Hypercalcemia of Malignancy

Objectives

Review mechanisms of hypercalcemia in the setting of malignancy

Identify individual malignancies associated with hypercalcemia

Discuss treatments of hypercalcemia

Hypercalcemia of Malignancy (HCM)

The most common cause in the hospitalized pt(1)

Up to 30% of patients with Cancer(1)

Associated with a poor prognosis(2)

(1) Horwitz, M.J., UpToDate.

(2) Ralston et al. (1990), Ann Intern Med, 112, 499-504.

Clinical symptoms of HCM

Higher degree of hypercalcemia is likely caused by cancer.

The rapider the onset, the severer the symptom.

Bushinski and Monk (1998), Lancet, 352, p.307.

“The symptoms of elevated

calcium level may overlap with

the symptoms of the patient’s

malignancy.”

Clinical symptoms of HCM

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Types of Hypercalcemia of Malignancy

Stewart, A.F. (2005), NEJM, 352, p.374.

Squamous cell cancer

Renal cancer, Ovarian caner,

Endometrial cancer, ATLL,

Breast cancer

PTHrPPTH

Limited Homology but Similar Activity

Strewler and Nissenson (1990), West J Med, 153, p.636.

Mechanism of Humoral HCM

Tumor cells

PTHrP

Modified from the original diagram in Shu, S.T., 2009 (p.28).

RANK

Mechanisms of HCM

(1) Humoral hypercalcemia- PTHrP mediated

From Horwitz, M.J., UpToDate

(2) Local osteolytic hypercalcemia

(3) 1,25-dihydroxyvitamin D mediated hypercalcemia.(4) Coexisting primary Hyperparathyroidism

(2) Local osteolytic hypercalcemiaLocal osteolytic hypercalcemia

Uncoupling in bone metastasis

Normal bone

Bone metastais

Roodman, G.D. (2004), NEJM, 350, p.1656.

Local Osteolytic HCM

The vicious cycle of osteolytic metastasis in breast cancer.

PTHrP in breast cancer- both endocrine and paracrine action.

Roodman, G.D. (2004), NEJM, 350, p.1660.

Osteolytic HCM in breast cancer

In breast cancer, bone metastases occurs in up to 70%.(1)

A reciprocal interaction between breast cancer cells and bone micro-environment; ‘Vicious Cycle.(1)

(1) Roodman, G.D. (2004), NEJM, 350, 1655-1664.

Osteolytic HCM in MM

Hypercalcemia present up to 30% at presentation. Purely osteolytic. Key factors; Interleukin 6, Interleukin 1, RANKL, MIP

1 and osteoblastic dysfunction.

(Roodman, 2004)

From American Society of Hematology (2002).

Biochemical features of HCM

Seymour and Gagel (1993), Blood, 82, p.1384.

1,25 (OH)2 D

1,25 (OH)2 D

Intervention for HCM

Redrawn from Stewart, A.F. (2005), NEJM, 352, p.376.

Intervention Adverse EffectHydration or calciuresisPhosphate repletionIV BisphosphonatesPamidronate Renal failue, flu-like syndromeZoledronateGluticorticoidsMithramycin Myelosuppression, renal toxicityCalcitonin Flushing, nauseaGallium nitrate Renal failue

Novel therapy: RANKL inhibitor

Inhibitor

www.rankligandincancer.com

Denosumab

Human monoclonal IgG2 anitibody to RANKL. Current Phase 3 studies: in subjects with CSC >

12.5mg/dL and not responding to recent treatment with IV bisphosphonate.

Pharmacokinetic goal: to maintain a constant level of maximal suppression of bone resorption.

Hypothesis:CSC 11.5mg/dL by day 10. Denosumab 120mg SC Q4W, with loading dose on

study days 8 and 15 to facilitate a rapid attainment of steady-state.

AMG 162 protocol # 20070315, May 2010

Summary

PTH-rP is the leading cause of hypercalcemia in malignancy.

RANKL is an essential mediator of bone resorption. The development of treatment is to break or at

least reduce the ‘vicious cycle’. Optimal tx should be tailored to underlying causes

and the degree of hypercalcemia.

References

[1] Bushinsky, D.A. and Monk, R.D. (1998). “Electolyte quintet: calcium.” The Lancet, 352, 305-311.

[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.

[3] Firkin, F. (1998). “PTHrP in hypercalcemia associated with hematological malignancy.” Leukemia and Lymphoma, 29, 499-506.

[4] Horwitz, M.J., “Hypercalcemia of malignancy.” UpToDate.

[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.

[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.

[7] Stewart, A.F. (2005). “Hypercalcemia associated with cancer.” NEJM, 352, 373-379.[8] Strewler, G.J. and Nissenson, R.A. (1990). “Hypercalcemia in malignancy.” West J Med, 153,

635-640.t[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.[10] Roodman, G.D. (2004). “Mechanisms of bone metastasis.” NEJM, 350, 1656-1660.