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Paul F. Schellhammer, MD Professor of Urology Eastern Virginia Medical School Norfolk, Virginia Treater to Target Reflections of a Survivor Participant

My Prostate Cancer Story by Paul Schellhammer

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With permission of Dr. Schellhammer this slide deck should be interesting to any PCa patient. Dr. Schellhammer is a former president of the American Urological Association and a leading authority on prostate cancer. He has fought i long battle. He and his colleague, Paul Lange operated on each other and had vastly different results.

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Page 1: My Prostate Cancer Story by Paul Schellhammer

Paul F. Schellhammer, MD

Professor of Urology

Eastern Virginia Medical School

Norfolk, Virginia

Treater to TargetReflections of a Survivor Participant

Page 2: My Prostate Cancer Story by Paul Schellhammer

http://surf-1.org/uploads/ViewsFromTheOtherSide.pdf

Page 3: My Prostate Cancer Story by Paul Schellhammer

“Doctors prescribe medicines of which they know little,

to cure diseases of which they know less,

in humans of whom they know nothing.”

Voltaire (1694-1778)

Page 4: My Prostate Cancer Story by Paul Schellhammer

Participant

Surgery Open R.P.; Bilateral SQ Mastectomy Clinical Trials

Radiation Salvage; Prostate Bed / Breast Stereotactic (Cyberknife) L1,3 ?Radium 223

Page 5: My Prostate Cancer Story by Paul Schellhammer

Participant

Hormonal Agents LHRH Agonist Bicalutamide Dutasteride Ketokonazole

Estradiol T. Dermal Abiraterone +P Enzalutamide

Bone Protective Agents Zoledronic Acid Denosumab

Page 6: My Prostate Cancer Story by Paul Schellhammer

Personal PSA History

Date PSA ng/ml Hx

1991 2.0 -0-

1993 2.02 -0-

1994 2.78 -0-

1995 2.32 -0-

1997 1.07Proscar

6/00 2.74Proscar

8/00 6.68 -0-

Bx=4+3

50 Yr Old

Page 7: My Prostate Cancer Story by Paul Schellhammer

Risk Directed Screen Strategy - T3/4

PSA @ age 44 – 50 (Malmo)

> 0.6 (50% of population) will detect 80% of T3/4

> 1.1 (20% of population) will detect 67% of T3/4

≥ 1.5 (10% of population) will detect 50% of T3/4

Nature Review 6:301, 2009

Page 8: My Prostate Cancer Story by Paul Schellhammer

Surgical Pros (Relative)

Removal of 2-10( or more) X 109 malignant cells

“Definition” pathology ( LN; SV; Margin; Grade)

Direction / rationale for adjuvant therapy

Eliminate risk of second tumor in retained organ(nadir +2)

Eliminate risk of XRT induced rectal/bladder cancer

Page 9: My Prostate Cancer Story by Paul Schellhammer

Radical Prostatectomy + PND

pT2, N0 ,PSA < 0.1

Gleason 4+3 (+5) = 4+4

Margin Negative

Organ Confined

High Grade

Page 10: My Prostate Cancer Story by Paul Schellhammer

Path Variation

Initial pT2 margin negative Gleason 4+3 (5) = 4 + 4

Reread for Trial pT3a margin positive Gleason 3 + 4

Page 11: My Prostate Cancer Story by Paul Schellhammer

Personal Post RP PSA

11/00 R.P. 6/01 <0.01 12/20/01 .14 2/14/02 .21 5/21/02 .33

PSA DT = 4 mos Salvage EBRT + AD (6 mos.)

Page 12: My Prostate Cancer Story by Paul Schellhammer

Personal Post Salvage EBRT + AD PSA 6/02 EBRT & AD 9/02 .00 1/05 .02 4/05 .04 8/05 .09 1/06 .31 3/06 .70 6/06 .85

PSA DT = 3.3 mos Start Clinical Trial – Lapatinib (TK1-dual)

ECOG-5803

Page 13: My Prostate Cancer Story by Paul Schellhammer

Personal Post – Lapatinib PSA

6/06 Lapatinib 7/06 0.72 9/06 0.91 11/06 1.31 1/07 1.3 2/07 2.3 3/07 4.0 (confirmed)

PSA DT = 8 mos CAB + Avodart

Page 14: My Prostate Cancer Story by Paul Schellhammer

Clinical Trial Experience

Time intense Testing and exam intense Scheduling rigidity Geographically inconvenient / impossible

ENDPOINTS – PSA and derivatives not adequate – Survival Necessary

Page 15: My Prostate Cancer Story by Paul Schellhammer

Personal Post CAB + Avodart

3/07 4.0 5/07 0.63 9 months to nadir 7/07 0.29 detectable nadir 10/07 0.29 12/07 0.34 stop Casodex (AAW)

