26.2 Hypercalcaemia of Malignancy & Tumour Lysis Syndrome

4. Hypercalcaemia of Malignancy

Hypercalcaemia occurs in up to 30% of patients with advanced malignancy and carries a poor prognostic significance. Corrected serum calcium must always be calculated: Corrected Calcium = Measured Calcium + 0.02 × (40 - Serum Albumin [g/L]).

                    Mechanisms of Hypercalcaemia in Malignancy
                                        |
    +-----------------------------------+-----------------------------------+
    |                                   |                                   |
1. Humoral Hypercalcaemia           2. Local Osteolytic                  3. 1,25-(OH)2-D Excess
   of Malignancy (~80%)                Metastases (~20%)                    (<1%)
   - Tumour-secreted PTHrP             - Direct osteoclast activation       - Tumour 1α-hydroxylase
   - Squamous cell (lung, ENT),         via RANKL, IL-1, IL-6, TNF-α        - Hodgkin & non-Hodgkin
     renal cell, breast                - Breast cancer, multiple myeloma      lymphomas
   - High Ca, Low PTH, High PTHrP      - High Ca, Low PTH, Normal PTHrP     - High Ca, Low PTH, High 1,25-D

Pathophysiological Subtypes

1. Humoral Hypercalcaemia of Malignancy (HHM, ~80%): Mediated by tumour secretion of Parathyroid Hormone-related Protein (PTHrP), which binds to parathyroid hormone 1 receptors (PTH1R) in bone and kidney, stimulating osteoclast bone resorption and renal tubular calcium reabsorption. Classically associated with squamous cell carcinomas (lung, oesophagus, cervix, head and neck) and renal cell carcinoma.
2. Local Osteolytic Hypercalcaemia (~20%): Extensive skeletal metastases secrete paracrine cytokines (RANKL, IL-1, IL-6, TNF-alpha) that trigger osteoclastic bone destruction. Classically seen in multiple myeloma and breast cancer.
3. 1,25-Dihydroxyvitamin D (Calcitriol) Production (<1%): Autonomous expression of the enzyme 1-alpha-hydroxylase by malignant lymphoid tissue converts 25-hydroxyvitamin D to active calcitriol, driving massive gastrointestinal calcium absorption. Seen in Hodgkin and non-Hodgkin lymphomas.

Clinical Features

• Renal: Polyuria, polydipsia (nephrogenic diabetes insipidus secondary to impaired ADH responsiveness in the medullary collecting duct), profound volume depletion, and nephrolithiasis.
• Gastrointestinal: Anorexia, nausea, intractable vomiting, constipation, obstipation, and acute pancreatitis.
• Neuromuscular: Muscle weakness, hyporeflexia, lethargy, cognitive slowing, delirium, psychosis, stupor, and coma.
• Cardiovascular: Shortened QTc interval, widened T waves, J-point elevation, bradycardia, heart block, and ventricular arrhythmias.

Emergency Management Protocol

1. Aggressive Intravenous Rehydration (Cornerstone): Patients are severely hypovolaemic (fluid deficit 3–6 L). Infuse intravenous 0.9% sodium chloride 3 to 4 litres in the first 24 hours (e.g. 1 L over 2 hours, then 200–300 mL/hour, carefully monitoring fluid balance, urine output, and central venous pressure to prevent pulmonary oedema). Saline restores intravascular volume and induces renal calciuresis.
2. Intravenous Bisphosphonates: Administer IV zoledronic acid 4 mg in 100 mL 0.9% NaCl infused over 15 minutes (or pamidronate 60–90 mg over 2–4 hours). Bisphosphonates inhibit farnesyl pyrophosphate synthase in osteoclasts, inducing osteoclast apoptosis. Clinical Pearl: Bisphosphonates require 48 to 72 hours to exert clinical effect, with the nadir in serum calcium occurring at 4 to 7 days. Renal function must be checked; zoledronic acid requires dose adjustment in moderate renal impairment and is avoided in severe renal failure.
3. Denosumab: A fully human monoclonal antibody that binds and neutralizes RANKL, blocking osteoclast maturation. Dosed at 120 mg subcutaneously (with loading doses on days 8 and 15 in month 1). Indicated for bisphosphonate-refractory hypercalcaemia or severe renal impairment (no renal excretion).
4. Adjunctive Agents:
   • Salmon Calcitonin (4–8 IU/kg SC/IM every 12 hours): Rapid onset (lowers calcium within 2–4 hours by promoting renal excretion and inhibiting bone resorption), but exhibits rapid tachyphylaxis (receptor down-regulation) within 48 hours. Used as an emergency bridge in life-threatening hypercalcaemia (> 3.5 mmol/L) while awaiting bisphosphonate onset.
   • Corticosteroids (Prednisolone 40–60 mg/day): First-line therapy for lymphoma-mediated or granulomatous hypercalcaemia, as steroids directly inhibit 1-alpha-hydroxylase.

