RUOLO DEI BISFOSFONATI NEL TRATTAMENTO DEL PAZIENTE ANZIANO CON NEOPLASIA METASTATICA ALLOSSO Daniele Santini Oncologia Medica Università Campus Bio-Medico.
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RUOLO DEI BISFOSFONATI NEL TRATTAMENTORUOLO DEI BISFOSFONATI NEL TRATTAMENTODEL PAZIENTE ANZIANO CON NEOPLASIADEL PAZIENTE ANZIANO CON NEOPLASIA
METASTATICA ALL’OSSOMETASTATICA ALL’OSSO
Daniele SantiniDaniele Santini
Oncologia MedicaOncologia MedicaUniversità Campus Bio-Medico di RomaUniversità Campus Bio-Medico di Roma
Presente e futuro della terapia di supporto in oncologia
Roma, 22-23 Giugno 2006
1. Ferlay J, et al. IARC Globocon 2000. Cancer Incidence, Mortality, and Prevalence.2. Coleman RE. Cancer Treat Rev. 2001;27:165-176.3. Coleman RE. Cancer. 1997;80:1588-1594.4. Zekri J et al. Int J Oncol. 2001;19:379-382.
5-year world prevalence,thousands1
Incidence of bone metastases
in cancers2Median survival,
Months2-4
Myeloma 144 70 - 95 6 - 54Renal 480 20 - 25 12Melanoma 533 14 - 45 6Bladder 1,000 40 6 - 9Thyroid 475 60 48Lung 1,394 30 - 40 6 - 7Breast 3,860 65 - 75 19 - 25Prostate 1,555 65 - 75 12 - 53
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Metastatic Bone Disease Is PrevalentMetastatic Bone Disease Is Prevalent
Prevalence of Skeletal-Related Events in Prevalence of Skeletal-Related Events in Clinical Trials (Placebo Group)Clinical Trials (Placebo Group)
% of patients
Pamidronate trials Zol trials
Disease Breast Myeloma Prostate Lung/Others
Observation time 24 months 21 months 24 months 21 months
Total SREs 68 51* 49 48
Radiation to bone 43 34 33 34
Fractures 52 37 25 22Hypercalcemiaof malignancy 13 9 1 4Surgery to bone 11 5† 4 5Spinal cordcompression 3 3† 8 4
*Excluding hypercalcemia
Key IssuesKey Issues End points nel trattamento delle metastasi ossee
Efficacia dei differenti bifosfonati nelle diverse patologie tumorali
Safety and elderly
Ruolo dei bifosfonati in adiuvante
Ruolo dei bifosfonati nella prevenzione dell’osteoporosi indotta dal trattamento antineoplastico
Possiamo ottimizzare l’efficacia dei bifosfonati?– Schedula ottimale– Altre opzioni teraputiche
etidronate clodronate tiludronateetidronate clodronate tiludronate
Different Classes of BisphosphonatesDifferent Classes of Bisphosphonates1,21,2
pamidronate alendronatepamidronate alendronate ibandronate ibandronate
zoledronic acidzoledronic acid
1. Thurlimann B. Bisphosphonates in Clinical Oncology: Focus on Pamidronate. 1999.
2. Fleisch H, Endocr Rev. 1998.
HO
HO OHOH
OH
O
O
P
P
CH3OH
OH
OH
OHO
OP
P
Cl
Cl
HOOH
OH
OHO
OP
PSCl
HO
O
OP
POH
OHOH
OHH2N
OHOH
OHO
ON P
P
OH
HO
CH3
CH3H2NHO
HO
OH
OH
OH
O
O
P
P
NN
O
O
P
P
HO OH
OH
OH
OH
1 gen
2 gen
3 gen
Efficacia dei diversi bisfosfonatiEfficacia dei diversi bisfosfonati
Relative inhibitory potency in vivo, hypercalcemic rat
10 0 10 1 10 2 103 10 4 10 5 106
100
101
102
103
Zoledronic acid
Risedronate
Ibandronate
AlendronateOlpadronate
Pamidronate
NeridronateClodronate
EtidronateRel
ativ
e in
hib
ito
ry p
ote
ncy
in v
itro
, b
on
e cu
ltu
res
R = 0.97
Green JR, et al. J Bone Miner Res. 1994;9:745-751.
