Prostate cancer progression

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Prostate cancer progression
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Probability of developing invasive prostate
cancer increases with age

• Age (Male) All Sites Prostate
• Birth?39 yr 1 in 73 1 in 12,833
• 40?59 yr 1 in 12 1 in 44
• 60?79 yr 1 in 3 1 in 7
• Lifetime risk 1 in 2 1 in 6

American Cancer Society, Inc. Available at
http//www.cancer.org/downloads/STT/CAFF_finalPWSe
cured.pdf
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Factors that may increase risk for developing
prostate cancer

• Obesity
• Dietary fat
• Smoking
• High testosterone levels
• Diabetes
• Infectious agents
• Occupational exposures

Giovannucci E et al. J Natl Cancer Inst.
2003951240 Giovannucci E et al. J Natl Cancer
Inst. 1993851571 Sharpe CR et al. Epidemiology.
200112546 Hoffman RM et al. J Natl Cancer
Inst. 200193388 Siddiqui MK et al. Biomed
Environ Sci. 200215298
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Family History

• Men with a first-degree affected are twice as
  likely to develop prostate cancer
• Men with two or three first degree relatives have
  a 5 and 11-fold increased risk of developing
  prostate cancer

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Hereditary aspects

• Hereditary (gt 3 relatives or gt 2 with early-onset
  disease
• Associated with early onset and a Mendelian
  autosomal dominant inheritance with incomplete
  penetrance
• Less than 10 of all cases
• More than 40 of cases in men younger than 55
  years

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Epidemiology-Nutrition

• Increased risk
• High content of animal fat in the diet
• Low intakes selenium, ligands and isoflavenoids
• Inversely related to sun exposure (Vitamin D)
• Deficient in vitamin E
• Decreased risk
• Diets rich with carotenoids (Vitamin A)

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Hippocrates

• It is more important to know what sort of person
  has a disease, than to know what sort of disease
  a person has.

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Willet F. Whitmore

• Is cure possible in those for whom it is
  necessary?
• Is cure necessary in those for whom it is possible

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American Cancer Society Guidelines for Screening

• Annual Digital Rectal Exam/PSA Screening
• Age 50
• Age 45 family history or African American
• PSA lt2.0 at yr 1 of screening, screen q 2 yr

American Cancer Society, Inc. Available
at http//www.cancer.org/downloads/STT/CAFF_final
PWSecured.pdf Han M et al. Med Clin North Am.
200488245
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The Gleason scoring system for prostate cancer

• Cells are assigned a no. between 1 and 5
• The scores of the 2 most common cell patterns are
  added together

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Gleason Grade

• The Sum of the most common pattern plus the
  second most common pattern yields the gleason
  score
• lt 6 well differentiated
• 7 moderately differentiated
• gt 8 poorly differentiated

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Prostatic Intraepithelial Neoplasia

• 85 carcinomas have associated PIN
• High grade PIN has 30-50 risk of CA on
  subsequent biopsies
• PIN does not cause elevated PSA
• Atypical foci in 3-5 of biopsies, 50 risk of
  cancer on repeat biopsy

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Diagnosis

• The need to pursue the diagnosis is based on
• symptom
• an abnormal DRE
• an abnormal PSA level
• The diagnosis is established by a TRUS-guided
  transrectal needle biopsy.
• Any palpable abnormality should be pursued,
• only 25 to 50 of men with an abnormal DRE prove
  to have prostate cancer
• a normal DRE does not exclude presence of cancer

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Symptoms of Prostate Cancer

• Frequent urination
• Inability to urinate
• Trouble starting and stopping urination
• Painful or burning urination
• Blood in the urine or semen
• Painful ejaculation
• Impotence
• Today, men rarely present with symptoms of
  metastatic disease

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Digital Rectal Exam

• Poorly reproducible
• Lacks sensitivity and specificity
• 25 of men with an abnormal DRE and a PSA lt 4.0
  have prostate cancer
• 50 of DRE-detected prostate cancer is non-organ
  confined

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DRE examination
T3
T1
T2
T4
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PSA

• PSA is a 28-kD protein of the kallikrein family,
  a group of serine proteases whose genes are found
  on chromosome 19q13
• PSA induces liquefaction of seminal fluid and the
  release of mobile spermatozoa
• PSA is synthesized in the ductal and acinar
  epithelium and is secreted into the lumina
• PSA is organ specific and not cancer specific

