OncologyTier 1Disease (DEADMAN)

Metastatic disease manifestations - hypercalcaemia of malignancy

Description

Commonest metabolic complication of malignancy - 20-30% of cancer patients at some point
A marker of advanced disease and, historically, of a poor prognosis
Distinguish from primary hyperparathyroidism: malignancy is acute, severe and symptomatic; PHPT is chronic, mild and incidental

Occurs in ~20-30% of all cancer patients
Commonest causes: breast, renal cell, multiple myeloma, lymphoma, squamous cell carcinoma (lung, head and neck, oesophagus)
~10-20% of hypercalcaemia in hospital inpatients (primary hyperparathyroidism dominates the outpatient setting)

Four mechanisms

1. Humoral hypercalcaemia of malignancy - PTHrP

*The commonest mechanism overall* - accounts for ~80%, and for the majority even in patients who also have bone metastases
PTHrP shares the N-terminal with PTH -> binds PTH1R
- -> inc osteoclastic bone resorption
- -> inc renal tubular calcium reabsorption
- -> dec phosphate reabsorption -> hypophosphataemia
*PTH is suppressed* - the key biochemical discriminator
Squamous cell carcinoma (lung, head and neck), renal cell, breast, ovarian, bladder, HTLV-1 adult T-cell leukaemia

2. Local osteolytic hypercalcaemia (~20%)

Tumour in marrow -> cytokines (IL-1, IL-6, TNF, RANKL) -> osteoclast activation
Multiple myeloma, breast cancer with extensive bone metastases, lymphoma
Myeloma also adds renal tubular injury from light chains -> impaired calcium excretion

3. 1,25-dihydroxyvitamin D production (<1%)

4. Ectopic PTH secretion

Clinical

"Stones, bones, abdominal groans and psychic moans"
Polyuria, polydipsia, dehydration (nephrogenic DI from calcium at the collecting duct)
Nausea, vomiting, constipation, anorexia, ileus
Confusion, lethargy, weakness, coma - often the presenting feature in the oncology setting
Short QT, bradycardia, arrhythmia
The rate of rise matters more than the absolute number

Severity

	Corrected calcium
Mild	2.60-3.00 mmol/L
Moderate	3.00-3.40

| Severe | >3.40 mmol/L - treat as an emergency regardless of symptoms |

Always correct for albumin (or measure ionised calcium): corrected Ca = measured + 0.02 x (40 - albumin)

Biochemical workup - the discriminating test is PTH

	PTH	Phosphate	Other
PTHrP (HHM)	Suppressed	Low	PTHrP raised, ALP variable
Osteolytic	Suppressed	Normal/high	ALP raised (normal in myeloma - no osteoblastic response)
1,25-vitD (lymphoma)	Suppressed	Normal/high	1,25-(OH)2D raised, 25-OH-D normal
Primary hyperparathyroidism	Normal or high	Low	Chronic, mild

Also: UEC, magnesium, ALP, myeloma screen (EPG/SFLC), 25-OH and 1,25-(OH)2 vitamin D
In a cancer patient, still consider co-existing primary hyperparathyroidism, thiazides, lithium, vitamin D/calcium excess and immobilisation

A. Immediate - volume repletion

IV 0.9% sodium chloride 200-300 mL/h, titrated to urine output 100-150 mL/h
- Patients are profoundly volume-deplete from calcium-induced nephrogenic DI and vomiting
- Restores GFR -> restores calciuresis
*Loop diuretics only after the patient is volume-replete* and where fluid overload threatens; they are not a calcium-lowering treatment
Stop the contributors: thiazides, calcium and vitamin D supplements, lithium, calcium-containing antacids
Mobilise where possible

B. Antiresorptive - the definitive treatment

IV bisphosphonate
- Zoledronic acid 4 mg IV over 15 min (reduce dose if eGFR <60; avoid if eGFR <30)
- Pamidronate 60-90 mg IV over 2-4 h as an alternative
- *Onset 2-4 days, nadir at 4-7 days - not* an acute treatment; give it early but hydrate for the immediate effect
- Acute-phase reaction (flu-like) in ~20%; osteonecrosis of the jaw with repeated use - dental review
Denosumab 120 mg SC
- For bisphosphonate-refractory disease or renal impairment (no renal dose adjustment)
- Faster and more effective in refractory hypercalcaemia
- *Watch for profound and prolonged hypocalcaemia* - correct vitamin D first, monitor closely

C. Situation-specific

Calcitonin 4 IU/kg SC/IM 12-hourly - works within 4-6 hours; bridges the gap until bisphosphonate takes effect
- *Tachyphylaxis within 48 hours* - a bridge only
Corticosteroids (prednisolone 40-60 mg or hydrocortisone) - only for 1,25-vitamin D mediated disease: lymphoma, myeloma, granulomatous disease
Haemodialysis with low-calcium dialysate - severe hypercalcaemia with renal failure or heart failure preventing hydration
Cinacalcet - for parathyroid carcinoma or ectopic PTH

D. Treat the cancer

*Hypercalcaemia recurs unless the underlying malignancy responds* - this is the definitive management
Discuss goals of care - hypercalcaemia often marks a transition point

Squamous cell carcinoma - lung, head and neck, oesophagus, cervix (PTHrP)
Renal cell carcinoma (PTHrP)
Breast cancer (PTHrP and osteolytic)
Multiple myeloma (osteolytic + renal impairment)
Lymphoma - Hodgkin and non-Hodgkin (1,25-vitamin D)
HTLV-1 adult T-cell leukaemia/lymphoma
Ovarian, bladder, endometrial cancer
Non-malignant mimics: primary hyperparathyroidism, sarcoidosis and other granulomatous disease, thiazides, lithium, vitamin D toxicity, immobilisation, thyrotoxicosis, adrenal insufficiency, milk-alkali

Historically median survival 3-4 months once hypercalcaemia of malignancy develops
- Modern systemic therapy has improved this in responsive disease (myeloma, lymphoma, breast) - but it remains a poor prognostic marker
Recurrence is expected unless the tumour is controlled; the interval between episodes shortens
Repeated bisphosphonate/denosumab use -> osteonecrosis of the jaw, atypical femoral fracture, hypocalcaemia
Complications: AKI and nephrocalcinosis, arrhythmia, coma, pancreatitis, peptic ulceration
Its appearance is a reasonable trigger for a goals-of-care conversation

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