Eventi scheletrici (SRE)Eventi scheletrici (SRE)rilevabili nei pazienti neoplasticirilevabili nei pazienti neoplastici
Necessità di radioterapia per il dolore osseo o per trattare o prevenire fratture patologiche o compressione spinale
Fratture patologiche
Compressione spinale
Necessità di chirurgia ortopedica
Ipercalcemia neoplastica (HCM)
Johnson R et al, J Clin Oncol, 2003
Stime di efficacia per la valutazione del Stime di efficacia per la valutazione del trattamento con bisfosfonatitrattamento con bisfosfonati
First event analysis– Percent of patients with 1 event– Time to first event
Skeletal morbidity rate (SMR)– Number of events per person per defined time period (usually
1 yr) Skeletal morbidity period rate (SMPR)
– Number of specific time intervals (eg, 12-week period) per person with new skeletal complications
Multiple event analysis– Considers all skeletal events and the time to each event
Efficacy of bisphosphonates in Efficacy of bisphosphonates in Patients With Breast CancerPatients With Breast Cancer
Ca. mammario: bisfosfonati vs. placeboCa. mammario: bisfosfonati vs. placebo
% pazienti con ≥1 SRE
% P BP placebo decrease value
Pamidronate1 51 64 20% <0.001
Oral Ibandronate2 45 52 13% 0.122
IV Ibandronate3 51 62 18% 0.052
Zoledronic acid4 30 50 40% 0.003
1Lipton, Cancer 2000; 2Body, Ann Oncol 2003; 3Body, Br J Cancer 2004; 4Kohno, J Clin Oncol 2005
Coleman R, 5th International Conference on CIBD, Davos 2005
Ca. mammario: bisfosfonati vs. placeboCa. mammario: bisfosfonati vs. placebo
% P BP placebo increase value
Clodronate1 9.4 5.6 68% 0.022
Pamidronate2 12.7 7.0 81% 0.001
Oral Ibandronate3 21.0 15.1 39% 0.089
IV Ibandronate4 11.8 7.7 53% 0.018
Zoledronic acid5 NR 12.0 110%* 0.007
1Pavlakis, Cochrane review 2004; 2Lipton, Cancer 2000; 3Body, Ann Oncol 2003; 4Body, Br J Cancer 2004; 5Kohno, J Clin Oncol 2005; *estimated
Coleman R, 5th International Conference on CIBD, Davos 2005
mediana del tempo a comparsa del primo SRE
PamidronateZoledronic acid 4 mg
P = .046
3 6 9 12 15 18 21 24Time since randomization, months
0.0
0.2
0.4
0.6
1.0
1.2
0
0.8
Cu
mu
lati
ve e
xpec
ted
SR
Es,
n
Major P, et al. Proc Am Soc Clin Oncol. 2003;22:762. Abstract 3062.
Independent Survival-Adjusted Multiple Event Analysis(Cook & Lawless approach)
Ca. mammario: Ac.Zoledronico vs. Ca. mammario: Ac.Zoledronico vs. pamidronatopamidronato
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
–HCM
Risk ratio (zoledronic 4 mg acid versus pam)
P value
.042
.025+HCM
In favor of zoledronic acid In favor of pamidronate
Riskreduction
18%
20%
.816
.799
Rosen LS, et al. Cancer. 2003;98:1735-1744.