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Factors Increasing PSA

• Cycling
• Prostate massage
• Cystoscopy
• Ejaculation
• Prostate biopsy
• Transrectal Ultrasound

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Serum PSA

• Normal PSA lt4.0 ng/mL
• Age- and race-basedreference ranges
• Sensitivity 67.5?80
• Improve sensitivity use lower PSA cut-off level
  of 2.5 ng/mL (higher false positive, decreased
  specificity)
• Improve specificity measure free
  PSA,complexed PSA (c-PSA)

American Urological Association. Oncology.
200014267 Tanguay S. Urology.
200259261 Okihara K. J Urol. 20021672017
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PSA Derivatives

• PSA velocity rise in PSA over time (gt0.75
  ng/ml/yr associated with cancer useful for men
  with PSA lt4)
• PSA density PSA/prostate volume (gt0.15 is
  associated with cancer useful in men with large
  glands)
• Free PSA measures unbound PSA (lt25 is
  associated with cancer useful in men with PSA
  between 4-10 ng/ml)

Circulating PSA is complexed covalently
(irreversibly) to the protease inhibitor
1-antichymotrypsin, which covers a specific
epitope on the kallikrein loop, allowing
immunoassays for the "free" form representing 10
to 35 of the total PSA
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PSA levels and cancer
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Transrectal Ultrasound - TRUS

• Classic picture of a hypoechoic area
• Many cancers are isoechoic and only detectable
  through systemic biopsies.
• TRUS has two potential roles in the diagnosis of
  CaP
• To identify lesions suspected of malignancy
• To improve the accuracy of prostate biopsy.
• TRUS detects 50 more patients with CaP than
  physical examination

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Radiographic staging

• CT
• Rarely useful for staging
• Bone scan
• more sensitive than plain films
• Lacks specificity
• If the patient has no symptoms referable to bone,
  the PSA is less than 8 ng/mL, and the tumor is
  not extensive (T3) or poorly differentiated, true
  positive results are rare
• Abnormal bone scans are often followed by other
  technology

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MRI

• Endorectal MRI more accurately identifies the
  presence of ECE and seminal vesicle invasion
  (SVI), helps to identify invasion in the area of
  the neurovascular bundles (NVBs), and improves
  staging accuracy compared to DRE and all other
  available staging studies

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Early Diagnosis and Outcomes

• Majority (86) of cases diagnosed in local and
  regional stages
• Usually no symptoms
• 5-yr survival with early detection 100
• Survival rates for all stages combined
  5 yr 98, 10 yr 84, 15 yr 56
• Sites of metastases lymph nodes, bone

American Cancer Society, Inc. Available
at http//www.cancer.org/downloads/STT/CAFF_final
PWSecured.pdf
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CaPSURE Risk Category at Diagnosis
100
High risk
16.0
25.1
30.2
36.6
80
37.2
60
38.5
Intermediate risk
37.3
Patients ()
33.8
40
46.8
Low risk
20
36.4
32.5
29.5
0
Reprinted with permission from Cooperberg MR et
al. J Urol. 2003170S21
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Preventing Prostate Cancer

• Prostate Cancer Prevention Trial (PCPT)
• Evaluated the potential of finasteride to
  decrease the incidence of PRCA
• Result decrease in PCA by about 25 but increase
  in higher Gleason grade tumors
• Selenium and Vitamin E Chemoprevention Trial
  (SELECT)
• Evaluating the role of selenium and vitamin E in
  preventing PRCA
• Dietary modification(?) soy, lycopene

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Localized prostate cancer What to do?
Dealing with localized prostate cancer
Requires a balancingact
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Prognostic models

• Partin tables
• Kattan nomograms
• Damicco prognostic groups

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Risk Classification for PSA Failure After RP or RT
Classification Criteria 5-yr
Outcome Low Risk PSA lt10 ng/mL and
Gleason lt7 lt25 PSA and AJCC T2a
Failure
Intermediate PSA 1020 ng/mL or Gleason
7 25?50 Risk or AJCC T2b
PSA Failure High Risk PSA ?20 ng/mL or
Gleason gt50 PSA gt7 or AJCC T2c Failure
The most clinically relevant prognostic factors
are Gleason, PSA and stage
Adapted with permission from D'Amico AV et al.
JAMA. 1998280969
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Risk StratificationLocalized Prostate Cancer
Low Risk
High Risk
100
100
90
90
80
80
70
70
60
60
PSA Survival ()
50
50
PSA Survival ()
40
40
30
30
20
164 147 117 83 55 36 109 77 42 17 4 2
10 8 5 2 1 0 6 4 3 3
2 1
20
239 158 102 47 26 11 309 218 99 38 12 0
23 14 3 0 0 0 19 13 4 0 0 0
10
10
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Time (yr)
Time (yr)
RP External Beam RT
Implant and Neoadjuvant Hormonal Therapy Implant
Reprinted with permission from DAmico AV et al.
JAMA. 1998280969
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Localized prostate cancerMedical decision making

