Hypercalcemia of malignancy

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  • Locally secreted PTHrP in absence of elevated serum PTHrP level.
  • Hypercalcemia of malignancy

    1. 1. Hypercalcemia of Malignancy
    2. 2. Objectives <ul><li>R eview mechanisms of hypercalcemia in the setting of malignancy </li></ul><ul><li>I dentify individual malignancies associated with hypercalcemia </li></ul><ul><li>D iscuss treatments of hypercalcemia </li></ul>
    3. 3. Hypercalcemia of Malignancy (HCM) <ul><li>The most common cause in the hospitalized pt (1) </li></ul><ul><li>Up to 30% of patients with Cancer (1) </li></ul><ul><li>Associated with a poor prognosis (2) </li></ul>(1) Horwitz, M.J., UpToDate . (2) Ralston et al. (1990), Ann Intern Med , 112 , 499-504.
    4. 4. Clinical symptoms of HCM  Higher degree of hypercalcemia is likely caused by cancer.  The rapider the onset, the severer the symptom. <ul><li>Bushinski and Monk (1998), Lancet , 352 , p.307. </li></ul>
    5. 5. <ul><li>“ The symptoms of elevated </li></ul><ul><li>calcium level may overlap with </li></ul><ul><li>the symptoms of the patient’s </li></ul><ul><li>malignancy .” </li></ul>Clinical symptoms of HCM <ul><li>www.cartoonstock.com </li></ul>
    6. 6. Types of Hypercalcemia of Malignancy <ul><li>Stewart, A.F. (2005), NEJM , 352 , p.374. </li></ul>Squamous cell cancer Renal cancer, Ovarian caner, Endometrial cancer, ATLL, Breast cancer
    7. 7. PTHrP PTH Limited Homology but Similar Activity <ul><li>Strewler and Nissenson (1990), West J Med , 153 , p.636. </li></ul>
    8. 8. Mechanism of Humoral HCM Tumor cells PTHrP <ul><li>Modified from the original diagram in Shu, S.T., 2009 (p.28). </li></ul>RANK
    9. 9. Mechanisms of HCM (1) Humoral hypercalcemia- PTHrP mediated From Horwitz, M.J., UpToDate (2) Local osteolytic hypercalcemia (2) Local osteolytic hypercalcemia (3) 1,25-dihydroxyvitamin D mediated hypercalcemia. (4) Coexisting primary Hyperparathyroidism
    10. 10. Uncoupling in bone metastasis Normal bone Bone metastais <ul><li>Roodman, G.D. (2004), NEJM , 350 , p.1656. </li></ul>
    11. 11. Local Osteolytic HCM The vicious cycle of osteolytic metastasis in breast cancer. PTHrP in breast cancer- both endocrine and paracrine action. <ul><li>Roodman, G.D. (2004), NEJM , 350 , p.1660. </li></ul>
    12. 12. Osteolytic HCM in breast cancer <ul><li>In breast cancer, bone metastases occurs in up to 70%. (1) </li></ul><ul><li>A reciprocal interaction between breast cancer cells and bone micro-environment; ‘Vicious Cycle. (1) </li></ul>(1) Roodman, G.D. (2004), NEJM , 350 , 1655-1664.
    13. 13. Osteolytic HCM in MM <ul><li>Hypercalcemia present up to 30% at presentation. </li></ul><ul><li>Purely osteolytic. </li></ul><ul><li>Key factors; Interleukin 6, Interleukin 1, RANKL , MIP 1  and osteoblastic dysfunction. </li></ul>( Roodman, 2004 ) <ul><li>From American Society of Hematology (2002). </li></ul>
    14. 14. Biochemical features of HCM <ul><li>Seymour and Gagel (1993), Blood , 82 , p.1384. </li></ul>1,25 (OH) 2 D 1,25 (OH) 2 D
    15. 15. Intervention for HCM <ul><li>Redrawn from Stewart, A.F. (2005), NEJM , 352 , p.376. </li></ul>
    16. 16. Novel therapy: RANKL inhibitor Inhibitor <ul><li>www.rankligandincancer.com </li></ul>
    17. 17. Denosumab <ul><li>Human monoclonal IgG2 anitibody to RANKL. </li></ul><ul><li>Current Phase 3 studies: in subjects with CSC > 12.5mg/dL and not responding to recent treatment with IV bisphosphonate. </li></ul><ul><li>Pharmacokinetic goal: to maintain a constant level of maximal suppression of bone resorption. </li></ul><ul><li>Hypothesis:CSC 11.5mg/dL by day 10. </li></ul><ul><li>Denosumab 120mg SC Q4W, with loading dose on study days 8 and 15 to facilitate a rapid attainment of steady-state. </li></ul><ul><li>AMG 162 protocol # 20070315, May 2010 </li></ul>
    18. 18. Summary <ul><li>PTH-rP is the leading cause of hypercalcemia in malignancy. </li></ul><ul><li>RANKL is an essential mediator of bone resorption. </li></ul><ul><li>The development of treatment is to break or at least reduce the ‘vicious cycle’. </li></ul><ul><li>Optimal tx should be tailored to underlying causes and the degree of hypercalcemia. </li></ul>
    19. 19. References <ul><li>[1] Bushinsky, D.A. and Monk, R.D. (1998). “Electolyte quintet: calcium.” The Lancet , 352 , 305-311. </li></ul><ul><li>[2] Clines, G.A. and Guise, T.A. (2005). “Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone.” Endocrine-Related Cancer , 12 , 549-583. </li></ul><ul><li>[3] Firkin, F. (1998). “PTHrP in hypercalcemia associated with hematological malignancy.” Leukemia and Lymphoma , 29 , 499-506. </li></ul><ul><li>[4] Horwitz, M.J., “Hypercalcemia of malignancy.” UpToDate . </li></ul><ul><li>[5] Seymour, J.F. and Gagel, R.F. (1993). “Calcitriol: The major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas.” Blood, 82 , 1383-1394. </li></ul><ul><li>[6] Shu, S.T. (2009). Pathogenesis and Treatments of Humoral Hypercalcemia of Malignancy in Adult T-Cell Leukemia/Lymphoma Induced by Human T Lymphotropic Virus Type 1, Ph.D dissertation of The Ohio State University, Ohio, USA. </li></ul><ul><li>[7] Stewart, A.F. (2005). “Hypercalcemia associated with cancer.” NEJM , 352, 373-379. </li></ul><ul><li>[8] Strewler, G.J. and Nissenson, R.A. (1990). “Hypercalcemia in malignancy.” West J Med , 153 , 635-640. t </li></ul><ul><li>[9] Ralston, S.H., Gallagher, S.J., Patel, U. and Campbell, J. (1990). “Cancer associated hypercalcemia; morbidity and mortality.” Ann Intern Med, 112 , 499-504. </li></ul><ul><li>[10] Roodman, G.D. (2004). “Mechanisms of bone metastasis.” NEJM , 350 , 1656-1660. </li></ul>

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