RUOLO DEI BISFOSFONATI NEL TRATTAMENTO

1
RUOLO DEI BISFOSFONATI NEL TRATTAMENTO DEL
PAZIENTE ANZIANO CON NEOPLASIA METASTATICA
ALLOSSO Daniele Santini Oncologia
Medica Università Campus Bio-Medico di Roma
Presente e futuro della terapia di supporto in
oncologiaRoma, 22-23 Giugno 2006
2
Metastatic Bone Disease Is Prevalent
Incidence of bone metastases in cancers2
5-year world prevalence,thousands1


Median survival, Months2-4

Myeloma
144
70 - 95
6 - 54
Renal
480
20 - 25
12
14 - 45
Melanoma
533
6
More lytic
1,000
Bladder
6 - 9
40
Thyroid
475
60
48
More blastic
6 - 7
Lung
1,394
30 - 40
Breast
65 - 75
19 - 25
3,860
Prostate
1,555
65 - 75
12 - 53
1. Ferlay J, et al. IARC Globocon 2000. Cancer
Incidence, Mortality, and Prevalence. 2. Coleman
RE. Cancer Treat Rev. 200127165-176. 3. Coleman
RE. Cancer. 1997801588-1594. 4. Zekri J et al.
Int J Oncol. 200119379-382.
3
Prevalence of Skeletal-Related Events in 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 22
• Hypercalcemia of malignancy 13 9 1 4
• Surgery to bone 11 5 4 5
• Spinal cord compression 3 3 8 4

Excluding hypercalcemia
4
Key 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
  dellosteoporosi indotta dal trattamento
  antineoplastico
• Possiamo ottimizzare lefficacia dei bifosfonati?
• Schedula ottimale
• Altre opzioni teraputiche

5
Different Classes of Bisphosphonates1,2
1 gen 2 gen 3 gen

• etidronate
  clodronate tiludronate

pamidronate alendronate
ibandronate
1. Thurlimann B. Bisphosphonates in Clinical
Oncology Focus on Pamidronate. 1999. 2.
Fleisch H, Endocr Rev. 1998.
zoledronic acid
6
Efficacia dei diversi bisfosfonati
Zoledronic acid
3
10
Ibandronate
Risedronate
10
2
Alendronate
Olpadronate
Relative inhibitory potencyin vitro, bone
cultures
Pamidronate
Clodronate
10
1
Neridronate
R 0.97
0
10
Etidronate
0
1
2
3
6
10
10
10
10
10
10
5
10
4
Relative inhibitory potency in vivo,
hypercalcemic rat
Green JR, et al. J Bone Miner Res. 19949745-751.
7
Eventi scheletrici (SRE)rilevabili 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
8
Stime di efficacia per la valutazione del
trattamento 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

9
Efficacy of bisphosphonates in Patients With
Breast Cancer
10
Ca. mammario bisfosfonati vs. placebo
pazienti con 1 SRE

• P
• BP placebo decrease value
• Pamidronate1 51 64 20 lt0.001
• 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
11
Ca. mammario bisfosfonati vs. placebo
mediana del tempo a comparsa del primo SRE

• 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
12
Ca. mammario Ac.Zoledronico vs. pamidronato
Independent Survival-Adjusted Multiple Event
Analysis (Cook Lawless approach)
Pamidronate
P .046
Zoledronic acid 4 mg
3
6
9
12
15
18
21
24
Time since randomization, months
Major P, et al. Proc Am Soc Clin Oncol.
200322762. Abstract 3062.
13
Ca. mammario Ac.Zoledronico vs. pamidronato
Multiple event analysis (Andersen-Gill)
Riskreduction
P value
.799
.025
20
HCM
.816
.042
18
HCM
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Risk ratio (zoledronic 4 mg acid versus pam)
In favor of zoledronic acid
In favor of pamidronate
Rosen LS, et al. Cancer. 2003981735-1744.
14
Ca. mammario Ac.Zoledronico vs. pamidronato
Presenza di dolore osseo allarruolamento
mean BPI change from baseline
Zoledronic acid
Pamidronate
12
24
36
48
0
Time on study (weeks)
Lipton, 5th International Conference on CIBD,
Davos 2005 (data not published)
15
Ca. mammario Ac.Zoledronico vs. pamidronato
Non dolore osseo allarruolamento
Pamidronate
mean BPI change from baseline
Zoledronic acid
12
24
36
48
0
Time on study (weeks)
Lipton, 5th International Conference on CIBD,
Davos 2005 (data not published)
16
Efficacia dei bisfosfonatiin neoplasie diverse
dal ca. mammario

• 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

Coleman R, 5th International Conference on CIBD,
Davos 2005
17
Efficacy of bisphosphonates in Patients With
Prostate Cancer
18
Stadio 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)

