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Paul F. Schellhammer, MD
Professor of Urology
Eastern Virginia Medical School
Norfolk, Virginia
Treater to TargetReflections of a Survivor Participant
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http://surf-1.org/uploads/ViewsFromTheOtherSide.pdf
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“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)
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Participant
Surgery Open R.P.; Bilateral SQ Mastectomy Clinical Trials
Radiation Salvage; Prostate Bed / Breast Stereotactic (Cyberknife) L1,3 ?Radium 223
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Participant
Hormonal Agents LHRH Agonist Bicalutamide Dutasteride Ketokonazole
Estradiol T. Dermal Abiraterone +P Enzalutamide
Bone Protective Agents Zoledronic Acid Denosumab
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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
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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
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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
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Radical Prostatectomy + PND
pT2, N0 ,PSA < 0.1
Gleason 4+3 (+5) = 4+4
Margin Negative
Organ Confined
High Grade
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Path Variation
Initial pT2 margin negative Gleason 4+3 (5) = 4 + 4
Reread for Trial pT3a margin positive Gleason 3 + 4
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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.)
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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
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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
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Clinical Trial Experience
Time intense Testing and exam intense Scheduling rigidity Geographically inconvenient / impossible
ENDPOINTS – PSA and derivatives not adequate – Survival Necessary
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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
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Estrogen
Role in active therapy – overlooked
Role in modifying A/E of ADT - underutilized
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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
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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
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Orchiectomy – LH & FSH
Estrogen – LH & FSH
FSH receptors reside on malignant cells & neo-vascular network
Urologic Oncology: Seminars 31,1403,2013
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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Androgen-Dependent PCa CRPC
AR “involved”
AR loss
Hypersensitive PathwayPromiscuous PathwaySteroidogenic PathwaySplice Variants PathwayOutlaw Pathway
AntiandrogensAndrogen Depletion
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CRPC M+
Abiraterone Enzalutamide Sip.T Stereotactic XRT Radium 223
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CRPC M+
Abiraterone + Prednisone T Enzalutamide AR
Fatigue; B.P. ??Glucocorticoid receptor (Hijack)
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Sip T:Muscle Cramps - ca++
“Antigen Spreading / Cascade”
Stereotactic XRT (9 gy x 3 days)(Cyberknife :Accuray)
280+ beamlets : 1 hr
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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
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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
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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
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Survivor War Cure
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Nixon Declares “War on Cancer”
Nixon Signing the National Cancer Act in 1972
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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
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“The people who do best are those who don’t battle the disease but
dance with it.”
- George Fisher, MD, PhD
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Cure
Curare
To Care For
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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
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“ 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