The Management of Hypercalcaemia in Advanced Cancer: Clinical

Clinical
The management of hypercalcaemia

in advanced cancer
Annie Pettifer, Sarah Grant
H
ypercalcaemia is a clinical condition
that occurs when the serum calcium
level rises above 2.6 mmol/l (Samphao
Abstract
Hypercalcaemia is common in patients with advanced cancer. If
et al, 2010). For patients with a diagnosis of
detected, it usually responds to palliative treatment and patients’
advanced cancer, hypercalcaemia is the most
distressing symptoms will improve markedly. However, if left untreated
common life-threatening metabolic condition and
hypercalcaemia is potentially fatal. It can be difficult to detect as its
is associated with a low survival rate, with a
symptoms can also be attributed to other common aspects of
median survival of 3–4 months (Bower and Cox,
advanced malignancy. It is therefore essential that nurses are aware of
2010). Hypercalcaemia affects between 10% and
the underlying physiology and can identify which patients are at risk of
30% of patients with cancer, depending on
becoming hypercalcaemic. Hypercalcaemia often recurs and can
the characteristics of the sample studied
become increasingly difficult to treat. Such refractory hypercalcaemia
(Watson et al, 2005). It is most frequently found
requires sensitive and considered management with advance care
in multiple myelomas and breast cancers, but is
planning, particularly as difficult treatment dilemmas may arise if and
also common in squamous cell carcinomas of
when malignancy advances.
the head and neck, lung, kidney, and cervix uteri.
Key words: Hypercalcaemia l Malignancy l Cancer l Advance care
It is much less common in cancer of the
planning l Nursing
prostate, small cell lung cancer, and gastric and
large bowel tumours (Twycross et al, 2009).
Hypercalcaemia can be distressing for both
patients and families. In the main, once diagnosed Roberts, 2007) by homeostatic mechanisms
it can be treated effectively, but without treatment operating within the bone, gastrointestinal (GI)
it is potentially fatal. tract, and kidneys. Bone and teeth act as a
This article reviews the physiology of normal calcium reservoir, storing around 90% of total
calcium regulation and the mechanisms by which calcium levels (Montague et al, 2005). Calcium
this may alter in patients with malignancy. It in bone is found crystallised into hydroxyapatite,
also describes the clinical manifestation of hyper which makes up the bone matrix. Bone matrix is
calcaemia, diagnostic testing, and therapeutic not static, but is constantly regenerating as
management. The implications of this distressing calcium and phosphate are released from bone by
complication for patients and carers are discussed the action of osteoclasts. The converse action of
together with the care that should be given to osteoblasts re-forms calcium and phosphate into
reduce the effects of this potentially life-threatening Annie Pettifer is
bone to maintain serum calcium levels. Senior Lecturer in Adult
condition. The care of patients with hyper The GI tract and the kidneys also have a role Nursing, Coventry
calcaemia in advanced cancer is illustrated by a in calcium homeostasis although, unlike the University, Priory Street,
Coventry, CV1 5FU,
case example that demonstrates the importance bone, they have no calcium storage function. England; Sarah Grant
of advance care planning. Calcium is ingested into the GI tract from foods is Macmillan Palliative
Care Clinical Nurse
such as dairy products and green leafy vegetables Specialist, St Michael’s
Physiology of normal (Clancy and McVicar, 2009). Once within the GI Hospice, The Cottage,
50 Lancaster Park
calcium regulation tract, depending on the demand for it, calcium Road, Harrogate,
may be absorbed into the serum or excreted HG2 7SX, England
Calcium is the most common mineral in the
© 2013 MA Healthcare Ltd
human body and is crucial to normal human within the faeces. Similarly, extracellular calcium Email:
can be reabsorbed into the serum as it passes A.Pettifer@
functioning, particularly in muscle and nerve coventry.ac.uk
action and blood clotting (Clancy and McVicar, through the kidney or can be excreted within the
urine as required to maintain constant optimal Or:
2009). Serum calcium is normally maintained sarah.grant2@
between 2.12 and 2.65 mmol/l (Tadman and serum levels. saintmichaelshospice.org
International Journal of Palliative Nursing 2013, Vol 19, No 7 327
onal Journal of Palliative Nursing. Downloaded from magonlinelibrary.com by 193.061.135.112 on November 24, 2015. For personal use only. No other uses without permission. . All rights r
Clinical
Table 1. Mechanisms and frequency of hypercalcaemia in different tumour types*

