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CARCINOMA DELLA PROSTATA. PROSTATE CANCER. Prostate Anatomy. 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. PROSTATE CANCER DEATHS BY AGE. - PowerPoint PPT Presentation
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CARCINOMA DELLA PROSTATA
PROSTATE CANCERPROSTATE CANCER
Prostate Anatomy
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
PROSTATE CANCER DEATHS BY AGEPROSTATE CANCER DEATHS BY AGE
Risk Factors for Prostate CancerRisk Factors for Prostate Cancer• Age – Found mainly in men over age 55. Average age
of diagnosis is 70• Family History – Men’s 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
Risk for DevelopingRisk for Developing Prostate Cancer Prostate Cancer
Genetic alterations associated with progression of prostate cancer
Hypothalamus pituitary testicular axis
Detailed schematic: Lateral sectionof a normal prostate
PROSTATE CANCERPROSTATE 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
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.
The Gleason scoring system for prostate cancer.
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
Symptoms of Prostate CancerSymptoms 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
Screening for Prostate CancerScreening 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
Screening … For & AgainstScreening … 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
Factors Increasing PSA• Cycling• Prostate massage• Cystoscopy• Ejaculation • Prostate biopsy• Transrectal Ultrasound• Prostate disease
Percentage risk of CaP
PSA < 4 (%)
4-10 (%)
>10 (%)
DRE neg 9 20 31
DRE pos 17 45 77
Screening - Improving the PSAScreening - Improving the PSA
• PSA Velocity > 0.75 ng/ml/yr
• PSA Density
• Age adjusted PSA
• Molecular forms- free / total PSA
PSA IsoformsPSA Isoforms
• Free and complexed PSA - ACT
• FREE / TOTAL ratio < 10% suggestive
• Complex now measurable
Digital Rectal Exam for Prostate Tumors
Transrectal ultrasound-guided biopsy of the prostate
Management AlternativesManagement Alternatives• Expectant -- Watchful Waiting
• Radical Prostatectomy
• Radiation Therapy -- EBRT, 3D - CRT,Brachytherapy: HDR,
Seed• Hormonal -- Mono Rx, MAB
• Combination
Trans-urethral Resection
Prostate CancerProstate CancerTreatment ParadigmsTreatment Paradigms
ClinicallyLocalized
HormoneRefractory
Local treatment Endocrine Chemotherapy
Relapsedand
Newly diagnosed M+
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
Endocrine control of prostate cancer
Strategies for Androgen Deprivation
LHRH = Luteinizing hormone-releasing hormone
5 R = 5-alpha reductase.
LH = Luteinizing hormone
AR = Androgen receptor
T = Testosterone
DHT = Dihydrotestosterone.
Types of Androgen Deprivation
Monotherapy Bilateral orchiectomy Medical castration Estrogen LHRH agonist: leuprolide, goserelin Steroidal antiandrogens Megesterol acetate Cyproterone acetate Nonsteroidal antiandrogens Flutamide Bicalutamide NilutamidePrimary gonadal suppression + antiandrogen
Side Effects of Androgen Deprivation
Impotence: 75%-100%Hot flashes: 60%Accelerated osteoporosis, muscle massGI upset, weight gain, leg edema, gynecomastiaUnknown effects: lipids, cognitive function, other biologic systemsCost
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.
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.
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.)
Adjuvant hormones. Adjuvant hormones after radical prostatectomy have demonstrated survival enhancement in patients with pathologically positive
lymph nodes. (Adapted from Messing et al.
SWOG Intergroup 0162 trial of continuous versus intermittent androgen deprivation
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.
Mitoxantrone + Steroids Versus Steroids Alone
ChemotherapyPatients, 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
HC+mitox 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
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.
Combined Androgen Deprivation Compared with Monotherapy in Advanced Prostate Cancer
AuthorTreatment Patients, n mPFS MS P value
Crawford et al. Leup+plac 300 13.9 28.3 0.03 (PFS)
Leup+flut 303 16.5 35.6 0.03 (OS)
Keuppens et al.
Orch 163 diff (s) 35 wks diff (ms) 7 m 0.009 (PFS)
Gos+flut 161 diff (o) 48 wks diff (c) 15 m 0.05 (OS)
Goserelin+flut arm superior in subjective and objective PFS, OS, and rate of cancer deaths.
Tyrrell et al. Gos 282 NR 37.7 0.08 (PFS)
Gos+flut 287 NR 42.4 0.14 (OS)
Hucher et al. Orch+Anan 545 NR NR 0.05 (PFS)
Orch+Plac 498 NR NR NS (OS)
Iversen et al. Orch 133 16.8 27.6 0.69 (RFS)
Gos+flut 129 16.5 22.7 0.49 (OS)
Eisenberger et al.
Orch+plac 687 18.6 29.9 0.26 (RFS)
Orch+flut 700 20.4 33.5 0.16 (OS
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?
TAX327TAX327Study DesignStudy Design
Stratification
Pain levelPPI ≥ 2 or AS ≥ 10
vs.PPI < 2 or AS < 10
KPS≤ 70 vs. ≥ 80
Docetaxel 75 mg/m2 q3 wks + Prednisone 5 mg bid
Mitoxantrone 12 mg/m2 q3 wks +
Prednisone 5 mg bid
RANDOMIZE
Docetaxel 30 mg/m2 wkly 5 of 6 wks +
Prednisone 5 mg bid
Treatment duration in all 3 arms = 30 wks
Overall Survival
Mediansurvival Hazard
(mos) ratio P-value Combined: 18.2 0.83 0.03D 3 wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –
Months0 6 12 18 24 30
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Docetaxel 3 wklyDocetaxel wklyMitoxantrone
Prob
abili
ty o
f Sur
vivi
ng
TAX 327Docetaxel 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%, p<.0005 – Pain response - 35% vs. 22%, p=.01 – Quality of life
Prostate CancerProstate CancerTreatment ParadigmsTreatment Paradigms
ClinicallyLocalized
HormoneRefractory
Local treatmentDocetaxel + P
q3 wks
Improves survival
Endocrine
Relapsedand
Newly diagnosed M+
Prostate CancerProstate CancerTreatment ParadigmsTreatment Paradigms
ClinicallyLocalized
HormoneRefractory
Local treatment Endocrine Docetaxel
Relapsedand
Newly diagnosed M+
?
?
Prostate CancerProstate CancerTreatment ParadigmsTreatment Paradigms
ClinicallyLocalized
HormoneRefractory
Local treatment EndocrineMitoxantrone+Pfor symptoms
Relapsedand
Newly diagnosed M+
No SurvivalBenefit
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