prostate cancer an update mohamed abdulla (m.d.) prof. of clinical oncology kasr el-aini school of...
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Prostate CancerAn Update
Mohamed Abdulla (M.D.)
Prof. of Clinical Oncology
Kasr El-Aini School of Medicine
Cairo University
Khartoum, 05/12/2009
Challenging Issues:
Increased Incidence; AGING. Better Understanding of Molecular Events. Higher Prevalence of Early Localized Disease;
(Screening & Early Detection). Watchful Strategies. Androgen Deprivation Strategies. Evolution of High Precision Radiation Therapy
Treatment. Improvements of Surgical Skills & Technology.
Molecular Events
No Major Predisposition Genes. A wide Number of Susceptibility Loci are
Identified Heterogeneity of Disease Behavior & Resistance to Treatment.
Dominant Inherited Susceptibility Genes (30-40% of Early Onset Disease).
Molecular EventsNormal Prostate Gland
Intraepithelial Neoplasia
Prostate Cancer
Advanced Stage
Metastatic Disease
Androgen Resistant Disease
Hereditary FactorsHormonal Factors
Receptor Polymorphism 1
2Early Oncogene Activation
Loss of Tumor Suppressor Gene
3Late Oncogene Activation
Loss of Tumor Suppressor Gene
4Stromal Factors
5Androgen Receptor Mutation
++ Growth Factors & Receptors
Rb Gene
P53 & ras
E-Cadherin
Androgen Synthesis & Receptor:
Hypothalamus
Pituitary
Testis Adrenals
Testosterone
LHRH
LH ACTH
Hormonal Deprivation Therapy
Androgen Synthesis & Receptor:
Testosterone 5∞Reductase DHT
DHT
AR
HSP
AR
DNA Specific Sequence
PSA
IGF-1
VEGF
Differentiation
Metastases Angiogenesis
Proposed Risk Factors:
Possible:
1. Age.
2. Race.
3. Premalignant PIN.
4. Affected Relatives.
5. Carnivorous Diet.
6. Dietary Fat.
7. Vitamin D.
8. Sexual Habits.
Controversial:
1. BPH.
2. Sexually Transmitted Diseases.
3. Cigarette.
4. Alcohol Intake.
5. Cadmium Exposure.
Morton RA Jr. Racial differences in adenocarcinoma of the prostate in North American men.Urology 1994;44(5):637–645.
Therapeutic Opportunities Through Prostate Cancer Progression:
Time
Tum
or B
urde
n
Expectant
Treatment
Bioche
mica
l Pro
gres
sion
Androgen Depletion
Hor
mon
e R
efra
ctor
y
Stage D3
Chemopreventive Studies:
Testosterone 5∞Reductase DHT
AR
HSP
AR
DNA Specific Sequence
PSA
IGF-1
VEGF
DHT
Dutasteride (Avodart Caps 0.5 mg)
Chemopreventive Studies:
Mostaghel E, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 1.
Men with clinically localized PCa aged 45-80 yrs;
Gleason sum ≤ 7.0;PSA 2.5-10.0 ng/dL
(N = 75)
Dutasteride 7.0 mg loading dose, 0.5 mg daily
(n = 26)
No therapy(n = 25)
Dutasteride 3.5 mg daily
(n = 24)
of Intra-prostatic DHT. Tissue Testosterone. 32 Genes; (ILGF). 98 Genes; (Trefoil factor 3 protein). Overall incidence of Prostate Cancer. Higher Incidence of High Grade Lesions. Better of DHT (98.8%) at 3.5 mg/day.
Chemopreventive Studies:
Mostaghel E, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 1.
Insignificant Prostate Cancer:Active Treatment Can Be Deferred= Active Surveillance
Serum PSA. Prostate Volume. Clinical Stage. Gleason Grade. Systematic Biopsy
Results.
Kattan et al. J Urol. 2003;170:17921797.