• Life expectancy (age, comorbidity) of the patient
  
• Probability of metastases and death from prostate
  cancer over time for the untreated (or
  conservatively managed) patient
• Particular characteristics of the primary tumor
  (prognostic features)
• Effectiveness of the treatment being considered
• Complication rates and side effects from the
  treatment
• Patient uses (values) for each health state
  affected by the cancer and its treatment

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Primary treatments for localizedprostate cancer

• Watchful waiting
• Active surveillance
• Interstitial brachytherapy
• External beam radiotherapy
• Radical prostatectomy
• Primary hormonal therapy
• Others (e.g., cryotherapy, HIFU)

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Radical prostatectomyMultiple approaches

• Transperineal (uncommon)
• Retropubic (most common)
• Laparoscopic (pure, robot assisted)

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Randomized Trial Comparing Surgery and Watchful
Waiting

• 695 men with early stage prostate cancer
  randomized to radical prostatectomy or watchful
  waiting
• Median of 8.2 years of follow-up 83 deaths in
  surgery group and 106 in watchful waiting group
  (P0.04).
• 30 of the 347 men assigned to surgery and 50 of
  the 348 men assigned to watchful waiting, death
  was due to prostate cancer

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Radical Prostatectomy Outcomes
Long-Term Survival Following Anatomic Radical
Retropubic Prostatectomy
1.00
T1a
T1c
0.75
T1b
T2a
Likelihood ofUndetectable PSA
T2c
0.50
T2b
T3a
0.25
0
0
5
10
15
20
Years Post-operative
Reprinted with permission from Han M et al. Urol
Clin North Am. 200128555
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Long-term biochemical disease-free Survival
following Radical Retropubic ProstatectomyPSA
Progression-Free vs Gleason Score

• Han,Partin,Pound,Epstein,Walsh Urol Clin N Am
  28(3)555, 2001

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Pathological findings

• Approximately 8 to 15 of cancers confined to
  the prostate pathologically do recur.
• Extracapsular invasion
• Seminal Vesicles involvement
• Positive surgical margins

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COMPLICATIONS

• Up to 80 will be impotent
• 57 of patients will be temporarily incontinent
• 10 urethral scarring
• 10 mild incontinence
• 7 rectal injury
• 3 severe incontinence
• 2 will be permanently incontinent

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Erectile disfunction

• Recovery
• Extent of preservation
• Age
• Quality of erections before the operation
• Experience of the operating surgeon
• With preservation of both nerves
• First erection- 4 months
• Continue to improve for 2 to 3 years

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Radiation Therapy

• 3D
• IMRT
• Brachytherapy
• External irradiation offers the same long-term
  survival results as surgery
• External irradiation provides a quality of life
  at least as good as that provided by surgery

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Radiation therapy dose effect

• Multiple studies support the notion that local
  tumor control is directly related to dose and
  indicate that more than 70 Gy is needed to
  control prostate cancer

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After the local therapy
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Natural history of progression afterPSA
elevation following radical prostatectomy

• 1997 men, 15 years after surgery
• Cancer-specific survival 91
• Biochemical disease-free survival 85
• Pound, Partin, Walsh, et al JAMA 2811591, 1999

• PSA elevation 15
• Of these, developed metastases 34

• Median actuarial time to metastases
• 8 years from time of PSA elevation
• Median actuarial time to death
• 5 years from developing metastases

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EORTC Trial

• Bolla et al NEJM 1997
• 415 patients with locally advanced prostate
  cancer were randomized to radiotherapy alone or
  radiotherapy plus immediate hormone therapy
• Therapy continued for 3 years
• Median follow-up 45 months
• Local control, metastases free and overall
  survival advantage to the adjuvant hormonal group

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Post Radical ProstatectomyRising PSA
Clinical variable Local recurrence Distant recurrence
Onset of PSA rise gt 2 years lt 2 years
PSA doubling time gt 1 year lt 6 months
PSA velocity (ng/mL/year) lt 0.75 gt 0.75
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Active surveillance

