1 Prostate Cancer for the non-Oncologist. 2 Overview Epidemiology Risk Factors/Genetics Screening Diagnosis and Treatment Consequences of Disease and.

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Prostate Cancer for the non-Oncologist

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Overview

• Epidemiology

• Risk Factors/Genetics

• Screening

• Diagnosis and Treatment

• Consequences of Disease and Treatment

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Why You Should Try and Stay Awake/Not Page Yourself Out

• You will manage patients who have prostrate cancer

• You will know people who have prostate cancer and they will ask your advice

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Case 1 & 2

“My dad had prostate cancer at age 52. What does that mean for me?”

“I am about to turn 74. Do I still need a PSA checked?”

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Introduction

• 192,280 new cases expected in 2009

• 27,360 deaths expected in 2009• 1 in 6 men will develop clinically significant

prostate cancer• 20% of men with prostate cancer die from their

disease

Jemal et al, CA Cancer, 2009

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Copyright ©2009 American Cancer Society

From Jemal, A. et al. CA Cancer J Clin 2009;59:225-249.

FIGURE 1 Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex, United States, 2009

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Familial/Hereditary Prostate Cancer vs. Sporadic Disease

• Diagnosed 6-7 years earlier

• Usually lower grade (less aggressive)

• No differences in PSA, stage, or PSA at recurrence

Nieder et al. Clin Genet , 2003

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Relative risk of Getting Prostate Cancer Compared

No Family History 1

1st degree relative (1) 2.57

Relative diagnosed <65

3.34

Relative diagnosed ≥65

2.35

2+ 1st degree relatives 5.08

2nd-degree relative 1.68

Prostate Cancer RisksProstate Cancer Risks

Nieder et al. Clin Genet, 2003

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Risks and Ethnicity• Risk of Prostate cancer varies with ethnicity

(diagnosis per 1000 people)• African Americans

– 257• Caucasians

– 159• Asian

– 101

Powell IJ et al. Urology 2001

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Screening Recommendations

• American Urologic Association

– Rectal Exams and PSA at age 50

– If a family history:

Rectal Exams and PSA at age 40

Carroll et al. Urology, 2001

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Screening Recommendations

• American Cancer Society

– Rectal Exams and PSA at age 50

– If any family history or African American:Rectal Exams and PSA at age 45

– If a first degree relative:Rectal Exams and PSA at age 45

Smith RA et al. CA Cancer J Clin , 2002

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Screening Recommendations

• American College of Physicians

and

• American College of Preventative Medicine

– No Routine Screening Recommended!

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Screening Recommendations

• We do not know!

• Several Studies are investigating this now.

• Rate of rise more important than absolute number

Nieder et al. Clin Genet, 2003

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Detection

• May be detected due to symptoms, physical findings or through PSA screening

• Most patients in the US are asymptomatic at the time of diagnosis.

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Digital Rectal ExamA – Central zoneB – Fibromuscular zoneC – Transitional zoneD – Peripheral zoneE – Periurethral zone

Seminal VesiclesSeminal Vesicles

ProstateProstate

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Incidence vs. MortalityProstate Cancer in the U.S.

250

200

150

100

50

01975 1980 1985 1990 1995 2000

New

Pro

stat

e C

ance

r Cas

es a

nd D

eath

s(p

er 1

00,0

00 m

en)

New cases

Deaths

(G. Welch, “Should I Be Tested for Cancer?”, 2004)

PSA Screening

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Does Screening Save Lives?

• PLCO Trial

– N=76,693 men (screen vs. no screen)

– After 7 years 50 vs. 44 deaths from PC

– ?Too early

– PSA test too available?

• ERSPC Trial

– N=182,000 (screen vs. no screen)

– At a median of 9 years, a 20% reduction in PC death

– Different patient population than US?

Schroder et al., NEJM 2009 & Andriole et al., NEJM 2009

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Screening Recommendations

“Health care providers can identify those men at an increased risk for developing prostate cancer. These men are candidates for increased surveillance using screening. However, there may be inherent emotional and physical risks involved with diagnosing and treating prostate cancer.”

Nieder et al. Clin Genet, 2003

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Screening: Conclusions• Patients at risk should be identified

– Detailed family history

– Age of diagnosis of family members

• Implications:

– A positive family history does not necessarily change course of disease if that disease actually occurs

• When to stop?

