1. The role of bisphosphonates in the treatment of bone metastases of genitourinary tumors
Nuno Gil
WHAT YOU HAVE TO KNOW
XIV WORKSHOP ON ONCOLOGICAL UROLOGY

2. Relevance of bone metastasis
Tumor
World prevalence
(5 years)
Incidence of bone metastasis
Median survival (months)
Multiple myeloma
70-95%
6-54
Kidney
20-25% 6
Melanoma
14-45%
Thyroid
60% 48
Lung
30-40%
Breast
65-75%
19-25
Prostate
12-53
A. Lipton, J Support Oncol 2004;2:205–220

3. Relevance of bone metastasis
> 500,000 patients in the United States/year
Myeloma: > 90% of patients
Breast: 2/3 of patients
Prostate: 2/3 of patients
Lung: 1/3 of patients
Often only site of metastatic disease
Prolonged survival; often measured in years
Major clinical consequences for patients, families, and society

4. SREs Consequences of bone metastasis Pathologic fractures
Nonvertebral
Vertebral compression
Spinal cord compression
Radiation therapy
Surgery to bone
Hypercalcemia
SREs

5. Patients Affected in Placebo Arms Zoledronic Acid Trials
Incidence of SREs
Patients Affected in Placebo Arms
Pamidronate Trials
Zoledronic Acid Trials
Disease
Breast
Myeloma
Prostate
Lung/Other
Observation time, mos 24 21
Total SREs, % 64 51 49 46
Radiation to bone 43 34 33
Pathologic fractures 52 37 25 22
Hypercalcemia of malignancy 13 9 1 4
Surgery to bone 11 5
Spinal cord compression 3 8

6. Incidence of SREs
1,2 3
4,5 5
1. Hortobagyi et al. J Clin Oncol. 1998;16: Theriault et al. J Clin Oncol. 1999;17: Berenson et al. J Clin Oncol. 1998;16:
4. Saad et al. J Natl Cancer Inst. 2002;94: Novartis. Data on file.

7. Incidence of SREs in GU cancers
John M. Fitzpatrick, European Urology Supplement S 8 (2009): 733–737

8. 396,200 patients diagnosed with cancer between 2000 and 2004
Costs associated with bone mets
396,200 patients diagnosed with cancer between 2000 and 2004
36500
Cost per patient, 2004 (USD)
MBD
(N=519)
No MBD
(n=520)
Schulman KL, Kohles J. Economic burden of metastatic bone disease in the US. Cancer. 2007

9. Prostate cancer

10. Incidence of SREs in prostate cancer (24 months)
Saad F, et al. Eur Urol Suppl. 2007;6 (Issue 11):

11. Bone mets = worse prognosis
Group N
(%)
1-year Survival
1-year adjusted mortality rate (95%CI)
After 1-year adjusted mortality rate (95%CI)
No bone metastasis
19.826
(86)
87%
Reference
Bone metastasis and no SREs
1.570
(7)
47%
4,7 times greater
6,1 times greater
Bone metastases and at least 1 SRE
1.691
40%
6,6 times greater
9,8 times greater
Fryzek JP, Cetin K, Nørgaard M, et al. The prognostic significance of bone metastases and skeletal-related events (SREs) in prostate cancer survival: A population-based historical cohort study in Denmark ( ). J Clin Oncol. 2009;27:15s. Abstract and Poster 5160.

12. Incidence of SRE with respect to symptoms
Eastham J, McKieman J, Gleason D, Zheng M, Saad F., J Clin Oncol. 2005;23:16s. Abstract 4561 and presentation.
Major P., EU J Onc Nursing. 2007;11:S32-S37.

13. Costs associated with SREs
cost, euros
Cost with
SREs
Total cost treatment of
metastatic prostate cancer
Groot et al. Eur Urol. 2003;43:

14. Costs associated with SREs
Lage M, Am J Manag Care. 2008;14(5): )

15. Phase III trials of bisphosphonates
Study
Population
Treatment
Endpoint
Results
NCIC Pr06
(N=204) (1)
Symptomatic
Mitoxantrone/
PDN ± clodronate
Palliative response
OS, PFS, QoL NS
032/INT 05
(N=350) (2)
Pamidronate vs placebo
Pain score, analgesic use
Pain, analgesic use, SREs
Zoledronic acid 039
(N=643) (3)
Asymptomatic
Zoledronic acid vs placebo
SREs
SRE: 44 vs 33% (p=0,021)
1. Ernst DS, et al. J Clin Oncol. 2003;21: ; 2. Small EJ, et al. J Clin Oncol. 2003;21: ; 3. Saad F, et al. J Natl Cancer Inst. 2002;94:

16. Bisphosphonates – what do they do?
100
Median, days P value
Zoledronic acid 4 mg
Placebo 321
Patients without SRE (%) 80 60
167 days 40 20
120
240
360
480
600
720
Days since beginning of treatment
Saad F. AUA Abstract 1472.

