d d e r
                                                                                   139




                                       L u e k e m ia
                                1998
                                                                               127




                                                 S kin
                                                                           108




                                           p r o s ta te
                                                                                               174




                                                Lung

                                           B la d d e r
                                                                                  146 137




                                       C o l o r e c ta l
                                                                                                                 Most common cancers among Jordanian male




                                                                            120




                                       L e u k e m ia
                                1999




                                          P r o s ta te
                                                                      101 93




                                                  NHL
                                                            0
                                                                50
                                                                     100
                                                                            150
                                                                                              200
                                                                                                          250

                                                                                                   198
                                                Lung




                                                                                             175
                                       C o l o r e c ta l




                                                                                 141
                                       L eu kem ia




                                2000
                                                                            129
                                          B lad d er


                                                                           123
                                          P r o s ta te
                                                                                                    208




                                                Lung




National Cancer Registry Data
                                                                                        163




                                       C o l o r e c ta l
                                                                                       158




                                          B lad d er




                                2001
                                                                                  151




                                          P r o s ta te
                                                                                  146




                                       L eu kem ia
                                                                                                    203




                                       C o l o r e c ta l
                                                                                        169




                                          B lad d er
                                                                                        168




                                               Lung
                                2002
                                                                                  146




                                           p r o s ta te
                                                                                 143




                                       L eu kem ia
                                                                                                    204




                                       C o l o r e c ta l
                                                                                         171




                                                Lung
                                                                                  149




                                          B lad d er
                                                                                                                Most common cancers among Jordanian male




                                2003
                                                                                  149




                                          P r o s ta te

                                       L eu kem ia
         Prostate Cancer in USA
• Estimated 234, 460 new cases in the US in 2006
  (33% of all new cases in men)
• Estimated 27.350 deaths (9% of all cancer deaths
  in men)
• Lefetime risk for US men: 17.9%
• The third-leading cause of death from cancer in
  men, after lung and colon & rectal cancer
• Approximately 30% of men over the age of 50 will
  have histologic cancer.
• 15 - 20% of men have Ca detected while PSA is a
  normal range.
• 20-25% of men with abnormal DRE have Ca at Bx.
Has prostate Cancer Screening
      been successful ?
       To Demonstrate Success

• Patients should have a long life expectancy
• Cancers detected should be potentially lethal
• Treatments should be effective
• Follow-up should be long
                 Total PSA level

Correlates with:
- Risk of prostate cancer
- Volume of cancer (in ~ 90%)
- PSA velocity
- Aggressiveness of cancer
- Prostate cancer-specific mortality
   US Preventive Services Task Force
           Dec. 2002 Report
Concluded: “The evidence is insufficient to recommend
for or against routine screening for PC using PSA or
DRE.”
 PSA screening can detect early-stage PC BUT, mixed &
inconclusive evidence that early detection improves OS.

Harms of Screening
# Frequent false-positive results
# Unnecessary anxiety
# Unnecessary biopsies
# Potential complications of treatment (Sx, RT) of some
cancers that may never have affected a pt’s health.
On The Other Hand
First Sign of Success: Stage Migration

- When the PSA screening era began (~ 1991), 20% of
  prostate cancer cases presented with metastases.
- By 2002, only 5% of cases presented with
 metastases, a 75% reduction in metastases at
 diagnosis.
- % low risk disease 30 % 1989 – 1992 p value < .ooo1
                    45 % 1999 – 2001
       Relative 5-Year Survival Rate


Increased:

 - Pre-PSA Era 1983 - 1985 : 75%

 - PSA Era        1999 - 2000 : 95%




Surveillance, Epidemiology, and End Results Program, 1975-2000,
Division of Cancer Control and Population Sciences, National
Cancer Institute, 2003
   The falling mortality rates in the tumor
    registry data are good evidence that
             screening is effective

• They would not have occurred if screening
  detected only harmless cancers


• Even prostate cancer found at low PSA levels can
  be aggressive
  American Cancer Society Guidelines for the Early
           Detection of Prostate Cancer
                              Revised Feb.28 , 2006

# Both the prostate-specific antigen (PSA) blood test and digital rectal
   examination (DRE) should be offered annually, beginning at age 50, to
   men who have at least a 10-year life expectancy.
# Men at high risk (African-American men and men with a strong family
   of one or more first-degree relatives [father, brothers] diagnosed before
   age 65) should begin testing at age 45. Men at even higher risk, due to
   multiple first-degree relatives affected at an early age, could begin
   testing at age 40. Depending on the results of this initial test, no further
   testing might be needed until age 45.
# Information should be provided to all men about what is known and
   what is uncertain about the benefits, limitations, and harms of early
   detection and treatment of prostate cancer so that they can make an
   informed decision about testing.
# Men who ask their doctor to make the decision on their behalf should be
   tested. Discouraging testing is not appropriate. Also, not offering
   testing is not appropriate.
    Has prostate Cancer
screening been Successful ?

