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Zometa Hcm Slide Kit

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Zometa Hcm Slide Kit

  1. 2. Pathogenesis of HCM Types of HCM Signs and symptoms of HCM Diagnosis of HCM Overview of treatment of HCM ZOMETA™ (zoledronic acid for injection) Overview of hypercalcemia of malignancy (HCM)
  2. 3. Pathogenesis of HCM <ul><li>Mechanisms of HCM 1 </li></ul><ul><ul><li>Increased bone destruction </li></ul></ul><ul><ul><li>Increased tubular reabsorption of calcium by the kidney </li></ul></ul><ul><ul><li>Decreased urinary calcium excretion </li></ul></ul><ul><ul><li>Decrease in bone formation </li></ul></ul>1. Fleisch H. In: Bisphosphonates in Bone Disease. San Diego, California: Academic Press; 2000;90-92.
  3. 4. Pathogenesis of HCM <ul><li>Factors involved in HCM 1,2 </li></ul><ul><ul><li>PTHrP </li></ul></ul><ul><ul><li>Bone-resorbing cytokines (TGFs, TNFs, IL-1) </li></ul></ul><ul><ul><li>1,25 (OH) 2 D </li></ul></ul><ul><ul><li>Prostaglandins </li></ul></ul>1. Mundy GR. (ed). Bone Remodeling and Its Disorders . 2nd ed. London, England: Martin Dunitz Ltd; 1999;107-122. 2. Mundy GR. Hosp Pract . 1999;81–94.
  4. 5. Factors involved in HCM <ul><li>Parathyroid hormone-related protein (PTHrP) </li></ul><ul><ul><li>Produced by tumor cells 1,2 </li></ul></ul><ul><ul><li>Stimulates vicious cycle of osteoclastic bone resorption contributing to HCM 1,2 </li></ul></ul><ul><ul><li>Also stimulates increased renal tubular calcium resorption 1,3 </li></ul></ul>1. Goltzman D, Kremer R, Rabbani SA. Molecular basis of the spectrum of skeletal complications of malignancy. Abstract presented at the Second North American Symposium on Skeletal Complications of Malignancy. October 15–16, 1999; Montréal, Canada. 2. Guise TA. Molecular mechanisms of osteolytic metastases. Abstract presented at the Second North American Symposium on Skeletal Complications of Malignancy. October 15–16, 1999; Montréal, Canada. 3. Mundy GR (ed). Bone Remodeling and Its Disorders . London, England: Martin Dunitz Ltd; 1989;113-119.
  5. 6. Factors involved in HCM <ul><li>Bone-resorbing cytokines </li></ul><ul><ul><li>Four types exhibit potent bone-resorbing activity </li></ul></ul><ul><ul><ul><li>Transforming growth factors (TGF-  and TGF-  ) 1 </li></ul></ul></ul><ul><ul><ul><li>Tumor necrosis factors (TNF-  and TNF-  ) 2,3 </li></ul></ul></ul><ul><ul><ul><li>Colony-stimulating factors (CSFs) 2 </li></ul></ul></ul><ul><ul><ul><li>Interleukins 4 </li></ul></ul></ul>1. Todaro GJ, Fryling D, DeLarco JE. Proc Natl Acad Sci USA. 1980;77:5258-5262. 2. Mundy GR (ed). Bone Remodeling and Its Disorders. London, England: Martin Dunitz Ltd; 1989;45-82; 113-119. 3. Mundy GR. Endocrinol Metab Clin North Am. 1989;18:795-806. 4. Kelly PJ, Eisman JA. Cancer Metastasis Rev. 1989;8:23-52.
  6. 7. Factors involved in HCM <ul><li>1,25 (OH) 2 D 1 </li></ul><ul><ul><li>Increased production by tumor cells leads to HCM </li></ul></ul><ul><ul><li>Increased production leads to increased serum calcium levels via </li></ul></ul><ul><ul><ul><li>Recruitment of osteoclast precursors </li></ul></ul></ul><ul><ul><ul><li>Production of osteoclast-stimulating factors from osteoblasts </li></ul></ul></ul>1. Mundy GR. (ed). Bone Remodeling and Its Disorders . 2nd ed. London, England: Martin Dunitz Ltd; 1989;45–82; 113-119.
