1. Daniele Santini RUOLO DEI BISFOSFONATI NEL TRATTAMENTO
DEL PAZIENTE ANZIANO CON NEOPLASIA
METASTATICA ALL’OSSO
Daniele Santini
Oncologia Medica
Università Campus Bio-Medico di Roma
Presente e futuro della terapia di supporto in oncologia Roma, Giugno 2006

2. Metastatic Bone Disease Is Prevalent
5-year world
prevalence, thousands1
Incidence of
bone metastases
in cancers2
Median survival,
Months2-4
Myeloma
144
6 - 54
Renal
480 12
Melanoma
533 6
More lytic
Bladder
1,000 40
6 - 9
Thyroid
475 60 48
More blastic
Lung
1,394
6 - 7
Incidence of bone metastases in cancers
High incidence of bone metastases sets the stage for skeletal complications
A wide range of cancer types is associated with a high incidence of skeletal involvement, and the resulting lesions vary in radiographic appearance across a continuum from osteolytic to osteoblastic
Approximately 80% of patients with multiple myeloma have radiographic evidence of predominantly osteolytic bone destruction
The prevalence (number of cases worldwide during a 5-year period) of bone metastases is greatest in breast and prostate cancer, reflecting both the high incidence and the relatively long clinical courses of these tumors.1 These 2 cancers probably account for more than 80% of cases of metastatic bone disease. Bone metastases associated with breast cancer are typically a mixture of osteolytic, mixed, and osteoblastic lesions, whereas prostate carcinoma is usually associated with sclerotic (osteoblastic) lesions
Bone metastases cause considerable morbidity—including pain, impaired mobility, pathologic fracture, spinal-cord or nerve-root compression, and hypercalcemia of malignancy (HCM)2
References
Ferlay J, Bray F, Pisani P, Parkin DM. IARC Globocon Cancer Incidence, Mortality, and Prevalence.
Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80:
Breast
3,860
Prostate
1,555
1. Ferlay J, et al. IARC Globocon Cancer Incidence, Mortality, and Prevalence.
2. Coleman RE. Cancer Treat Rev. 2001;27:
3. Coleman RE. Cancer. 1997;80:
4. Zekri J et al. Int J Oncol. 2001;19:

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
Fractures
Hypercalcemia of malignancy
Surgery to bone 11 5† 4 5
Spinal cord compression 3 3† 8 4
In the placebo-controlled trials of pamidronate and zoledronic acid, the placebo arm provides an accurate picture of the extent to which patients suffer these various skeletal complications
Radiation to bone and pathologic fractures are the most common events, reflecting the burden of bone pain and the fragility of patients’ bones
Patients with breast cancer have the highest incidence of skeletal complications—approximately half the patients in the placebo arm experienced a fracture over the 2 years on study, and 11% of patients required orthopedic surgery
Therefore, there is a great need to provide effective therapy to reduce the risk of these painful and debilitating skeletal complications
*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 dell’osteoporosi indotta dal trattamento antineoplastico
Possiamo ottimizzare l’efficacia 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
2. Fleisch H, Endocr Rev
zoledronic acid

6. Efficacia dei diversi bisfosfonati
Zoledronic acid 10 3
Ibandronate
Risedronate 10 2
Olpadronate
Alendronate
Relative inhibitory potency in vitro, bone cultures
Pamidronate
Clodronate 10 1
Neridronate
L’acido zoledronico, con l’inclusione di due atomi di azoto nell’anello eterociclico, ha una potenza da 100 a volte maggiore rispetto agli altri bisfosfonati. 10
R = 0.97
Etidronate 10 10 1 10 2 10 3 10 4 10 5 10 6
Relative inhibitory potency in vivo, hypercalcemic rat
Green JR, et al. J Bone Miner Res. 1994;9:

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
Sulla base della rilevazione del “composite endpoint” SREs vengono di norma utilizzate varie metodiche di stima di efficacia basate :
sul primo SRE rilevato
sul numero di SREs osservati nel tempo per ciascun soggetto
sul numero di definiti intervalli di tempo con SRE per ciascun soggetto (metodica peculiare per l’Ibandronato)
sul tempo alla comparsa di ciascun SRE, per tutti gli SREs complessivamente osservati