• Definition selected men are managed expectantly
  with the intention to apply curative treatment if
  signs of progression occur

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Active surveillance eligibility criteria

• PSA-level at diagnosis lt 10 ng/mL
• PSA density (PSA D) less than 0.2 ng/ml/cc
• Clinical stage T1C or T2
• Appropriate biopsy sampling
• Gleason score 336 (or less)
• One or 2 biopsy cores invaded with prostate
  cancer
• Participants must be willing to attend the
  follow-up visits

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Active Surveillance Criteria

• Epstein criteria for insignificant disease
• Gleason score of 6 or less
• lt 1/3 of positive cores
• An involvement of 50 or less of individual cores
  
• The criteria for tumor volume can be relaxed for
  patients over the age of 65 years
• Patients over 75 years might be candidates if
  they have a Gleason score of 7 (3 4)
• PSA DT gt 3 years
• PSA velocity lt 2.0 ng/ml per year

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Active surveillance monitoring disease and
continuation criteria

• PSA test (every 3 months) / PSA (kinetics)
• DRE (every 6 months)
• Biopsy (every 1,4,7, and 10 years, according to
  biopsy scheme)
• Patient content to continue active surveillance

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New approaches

• Cryotherapy
• Patients with low-risk or intermediate-risk
  represent potential candidates for CSAP.
• Prostate size should be lt 40 mL
• Long-term results are lacking and 5-year
  biochemical progression-free rates are inferior
  to those achieved by radical prostatectomy in
  low-risk patients
• Patients have to be informed according
• HYPO
• Radiofrequency interstitial tumour ablation (RITA)

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PSA progression after local therapy

• After prostatectomy
• PSA is expected to be undetectable within 3 weeks
  after a successful radical prostatectomy
• Two consecutive values of 0.2 ng/mL or greater
• After radiotherapy
• ASTRO defines failure after radiation therapy as
  three consecutive rises in PSA level, gt 2 ng/ml,
  irrespective of the nadir value

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Evaluation of PSA progression

• PSA DT
• DRE is not useful
• ? 5 had an abnormal DRE
• Endorectal coiled MRI
• local recurrence was correctly identified in 81,
  with the mean PSA at time of diagnosis being 2
  ng/mL
• TRUS and biopsy
• In the presence of a palpable lesion or a
  hypoechoic lesion on transrectal ultrasound yield
  ? 80
• Bone scintigraphy and CT scans
• Of no additional diagnostic value unless the PSA
  gt 20 ng/mL or unless the PSA velocity gt 20
  ng/mL/year
• CT-PET

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Management of biochemical progression after local
therapy

• After radical prostatectomy
• Salvage radiation therapy at a PSA serum level
  1.5 ng/mL
• Expectant management is an option
• Early hormonal therapy reduces frequency of
  clinical metastases therapy (grade A
  recommendation
• After radiation therapy
• Salvage radical prostatectomy in carefully
  selected patients
• Cryotherapy and interstitial brachytherapy are
  alternative experimental procedures in patients
  not suitable for surgery
• Hormonal therapy

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Metastatic prostate cancer
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CHARLES HUGGINS
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Evolution of Hormone Blockade
LHRHAgonist Anti-androgen (CAB)
LHRHAgonist
GnRHAntagonists
DES
Orchiectomy
lt1940
1940
1985
1989
200203

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Hormonal therapy
Hypothalamus
LHRH
LHRH Agonists/ Antagonists Orchiectomy
Pituitary
Ketoconazole
FHS, LH
Adrenals
Testicles
Testosterone
Direct antagonists DES
Prostate cancer cell
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Hormonal Therapy

• LHRH Agonists
• LHRH agonists initially act at the level of the
  pituitary  to stimulate LH release , resulting in
  a temporary surge in serum testosterone levels
• Subsequent LHRH downregulation to castrate
  levels of testosterone
• Onset 2-4 weeks

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Hormonal therapy

• Bilateral orchiectomy
• Rapid effect 2-6 hrs.
• Eliminates 95 of sex steroids
• Emotional effect
• Estrogens
• down-regulation of LHRH secretion, androgen
  inactivation, direct suppression of Leydig cell
  function and direct cytotoxicity to the prostate
  epithelium
• Cardiotoxic (parental, topical application)

