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男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
How Low Should Serum Testosterone Level Be in the Treatment of Metastatic Prostate
Cancer
Wayne Yen-Hwa Chang, MD, PhD.
Department of Urology
Taipei Veterans General Hospital and
National Yang-Ming University School of Medicine
Taipei, Taiwan, R.O.C
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Therapy-induced HeterogeneityThe Androgen-receptor (AR)
Pathway
1. Heinlein CA & Chang C. Endocr Rev, 2004; 25: 276-308;2. Hu R et al. Expert Rev Endocrinol Metab, 2010; 5: 753-64
PI3K/AKT/ERK/mTOR
NUCLEUS
AR
T/DHT
Androgen production by adrenal glands
and prostate tumor2
AR overexpression2
AR splice variants2
AR mutants2
Signalling cross-talk1,2
Upregulation of AR cofactors1,2
1. Heinlein CA & Chang C. Endocr Rev 25:276-308, 20042. Hu R et al. Expert Rev Endocrinol Metab 5:753-64, 2010
DHT: dihydrotestosterone; ERK: extracellular signal-regulated kinase; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol-3 kinase; T: testosterone
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Castration-Resistant Prostate Cancer (CRPC): Definition
Biochemical Progression: 3 consecutive increases in PSA, one week apart, resulting in two 50% increases over the nadir, with PSA >2 ng/mL
Radiological Progression: The appearance of ≥2 bone lesions on a bone scan or enlargement of a soft tissue lesion using RECIST criteria
+ either
Castrate Serum Testosterone <50 ng/dL or 1.7nmole/L
OR
PSA: prostate-specific antigenEAU guidelines on prostate cancer (2014 update)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Testosterone Characteristics
A principal male androgen, sex hormone and anabolic steroid
Synthesis: Leydig cells in testicles, theca cells in ovaries, small amount by zona reticularis of adrenal cortex and placenta
Metabolism: 10% is converted by 5-a reductase to DHT (dihydrotestosterone), < 0.5% by aromatase to estradiol. Most of testosterone is deactivated and excreted as glucoronides
C19H28O2
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Methods for Serum Testosterone MeasurementType Characteristics
Chemiluminescet uses antibodies, direct, most laboratory platforms (Abbott, Siemens, Roche) have their own antibodies, which all cross react to some extent to other substances and give consistent, but different results, typically higher than reference methods in/near castrate range
Rradioimmuoassay(RIA)
uses antibodies, typically good results if indirect RIA’s- detection after chromatography step, for direct RIA's, same as for chemiluminescence – problems with antibody selectivity
LC-MS/MS: liquidchromatography –tandem massspectrometry
uses molecular mass based identification, indirect, uses different liquid chromatography methods to extract testosterone from sample (for example “high turbulent flow”) and tandem mass spectrometry to confirm and quantify sample, gold standard
GC-MS: gaschromatography – mass spectrometry
uses molecular mass based identification, indirect, research mainly, useful for profiling different steroids in the sample, reference method, issues with “in-house” development, sample preparation, most labor and resource intensive
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Typical Serum Testosterone Values arePresented in Different Units
Clinical Setting Serum Testosterone Value
Normal morning value for males, above 12 nmol/l (= 346 ng/dl = 3.46 ng/ml)
Advised supplementation for healthy males, regardless of symptoms, below
8 nmol/l (= 231 ng/dl = 2.31 ng/ml)
“Medical” castration value 1.73 nmol/l (= 50 ng/dl = 0.5 ng/ml)
Median value for premenopausal females 1.39 nmol/l (= 40 ng/dl = 0.4 ng/ml)
“Morote's” value 1.11 nmol/l (= 32 ng/dl = 0.32 ng/ml)
“Surgical” castration value 0.69 nmol/l (= 20 ng/dl = 0.2 ng/ml)
Conversion Factors: The molecular mass of testosterone (C19H28O2) is 288.42 g/mol. Therefore, if value in ng/dl is available, multiply it with 0.0347 nmol/l / ng/dl to get value in nmol/l. If value in nmol/l is available, multiplied by 28.8 ng/dl / nmol/l to get ng/dl. 1 ng/ml (or microg/l) = 100 ng/dl
Oefelein et al. Urology 56(6):1021, 2000; Djaavan et al. BJU Int 110(3):344, 2012
A recent review found that up to12.5%of patients do not reach the 1.7 nmol/L (50 ng/dL) serum testosterone target, and up to 37.5% do not attain levels <0.7 nmol/L (20 ng/dL).
