Post on 16-Jan-2017
transcript
2016 Urology UpdatesOncologist’s Perspectives:
“Focus on Prostate Cancer”
Mohamed Abdulla M.D.Prof. of Clinical Oncology
Cairo University
Sudanese Urology Association Annual MeetingCorinthia Hotel – KhartoumFriday, 25/03/2016
Basic Facts:
• 2nd most cancer in men (27%).• 1/6 men prostate cancer.• 2nd leading cause of cancer related death in men
(10%).• World Wide: > 1000000 new case annually.• > 300000 death/year.• Closely related to age & Androgens• Wide geographic and ethnic variations.• Pre- and post-PSA era.
MJA 2008; 189: 315–318
Prostate Cancer: The Story:
Dr. Huggins(1941): Orchiectomy and DES Effective Disease Control Noble Price 1966.
Dr. Shcally et al: (1977): LHRH Analogue Effective disease Noble Price
Prostate Cancer: Best Identity:
Natural History
Androgen Biosynthesis
Androgen Receptor Activity
Aggressiveness
AndrogenicDisease
HypothalamusLHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an Androgenic Disease:
LHRH Analogue
Bilateral Orchiectomy
Prostate Cancer:Natural History:
Locoregional Disease
Biochemical Failure
Metastatic “Sensitive”
Metastatic “Refractory”
Deat
h
TIME
Tum
or B
urde
n
Risk Stratification
A.S.Local Therapy+/- Hormonal
Local Therapy+/- Hormonal
Hormonal+/- Others
2nd HormonalOthers
Prostate Cancer:Disease Progression:
Abnormal Cellular
Proliferation
Androgen Receptor Activity
Physiological Pathway Axis
Other Sources& Hormone
Independent Proliferation
Abnormal Receptor Activity
Disease Progression
Steroidogenesis & Prostate Cancer :
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone
Prostate = Androgen Self Sufficient Organ
NTD DBDHingeLBD
Nuclear & Steroid
Superfamily
Androgen
EstrogenGlucocorticoidMineralocorticoid
Progesterone
Constitutively Active DNA
Promoter Gene
Androgen N/C
HSP
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Structure”
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”
Testosterone DHT5@ Reductase
DHT+AR+HSP Active AR
Active AR Active AR Active AR
Proliferation
Angiogenesis
Metastases
AREAR
Degraded
Genomic ActivityPSA, IGF, …
Testosterone 5 α Reductase DHT + AR (LBD)
PI3KCaveolae
RTKGPCR
AR Activation & Dimerization
HSP
AKTSrc
MAPKERK1/2
Nuclear Transcription Factors
• Proliferation, Angiogenesis, …• No AR Degradation.
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”
Non Genomic Activity
Androgen Receptor in Prostate Cancer:
Tips & Tricks for Daily Practice
Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27
Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27
Long Term ADT > Short Term ADT
Biochemical Failure Free Survival
OAS
Metastasis Free Survival
Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27
Practice Changing Guidelines:
Primary Hormonal Manipulation:1. Surgical Castration:
Bilateral Sub-Capsular
Orchiectomy
1 2 3 4 50
100
200
300
Serum Testosterone Fol-lowing Bilateral Or-
chiectomy
Days following Bilateral orchiectomySe
rum
Tes
tost
eron
e (n
g/m
l)
Primary Hormonal Manipulation:2. Medical Castration:
PituitaryLHRH Agonist LHRH Antagonist
+ LH & FSH
+ Testes
+ Testosterone
Neg
ative
Fee
d Ba
ck M
echa
nism
+ Symptoms FLARE
3 –
4 W
eeks
Castrate Level
Castrate Level
72 –
96
Hour
s
Disease Control
Primary Hormonal Manipulation:Medical Castration Surgical Castration Items
GnRH Agonists Bilateral Sub-Capsular Orchiectomy
Procedure
Reversible Irreversible Castration
3-4 weeks Rapidly Achieved Castrate Level of Testosterone
Elective Emergency Application
Yes no Flare
May be Required Not Required Prior Anti-Androgens
More Less Cost
More Preferred Less Preferred Psychological Element
Discussion
Surgical versus Medical Castration?
Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132:566.
Meta-AnalysisOf 1908 Patients
Surgical Castration
Medical Castration
EquivalentOASPFSTTF
Maintaining testosterone <32 ng/dL was associated with significantly longer mean survival free of CRPC compared with levels >32 ng/dL
Survival free of CRPC in 73 patients with non-metastatic prostate cancer receiving ADT.*Patients with three serum testosterone determinations <32 ng/dL; †Patients with breakthrough increases >32 ng/dL.Serum testosterone was measured every 6 months. ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer.Figure adapted from Morote J, et al. J Urol 2007;178:1290–5.
