Transcript Prostate cancer progression

Prostate cancer progression
OBJECTIVES BY CLINICAL STATE
INITIAL
LOCALIZED
EVALUATION:
DISEASE
NO CANCER
DIAGNOSIS
PREVENTION
RISING
PSA
CLINICAL
CLINICAL
METASTASES: METASTASES:
NON-CASTRATE CASTRATE
MINIMIZE
PREVENT
MORBIDITY/ METASTASES
MAXIMIZE
CURE
ELIMINATE /
PREVENT
SYMPTOMS
DEATH OF
DISEASE
2006 Estimated US Cancer Cases*
Men
720,280
Women
679,510
Prostate
33%
31%
Breast
Lung & bronchus
13%
12%
Lung & bronchus
Colon & rectum
10%
11%
Colon & rectum
Urinary bladder
6%
6%
Uterine corpus
Melanoma of skin
5%
4%
Non-Hodgkin
lymphoma
4%
Non-Hodgkin
lymphoma
4%
Melanoma of skin
Kidney
3%
3%
Thyroid
Oral cavity
3%
3%
Ovary
Leukemia
3%
2%
Urinary bladder
Pancreas
2%
2%
Pancreas
18%
22%
All Other Sites
All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2006.
Cancer Incidence Rates* for Men, 1975-2002
Rate Per 100,000
250
Prostate
200
150
Lung
100
Colon and rectum
50
Urinary bladder
Non-Hodgkin lymphoma
Melanoma of the skin
0
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
*Age-adjusted to the 2000 US standard population.
Source: Surveillance, Epidemiology, and End Results Program, 1975-2002, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2005.
2006 Estimated US Cancer Deaths*
Lung & bronchus
31%
Colon & rectum
10%
Men
291,270
Women
273,560
26%
Lung & bronchus
15%
Breast
Colon & rectum
Prostate
9%
10%
Pancreas
6%
6%
Pancreas
Leukemia
4%
6%
Ovary
Liver & intrahepatic
bile duct
4%
4%
Leukemia
3%
Esophagus
4%
Non-Hodgkin
lymphoma
Non-Hodgkin
lymphoma
3%
3%
Uterine corpus
2%
Multiple myeloma
Urinary bladder
3%
2%
Brain/ONS
Kidney
3%
All other sites
23%
ONS=Other nervous system.
Source: American Cancer Society, 2006.
23%
All other sites
Cancer Death Rates*, for Men, US,1930-2002
100
Rate Per 100,000
Lung
80
60
Stomach
Prostate
40
Colon & rectum
20
Pancreas
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Public Use Data Tapes 1960-2002, US Mortality Volumes 1930-1959,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2005.
2000
1995
1990
1985
1980
1975
1970
1965
1960
1955
Liver
1950
1945
1935
1930
0
1940
Leukemia
Probability of developing invasive
prostate cancer increases with age
Age (Male)
Birth39 yr
4059 yr
6079 yr
Lifetime risk
All Sites
1 in 73
1 in 12
1 in 3
1 in 2
American Cancer Society, Inc. Available at:
http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf
Prostate
1 in 12,833
1 in 44
1 in 7
1 in 6
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. 2003;95:1240
Giovannucci E et al. J Natl Cancer Inst. 1993;85:1571
Sharpe CR et al. Epidemiology. 2001;12:546
Hoffman RM et al. J Natl Cancer Inst. 2001;93:388
Siddiqui MK et al. Biomed Environ Sci. 2002;15:298
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
Hereditary aspects
• Hereditary (> 3 relatives or > 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
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)
Hippocrates
• It is more important to know what sort of
person has a disease, than to know
what sort of disease a person has.
Willet F. Whitmore
• Is cure possible in those for
whom it is necessary?