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Management of CRPC: Maintenance of Castrate Testosterone
Levels
- ECOG retrospective analysis of 341 patients treated in 4 clinical trials for HRPC- Correcting for weight loss, age, and performance status, continued androgen suppression was a predictor of survival
Androgen deprivation should be continued even in CRPC
If the patient cannot continue LH-RH treatment , the option would then be bilateral orchiectomy
In the absence of further treatment to block androgen production, his testosterone levels should be tested on a regular basis
No orchiectomy, hormone therapy discontinued prior to study entry
Orchiectomy plus continued hormonal therapy
Mos
Pro
bability
0 6 12
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Taylor CD, et al. J Clin Oncol. 11:2167-2172, 1993.
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Testosterone levels during ADT may Serve as anEarly Predictor of Prostate Cancer Progression
Freedom from CRPC based on 9 month testosterone levels
1.0
0.8
0.6
0.4
0.2
0
Fre
edo
m f
rom
CR
PC
0 1 2 3 4
Time since commencing ADT (years)
Median PFS12.5 months
Median PFS33.1 months
9-month absoluteT ≥32 ng/dL
9-month absolute T <32 ng/dL
Log rank p=0.001
Patients with mean testosterone <32 ng/dL at 9 months had a significantly longer time to CRPC compared to those with mean testosterone 32-50 ng/dL
First-year mean testosterone also associated with time to CRPC
Median PFS: 33.1 months for <32 ng/dL versus 12.5 months for 32–50 ng/dL (p=0.05)
*Patients with recurrence after local therapy, locally advanced disease, metastatic disease and for concurrent treatment with primary external beam radiotherapy for D’Amico intermediate- or high-risk disease.ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer; LHRH=luteinising hormone-releasing hormone; PFS=progression-free survival.
Dason S, et al. Can Urol Assoc J 7:E263-7, 2013
This study supports a lower testosterone threshold to define optimal medical castration (T <32 ng/dL) than the previously accepted standard of 50 ng/dL.
Testosterone levels during ADT serve as an early predictor of disease progression and thus should be measured in conjunction with PSA
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Testosterone Levels during ADT may Predict Risk of Disease Progression
1.0
Cum
ulati
ve s
urvi
val f
ree
of A
IP (%
)
0
Follow up (months)
0.2
0.4
0.6
0.8
0 50 100 150 200 250
p=0.0258
Survival free of CRPC analysis according toserum testosterone behavior Patients with breakthrough
increases in serum testosterone >32 ng/dL (1.1 nmole/L) had a significantly shorter mean survival free of CRPC (88 months) than patients with all three determinations of serum testosterone <32 ng/dL (137 months; p<0.03)
CRPC was defined as three consecutive PSA increases after the nadir
Patients with all serum testosterone determinations less than 32 ng/dL (n=33)
Patients with breakthrough increases greater than 32 ng/dL (n=40)
Morote et al. J Urol 178: 1290-95, 2007
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
0 24 48 72 96 120 144 168
Months under ADT
192 216 240
0,0
0,2
0,4
0,6
0,8
1,0C
um
su
rviv
al
fre
e o
f P
SA
p
rog
res
sio
n
Group 3
Group 2
p = 0.0207
Group 1Group 1 (43.6%): all 3 serum testosterone 20 ng/dL
Group 2 ( 31.5%): with breakthrough
increases between 20 and 50 ng/dL
Group 3 (24.7%): with breakthrough
≥50 ng/dL
106 months
90 months
72months
AIP, Androgen independent
progression
20 ng/dL = 0.7 nmol/L50 ng/dL = 1.7 nmol/L
Survival Free of AIP According to Serum Testosterone Level
Morote et al. J Urol 178: 1290-95, 2007
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Sustained Profound Suppression of Testosterone May Affect Prognosis and Survival
Hazard ratio* (95% CI) for cancer-specific survival
0.8 0.9 1.2 1.6 1.81.0 1.1 1.3 1.4 1.5 1.7
Gleason score
6-month PSA
HR 1.31, p<0.01
HR 1.39, p<0.01
Increased risk of death
6-month testosteroneHR 1.33, p<0.05
AgeHR 1.04, p=0.08
Retrospective analysis in 129 prostate cancer patients with bone metastases suggests a direct correlation between testosterone levels at 6-months after ADT and risk of cancer-specific death
Treated with Goserelin
Monitor every 3 month
Mean follow up: 47.5 months
Mean testosterone:
Baseline: 440 ng/dL
6 months: 40 ng/dL
Nadir: 21 ng/dL
*Cox’s proportional hazard model.
