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  • Survival is also reduced in pats with other tumours who have fractures.
  • Three Randomized Phase III Trials: Zoledronic Acid in Bone Metastases The efficacy and safety of zoledronic acid in the treatment of bone metastases in patients with solid tumors and multiple myeloma have been evaluated in 3 phase III, randomized clinical trials: Trial 010: Zoledronic acid versus pamidronate in patients with breast cancer and multiple myeloma (treatment duration: 24 months) Trial 039: Zoledronic acid versus placebo in patients with prostate cancer (treatment duration: 24 months) Trial 011: Zoledronic acid versus placebo in patients with solid tumors other than breast or prostate cancer (treatment duration: 21 months) References 1. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer . 2003;98:1735-1744. 2. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst . 2004;96:879-882 . 3. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung cancer and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer . 2004;100: 2613-2621.
  • How long should BPs be given? There is evidence from BC patients that the benefit continues during the 2nd year of Tx; note that Zol continues to be superior to pam during this period.
  • Compared with pamidronate, zoledronic acid also reduced the risk of experiencing a second SRE by about one-third, indicating that BP therapy should not be stopped when a patient expereinces an SRE.
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    1. 1. “ Bone Health” della paziente con carcinoma della mammella: approccio multidisciplinare F. Bertoldo, P. Pronzato
    2. 2. Balancing cost & benefit of maintaining bone health by bisphosphonates <ul><li>Bisphosphonates prevent bone complications in patients with osseous metastases and represent the treatment of osteoporosis </li></ul><ul><li>Pts receiving bisphosphonates may be at risk of ONJ </li></ul>
    3. 3. Balancing cost & benefit of maintaining bone health by bisphosphonates <ul><li>Bisphosphonates prevent bone complications in patients with osseous metastases and represent the treatment of osteoporosis </li></ul><ul><li>Pts receiving bisphosphonates may be at risk of ONJ </li></ul>
    4. 4. Bisphosphonates in breast cancer – Pts with bone metastases <ul><li>Reduction in skeletal events with pamidronate, zolendronate or ibandronate in trials of long-term treatment </li></ul><ul><li>Risk of ONJ in this context is not negligible </li></ul>
    5. 5. Metastatic Bone Disease is an Important Clinical Problem in Cancer Patients Annual estimate new cases - US, x1000 Incidence of bone metastases, % Median survival, months Myeloma 16 70 - 95 50 - 67 Renal 36 20 - 25 8 - 21 Melanoma 60 14 - 45 5 - 31 Bladder 63 40 9 - 20 Thyroid 26 60 49 Lung 173 30 - 40 17 - 33 Breast 213 65 - 75 18 - 24 Prostate 232 65 - 75 16 - 24
    6. 6. Incidence of Skeletal Related Events in Patients with Bone Metastases
    7. 7. Incidence of Skeletal Related Events in Patients with Bone Metastases
    8. 8. Bone Metastases Have Debilitating Consequences Fracture Hypercalcemia Surgery to bone Rx therapy to bone Disease Skeletal-related events Loss of autonomy Bone pain Consequences to functional independence and QOL Bone metastases Spinal cord compression QOL = Quality of life.
