Fluid and electrolyte disturbances in cancer patients

At a glance

• Electrolyte problems in cancer come from the tumour (SIADH, PTHrP, ectopic ACTH, tumour lysis), the treatment (platinum, ifosfamide, EGFR antibodies, immunotherapy) and the illness around it (vomiting, diarrhoea, poor intake, sepsis, AKI).
• Hyponatraemia is the commonest. In a patient on immune checkpoint inhibitors, exclude adrenal insufficiency before diagnosing SIADH.
• Magnesium is the hidden driver of refractory hypokalaemia and hypocalcaemia on cisplatin and EGFR antibodies.
• Tumour lysis syndrome is mostly a haematological problem, but bulky chemosensitive solid tumours can do it too.
• Check for spurious results (very high white cells or platelets, paraproteins) before treating a number.
• In the last weeks of life, decide with the patient and family whether correcting a result will help how they feel.

Disorder-specific detail is in Hyponatraemia and hypernatraemia, Hypocalcaemia and hypercalcaemia, Potassium, magnesium and phosphate disorders and Hyperkalaemia. This note covers what is different in cancer.

Causes

Disturbance	Tumour-related	Treatment-related	Other common causes in cancer
Hyponatraemia	SIADH: small cell lung cancer (up to 15%), head and neck, other lung cancers; adrenal or pituitary metastases	Cyclophosphamide, vincristine, cisplatin (SIADH or renal salt wasting), ifosfamide; checkpoint inhibitor hypophysitis or adrenalitis	Opioids, SSRIs, carbamazepine, nausea and pain (ADH stimuli), vomiting, hypotonic fluids
Hypercalcaemia	PTHrP (squamous cancers, renal, breast), osteolytic metastases, myeloma, calcitriol from lymphoma	Rarely tamoxifen flare	Dehydration
Hypokalaemia	Ectopic ACTH (small cell, carcinoid), lysozymuria in monocytic AML, VIPoma	Ifosfamide (Fanconi syndrome), cisplatin, amphotericin, high-dose steroids, diuretics	Diarrhoea, vomiting, low magnesium
Hypomagnesaemia		Cisplatin (dose-related, can last years), cetuximab, panitumumab, calcineurin inhibitors after transplant	PPIs, diarrhoea, poor intake
Hypophosphataemia	Tumour-induced osteomalacia (FGF23-secreting mesenchymal tumour), hungry bone after treating osteoblastic metastases	Ifosfamide, ferric carboxymaltose, some kinase inhibitors	Refeeding, alcohol
Hypocalcaemia	Osteoblastic metastases (prostate, breast)	Denosumab and zoledronic acid, cisplatin (via magnesium)	Tumour lysis, vitamin D deficiency
High potassium, phosphate and urate	Tumour lysis, rhabdomyolysis	Venetoclax ramp-up, first cycle of chemotherapy	AKI, adrenal insufficiency
Hypernatraemia	Central diabetes insipidus from pituitary or hypothalamic metastases (breast, lung)	Ifosfamide or hypercalcaemia causing nephrogenic DI	Poor access to water in the frail or dying

Pitfall: nausea and pain are powerful ADH stimuli. Treating them is part of treating "SIADH" on an oncology ward.

Focused history

• Tumour type and extent: small cell lung cancer, haematological malignancy with high counts or bulky disease, bone or pituitary metastases.
• Treatment timeline: drug names and dates of the last cycle. Ask specifically about immunotherapy (even months ago), platinum, ifosfamide, EGFR antibodies, bone-targeted agents and recent IV iron.
• Losses and intake: vomiting, diarrhoea or stoma output, oral intake, weight change, enteral or parenteral feeding (refeeding risk).
• Symptoms of the disturbance: confusion, falls, seizures (sodium), constipation, polyuria and thirst (calcium), weakness and palpitations (potassium), cramps, tetany and paraesthesia (calcium and magnesium).
• Symptoms pointing at an endocrine cause: headache and fatigue (hypophysitis), postural dizziness and salt craving (adrenal), polyuria with nocturia (diabetes insipidus).
• Goals of care: what the patient wants, prognosis and current ceiling of treatment.