Perachino M, et al. BJUI 105:648-51, 2009.
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
The Cumulative Side Effects ofAndrogen Deprivation Syndrome
Visible Non-visible
Most common What you see What you don’t see What you feel
Loss of libido
Erectile dysfunction
Hot flashes
Weight gain (Obesity)
Gynecomastia
Loss of muscle mass, strength
(Sarcopenia)
Decreased size of penis and testes
Hair changes
Loss of BMD (Osteoporosis
/Fraccture)
Anemia
Hypertension, Diabetes, Lipid profile changes (Metabolic syndrome)
Fatigue
Lack of energy
Lack of initiative
Depression
Emotional distress
Alterations in cognitive function
Adapted from Higano et al. Urology 61:32-8, 2003
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Long-term Side Effects of ADT
Bone lossObesity and Sarcopenia
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Rationale of Intermittent Androgen Deprivation (IAD)
Heterogeneity of prostate cancer cells response to testosterone in vivo (demonstrated in vitro)
Concept: Advantageous to hit cells hard in induction phase, targeting androgen sensitive and less sensitive cells
Recovery of androgen sensitive cells in off treatment interval
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ADT in Advanced Prostate Cancer:Is IAD the New Standard of Care?
Klotz and Toren Current Oncol 19(3):S13-21, 2012
Partially insensitive
Stem cells, androgen insensitive
Androgen sensitive
T < 20
T >> 20
On treatment
On treatment
Off treatment
Off treatment
Less androgen dependence
Eventual adaptation/selection pressure
Greater androgen dependence
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Intermittent versus Continuous Androgen Deprivation in Metastatic Hormone
Sensitive Prostate Cancer
Hussain et al. N Engl J Med 368:1314-25, 2013
HR 1.10 (0.99-1.23)
7 year Surviva
l (%)
42%
38%
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Klotz et al. JCO 33(10):1151-6, 2015
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Low Nadir Serum Testosterone (<20 ng/dL) within the first year of ADT Predicts Treatment
Outcomes
Klotz et al. JCO 33(10):1151-6, 2015
Prospective study N=626 Continuous ADT
Monitor every 2 month, Median follow up of 6.9 years
Time to CRPC Cancer-specific survival
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Clinical Implication for Patients on Androgen Deprivation Therapy
Serum testosterone and PSA levels should be monitored regularly during the first year of ADT
Testosterone not achieving testosterone <0.7 nmol/L (0.2 ng/ml) within the first year warrants consideration of a change in hormone therapy, either to another LHRH-agonist, to an LHRH-antagonist, or to orchiectomy (if continuous therapy is intended)
However: Intracrine synthesis of androgens by prostate cancer
cells with autocrine stimulation is a primary mechanism for CRPC
Klotz et al. JCO 33(10):1151-6, 2015
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Bipolar Androgen Therapy (BAT): Adaptive auto-regulation of AR and induction of DNA damage with testosterone therapy
By actively exposing cells with “adaptive changes in AR function” to supraphysiologic levels of androgen, nuclear AR loses the flexibility to be removed from origin of DNA replication sites (AR degradation) thereby interrupting mitosis and causing tumor cell death
This is then followed by a return to a castrate level of testosterone leaving surviving cells with baseline low AR or adaptive down-regulated AR again vulnerable to cell death
Isaacs JT et al. Prostate 72:1491-505, 2012 Haffner MC et al. Nat Genet 42:668-75, 2010
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
METHODS: 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg IM; day 1 of 28) and etoposide (100 mg PO daily; days 1 to 14 of 28). After three cycles, those with a declining PSA continued on intermittent testosterone therapy monotherapy.
RESULTS: BAT was well tolerated & produced high rates of PSA responses (7/14 pts) and radiographic responses (5/10 pts). Eventually all men showed PSA progression, but 4 men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen ablative therapies after BAT, suggesting that BAT may help restore sensitivity to ADTs.
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Thank You for Your Attentions
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Thank You for Your Attentions
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