    9. 9. Impact on Survival: Fractures Negatively Affect Survival <ul><li>Pathologic fractures correlate with a significantly increased relative risk of death 1,2 </li></ul><ul><ul><li>Breast Cancer 1.32 (1.10, 1.59) P=0.003 </li></ul></ul><ul><ul><li>Multiple Myeloma 1.44 (1.06, 1.95) P=0.02 </li></ul></ul><ul><ul><li>Prostate Cancer 1.29 (1.01, 1.65) P=0.04 </li></ul></ul><ul><ul><li>Lung Cancer / other 1.08 (0.87, 1.34) P=0.49 </li></ul></ul>1 Saad F, et al. ECCO, 2005. Abstract 1265; 2 Hei Y et al. Presented at SABCS 2005, Abstract 6036
    10. 10. Riduzione del rischio calcolato di eventi scheletrici nel tumore metastatico della mammella 1.Body JJ et al. ASCO 2003; 2. Estimated from Coleman et al. SABCS 2002; 3. Lipton A et al. Cancer 2000; 88: 1082-90; 4. Pavlakis N, Stockler M. The Cochrane Library 2002 16 33 37 38 40 0 10 20 30 40 50 Clodronato 4 Pamidronato 3 Zoledronato 2 Ibandronato os 50 mg 1 Ibandronato ev 6 mg 1 Riduzione degli eventi scheletrici (%)
    11. 11. Zoledronic Acid Randomized Phase III Trials in Patients With Bone Metastases 1. Major P, et al. J Clin Oncol . 2001;19:558-567. 2. Rosen LS, et al. Cancer . 2003;98:1735-1744. 3. Kohno N, et al. J Clin Oncol . 2005;23:3314-3321. 4. Saad F, et al. J Natl Cancer Inst . 2004;96:879-882. 5. Rosen LS, et al. Cancer . 2004;100:2613-2621. Trial N Zoledronic acid versus: Patient population Treatment duration, mo 036/037 1 287 Pamidronate Hypercalcemia of malignancy 1 infusion 010 2 1,648 Pamidronate Breast cancer Multiple myeloma 24 1501 3 227 Placebo Breast cancer 12 039 4 643 Placebo Prostate cancer 24 011 5 773 Placebo NSCLC and other solid tumors 21
    12. 12. Zoledronic Acid in Metastatic Breast Cancer: Continuing Reduction in SRE Risk (subset analysis) Zheng M et al. St. Gallen 2005. Poster 104 During the second year on zoledronic acid, the relative risk of experiencing an SRE remains lower than with pamidronate.
    13. 13. Continuing Reduction in the Risk of a Second SRE (Breast ca., 2nd event subset analysis; multiple event analysis) Zheng M et al. St. Gallen 2005. Poster 104 Compared with pamidronate, zoledronic acid in breast cancer reduced the risk of experiencing a second SRE by about one-third.
    14. 14. Bisphosphonates in breast cancer – Pts without bone metastases <ul><li>Pts with breast cancer, mainly because of chemotherapy or endocrine-therapy induced suppression of estrogen action are at higher risk of osteoporosis and bone fracture </li></ul><ul><li>The risk of ONJ in this context is very low! (understimated?) </li></ul>
    15. 17. ONJ
    16. 18. Osteonecrosis of the Jaw <ul><li>Few literature reports before 2003 1-3 </li></ul><ul><ul><li>Most often reported: osteoradionecrosis (ORN) following head and neck radiation (reported incidence from 0.4% to 8.2% 4) </li></ul></ul><ul><li>Since 2003, a growing number of cases of ONJ have been reported in patients who had not been treated with H&N radiation therapy </li></ul><ul><li>A common finding among these patients was the active treatment with bisphosphonates (BPs)  an association between BPs exposure and ONJ has been described </li></ul>1. Winer et al. J Am Dent Assoc . (1972) 2. Schwartz. Head Neck Surg . ( 1982) 3. Sung et al. Spec Care Dent . (2002) 4. Reuther et al. Oral Max Surgery . (2003)
    17. 19. <ul><li>Reduced osteoclastic activity in an area where bone remodeling is critical for bone healing and survival </li></ul><ul><li>Alteration of vascular supply resulting in ischemia and necrosis of the bone </li></ul><ul><li>Direct antiangiogenic effect of bisphosphonates: </li></ul><ul><ul><li>Significant decrease in circulating levels of VEGF in MBC (pamidronate) * </li></ul></ul><ul><ul><li>Inhibition of endotelial cell function in vitro and in vivo (clodronate, risedronate, ibandronate, and zoledronic acid) ° </li></ul></ul><ul><ul><li>Inhibition of vessel sprouting in chick embryo model (zoledronic acid) ^ </li></ul></ul><ul><li>ONJ has been described almost exclusively after exposure to nitrogen-containing bisphosphonates (more potent) </li></ul><ul><li>A few cases have been described in patients taking alendronate for osteoporosis </li></ul>ONJ: Pathogenesis * Santini et al: Clin Cancer Res 2002; ° Fournier et al, Cancer Res 2002; ^ Wood et al J Pharmacol Exp Ther, 2002