Insignificant Prostate Cancer:Active Treatment Can Be Deferred= Active Surveillance
DRE
PSA
Stage
GleasonGrade
Extremes of Biological Behavior
& Natural History
The Concept of PSA Velocity:
Velocity Threshold
PSA Level Age Indication Ref.
0.75 ng/ml/Year
> 4 ng/ml -- Biopsy 1
0.3-0.5 ng/ml/Year
< 4 ng/ml -- Biopsy 1
0.2-0.4 ng/ml/Year
-- < 60 Biopsy 2
PSA Velocity > 2.0 ng/ml/Year Shorter Time to Biochemical Recurrence & Disease Specific Mortality No A.S.
1. Loeb S, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 2. 2. Connolly DJ, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 6.
The Concept of PSA Velocity:
1. Loeb S, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 2. 2. Connolly DJ, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 6.
Active Surveillance Program:
DRE. Free & Total PSA. Endo-rectal MRI with Spectroscopy
(TRUS). TRUS Systematic Needle Biopsies.
6 Months
12-18
Months
2 – 3 Years
Patel MI, DeConcini DT, Lopez-Corona E, Ohori M, Wheeler T, Scardino PT. An analysis of men with clinically localized prostate cancer who deferred definitive therapy. J Urol. 2004;171:1520-1524.
Importance of Strict Protocol:
Controversy & Debate:
Masking of Symptoms
CatastrophicEvents
Reduce Survival
Local Progression Needs Intervention
Less Hormone Sensitive onProgression
Potential HazardsOf Deferring
Treatment
Chronic Toxicity ofProlonged Androgen
Deprivation
Localized Disease:
Risk of Recurrence
Low Intermediate High
•T1-2a.•Gleason Score 2-6•PSA < 10 ng/ml
•T2b-c.•Gleason Score 7•PSA 10-20 ng/ml
•T3a•Gleason Score 8-10•PSA > 20 ng/ml
Very High
T3b-T4
Localized Disease
Therapy
SurgeryRadiation Therapy
Ablative Therapies
Medical Imaging
Androgen Deprivation Therapy
Therapy
SurgeryRadiation Therapy
Ablative Therapies
Imaging Modalities:Limitations & New Arrivals:
L.Ns. Size Does not Correlate with The Presence of Prostate Cancer Metastases (CT & MRI).(1)
FDG-PET Scan is not Ideal in Staging of Prostate Ca
1. Relatively Slow Growth Of Prostate Cancer Cells. (2)
2. Excretion of FDG into Adjacent Bladder. (3)
3. Equal Sensitivity with Bone Scan. (4)
1. Tiguert R, Gheiler EL, Tefilli MV, et al. Lymph node size does not correlate with the presence of prostate cancer metastasis. Urology. 1999;53:367-371.2. Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for
positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol. 2002;168:273-280.3. Kwee SA, Coel MN, Lim J, Ko JP. Prostate cancer localization with 18fluorine fluorocholine positron emission tomography. J Urol. 2005;173:252-255.4. Langsteger W, Heinisch M, Fogelman I. The role of fluorodeoxyglucose, 18F-dihydroxyphenylalanine, 18F-choline, and 18F-fluoride in bone imaging
with emphasis on prostate and breast. Semin Nucl Med. 2006;36:73-92.
Choline is a More Suitable Metabolic Marker Than FDG.(1,2)
C-Choline-PET/CT(3)
1. 83% Sensitivity in Localizing Nodules < 5 mm.
2. Equal Sensitivity to TRUS/Biopsy but < Specific (84 vs 97%).
3. Lower Sensitivity than MRI (22 vs 63%). The Use of Mega-Voltage Cone beam CT. Endo-rectal MRI & Spectroscopy.
Imaging Modalities:Limitations & New Arrivals:
1.Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol. 2002;168:273-280.2. Kwee SA, Coel MN, Lim J, Ko JP. Prostate cancer localization with 18fluorine fluorocholine positron emission tomography. J Urol. 2005;173:252-255.3. Martorana G, Schiavina R, Corti B, et al. 11C-choline positron emission tomography/computerized tomography for tumor localization of primary prostate cancer in comparison with 12-core biopsy. J Urol. 2006;176:954-960.