Focused examination

• Volume status: postural BP, JVP, mucous membranes, oedema, ascites. This sorts hypovolaemic from euvolaemic hyponatraemia, and is often hard in cachectic patients.
• Neurology: conscious state, confusion, asterixis, Chvostek and Trousseau signs, proximal weakness.
• Cushingoid or hypertensive with oedema and hypokalaemia: ectopic ACTH.
• Bulky disease: lymphadenopathy, hepatosplenomegaly, mediastinal mass (tumour lysis risk).
• Bone tenderness and the spine (metastases, hypercalcaemia, cord compression).

Red flags

• Hyponatraemia with severe symptoms (vomiting, seizures, somnolence or coma): needs a 3% saline bolus now, whatever the sodium. Confusion alone is moderately severe (Spasovski 2014).
• Potassium 6.5 mmol/L or more, or ECG changes. Rising creatinine with high urate and phosphate after the first dose of chemotherapy or venetoclax: tumour lysis.
• Hyponatraemia with hyperkalaemia and hypotension, or any hyponatraemia on immunotherapy with fatigue: adrenal crisis until proven otherwise.
• Corrected calcium over 3.5 mmol/L or a falling conscious state.
• Lactic acidosis without shock in leukaemia or high-grade lymphoma: type B lactic acidosis, a sign of very active disease.

Investigations

• Baseline: sodium, potassium, chloride, bicarbonate, urea, creatinine, calcium (corrected and ionised where albumin is low), magnesium, phosphate, glucose, LDH and urate.
• Hyponatraemia: serum and urine osmolality, urine sodium, TSH, early morning cortisol (and ACTH if on immunotherapy). The criteria for SIADH need normal adrenal and thyroid function and no recent diuretic.
• Hypokalaemia: urine potassium-to-creatinine ratio, blood gas, BP; cortisol (late-night salivary or 24-hour urine) and ACTH if ectopic ACTH is possible.
• Hypercalcaemia: PTH first, then PTHrP and vitamin D metabolites if PTH is suppressed.
• Hypophosphataemia without an obvious cause: fractional excretion of phosphate and FGF23 (tumour-induced osteomalacia, ferric carboxymaltose).
• Tumour lysis: urate (on ice if rasburicase given), potassium, phosphate, calcium, creatinine, LDH, 6- to 12-hourly in high-risk patients during the first 24 to 72 hours.

Spurious results

Result	Setting	Check with
Pseudohyperkalaemia	Thrombocytosis (potassium released during clotting, so serum reads high), haemolysed or pneumatic-tube sample	Plasma (heparinised) or blood gas potassium
Reverse pseudohyperkalaemia	Very high white cells (CLL): fragile cells leak potassium in heparinised samples and with pneumatic transport; serum may read lower	Whole-blood gas analysed immediately, hand-carried (or hand-carried serum); avoid the pneumatic tube
Pseudohyponatraemia	Paraprotein (myeloma), severe hypertriglyceridaemia	Direct ion-selective electrode (blood gas); normal measured osmolality
Pseudohypoglycaemia	Very high white cells keep consuming glucose in the tube	Capillary or promptly analysed sample
Spurious hypercalcaemia or hyperphosphataemia	Paraprotein binding or assay interference	Ionised calcium; discuss with the laboratory

Management

Hyponatraemia

• Severe symptoms: 3% saline 150 mL over 10 to 20 minutes, repeated up to twice, then follow the correction limits (no more than 10 mmol/L in the first 24 hours, less if high risk). Details are in Hyponatraemia and hypernatraemia.
• SIADH from the tumour usually resolves when the cancer responds. In small cell lung cancer, starting chemotherapy is the most effective treatment.
• Fluid restriction often fails in cancer: patients are thirsty, need fluid with cisplatin, and have urine osmolality well above serum. Oral urea, salt tablets with a loop diuretic, or tolvaptan (short course, start in hospital, avoid in liver disease) are second-line.
• Cisplatin salt wasting looks like SIADH but with hypovolaemia and high urine sodium. It needs salt and water, not restriction.
• Checkpoint inhibitor hypophysitis or adrenalitis: hydrocortisone replacement (stress doses if unwell), sick-day rules and a steroid alert card. Replacement is usually lifelong for adrenal insufficiency. Immunotherapy can usually continue once the patient is stable (ESMO 2022).

