"Creating a Prostate Cancer Center of

Excellence"Paul Sieber MD FACS

Lancaster Urology

ADT Clinic• Why 1. Consistency of care 2. Improved outcomes 3. Better economics• What does it take 1. Discipline 2. Mid-level providers 3. Planning• Who cares 1. Insurers 2. Patients• How 1. Implementation

Bone Clinic

Journal of UrologyFebruary 1997

Osteoporosis after Orchiectomy for Prostate Cancer

Harry W Daniell

UC Davis, Department of Family Practice First article attributing orchiectomy with

accelerated osteoporosis and questions risks to long term survivors.

ADT and Fracture Risk

Author Population

N FractureIncidence

Time

Smith Pharmacybenefit

3779 15.1% 22 months

Oefelein Community

181 20% 10 years

Shahinian SEER 14,394 19.4 1-5 years

Krupski Medicare 716 45.5% 7 years

Melton Rochester 429 73% 15 years

ADT Is Associated With Fracture

• In men surviving at least 5 years after diagnosis:– Of those receiving ADT, 19.4% experienced a fracture– Of those NOT receiving ADT, 12.6% experienced a fracture– ADT resulted in an excess risk of fracture of 45%

Shahinian VB, et al. N Engl J Med. 2005;352:154-164.

No ADT (n = 32,931)GnRH agonist, 1–4 doses (n = 3763)GnRH agonist, 5–8 doses (n = 2171)GnRH agonist, ≥ 9 doses (n = 5061)Orchiectomy (n = 3399)

Years After Diagnosis2 3 4 5 6 7 8 9 101

Un

ad

juste

d F

ractu

re-F

ree

Su

rviv

al (%

)

0

100

90

80

70

60

50

40

30

20

10

ADT-Related Fracture-Free Survival

Fractures in Men Receiving ADT and Survival

Oefelein MG, et al. J Urol. 2002:168:1005-1007; Department of Health and Human Services. A report of the Surgeon General. 2004.

0 20 40 60 80 100 120 140 160 180 200Months

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0C

um

ula

tive P

rop

ort

ion

S

urv

ivin

g

History of fracture (n = 24)No history of fracture (n = 171) P = 0.04

• In men receiving ADT for prostate cancer, median overall survival was reduced in those who sustained a skeletal fracture since diagnosis of prostate cancer (121 vs 160 months, P = 0.04)

• Skeletal fracture was a negative predictor of survival (Relative Death Risk = 7.4, P = 0.007)

Bone Clinic Protocol

• 1. All patients on ADT seen by mid-level at least yearly

• 2. All patients undergo DEXA• 3. All patients have metabolic studies• 4 All patients assessed/counseled for

risk: FRAX,fall,glasses,smoking,EtOH consumption,calcium/vitamin D

Screening for Bone Loss

• DXA(Dual X-ray Absorptiometry) = Gold Standard

• Total hip, femoral neck and lumbar spine standard areas of interest

• Heel ultrasound, finger or forearm DXA, and quantitative CT other options but numerous weaknesses

Metabolic workup

• CMP, CBC, Vitamin D minimum• Stone formers 24 hour urine• Options; TSH, evaluate for GI

malabsorption, Endocrine consult

TREATMENT DECISION

• 2 clinical trials with level 1 evidence of both BMD and fracture reduction

• Patient population included men< 70 with osteopenia and >70 without regard to BMD

• NOF recommends treat osteoporosis follow FRAX for others

• What is risk level for osteopenics on ADT

BMD vs Fracture Rate & Incidence

>1.0 1.0 to 0.5 0.5 to 0.0 0.0 to -0.5

-0.5 to -1.0

-1.0 to -1.5

-1.5 to -2.0

-2.0 to -2.5

-2.5 to -3.0

-3.0 to -3.5

<-3.50

5

10

15

20

25

30

35

40

45

50

0

50

100

150

200

250

300

350

400

450

Fracture Rate

No. of fractures

BMD

Fra

ctu

re R

ate

No

. of F

ractu

res

BMD

Minimum treatment

• Ensure adequate calcium/vitamin D intake 1200/800

• Vitamin D >30• Reduce alcohol, smoking cessation,

and weight bearing exercises• Fall reduction strategies

Pharmacologic Therapy

• 1. Prolia-RANK ligand monoclonal antibody • 2.

