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.

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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

Relevance of bone metastasis Tumor World prevalence (5 years) Incidence of bone metastasis Median survival (months) Multiple myeloma 144.000 70-95% 6-54 Kidney 480.000 20-25% 6 Melanoma 533.000 14-45% Thyroid 475.000 60% 48 Lung 1.394.000 30-40% Breast 3.860.000 65-75% 19-25 Prostate 1.555.000 12-53 A. Lipton, J Support Oncol 2004;2:205–220

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

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

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

Incidence of SREs 1,2 3 4,5 5 1. Hortobagyi et al. J Clin Oncol. 1998;16:2038-2044. 2. Theriault et al. J Clin Oncol. 1999;17:846-854. 3. Berenson et al. J Clin Oncol. 1998;16:593-602. 4. Saad et al. J Natl Cancer Inst. 2002;94:1458-1468. 5. Novartis. Data on file.

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

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

Prostate cancer

Incidence of SREs in prostate cancer (24 months) Saad F, et al. Eur Urol Suppl. 2007;6 (Issue 11):683-688.

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 (1999-2007). J Clin Oncol. 2009;27:15s. Abstract and Poster 5160.

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.

Costs associated with SREs cost, euros Cost with SREs Total cost treatment of metastatic prostate cancer Groot et al. Eur Urol. 2003;43:226-232.

Costs associated with SREs Lage M, Am J Manag Care. 2008;14(5):317-322)

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;21:3335-3342; 2. Small EJ, et al. J Clin Oncol. 2003;21:4277-4284; 3. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

Bisphosphonates – what do they do? 100 Median, days P value Zoledronic acid 4 mg 488 .009 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 2003. Abstract 1472.

Renal cell carcinoma

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

Bladder carcinoma

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%

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

Conclusions

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;23:3314-332. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882. Rosen LS, et al. Cancer. 2004;100:2613-2621. Lipton A, et al. Cancer. 2003;98:962-969.

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

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;43:226-232. 2. Weinfurt KP, et al. Ann Oncol. 2002;13(suppl 5):180. 3. Weinfurt KP, et al. Med Care. 2004;42:164-175. 4. Saad F, et al. Eur Urol. 2004;46:731-740. 5. Oefelein MG, et al. J Urol. 2002;168:1005-1007. 6. Riggs BL, et al. Bone. 1995;17:505S-511S.

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

Bisphosphonates – don’t forget

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 2006. Abstract 8528. 2. Durie GM, et al. N Engl J Med. 2005;353:99-102. 3. Pozzi S, et al. ASH 2005. Abstract 5057. 4. Badros A, et al. J Clin Oncol. 2006;24:945-952. 5. Tosi P, et al. ASH 2005. Abstract 3461. 6. Zervas K, et al. Br J Haematol. 2006;134:620-623. 7. Dimopoulos M, et al. Haematologica. 2006;91:968-971. 8. Cafro A, et al. ASH 2005. Abstract 5152. 9. Berenson J, et al. Clin Lymphoma Myeloma. 2009;9:311-315.

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

Thank you for your attention