9. Efficacy of bisphosphonates in Patients With Breast Cancer

10. Ca. mammario: bisfosfonati vs. placebo
% pazienti con ≥1 SRE
% P
BP placebo decrease value
Pamidronate % <0.001
Oral Ibandronate % 0.122
IV Ibandronate % 0.052
Zoledronic acid % 0.003
1Lipton, Cancer 2000; 2Body, Ann Oncol 2003; 3Body, Br J Cancer 2004; 4Kohno, J Clin Oncol 2005
L’acido zoledronico riduce del 40% la percentuale di pazienti con almeno un SRE
raddoppia l’efficacia a sua volta dimostrata dal pamidronato vs. placebo
dimostra un’efficacia di gran lunga superiore rispetto alle due formulazioni di ibandronato* nei confronti di placebo
NB I confronti indiretti del tipo “se A è migliore di B e C non è migliore di B, allora A è migliore di C” hanno solo valore informativo, non assoluto!
* Il confronto fra ciascuna delle due formulazioni di ibandronato vs placebo non ha raggiunto la significatività statistica in entrambi i casi
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
Clodronate % 0.022
Pamidronate % 0.001
Oral Ibandronate % 0.089
IV Ibandronate % 0.018
Zoledronic acid5 NR %* 0.007
1Pavlakis, Cochrane review 2004; 2Lipton, Cancer 2000; 3Body, Ann Oncol 2003; 4Body, Br J Cancer 2004; 5Kohno, J Clin Oncol 2005; *estimated
L’acido zoledronico incrementa di oltre il 100% il tempo a comparsa del primo SRE
quasi raddoppia l’effetto a sua volta dimostrato dal clodronato vs. placebo
aumenta del 25% l’effetto del pamidronato vs. placebo
dimostra un’efficacia di gran lunga superiore rispetto alle due formulazioni di ibandronato* nei confronti di placebo
NB I confronti indiretti del tipo “se A è migliore di B e C non è migliore di B, allora A è migliore di C” hanno solo valore informativo, non assoluto!
* Il confronto fra la formulazione orale di ibandronato vs placebo non ha raggiunto la significatività statistica
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)
0.0
0.2
0.4
0.6
1.0
1.2
0.8
Cumulative expected SREs, n
L’acido zoledronico riduce in maniera significativa l’incidenza nel tempo degli SREs, per tutti gli SREs complessivamente osservati (multiple-event analysis) rispetto al pamidronato
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. 2003;22:762. Abstract 3062.

13. Ca. mammario: Ac.Zoledronico vs. pamidronato
Multiple event analysis (Andersen-Gill)
Risk reduction
P value
.799
+HCM
20%
.025
.816
–HCM
18%
.042
L’acido zoledronico è in grado di ridurre il rischio globale di SREs (multiple-event analysis) del 20% circa rispetto al pamidronato, indipendentemente dalla presenza o meno di ipercalcemia neoplastica.
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. 2003;98:

14. Ca. mammario: Ac.Zoledronico vs. pamidronato
Presenza di dolore osseo all’arruolamento
mean BPI change from baseline
Zoledronic acid
L’acido zoledronico riduce il dolore osseo (già presente al momento dell’instaurazione del trattamento) in maniera paragonabile a quanto ottenibile con il pamidronato
Pamidronate 12 24 36 48
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 all’arruolamento
Pamidronate
mean BPI change from baseline
Zoledronic acid
L’acido zoledronico previene la comparsa di dolore osseo (non presente al momento dell’instaurazione del trattamento) in maniera sostanzialmente maggiore a quanto ottenibile con il pamidronato 12 24 36 48
Time on study (weeks)
Lipton, 5th International Conference on CIBD, Davos 2005 (data not published)

16. Efficacia dei bisfosfonati in 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)
Data
from september 2000 to december 2001
115 ps underwent SNB under local anesthesia in our centre
the median age was 54 years old (with a range of years old)
the diameter of primary tumor (T) was 1,4 cm

19. Stadio : HRPC
43% di SREs (vertebral collapse=20.5%; fracture=12.5%; spinal cord compression=10%)
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 l’estesione della malattia ossea sono due fattori indipendenti predittivi per SREs
Data
from september 2000 to december 2001
115 ps underwent SNB under local anesthesia in our centre
the median age was 54 years old (with a range of years old)
the diameter of primary tumor (T) was 1,4 cm

20. Ca. prostatico: A. Zoledronico vs. placebo
Independent Survival-Adjusted Multiple Event Analysis
(Cook & Lawless approach)
0.0
0.2
0.4
0.6
1.0
1.2
0.8
Cumulative expected SREs, n
L’acido zoledronico riduce in maniera significativa l’incidenza nel tempo degli SREs, per tutti gli SREs complessivamente osservati (multiple-event analysis) rispetto al placebo
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. 2003;22:762. Abstract 3062.