Aledronate(Fosamax).Risedronate(Actonel)

• 2. Zoledronic acid(Zometa,Reclast)• 2.Raloxifene(Evista)• 3.? Teriparatide(Forteo) blackbox warning

with radiation therapy• 3. Calcitonin(Miacalcin) no data in men

Clinical Impact of Low Testosterone Levels: Two Peer-Reviewed Articles

Perachino et al – BJUI. 2009

Morote et al – Urology. 2007

Testosterone Escapes OccurFrequently During LHRH Agonist Therapy

Adapted from Morote J et al. J Urol. 2007;178:1290–5

Serum testosterone

Survival-Free of AIP According toSerum Testosterone Behavior

Adapted from Morote J et al. J Urol. 2007;178:1290–5

Testosterone increases

Group 1: <20 ng/dL

Group 2: 20–50 ng/dL

Group 3: >50 ng/dL

0 24 48 72 96 120 144 168 192 216 240

Months under ADT

0.0

0.2

0.4

0.6

0.8

1.0

Group 3 (72 months)

Group 2 (90 months)

P=0.0207

Group 1 (106 months)

Cu

mu

lati

ve s

urv

ival fr

ee o

f P

SA

pro

gre

ssio

n

AIP, androgen-independent progression

Higher 6-Month Testosterone Levels Increase Risk of Death by 1.33 Times

Variable Coefficient (SEM)

Coefficient/SEM Hazard ratio(95% CI)

P value

Age, years 0.0359 (0.0200) 1.795 1.037(0.996–1.078) 0.08

Gleason score 0.3301 (0.1002) 3.295 1.391(1.141–1.696) <0.01

Ln (6-month PSA level) 0.2690 (0.0492) 5.468 1.309

(1.187–1.443) <0.01

(6-month testosterone)2 0.2874 (0.1190) 2.415 1.333

(1.053–1.687) <0.05

Predictors of survival probability (Cox regression model)

Perachino M et al. B J U Int 2010; 105(5); 648-51

SEM, standard error of the mean; Ln, natural logarithm

Goserelin 10.8 mg every 3 months; bone-only prostate cancer patients (N=117)

Bone Clinic

ADT Clinic

21

Urologists Provided Most Overall Healthcare Services to Patients with Prostate Cancer Over the Course of Disease Progression

% P

ros

tate

Ca

nce

r H

ealt

h S

ervi

ces

Initial Care Continuing Care

End of Life Care

Overall Care

*Medical oncology and hematology/oncology†Internal medicine, family practice and general practiceSkolarus 2010 J Urol 184:2279-2284

0

10

20

30

40

50

60

36.9

56.5

29.7

45.2

27.4

5.5 5.7

14.4

2.6

9.8

31.4

9.6

3.25.5

9.3

5.1

25.7

Urologists

Radiation oncologists

Medical oncologists*

Primary care provider

Other†

• Initial care: first 12 months after diagnosis

• Continuing care: between initial and end of life

• End of life care: final 12 months of life

Abbreviation: LHRH=luteinizing hormone-releasing hormone.

Natural History of Prostate Cancer

• Typical presentation of patients as they move through the different stages. The line represents level burden of disease. Time is not proportional

Under the care of ONCOLOGIST

Castration Sensitive

Asymptomatic

Non Metastatic

Castration Resistant

Metastatic

Symptomatic

Local Therapy

Androgen Deprivation

Therapies After LHRH Agonists and Antiandrogen

Chemotherapy

Post Chemo

Death

New Paradigms

1.Bone Agents Xgeva ?Radium 223 2. Provenge 3. Abiraterone 4. Enzulutamide

Metastatic Disease

• Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer.

• Yu EY J Urol July 2012• 31% of men with apparent M0 disease

were M1

Bone Metastasis

• Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.

Smith MR et al Lancet Jan 2012 396 23% of men with apparent MO

disease were M1

Provenge SurvivalBaseline PSA

<22.1 >22.1-50.1 >50.1-134.1

>134.1

Provenge OS

41.3mon 27.1mon 20.4mon 18.4mon

Control OS 28.3mon 20.1mon 15.0mon 15.6mon

Chodak G ASCO 2012 Abstract 4648

Prior SRE Associated with Greater Risk of Subsequent SRE

No prior SRE Prior SRE0

0.5

1

1.5

2

2.5

3

Saad F Clin GU Cancer 5:390-6

ADT Clinic

• Bone Clinic plus 1. ROS for side effects 2. Additional labs include annual CBC,CMP,HgbA1c,Lipid profile 3. PSA doubling time if appropriate 4. Update to PCP

Keys to Success

• Physician champion• Motivated mid-level as well• Group Buy-in• Make it easy for group members

William Penn

“Liberty without discipline equals chaos

Discipline without liberty equals slavery”