Hypercalcaemia of malignancy
Hypercalcaemia due to malignancy is a common problem in advancing cancer. Patients often present with progressive fatigue or increasing confusion. It can also cause dehydrated and acute renal impairment. Hypercalcaemia tends to be a prognostic marker suggesting progressive cancer although it often improves temporarily (for a number of weeks or months) after treatment with a bisphosphonate such as zolendronic acid. As with all things in palliative medicine, deciding when to investigate and treat is key, although, in general, treatment of hypercalcaemia often brings about reduced symptoms and improved quality of life and so treatment is often appropriate, even in patients in their last few weeks of life.
Around a quarter of patients with advancing malignancy will develop hypercalcaemia at some stage.
Any cancer can cause hypercaelcaemia but it is more common in some. Some of the malignancies that are particularly associated with hypercalcaemia include:
- Multiple myeloma
- Metastatic breast cancer
- Lung cancer
- Head and neck squamous cell cancers
- Renal cell cancer
- Bladder cancer
Various mechanisms can lead to hypercalcaemia of malignancy as shown in the list below. The first two mechanisms are common whereas the third and fourth are rare causes.
- A paraneoplastic effect due to systemic release of parathyroid-related protein (PTHrP) from malignant cells (e.g. lung cancer, head and neck squamous cell cancer, renal cell cancer and bladder cancer)
- Bone destruction by stimulated osteoclasts in the presence of osteolytic metastases (e.g. in breast cancer and multiple myeloma)
- Production of 1,25-vitamin D by tumour cells (e.g. in Hodgkin's lymphoma)
- Production of ectopic parathyroid hormone (e.g. thyroid papillary carcinoma)
In about 80% of patients with hypercalcaemia of malignancy, the underlying mechanism is release of PTHrP by malignant cells. PTHrp stimulates osteoblasts to produce RANKL (receptor activator of nuclear factor-K ligand) which in turn activates the precursor cells of osteoclasts which results in destruction of bone and release of calcium.
Pathophysiology and clinical features
Mild hypercalcamia is often asymptomatic or causes only mild fatigue however as hypercalcaemia worsens, some of the classic "stones, bones, groans and psychic moans" symptoms develop. Typically symptoms such as poor appetite, fatigue and nausea occur with calcium levels greater than 3; drowsiness and coma is likely with levels greater than 4. The rate of rise of calcium also plays a role in symptom develop (i.e. a more rapid rise is more likely to cause severe symptoms; very gradually rising calcium over months and years, e.g. in primary hyperparathyroidism, may cause only very minimal symptoms).
Hypercalcaemia causes a nephrogenic diabetes insipidus in many patients although the mechanism is poorly understood. This results in polyuria and dehydration with subsequent thirst and the development of renal failure. Renal impairment does not typically occur until the calcium level rises above 3 and tends to be reversible with fluids and treatment of the hypercalcaemia. Hypercalciuria occurs which increases the risk of developing renal stones.
Gastrointestinal and abdominal effects
Hypercalcaemia tends to effect gut motility and peristalsis through its effect on smooth muscle and the autonomic nervous system. Patients usually note constipation, poor appetite and nausea. Often there is abdominal discomfort as well. Rarely a peptic ulcer or acute pancreatitis complicates hypercalcaemia.
Bone and musculoskeletal effects
Patients often feel fatigued with general weakness. Bony aches and pains are also common.
Neurological and psychiatric effects
Many patients have very subtle cognitive impairment with slower than usual thinking and forgetfulness. Overt confusion and agitation often develops as the hypercalcaemia worsens. Drowsiness with development of coma occurs. Less commonly patients become anxious or profoundly depressed.
Severe hypercalcaemia can cause QT shortening. An unusual change in the QRS complex known as a J wave sometimes occurs. Very severe hypercalcaemia has been associated with VF.
