Contents:
Treatment
There are times where HM can be recognised to be part of a terminal decline and the burdens of treatment outweigh the benefits. It is important to assess the stage of disease, and discuss with the patient, and if not competent with the relatives or advocate, the context of the current exacerbation and if treatment would be acceptable and appropriate.
It is important to:
‘Stop and think! Is it appropriate to treat? Or is the patient in the final days of life?’
Points to consider prior to treatment:
- First episode or long interval since previous episode
- Patient reports good quality of life prior to episode
- Multi-disciplinary team expectation is that treatment will have durable effect
- Patient is willing and able to have intravenous treatment and blood tests
The patient will have lost fluid and electrolytes and the immediate treatment is rehydration with saline and potassium depending on the laboratory measurements. Intravenous fluids reverse the dehydration cycle, improve the glomerular filtration rate and increase sodium linked calcium diuresis via the kidney, such that the serum calcium falls by up to 0.5mmol/l. The patient improves at this point and a common error is to declare them better and take the drip down. The process that caused the hypercalcaemia is however unresolved and the condition rapidly recurs. After initial rehydration maintenance fluids should continue until the patient is euvolaemic. Medications which reduce renal blood flow or renal calcium excretion should be discontinued/avoided where appropriate e.g.NSAIDS, thiazide diuretics. Stop Vitamin A, D and calcium supplements which can all increase calcium levels.
Bisphosphonates are the drugs of choice to treat HM. They are analogues of inorganic pyrophosphate that bind to hydroxyapatite crystals in bone and are released by bone resorption. Once taken up by the osteoclast they are cytotoxic and inhibit signalling pathways. When given for HM bisphosphonates stop the release of calcium from the bones allowing the rehydrated patient to normalise their serum calcium by excretion of excess calcium in the urine.
Disodium Pamidronate has been used for many years. The manufacturer gives a schedule of dosing for Pamidronate dependent upon the serum calcium but systematic review evidence suggests 90mg should be given whatever the serum calcium level to effectively combat the ongoing HM process.
Zoledronic acid belongs to the third generation. Studies have revealed rapid onset of action and longer duration when compared to Disodium Pamidronate, and so therefore Zolendronic acid is usually the preferred bisphosphonate in treatment of HM.
Ibandronate is also the third generation bisphosphonate with better renal profile. Other bisphosphonates are Clodronate, Etidronate and Alendronate although these are difficult to obtain in the UK.
The actual selection of bisphosphonate is usually dictated by local policies.
Zoledronic acid 100 to 850 times more potent than pamidronate
Ibandronic acid 50 times more potent than pamidronate
Bisphosphonates are well tolerated such that even a seriously ill patient has the option of a trial of therapy. The main side effects are mild pyrexia and flu like symptoms for 24-48 hours; fatigue, headache, myalgia, bone pain and hypocalcaemia which occasionally requires calcium replacement if the patient has excreted large amounts of calcium whilst serum levels were high. A very rare but challenging side effect is osteonecrosis of the jaw but this is usually develops only in patients on long term bisphosphonate treatment.
Bisphosphonates can affect renal function that’s why administration in moderate to severe renal failure ( eGFR< 30) is contraindicated and should be only considered when potential benefits outweigh the risks and safer medication can`t be used.
Disodium Pamidronate rarely causes acute renal failure in patients with normal or mildly impaired renal function. Renal failure has occurred with Zoledronic acid, especially with high doses, but it is uncommon with Ibandronic acid.
Management of hypercalcaemia of malignancy
Typical presentations of hypercalcaemia:
- Nausea and vomiting
- Confusion
- Polydipsia and polyuria
- Constipation and abdominal pain
- Clinical dehydration
- Agitation, decreased consciousness, seizures
“Bones, stones, groans and moans”
Investigations:
- FBC, Urea and Electrolytes, Liver function tests
- Bone profile (adjusted calcium)
- PTH level
- Low in hypercalcaemia if malignancy
- If high – consider primary hyperparathyroidism
- ECG
- Assessment of fluid status
WITHHOLD any contributing drugs e.g. NSAIDs, ACEI, ARBs, thiazide diuretics, Ca2+/VIT D supplements.