  7. 8. Factors involved in HCM <ul><li>Prostaglandins </li></ul><ul><ul><li>Involved in regulatory functions throughout the body </li></ul></ul><ul><ul><li>Associated with pain and inflammation </li></ul></ul><ul><ul><li>Role in HCM is unclear </li></ul></ul><ul><ul><ul><li>Possible bidirectional effect on osteoclasts 1 </li></ul></ul></ul><ul><ul><ul><ul><li>transient effect to slow bone resorption </li></ul></ul></ul></ul><ul><ul><ul><ul><li>sustained effect to increase bone resorption </li></ul></ul></ul></ul><ul><ul><ul><li>Could be produced by host immune cells in response to tumor </li></ul></ul></ul>1. Mundy GR (ed). Bone Remodeling and Its Disorders . 2nd ed. London, England: Martin Dunitz Ltd; 1999;56-59, 118.
  8. 9. Types of HCM <ul><li>Humoral hypercalcemia of malignancy </li></ul><ul><li>Local osteolytic hypercalcemia associated with bone metastases </li></ul><ul><li>Hypercalcemia associated with hematologic malignancies </li></ul>
  9. 10. Types of HCM <ul><li>Humoral hypercalcemia of malignancy (HHM) </li></ul>1. Mundy GR. In: Mundy GR (ed). Calcium Homeostasis: Hypercalcemia and Hypocalcemia. 1990;69-99. Adapted with permission from Mundy GR. 1 Increased Ca reabsorption Inhibition of Pi reabsorption Increased cAMP excretion Inhibition of Ca ++ absorption Stimulation of osteoclastic resorption Inhibition of bone formation Ca ++
  10. 11. Types of HCM <ul><li>Local osteolytic HCM associated with bone metastases 1-3 </li></ul>1. Guise TA, Mundy GR. Cancer and bone. Endocr Rev. 1998;19:18-54. 2. Mundy GR (ed). Cellular mechanisms of bone resorption. In: Bone Remodeling and Its Disorders . 2nd ed. London, England: Martin Dunitz Ltd; 1999;23-25. 3. Mundy GR. Cancer. 1997;80 (suppl 8):1546-1556. 1 Metastatic tumor cells release factors—PTHrP, prostaglandin E, growth factors, and cytokines—that directly stimulate osteoclast activity 1,2 2 Osteoclastic activity releases growth factors (ie, TGF-  ) that stimulate tumor-cell growth, perpetuating a vicious cycle of bone resorption 2 3 Bone resorption releases calcium from the skeleton, increasing the flow of calcium through the extracellular space, resulting in elevated serum calcium 1 PTHrP Tumor cells Ca ++ Ca ++ Ca ++ Osteoclast 2 Bone-derived growth factors (ie,TGF-ß) 3 Ca ++ 1 Adapted with permission from Mundy GR, Guise TA, Place N.