– When life expectancy less than 10 years

Nieder et al. Clin Genet , 2003

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Case 1 & 2

“My dad had prostate cancer at age 52. What does that mean for me?”

“I am about to turn 74. Do I still need a PSA checked?”

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Which is more concerning?• PSA = 3.8 (ULN =4.0)

• PSA rise from 1.2 to 2.6 in 1 year

• PSA rise from 2.0 to 2.5 in 1 year

• PSA rise from 1.5 to 2.8, then decline to 1.5

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“Hey Doc, What Can I take to prevent prostate cancer? I heard

about some things on TV. My family has a lot of prostate cancer and I want to minimize my risk.”

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Prevention

• 5--reductase inhibitors – Finasteride

• Selective inhibitor of type II enzyme• Decreases DHT by about 70%• PCPT (Prostate Cancer Prevention Trial)

– Dutasteride• Inhibits type I and II enzymes• Decreases DHT by >90%• REDUCE trial (Reduction by Dutasteride of Prostate Cancer

Events)

• SELECT Trial (Vitamin E and Selenium)• (Lippman et al, JAMA 2009)

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Histologic Grading• Gleason Grade

– most common grading system

– Tumors are graded from 1-5 with the

– higher number indicates a more aggressive tumor

– Two most predominant patterns added together for a score from 2-10

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StagingStage TNM Description

I (A) T1a (incidental) Localized

II (B) T1b, T1c, T2a,b,c (within prostate)

III (C) T3a (through capsule)

T3b (seminal vesicles)

Locally

Advanced

IV (D) T4 (fixed, invades)

N1, M1 Metastatic

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Prognosis

• PSA at diagnosis

• percent of tumor in a biopsy specimen

• number of positive biopsies

• Gleason Score (aggressiveness of pathology)

• clinical stage

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Treatment

• Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance

• Primary hormone therapy is an option for patients not suitable for definitive local therapy

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Albertsen, P. C. et al. JAMA 2005;293:2095-2101.

Active Surveillance

The chance of dying of prostate cancer decreases with:

•Lower Gleason score•Older age (more competing causes of mortality)

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Definitive Treatment

• Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years– Radical Prostatectomy – External-beam Radiation– Brachytherapy

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Radical Prostatectomy

• Surgical removal of the prostate• May be done with a retropubic, perineal, or

laproscopic approach• Most common side effects are impotence and

incontinence

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Randomized Trial Comparing Surgery and Watchful Waiting

• Early stage prostate cancer (n=695) • Deaths at median 8.2 years of follow-up

– Also less metastasis (RR of Surg 0.60)

• Caveats:– More advanced clinically then current US patients

• Only 5% of men had screen detected PC– Advantage largely in men <65 y.o. Bill-Axelson et al, NEJM, 2005

Deaths from Surgery WW P

Prostate Cancer 30 50 0.01

All causes 83 106 0.04

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External-beam Radiation

• Radiation to the prostate (and pelvis) from outside the body

• Evidence that higher doses are associated with better efficacy

• Newer techniques (such as IMRT) aim to increase radiation delivery and to decrease toxicity

• Most common side effects are impotence and rectal irritation

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Brachytherapy

• Radiation implants placed directly into the prostate under ultrasound or CT guidance

• Very high dose radiation to the prostate with little radiation outside the prostatic bed

• Acute urinary symptoms common, some patients with impotence

• Procedure completed in one day

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“Biochemical Recurrence”

• May be occult local or metastatic disease

• Options include additional local therapy, hormonal treatment or watchful waiting

• Virtually impossible to predict the impact of treatment on survival

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What happens after PSA Recurrence?

• Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse.

• Of the 304, 103 (34 %) developed metastatic disease.

Pound et al, JAMA, 1999Freedland et al. JAMA, 2005

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Natural History of the Disease (circa 1995)

• No patients received hormonal therapy without clinically evident metastatic disease.

• Median time from PSA elevation to metastatic disease was 8 years

• Median time to death after metastatic disease was 5 years.

• Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time.