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5. Tumour Lysis Syndrome (TLS)

Tumour lysis syndrome is an oncological emergency characterized by the massive, rapid breakdown of neoplastic cells and release of intracellular ions, nucleic acids, and proteins into the systemic circulation following cytotoxic chemotherapy, radiotherapy, or occasionally spontaneously.

High-Risk Malignancies

• Haematological: Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma (DLBCL), Acute Lymphoblastic Leukaemia (ALL), and Acute Myeloid Leukaemia (AML with hyperleukocytosis > 100 × 10⁹/L).
• Solid Tumours: Rare, but occurs in bulky, highly chemosensitive tumours (small cell lung cancer, metastatic germ cell tumours, neuroblastoma).

The Metabolic Tetrad & Pathophysiology

1. Hyperkalaemia (> 6.0 mmol/L): Release of intracellular potassium; causes fatal ventricular arrhythmias and asystole.
2. Hyperphosphataemia (> 1.45 mmol/L): Malignant lymphoblasts contain up to 4 times more organic phosphate than normal leukocytes; causes hypocalcaemia and calcium phosphate crystal precipitation.
3. Hypocalcaemia (Corrected Calcium < 1.75 mmol/L): Secondary to rapid precipitation of insoluble calcium phosphate ($Ca_3(PO_4)_2$) crystals in soft tissues and renal tubules; causes tetany, carpopedal spasm (Trousseau's sign), facial twitching (Chvostek's sign), laryngospasm, seizures, and prolonged QTc.
4. Hyperuricaemia (> 476 µmol/L): Catabolism of purine nucleic acids (adenine and guanine) via xanthine oxidase into uric acid; uric acid crystallizes in the acidic environment of renal collecting ducts, causing obstructive nephropathy and acute kidney injury (AKI).

Cairo-Bishop Diagnostic Criteria

Prophylaxis & Management Protocols

• Vigorous Intravenous Hydration: High-volume hydration with 0.9% sodium chloride at 2.5–3.0 L/m²/day to maintain brisk diuresis (> 100 mL/m²/hour). CRITICAL PRACTICE PEARL: Urinary alkalinisation with sodium bicarbonate is no longer recommended; while bicarbonate increases uric acid solubility, it markedly decreases calcium phosphate solubility, dramatically accelerating nephrocalcinosis and fatal renal failure, while worsening symptomatic hypocalcaemic tetany.
• Hypouricaemic Pharmacotherapy:
  • Allopurinol (Xanthine Oxidase Inhibitor): Dosed 300 mg/m²/day (up to 500 mg daily). Prevents de novo formation of uric acid from hypoxanthine and xanthine. Limitation: Does NOT degrade pre-existing uric acid; requires 24–48 hours to attenuate urate levels. Indicated for low-to-intermediate risk TLS prophylaxis.
  • Rasburicase (Recombinant Urate Oxidase): Catalyses the enzymatic oxidation of uric acid into allantoin, an inert, highly water-soluble metabolite (5–10 times more soluble in urine than uric acid) that is readily excreted by the kidneys. Lowers uric acid levels within 4 hours. Indicated for established TLS or high-risk patients (Burkitt lymphoma, baseline uric acid > 450 µmol/L, high tumor burden).
  • CRITICAL CONTRAINDICATION: Rasburicase is strictly contraindicated in Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. The enzymatic breakdown of uric acid generates hydrogen peroxide ($H_2O_2$); in G6PD-deficient erythrocytes deficient in NADPH and reduced glutathione, hydrogen peroxide induces catastrophic acute intravascular haemolytic anaemia and life-threatening methaemoglobinaemia (manifesting as cyanosis unresponsive to oxygen, Heinz bodies, and bite cells on blood film).
• Electrolyte Management:
  • Hyperkalaemia: Immediate 10% calcium gluconate (10 mL IV over 10 minutes) for cardiac membrane stabilization, followed by nebulized salbutamol, IV regular insulin (10 units) in 50 mL 50% dextrose, and oral potassium binders (sodium zirconium cyclosilicate). Emergent continuous veno-venous haemofiltration (CVVHF) if refractory.
  • Hypocalcaemia Caution: Asymptomatic hypocalcaemia must NOT be treated with intravenous calcium, because infused calcium binds circulating phosphate, precipitating massive metastatic calcium phosphate deposition in the kidneys, myocardium, and lungs. Reserve IV calcium gluconate strictly for severe symptomatic hypocalcaemia (tetany, seizures, or life-threatening QTc prolongation).