MALATTIA METASTATICA
ORMONOSENSIBILE
Nel paziente in trattamento ormonale
c'è una relazione fra livelli circolanti
di testosterone raggiunti e risposta
alla terapia?
MALATTIA METASTATICA
ORMONOSENSIBILE
Nel paziente in trattamento ormonale c'è una relazione
fra livelli circolanti di testosterone
raggiunti e risposta alla terapia?
BJU Int. 2010;105(5):648-51
J Urol 178: 1290-1295, 2007
<20 ng/dl
<32 ng/dl
20-50 ng/dl
>50 ng/dl
>=32 ng/dl
Clin Genitourin Cancer 3: 325-330, 2013
Metastatic patients
Non metastatic patients
Overall survival from PSA progression
<0.30 ng/ml
>=0.30 ng/ml
Prognostic role
=
Surrogacy
PRENTICE’s criteria
1.
2.
3.
4.
Treatment effect on the surrogate
Treatment effect on the primary
Correlation between primary and surrogate
Treatment effect on the primary disappears when the
surrogate is adjusted for
Fig 1. Kaplan-Meier estimates of overall survival in TAX327 according to >= 30% prostate-specific
antigen (PSA) decline status within first 3 months of treatment initiation
Armstrong, A. J. et al. J Clin Oncol; 25:3965-3970 2007
PSA as a surrogate parameter of docetaxel efficacy
SWOG study
P value
HR 0.76 (0.49-0.98)
Univariate
analysis
docetaxel /E
Vs mitox/P
0.052
HR 0.43 (0.34-0.55)
PSA decline >30%
Vs no decline
Multivariate
analysis
0
HR 0.86 (0.69-1.07)
0.25
0.50
0.75
Docetaxel/E
Vs mitox/P
1
<0.001
0.16
1.25
Hazard ratio (HR) and (95% CI)
Proportion of Treatment effect Esplained (PTE): 1 (0.73-1)
Patrylack DP et al JNCI 98: 516-521, 2006.
J Clin Endocrinol Metab 95: 4542–4548, 2010
Mass spectrometry as reference method for
assessment of circulating testosterone in
lower range
MALATTIA METASTATICA
ORMONOSENSIBILE
La terapia intermittente IAD: quali farmaci,
quali indicazioni e quali vantaggi ?
Conclusion
There is fair evidence to recommend use of IAD instead of CAD for
the treatment of men with relapsing, locally advanced, or metastatic
prostate cancer who achieve a good initial response to
androgen deprivation.
This recommendation is based on evidence against superiority of
either strategy for time-to-event outcomes and substantial decrease
with IAD in exposure to androgen deprivation, resulting in less cost,
inconvenience, and potential toxicity.
Overall survival
Time to progression
Cancer specific
survival
Quali farmaci
LHRH-A + antiandrogeni?
Quali indicazioni
Paziente asintomatico con incremento di PSA specie se in
assenza di metastasi
Quali vantaggi
Migliore tollerabilita?
Minori costi
Durata del periodo off come fattore prognostico aggiuntivo
MALATTIA METASTATICA
ORMONOSENSIBILE
Confronto LHRH analoghi ed antagonisti:
chi e’ il vincitore ? O esistono diverse indicazioni
e sequenzialita ?
GNRH antagonists: Advantages
 immediate reduction of serum testosterone
- 72 h: 96% <0.5 ng/ml
 absence of testosterone initial flare up
 rapid reduction in PSA levels
 reduction in prostate volume already at 30 days
 reduction and stability on FSH
 limited half-life (10 days approximately)
Klotz L, Boccon-Gibod L, Shore ND, et al.
The efficacy and safety of degarelix: a 12-month, comparative,
randomized, open-label, parallel-group phase III study in patients
with prostate cancer.
BJU Int 2008;102:1531–8
Primary aim:
to demonstrate the non inferiority of degarelix versus leuprolide for
the primary end point (probability of patients having testosterone
0.5 ng/ml at each monthly measurement for 1 yr)
FSH
Clin Oncol 2013 in press
Degarelix non inferiore in termini di
efficacia rispetto a Leuprolide + antiandrogeno
Potenzialità di Degarelix
In pazienti con malattia ossea estesa
In pazienti con LUTS
MALATTIA METASTATICA
ORMONOSENSIBILE
Esiste ancora un ruolo per gli estrogeni ?
Mechanisms of action of DES
Reduction of luteinizing hormone, testosterone and
androgenic steroid levels1
Inhibition of telomerase activity2
direct binding of the androgen receptor (AR)3
Suppression of b-tubulin isotypes4
1Bosset
PO et al BJU Int 2012; 110: E826–E829
2Geier R et al Prostate 2012; 70(12): 1307–1312.
3Wang H et al Asian J Androl 2010; 12(4): 535–547.
4Montgomery RB, et al: Prostate 2005; 65: 141–150.
BJC: 2013; 109: 1079-1084
Lancet Oncol 2007; 8: 994–1000
MALATTIA METASTATICA
ORMONOSENSIBILE
Quale follow-up nel paziente sottoposto ad
ormonoterapia ?
Main objectives of following-up during ADT
•
•
•
•
monitor the response to treatment;
ensure compliance with treatment;
detect potential complications of endocrine therapy;
guide the modalities of palliative symptomatic
treatment at the time of CRPC
EAU guidelines 2013
Prognostic role of serum PSA levels
Patients with the lowest absolute value of serum PSA (< 0.2
ng/mL) have been shown to have the best survival
compared to patients with a value of 0.2-4.0 ng/mL or > 4.0
ng/mL 1
The PSA response in patients treated with hormonal therapy,
following a rising PSA after treatments with curative intent
(radical prostatectomy, radiation therapy) correlates with the
best survival 2,3
1 Hussain
2,D’Amico
M, et al J Clin Oncol 2006; 24(24):3984-90.
AV et al J Natl Cancer Inst 2004 ; 96 (7) :509-15.
3 Stewart AJ et al J Clin Oncol 2005; 23 (27): 6556-60
Biochemistry: hemocrome, liver function tests, testosterone,
Vitamin D
Monitoring metabolic complications
Imaging techniques
Bone scan, ultrasonography. CT (?)
on the basis of PSA changes and or clinics
Dexa scan