  11. 12. Types of HCM <ul><li>Hypercalcemia associated with hematologic malignancies </li></ul><ul><li>HCM in multiple myeloma </li></ul><ul><ul><li>Extensive destruction of bone adjacent to myeloma cells </li></ul></ul><ul><ul><li>Impaired glomerular filtration and excessive calcium load exacerbate hypercalcemia </li></ul></ul><ul><li>HCM in malignant lymphomas and leukemia </li></ul><ul><ul><li>Possibly mediated by tumor-produced factors that have bone-resorbing activity </li></ul></ul>
  12. 13. Signs and symptoms of HCM 1 1. Morton AR, Lipton A. Clin Oncol. 1995;527-542. 2. Barnett ML. Semin Oncol Nurs. 1999;190-201. CNS Altered levels of consciousness; lethargy; somnolence; stupor; coma; depression; psychosis; ataxia Neuromuscular Muscle weakness; proximal myopathy; hypertonia CV Hypertension; bradycardia; shortened QT interval Renal Kidney stones; decreased glomerular filtration; polyuria; acidosis; increase in corrected serum calcium GI Nausea; vomiting; constipation; anorexia Skeletal 2 Bone pain
  13. 14. Diagnosis (Dx) of HCM <ul><li>Consider Dx in any person with cancer showing symptomatic deterioration 1 </li></ul><ul><li>Confirm by measuring corrected serum calcium (CSC) 2-4 : </li></ul><ul><ul><li>CSC, mg/dL = Serum Ca, mg/dL + 0.8 (4.0 – serum albumin, g/dL) </li></ul></ul>1. Ralston SH. In: Body JJ (ed). Tumor Bone Diseases and Osteoporosis in Cancer Patients. New York, NY: Marcel Dekker; 2000;393-407. 2. Iqbal SJ, Giles M, Ledger S, Nanji N, Howl T. Lancet . 1988;ii:1477-1478. 3. Payne RB, Little AJ, Williams RB, Milner JR. BMJ . 1973;4:643. 4. Morton AR, Hercz G. Dialysis Transplant. 1991;20:661.
  14. 15. Overview of treatment of HCM <ul><li>Principles of antihypercalcemic treatment </li></ul><ul><ul><li>Treatment of mild HCM (CSC levels ≥12mg/dL): </li></ul></ul><ul><ul><ul><li>Ambulation; avoid inactivity; avoid salt restriction and dehydration; force fluids; in lymphoma patients, restrict dietary calcium </li></ul></ul></ul><ul><ul><li>Treatment of moderate HCM (CSC levels >12.8mg/dL) to severe HCM (CSC levels >13.5mg/dL): </li></ul></ul><ul><ul><ul><li>Rehydration with intravenous fluid therapy to promote urinary excretion of calcium </li></ul></ul></ul><ul><ul><ul><li>Antiresorptive drug therapy to inhibit osteoclastic bone resorption </li></ul></ul></ul>
  15. 16. Overview of treatment of HCM <ul><li>Treatment of moderate-to-severe HCM by rehydration 1 </li></ul><ul><ul><li>Aggressively rehydrate with isotonic saline depending on cardiac status </li></ul></ul><ul><ul><li>Confirm good urine flow </li></ul></ul><ul><ul><li>Loop diuretic, plus maintenance of volume expansion </li></ul></ul><ul><ul><ul><li>Match volume output </li></ul></ul></ul><ul><ul><ul><li>Monitor serum levels, and administer potassium and magnesium as necessary </li></ul></ul></ul>1. Barnett ML. Hypercalcemia. Semin Oncol Nurs . 1999;15(3):190-201.
  16. 17. Overview of treatment of HCM <ul><li>Treatment of moderate-to-severe HCM by antiresorptive therapy </li></ul><ul><ul><li>Salmon calcitonin </li></ul></ul><ul><ul><li>Gallium nitrate </li></ul></ul><ul><ul><li>IV bisphosphonate: </li></ul></ul><ul><ul><ul><li>Pamidronate disodium for injection: 4-to-24-hour infusion </li></ul></ul></ul><ul><ul><ul><li>ZOMETA™ (zoledronic acid for injection): 15-minute infusion </li></ul></ul></ul>
  17. 18. Treatment of moderate-to-severe HCM by antiresorptive therapy <ul><li>Salmon calcitonin 1 </li></ul><ul><ul><li>Mechanism of action </li></ul></ul><ul><ul><ul><li>Antiosteoclast </li></ul></ul></ul><ul><ul><ul><li>Calciuric effect </li></ul></ul></ul><ul><ul><li>Dosage/route: 4–8 IU/kg IM or SC q6–12h </li></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Nausea </li></ul></ul></ul><ul><ul><ul><li>Vomiting </li></ul></ul></ul><ul><ul><ul><li>Skin rashes </li></ul></ul></ul><ul><ul><ul><li>Allergic reactions </li></ul></ul></ul>1. Mundy GR, Martin TJ. Metabolism. 1982;31(12):1247-1277.