4/08 0.38 estradiol TD

T < 20 ng/ml

Page 16: My Prostate Cancer Story by Paul Schellhammer

Estrogen

Role in active therapy – overlooked

Role in modifying A/E of ADT - underutilized

Page 17: My Prostate Cancer Story by Paul Schellhammer

LHRH: The Backbone of Hormonal Therapy

Hormone Therapy % of Patients

LHRH analog only, continuous 38.2CAB, continuous 25.5LHRH analog, intermittent 17.3CAB, intermittent 9.2Orchiectomy only 5.0Antiandrogen only 2.75-alpha-reductase inhibitor only 1.4

Diethylstilbestrol only 0.8Abbreviation: CAB=complete androgen blockade.

Source: Survey of 128 physicians who treat a total of 10,741 prostate cancer patients monthly, conducted in August 2008; Mattson Jack DaVinci, The Mattson Jack Group, Inc.

First-Line Hormone Therapy, Prostate Cancer, United States, 2008

Page 18: My Prostate Cancer Story by Paul Schellhammer

Estrogens ReduxFinal Conclusions of VAURG Trials

“We suggest that the equivalence of the 1.0 and 5.0 mg doses plus the apparent superiority of 5.0 mg DES over orchiectomy alone in retarding cancer growth indicated that DES acts directly on the cancer cells in addition to inhibiting testosterone secretion.”

Byer

NCI Mongr 1998;7:165-170

Page 19: My Prostate Cancer Story by Paul Schellhammer

Orchiectomy – LH & FSH

Estrogen – LH & FSH

FSH receptors reside on malignant cells & neo-vascular network

Urologic Oncology: Seminars 31,1403,2013

Page 20: My Prostate Cancer Story by Paul Schellhammer

Traditional LhRh Agonist / Antagonist

T

♦ Erectile dysfunction♦ Sarcopenia♦ Weight gain♦ Diabetes♦ Decreased Libido

E

♦ Osteoporosis♦ Lipid changes♦ Hot flashes♦ Cognitive dysfunction♦ Decreased Libido

No aromatization

Page 21: My Prostate Cancer Story by Paul Schellhammer

Traditional LhRh Agonist / Antagonist

T

♦ Erectile dysfunction♦ Sarcopenia♦ Weight gain♦ Diabetes♦ Decreased Libido

E

♦ Osteoporosis♦ Lipid changes♦ Hot flashes♦ Cognitive dysfunction♦ Decreased Libido

No aromatization

Page 22: My Prostate Cancer Story by Paul Schellhammer

Behav Brain Res. 2012 Jan 15;226(2):456-64

, et al.

¨ Estradiol facilitates recovery of REM sleep

¨ Daytime fatigue secondary to night hot flashes and sleep disturbance may be mitigated by supplemental E in men receiving ADT

Page 23: My Prostate Cancer Story by Paul Schellhammer

In the castrated rat, mounting, a proxy for libido in the human male, is restored with E2 delivered immediately or sometime later

Physiology and Behavior submitted for publicationWibowo et. Al.

Page 24: My Prostate Cancer Story by Paul Schellhammer

Gonadal Steroids and Body Composition, Strength, and Sexual Function in MenJoel S. Finklestein, et. al.

Sexual Function is regulated by T and E

NEJM - Sept. 12, 2013369:11, p. 1011

Page 25: My Prostate Cancer Story by Paul Schellhammer

Estrogen Patch TrialUnited Kingdom

Newly diagnosed or relapsing patients with locally advanced or metastatic prostate cancer

2200

RandomizationInvestigational

Arm

Transcutaneous estrogen patches

indefinitely

LHRH analogues given as per local practice indefinitely

Control Arm

Primary endpoint: Overall SurvivalSecondary Endpoint: Castrate T, PSA failure, Toxicity, QOL, Prostate Specific Mortality

Page 26: My Prostate Cancer Story by Paul Schellhammer

Patch Trial BMD Study

Lumbar Spine

1 Year 2 Years p=.014

• LHRHa -1.3% -2.3%

• TD Estradiol +9.3% +4.9%

ASCO 2014

Page 27: My Prostate Cancer Story by Paul Schellhammer

Participant ( Castration Resistant PC )CRPC – M0 PSA Estradiol (T.Dermal) 2008 1

CRPCM+ L3 2012 10 Clinical Trial (Abby/MDV) 6-12/12 20 Stereotactic XRT – L3 3/13 10 stable Sip.T* 7/13 10

5

M+ L3, L1 11/13 4 Stereo XRT – L1 1/14 2

3/14 1.5 Future: Stereo XRT : Radium 223 : CTX

PSADT13m

Page 28: My Prostate Cancer Story by Paul Schellhammer

What is Serum Castrate T ?A Moving Target

< 50 ng/ml – Traditional FDA cut point (RIA - LHRH assay limitation)