21. Ca. prostatico: A. Zoledronico vs. placebo
Multiple event analysis (Andersen-Gill)
Risk reduction
P value
0.640
36%
.002
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
L’acido zoledronico è in grado di ridurre il rischio globale di SREs (multiple-event analysis) del 36% rispetto al placebo
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 < .05 1
0.8
Mean change from baseline * *
0.6 *
Mean n baseline BPI
Zol 4 mg
Placebo
0.4
L’acido zoledronico è in grado di assicurare una significativa riduzione del dolore nel tempo (in termini di modificazioni del questionario BPI dal livello basale) rispetto al placebo
0.2 * 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 m
Placebo 15.6 m
Zol 4 mg Placebo
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)
0.0
0.2
0.4
0.6
1.0
1.2
0.8
Cumulative expected SREs, n
L’acido zoledronico riduce in maniera significativa l’incidenza nel tempo degli SREs, per tutti gli SREs complessivamente osservati (multiple-event analysis) rispetto al placebo
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. 2003;22:762. Abstract 3062.

25. Altre neoplasie: A. Zoledronico vs. placebo
Multiple event analysis (Andersen-Gill)
Risk reduction
P value
0.693
All patients
31%
.003
0.675
NSCLC
32%
.016
0.418
RCC
58%
.010
L’acido zoledronico è in grado di ridurre il rischio globale di SREs (multiple-event analysis) del 31% rispetto al placebo
Particolarmente interessante è l’entità della riduzione del rischio (58%) osservata nei pazienti con ca. renale
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. 2003;98:

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. …thus NO higher risk than young patients
Breast cancer and Myeloma Renal safety in elderly versus young population
…thus NO higher risk than young patients

32. …thus NO higher risk than young patients
Prostate cancer and other cancers Renal 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 > 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:

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: )
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: )
Clinically insignificant
 SCr
Guarneri^ 57
3 Pam.
11 Zoledronate
43 Both
3.5 yrs
(range:2-10)
Significant  SCr (G1) 12.2%
Both ZOL and PAM are safe to use long-term if prescription protocols are adhered with.
Ali SM, Esteva FJ, Hortobagyi G. J Clin Oncol. 2001;19:
^ 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 < 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 mg/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)
nell’osteoporosi postmenopausale
è presente nel 30% dei maschi con cr prostata
è presente nel 70% dei soggetti > 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 (< 7 mg) ASINTOMATICA
Rocaltrol 0.5 y 2 volte die mg Calcio per OS
Calcio gluconato I.V. solo nel caso TETANIA

42. Studi di terapia adiuvante con 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. /

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
Patients 6,000 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

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 > 18 y/o and ECOG PS = 0
Gleason score > 8 a/o presence of positive lymphnodes a/o PSA > 20 at diagnosis.

49. Study Outline Zometa 4 mg every 3 months Control group
In both groups a supplement of 500 mg calcium and 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
nell’uomo
andropausa precoce da chemioterapia
orchiectomia / LHRH-analoghi
Altri fattori
chemioterapia (effetto diretto)
glucocorticoidi

52. Risk of Osteoporosis after LHRH Treatment
In men osteopenic
at baseline
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.

53. Androgen Deprivation Therapy (ADT) Increases Fracture Risk50
Orchiectomy
Control 40 30
Cumulative fracture incidence (%) 20
Similar to the effects of estrogen deprivation in postmenopausal women, osteoporotic fractures were found to increase in men who had received therapeutic orchiectomy to induce androgen deprivation as treatment for prostate cancer1
The cumulative incidence of first fractures 7 years after diagnosis with nonstage A prostate cancer was 1% for patients who did not undergo therapeutic orchiectomy (dark line) and 28% for patients who underwent orchiectomy (dashed line)
Although there are limited long-term data on osteoporotic fracture rates in patients who have been treated with nonsurgical ADT regimens, androgen depletion has been shown to greatly accelerate bone loss2
References
Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol. 1997;157:
Daniell HW, Dunn SR, Ferguson DW, et al. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol. 2000;163: 10 1 2 3 4 5 6 7 8 9
Years
Daniell. J Urol. 1997;157:439.