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Hormonal therapy

• LHRH Antagonist
• Binds immediately and competitively to LHRH
  receptors in the pituitary gland
• Effect is a rapid decrease in LH, FSH and
  testosterone levels without any flare

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Hormonal therapy

• Antiandrogens
• Steroidal
• synthetic derivatives of hydroxyprogesterone. In
  addition to peripherally blocking androgen
  receptors, they have progestational properties
  and inhibit gonadotrophin (LH and FSH) release
  and suppress adrenal activity
• Non-steroidal
• Adds to LHRH therapy
• High dose monotherapy emerged as an alternative
  to castration for patients with locally advanced
  (M0) and in highly selected, well-informed cases
  of M1

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Combination hormonal therapy

• Complete androgen-blockage
• Minimal androgen blockage
• Finasteride antiandrogen
• Peripheral androgen blockage
• High dose Casodex
• Intermittent therapy
• Immediate vs differed
• Adjuvant for microscopic nodal disease
• MRC trial

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The patient-based meta-analysis showed no
significant benefit of MAB after 8000 pts and 27
trials
MAB is expensive, has increased toxicity and
should not be used
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2nd and 3rd line hormonal therapy

• About 90 of men respond to initial therapy with
  orchidectomy or LHRH agonist
• At progression about one third respond to
  addition of a peripheral antiandrogen (e.g.
  flutamide, bicalutamide)
• Of those who respond and then progress about 20
  respond to withdrawal of the peripheral
  antiandrogen
• Men may respond to further hormonal treatments
  such as dexamethasone, estrogen, or ketoconazole
  and hydrocortisone

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????? ????? Testosterone ????? ?????-?????
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Abiraterone in Androgen-independent prostate
cancer

• ???? ????? ?????????
• PSA response 27/44 (61)
• RECIST response 12/21 (57)

• ???? Taxotere
• PSA response 14/28 (50)
• RECIST response 4/18 (22)

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Side Effects of Androgen-supression

• Hot flashes
• Loss of libido
• Impotence
• Gynecomastia and breast tenderness
• Increased appetite
• Weight redistribution
• Muscle wasting
• Bone loss

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Metabolic Syndrome and Prostate Ca
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gt73,000 men agegt65 treated for localized Ca
prostate 1992-1999, observed through 2001
gt1 in 3 received ADT
Events per 1000 person-years Diabetes CHF MI Sudden death
No treatment 20.9 61.3 10.9 9.0
LHRH agonist 29.0 72.3 13.6 12.9
Orchiectomy 24.5 63.3 13.2 12.5
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Bisphosphonates Conclusions
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Androgen-independent prostate cancer
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Hormone Refractory Prostate Cancer Characteristics

• Median survival of 9-12 months
• Only 20-30 have measurable disease
• Bone only disease in 90-95
• Considerable decrease of life quality
  Intense bone pain, Pathological fractures,
  Spinal Cord Compression, Myelosuppression
  Bone hunger syndrome, Hyper/hypocalcemia
  Oncogenic Hypophosphatemia,Osteomalacia, Anemia,
  cachexia, sepsis, death

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Brief History of FDA Approval of Agents for
Prostate Cancer

• AGENT YEAR ENDPT.
• Docetaxel 2004 survival
• Zomera 2003 QOL
• Mitoxantrone 1996 QOL
• Estramustine 1981 old rules

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Phase III Docetaxel Studies in HRPC Demonstrating
Survival Benefit
Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
TAX 327
Randomize
Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5
on 1 off x 6 cycles
N1006
Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
SWOG 9916
Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21
days
Randomize
N770
Docetaxel 60 mg/m2 d 2 Estramustine 280 mg
d1-5 Dexamethasone 20 mg, tid d 1 2
Warfarin and aspirin
Tannock et al. N Engl J Med 20043511502-1512
Petrylak et al. N Engl J Med 20043511513-1520.
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Chemotherapy for HRPC
SWOG 9916 TAX 327
Docetaxel PSA response rate 50 45.4
Mitoxantrone PSA response rate 27 32
Docetaxel overall survival (months) 18 18.9
Improvement in survival (months) 2 2.5
p-value 0.01 0.009
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HRPC potential new compounds in Phase III
Advanced disease
Taxotere combo
First-line chemo
Monotherapy
Second-line
GVAX
M1
Atrasentan
DN101
Avastin
Denosumab
Taxotere
M1window
Provenge
GVAX
Denosumab
M0
Aflibercept Strontium89
Earlydisease
2004 2005 2006 2007
2008 2009 2010
2011
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