100
80
60
40
20
0
Cum
ulat
e su
rviv
al fr
ee o
f CRP
C (%
)
0 50 100 150 200 250
Follow up (months)
>32 ng/dL†
<32 ng/dL*
p=0.0258
Testosterone ≤30 ng/dL has been associated with longer overall survival versus >30 ng/dL
VariableTestosteroneContinuous variable*
Testosterone<50 ng/dL
(n=94)
Testosterone≤30 ng/dL
(n=56)
Testosterone<20 ng/dL
(n=25)Time to progressionHR (95% CI)p value
1.76 (0.62–5.01)0.29
0.84 (0.52–1.37)0.51
0.76 (0.46–1.26)0.30
0.58 (0.30–1.15)0.12
Overall survivalHR (95% CI)p value
2.47 (0.70–8.75)0.16
0.74 (0.42–1.33)0.32
0.45 (0.22–0.94)0.034
0.19 (0.04–0.76)0.020
*Testosterone was considered a continuous (values were measured on a continuous scale) not categorical variable in this analysis. CI=confidence interval; HR=hazard ratio.Bertaglia V, et al. Clin Genitourin Cancer 2013;11:325–30.
Maintaining testosterone levels at <20 ng/dL correlated with improved duration of response to ADT*
*Investigators defined CRPC as rising PSA >4 ng/mL with testosterone <3.0 nmol/L. Retrospective analysis of patients with biochemical failure after radiation or surgery plus radiation; n=626 patients with ≥3 testosterone levels in first year. Secondary analysis of PR-7 intermittent vs. continuous ADT trial. Conversion of testosterone values: 0.7 nmol/L=20 ng/dL; 1.7 nmol/L=50 ng/dL.ADT=androgen-deprivation therapy; CI=confidence interval; CRPC=castration-resistant prostate cancer; HR=hazard ratio.Figure adapted from Klotz L, et al. Nadir testosterone on ADT predicts for time to castrate resistant progression: A secondary analysis of the PR-7 intermittent vs continuous ADT trial. Poster. Presented at: 29th Annual Congress of the European Association of Urology, 11–15 April 2014, Stockholm, Sweden.
100
80
60
40
20
0
Perc
ent
0 2 4 6 8 12Time (years)
10
Log rank p=0.0092HR (95% CI): 0.7<testosterone<1.7/testosterone ≤0.7: 1.41 (1.07–1.84)Testosterone ≥1.7/testosterone ≤0.7: 1.91 (1.11–3.29)
Median testosterone ≤0.7 nmol/L0.7 nmol/L <median testosterone <1.7 nmol/LMedian testosterone ≥1.7 nmol/L
ADT: Key points from EAU guidelines 2014
ADT=androgen-deprivation therapy; EAU=European Association of Urologists; mCRPC=metastatic castration-resistant prostate cancer.Mottet N, et al. EAU Guidelines on Prostate Cancer 2014. Available at: http://www.uroweb.org. Last accessed January 2015.
Optimal castration testosterone level is defined as <20 ng/dL
In high-risk localised and locally advanced prostate cancer, the combination of radiotherapy and ADT is recommended because it improves survival
First-line ADT is the standard of care for metastatic prostate cancer
Testosterone suppression should be continued indefinitely even when the disease becomes castration resistant
Second-line therapies for mCRPC should not be started unless patient testosterone levels are <50 ng/dL
Monitoring testosterone levels should be considered as part of routine clinical practice
Slide 5
Continuous (CAD) vs Intermittent Androgen Deprivation (IAD): Trials in mHNPC Patients & Survival End Point
Slide 7
Slide 10
Therapy Was Feasible:<br />Majority of Patients Received all 6 Cycles of Docetaxel
Slide 12
Chemotherapy in M0 HSPC?
Chemotherapy in non-metastatic prostate cancer
Results
More evidence for chemotherapy
Trial design
Disease free survival
Metastases free survival
Overall survival
Conclusion
Localized Metastatic HRPC
Loco-Regional Treatment ADT ADT
ADT – Short Term +/- Anti-Androgen Biosynthesis Abiraterone Acetate
ADT – Long Term +/- Chemotherapy AR – Signaling Enzalutamide
Anti-Androgen (Flare) +/- Radiation Therapy Cytotoxic Docetaxel
Cabazitaxel Anti-Androgen + RTH Bone Targeted Agents Immunotherapy
Sipuleucel TBone Targeted
Radium 223
Take Home Message:
Take Home Message:• Prostate cancer is a prevalent and lethal disease.• Prostate cancer is an ANDROGENIC disease.• Androgen receptors are ACTIVE & ADDICTED TO STIMULATION ADT is
an INTEGRAL part of therapy across disease spectrum after active surveillance.
• Long term ADT (2-3 years) plus radiation therapy is mandatory for high risk and very high risk patients.
• Castrate level should be ensured for patients with CRPC.• Keep an eye on ADT related adverse events. • Post-Receptor directed therapies would be of interest in the nearby
future.• Continuous ADT is the back – bone of therapy.
Thank You