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IL TRATTAMENTO DEL
MICROAMBIENTE OSSEO
Alfredo Berruti
Università degli Studi
di Brescia
Azienda Ospedaliera
Spedali Civili
Brescia
THE VICIOUS CIRCLE
Kingsley LA et al Mol Cancer Ther 2007;6(10):2609–2617
Skeletal-Related Events Are Prevalent
in the Absence of Therapy
Placebo
arm*
90
Patients with SRE,
%
80
79%
70
60
50
50%
49%
51%
46%
40
30
20
10
0
Breas
RC
NSCLC
Prostat Multiple
t
C5
and
myelom
e
cance
OST4
a3
cancer
2
1
r
NSCLC = Non-small cell lung cancer; OST = Other solid tumors; RCC = Renal cell carcinoma.
*Placebo arm from zoledronic acid and pamidronate clinical trials.
1. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321; 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882; 3. Berenson JR, et
al. J Clin Oncol. 1998;16:593-602; 4. Rosen LS, et al. Cancer. 2004;100:2613-2621; 5. Mulders PF. Presented at: EAU 2007.
Bisphosphonates and SRE and Bone Pain in Advanced Postate
Cancer
SREs
Bone Pain
Yuen KK et al Cochrane Database Syst Rev 2006
Quesiti aperti
Possono gli inibitori del riassorbimento osseo migliorare
la prognosi dei pazienti?
Sono efficaci anche nel paziente metastatico
ormono sensibile?
Quale il loro ruolo in adiuvante?
27
Prostate Cancer
Survival
100
Median, days
Percent surviving
ZOMETA®
80
4 mg
Placebo
P value
546
469
.103
60
40
20
0
0
120
240
360
480
600
720
840
960
Days*
Zol 4 mg
Placebo
214
208
162
148
*Time after start of study drug.
113
94
56
40
10
5
SURVIVAL POOLED ANALYSIS
Hazard Ratio
Study or Subgroup
log[Hazard Ratio]
SE Weight IV, Fixed, 95% CI Year
Dearnaley
-0.223 0.129 46.4%
0.80 [0.62, 1.03] 2003
Smith 2014
-0.128
0.88 [0.70, 1.11] 2014
Total (95% CI)
0.12 53.6%
Hazard Ratio
IV, Fixed, 95% CI
100.0% 0.84 [0.71, 1.00]
Heterogeneity: Chi² = 0.29, df = 1 (P = 0.59); I² = 0%
Test for overall effect: Z = 1.96 (P = 0.05)
0.5 0.7
1
1.5 2
Favours BP Favours no BP
Valcamonico F Petrelli F, Barni S, et al, J Clin Oncol 2014 in press
Key Inclusion Criteria
•Adults with prostate,
•and ≥ 1 bone metastasis / lesion
Key Exclusion Criteria
Denosumab 120 mg SC and Placebo IV*
every 4 weeks (N = 951)
1:1
•No current or prior IV
bisphosphonate administration
for treatment
of bone metastases
Daily Supplements of Calcium and Vitamin D
Zoledronic acid 4 mg IV* and
Placebo SC every 4 weeks (N = 953)
Lancet 2011; 377: 813–22
Lancet 2011; 377: 813–22
Targeting
Tumor cell
Tumor (bone)
microenvironment
J Natl Cancer Inst 2011;103:1665–1675
… e in adiuvante?
Parasitism of the bone
microenvironment by prostate cancer
Yu C et al, Critical ReviewsTM in Eukaryotic Gene Expression, 22: 131–148 (2012)
Brian Ell and Yibin Kang Cell 151, October 26, 2012
 GNRH AGONISTI
 Aromatasi Inhibitors
CHEMIOTERAPIA
 Menopause
 Age
Low vitamin D leves
High Bone Turnover
Cancer cell Homing
New Bone Metastasis
Osteoporosis
Fragility
Fractures
SRE
Fractures
Hypercalcemia
Radiotherapy
Othopedic Surg.
Pain
Bone
Metastasis
Gowth
BP
Brian Ell and Yibin Kang Cell 151, October 26, 2012
Eur Urol 2014, in press
Non metastatic 508 pts
Metastatic 311 pts
Lancet Oncol. 2009 September 9; 10(9): 872–876.
Lessons From 60 Years of
Practice: PSA Era
Radical
prostatectomy
90
First M+ event
Radiotherapy
PSA (ng/ml)
80
70
60
Hormonal therapy
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time post diagnosis (years)
Courtesy Abrahamsson PA
Primary endpoint: Time to development of bone metastasis or death
Secondary endpoint: Time to development of bone metastasis (excluding death)
N = 1.435
Prostate cancer (non metastatic)
Hormone-refractory disease
High risk of bone metastases
Adequate organ function
R
A
N
D
O
M
I
Z
A
T
I
O
N
Denosumab
120 mg SC every 4 weeks
Placebo
Daily supplementation with calcium (≥500 mg) and vitamin D (≥400 IU) strongly recommended
Lancet 2012; 379: 39–46
Time to bone metastases or death
Lancet 2012; 379: 39–46
PSA DT
<10
<6
<4