Pound et al, JAMA, 1999Freedland et al. JAMA, 2005

8 Years 5 years

Biochemical failure Metastasis Death

2 years

RP

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Spinal Cord Compression

• The “rule out MI” of oncology

• Classic Triad

– Back pain

– Incontinence (urine and stool)

– Lower Extremity Weakness

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Case 3 (ER Rotation)• 66 yo male hx of CAD, COPD, OSA, HTN, HLD,

DM and prostate cancer dx 4 years ago.

• “I don’t like doctors – they always give me a new disease”

• “My back hurts – but it always hurts. I get tired when I walk – but I am getting old. Now I’ve been soiling my pants. Don’t ever get old Doc!”

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Spinal Cord Compression

• Maintain a high level of suspicion

• MRI of the Spine

• Dexamethasone – 10 mg IV bolus, then 4 mg q6 hours

• Intervention– Neurosurgical or Radiation

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Metastatic Prostate Cancer

• Prostate Cancer tends to spread to bone and lymph nodes

• However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs.

Therapeutics for Metastatic Prostate Cancer

Tumor volume

& activity

Time

Castration

ChemotherapyDeath

LocalTherapy

Metastatic

Symptomatic

Castration Resistant

Non-Metastatic

Asymptomatic

Castration Sensitive

2nd-line Hormones

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• 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone.

• 1966 Nobel Prize in Medicine

Huggins and Hodges, Cancer Research, 1941

ADT Treatment of metastatic PC

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• Testosterone lowering therapies– Leuprolide and Goserelin GnRH agonists

• Both agents are expensive• May initially result in an increase in testosterone

– Degarelix GnRH antagonist• Similar cost issues without an increase in

testosterone

– Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more.

ADT Treatment of metastatic PC

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Side Effects of ADT Sexual Side Effects

Decreased Libido Erectile dysfunction

Physical changes

Hot Flashes Fatigue

Weight Gain Gynecomastia

Decreased muscle mass Decreased bone mineral density

Hair Changes Decrease size of penis / testis

Breast pain

Metabolic Changes

Lipid changes (may lead to heart disease) Anemia

Increased risk of Diabetes Mellitus

Mental Changes

Lack of Initiative Decreased memory

Emotional lability Decreased cognitive function

Sharifi et al, JAMA 2005Keating et al, JCO 2006

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Androgen Receptor Antagonists

• bicalutamide, nilutamide and flutamide

• Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects

• Different dosing schedules and potency

• Different side effect profile

• Similar activity and all may show “withdrawal response”

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Combined Androgen Blockade

• Combination of anti-androgen with orchiectomy or GnRH-A

• Controversial results

• Not significantly more effective, but more expensive and may add toxicity

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Notable Other Hormonal Agent

• Ketoconazole

• Patients may respond to multiple sequential hormonal manipulations

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Chemotherapy

• Studies prior to 2004 disappointing

• Quality of life measurements

• Difficulty in evaluating response

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Mitoxantrone + Glucocorticoids

• Inhibits RNA and DNA synthesis and intercalates DNA

• Improved quality of life when compared to Glucocorticoids alone (No survival advantage)

• FDA approval for the palliation of painful lesions in 1996

Tannock, JCO, 1996Kantoff, JCO, 1999

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Docetaxel: Preclinical Data

• Docetaxel inhibits the growth of prostate cancer cell lines LNCaP, PC3, and DU145.

• Mechanism of Action:

– Disruption of the cellular microtubule network

• promotes assembly of stable microtubules

• inhibits disassembly

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TAX327A Multicenter, Randomized Phase III Study of Intermittent

Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with

Hormone-Refractory Prostate Cancer

Castration Resistant ProstateCancer

RA

ND

OM

IZE

RA

ND

OM

IZE

Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily

Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily

Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily

1006 Patients EnteredTannock, NEJM, 2004

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Should I get Chemo? I heard it only improves survival by 3 months.

What’s the point?

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TAX 327: Survival Advantage Only Shown for Q3W Docetaxel

Mediansurvival Hazard

(mos) ratio P-value

D 3wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Months

Pro

bab

ilit

y o

f S

urv

ivin

g

0 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 wkly

Docetaxel wkly

Mitoxantrone

Tannock, NEJM, 2004

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Its More than a 3 month Improvement!