Localized Disease:The Ideal Trifecta:
Cancer Free (No Pathology, No detectable PSA).
Continence Free. Erectile Dysfunction
Free.
Kupelian PA, Katcher J, Levin HS, Klein EA. Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys. 1997;37:1043-1052.
Localized Prostate Cancer:Radical Prostatectomy vs Watchful Waiting:
OAS Benefit 5%
10 Years.
PSADetected Disease
Screen-DetectedDisease
Patients < 65 Years of Age
Localized Disease:Advances in Radiation Treatment Delivery: Conformal, IMRT, Proton Beam Rth:
Pollack et al(1): Higher Local Failures with < 70 Gy.
Zeitman et al(2): Higher DFS with 79 Gy vs. 70 Gy.
Dutch Trial(3): Higher Benefit with 78 Gy vs. 68 Gy.
IMRT is now the Standard of Care Than Conformal & Non Conformal Methods of Treatment Delivery.
IGRT: is the most significant achievement in High Precision Treatment Delivery Tracking The Daily Motions of Prostate Through Treatment Plans.
Major Concern About 2nd Malignancy Particularly Rectal Cancer in Patients Living > 10 Years.
Proton Beam IMRT ???
(1) Pollack A, Zagars GK, Smith LG, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol. 2000;18:3904-3911.(2) Zietman A, DeSilvio M, Slater J, et al. A randomized trial comparing conventional dose (70.2GyE) and high-dose (79.2GyE) conformal radiation in early stage adenocarcinoma of the prostate: results of an interim analysis of PROG 95–09. Int J Radiat Oncol Biol Phys. 2004;60:S131-S132. Copyright © 2007 Clinical Care Options, LLC. All rights reserved. 22(3) Peeters ST, Heemsbergen WD, Koper PC, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol. 2006;24:1990-1996.
Localized Disease:Focal Therapy: Treatment of only Diseased Portion. Limitations:1. Underestimation of the volume of cancer.2. The disease is multi-focal.3. The largest identified neoplastic lesion may
not be the most biologically significant. Questions to be Answered:1. Ideal Imaging Modality.2. Patient Selection.3. The Ideal Method of Application.
Barqawi A, Crawford ED. Focal therapy in prostate cancer: future trends. BJU Int 2005;95:273-274.
Neoadjuvant Androgen Depravation + Radiation Therapy:
RT01: phase III study of 2 doses of conformal RT + neoadjuvant androgen deprivation (NAAD) in localized PCa
Dearnaley DP, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 295.
Localized prostate cancer
(N = 843)
Escalated-dose conformal RT 74 Gy/32f + NAAD 3-6 months* before, during RT
(n = 422)
Standard-dose conformal RT 74 Gy/37f +NAAD 3-6 months* before, during RT
(n = 421)
5-year biochemical progression-free survival (PFS) significantly longer with high-dose vs standard-dose RT 72% vs 60% (HR: 0.66; 95% CI: 0.52-0.84; P
< .001) 5-year PFS significantly longer with high-dose
vs standard-dose RT 92% vs 86% (HR: 0.57; 95% CI: 0.38-0.87; P
= .010) Increased incidence of long-term adverse
events with high-dose RT Significantly more late bowel, bladder toxicity
Neoadjuvant Androgen Depravation + Radiation Therapy:
Dearnaley DP, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 295.
Neoadjuvant Androgen Depravation + Radiation Therapy:
Rth
Rth + ADT 6 months
Rth + ADT 2.5 Years
Rth
Rth + ADT 6 months
Rth + ADT 2.5 Years
Rth
Rth + ADT 6 months
Androgen Deprivation Therapy + Surgery:
Prostate CancerT2b
)282(
ADT (3 months)
No ADT
RP
# 5-YearBiochemical
Failure
+ve S.M.
