Therapy in Prostate Cancer:
Cure or Regression
F. Di Silverio
Department of Urologia U Bracci
University La Sapienza Rome
Objectives and classification of the results
obtained from therapies in oncology
9 Cure
9 Complete Remission
9 Partial Remission
9 Stable Disease
9 Progression
(C.R.)
(P.R.)
(S.D.)
(Pr)
F. Di Silverio, Roma 2005
To CURE is possible when :
it is present a marker for
biological activity of the tumor
9 Prostate cancer = PSA
9 Testis cancer
= α feto, βHGC
F. Di Silverio, Roma 2005
Objectives and classification of the results
obtained from therapies in oncology
Surgical Radicality
=
Pathology
+
Biological Radicality =
undetectable PSA
To CURE
F. Di Silverio, Roma 2005
Response to therapy is influenced
by a crucial variable
9 TIME (t)
F. Di Silverio, Roma 2005
Variable TIME (t) in results of
therapies in oncology
TIME (t)
9 Cure
indefinite
9Complete Remission (C.R.)
9 Partial Remission
(P.R.)
9 Stable Disease
(S.D.)
9 Progression
(Pr)
> 10 yrs
5-10 yrs
months
months
F. Di Silverio, Roma 2005
Variable TIME (t) in results of
therapies for prostate carcinoma
yrs14
CURE
12
10
8
t
6
4
2
0
RRP
RTE
HT
Chemio
F. Di Silverio, Roma 2005
Variable TIME (t) in results of
therapies for prostate carcinoma
Variable TIME (t) is related to:
9 Time to diagnosis
• Early
• Deferred
F. Di Silverio, Roma 2005
Variable TIME (t) in results of
therapies for prostate carcinoma
Variable
Early diagnosis
Deferred
Diagnosis
Stage
localized
advanced
Grading Gleason </= 7(3+4)
>/= 7 (4+3)
DNA
diploid
aneuploid
AR
expressed
no expressed
Variable TIME (t) in results of
therapies for prostate carcinoma
QUESTION
When and from which therapy
we can obtain CURE ?
F. Di Silverio, Roma 2005
When and from which therapy we can
obtain CURE ?
ANSWER
Radical Prostatectomy if:
o Localized stage
o Gleason </= 7(3+4)
o PSA < 10 ng/ml
F. Di Silverio, Roma 2005
Why we can not obtain CURE after
radiotherapy but only Complete Remission ?
ANSWER
Only C.R. because:
o prostate gland remains
o no pathological stage (pT,pN)
o prolonged half-time for PSA
o positivity to tissue PSA also after 5 years
F. Di Silverio, Roma 2005
Evaluation of limits of therapies for
prostate carcinoma
TIME (t) = lenght of therapeutic efficacy
QUESTION
Can we increase TIME (t) of therapeutic
efficacy ?
F. Di Silverio, Roma 2005
Can we increase TIME of therapeutic efficacy
Therapy
Modality
RRP (high risk cases)
Hormone-therapy
RT
Hormone-therapy
HT
Early, not deferred
Choice of the drug
Sequenziality
Intermittence
HRPC therapy
Estrogens
Somatostatin analogues (NE)
Can we increase TIME of therapeutic efficacy of RRP
Progression-free survival:
locally advanced radical prostatectomy
Proportion
not
progressing
1.0
0.8
0.6
0.4
0.2
Bicalutamide (‘Casodex’) 150 mg
Placebo
0.0
0
1
2
3
4
5
6
Time to progression (years)
HR 0.71; 95% CI 0.57, 0.89; p=0.00340
Bicalutamide (‘Casodex’) 150 mg events = 136 (15.6%)
Placebo events = 170 (20.0%)
7
8
EPC Study
Can we increase TIME of therapeutic efficacy
Radiotherapy RT
RT
RT + HT
Local control
10 yrs
56%
70%
Survival
10 yrs
28%
46%
J Oncol. Biol. 1995
Can we increase TIME of therapeutic efficacy of RT
Progression-free survival:
locally advanced radiotherapy
Proportion
not
progressing
1.0
0.8
0.6
0.4
0.2
Bicalutamide (‘Casodex’) 150 mg
Placebo
0.0
0
1
2
3
4
5
6
Time to progression (years)
HR 0.58; 95% CI 0.41, 0.84; p=0.00348
Bicalutamide (‘Casodex’) 150 mg events = 54 (33.5%)
Placebo events = 70 (48.6%)
7
8
EPC Study
Can we increase TIME of therapeutic efficacy
Hormone- Therapy
9 choice of the drug
9 sequentiality
9 modality of administration
F. Di Silverio, Roma 2005
HT can reduce androgen sensibility of PC
Influence on TIME (t) of response
Throught
™ selection of androgen-independent cells
™ cellular re-differentiation
™ hyperactivation Neuroendocrine system (NE)
F. Di Silverio, Roma 2005
Choice of the drug during HT
9 primary use of antiandrogen
9 maintenance of AR
Cgr A
ng/ml
55
50
Locally advanced PC
Bicalutamide: KW=19.707 p=0.0031
LH-RH analogue KW= 46.347 p<0.0001
LHRH-analogue
Bicalutamide
45
40
35
24
18
12
6
3
Months
1
ba
se
lin
e
30
F. Di Silverio, A. Sciarra
EAU 2003, Urology 2004
Cgr A
ng/ml
110
Metastatic PC
IAD: F=3.206; p=0.124
Continuous: F=17.233;p=0.006
Continuous
90
IAD
70
24
18
12
6
3
1
0
ba
se
lin
e
50
Months
F. Di Silverio, A. Sciarra
The Prostate 2003
No Conclusions but a possible Future
Microenvironment in which tumor cells are located
has a potential effect in reducing anti – tumor effect
of therapies
Microenvironment
Cells
Microenvironment can influence TIME (t) in PC
Role of Microenvironment in the induction,
progression and response to therapy for PC
Nature 2000;
405:287-288
Role of Microenvironment on TIME (t) in PC
¾ Nitric Oxide
9 N.O. promotes angiogenesis
9 N.O. promotes tumor growth
Jenikins DC et al . Proc Natl Med Sci 1995;92:4392
Cyclo-Oxigenase
F. Di Silverio, Roma 2005
Role of Microenvironment on TIME (t) in PC
¾ COX-2
9 promotes angiogenesis
9 promotes tumor growth
9 increases resistance to therapies
Jenikins DC et al . Proc Natl Med Sci 1995;92:4392
When to act on Microenvironment so to
influence TIME (t) in PC
¾ use of anti - COX-2 in the prevention of PC
(Atrophy, HGPIN)
¾ in association with hormone - therapy
¾ in “off” phases of IAD
¾ prevention of HRPC
F. Di Silverio, Roma 2005
Conclusions
9 The best knowledge of the natural history and of
microenvironment consent to obtain a better
prognosis, quality of life and survival
9 To delay the development of HRPC represents
the primary target in the management of HT and of
the patient with prostate carcinoma
F. Di Silverio, Roma 2005