TREATMENT - Stop and think: is it appropriate to treat?
Is this likely to be a terminal event? Is there going to be any benefit to treating hypercalcaemia if proven?
If likely to represent a terminal decline:
Consider referral to a specialist palliative care team. Have open and honest discussions with patient and family around prognosis and advance care planning.
If unlikely to represent a terminal decline:
Asymptomatic Hypercalcaemia
Asymptomatic Hypercalcaemia is more commonly associated with raised corrected calcium levels <3.
Consider:
- Whether a watch and wait approach is appropriate.
- PTH levels to exclude primary hyperparathyroidism.
- Referral to endocrinology.
Symptomatic Hypercalcaemia
Symptomatic Hypercalcaemia is more commonly associated with raised corrected calcium >3 BUT not exlusively.
IV rehydration 0.9% NaCI typically 3L/24 hours*
Give Zoledronic acid 4mg diluted in 100 ml sodium chloride 0.9% IV over 15 minutes.
In renal failure reduce the dose:
eGFR:
50-60 ml/min/1.73m2: 3.5mg zoledronic acid
40-49 ml/min/1.73m2: 3.3mg zoledronic acid
30-39 ml/min/1.73m2: 3.0mg zoledronic acid
If eGFR is <30 reduce the does and treat only when benefit is more likely than harm (consider special advice).
*Caution in patients with reduced ejection fraction/those on dialysis.
Advise patient and family to be aware of signs of hypercalcaemia.
Discuss preferences around future management and advance care planning if hypercalcaemia recurs.
Re-check serum calcium in 5-7 days.
Review hydration status daily and check U&E as indicated.
Ongoing Management:
If hypercalcaemia persists OR if this recurrent high calcium or chronic problems discuss with patient’s parenting Oncologist or Specialist Palliative Care Team. May need to consider oral bisphosphonate for persistent hypercalcaemia.
It is important to be cautious when treating hypercalcaemia in renal failure attention should be paid to rehydration and on-going monitoring of renal function because the drug itself can cause renal tubular damage and acute renal failure. Zoledronic acid must be dose adjusted for patients with mild-moderate renal impairment, where Disodium Pamidronate is safer in mild-moderate renal impairment but must not exceed a rate of 90mg/4hr.
Where eGFR < 30, PCF8 (Palliative Care Formulary) states consider using ibandronate or denosumab and seek specialist renal/endocrinology advice.
If at 7-10 days post bisphosphonate infusion, the corrected calcium level is greater than 3.0mmol/l or symptoms of hypercalcaemia persist, it may be appropriate to consider another bisphosphonate infusion. At least 7 days should elapse before a further treatment is given to ensure a maximal response to the initial dose, although the Palliative Care formulary suggests waiting three weeks.
Options for treatment include:
- Repeat the same dose of bisphosphonate
- Increased dose of same bisphosphonate
- Change to alternative bisphosphonate
Further episodes of hypercalcaemia may be treated as above. Relapsing hypercalcaemia usually does not respond as well to bisphosphonates as in the initial episode.
For patients with hypercalcaemia resistant to bisphosphonates (initial or recurrent), Denosumab should be considered.
If levels normalise, consider ongoing plan for monitoring and therapy, referring to Oncology or Specialist Palliative Care as needed. Calcium should be re-checked if symptoms recur and at four weekly intervals if risk of recurrent hypercalcaemia and regular (monthly) infusions of bisphosphonates should be considered.
Disclaimer
These Guidelines are intended for use by healthcare professionals and the expectation is that they will use clinical judgement, medical, and nursing knowledge in applying the general principles and recommendations contained within. They are not meant to replace the many available texts on the subject of palliative care.
Some of the management strategies describe the use of drugs outside their licensed indications. They are, however, established and accepted good practice. Please refer to the current BNF for further guidance.
Whilst SPAGG takes every care to compile accurate information , we cannot guarantee its correctness and completeness, and it is subject to change. We do not accept responsibility for any loss, damage or expense resulting from the use of this information.