Diapositiva 1

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CARCINOMA DELLA PROSTATA
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PROSTATE CANCER
Prostate Anatomy
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Prostate cancer is a disease predominantly of the
older male population. Autopsy series have
indicated that 15 to 30 of men older than the
age 50 years have histologic evidence of prostate
cancer
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PROSTATE CANCER DEATHS BY AGE
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Risk Factors for Prostate Cancer

• Age Found mainly in men over age 55. Average
  age of diagnosis is 70
• Family History Mens risk is higher if father
  or brother is diagnosed before the age of 60
• Race Prostate cancer is found more often in
  African American men then White men. It is less
  common in Asian and American Indian men
• Dietary factors Evidence suggests that a diet
  high in fat may increase the risk of prostate
  cancer and diets high in fruits and vegetables
  decrease the risk

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Risk for Developing Prostate Cancer
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Genetic alterations associated with progression
of prostate cancer
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Hypothalamus pituitary testicular axis
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Detailed schematic Lateral section
of a normal prostate
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PROSTATE CANCER
Stage A Deep tumor may not be detected by
digital-rectal exam
Stage B Tumor may be detected by DRE or
ultrasound
Stage C Spread to surrounding tissue
Stage D Metastasis to bone and lymph nodes
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The Gleason scoring system for prostate cancer.
The Gleason grading system is used to evaluate or
grade prostate cancer cells obtained by needle
biopsy. The cells are assigned a number between
1 and 5 nearly normal cells are grade 1, and the
most abnormal are grade 5. The scores of the two
most common cell patterns are added together.
Gleason scores range from 2 to 10. The higher
the grade, the more aggressive the cancer.
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Prostatic Intraepithelial Neoplasia

• 85 carcinomas have associated PIN
• High grade PIN has 30-50 risk of CA on
  subsequent biopsies cf 13 in controls
• PIN does not cause elevated PSA
• Atypical foci in 3-5 of biopsies, 50 risk of
  cancer on repeat biopsy

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Symptoms of Prostate Cancer

• Frequent urination
• Inability to urinate
• Trouble starting and stopping urination
• Blood in the urine or semen
• Painful ejaculation
• Painful or burning urination

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Screening for Prostate Cancer

• Prostate-Specific Antigen Blood Test (PSA)
  Measures substance made by the prostate gland
• Digital Rectal Exam (DRE) Physical exam of the
  Prostate Gland
• Transrectal Ultrasound (TRUS)
• Uses sound waves to make an image
• of the prostate on a video screen

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Screening For Against

• Organ confined prostate cancer is curable
• Advanced prostate cancer is incurable
• Screening offers earlier diagnosis
• Early detection is our only hope for mortality
  reduction

• More men die with Prostate cancer than of it
• PSA test not accurate enough
• Biopsy and treatment may cause morbidity
• No trial to show mortality reduction

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Factors Increasing PSA

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

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Percentage risk of CaP
PSA lt 4 () 4-10 () gt10 ()
DRE neg 9 20 31
DRE pos 17 45 77
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Screening - Improving the PSA

• PSA Velocity gt 0.75 ng/ml/yr
• PSA Density
• Age adjusted PSA
• Molecular forms- free / total PSA

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PSA Isoforms

• Free and complexed PSA - ACT
• FREE / TOTAL ratio lt 10 suggestive
• Complex now measurable

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Digital Rectal Exam for Prostate Tumors
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Transrectal ultrasound-guided biopsy of the
prostate
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Management Alternatives

• Expectant -- Watchful
  Waiting
• Radical Prostatectomy
• Radiation Therapy -- EBRT, 3D -
  CRT, Brachytherapy HDR, Seed
• Hormonal -- Mono Rx, MAB
• Combination

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Trans-urethral Resection
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Prostate CancerTreatment Paradigms
Hormone Refractory
Relapsed and Newly diagnosed M
Clinically Localized
Local treatment
Endocrine
Chemotherapy
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Prostate Cancer Treatment Background

• 50 fail after local treatment
• 10-15 have distant metastasis at presentation
• Virtually all progress after endocrine treatment
• Chemotherapy used for symptomatic control
• No survival advantage in phase-III trials

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Endocrine control of prostate cancer
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Strategies for Androgen Deprivation
LHRH Luteinizing hormone-releasing hormone
LH Luteinizing hormone
T Testosterone
5  R 5-alpha reductase.
DHT Dihydrotestosterone.
AR Androgen receptor
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Types of Androgen Deprivation
Monotherapy
    Bilateral orchiectomy
    Medical castration
        Estrogen
        LHRH agonist leuprolide, goserelin
    Steroidal antiandrogens
        Megesterol acetate
        Cyproterone acetate
    Nonsteroidal antiandrogens
        Flutamide
        Bicalutamide
        Nilutamide
Primary gonadal suppression antiandrogen