Soloway MS, Pareek K, Sharifi R, et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002;167:112-116.
Not The Standard of Care Outside Clinical trials.
Androgen Deprivation Therapy + Surgery:
Prostate CancerL.Ns. +ve
(98 Patients)
ADT
Observation
RP
Updated 10-Year Result
72.4% vs 49%
Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared withobservation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341:1781-1788.
ADT & Chemotherapy:
CTh in Metastatic Hormone Refractory Prostate Cancer Survival Benefit(1).
CTh + Rth or Prior to Prostatectomy in Early Disease Starting Progression(2).
1. Goodin S, Medina P, Capanna T, et al. Effect of docetaxel in patients with hormonedependent prostate-specific antigen progression after local therapy for prostate cancer. J Clin Oncol. 2005;23:3352-3357.2. Oh WK. High-risk localized prostate cancer: integrating chemotherapy. Oncologist. 2005;10 Suppl 2:18-22.
Timing of ADT in Metastatic Disease:
17% Mortality Risk Reduction
15% Non-Prostate Cancer Specific Mortality
No Overall Survival Advantage for Early vs Late ADT
Symptomatic & Rapidly Progressive Disease Immediate ADT
17% Mortality Risk Reduction
Loblaw DA, Virgo KS, Nam R et al. Initial hormonal management of androgen sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007; 25: 1596–1605
Intermittent ADT:
• Non Inferiority in Time of Disease Progression & Survival.
• Better Quality of Life.
• Lower Treatment Cost.
Adding an Anti-Androgen; Bicalutamide. Withdrawal of Anti-Androgen. The Use of Ketoconazole. Treatment with Estrogen. Adding an Alternative Anti-Androgen. Targeting The Androgen Receptors; Abirterone.
Strategies to Overcome Initial Hormone Unresponsiveness:
Androgen Deprivation Therapy:Co-Morbid Events
CVS Therapy Induced Events. Decreased Bone Mineral Density. Decreased Muscular Bulk.
Bisphosphonate Indications—Focus on PC Indication
Prevention of SREs
HCMMultiple
myelomaBreast cancer
Prostate cancera
Other solidtumors
Clodronate (oral)
Pamidronate (IV) Zoledronic acid (IV) Ibandronate (oral and IV)
= European Registration = Worldwide Registration
PC, prostate cancer; SREs, skeletal-related events; HCM, hypercalcemia of malignancy; IV, intravenous.a In the United States, prostate cancer must have progressed despite hormone therapy.Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com.
Test drug N Results Reference
Etidronate 57 Transient pain reduction Smith 1989, J Urol
Clodronate 75 Only transient Elomaa 1992,symptomatic benefit Int Urol Nephrol
Placebo-Controlled Studies
Clodronate 311 No significant benefit Dearnaley 2003, JNCI
Pamidronate 378 No significant benefit Small 2003, JCO
Clodronate 209 No significant benefit Ernst 2003, JCO
Zoledronic acid 643 Significant objective and Saad 2002-4, JNCIdurable benefits
Bisphosphonates in the Treatmentof Bone Metastases From Prostate Cancer
Methods of Androgen Deprivation:
Castration. GnRH Agonists. Anti-Androgen.