      Probably Yes
Treatment: Is there any change
     in the CONCEPT ?
     Organ confined Disease (T1, T2)
      Locally advanced disease (T3)
            Metastatic disease



Better understanding the biology of disease
         (Pattern of relapse, OS, …)




            Risk Stratification
Patients risk of Recurrence and Death


  How should “Risk” be defined ?
  How should “Risk” guide therapy ?
  Why not just use the AJCC staging ?
                   Tools for prostate cancer
                   risk/outcome assessment

           Partin Nomograms(pathologic stage)
           MD Anderson and D’Amico formulas
           Roach Formula
           Kattan Nomograms




CPDR=Center for Prostate Disease Research
XRT=external radiation therapySemin Urol Oncol. 2002;20 (series).
            Pretherapy Clinical Factors
                in Risk Prediction
                    D’Amico et al, JAMA, 1998


Extent of Risk   Clinical/Pathologic    Estimated 5 year
                      features          PSA- failure free
                                            survival
    Low          • Stage- Tlc or T2a
                 • PSA< 10ng/ml              > 85%
                 • Gleason score <6
                 • Stage- T2b or
Intermediate     • PSA11- 20ng/ml or         60%
                 • Gleason score of 7

    High         • Stage>T2c or              <30%
                 • PSA>20ng/ml
                 • Gleason score >7
Example:

60 yr male patient with ca-Prostate

     T2a GS     6    PSA 8
     T2a GS     6    PSA 29
     T2a GS     8    PSA 10-20
 Outcome Based on Pretreatment Risk Factors




         LOW RISK                    HIGH RISK
PSA <10, Gleason 6, and T1-2   PSA >20, Gleason 8, or T3

                               D’Amico JAMA 280:969,1998
                         Disease Specific Survival by
                1.0
                 0.8   Risk Groups RT Alone (n=1500)

                                                                                                         GS=2-6, T1-2
                 0.6
survival rate




                                                                                          GS=2-6, T3;GS=7, T1-2
                 0.4




                                                                                          GS=7, T3;GS>7, T1-2
                                   Gro up 1    53/3 63
                 0.2




                                   Gro up 2    84/4 43

                                                                GS>7, T3/node+
                                   Gro up 3    92/3 38
                                   Gro up 4   154/324
                 0.0




                       0   1   2   3      4         5     6    7    8     9   10     11   12   13   14    15   16

                                                         years since randomization
          The prognostic significance of
                 Gleason Score
            Potters et al. IJROBP 56: 749, 2003

    Gleason
     Score          LN Positive (%)          5 yr bNED
     ≤3+3                  1.2                    85%
      3+4                 11.3                    78%
      4+3                 13.7                    55%
      4+4                  40                     50%

N=1029, T1-2 , median PSA 8.6 ng/ml
              Active Surveillance

  Active surveillance with selective delayed
intervention for favorable risk prostate cancer


• Gleason ≤ 6
• PSA ≤ 10
• T1c – T2a
• In younger patients: ≤ 33% of cores positive
Active surveillance for prostate cancer: for whom?
    Klotz L, JCO. 2005 Nov 10;23 (32): 8165-9
     Criteria for radical intervention on active
    surveillance: PSA DT or grade progression

Rapid PSA DT
  - PSA q3 months x 2 years
  - In most patients, decision to intervene at 2 years,
    based on 8-9 PSA determinations

Gleason grade progression

   - Biopsy at 1 year, then every 3-4 years (stop
     age 80)
   - Treat if progression to GS 4+3 or more
     (5-10% of pts )
         Delayed treatment after active
        monitoring : Toronto Experience

• 200 patients followed for up to 10 years
• About 60% of patients remained on active monitoring.
• But, of patients who underwent radical prostatectomy
  for progression :
  # The tumor was organ confined in only 42%.
  # 58% had tumor extension beyond the prostate and
    8 % had lymph node metastases



 Klotz L, Urol Oncol 24: 46, 2006
     Advantages of Active Surveillance


• Avoid side effects of definitive therapy
• Quality of life/normal activities retained
• Risk of unnecessary treatment of small, indolent
  cancers is reduced
   Disadvantages of Active Surveillance

• Risk of progression and / or metastases
• Subsequent treatment may be more intense with
  increased side effects
• Increased anxiety
• Requires frequent medical exams and periodic
  biopsies
• Uncertain long term natural history of prostate
  cancer
• Timing and value of periodic imaging studies is not
  yet determined.
      START Trial (Standard Treatment Against
              Restricted Treatment)
                      Good risk (PSA ← 10, Gleason ← 6, T1c/T2a)

                                                  Surgery, EBRT, or Brachytherapy
              Active surveillance
                                                          (Patient’s choice)

                             Close monitoring, repeat biopsies

       Stable PSA, no grade progression        PSA DT < 2 years, or grade progression
                                                     (to Gleason 4+3 or higher)

             Continue to monitor                  Definitive appropriate therapy



Primary end point: Prostate Cancer Survival
Secondary end points: Overall survival, QOL,
(N = 2100)
Is active surveillance in low risk
    group is a valid option ?