17. Renal cell carcinoma

18. Bisphosphonates – what do they do?
Saad F, Seminars in Oncology, Vol 37, No 3, Suppl 1, June 2010, pp S38-S44

19. Bladder carcinoma

20. Bisphosphonates – what do they do?
ASCO 2008 (abst. 5033) Zaghloul et al. A controlled prospective randomized placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer patients. (N=40)
Median time for first SRE: 56 vs 118 days (p=0,0004)
OS (1 year): 5 vs 30%

21. Bisphosphonates – what do they do?
ASCO 2010 (abst. E15096) Hoshi et al. The impact of zoledronic acid therapy in survival of bladder cancer patients with bone metastasis. (N=30)
OS: 17 vs 7 months (p=0,003)
Pain score: NS

22. Conclusions

23. Bisphosphonates – what do they do?
Prostate
Solid tumors
Lung
Kidney
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
SRE relative risk
Breast
36%
.002
31%
.003
32%
.016
58%
.010
41%
.019
Risk redution
P value
ZOL better
Placebo better
Kohno N, et al. J Clin Oncol. 2005;23: Saad F, et al. J Natl Cancer Inst. 2004;96: Rosen LS, et al. Cancer. 2004;100: Lipton A, et al. Cancer. 2003;98:

24. Zoledronic acid and SREs in GU cancers
John M. Fitzpatrick, European Urology Supplement S 8 (2009): 733–737

25. Impact of bone metastasis
Increased medical costs[1]
Treatment of bone complications more than doubles the total treatment costs for patients with bone metastases
Diminished quality of life[2-4]
History of a skeletal
complication is associated
with lower QoL in breast and prostate cancer
Impaired mobility[6]
Hip fracture associated with a 50% disability rate; 25% of these require nursing home care
Skeletal
Complications
Negative impact on survival[5]
Men with prostate cancer without skeletal fracture survived 39 months longer than those with a fracture
1. Groot MT, et al. Eur Urol. 2003;43: Weinfurt KP, et al. Ann Oncol. 2002;13(suppl 5): Weinfurt KP, et al. Med Care. 2004;42: Saad F, et al. Eur Urol. 2004;46: Oefelein MG, et al. J Urol. 2002;168: Riggs BL, et al. Bone. 1995;17:505S-511S.

26. Bisphosphonates – don’t forget
Adjust the dose to kidney function!

27. Bisphosphonates – don’t forget

28. Pts With Suspect or Proven ONJ, n
ONJ - prevalence
Study
Study Type
Pts Treated With BP, n
Pts With Suspect or Proven ONJ, n
Frequency, %
Hoff et al, MDACC
ASCO 2006[1]
Chart review
4019 34
0.8
Durie et al[2]
Web-based survey
1203
152
12.6
Pozzi et al, Italian Multicenter study[3]
888 16
1.8
Badros et al[4]
Chart review/ observational
340 11
3.2
Tosi et al, analysis of Bologna 2002 trial[5]
Retrospective review of trial database
259 6
2.7
Zervas et al[6]
Observational
254 28
11.0
Dimopoulos et al[7]
202 15
7.4
Cafro et al[8]
118 14
11.9
Berenson et al[9]
300
4.7
1. Hoff AO, et al. ASCO Abstract Durie GM, et al. N Engl J Med. 2005;353: Pozzi S, et al. ASH Abstract Badros A, et al. J Clin Oncol. 2006;24: Tosi P, et al. ASH Abstract Zervas K, et al. Br J Haematol. 2006;134: Dimopoulos M, et al. Haematologica. 2006;91: Cafro A, et al. ASH Abstract Berenson J, et al. Clin Lymphoma Myeloma. 2009;9:

29. Bisphosphonates – don’t forget
Check the teeth of your patients BEFORE bisphosphonates
Avoid invasive dental procedures during therapy
If you have to, STOP bisphosphonates at least for 3 months before planned dental procedure

30. Thank you for your attention