Multiple event analysis (Andersen-Gill)
Ca. mammario: Ac.Zoledronico vs. Ca. mammario: Ac.Zoledronico vs. pamidronatopamidronato
Presenza di dolore osseo all’arruolamento
Lipton, 5th International Conference on CIBD, Davos 2005 (data not published)
12 24 36 48Time on study (weeks)
Zoledronic acid
Pamidronate-0,9
-0,8
-0,7
-0,6
-0,5
-0,4
-0,3
-0,2
-0,1
-0
0,1
0mean
BP
I ch
an
ge f
rom
baselin
e
Ca. mammario: Ac.Zoledronico vs. Ca. mammario: Ac.Zoledronico vs. pamidronatopamidronato
Non dolore osseo all’arruolamento
Lipton, 5th International Conference on CIBD, Davos 2005 (data not published)
12 24 36 48Time on study (weeks)
Zoledronic acid
Pamidronate
0
0,5
1
1,5
2
0mean
BP
I ch
an
ge f
rom
baselin
e
Ca. mammario: Ac.Zoledronico vs. Ca. mammario: Ac.Zoledronico vs. pamidronatopamidronato
Etidronate– ineffective
Intravenous clodronate– no significant effect on pain in prostate cancer
Oral clodronate– no significant effect on progression/survival in prostate
cancer
Oral / intravenous ibandronate– Pain relief in urological malignancies
Efficacia dei bisfosfonatiEfficacia dei bisfosfonatiin neoplasie diverse dal ca. mammarioin neoplasie diverse dal ca. mammario
Coleman R, 5th International Conference on CIBD, Davos 2005
Efficacy of bisphosphonates in Efficacy of bisphosphonates in Patients With Prostate CancerPatients With Prostate Cancer
Stadio : M+ osseeStadio : M+ ossee
Metastasi ossea è associata ad una significativa morbidità (dolore a volte intrattabile e fratture patologiche)
30% - 50% dei pazienti PCa M+ hanno un episodio di SREs nei due anni di follow up
(Berruti, 2000 – Saad, 2004)
7% – 16% di fratture secondarie a M+ ossee (Melton, 2003 – Townsend,1997)
Frattura può correlarsi con la diminuzione della sopravvivenza (10% - 20% degli uomini anziati muore entro 6 m dalla frattura del collo del femore) (Oefelein, 2002 – Riggs, 1995)
Stadio : HRPCStadio : HRPC
43% di SREs (vertebral collapse=20.5%; fracture=12.5%; spinal cord compression=10%)
5% di SREs avvenuti prima di HRPC38% di SREs avvenuti in HRPC
100% radioterapia in pts con SREs6.5% sottoposti a chirurgia
Conclusioni:
In analisi multivariata il dolore osseo e l’estesione della malattia ossea sono due
fattori indipendenti predittivi per SREs
Ca. prostatico: A. Zoledronico vs. placeboCa. prostatico: A. Zoledronico vs. placebo
PlaceboZoledronic acid 4 mg
P = .0023
3 6 9 12 15 18 21 24Time since randomization, months
0.0
0.2
0.4
0.6
1.0
1.2
0
0.8
Cu
mu
lati
ve e
xpec
ted
SR
Es,
n
Major P, et al. Proc Am Soc Clin Oncol. 2003;22:762. Abstract 3062.