             Probably
                Yes
           in selected pts
          LOW RISK Patients

EBRT
Brachy
RP
Active Surveillance !
       Intermediate Risk patient

Example :

  • T2c GS 7 (4+3) PSA 19
  • T2a/b GS 6 PSA 11

# RP

# Neoadjuvant HT → XRT
          Potential Complications of
         Androgen Deprivation Therapy


    The "Big 3"          What Your Feel        What You See         What you Don't See

•Loss of libido         • Fatigue           • Weight gain           • Loss of bone
•Erectile dysfunction   • Lack of energy    • Gynecomastia            density
•Hot flashes            • Lack of           • Loss of muscle        • Anemia
                          initiative          mass                  • Alterations of
                        • Aches and pains   • Loss of strength        serum lipids
                        • Depression        • Decreased size        • Exacerbation of
                        • Emotional           testicles and penis     hypertension,
                          lability          • Hair changes            diabetes, heart
                        • Cognitive                                   disease
                          changes
          Intermediate Risk Pts
    What About short term Hormonal
              Therapy ?

1. Is there consistent support for NHT?
2. If justified how long should NHT be used?
3. Should adjuvant HT be added as well ?
4. What volume should be irradiated?
                   The Data

•   Seven randomized trials reported in six
    papers including pts treated NHT in
    combined with EBRT on one or more
    arms were identified.

•   In total 17 arms compared either EBRT
    alone (n=3); NHT & concurrent
    hormonal therapy (N&CHT) (n=12) +/-
    short-term adjuvant hormonal therapy
    (SAHT) (n=5) or long term HT (n=1).
             Randomized Trials Using NHT
  First         Total / PreTx                       First      PreTx
 Author         No. Pts  PSA                       Author       PSA
 (Year)      with NHT (Med)^       Comments:                           Comments:
                                                   (Year)     (Med)^
                   +/-
             concurrent
                   HT
Laverdeire                         PSA failure     Pilepich              Survival
(2004) ##                          rates higher     (2001)             advantage
              161 / 63        10                   RTOG         26     for GS <7,
 Quebec                            with EBRT                  ng/ml
  Trials                  ng/ml^      alone,         8610               Included
              296 / 148                                                  N+ pts
               (3 mo.)        12    otherwise
                           ng/ml        no         Hanks                 Disease
                                   difference s    (2003)                specific
                                                   RTOG         20     survival and
D’Amico                             Overall &       9202      ng/ml     Overall for
 (2004)                               disease                          GS = 8-10.
Harvard       206 / 104     11       specific
 Study       (4 months)   ng/ml      survival
                                    advantage      Roach               Progression
                                                   (2003)              free survival
 Crook       378 / 378              Overall no     RTOG         23      advantage
(2004) *      (3 vs 8               difference      9413      ng/ml     with short
Princess     months)       ~10        in PSA
                          ng/ml                                          follow-up
Margaret                           failure rates
Randomized Trials of Androgen Deprivation + Radiation
                      Therapy

        References                No of patients   OS
        RTOG 8610
        Pilepich et al
        RT                             230         NS
        Neoadj AD+RT                   226

        RTOG 8513
        Pilepich et al ASTRO 04
        RT                             489         71% @5y, 38% @ 10y
        RT+adj AD                      488         75% @5y, 53% @ 10y
        EORTC
        Bolla et al 02
        RT                             208         62% @ 3y, 62% @ 5y
        RT+AD                          207         79% @ 3y, 78% @ 5y

        RTOG 9202
        Hanks et el JCO 03
        RT+STAD(4mo)                   761         78.5% @ 5y
        RT+LTAD(2yrs)                  753         80 %
                       Progression- Free Survival
             1.0
                        in intermediate risk pts

             0.8


             0.6
Nonfailure
  Rate
             0.4



             0.2
                          NHT + WP RT
                          NHT + PO RT
             0.0
                   0          1              2             3        4   5

RTOG 9413 Roach, et al.                 Years since Randomization
          Progression-Free Survival
       in high risk group : RTOG 9413
                1.0


                0.8


                0.6
   Nonfailure
     Rate
                0.4

                          NHT + WP RT
                0.2       NHT + PO RT
                          WP RT + AHT
                          PO RT + AHT
                0.0
                      0     1           2          3          4   5
P=.008                             Years since Randomization
NHT=neoadjuvant hormonal therapy; AHT=adjuvant hormonal therapy
Roach, et al.
   4-5 Year bNED for Gleason 8-10