MonotherapyMaximum Androgen Blockade
MAB
Methods of Androgen Deprivation:
LHRHLHRH Hypothalamus
Pituitary gland
LH
ACTH
Adrenal gland
Testis
Circulating testosterone
Androgens
Othertarget tissues
DHT
‘Casodex’(bicalutamide)
Prostate cell
Androgenreceptor
-ve feedback control
DHT
X
‘Zoladex’(goserelin)
Overall survival in M0 patients: median 6.3 years’ follow-up
% patients surviving
0
20
40
60
80
100
Time (days)
0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600
HR 1.05; 95% CI 0.81, 1.31; p=0.70 Iversen et al 2000
‘Casodex’ (bicalutamide) 150 mg Castration
2800
Pharmacological adverse events in M0 patients
Adapted from Iversen et al 2000
Adverseevent
Hot flushes
Gynaecomastia
Breast pain
‘Casodex’ (bicalutamide)150 mg (n=314)
41 (13.1%)
155 (49.4%)
126 (40.1%)
Castration(n=160)
80 (50.0%)
7 (4.4%)
3 (1.9%)
Only 4 (1.3%) patients withdrew due to breast pain and/or gynaecomastia
Quality of life: M0 patients
-2 -1 1 2 3 4 50
Physical capacity
Emotional wellbeing
Sexual interest
Vitality
Social functioning
Pain
Activity limitation
Bed disability
Overall health
Favours castration Favours ‘Casodex’ (bicalutamide) 150 mg
Treatment effect and 95% 2-sided CI
*
**
Iversen et al 2000*p=0.046; **p=0.029
‘Casodex’ (bicalutamide) 50 mg (Schellhammer): study design
Schellhammer et al 1995
Randomisedn=813
‘Casodex’ (bicalutamide) +
‘Zoladex’ (goserelin)n=268
‘Casodex’ (bicalutamide)
+ leuproliden=136
Flutamide + ‘Zoladex’ (goserelin)
n=272
Flutamide + leuprolide
n=137
‘Casodex’ (bicalutamide) + LHRH agonist
n=404
Flutamide + LHRH agonist
n=409
Sarosdy et al 1998
‘Casodex’ (bicalutamide) 50 mg and
flutamide in MAB: an exploratory analysis 100
0 365 730 1095 1460 1825
‘Casodex’ + ‘Zoladex’
‘Casodex’ + leuprolide
Time (days)
% patientssurviving
80
60
40
20
0
Flutamide + ‘Zoladex’
Flutamide + leuprolide
p=0.26
p=0.008p=0.99
p=0.047
Sarosdy et al 2000
Overall survival for prolonged versus short-term MAB therapy: an exploratory analysis
A. All patients (n=810)* B. Patients who lived longer than 2 years (n=544)**
*HR 0.28; 95% CI 0.21, 0.36; p=0.0001
**HR 0.42; 95% CI 0.25, 0.70; p=0.0001
0 365 730 1095 1480 1825 2190
>120 days<120 days
% p
atie
nts
su
rviv
ing
Time (days) Time (days)
0 365 730 1095 1480 1825 21900
20
40
60
80
100
Adverse eventsMost frequently occurring adverse events regardless of causality
Schellhammer et al 1997
Abnormal LFT
DizzinessAnaemia
Abdominal painHaematuria
NocturiaDiarrhoea
Peripheral oedema
Infection
AstheniaBack pain
PainHot flushes
‘Casodex’ (bicalutamide) 50 mg + LHRH agonistFlutamide + LHRH agonist
Dyspnoea
Nausea
Pelvic pain
Bone pain
Constipation
*26% vs 12%, p<0.0001; **12% vs 6%, p=0.007
% patients0 3010 20 40 50
LFT, liver function test
**
*
1:1 randomisation
8113 patientsrecruited
Placebo + standard care
(RP, RT, WW) [n=4061]
‘Casodex’ (bicalutamide) 150 mg/day
+ standard care (RP, RT, WW) [n=4052]
First analysis at 2 years’ minimum follow-upMedian 3 years’ (minimum 2 years’) follow-up
Average 2 years’ duration of therapy
EPC programme: design
‘Casodex’ (bicalutamide) 150 mg reduces the risk of disease progression
HR 0.58; 95% CI 0.51, 0.66; p<<0.0001