Independent Survival-Adjusted Multiple Event Analysis(Cook & Lawless approach)
Risk ratio (zoledronic acid 4 mg versus placebo)
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
In favour of zoledronic acid In favour of placebo
.002
P value
36%
Riskreduction
0.640
Saad et al. J Natl Cancer Inst. 2004
Multiple event analysis (Andersen-Gill)
Ca. prostatico: A. Zoledronico vs. placeboCa. prostatico: A. Zoledronico vs. placebo
Change from baseline pain score (BPI)
0
0.2
0.4
0.6
0.8
1
1.2
0 3 6 9 12 15 18 21 24Time on study, months
*P < .05
*
* *
*
Mea
n c
han
ge
fro
m b
asel
ine
Meann baseline BPI
Zol 4 mg 214 2.0
Placebo 208 2.1
Saad et al. J Natl Cancer Inst. 2004
Ca. prostatico: A. Zoledronico vs. placeboCa. prostatico: A. Zoledronico vs. placebo
Overall Survival: Zoledronic Acid Overall Survival: Zoledronic Acid
0
20
40
60
80
100
0 120 240 360 480 600 720 840 960
Days*
Per
cent
sur
vivi
ng
Median, daysP value
Zol acid 4 mg 18.2 m .103Placebo 15.6 m
Zol 4 mg 214 162 113 56 10Placebo 208 148 94 40 5
Saad F, et al. JNCI June 2004
Altre neoplasie (NSCLC, RCC)Altre neoplasie (NSCLC, RCC)A. Zoledronico vs. placeboA. Zoledronico vs. placebo
PlaceboZoledronic acid 4 mg
P = .010
3 6 9 12 15 18 21 24Time since randomization, months
0.0
0.2
0.4
0.6
1.0
1.2
0
0.8
Cu
mu
lati
ve e
xpec
ted
SR
Es,
n
Major P, et al. Proc Am Soc Clin Oncol. 2003;22:762. Abstract 3062.
Independent Survival-Adjusted Multiple Event Analysis(Cook & Lawless approach)
Altre neoplasie: A. Zoledronico vs. placeboAltre neoplasie: A. Zoledronico vs. placebo
Multiple event analysis (Andersen-Gill)
*Hypercalcemia of malignancy is included as a skeletal-related event.Data from Rosen et al. Cancer. 2004; RCC subset: Lipton A. Cancer. 2003;98:962-969.
In favour of zoledronic acid In favour of placebo
P value
Risk ratio (zoledronic acid 4 mg versus placebo)
.003
.016
All patients
NSCLC
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
Riskreduction
31%
32%
0.693
0.675
.01058%RCC0.418
Start– no specific data– ASCO recommends initiation at time of bone
metastasis diagnosis
Stop– no data– continue despite SRE or disease progression– “resistance” not defined
Tempi di somministrazione dei bisfosfonatiTempi di somministrazione dei bisfosfonati
Coleman R, 5th International Conference on CIBD, Davos 2005
BIFOSFONATIBIFOSFONATI
SAFETY
Advisory Board on Bisphosphonates Advisory Board on Bisphosphonates in the elderlyin the elderly
Osteonecrosi e elderlyOsteonecrosi e elderly
Elderly and renal functionElderly and renal function
Breast cancer and MyelomaBreast cancer and MyelomaRenal safety in elderly versus young populationRenal safety in elderly versus young population
…thus NO higher risk than young patients
Prostate cancer and other cancersProstate cancer and other cancersRenal safety in elderly versus young populationRenal safety in elderly versus young population
…thus NO higher risk than young patients
Renal safety and elderlyRenal safety and elderly
Renal Safety of Zoledronic Acid in Renal Safety of Zoledronic Acid in Patients With Solid TumorsPatients With Solid Tumors
Bisphosphonates and renal function Bisphosphonates and renal function
Bisphosphonates have been associated with subacute or acute renal insufficiency (renal biopsy: acute tubular necrosis )
iv bisphosphonates are associated with dose- and infusion rate dependent effects on renal function
- iv pamidronate > 90 mg: higher risk of nephrotoxicity- Zoledronic acid : infusion time lenghtened from 5 to 15 min. and 8mg
dose discontinued Clinically relevant serum creatinine increases are rare (< 10%), and
generally reversible. However ASCO guidelines and FDA recommend SCr evaluation prior to each dose
Saad F, et al: (In press); Rosen LS, et al: (In press)Rosen LS, et al: Cancer 2003;98:1735-1744.
Few data on long term safety of bisphosphonates, in particular in combination with other anticancer treatments
SM Ali et al, JCO 2001
iv pamidronate (18 pts) iv zoledronic acid (4 pts) Mean treatment duration 3.6 yrs (range: 2.2-6.0)clinically insignificant increase in SCr
Safety of iv Bisphosphonates beyond two years
•Ali SM, Esteva FJ, Hortobagyi G. J Clin Oncol. 2001;19:3434-3437.