In patients with malignancy who have hypercalcaemia, malignancy is almost always the cause. It is worth considering other differentials however, including:
- Primary hyperparathyroidism - these patients will often have a long history of mildly raised calcium
- Excess exogenous vitamin D or calcium intake
Calcium level (and albumin)
A significant proportion of circulating calcium is bound to albumin and inactive. As albumin drops, proportionally the ionized (i.e. active) calcium is higher. Most laboratories give a "corrected" calcium level which takes this into account and gives an estimation of what the calcium level would be with an albumin of 40. The corrected calcium level can also be calculated by using the following formula:
Corrected calcium = total calcium + 0.02 x (40 - albumin)
PTH, PTHrP and Vitamin D levels
In cases of uncertainty, the PTH level can be measured. This is generally not needed as it is usually relatively clear that advancing malignancy is causing a new hypercalcaemia in palliative care patients. PTH should generally be suppressed (i.e. low) in cases of hypercalcaemia of malignancy whereas it will not be suppressed but will be inappropriately high in patients with primary hypercalcaemia. When the PTH level is in the normal range, a level nearer the lower end suggests a malignant cause, whereas a level nearer the higher end is indicative of primary hyperparathyroidism.
In the vast majority of malignant hypercalcaemia cases the PTHrp will be elevated, although it is not generally necessary to measure this as the diagnosis is usually clear.
In lymphomas (and granulomatous diseases) hypercalcaemia tends to be due to endogenous production of vitamin D and this can be measured if this is suspected. Likewise, if exogenous vitamin D is suspected, then the vitamin D level may be measured to confirm this as the cause.
|Condition||Parathyroid hormone level||Parathyroid hormone related peptide level||Vitamin D level||Phosphoate|
|Paraneoplastic (humoral) hypercalcaemia of malignancy||Reduced (or low normal)||Detectable||Decreased or normal||Decreased|
|Osteolytic lesions causing hypercalcaemia of malignancy||Reduced (or low normal)||Undetectable||Decreased or normal||Normal|
|Primary hyperparathyroidism||Raised (or high normal)||Undetectable||Decreased or normal||Decreased|
|Lymphomas or grandulatomous diseases||Reduced (or low normal)||Undetectable||High||Normal or increased|
Tests to look for progression of disease
Malignant hypercalcaemia usually indicates progressive disease and it may be appropriate to look for other signs of this (e.g. with imaging).
Treatment of very mild hypercalcaemia is not urgent, and may not be required at all. In generally, treatment of malignant hypercalcaemia usually brings about symptom relief in patients with corrected calciums greater than 3; many physicians actively treat levels above 2.75 or so.
In patients who are not conscious and appear to be in their last few days of life, treatment is probably generally not apprporiate, however, even for patients who are in their last few weeks of life, treatment is worth considering it is often very effective at improving symptoms of confusion, drowsiness and even reducing pain.
If a decision is made to intervene to reverse hypercalcaemia, there two mainstays of treatment are:
- Hydration with IV fluids
- IV bisphosphonates
Most patients with hypercalcaemia are dehydrated and a significant proportion ave pre-renal acute renal failure. In addition ot encouraging oral fluids, IV fluids are usually indicated. Fluid replacement helps by improving dehydartion and calcium excretion in the the urine. Traditionally high amounts of fluid have been recommended (e.g. 6 litres in 24 hours followed by IV fluids aiming to maintain a urine output of 100 ml/hour) however in frail patients this may seem too aggressive. 2-3 litres of normal saline daily for 2-3 days is often adequate although this should be varied based on clinical examination of fluid status and blood tests.
Diuretic therapy with frusemide has traditionally been part of the treatment for hypercalcaemia of malignancy. Frusemide causes calcium excretion, but the main reason for its use, was to avoid fluid overload in patients receiving very large volumes of IV fluids. Frusemide is generally no longer used except for patients with heart failure who cannot tolerate 2-3 litres of IV fluids without it.
Bisphonoates act by binding to calcium in the bones where they are phagocytosed by osteoclasts. From within the osteoclasts, bisphosphonates induce apoptosis. They are very effective at reducing calcium, usually within 3-5 days. If an inadequate reduction in calcium has occurred at 7 days, the dose can be repeated (or denosumab can be given), although this is a poor prognostic sign.
