Prostate Cancer An Update Mohamed Abdulla (M.D.) Prof. of Clinical Oncology Kasr El-Aini School of...

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)


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.


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.


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.

Localized Disease:Androgen Deprivation Therapy (ADT):

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


Dearnaley DP, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 295.


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

ADT + Radiation Therapy “Summary of RCTs”:

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.

ADT & Chemotherapy:

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)

‘Casodex’ (bicalutamide) 150 mg monotherapy

in M0 disease

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 in advanced disease

‘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

**

*

‘Casodex’ (bicalutamide) 150 mg monotherapy in early

prostate cancer (EPC)

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


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


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


n=321/4061

n=214/4052

See et al 2002


+ 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


+ 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


+ 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


+ standard care (n=4022)

25.85.83.56.4

2.6

2.1

6.2

1.4

38.1


(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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Prostate Cancer An Update Mohamed Abdulla (M.D.) Prof. of Clinical Oncology Kasr El-Aini School of...

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