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Hypercalcaemia of malignancy |
Hypercalcaemia is a common problem in advanced malignancy affecting 10% of patients to varying degrees. Despite its frequency, however, there are really only two questions you need to ask clinically;
1. Does this patient have hypercalcaemia?
2. Should it be treated?
Does this patient have hypercalcaemia?
The diagnosis should be made as a clinical suspicion confirmed by a blood test rather than an incidental biochemical finding. Clinical suspicion should be aroused if a patient has a malignancy strongly associated with hypercalcaemia ie.:
- Breast cancer
- Squamous cell lung cancer
- Myeloma
- Genito-urinary cancers (renal, cervix, uterus, ovary)
Some malignancies are less often associated with hypercalcaemia, ie. adenocarcinomas (prostate, stomach, colon, lung) and small cell lung cancer. Thus, if a patient with one of these malignancies becomes unwell, hypercalcaemia is unlikely to be the cause.
Suspicion should also be aroused if the patient shows signs and symptoms of hypercalcaemia. Clinically these features can be quite nebulous and include fatigue, lethargy, mental dullness, weakness, anorexia and constipation. Many of these features are common in advanced cancer regardless of calcium level. At the other extreme, patients can present with nausea, vomiting, ileus, delirium, drowsiness and coma.
Neurological symptoms and signs are seen occasionally, eg. upper motor neurone deficits, ataxia and fits, which can mimic cerebral secondaries. Pain can also be exacerbated by hypercalcaemia. Polydipsia and polyuria, although commonly mentioned in textbooks are not constant features of hypercalcaemia.
The severity of symptoms does not always relate to the level of hypercalcaemia, eg. a mildly elevated calcium can cause severe symptoms and vice versa. Severity can also relate more to the rate of change of calcium.
Therefore patients with hypercalcaemia may not present with clear clinical signs and symptoms but more often just do not appear to be themselves. Thus if you have a patient who has a malignancy associated with hypercalcaemia and they are becoming non-specifically unwell or just "going off", it is always worth considering hypercalcaemia.
Should it be treated?
Hypercalcaemia of malignancy is a feature of advanced disease and carries with it a poor prognosis. In one study the median survival was five weeks, after correction of the hypercalcaemia, with a range of one week to one year (1). Thus it is justifiable to consider whether to treat or not (2). Some useful guidelines are:
1. Symptoms attributable to hypercalcaemia.
2. First episode or long interval since previous one.
3. Previous good quality of life (patient's opinion).
4. Medical opinion that treatment will have a durable effect based on the previous response to treatment.
5. Patient is willing to be admitted to hospital for intravenous therapy and blood tests.
Pathophysiology of hypercalcaemia of malignancy
Before considering specific treatments, it is worth considering the pathophysiology of hypercalcaemia of maligancy.
In solid tumours hypercalcaemia is caused by parathyroid hormone related protein (PTHrP), which is produced by the tumour. This acts on ostoeclasts in bone to increase bone resorption and promote calcium release from bone. It also inhibits calcium excretion in the distal tubule of the kidney. In myeloma, hypercalcaemia is produced by the stimulation of osteoclasts by interleukin-1 and tumour necrosis factor, which again promotes calcium loss from bone. The main point is that hypercalcaemia of malignancy is not a product of widespread boney metasteses and bone destruction as was previously thought.
Treatment
1. Rehydration
If the patient has only mild symptoms and a corrected calcium of 2.6 -2.8mmol/l, then rehydration of 6-8l of fluid over 48 hours with potassium supplements may be appropriate. This can be oral rehydration, but is often difficult for frail patients, in which case IV rehydration is preferable. This can reduce the calcium by 0.2-0.4mmol/l by promoting sodium-linked calcium diuresis.
2. Bisphosphonates
Bisphosphonates have revolutionised hypercalcaemia management and remain the mainstay of treatment. They work by inhibiting osteoclast activity. They are usually given intravenously because they are poorly absorbed orally. Aredia is the most commonly prescribed, usually as 60mg in 500ml saline over 2-4 hours. Normocalcaemia is restored in <90% with maximal effect in 5-7 days and lasting 3-4 weeks.
Some breast cancer patients have been maintained on monthly infusions for 12-18 months. However, hypercalcaemia can become resistant to treatment with further infusions being futile.
60 mg Aredia = $329.70
3.Calcitonin
Calcitonin inhibits osteoclasts and renal reabsorption of calcium. The dose is 500IU/day SC or IM. It has a very rapid effect of lowering calcium in 2-3 hours but the effect lasts only 2-3 days. It is mainly used for emergency treatment of hypercalcaemia in conjunction with a bisphosphonate.
Other agents used include mithramycin, loop diuretics and phosphate. These are rarely used in the palliative care setting however. Dexamethasone 8mg/day has been used in patients with breast cancer, myeloma, lymphoma and renal cell cancer with variable benefit. Smaller doses are unlikely to have any benefit.
Useful note
Hypercalcaemia is an ionized plasma calcium concentration above the upper limit of normal. A corrected calcium level allows for hypoproteinaemia: add 0.02mmol/l to the serum calcium level for every 1g/l of albumin below 40. Eg. If Ca =2.6, Alb=20, Corrected Ca= [(40-20) x 0.02] +2.6 =3.0
Joanne Doran is the area medical director for palliative care based at St Vincent's Hospital, Lismore, NSW, Australia.
References
1. Analysis of survival following treatment of tumour induced hypercalcaemia with intravenous pamidronate. LingPJ et al. British Journal of Cancer. 1995, 72:206-209.
2. Symptom Management in Advanced Cancer. Twycross.Radcliff Medical Press,1997.
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