Mechanism Frequency Common tumour type(s)
Squamous: cell, renal, ovarian,
Parathyroid hormone-related protein production 80% endometrial, and breast cancers
Action of cytokines 20% Breast cancer, myeloma, lymphoma
Increased 1,25-dihydroxycholecalciferol (vitamin D) production <1% Lymphoma
Ectopic parathyroid hormone secretion <1% Various types
*Adapted from Samphao et al (2010)
Homeostatic control of calcium of the bone, hormone-related peptide (PTHrP) is released

GI tract, and kidneys is regulated by the from the tumour. This mimics the action of
parathyroid hormone, vitamin D, and calcitonin parathyroid hormone on the osteoclasts and
(Unglaub Silverthorn, 2010). Homeostatic kidneys, causing elevated serum calcium. This is
mechanisms maintain a normal serum calcium the most common form of hypercalcaemia
level by monitoring and balancing the amount (Heatley, 2004). Second, in osteolytic hyper
of calcium released from bone, the quantity calcaemia, primary or metastatic tumours produce
needed to rebuild new bone, the amount that is substances such as cytokines, which locally
absorbed from food within the GI tract, and the increase the calcium-releasing activity of osteo-
amount excreted by the kidneys (Unglaub clasts, thus raising the serum calcium level. This
Silverthorn, 2010). mechanism is associated with bone metastases.
Parathyroid hormone is synthesised and Third, some lymphomas mediate increased
secreted within the parathyroid glands located in production of 1,25 -dihydroxycholecalciferol
the thyroid. It is secreted in response to low thus raising serum calcium through increased
serum calcium levels and potentiates the action absorption of calcium from the GI tract and
of osteoclasts to reabsorb the hydroxyapatite increased osteoclastic activity. A fourth effect of
bone matrix, releasing calcium into the serum. cancer on calcium regulation, ectopic secretion
Simultaneously, parathyroid hormone potentiates of parathyroid hormone, is rare (Stewart, 2005).
the reabsorption of calcium in the kidneys More than one of these mechanisms may be
(Unglaub Silverthorn, 2010). causing hypercalcaemia simultaneously.
‘Vitamin D’ is a collective term for a group of Given the varied mechanisms by which
closely related substances. It is ingested in the malignancy can disrupt normal calcium
diet from foods such as oily fish and eggs, and regulation, it is apparent that patients with a
made in skin through the action of direct sun- range of cancer diagnoses are susceptible to
light. It is stored as 25-dihydroxycholecalciferol hypercalcaemia. Indeed, although 80% of
in the liver. Parathyroid hormone’s third action in patients with hypercalcaemia have bone
response to low serum calcium is to stimulate the metastases, these mechanisms are also commonly
synthesis of 1,25-dihydroxycholecalciferol from active in patients without bone metastases
25-dihydroxycholecalciferol in the kidneys. In (Bower and Cox, 2010). This is illustrated in
turn, this activated form of vitamin D increases Table 1.
the absorption of calcium from the GI tract.
Calcitonin is secreted from the parafolicular Clinical presentation
cells of the thyroid glands in response to high Familiarity with the clinical presentation of
levels of serum calcium. It causes a reduction hypercalcaemia is crucial as clinical suspicion is
of serum calcium levels by stimulating the action key to diagnosis. Hypercalcaemia affects multiple
of osteoblasts to form bone matrix from the organ systems, so the symptoms patients present
serum calcium (Patton and Thibodeau, 2007). with can be varied. Table 2 lists the signs and
symptoms commonly experienced by patients
The effect of cancer on with hypercalcaemia. Other rarer symptoms
calcium regulation include bradycardia, a shortening of the QTc
Normally the human body maintains serum interval, wide T waves, cardiac arrythmias, and
calcium effectively. However, in patients with prolonged PR interval (Woodruff, 2004).

