Transcript Diapositiva 1 - University of Cagliari

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
Risk 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 Developing
Prostate Cancer
Genetic alterations associated with progression of prostate cancer
Hypothalamus pituitary testicular axis
Detailed schematic: Lateral section
of a normal prostate
PROSTATE CANCER
Stage A : Deep tumor: may
not be detected by digitalrectal 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 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.
Prostatic Intraepithelial Neoplasia
• 85% carcinomas have
associated PIN
• High grade PIN has 3050% 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 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 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 & 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 PSA
• PSA Velocity > 0.75 ng/ml/yr
• PSA Density
• Age adjusted PSA
• Molecular forms- free / total PSA
PSA 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 Alternatives
• Expectant
-- Watchful Waiting
• Radical Prostatectomy
• Radiation Therapy -- EBRT, 3D - CRT,
Brachytherapy:
HDR, Seed
• Hormonal
-- Mono Rx, MAB
• Combination
Trans-urethral Resection
Prostate Cancer
Treatment Paradigms
Clinically
Localized
Local treatment
Relapsed
Newly diagnosed M+
Hormone
Refractory
Endocrine
Chemotherapy
and
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
LH = Luteinizing hormone
T = Testosterone
5 R = 5-alpha reductase.
DHT = Dihydrotestosterone.
AR = Androgen receptor
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
Side Effects of Androgen Deprivation
Impotence:
Hot flashes:
75%-100%
60%
Accelerated osteoporosis,  muscle mass
GI upset, weight gain, leg edema, gynecomastia
Unknown effects: lipids, cognitive function, other biologic
systems
Cost
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
Patients, n
RR
MS
Chemotherapy
Tannock et al. [33]
Pred
81
P
12%
P
18 wk
Mitox + pred
80
P
29%
P
43 wk
HC
121
PSA
14%
12.3 mo
HC+mitox
121
PSA
19%
12.6 mo
Kantoff et al. [34]
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
Treatment
Patients, n
mPFS
MS
P value
300
13.9
28.3
0.03 (PFS)
Leup+flut
303
16.5
35.6
0.03 (OS)
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)
Author
Crawford et al. Leup+plac
Keuppens et
al.
Goserelin+flut arm superior in subjective and objective PFS, OS, and rate of cancer deaths.
Tyrrell et al.
Hucher et al.
Iversen et al.
Eisenberger et
al.
Gos
282
NR
37.7
0.08 (PFS)
Gos+flut
287
NR
42.4
0.14 (OS)
Orch+Anan
545
NR
NR
0.05 (PFS)
Orch+Plac
498
NR
NR
NS (OS)
Orch
133
16.8
27.6
0.69 (RFS)
Gos+flut
129
16.5
22.7
0.49 (OS)
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?
TAX327
Study Design
Stratification
Pain level
PPI ≥ 2 or AS ≥ 10
vs.
PPI < 2 or AS < 10
KPS
≤ 70 vs. ≥ 80
R
A
N
D
O
M
I
Z
E
Docetaxel 75 mg/m2 q3 wks +
Prednisone 5 mg bid
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
Overall Survival
1.0
Docetaxel 3 wkly
Probability of Surviving
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
0.5
0.4
0.3
Combined:
D 3 wkly:
D wkly:
Mitoxantrone
0.2
0.1
Median
survival
(mos)
Hazard
ratio
P-value
18.2
18.9
17.3
16.4
0.83
0.76
0.91
–
0.03
0.009
0.3
–
0.0
0
6
12
18
Months
24
30
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%, p<.0005
– Pain response - 35% vs. 22%, p=.01
– Quality of life
Prostate Cancer
Treatment Paradigms
Clinically
Localized
Local treatment
Relapsed
Newly diagnosed M+
Hormone
Refractory
Endocrine
Docetaxel + P
q3 wks
and
Improves survival
Prostate Cancer
Treatment Paradigms
Relapsed
Clinically
Localized
and
Newly diagnosed M+
Hormone
Refractory
?
Local treatment
Endocrine
?
Docetaxel
Prostate Cancer
Treatment Paradigms
Clinically
Localized
Local treatment
Relapsed
Newly diagnosed M+
Hormone
Refractory
Endocrine
Mitoxantrone+P
for symptoms
and
No Survival
Benefit