• Is cure necessary in those for
whom it is possible
American Cancer Society
Guidelines for Screening
Annual Digital Rectal Exam/PSA
Screening
• Age 50
• Age 45: family history or African
American
• PSA <2.0 at yr 1 of screening, screen
q 2 yr
American Cancer Society, Inc. Available at:
http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf
Han M et al. Med Clin North Am. 2004;88:245
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
Gleason Grade
• The Sum of the most common
pattern plus the second most
common pattern yields the gleason
score
– < 6: well differentiated
– 7: moderately differentiated
– > 8: poorly differentiated
Prostatic Intraepithelial Neoplasia
• 85% carcinomas have
associated PIN
• High grade PIN has 3050% 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
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
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
Digital Rectal Exam
• Poorly reproducible
• Lacks sensitivity and specificity
• 25% of men with an abnormal DRE and a
PSA < 4.0 have prostate cancer
• 50% of DRE-detected prostate cancer is
non-organ confined
DRE examination
T1
T3
T2
T4
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
Factors Increasing PSA
•
•
•
•
•
•
Cycling
Prostate massage
Cystoscopy
Ejaculation
Prostate biopsy
Transrectal Ultrasound
Serum PSA
• Normal PSA: <4.0 ng/mL
– Age- and race-based
reference 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. 2000;14:267
Tanguay S. Urology. 2002;59:261
Okihara K. J Urol. 2002;167:2017
PSA Derivatives
• PSA velocity: rise in PSA over time
(>0.75 ng/ml/yr associated with cancer;
useful for men with PSA <4)
• PSA density: PSA/prostate volume (>0.15
is associated with cancer; useful in men
with large glands)
• Free PSA: measures “unbound” PSA
(<25% 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
PSA levels and cancer
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
Screening recommendations
Screen any man > 50 years old with a 10
year life expectancy.
• Screen any man > 45 years old if:
African-American
Positive family history.
• Stop screening when life expectancy is <10
years.
•
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
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
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_finalPWSecured.pd
f
CaPSURE: Risk
Category at Diagnosis
100
Patients (%)
80
High risk
36.6%
30.2%
25.1%
16.0%
37.2%
60
Intermediate risk
37.3%
38.5%
33.8%
40
20
46.8%
Low risk
29.5%
32.5%
36.4%
0
1989 1990 1991 1992 1993 1994 1995 1996 1997 1999 2000 2001 2002
Reprinted with permission from Cooperberg MR et al. J Urol. 2003;170:S21
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
Localized prostate cancer
What to do?
Dealing
with
localized
prostate
cancer
Requires a
balancing
act
Prognostic models
• Partin tables
• Kattan nomograms
• D’amicco prognostic groups
Risk Classification for PSA
Failure After RP or RT
Classification
Low Risk
Intermediate
Risk
High Risk
Criteria
PSA <10 ng/mL and Gleason <7
and AJCC ≤T2a
PSA 10–20 ng/mL or Gleason 7
or AJCC T2b
PSA 20 ng/mL or Gleason
>7 or AJCC ≥T2c
5-yr Outcome
<25% PSA
Failure
25%50%
PSA Failure
>50% PSA
Failure
The most clinically relevant prognostic
factors are: Gleason, PSA and stage
Adapted with permission from D'Amico AV et al. JAMA. 1998;280:969
Risk Stratification:
Localized Prostate Cancer
Low Risk
High Risk
100
100
90
80
90
70
70
60
60
50
50
40
40
30
30
20
10
0
80
164
109
10
6
147
77
8
4
117
42
5
3
83
17
2
3
55
4
1
2
36
2
0
1
20
10
0
0
1
2
3
4
5
239
309
23
19
158
218
14
13
0
1
Time (yr)
102
99
3
4
2
47
38
0
0
26
12
0
0
11
0
0
0
3
4
5
Time (yr)
RP
Implant and Neoadjuvant Hormonal Therapy
External Beam RT
Implant
Reprinted with permission from D’Amico AV et al. JAMA. 1998;280:969
Localized prostate cancer
Medical 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
Primary treatments for localized
prostate cancer
•
•
•
•
•
•
•
Watchful waiting
Active surveillance
Interstitial brachytherapy
External beam radiotherapy
Radical prostatectomy
Primary hormonal therapy
Others (e.g., cryotherapy, HIFU)
Radical prostatectomy
Multiple approaches
• Transperineal (uncommon)
• Retropubic (most common)
• Laparoscopic (pure, robot
assisted)
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 (P=0.04).
• 30 of the 347 men assigned to surgery
and 50 of the 348 men assigned to
watchful waiting, death was due to
prostate cancer
Radical Prostatectomy:
Outcomes
Long-Term Survival Following
Anatomic Radical Retropubic Prostatectomy
Likelihood of
Undetectable PSA
1.00
T1a
T1c
0.75
T1b
T2a
T2c
0.50
T2b
T3a
0.25
0
0
5
10
15
Years Post-operative
Reprinted with permission from Han M et al. Urol Clin North Am. 2001;28:555
20
Long-term biochemical disease-free Survival
following Radical Retropubic Prostatectomy
PSA Progression-Free vs Gleason Score
Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001
Pathological findings
• Approximately 8% to 15% of
cancers confined to the prostate
pathologically do recur.