  18. 19. Treatment of moderate-to-severe HCM by antiresorptive therapy <ul><li>Gallium nitrate 1 </li></ul><ul><ul><li>Mechanism of action </li></ul></ul><ul><ul><ul><li>Stabilizes bone crystal </li></ul></ul></ul><ul><ul><ul><li>No morphologic cellular changes </li></ul></ul></ul><ul><ul><li>Dosage/route </li></ul></ul><ul><ul><ul><li>200 mg/m 2 body surface/day IV for 5 days </li></ul></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Nephrotoxicity (hydrate, avoid aminoglycosides) </li></ul></ul></ul><ul><ul><ul><li>Mild alkalosis </li></ul></ul></ul><ul><ul><li>Contraindications </li></ul></ul><ul><ul><ul><li>Renal insufficiency </li></ul></ul></ul>1. Warrel RP Jr. Gallium nitrate and bone metastases. In: Body JJ (ed). Tumor Bone Diseases and Osteoporosis in Cancer Patients. New York, NY: Marcel Dekker; 2000;483-492.
  19. 20. Treatment of moderate-to-severe HCM by antiresorptive therapy <ul><li>IV bisphosphonates for HCM </li></ul><ul><ul><li>The treatment of choice for HCM for reducing or inhibiting osteoclastic activity </li></ul></ul><ul><ul><li>Available IV bisphosphonates for HCM: </li></ul></ul><ul><ul><ul><li>Pamidronate disodium for injection </li></ul></ul></ul><ul><ul><ul><li>ZOMETA™ (zoledronic acid for injection) </li></ul></ul></ul>
  20. 21. ZOMETA™ (zoledronic acid for injection) <ul><li>ZOMETA belongs to a new class of highly potent bisphosphonates 1,2 </li></ul><ul><li>Heterocyclic, nitrogen-containing bisphosphonate composed of: </li></ul><ul><ul><li>A core bisphosphonate moiety </li></ul></ul><ul><ul><li>An imidazole-ring side chain containing 2 critically positioned nitrogen atoms </li></ul></ul>1. Green J, et al. J Bone Miner Res . 1994;9(5):745-751. 2. Green J, et al. Pharmacol Toxicol. 1997;80(5):225-230.
  21. 22. Evaluation of potency of bisphosphonates <ul><li>Potency relative to pamidronate in vivo (hypercalcemic rat), linear scale 1 </li></ul>1. Green J, et al. J Bone Miner Res . 1994;9(5):745-751. pamidronate disodium for injection ZOMETA™ (zoledronic acid for injection)
  22. 23. ZOMETA™ (zoledronic acid for injection) — mechanisms of action <ul><li>ZOMETA reduces bone resorption by potently inhibiting osteoclast hyperactivity </li></ul><ul><li>Proposed mechanisms of action include: </li></ul><ul><ul><li>Functional suppression of mature osteoclast 1 </li></ul></ul><ul><ul><li>Inhibition of osteoclast maturation 2 </li></ul></ul><ul><ul><li>Inhibition of osteoclast recruitment to the site 2 </li></ul></ul><ul><ul><li>Reduction in the production of cytokines, eg, IL-1, IL-6 3 </li></ul></ul><ul><ul><li>Inhibition of tumor-cell invasion and adhesion to bone matrix 4,5 </li></ul></ul>1. Green J, et al. J Bone Miner Res. 1994;9(5):745-751. 2. Evans CE, Braidman IP. Bone Miner. 1994;26:95-107. 3. Derenne S, et al. J Bone Miner Res. 1999;14:2048-2056. 4. Boissier S, et al. Cancer Res. 2000;60:2949-2954. 5. Marion G, et al. Bone . 1998;33:S379.
