Hypercalcemia of Malignancy

Question 1

Symptoms of hypercalcemia of malignancy

Answer 1

GI Symptoms

• Nausea
• Constipation/ileus
• Anorexia

Neuro

• Delirium
• Weakness
• Somnolence
• Confusion, agitation
• Hyporeflexia

Cardiac

• Arrhythmias
• Long PR, reduced QT

Other

• Polydipsia
• Polyuria

Typical onset is lethargy and malaise, followed by thirst, nausea, and constipation with neurologic and cardiac symptoms occurring later

Question 2

Epidemiology of hypercalcemia

Answer 2

10-40% of cancer patients

Most common life threatening metabolic disorder associated with malignancy

80% die within one year, median survival is 3-4 months

Question 3

Cancers commonly associated with hypercalcemia

Answer 3

Myeloma
Breast
Lung
Renal

Typically associated with metastatic disease, bony mets, and is a poor prognostic indicator.

Question 4

Pathophysiology of hypercalcemia of malignancy

Answer 4

1. Increased osteoclastic bone resorption
   - RANKL stimulates osteoclast activity, while OPG (osteoprotegerin) is a decoy receptor for RANKL decreasing its activity at the bone
   - Tumours either release RANKL, stimulate bone stromal cells to produce RANKL due to release of cytokines, or may decrease OPG production (esp in myeloma and met prostate CA)
   - PTHrp released by some cancers increases RANKL expression and decreases OPG expression without regulatory feedback of regular PTH
2. Decreased renal clearance of calcium
   - Occurs due to increased PTHrp
   - Occurs with low GFR
3. Enhanced calcium absorption from the gut
   - Rare cases, heme malignancies may produce calcitriol and increase GI absorption of calcium

Question 5

Calculation of corrected serum calcium

Answer 5

Corrected Ca = Increase measure of sCa2+ by 0.2 mmol/L for every decrease of 10 g/L (below 40 g/L0 in serum albumin.

Question 6

Normal serum calcium

Answer 6

less than 2.65

Question 7

Best way to measure serum calcium

Answer 7

Ionised Ca+ level. Particularly preferred in myeloma patients as the myeloma paraproteins can bind calcium and artificially elevate calcium levels (pseudohypercalcemia)

Question 8

Treatment of Hypercalcemia

Answer 8

Depends on severity of symptoms, prognosis, patient’s wishes.

Mild (<3, asymptomatic or mild symptoms):

• Avoid thiazide diuretics and lithium carbonate therapy, supp Vitamin A and D
• Avoid volume depletion, in activity, high calcium diet
• Hydration to reduce risk of nephrolithiasis

Moderate with moderate symptoms (3 - 3.5)

• IV hydration with saline (2-3 L/day) with daily lytes
• Treatment with bisphosphonate (Zoledronic acid, 4mg in 100ml NS IV over 15 mins)

Severe (>3.5)

• Volume expansion with isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour
• Calcitonin 100 U subcut TID for 1-2 days, repeat measurement of serum calcium in several hours to ensure patient is responsive. Note that effects will not be sustained and can cause tachyphlaxis after 24 hrs.
• IV bisphosphonate (usually Zoledronic acid 4mg IV over 15 mins) and repeat Calcium level in 3-7 days. Clodronate can be given subcut, but only lasts 2 weeks.

May consider steroids in hematologic malignancies as it can has cytostatic effects on them (may take 4-10 days to lower serum calcium).

Question 9

Calcitonin for Hypercalcemia (dose, side effects, etc.)

Answer 9

Calcitonin 100 U subcut TID for 1-2 days

Reduces osteoclastic bone resorption and increases calciuresis. Onset of action within 4 hours, but effect is short lived.

Side effect most common is nausea, though hypersensitivity reactions can occur

After first dose, check serum calcium a couple hours later to ensure patient is sensitive to the medicine. Note that this is only a temporary measure and patients typically experience tachyphlaxis after 1-2 days, so give a bisphosphonate along with.

Question 10

Bisphosphonates for hypercalcemia (dose, side effects, mechanism)

Answer 10

Zoledronic acid 4mg in 100ml NS IV over 15 minutes
Clodronate can be given subcut (and is the only one possible to do this with)

Onset within 3-7 days, effect for 4-6 weeks

Often patients will require regular dosing every 4 weeks.

Note that these can aggravate renal impairment, including pre-renal failure and can cause osteonecrosis of the jaw (esp if prolonged use, older age, or recent dental extraction). Rx abx and surgical debridement.

Work by binding hydroxyapatite crystals, inhibiting osteoclast function (but do not alter PTHrp levels, renal calcium resorption, RANKL or OPG levels) and so many fail to control hypercalcemia in cases where there are not bone mets. Patients with elevated PTHrp may require higher doses.

Question 11

Denosumab for Hypercalcemia

Answer 11

• Monoclonal antibody to RANKL used in the management of postmenopausal women with osteoporosis and to prevent skeletal events in myeloma
• May be used in patients with severe renal failure (unable to take bisphosphonates) OR refractory to zoledronic acid
• Dosed 120mg IV subcut q4 weeks (q weekly in first month)