    18. 23. ONJ in Cancer Patients Treated With BPs Frequency Estimates * Observation period typically 12 months Source Frequency estimate Spontaneous reports Aredia Zometa Both (estimated total # pts exposed) 305 of 1.9 million (0.016%) 1335 of 1.15 million (0.12%) 587 of 3.05 million (0.019%) Retrospective review of Zometa clinical trials* 16 of 16,900 (0.10%) Web-based survey (Durie) 75 of 1203 (6.2%) of respondents reported ONJ MDACC 33 cases of 4029 charts (0.8%) MSKCC 6 cases of 934 charts (0.6%)
    19. 24. Prospective assessment of ONJ in cancer patients receiving bisphosphonates <ul><li>Prospective assessment of ONJ since 2003 </li></ul><ul><li>1st BPS administration among ONJ pts: 1997 </li></ul><ul><li>252 pts treated since 01/97 were included in this analysis ( MBC: 70 ; MM: 111; PC: 46; other: 25) </li></ul><ul><li>To ensure adequate exposure to BPS: exclusion of pts who received < 6 doses </li></ul><ul><li>All pts with dental problems were referred to maxillofacial surgeon to confirm diagnosis </li></ul><ul><li>Review of medical records to exclude sign/symptoms of ONJ </li></ul>Bamias A, J Clin Oncol 2005
    20. 25. Prospective assessment of ONJ in cancer patients receiving bisphosphonates <ul><li>17 pts (6.7%) were diagnosed with ONJ </li></ul><ul><ul><li>MM: 11/111(9.9%) </li></ul></ul><ul><ul><li>BC: 2/70 (2.9%) </li></ul></ul><ul><ul><li>PC: 3/46 (6.5%) </li></ul></ul><ul><ul><li>Other: 1/25 (4%) </li></ul></ul><ul><li>Type of bisphosphonate </li></ul><ul><ul><li>8 Zoledronic acid </li></ul></ul><ul><ul><li>9 Zoledronic acid after pamidronate </li></ul></ul>Bamias A, J Clin Oncol 2005
    21. 26. Cumulative hazard of developing osteonecrosis of the jaw from the date of initiation of treatment
    22. 27. Wilkinson, G. S. et al. J. Natl. Cancer Inst. 2007 99:1016-1024
    23. 28. Indipendent from other risk factors considered: diabetes, alcoholism, smoking, obesity, hyperlipidemia, pancreatitis, CT with L-asparaginase Wilkinson, G. S. et al. J. Natl. Cancer Inst. 2007 99:1016-1024
    24. 29. Copyright restrictions may apply. Wilkinson, G. S. et al. J. Natl. Cancer Inst. 2007 99:1016-1024; doi:10.1093/jnci/djm025 Kaplan-Meier estimates for adverse bone outcomes for matched cancer patients who did or did not receive intravenous bisphosphonates Absolute Risk at 6 years was 5.48 events/100 pts
    25. 30. Bisphosphonate-associated ONJ in pts with osteoporosis or Paget’s Disease Study n disease BP Ruggiero 7 Osteop (7) A (6); A+Z(1) Cheng 8 Osteop(3); Paget (5) A(5); P(2); A+P(2) Marx 3 Osteop (3) A (3) Marunick 2 Osteop (2) A(2) Migliorati 1 Osteop (1) A(1) Purcell 1 Osteop (1) A (1) Farruggia 5 Osteop (4); Paget (1) A (5) Chang 11 Osteop (11) A(11) Mavrokokki 32 Osteop (26); Paget (6) A (25); P (2); R (2); A+R (2); A+P (1) Starck 1 Osteop (1) E Hoefert 3 Osteop (3) Najm 3 Osteop (3) A(2); P+Z (1) Carter 3 Paget (3) A(1); P(2) Pozzi 1 Osteop (1) TOTAL (excl overlapping) 64 Osteop (57); Paget(7)
    26. 31. Facing the problem of ONJ risk in pts with bone metastases receiving BPs <ul><li>Applying the least “bone-toxic” drugs </li></ul><ul><li>Applying prevention tools </li></ul><ul><li>Avoiding BPs? </li></ul><ul><li>Limiting duration of treatment? </li></ul><ul><li>Selecting a certain BP? </li></ul><ul><li>Estimating risk and benefit </li></ul>
    27. 32. Application of BPs in pts without metastases <ul><li>Waiting for definitive results of clinical trials </li></ul><ul><li>Applying the least “bone-toxic” drugs </li></ul><ul><li>Applying prevention tools </li></ul><ul><li>Avoiding BPs? </li></ul><ul><li>Limiting duration of treatment? </li></ul><ul><li>Selecting a certain BP? </li></ul><ul><li>Estimating risk and benefit </li></ul>

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