^ Guarneri et al, The Oncologist, 2005
SAFETY OF ZOLEDRONIC ACID AND PAMIDRONATE BEYOND TWO YEARS
Author # pts BPS therapy Mean Treatment duration
Renal function
Ali* 22 18 Pam.
4 Zoledronate
3.6 yrs
(range: 2.2-6.0)
Clinically insignificant
SCr
Guarneri^ 57 3 Pam.
11 Zoledronate
43 Both
3.5 yrs
(range:2-10)
Significant SCr (G1) 12.2%
Ibandronate: renal safetyIbandronate: renal safety
Monitoring of SCr prior to each administration: not mandatory
Can be administered in case of renal failure (creatinine clearance < 30 mL/min)
- iv 2 mg over 1 hour every 3-4 weeks
- oral 50 mg once a week
No restriction for use in combination with nephrotoxic agents
European Bondronat SmPC. F Hoffman-La Roche Ltd
Hypocalcemia induced by Hypocalcemia induced by bisphosphonatesbisphosphonates
IPOCALCEMIA DA ZOLEDRONATO /PAMIDRONATO
• Modesta e graduale (7.5-8 mg/dl (vn 8.5-10mg/dl)• Asintomatica • Transitoria (può persistere a lungo se Insuff. Renale anche modesta)
GENERALMENTE
PRATICAMENTE SEMPRE: IPERPARTORIDISMO SECONDARIO• persiste per tutta la durata del trattamento con BPs • frequente anche con basse dosi di BPs per os (alendronato, risedronato) nell’osteoporosi postmenopausale• è presente nel 30% dei maschi con cr prostata• è presente nel 70% dei soggetti > 60 anni (ipovitaminosi D)
SUPPLEMENTAZIONE CON CALCIO E VITAMINA D
• 500 /1000 mg /die calcio gluconato (bassa compliance/ stipsi)
• 25 OH vit D (10 gtt Didogyl / settimana)
Se ipocalcemia severa (< 7 mg) ASINTOMATICA
Rocaltrol 0.5 y 2 volte die + 1000 mg Calcio per OS
Calcio gluconato I.V. solo nel caso TETANIA
Studi di terapia adiuvanteStudi di terapia adiuvantecon Acido Zoledronicocon Acido Zoledronico
Neoplasia Studio Scopo
Ca. mammario AZURE Prevenz. MO
IG-S0307 Prevenz. MO
Ca. prostatico RADAR Prevenz. MO
CECOG Prevenz. MOEAU-ZEUS Prevenz. MO
MRC-STAMPEDE Prevenz. /ritardo MO
NSCLC (IIIA-IIIB) G2419 Prevenz. /ritardo MO
Definitive Adjuvant Bisphosphonate Definitive Adjuvant Bisphosphonate Trials - NSABP B34Trials - NSABP B34
Patients: 4,200 patients with stage I or II breast cancer; may receive chemotherapy, hormonal therapy, both, or neither
RANDOMI SE
Clodronate 1,600 mg OD 3 yr
Placebo 3 yr
Recruitment completed
Acido Zoledronico adiuvante nel ca. mammarioAcido Zoledronico adiuvante nel ca. mammario
The AZURE study
3
Zoledronic Acid vs. Clodronate / Risedronate in Adjuvant Primary BC
Patients6,000 stage I, II, IIIa breast cancer patients receiving “standard” systemic therapy
Treatment (3 years)– Clodronate 1,600 mg po qd
vs.– Risedronate 30 mg po qd
vs.– Zoledronic Acid 4 mg IV q month x 6, followed by
q3 months
Intergroup Trial S0307
“Effectiveness of Zometa® treatment for the prevention of bone metastases in
high risk prostate cancer patients.