<20 ng/ml - Orchiectomy cut point more sensitive assay

<1 or 0.1 ng/ml – Ultrasensitive assay(CL-NS)

Furthermore, serum T ≠ tissue T

Page 29: My Prostate Cancer Story by Paul Schellhammer

Time to Androgen Independence(3 Consecutive Rising PSA Levels)insert

0Testosterone (ng/dL)

106

90

72

20

40

60

80

100

120

< 20 ng/dL

20-50 ng/dL

> 50 ng/dL

P = .0207

AIP

C S

urv

iva

l (m

o)

Morote et al. J Urol 2007;178:1290-1295

Page 30: My Prostate Cancer Story by Paul Schellhammer

626 patients ADT for BCR

Median Time to CRPC

T<20 N.R. (50%)

T 21-50 6.4 yrs (45%)

T>50 4.2 yrs ( 5%)

Klotz: AUA 2014 MP 74-01

Page 31: My Prostate Cancer Story by Paul Schellhammer

Expression of Steriodogenic ENZ Transcipts in Metastatic Tissue

Not only is androgen present in the tissue, but enzymes needed to generate androgens are there – it is self-sustaining

Montgomery R et al. Cancer Res 2008;68(11):4447-4454

Page 32: My Prostate Cancer Story by Paul Schellhammer

Androgen-Dependent PCa CRPC

AR “involved”

AR loss

Hypersensitive PathwayPromiscuous PathwaySteroidogenic PathwaySplice Variants PathwayOutlaw Pathway

AntiandrogensAndrogen Depletion

Page 33: My Prostate Cancer Story by Paul Schellhammer

CRPC M+

Abiraterone Enzalutamide Sip.T Stereotactic XRT Radium 223

Page 34: My Prostate Cancer Story by Paul Schellhammer

CRPC M+

Abiraterone + Prednisone T Enzalutamide AR

Fatigue; B.P. ??Glucocorticoid receptor (Hijack)

Page 35: My Prostate Cancer Story by Paul Schellhammer

Sip T:Muscle Cramps - ca++

“Antigen Spreading / Cascade”

Stereotactic XRT (9 gy x 3 days)(Cyberknife :Accuray)

280+ beamlets : 1 hr

Page 36: My Prostate Cancer Story by Paul Schellhammer

Stereotactic body radiation therapy in the treatment of oligometastatic prostate cancerKamran A Ahmed, et. al.

Excellent LC Undet. PSA in 50%

Frontiers in Oncology - Jan. 22, 2013Vol.2 P.1

Page 37: My Prostate Cancer Story by Paul Schellhammer

Clinical Trial: Biologic Profile

Vertebral Bone Biopsy Adenocarcinoma PSA, PAP 4+

AR 4+SRC weakly +Neuro / Endo -Splice Variant -

Bone Marrow AR amplification No Malignant Cells

Page 38: My Prostate Cancer Story by Paul Schellhammer

Evolving Concepts

Sequencing – Darwin Wins

Combinations – Overcome Adaptation ? PO in primary

Immune System – Flexible, Adaptable Durable, Personalized, Dynamic

“Keeps Pace with the Tumor” Antigen Spreading

Page 39: My Prostate Cancer Story by Paul Schellhammer

Survivor War Cure

Page 40: My Prostate Cancer Story by Paul Schellhammer

Nixon Declares “War on Cancer”

Nixon Signing the National Cancer Act in 1972

Page 41: My Prostate Cancer Story by Paul Schellhammer

The War on Cancer may have to be won by redefining the meaning of Victory –

The Emperor of all MaladiesSiddhartha Mukherjee

For some prostate cancers this may involve a negotiation whereby a patient learns to live long and well with cancer

Thrival / Survival

Page 42: My Prostate Cancer Story by Paul Schellhammer

“The people who do best are those who don’t battle the disease but

dance with it.”

- George Fisher, MD, PhD

Page 43: My Prostate Cancer Story by Paul Schellhammer

Cure

Curare

To Care For

Page 44: My Prostate Cancer Story by Paul Schellhammer

Prostate Cancer

Is often not cured (completely eradicated) Can be reduced to a chronic disease which

may be controlled Mimics life with slow attrition but with a

specific “named” focus Patients can be considered participants and

partners with their physicians. Active surveillance warrants discussion,

consideration, and further study

Page 45: My Prostate Cancer Story by Paul Schellhammer

“ I Have Today ”

My cancer didn’t make life uncertain; it exposed the uncertainty of life. In losing my sense of tomorrow, I appreciated what time I had – in a way I never had before – and found today.

Wendy Harpham, MD