    First Au.      No. pts   Tx Type      bNED (%)
Ohari                66      Surgery         28
(Bayl or)
Partin               72      Surgery        ~ 25
(Hopkins)
Oefelein             22      Surgery         38
(N. Western)
Fiveash             102         NHT          79
                             +3DCRT+AHT
(UM, UCSF, FCCC)
Based on the data from these studies the
following conclusions seem reasonable:

1. NHT is beneficial with EBRT in intermed. risk pts
   (RTOG 8610, Quebec study #1, Harvard).

2. NHT without long term adj HT is inadequate for
   high-risk pts (RTOG 9202).
                    Cont.,

3. Three to six mon. of NHT + EBRT appears to
   be adequate for intermediate risk pts with no
   additional benefit for longer period.

4. Pts with a risk of + nodes > 15% should
  undergo prophylactic WP EBRT with NHT
  (RTOG 9413, RTOG 8610 & RTOG 9202).

5. High-risk pts should probably receive short-
   term NHT & long-term adjuvant HT (RTOG
   9413, RTOG 9202, RTOG 8610) 2-3 yrs.
HRPC
Prostate Cancer Chemotherapy Trials
 1985     Measurable disease: SWOG/ECOG
 1990     PSA outcomes
 1993     Palliative endpoints:
          Canadian studies, CALGB
 1996/9   2 Mitoxantrone phase III trials reported
          - Relieves pain due to metastatic disease
          - Does not improve survival
 2004     2 Taxotere phase III trials + FDA & EU approval
          - Significant improvement in overall survival   -
            (med. OS 19 months)
          - QoL benefit
Mitoxantrone plus Steroids Phase
     III Trials: 1996–1999
First     Treatment         PSA      Time to   Pain     Quality
Author                    Response Progression Relief   of Life


Tannock   Mitoxantrone      Yes        Yes      Yes      Yes
1996      + steroids vs
          steroids

Kantoff   Mitoxantrone      Yes        Yes       No      No
1999      + steroids vs
          steroids


            No Survival improvement noted
        Docetaxel and Estramustine versus
      Mitoxantrone and Prednisone: Results of
        SWOG -Intergroup Protocol 99-16

                        Docetaxel 60 mg/m2 IV D2 every 21 days
                        Estramustine 280 mg po TID, D1-5
                        Premedication: Dexamethasone 20 mg PO TID starting evening of D1


    R
                      Mitoxantrone 12 mg/m2 IV every 21 days
                      Prednisone 5 mg po BID continuously



D. Petrylak, C. Tangen, M. Hussain, et al NEJM 04
            SWOG 9916
           Overall Survival
100%                                 # at    # of    Median
                                     Risk   Deaths in Months
                               D+E   338     217       18
80%                            M+P   336     235       16

                    HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
60%


40%


20%


 0%
       0    12            24           36          48
                 Months
                                                      TAX327
                                                    Overall Survival
                           1.0

                           0.9                                                        Docetaxel 3 wkly
                                                                                      Docetaxel wkly
                           0.8
Probability of Surviving




                                                                                      Mitoxantrone
                           0.7

                           0.6

                           0.5

                           0.4                      Median
                                                    survival    Hazard
                           0.3                       (mos)       ratio     P-value
                                     Combined:       18.2           0.83   0.03
                           0.2       D 3 wkly:       18.9           0.76   0.009
                           0.1       D wkly:         17.3           0.91    0.3
                                     Mitoxantrone    16.4             –      –
                           0.0
                                 0             6               12    Months 18       24          30
     Survival in Subgroups
Taxotere Q 3 Wks vs Mitoxantrone
                      Hazard ratio in favor of
                        Taxotere Mitoxantrone
        ITT

   Age < 65
   Age ≥ 65
   Age ≥ 75

    Pain no
   Pain yes

   KPS ≥ 80
   KPS ≤ 70
          0.2   0.4   0.6   0.8   1.0   1.2   1.4
       Newer Approaches in Systemic
                Therapy

Cytotoxic Agents
New agents: Epothilones

Novel Biologic Approaches
Integrin inhibitors (Cilengitide)
endothelin-1 (ET-1) receptor inhibitor (Atrasentan- (ABT-
627)
Anti-angiogenesis
Immunotherapy/vaccines
Antisense
Targeting the bone
Cytotoxic + Biologic Agents
                 Conclusion
        Progress in the Last 15 Years
# Discovery of PSA and its introduction to the clinic
# Improved definition of risk categories
# Increased funding for basic and clinical research (West)
# Recognition of importance of QOL
# Chemotherapy can palliate & prolongs survival &
  reduces risk of death
# Improved safety and efficacy of local therapy (Sx,RT)
# Active investigation of systemic therapy
Signs that prostate cancer-related mortality is decreasing

				
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