  23. 24. ZOMETA™ (zoledronic acid for injection)— product summary <ul><li>Nitrogen-containing bisphosphonates are more potent inhibitors of bone resorption </li></ul><ul><li>ZOMETA has 2 nitrogens in an imidazole side-ring and is the most potent bisphosphonate </li></ul><ul><li>Zoledronic acid is a 100 to 850 times more potent inhibitor of osteoclasts than pamidronate </li></ul>
  24. 25. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM <ul><li>Design </li></ul><ul><ul><li>Two randomized, double-blind, double-dummy, parallel-group trials of ZOMETA vs pamidronate </li></ul></ul><ul><ul><li>287 HCM patients 1 </li></ul></ul><ul><ul><li>Single dose of ZOMETA (4 mg or 8 mg) as a 5-minute infusion, or a single 90-mg dose of pamidronate as a 2-hour infusion 1 </li></ul></ul><ul><ul><li>A planned pooled analysis of the data was conducted </li></ul></ul><ul><li>Primary end point </li></ul><ul><ul><li>Comparative efficacy </li></ul></ul><ul><li>Secondary end point </li></ul><ul><ul><li>Comparative tolerability </li></ul></ul>1. Major P, et al. J Clin Oncol. In press.
  25. 26. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM <ul><li>Patient demographics 1 </li></ul>1. Major P, et al. J Clin Oncol. In press. Sex Male n (%) 46 (53.5) 60 (66.7) 56 (56.6) 162 (58.9) Female n (%) 40 (46.5) 30 (33.3) 43 (43.4) 113 (41.1) Age Mean years 60.0 58.7 59.0 59.0 Range years 33–84 21–84 25–87 21–87 Primary cancer site Lung n (%) 15 (17.4) 25 (27.8) 23 (23.2) 63 (22.9) Breast n (%) 22 (25.6) 14 (15.6) 15 (15.2) 51 (18.5) Multiple myeloma n (%) 9 (10.5) 5 (5.6) 9 (9.1) 23 (8.4) Head and neck n (%) 9 (10.5) 9 (10.0) 12 (12.1) 30 (10.9) Renal n (%) 9 (10.5) 10 (11.1) 11 (11.1) 30 (10.9) Unknown n (%) 2 (2.3) 1 (1.1) 4 (4.0) 7 (2.5) Hematologic n (%) 9 (10.5) 7 (7.8) 7 (7.1) 23 (8.4) Other n (%) 11 (12.8) 19 (21.1) 18 (18.2) 48 (17.5) ZOMETA 4 mg (N=86) ZOMETA 8 mg (N=90) pamidronate 90 mg (N=99) Total (N=275) Units
  26. 27. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM <ul><li>Patient demographics 1 (continued) </li></ul>1. Major P, et al. J Clin Oncol. In press. Bone metastases No n (%) 37 (43.0) 40 (44.4) 54 (54.5) 131 (47.6) Yes n (%) 49 (57.0) 50 (55.6) 45 (45.5) 144 (52.4) Baseline PTHrP  2 pmol/L n (%) 62 (72.1) 59 (65.6) 65 (65.7) 186 (67.6) >2 pmol/L n (%) 20 (23.3) 25 (27.8) 24 (24.2) 69 (25.1) Bisphosphonate use in past year No n (%) 77 (89.5) 86 (95.6) 91 (91.9) 254 (92.4) Yes n (%) 9 (10.5) 4 (4.4) 8 (8.1) 21 (7.6) ZOMETA 4 mg (N=86) ZOMETA 8 mg (N=90) pamidronate 90 mg (N=99) Total (N=275) Units
  27. 28. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection HCM <ul><li>Mean CSC by day 1 </li></ul>1. Major P, et al. J Clin Oncol. In press. 13.95 11.04 ( P =.005) 10.08 ( P =.001) 9.96 ( P =.001) 13.96 11.47 10.63 10.59 8 10 12 14 16 Baseline Day 4 Day 7 Day 10 Corrected Day ZOMETA 4 mg (N=86) pamidronate 90 mg (N=99) 10.8 Mean CSC, mg/dL
  28. 29. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM <ul><li>Median duration of relapse of HCM 1 </li></ul>1. Major P, et al. J Clin Oncol. In press. *( P =.001) 5 10 15 20 25 0 30 17 pamidronate 90 mg (N=99) 30* ZOMETA 4 mg (N=86)
  29. 30. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM Time to relapse 1 ZOM 4 mg vs pam 90 mg: P =.001 0 .2 .4 .6 .8 1.0 Days since start of treatment (= Day 1) Censored time = 0 7 14 21 28 35 42 49 56 63 ZOMETA 4 mg — median 30 days pamidronate 90 mg — median 17 days Proportion of patients without relapse 1. Major P, et al. J Clin Oncol. In press.