Traditionally either pamidronate or zolendronic acid have been given, but recent analysis suggests zolendronic acid is superior to pamidronate. One study showed that zolendronic reverses hypercalcaemia of malignancy almost 90% of patients compared to about a 70% efficacy rate with pamidronate. In addition, zolendronic acid is more straight-forward to give as it is given as an IV infusion over 15-30 minutes. Dose reduction is required in renal failure. A typical dose in a patient with normal renal function is:
Zolendronic acid 4mg IV over 20 minutes
Following effective zolendronic acid treatment, the calcium stays down in the normal range on average about 5 weeks.
Zolendronic acid requires dose reduction in renal impairment (drop dose to 3mg and infuse over 30-60 minutes) and should be avoided in severe renal impairment when the estimated GFR < 30 ml/min.
Pamidronate is an alternative to zolendronic acid, but as already noted, it is probably less effective and it is less convenient. The usual dose is either 60mg or 90mg infused IV over 2 hours.
Ibandronate has also been shown to be effective at reducing calcium and this is an alternative in patients with renal failure. Studies have confirmed that it is as effective as pamidronate. The usual dose is 2 or 4 mg IV.
Multiple repeat doses of bisphosphonates is associated with the serious and extremely painful complication of jaw ostenecrosis with ulceration. This is unlikely to be an issue in patients who are in their last few weeks or months of life with hypercalcaemia of malignancy, but is an important consideration in patients who have a longer life-expectancy.
More immediate side effects include joint and muscle aches and pains and worsened renal function.
Denosumab appears to be more effective than zolendronic acid in reducing calcium and it is worth considering as a second line agent where bisphosphonates have been unsuccessful. In one study, patients who had hypercalcaemia of malignancy refractory to bisphosphonates were given Denosumab 120mg weekly for 4 weeks, with about 65% of patients responding successfully.
Denosumab is not renally cleared and is safe to give in renal failure, making it a reasonable alternative to zolendronic acid when renal failure is present.
The dose is:
Denosumab 120mg subcutaneously
Salmon calcitonin is often effective and works very acutely within 12 hours. It is not used commonly as bisphosphonates are generally preferred due to their much longer duration of effect. It is reasonable to consider calcitonin for patients who have very severe symptoms with very severe hypercalcaemia (e.g. > 3.5) to bring about a more acute reduction in calcium levels than can be achieved with bisphosponates.
The dose is 4 international units per kg and calcium should be rechecked 2-4 post treatment to check efficacy. If calcitonin is effective it will require frequent re-adminsitratoin (every 6-12 hours) as it's duration of action is relatively short. Additionally, calcitonin usually becomes ineffective after 48 hours of use. The mechanism for this is unknown but may be related to down-regulatoin of the calcitonin receptor.
Haemodialysis is technically an option for severe hypercalcaemia (levels above 4.5) with neurological symptoms or renal failure but is generally not going to be appropriate for palliative care patients with severe hypercalcaemia of malignancy as these patients are typically in their last few weeks of life.
Steroids tend not be effective for hypercalcaemia of malignacy. The exception to this rule is patients with hypercalcaemia due to the rare mechanisms of endogenous vitamin D production as occurs in lymphoma (or sarcoidosis).
Other general advice
Various factors can worsen hypercalcaemia, including:
- Bed rest
- Thiazide diuretics
- Vitamin D and/or calcium supplements
- High calcium diet
Where possible, these exacerbating factors should be reduced / avoided.
Hypercalcaemia of malignant indicates progressive disease and further chemotherapy should be considered in appropriate circumstances.
Follow-up and prognosis
Malignant hypercalcaemia usually indicates progressive cancer and, despite treatment, around half of the patients who develop it will die within a month. The prognosis tends to better however in multiple myeloma and breast cancer.
In patients who improve with treatment, regular follow-up (e.g. monthly) of calcium levels should be considered. Further episodes of hypercalcaemia may be treated with additional bisphosphonates.
- P Major. Zolendronic acid is superoir to pamidronate in the treatment of hypercalcaemia of malignancy. J Clin Oncol. 2001; 19(2):558.
- M.I. Hu et al. Denosumab for the treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014; 99(9)::3144.
- M.I. Hu et al. Denosumab for the treatment of hypercalcemia of Malignancy. J Clin Endocrinol Metab. 2014; 99(9):3144–3152.
- F. Lumachi. Cancer-induced hypercalcemia. Anti-cancer Research 29: 1551-1556 (2009).