RUOLO DEI BISFOSFONATI NEL TRATTAMENTO DEL PAZIENTE ANZIANO CON NEOPLASIA METASTATICA ALLOSSO Daniele Santini Oncologia Medica Università Campus Bio-Medico.

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

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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


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

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SR

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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)


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


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


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


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


0.0

0.2

0.4

0.6

1.0

1.2

0

0.8

Cu

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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



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


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


0.0

0.2

0.4

0.6

1.0

1.2

0

0.8

Cu

mu

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ve e

xpec

ted

SR

Es,

n



Altre neoplasie: A. Zoledronico vs. placeboAltre neoplasie: A. Zoledronico vs. placebo


*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


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

RUOLO DEI BISFOSFONATI NEL TRATTAMENTO DEL PAZIENTE ANZIANO CON NEOPLASIA METASTATICA ALLOSSO Daniele Santini Oncologia Medica Università Campus Bio-Medico.

Documents

event slide

gen slide

hypercalcemia slide

prevalent slide

breast cancer slide

safety of zoledronic

event time

scr safety