cancer, calcium regulation can be impeded Challengingly, the symptoms of hypercalcaemia
causing hypercalcaemia. There are four possible often mimic those experienced during the general
mechanisms through which this can occur. First, deterioration of a person’s condition when
in humoral hypercalcaemia, parathyroid entering the dying phase, or can be attributed to
328 International Journal of Palliative Nursing 2013, Vol 19, No 7
Clinical
side-effects of chemotherapy or analgesia Table 2. Signs and symptoms of hypercalcaemia*

(Robotin et al, 2010). Therefore the possibility of
Mild symptoms Severe symptoms
hypercalcaemia should always be considered if a
● Drowsiness
patient with advanced cancer suffers any sudden
● Fatigue/lethargy ● Delirium
onset of symptoms or decline in condition.
● Mental dullness ● Nausea
● Weakness ● Vomiting
Diagnosis
● Anorexia ● Confusion
While clinical suspicion, based on the patient’s
● Thirst ● Dehydration
condition and knowledge of the tumours likely to
● Polyuria (rarely a significant feature) ● Coma
cause hypercalcaemia, is the mainstay for detec-
● Constipation ● Fitting
tion of hypercalcaemia, a diagnosis needs to be
confirmed through blood testing. Calcium is *Adapted from Twycross et al (2009)
present within the serum predominantly in two
forms: either bound to the proteins albumin and are present. For more severe hypercalcaemia,
globulin or ionised, in which case it is unbound symptoms can markedly improve with treatment,
(Higgins, 2007). Calcium biochemistry will even when the patient has advanced disease and
detect and include calcium that is present in a limited life expectancy. Hypercalcaemia can be
either form. Calcium normally exists in these two successfully treated in at least 90% of cases by
forms in equal amounts; however, only the ion- rehydration and bisphosphonates (Body and
ised form is significant physiologically in calcium Mancini, 2003).
regulation. In patients with advanced cancer If hypercalcaemia is suspected and the presenting
whose albumin levels are low, which is common, patient would be appropriate for treatment, the
the balance of the distribution of calcium serum levels of urea, electrolytes, albumin, and
between these two forms may become unequal, calcium should be checked and sent as an emer-
with less calcium being bound to albumin and gency sample to the biochemistry laboratory. It is
more existing in the unbound or ionised form the corrected calcium result that should be used
(Higgins, 2007). In such cases overall serum to determine the clinical management.
calcium levels can appear normal when in fact Uncontrolled diabetes mellitis should be excluded
patients are hypercalcaemic. Serum calcium concurrently as the clinical features are similar. It
measurements therefore need to be adjusted for is important to discontinue any medication that
albumin levels (Stewart, 2005). Biochemistry would cause an elevation in calcium levels such
laboratories are usually able to calculate these as diuretics, vitamins A and D, and thiazides.
levels and may do so as a matter of routine. Also, consideration should be given to discon
tinuing those drugs that may affect renal blood
Management flow such as non-steroidal anti-inflammatories,
The severity of the symptoms experienced does diuretics, angiotensin-converting enzyme (ACE)
not always reflect the serum level of hyper inhibitors, and angiotensin II receptor antagonists
calcaemia, as the symptoms seem to reflect the (MacLaran et al, 2012).
rate of serum calcium rise not the serum calcium Definitive treatment should be started as soon
level per se. However, untreated severe hyper as possible, as the metabolic disturbance may
calcaemia can be fatal (Seccareccia, 2010), so if cause severe symptoms to develop rapidly
the corrected calcium serum level is greater than (Twycross et al, 2009). Treatment will take the
3.0 mmol/l treatment should always be consid- form of one or more of the following:
ered. Twycross et al (2009, p218) suggested a set ●●Fluids
of indicators for treating hypercalcaemia: ●●Bisphosphonates
●●Corrected serum calcium >2.8 mmol/l ●●Calcitonin.
●●Symptoms attributable to hypercalcaemia
●●First episode or long interval since previous one Fluids
●●Previous good quality of life in patient’s opinion Although mild hypercalcaemia may respond to
●●Medical expectation that treatment will IV fluids alone, in patients with grossly abnormal
achieve a durable effect (based on the results of calcium levels large volumes of fluid are unlikely
previous treatment) to achieve a totally normal calcium level unless
●●Patient willing to have intravenous (IV) therapy bisphosphonates are added. Such patients are
and requisite blood tests. often more susceptible to the added complication
Mild hypercalcaemia (corrected calcium of fluid overload, so daily electrolyte checks
<3.0 mmol/l) is usually asymptomatic, and so should be taken to monitor for any signs of this
treatment should be given only if symptoms during infusion. Loop diuretics are recommended
Clinical
Table 3. Administration of intravenous bisphosphonates*