54. Fractures May Reduce Survival

55. Can Bisphosphonates Prevent Bone Loss Due to ADT?

56. Zoledronic Acid Bone Loss Study
M0 prostate cancer (n=106)
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. 2003;169:2008.

57. Results: change from baseline LS mean percent P<0.001 P<0.001
Mean percent change from baseline lumbar spine BMD are presented here
Patients in the placebo group had a significant decrease from baseline BMD
Loss of BMD was greatest in patients receiving combined therapy with a GnRH agonist and an antiandrogen
ZOMETA not only prevented the bone loss associated with ADT, but also increased BMD. The differences in BMD between the ZOMETA and placebo treatment groups were significant for the overall population and for patients receiving each type of ADT
Smith et al. J Urol. 2003;169:2008.

58. Fracture Rates in Adjuvant Trials of Aromatase Inhibitors
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-Femara Adjuvant Synergy Trial)
D O M I Z E D
Eligibility
ER+/PgR+ tumor
PMW with T score ≥2
Stratification
 adjuvant chemo
T score >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*
1 y
3 y
5 y
(Final analysis)
Accrual complete: N=602
*Plus daily calcium ( mg) and vitamin D ( 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.

60. Z-FAST: Changes in Bone Mineral Density at Months 6 and 12
Upfront group
Delayed group 4 2
Mean % change (± SD) in BMD (g/cm2) -2 -4 -6
P<0.0001
P<0.0001 -8
Month 6
Month 12
Month 6
Month 12
Lumbar spine
Total hip
SD = standard deviation; BMD = bone mineral density.
Update of Brufsky et al. J Clin Oncol. 2005;23(16S):12s. Abstract 533.

61. Possiamo ottimizzare l’efficacia dei bifosfonati?
Schedula ottimale
Altre opzioni teraputiche

62. Bone marker (NTX) directed therapy Zoledronic acid 4mg iv 3-4 weekly
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
The OPG, OPGL, RANK pathway has been found to be central to the regulation of bone resorption. Hormones, such as PTH and 1,25(OH)2D3, inflammatory cytokines and cancer products such as PTHrP, increase bone resorption by binding to their receptors on osteoblasts. Osteoblasts (the cells which make bone) then express OPG ligand which acts on osteoclast precursors to induce osteoclast formation and on mature osteoclasts to increase activity and survival. OPG opposes this process and is also produced by osteoblasts.
Osteoclast
Osteoblasts
BONE 3

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. Urinary NTx/Creatinine % of Baseline (Mean ± SD)
Breast Cancer Phase 1: Inhibition of Bone Turnover in AMG 162 vs. Pamidronate
Urinary NTx/Creatinine % of Baseline (Mean ± SD)
In breast cancer patients, AMG 162 produced rapid (within 24 hours) and sustained reductions in bone turnover as assessed by percent change from baseline in uNTx/creatinine. Inhibition of bone turnover was more sustained with AMG 162 (1.0 and 3.0 mg/kg) compared to pamidronate. At doses greater than 0.3 mg/kg, AMG 162 produced marked suppression in uNTx/creatinine with median maximal suppression greater than 75%. A 1.0 mg/kg dose produced sustained median suppression (>70%) for the duration of the study (84 days).1,2
Peterson MC, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of AMG 162, a fully human monoclonal antibody to Receptor Activator of NF kappa B Ligand (RANKL), following a single subcutaneous dose to patients with cancer-related bone lesions. Poster presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, St Louis, MO.
Peterson MC, Martin SW, Stouch B, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of AMG 162, a fully human monoclonal antibody to Receptor Activator of NF kappa B Ligand (RANKL), following a single subcutaneous dose to patients with cancer-related bone lesions. J Clin Oncol 2004;22(July 15 Supplement):14S. Abstract 8106.
Peterson MC, et al. Proc. ASCO 2004

66. VI RINGRAZIO PER L’ATTENZIONE!
Courtesy by Donatella Decise