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

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

“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)

Participant

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

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

Participant

Hormonal Agents LHRH Agonist Bicalutamide Dutasteride Ketokonazole

Estradiol T. Dermal Abiraterone +P Enzalutamide

Bone Protective Agents Zoledronic Acid Denosumab

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

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

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

Radical Prostatectomy + PND

pT2, N0 ,PSA < 0.1

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

Margin Negative

Organ Confined

High Grade

Path Variation

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

Reread for Trial pT3a margin positive Gleason 3 + 4

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.)

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

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

Clinical Trial Experience

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

ENDPOINTS – PSA and derivatives not adequate – Survival Necessary

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

Estrogen

Role in active therapy – overlooked

Role in modifying A/E of ADT - underutilized

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

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

Orchiectomy – LH & FSH

Estrogen – LH & FSH

FSH receptors reside on malignant cells & neo-vascular network

Urologic Oncology: Seminars 31,1403,2013

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

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

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

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.

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

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

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

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

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

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

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

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

Androgen-Dependent PCa CRPC

AR “involved”

AR loss

Hypersensitive PathwayPromiscuous PathwaySteroidogenic PathwaySplice Variants PathwayOutlaw Pathway

AntiandrogensAndrogen Depletion

CRPC M+

Abiraterone Enzalutamide Sip.T Stereotactic XRT Radium 223

CRPC M+

Abiraterone + Prednisone T Enzalutamide AR

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

Sip T:Muscle Cramps - ca++

“Antigen Spreading / Cascade”

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

280+ beamlets : 1 hr

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

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

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

Survivor War Cure

Nixon Declares “War on Cancer”

Nixon Signing the National Cancer Act in 1972

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

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

dance with it.”

- George Fisher, MD, PhD

Cure

Curare

To Care For

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

“ 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