19
Stadio HRPC

• 43 di SREs (vertebral collapse20.5
  fracture12.5 spinal cord compression10)
• 5 di SREs avvenuti prima di HRPC
• 38 di SREs avvenuti in HRPC
• 100 radioterapia in pts con SREs
• 6.5 sottoposti a chirurgia
• Conclusioni
• In analisi multivariata il dolore osseo e
  lestesione della malattia ossea sono due fattori
  indipendenti predittivi per SREs

20
Ca. prostatico A. Zoledronico vs. placebo
Independent Survival-Adjusted Multiple Event
Analysis (Cook Lawless approach)
Placebo
P .0023
Zoledronic acid 4 mg
3
6
9
12
15
18
21
24
Time since randomization, months
Major P, et al. Proc Am Soc Clin Oncol.
200322762. Abstract 3062.
21
Ca. prostatico A. Zoledronico vs. placebo
Multiple event analysis (Andersen-Gill)
Riskreduction
P value
0.640
36
.002
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0
0.2
Risk ratio (zoledronic acid 4 mg versus placebo)
In favour of zoledronic acid
In favour of placebo
Saad et al. J Natl Cancer Inst. 2004
22
Ca. prostatico A. Zoledronico vs. placebo
Change from baseline pain score (BPI)
1.2
P lt .05
1
0.8
Mean change from baseline


0.6

0.4
0.2

0
0
3
6
9
12
15
18
21
24
Time on study, months
Saad et al. J Natl Cancer Inst. 2004
23
Overall Survival Zoledronic Acid
Median, days P value Zol acid 4 mg 18.2 m
.103 Placebo 15.6 m
Zol 4 mg 214 162 113 56 10Placebo 208 148 94
40 5
Saad F, et al. JNCI June 2004
24
Altre neoplasie (NSCLC, RCC)A. Zoledronico vs.
placebo
Independent Survival-Adjusted Multiple Event
Analysis (Cook Lawless approach)
Placebo
P .010
Zoledronic acid 4 mg
3
6
9
12
15
18
21
24
Time since randomization, months
Major P, et al. Proc Am Soc Clin Oncol.
200322762. Abstract 3062.
25
Altre neoplasie A. Zoledronico vs. placebo
Multiple event analysis (Andersen-Gill)
Riskreduction
P value
0.693
All patients
.003
31
0.675
NSCLC
.016
32
0.418
RCC
58
.010
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Risk ratio (zoledronic acid 4 mg versus placebo)
In favour of zoledronic acid
In favour of placebo
Hypercalcemia of malignancy is included as a
skeletal-related event. Data from Rosen et al.
Cancer. 2004 RCC subset Lipton A. Cancer.
200398962-969.
26
Tempi di somministrazione dei bisfosfonati

• 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

Coleman R, 5th International Conference on CIBD,
Davos 2005
27
BIFOSFONATI

• SAFETY

28
Advisory Board on Bisphosphonates in the elderly
29
Osteonecrosi e elderly
30
Elderly and renal function
31
Breast cancer and MyelomaRenal safety in elderly
versus young population
thus NO higher risk than young patients
32
Prostate cancer and other cancersRenal safety in
elderly versus young population
thus NO higher risk than young patients
33
Renal safety and elderly
34
Renal Safety of Zoledronic Acid in Patients With
Solid Tumors
35
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 gt 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 (lt 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
2003981735-1744.
36
Safety of iv Bisphosphonates beyond two years

• 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

37
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 (range2-10) Significant ? SCr (G1) 12.2

• Ali SM, Esteva FJ, Hortobagyi G. J Clin Oncol.
  2001193434-3437.
• Guarneri et al, The Oncologist, 2005

38
Ibandronate renal safety

• Monitoring of SCr prior to each administration
  not mandatory
• Can be administered in case of renal failure
  (creatinine clearance lt 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
39
Hypocalcemia induced by bisphosphonates
40
IPOCALCEMIA DA ZOLEDRONATO /PAMIDRONATO
GENERALMENTE

• Modesta e graduale (7.5-8 mg/dl (vn 8.5-10mg/dl)
• Asintomatica
• Transitoria (può persistere a lungo se Insuff.
  Renale anche modesta)

• PRATICAMENTE SEMPRE
• IPERPARTORIDISMO SECONDARIO
• persiste per tutta la durata del trattamento con
  BPs
• frequente anche con basse dosi di BPs per os
  (alendronato, risedronato)
• nellosteoporosi postmenopausale

• è presente nel 30 dei maschi con cr prostata
• è presente nel 70 dei soggetti gt 60 anni
  (ipovitaminosi D)

41
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 (lt 7 mg)
ASINTOMATICA Rocaltrol 0.5 y 2 volte die 1000
mg Calcio per OS Calcio gluconato I.V. solo nel
caso TETANIA
42
Studi di terapia adiuvantecon Acido Zoledronico

