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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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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Familial aspects

• 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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Racial aspects

• Afro-American
• Highest incidence of prostate cancer in the world
• Diagnosis at a younger age
• Higher tumor burdens
• Lower survival rates
• Asians
• Migration to USA leads higher incidence of the
  disease, which increases with each succeeding
  generation

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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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PCA 3

• A segment of noncoding mRNA from chromosome
  9q2122 that is overexpressed by more than 95 of
  all prostate cancers tested .
• PCA3 expression is normalized against a
  background of PSA mRNA PCA3 score
• The PCA3 score is much more cancer-specific than
  serum PSA levels

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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
  speficity)
• 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

• The normal range of PSA lt 4 ng/mL
• The sensitivity for detecting cancer with PSA gt 4
  ng/mL is approximately 80
• 20 of men with a normal DRE and PSA level
  between 2.5 and 4.0 have cancer.
• With PSA 4 - 10 ng/mL, TRUS biopsies detect
  cancer in 25, of which 75 are pathologically
  confined
• Men with a PSA of 2 to 3 ng/mL are 5.5 times more
  likely to be diagnosed with cancer within 5 years
  than men with a PSA less than 1 ng/mL

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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 Doubling Time
• 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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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 DRE

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Radiographic staging

• CT
• Rarely useful for staging
• Bone scan
• more sensitive than plain films
• Lacks specificity
• Abnormal bone scans are often followed by other
  technology

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CT-PET
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Endorectla MRI

• More accurately identifies the presence of ECE
  and seminal vesicle invasion (SVI)
• Identifies invasion in the area of the
  neurovascular bundles (NVBs)
• Improves staging accuracy

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Early detection

• Healthy men should be informed of the risks and
  benefits of screening if they are older than 50
  years and have a life expectancy of at least 10
  years
• If they agree, these men should have a DRE and
  PSA test annually

• Goals
• Reduction of CaP-specific mortality
• Not to detect more and more carcinomas
• Not survival because survival is heavily
  influenced by lead-time
• Improvement in quality of life (QUALYs)

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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 reduces the overall risk of prostate
  cancer by 30
• Selenium and Vitamin E Chemoprevention Trial
  (SELECT)
• Evaluating the role of selenium and vitamin E in
  preventing PRCA
• Results Negative
• 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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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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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 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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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, IGRT
• 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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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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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
• PSA level typically declines over 1-2 years and
  may not reach undetectable levels
• ASTRO defines failure after radiation therapy as
  3 consecutive rises in PSA level, gt 2 ng/ml,
  irrespective of the nadir value

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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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Post Radical ProstatectomyRising PSA
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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
Abiraterone
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
• Block androgen receptors
• 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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Adrenal androgen suppressions
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Abiraterone in Androgen-independent prostate
cancer

• After androgen suppression
• PSA response 27/44 (61)
• RECIST response 12/21 (57)

• After 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
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Bisphosphonates Conclusions
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Castration resistant 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
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Castration resistant prostate cancerTargets for
development

• Angiogenesis
• Androgen axis
• Endothelin receptor
• SRC Inhibitors
• Immunotherapy

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VEGF The Key Mediator of Angiogenesis,
Endothelial Cell Growth and Vascular Permeability
Environmental factors (Hypoxia, pH) Growth
factors (EGF, bFGF, PDGF, IGF-1, IL-1?,
IL-6) HIF-1a
Genes involved in tumorigenesis (p53, p73, src,
ras, vHL, Bcr-Abl)
Upregulated VEGF binds and activates its receptor
Docetaxel
Stimulating signaling cascades
Endothelial cell activation
Overexpression of VEGF and PDGF receptors in bone
metastasis Elevated VEGF independent prognostic
factor in CRPC
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CALGB 9040 Phase III study of Docetaxel/-
Bevacizumab in HRPC (n1,020 pts)
Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po
daily Bevacizumab 15 mg/Kg Q3 wks
R A N D O M I Z E
Stratification Halabi nomogram
Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po
daily Placebo

CALGB, ECOG, NCIC
Primary end point- PFS
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VEGF Trap afliberceptA unique anti-angiogenic
agent
Fully human insoluble VEGF receptor fusion protein

• Innovative concept
• Increased affinity for VEGF compared to mAbs
• Blocks VEGF-A, and placental growth factor

Bound VEGF

• Potential for broader/better spectrum of activity
  

VEGF Trap
mAb - monoclonal Antibody VEGF - Vascular
Endothelial Growth Factor PIGF - Placental Growth
Factor
Verheul HM, Clin Cancer Res. 2007 Jul
1513(14)4201-8
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VEGF-Trap-aflibercept in CRPC VENICE Study
Design (n1,200)
Aflibercept 6 mg/kg IV, over 1hr Docetaxel 75
mg/m2 , Q3 wks Prednisone 10 mg po daily
R A N D O M I Z E
CRPC 1st line
Stratification PS 0, 1 vs. 2
Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po
daily Placebo

Primary end point- OS
Tannock I, coordinator
92
Sunitinib for CRPC following Docetaxel

• PFS- 21.1 weeks
• 95 C.I 14.3-33.3
• 12 weeks PFS- 78.9
• 50 PSA response-
• 9, 18

Periman, ASCO 2008 Smith, ASCO 2008
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Phase III Trial Post Docetaxel-Based Chemotherapy
(n819)
R A N D O M I Z E
Sunitinb 37.5 Prednisone 5 mg po bid (n546)
CRPC docetaxel up to 1 prior chemo regimen

Placebo Prednisone 5 mg po bid (n273)
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Primary end point- OS 35 increase in OS (12 mo
vs. 16.2 mo) Secondary- PFS,RR, QoL
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AR in CRPC
A- gene amplification and increased expression
of the AR mRNA and protein
B- selection of mutations in the AR that confer
broader ligand specificity
C- changes in the ratios or expression between
the AR and its coregulators
E- up-regulation of cross-talk signal
transduction pathways that can activate the AR in
a ligand-independent manner
D- increased expression of steroidogenic enzymes
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MDV3100AR antagonist

• Novel mechanism of action
• blocks nuclear translocation of AR
• no agonist activity when AR is overexpressed
• Identified from a cell-based screen that mimics
  castration-resistant tumors with overexpressed AR
• Active in bicalutamide-resistant prostate cancer
  models overexpressing AR

C.L Sayers, ASCO 2007
96
MDV3100Second generation Antiandrogen

• Engineered for activity in prostate cancer cells
  that over express androgen receptor (AR)
• Binds AR more potently than Casodex
• Unlike Casodex, MDV3100 inhibits nuclear
  translocation of the AR and its binding to DNA
• Induces apoptosis in prostate cancer cells

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Response with MDV3100
Scher, ASCO 2009
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Phase III Trial Post Docetaxel-Based
Chemotherapy- AFFIRM (n1,200)
R A N D O M I Z E
MDV3100 160 mg/day
CRPC

placebo
Primary end point OS Secondary Endpoints
progression-free survival, safety and
tolerability
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