‘Casodex’ (bicalutamide) 150 mg
+ standard care
Placebo + standard care
0
100
200
300
400
500
600Number of patients
n=363/4052
n=559/4061
See et al 2002
Incidence of objective clinical progression
‘Casodex’ (bicalutamide) 150 mg reducesthe risk of disease progression by 42%
Time (months)
0 6 12 24 30 36 42 48 540.0
0.2
0.4
0.6
0.8
1.0
‘Casodex’ (bicalutamide) 150 mg + standard care
Placebo + standard care
60
See et al 2002
Proportion without event
(progression-free survival)
HR 0.58; 95% CI 0.51, 0.66; p<<0.0001
‘Casodex’ (bicalutamide) 150 mg reduces the incidence of bone metastases by 33%
0
50
100
150
200
250
300
350Number of patients
Placebo + standard care
n=321/4061
n=214/4052
See et al 2002
‘Casodex’ (bicalutamide) 150 mg
+ standard care
RR 0.67; 95% CI 0.56, 0.79; p<<0.0001
‘Casodex’ (bicalutamide) 150 mg reducesthe risk of PSA progression
200
400
600
800
1000
1200
1400
n=689/4052
n=1340/4061
See et al 2002
Number of patients
‘Casodex’ (bicalutamide) 150 mg
+ standard care
Placebo + standard care
0
HR 0.41; 95% CI 0.38, 0.45; p<<0.0001
EPC programme: tolerability
Gynaecomastia alone
Breast pain alone
Gynaecomastia plus breast pain
Hot flushes
Impotence
Asthenia
Diarrhoea
Weight gain
Loss of libido
Abnormal liver function test
‘Casodex’ (bicalutamide) 150 mg
+ standard care(n=4022)
13.1
19.7
53.19.0
9.0
10.2
6.3
5.7
3.6
3.4
Placebo+ standard care
(n=4031)
4.8
4.3
2.95.2
6.1
7.2
6.4
2.8
1.1
1.9
Patients (%)
See et al 2002
Withdrawals due to: all adverse events breast pain alone gynaecomastia alone breast pain plus gynaecomastia
Progression
Death
Lost to follow-up/patient’s choice
Investigator’s decision
Withdrawals from therapy
‘Casodex’ (bicalutamide) 150 mg
+ standard care (n=4022)
25.85.83.56.4
2.6
2.1
6.2
1.4
38.1
Placebo + standard care
(n=4031)
8.10.20.20.1
9.3
1.7
6.5
6.2
31.8
EPC programme: withdrawals
See et al 2002
Patients (%)
E, no. events
EPC Program: overall subgroup analyses
0.125 0.25 0.5 1.0 2.0 4.0
Overall analysis
Localised disease
Locally advanced disease
Pre-therapy PSA >10 ng/mL
Gleason score 2–4
Gleason score 5–6
Gleason score 7–10
Pre-therapy PSA <4 ng/mL
Pre-therapy PSA 4–10 ng/mL
N-
N+
Nx
RP
RT
WW
(n=4454, E=285)
(n=1370, E=178)
(n=2285, E=458)
(n=5429, E=480)
(n=2682, E=442)
(n=3719, E=592)
(n=1792, E=208)
(n=3598, E=376)
(n=2648, E=327)
(n=3157, E=501)
(n=4806, E=378)
(n=8113, E=922)
(n=150, E=43)
(n=3230, E=226)
(n=918, E= 72)
HR plus 95% CI
AstraZeneca, data on file
Keep in Mind:
ADT is being used increasingly in Localized Prostate Cancer in Conjunction with Standard Care Options.
The Gold Standard in Advanced and Metastatic Disease. Immediate Use is Superior to Deferred Therapy in Non-
Metastatic Disease. Long Term is Superior to Short Term Use. Chemotherapy is Being Integrated in Different Manners
(Not State of ART). The Use of Bisphosphonate is Crucial in Preventing
Skeletal Related Events & Preservation of BMD. Targeting the AR is The Upcoming Event.
Give an Attention to PSA Velocity. Give an Attention to Therapy Related
Events especially in The Indolent Course of Disease.
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