A randomized, open label, multicenter study of the European Association of Urology (EAU) in cooperation with the Scandinavian Prostate Cancer Group (SPCG) and thye Arbeitsgemeinschaft
Urologische Onkologie (EAU) “
Study ObjectiveStudy Objective
Evaluate if the early administration of Zometa in high risk prostate cancer patients can prevent or delay the appearance of bone metastases.
Study EligibilityStudy Eligibility
Non metastatic patients > 18 y/o and ECOG PS = 0
Gleason score > 8 a/o presence of positive lymphnodes a/o PSA > 20 at diagnosis.
Study Study OutlineOutline
RANDOMIZATION
Zometa 4 mg every 3 months
Control group
In both groups a supplement of 500 mg calcium and 400-500 IU of vitamin D will be administered.In case of appearance of bone mets, treatment with BP every 4 weeks is recommended.
Bifosfonati e osteoporosi Bifosfonati e osteoporosi correlata alla neoplasia correlata alla neoplasia
Neoplasia prostatica
Neoplasia mammaria
Ipogonadismo
– nella donna menopausa precoce da chemioterapia menopausa precoce da LHRH-analoghi deficit di estrogeni da inibitori delle aromatasi
– nell’uomo andropausa precoce da chemioterapia orchiectomia / LHRH-analoghi
Altri fattori chemioterapia (effetto diretto) glucocorticoidi
Meccanismi implicati nella diminuzione Meccanismi implicati nella diminuzione della Densità Minerale Ossea (BMD)della Densità Minerale Ossea (BMD)
36
62
0
10
20
30
40
50
60
70
80
90
100
% o
f p
atie
nts
w
ith
ost
eop
oro
sis
12 months 24 months
Risk of Osteoporosis after LHRH Risk of Osteoporosis after LHRH TreatmentTreatment
P<0.001
P<0.001
Weston R, Hussain A, Stephenson RN, George E, Parr NJ. Presented at the British Association of Urological Surgeons Annual Meeting June 23-27, 2003, in Manchester, UK.
In men osteopenicat baseline
Androgen Deprivation Therapy (ADT) Androgen Deprivation Therapy (ADT) Increases Fracture RiskIncreases Fracture Risk
0
10
20
30
40
50
Cu
mu
lati
ve f
ract
ure
inc
iden
ce
(%
)
0 1 2 3 4 5 6 7 8 9
YearsDaniell. J Urol. 1997;157:439.
Orchiectomy
Control
Fractures May Reduce SurvivalFractures May Reduce Survival
Can Bisphosphonates Can Bisphosphonates Prevent Bone Loss Prevent Bone Loss
Due to ADT?Due to ADT?
ADT + zoledronic acid (4 mg q3mo)
ADT + placebo
M0 prostate cancer (n=106)
RANDOMIZE
Zoledronic Acid Bone Loss StudyZoledronic Acid Bone Loss Study
*Both arms received a daily oral vitamin D 400 IU and calcium 500 mg
Smith et al. J Urol. 2003;169:2008.
Results:Results:
5,6
7,0
-1,9-2,7
3,9
-2.2-3,6
-1,6
0,4
2,4
4,4
6,4
8,4 Zoledronic acid Placebo
All GnRH GnRH +antiandrogen
P<0.001
P<0.001
P<0.001
Smith et al. J Urol. 2003;169:2008.