Hypercalcaemia

• IV 0.9% saline, then zoledronic acid 4 mg (first line in Australia), calcitonin for the first 48 hours if severe, and denosumab if bisphosphonate-refractory or in severe renal impairment. Full management is in Hypocalcaemia and hypercalcaemia.
• Calcitriol-mediated hypercalcaemia in lymphoma responds to glucocorticoids.
• Hypercalcaemia of malignancy carries a median survival measured in months. Discuss goals of care at the same time.

Potassium, magnesium and phosphate

• Replace magnesium first in refractory hypokalaemia or hypocalcaemia. IV magnesium sulfate 10 to 20 mmol over several hours for symptomatic or severe deficiency.
• Cisplatin: hydration regimens on eviQ include magnesium and potassium; check levels before each cycle and between cycles if symptoms.
• EGFR antibodies: hypomagnesaemia appears weeks to months into treatment and settles within weeks of stopping. Oral magnesium causes diarrhoea and often isn't enough; scheduled IV replacement is common.
• Ectopic ACTH: large doses of potassium with spironolactone, and cortisol blockade (metyrapone or ketoconazole) while the tumour is treated. Watch for infection and VTE.
• Refeeding: start feeds slowly and replace phosphate, potassium and magnesium daily, with thiamine before feeding (see Potassium, magnesium and phosphate disorders).

Tumour lysis syndrome

Risk: highest in Burkitt lymphoma, ALL and AML with high white cells, bulky high-grade lymphoma, and CLL starting venetoclax. Pre-existing renal impairment, dehydration, high LDH and high urate all raise it. In solid tumours it is uncommon (bulky small cell, germ cell tumours, some after immunotherapy or targeted therapy).

Risk	Prevention
Low	Oral or IV fluids, monitoring; allopurinol optional
Intermediate	IV fluids about 3 L/m² a day (urine output 100 mL/m² an hour or more) and allopurinol 300 mg daily started 1 to 2 days before treatment
High	IV fluids and rasburicase (after G6PD testing where indicated), 6- to 12-hourly bloods, cardiac monitoring; nephrology aware

• Established TLS: fluids, rasburicase, treat hyperkalaemia, and stop phosphate intake. Give calcium only for symptomatic hypocalcaemia or arrhythmia, because calcium with high phosphate precipitates in tissues.
• Dialysis for refractory hyperkalaemia, fluid overload, severe acidosis, rising phosphate with oliguria, or symptomatic hypocalcaemia with high phosphate.
• Allopurinol inhibits xanthine oxidase, so reduce azathioprine and mercaptopurine doses. It doesn't lower existing urate.
• Pitfall: urinary alkalinisation is no longer recommended.

Special populations

• Older people: less thirst, more drug causes (thiazides, SSRIs), and hyponatraemia causes falls and confusion that look like progression.
• Renal impairment: the highest TLS risk; adjust allopurinol dose; denosumab causes severe hypocalcaemia in advanced CKD.
• Palliative patients: aim treatment at symptoms. A dying patient with a sodium of 128 mmol/L doesn't need fluid restriction, and stopping routine bloods is often the right decision.

Pitfalls

• Diagnosing SIADH in a patient on immunotherapy without checking cortisol.
• Chasing potassium for days without checking magnesium.
• Treating pseudohyperkalaemia in CLL with insulin and dextrose, causing hypoglycaemia.
• Giving calcium to an asymptomatic patient with tumour lysis and high phosphate.
• Fluid-restricting a patient with cisplatin salt wasting, who needs volume.
• Forgetting IV iron (ferric carboxymaltose) as a cause of severe hypophosphataemia.