• Extracapsular invasion
• Seminal Vesicles involvement
• Positive surgical margins
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
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
Radiation Therapy
•
•
•
•
3D
IMRT
Brachytherapy
External irradiation offers the same longterm survival results as surgery
• External irradiation provides a quality of
life at least as good as that provided by
surgery
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
After the local therapy
Natural history of progression after
PSA elevation following radical prostatectomy
1997 men, 15 years after surgery
• Cancer-specific survival = 91 %
• Biochemical disease-free survival = 85 %
• 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
Pound, Partin, Walsh, et al JAMA 281:1591, 1999
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
Post Radical Prostatectomy
Rising PSA
Clinical variable
Local
Distant
recurrence recurrence
• Onset of PSA rise
> 2 years
< 2 years
• PSA doubling time
> 1 year
< 6 months
< 0.75
> 0.75
• PSA velocity
(ng/mL/year)
Active surveillance
• Definition: selected men are managed
expectantly with the intention to apply
curative treatment if signs of progression
occur
Active surveillance: eligibility criteria
•
•
•
•
•
•
PSA-level at diagnosis <= 10 ng/mL
PSA density (PSA D) less than 0.2 ng/ml/cc
Clinical stage T1C or T2
Appropriate biopsy sampling
Gleason score 3+3=6 (or less)
One or 2 biopsy cores invaded with prostate
cancer
• Participants must be willing to attend the
follow-up visits
Active Surveillance Criteria
• Epstein criteria for insignificant disease
– Gleason score of 6 or less
– < 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 > 3 years
• PSA velocity < 2.0 ng/ml per year
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
New approaches
• Cryotherapy
– Patients with low-risk or intermediate-risk represent
potential candidates for CSAP.
– Prostate size should be < 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)
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, > 2
ng/ml, irrespective of the nadir value
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 >
20 ng/mL or unless the PSA velocity > 20
ng/mL/year
• CT-PET
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
Metastatic prostate cancer
CHARLES HUGGINS
Evolution of Hormone Blockade
Orchiectomy
<1940
DES
1940
LHRH
Agonist
1985
LHRH
Agonist +
Antiandrogen
(CAB)
1989
GnRH
Antagonists
2002–03
Hormonal therapy
Hypothalamus
LHRH
Agonists/
Antagonists
LHRH
Pituitary
Ketoconazole
FHS, LH
Orchiectomy
Testicles
Testosterone
Direct
antagonists
DES
Prostate cancer cell
Adrenals
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
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)
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
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
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
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
7/18/2015
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
‫דיכוי יצירת ‪Testosterone‬‬
‫ממקור יותרת‪-‬הכליה‬
Abiraterone in Androgenindependent prostate cancer
‫אחרי טיפול‬
‫הורמונאלי‬
• PSA response
27/44 (61%)
• RECIST response
12/21 (57%)
Taxotere ‫אחרי‬
• PSA response
14/28 (50%)
• RECIST response
4/18 (22%)
Side Effects of Androgensupression
•
•
•
•
•
•
•
•
Hot flashes
Loss of libido
Impotence
Gynecomastia and breast tenderness
Increased appetite
Weight redistribution
Muscle wasting
Bone loss
Metabolic Syndrome and
Prostate Ca
>73,000 men age>65 treated for localized Ca
prostate 1992-1999, observed through 2001
>1 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
Androgen-independent
prostate cancer
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
Brief History of FDA Approval of Agents
for Prostate Cancer
AGENT
•
•
•
•
Docetaxel
Zomera
Mitoxantrone
Estramustine
YEAR
ENDPT.
2004
2003
1996
1981
survival
QOL
QOL
old rules
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
N=1006
Randomize
TAX 327
N=770
*Warfarin and aspirin
Randomize
SWOG 9916
Docetaxel 30 mg/m2/wk
Prednisone 10 mg q day
5 on; 1 off x 6 cycles
Docetaxel 75 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
Mitoxantrone 12 mg/m2
Prednisone 5 mg bid
Q 21 days
Docetaxel 60 mg/m2 d 2
Estramustine 280 mg d1-5*
Dexamethasone 20 mg, tid d 1 & 2
Tannock et al. N Engl J Med 2004:351;1502-1512; Petrylak et al. N Engl J Med 2004;351:1513-1520.
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
0.01
0.009
p-value
HRPC potential new compounds in
Phase III
Advanced
disease
Taxotere combo
Monotherapy
Secondline
GVAX
M1
First-line
chemo
M1
DN101
Atrasentan
Avastin
Taxotere
Denosumab
Provenge
window
GVAX
Denosumab
M0
Early
disease2004
Aflibercept
2005
2006
2007
2008
2009
2010
89
Strontium
2011