LS
me
an p
erce
nt
ch
ang
e f
rom
ba
sel
ine
Fracture Rates in Adjuvant Trials of Fracture Rates in Adjuvant Trials of Aromatase InhibitorsAromatase InhibitorsAromatase Inhibitor
Tamoxifen /Placebo*
Reference
ATAC 340 (11%) 237 (7.7%) Howell 2005
BIG 1-98 228 (5.8%) 162 (4.1%) Thurlimann 2005
IES 111 (5.0%) 82 (3.5%) Coleman 2004
ABCSG/ARNO MA-17*
34(2.0%)
137(5.3%)
16 (1.0%)
119 (4.6%)
Jakesz 2005
Perez 2004
0 5 y(Final analysis)
RRAANNDDOOMMIIZZEEDD
3 y1 y
Eligibility• ER+/PgR+ tumor• PMW with
T score ≥2
Stratification adjuvant chemo• T score >1 or
between 1 and 2
Z-FAST (Zometa-FemaraZ-FAST (Zometa-FemaraAdjuvant Synergy Trial)Adjuvant Synergy Trial)
+ letrozole 2.5 mg/d*
UPFRONT zoledronic acid 4 mg q6mo
+ letrozole 2.5 mg/d*
DELAYED† zoledronic acid 4 mg q6mo
Accrual complete: N=602
*Plus daily calcium (1000-1200 mg) and vitamin D (400-800 IU).†Initiation determined by postbaseline T score below 2, clinical fracture, or asymptomatic fracture at 36 months.PMW = postmenopausal women.Update of Brufsky et al. J Clin Oncol. 2005;23(16S):12s. Abstract 533.
Z-FAST: Changes in Bone Mineral Z-FAST: Changes in Bone Mineral Density at Months 6 and 12Density at Months 6 and 12
Lumbar spine
Total hip
P<0.0001
P<0.0001
Month 6 Month 12 Month 6 Month 12
SD = standard deviation; BMD = bone mineral density.Update of Brufsky et al. J Clin Oncol. 2005;23(16S):12s. Abstract 533.
-8
-6
-4
-2
0
2
4
6
Me
an
% c
ha
ng
e (
± S
D)
in B
MD
(g
/cm
2)
Upfront group
Delayed group
Possiamo ottimizzare l’efficacia dei Possiamo ottimizzare l’efficacia dei bifosfonati?bifosfonati?
Schedula ottimaleSchedula ottimale
Altre opzioni teraputicheAltre opzioni teraputiche
Use of Bone Resorption Markers to Direct Use of Bone Resorption Markers to Direct Zoledronic Acid Therapy - BISMARKZoledronic Acid Therapy - BISMARK
1400 patients with bone metastases from breast cancer Bone resorption assessed every 16 weeks- Urinary NTX Primary endpoint: Risk of skeletal events (SRE) with time Non-inferiority design
RANDOMI SE
Bone marker (NTX) directed therapy
Q 4, 8 or 16 weeks
Zoledronic acid 4mg iv 3-4 weekly
Cell Signaling in the Control of Bone Cell Cell Signaling in the Control of Bone Cell Function-The RANK / RANK-L and OPG Function-The RANK / RANK-L and OPG
SystemSystem
RANK ligand
Hormones,Inflammationand Cancer
products
BONE
OPG
OsteoblastsOsteoclast
Osteoclast Precursor
AMG 162AMG 162
Fully Human MoAb with high affinity and specificity for RANKL that can bind and neutralize the activity of human RANKL similar to the action of native OPG.
Clinical experience:– Single doses of up to 3 mg/kg sc or iv have been
studied– A single sc or iv dose was effective in reducing
markers of bone turnover (urinary NTX), and the duration of effect was at least 6 months at higher doses in healthy postmenopausal women, and 3 mos in MM or MBC
Breast Cancer Phase 1: Inhibition of Bone Breast Cancer Phase 1: Inhibition of Bone Turnover in AMG 162 vs. PamidronateTurnover in AMG 162 vs. Pamidronate
Time (day)
0 14 28 42 56 70 84
Uri
na
ry N
Tx
/UC
RT
% o
f B
as
eli
ne
0
20
40
60
80
100
120
140
160
180
200
0.1 mg/kg (n=5-7)0.3 mg/kg (n=5-7)1.0 mg/kg (n=6-7)3.0 mg/kg (n=3)pamidronate 90 mg
Uri
nar
y N
Tx/
Cre
ati n
ine
% o
f B
asel
i ne
(Mea
n ±
SD
)
Peterson MC, et al. Proc. ASCO 2004
VI RINGRAZIO PER L’ATTENZIONE!VI RINGRAZIO PER L’ATTENZIONE!
Courtesy by Donatella Decise
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