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Side Effects of Androgen Deprivation
Impotence    75-100
Hot flashes     60
Accelerated osteoporosis, ? muscle mass
GI upset, weight gain, leg edema, gynecomastia
Unknown effects lipids, cognitive function, other biologic systems
Cost
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Adjuvant trials. SWOG 9921 adjuvant androgen
deprivation versus mitoxantrone plus prednisone
plus androgen deprivation in selected high-risk
prostate cancer patients following radical
prostatectomy, phase III. Prior neoadjuvant
therapy is permitted if the duration is 4 months
or less and if clinical criteria (PSA? 15 ng/mL
or biopsy GS ?   7 or PSA ?  10 ng/mL and GS
?  6) are satisfied prior to surgery.
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Adjuvant trials. RTOG 99-02 phase III protocol
of androgen suppression (AS) and radiation
therapy (RT) versus AS and RT followed by
chemotherapy with paclitaxel, estramustine, and
etoposide for localized high-risk prostate
cancer.
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Adjuvant hormonal therapy. Survival improvements
were noted only in one trial conducted by the
European Organization for Research and Treatment
of Cancer with the use of adjuvant hormonal
therapy. (Adapted from Bolla et al.)
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Adjuvant hormones. Adjuvant hormones after
radical prostatectomy have demonstrated survival
enhancement in patients with pathologically
positive lymph nodes. (Adapted from Messing et
al.
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SWOG Intergroup 0162 trial of continuous versus
intermittent androgen deprivation
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Hormone-independent prostate cancer. The
development of hormonal escape is depicted.
Despite a high initial response rate to androgen
deprivation, essentially all men will fail and
progress to androgen independence and ultimately
hormone refractory status. Treatment for patients
with hormone-refractory prostate cancer must be
tailored individually, and take into account the
need to maintain quality of life in this terminal
stage of the disease. Antiandrogen withdrawal,
second-line hormonal therapy, palliative
supportive care measures including radiation
therapy (external or systemic) and pain control,
and chemotherapy are all valid options.
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Mitoxantrone Steroids Versus Steroids Alone
Chemotherapy Patients, n RR MS

Tannock et al. 33
Pred 81 P         12 P         18 wk
Mitox pred 80 P         29 P         43 wk
Kantoff et al. 34
HC 121 PSA         14 12.3 mo
HCmitox 121 PSA         19 12.6 mo

Table of randomized chemotherapy trials in
metastatic disease. Although chemotherapy has not
demonstrated an impact on survival yet, the use
of mitoxantrone and steroids has, however,
demonstrated a significant palliative effect in
randomized trials
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SWOG trial of chemotherapy in metastatic disease.
SWOG Intergroup 9916 randomized phase III study
of docetaxel estramustine versus mitoxantrone
prednisone in patients with hormone-refractory
prostate cancer 620 patients must be entered to
detect a 33 survival difference. Future
directions include exploring biologic therapies
such as epithelial growth factor receptor
inhibitors and antiangiogenesis strategies.
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Combined Androgen Deprivation Compared with
Monotherapy in Advanced Prostate Cancer
Author Treatment Patients, n mPFS MS P value

Crawford et al. Leupplac 300 13.9 28.3 0.03 (PFS)
Leupflut 303 16.5 35.6 0.03 (OS)
Keuppens et al. Orch 163 diff (s) 35 wks diff (ms) 7 m 0.009 (PFS)
Gosflut 161 diff (o) 48 wks diff (c) 15 m 0.05 (OS)
Goserelinflut arm superior in subjective and objective PFS, OS, and rate of cancer deaths. Goserelinflut arm superior in subjective and objective PFS, OS, and rate of cancer deaths. Goserelinflut arm superior in subjective and objective PFS, OS, and rate of cancer deaths. Goserelinflut arm superior in subjective and objective PFS, OS, and rate of cancer deaths. Goserelinflut arm superior in subjective and objective PFS, OS, and rate of cancer deaths. Goserelinflut arm superior in subjective and objective PFS, OS, and rate of cancer deaths.
Tyrrell et al. Gos 282 NR 37.7 0.08 (PFS)
Gosflut 287 NR 42.4 0.14 (OS)
Hucher et al. OrchAnan 545 NR NR 0.05 (PFS)
OrchPlac 498 NR NR NS (OS)
Iversen et al. Orch 133 16.8 27.6 0.69 (RFS)
Gosflut 129 16.5 22.7 0.49 (OS)
Eisenberger et al. Orchplac 687 18.6 29.9 0.26 (RFS)
Orchflut 700 20.4 33.5 0.16 (OS
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Docetaxel in HRPC

• Multiple phase II studies
• Responses in 45-82 (similar 95 CI duration)
• Estramustine based RR higher but more toxic
• Single agent data (weekly and every 3 wks)
  consistently safe and effective
• Superior to mitoxantrone prednisone?

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TAX327 Study Design
Docetaxel 75 mg/m2 q3 wks Prednisone 5 mg bid
Stratification Pain level PPI 2 or AS
10 vs. PPI lt 2 or AS lt 10 KPS 70 vs. 80
R A N D O M I Z E
Docetaxel 30 mg/m2 wkly 5 of 6 wks Prednisone
5 mg bid
Mitoxantrone 12 mg/m2 q3 wks Prednisone 5 mg
bid
Treatment duration in all 3 arms 30 wks
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Overall Survival
1.0
Docetaxel 3 wkly
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
Probability of Surviving
0.5
Median survival Hazard
(mos) ratio P-value Combined 18.2 0.83 0.03
D 3 wkly 18.9 0.76 0.009 D wkly
17.3 0.91 0.3 Mitoxantrone 16.4
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
Months
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TAX 327 Docetaxel 3 Weekly

• Safe
• Significantly improves
• Survival (18.9 vs 16.5 months)
• 24 reduction in the risk of death
• (95 CI 0.62-0.94, p.009)
• PSA decline - 45 vs. 32, plt.0005
• Pain response - 35 vs. 22, p.01
• Quality of life

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Prostate CancerTreatment Paradigms
Hormone Refractory
Relapsed and Newly diagnosed M
Clinically Localized
Local treatment
Docetaxel P q3 wks
Endocrine
Improves survival
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Prostate CancerTreatment Paradigms
Hormone Refractory
Relapsed and Newly diagnosed M
Clinically Localized
?
Local treatment
Endocrine
Docetaxel
?
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Prostate CancerTreatment Paradigms
Hormone Refractory
Relapsed and Newly diagnosed M
Clinically Localized
Local treatment
Endocrine
MitoxantroneP for symptoms
No Survival Benefit
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