• Neoplasia Studio Scopo
• Ca. mammario AZURE Prevenz. MO
• IG-S0307 Prevenz. MO
• Ca. prostatico RADAR Prevenz. MO
• CECOG Prevenz. MO EAU-ZEUS Prevenz. MO
• MRC-STAMPEDE Prevenz. /
• ritardo MO
• NSCLC (IIIA-IIIB) G2419 Prevenz. /
• ritardo MO

43
Definitive Adjuvant Bisphosphonate Trials - NSABP
B34

• Patients 4,200 patients with stage I or II
  breast cancer may receive chemotherapy, hormonal
  therapy, both, or neither

R A N D O M I SE
Clodronate 1,600 mg OD ? 3 yr
Placebo ? 3 yr
Recruitment completed
44
Acido Zoledronico adiuvante nel ca. mammario
The AZURE study
3
45
Zoledronic Acid vs. Clodronate / Risedronate in
Adjuvant Primary BC
Intergroup Trial S0307

• 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 qdvs.
• Zoledronic Acid 4 mg IV q month x 6, followed by
  q3 months

46
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)
47
Study Objective

• Evaluate if the early administration of Zometa in
  high risk prostate cancer patients can prevent or
  delay the appearance of bone metastases.

48
Study Eligibility

• Non metastatic patients gt 18 y/o and ECOG PS 0
• Gleason score gt 8 a/o presence of positive
  lymphnodes a/o PSA gt 20 at diagnosis.

49
Study Outline
Zometa 4 mg every 3 months
R A N D O M I Z A T I O N
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.
50
Bifosfonati e osteoporosi correlata alla
neoplasia

• Neoplasia prostatica
• Neoplasia mammaria

51
Meccanismi implicati nella diminuzione della
Densità Minerale Ossea (BMD)

• Ipogonadismo
• nella donna
• menopausa precoce da chemioterapia
• menopausa precoce da LHRH-analoghi
• deficit di estrogeni da inibitori delle aromatasi
• nelluomo
• andropausa precoce da chemioterapia
• orchiectomia / LHRH-analoghi
• Altri fattori
• chemioterapia (effetto diretto)
• glucocorticoidi

52
Risk of Osteoporosis after LHRH Treatment
Plt0.001
In men osteopenic at baseline
Plt0.001
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.
53
Androgen Deprivation Therapy (ADT) Increases
Fracture Risk
50
40
30
Cumulative fracture incidence ()
20
10
0
0
1
2
3
4
5
6
7
8
9
Years
Daniell. J Urol. 1997157439.
54
Fractures May Reduce Survival
55
Can Bisphosphonates Prevent Bone Loss Due to ADT?
56
Zoledronic Acid Bone Loss Study
M0 prostate cancer (n106)
RANDOMIZE
ADT zoledronic acid (4 mg q3mo)
ADT placebo
Both arms received a daily oral vitamin D 400
IU and calcium 500 mg
Smith et al. J Urol. 20031692008.
57
Results
Plt0.001
Plt0.001
Plt0.001
LS mean percent change from baseline
Smith et al. J Urol. 20031692008.
58
Fracture Rates in Adjuvant Trials of Aromatase
Inhibitors
Aromatase 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
59
Z-FAST (Zometa-FemaraAdjuvant Synergy Trial)
R A N DO M I Z E D

• Eligibility
• ER/PgR tumor
• PMW withT score ?2
• Stratification
• ? adjuvant chemo
• T score gt?1 or between ?1 and ?2

UPFRONT zoledronic acid 4 mg q6mo
letrozole 2.5 mg/d

DELAYED zoledronic acid 4 mg q6mo
letrozole 2.5 mg/d
0
5 y (Final analysis)
3 y
1 y
Accrual complete N602
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. 200523(16S)12s. Abstract 533.
60
Z-FAST Changes in Bone Mineral Density at Months
6 and 12
6
Upfront group
Delayed group
4
2
0
Mean change ( SD)in BMD (g/cm2)
-2
-4
Plt0.0001
-6
Plt0.0001
-8
Month 12
Month 6
Month 6
Month 12
Total hip
Lumbar spine
SD standard deviation BMD bone mineral
density. Update of Brufsky et al. J Clin Oncol.
200523(16S)12s. Abstract 533.
61
Possiamo ottimizzare lefficacia dei bifosfonati?
Schedula ottimale Altre opzioni teraputiche
62
Use of Bone Resorption Markers to Direct
Zoledronic 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

R A N D O M I SE
Bone marker (NTX) directed therapy Q 4, 8 or 16
weeks
Zoledronic acid 4mg iv 3-4 weekly
63
Cell Signaling in the Control of Bone Cell
Function-The RANK / RANK-L and OPG System
Hormones,
Inflammation
and
Cancer
Osteoclast Precursor
products
OPG
RANK ligand
Osteoclast
Osteoblasts
BONE
64
AMG 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

65
Breast Cancer Phase 1 Inhibition of Bone
Turnover in AMG 162 vs. Pamidronate
Urinary NTx/Creatinine of Baseline(Mean SD)
Peterson MC, et al. Proc. ASCO 2004
66
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