Corrected calcium
(mmol/l) Dose of disodium pamidronate Dose of zoledronic acid
<3.0 30 mg in 250 ml 0.9% sodium chloride over 30 minutes
3.0–3.5 60 mg in 500 ml 0.9% sodium chloride over 60 minutes 4 mg in 100 ml 0.9% sodium
>3.5 90 mg in 1 litre 0.9% sodium chloride over 90 minutes chloride over 15 minutes
*Joint Formulary Committee (2013)
to manage fluid overload only. There is insufficient Refractory hypercalcaemia

evidence to support their use in promoting Although treatment with IV fluids, bisphos
calciuresis (Le Grand et al, 2008). phonates, or calcitonin is likely to be effective in
restoring serum calcium levels and relieving
Bisphosphonates symptoms, it will not alter the physiological
Before administering bisphosphonates, adequate mechanisms underlying the hypercalcaemia. The
hydration of IV fluids (at least 2 litres) is condition is therefore likely to recur in patients
essential. The most commonly used IV with advanced malignancy. For example, the
bisphosphonates are disodium pamidronate and median duration of effect of disodium pamidro-
zoledronic acid. Rehydration is an integral nate is 4 weeks (Twycross et al, 2009). An ongoing
component of the management of hyper management plan is therefore vital to care.
calcaemia (MacLaran et al, 2012), and it may Prophylactic treatment with bisphosphonates
also be required following administration of may be indicated. Patients and relatives should be
bisphosphonates. Bisphosphonates inhibit the made aware of the early signs of hypercalcaemia
activity of osteoclasts and therefore of bone and encouraged to alert clinicians accordingly.
resorption. They have no impact on PTHrP. Malignancy-related hypercalcaemia is usually
Bisphosphonates bind to hydroxyapatite follow- linked to advanced metastatic disease and can be
ing absorption on the surface of the bone, and indicative of a poor prognosis (Makras and
can remain bound there for weeks or months. Papapoulos, 2009). Twycross et al (2009) advise
The mainstay of treatment has been disodium that survival is often less than 3 months and only
pamidronate. More potent bisphosphonates such 20% of patients with hypercalcaemia will survive
as zoledronic acid can be more effective a further 12 months. Although poorly researched,
(Seccareccia, 2010), but disodium pamidronate is it would appear that subsequent episodes of
cheaper (Lumachi et al, 2009) and its hypocal- hypercalcaemia become increasingly difficult to
caemic effect resolves sooner. Bisphosphonates treat (Saunders et al, 2004). Therefore, as with
are commonly given intravenously, as oral any treatment decision made in the symptomatic
bisphosphonates tend to be poorly absorbed management of a palliative care patient, careful
(Table 3). consideration should be given to balancing the
Bisphosphonates are generally well tolerated, benefits of intervention against the impact on
but known adverse effects include renal failure quality of life. It may be appropriate to consider
and transient flu-like symptoms (Samphao et al, advance care planning (ACP) when hypercalcaemia
2009). Consequently bisphosphate doses must be is first presented. ACP is:
reduced in patients with renal failure (Ashley and
Currie, 2009). ‘A process of discussion between an individual
and their care providers ... to make clear a
Calcitonin person’s wishes, and will usually take place in
Calcitonin inhibits both osteoclast activity and the context of an anticipated deterioration
renal tubular resorption. A fall in serum calcium in the individual’s condition in the future, with
is often evident after a couple of hours of attendant loss of capacity to make decisions
treatment with calcitonin. Although the initial and/or ability to communicate wishes to
response is usually quicker, calcitonin has proved others.’ (National End of Life Care Programme,
less effective over the long term than bisphospho- 2008, p4)
nates, and so its use is now uncommon. The