• Quality of Life

– Better on docetaxel / prednisone than mitoxantrone prednisone

• Is it really just 3 months?

– Compared against an active agent (not against placebo)

– Cross over allowed• If no patients on the mitoxantrone arm had gone on to get

docetaxel at PD, the survival difference might have been much greater.

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Life on Chemotherapy

• Overall, treatment is well tolerated

• Patients often get treatment and continue to work

• Administration once every 3 weeks

• Treatment length is indefinite

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On the Horizon

• The next 1-2 years likely will see several significant changes in the treatment of metastatic prostate cancer

• Therapeutic Cancer Vaccines (Provenge)

• New Hormonal Agents (Abiraterone)

Therapeutics for Metastatic Prostate Cancer: A lot Can Change in 6 months

Tumor volume

& activity

Time

Castration

ChemotherapyDeath

LocalTherapy

Metastatic

Symptomatic

Castration Resistant

Non-Metastatic

Asymptomatic

Castration Sensitive

2nd-line Hormones

Provenge

Cabazitaxel

Abiraterone

Abiraterone?

MDV3100?

MDV3100?

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Therapeutic Cancer Vaccine: Sipuleucel-T

Day 1Leukapheresis

Day 2-3sipuleucel-T is manufactured

Day 3-4Patient is infused

Apheresis Center Company (Dendreon) Doctor’s Office

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IMPACT Overall Survival: Phase III TrialIMPACT Overall Survival: Phase III Trial

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Per

cent

Sur

viva

l

Survival (Months)

P = 0.032 (Cox model)HR = 0.775 [95% CI: 0.614, 0.979]

Median Survival Benefit = 4.1 Mos.

Sipuleucel-T (n = 341)Median Survival: 25.8 Mos.

Placebo (n = 171)Median Survival: 21.7 Mos.

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Vector Based Vaccines

Infect Antigen Presenting Cells (APCs)

APCs activate T-cells

T-cell Mediated Tumor Destruction

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The median OS was 24.5 mos for vaccine compared to 16.0 mos for placebo (p=0.016)

Ligand

1. AR Binding Affinity• DHT ~ 5nM• Bicalutamide ~160 nM• MDV3100 ~35 nM

2. Nuclear Import• DHT: ++++• Bicalutamide: ++++• MDV3100: ++

3. DNA Binding• DHT: ++++• Bicalutamide: ++• MDV3100: -

4. Coactivator recruitment• DHT: ++++• Bicalutamide: ++• MDV3100: -

MDV3100: MODERN Androgen Receptor Antagonist

1

2

Chen Y, Lancet Oncol, 2009

3

4

DNA

POL II

HSP

90

LBD

HD

DBD

NTD

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BACK TO THE FUTURE: Waterfall Plot of Best Percent PSA Change from Baseline

Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75)

62% (40/65)

>50% Decline

51% (38/75)

>50% Decline

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Bisphosphonates

• Commonly used to treat hypercalcemia, treat osteoporosis and to decrease bone complications in cancer patients.

• Zoledronate (I.V. bisphosphonate) approved for the prevention of bone complications in metastatic CRPC.

• May be of value in patients with risk of osteopenia on long-term hormonal therapy.

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Zoledronate Reduced the Proportion (%) of Patients With Skeletal Related Events (SREs)

Perc

en

t of

pati

en

ts

N =

P = . 021

Zoledronate

%

%

33

44

0

10

20

30

40

50

Placebo

214 208

Saad et al., JNCI, 2002

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Selected Side Effects

• Renal dysfunction• Osteonecrosis of the Jaw (ONJ)

– Similar to osteoradionecrosis– Poorly healing bone lesions following invasive dental procedures– Multifactorial

• Very frequent micro trauma increased bone turn over• Thin membrane• Diverse oral flora• Single blood supply in mandible (lower jaw) vs. dual blood supply in

maxilla (upper jaw). Therefore because of its anti-angiogenic properties of zoledronate ONJ more frequent in mandible

– All patients should see dentist prior to initiating long term IV bisphosphonates

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Future Directions• Does prevention work?

• Which patients need treatment? And what treatment?

• Adjuvant therapy for high risk patients

• Timing of hormonal therapy

• Multimodality therapy

• New agents / combinations