  30. 31. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM <ul><li>Complete response rate 1 : </li></ul><ul><li>Normalization of corrected serum calcium  10.8 mg/dL (  2.7 mmol/L) </li></ul>* Denotes statistical significance vs pamidronate. 0 20 40 60 80 100 0 4 7 10 Day ZOMETA 4 mg pamidronate 90 mg P =.002* P =.005* Complete response, % 1. Major P, et al. J Clin Oncol. In press.
  31. 32. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM <ul><li>Results 1 : </li></ul><ul><ul><li>Significantly superior to pamidronate in the treatment of HCM 1 : </li></ul></ul><ul><ul><ul><li>Significantly faster normalization of corrected serum calcium ( P  .05) </li></ul></ul></ul><ul><ul><ul><li>Significantly longer therapeutic effect ( P =.001) </li></ul></ul></ul><ul><ul><ul><li>Significantly higher response rate ( P =.002) </li></ul></ul></ul><ul><ul><li>Well tolerated at 4 mg </li></ul></ul><ul><ul><li>More rapid infusion than pamidronate </li></ul></ul>1. Major P, et al. J Clin Oncol. In press.
  32. 33. ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCM <ul><li>Summary—ZOMETA </li></ul><ul><ul><li>Highly effective in the treatment of HCM </li></ul></ul><ul><ul><li>ZOMETA 4 mg was more effective than pamidronate 90 mg </li></ul></ul><ul><ul><li>4-mg dose is recommended </li></ul></ul>
  33. 34. ZOMETA™ (zoledronic acid for injection)— Administration <ul><li>Rapid administration </li></ul><ul><ul><li>Recommended dose in HCM </li></ul></ul><ul><ul><ul><li>ZOMETA 4 mg via 15-minute infusion 1 </li></ul></ul></ul>1. Data on file. Novartis Oncology.
  34. 35. ZOMETA™ (zoledronic acid for injection)— Safety and tolerability <ul><li>Well tolerated, with a safety profile similar to that of pamidronate </li></ul><ul><li>The most common treatment-related adverse experiences in clinical trials 1 </li></ul><ul><li> ZOMETA pamidronate </li></ul><ul><li>Adverse event 4 mg (N = 86) 90 mg (N = 99) </li></ul><ul><li>Fever 7.0% 9.7% </li></ul><ul><li>Hypocalcemia 5.8% 1.9% </li></ul><ul><li>Hypophosphatemia 3.5% 1.0% </li></ul><ul><li>Nausea 1.2% 1.0% </li></ul><ul><li>Pruritus 1.2% 0% </li></ul>1. Data on file. Novartis Oncology.
  35. 36. HCM: Current clinical perspectives summary <ul><li>Hypercalcemia of malignancy (HCM) is a serious and common metabolic complication of malignancy </li></ul><ul><li>Consider the possibility of hypercalcemia in any person with cancer who starts to experience symptomatic deterioration </li></ul><ul><li>Confirm diagnosis by measuring corrected serum calcium </li></ul><ul><li>Tailor treatment to degree of hypercalcemia present </li></ul><ul><li>IV bisphosphonates remain the treatment of choice for HCM </li></ul><ul><li>ZOMETA™ (zoledronic acid for injection) is a new, highly potent bisphosphonate that is significantly superior to pamidronate in the treatment of HCM 1 </li></ul>1. Major P, et al. J Clin Oncol. In press.

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