route of administration is usually subcutaneous ACP encompasses all kinds of anticipatory
or intramuscular; however, the rectal route is also decision making, including advance refusal or
advocated. Side effects of calcitonin are minimal acceptance of future treatment interventions. It is
(Bower and Cox, 2010). dependent on health professionals engaging with
330 International Journal of Palliative Nursing 2013, Vol 19, No 7
Clinical
patients to explore their wishes while ensuring Box 1. Case example

their decisions are made based on informed
choices (Watson et al, 2005). Mr A, a 63-year-old gentleman diagnosed with advanced lung cancer, presented to his
For those patients who are thought highly GP with sudden onset of nausea, constipation, and confusion. A serum investigation
likely to develop recurrent hypercalcaemia in the determined that he had a corrected calcium level of 3.6 mmol/l. An emergency admis-
future, discussions should take place around sion to the local oncology unit followed, where Mr A was treated with intravenous
fluids and disodium pamidronate 90 mg/l infusion over 90 minutes. Mr A remained an
the treatment options available, and any wishes
inpatient for a further 5 days until his serum calcium level could be accurately checked
the patient expresses for the management of the and his full response to the treatment assessed.
condition should be documented. Adults over 18
Mr A’s clinician initiated a discussion with Mr A and his wife. The mechanism underlying
may wish to make a legally binding advance the hypercalcaemia was explained, together with the risk of a possible recurrence in
decision to refuse treatment should they lose the near future. In the following 4 months Mr A was treated twice for raised calcium,
capacity to make decisions in the future. In order but the interval between episodes shortened with each treatment. In addition, Mr A’s
to be valid, advance decisions to refuse life-saving general condition deteriorated and he experienced increasing weight loss, weakness,
and debility.
treatment must be made in writing, witnessed,
signed, and dated, and must include the phrase At this stage, a discussion of Mr A’s future care preferences took place, based on the
principles of advance care planning. Mr A did want any subsequent hypercalcaemia to
‘even if my life is at risk’ (National End of Life
be treated, but for that treatment to be withdrawn quickly should it prove refractory.
Care Programme, 2011, p26). In this situation he wanted to be admitted to his local hospice to die. This was
The case example in Box 1 illustrates how documented in his advance care plan as an advance decision.
APC may assist with the management of Shortly after the discussion, Mr A became hypercalcaemic for the fourth time. He
refractory hypercalcaemia. was initially treated with zoledronic acid but treatment was withdrawn after 2 days
when his symptoms, including agitated confusion, worsened and his serum calcium
Conclusion continued to climb. He was transferred to his local hospice where the confusion was
managed with subcutaneous midazolam. He died peacefully surrounded by his family.
Hypercalcaemia is a common and distressing
occurrence in patients with advanced malignancy.
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