Oncology Emergency: Malignant Hypercalcemia

Introduction

Hypercalcemia secondary to malignancy is one of the oncology emergencies and most common life-threatening metabolic abnormality in advanced stage malignancies ². Cancer is the most frequent cause of elevated calcium in inpatient population whilst primary hyperparathyroidism is the commonest cause of hypercalcemia in the general population ^{2, 3}. The incidence of malignant hypercalcemia is low (1-5%) in the early stage of cancer, but, this rises in advanced stage and is in association with poor prognosis and a median survival duration for those patients is estimated 2-6 months from the onset of the disease ¹⁵. It is associated with haematological malignancies and solid cancers. Among them, multiple myeloma is the highest prevalence followed by non-Hodgkin lymphoma and leukaemia. Solid cancers include particularly renal, lungs, breast and squamous carcinomas of any origin ^{2, 3, 4}. The severity of symptoms depends on the level of serum calcium which varies from mild hypercalcaemia with being asymptomatic incidentally recognized on screening blood test to severe hypercalcemia with neurocognitive dysfunction, volume depletion and renal insufficiency or even failure ^{11, 12}. There are several mechanisms of developing malignancy related high calcium level such as the osteolytic related, parathyroid hormone related peptide (PTHrP) mediated, extra-renal 1, 25 dihydroxy vitamin D (calcitriol) and PTH related either ectopic production or hypersecretion due to parathyroid carcinoma.

Clinical history and physical examination directed towards the diagnosis and confirmed by appropriate investigation and biochemical mediators of hypercalcemia. Immediate treatment is very important to improve symptoms and avoid delays for anticancer treatment to target the root cause.

Definition

Hypercalcaemia is defined as a serum calcium level greater than the upper limit of normal reference range of 2.6 mmol/L or 10.5mg/dL, following adjustment (correction) for the serum albumin concentration. There are three categories of hypercalcemia according to total serum calcium level as follows ^{9, 11}:

• Mild hypercalcaemia is an adjusted serum calcium concentration of greater than 2.6 but less than 3 mmol/L (10.5-11.9 mg/dL).
• Moderate hypercalcaemia is an adjusted serum calcium concentration of 3 to 3.5 mmol/L (12-13.9 mg/dL).
• Severe hypercalcaemia is an adjusted serum calcium concentration of greater than 3.5 mmol/L (≥14mg/dL).

There are two forms of calcium existing in the serum: as free ionized calcium and bound calcium. The majority of the bound calcium (40% – 45%) is attached to albumin with the remainder bound to small anions or other proteins. Total calcium levels in serum measure both forms, however, the result can be affected by the levels of calcium binding proteins. In case of hypoalbuminemia, total serum calcium may appear lower than normal and corrected calcium level should be calculated. An alternative approach is direct measurement of ionized calcium which is a better indicator of bioavailable calcium in serum ^{1, 7}.

Epidemiology

Approximately 20%-30% of all cancer patients are affected by malignant hypercalcemia during their clinical course ^{1, 16, 5}. The highest prevalence of malignant hypercalcemia as well as the most common associated cancer is multiple myeloma followed by squamous cell lungs cancer, breast cancer, renal cancer, etc. Hypercalcemia of malignancy is reported 2%- 3% of patients with a cancer diagnosis and it has been steadily decreasing over the years due to better treatment options ⁸.

Pathophysiology

There are several mechanisms of hypercalcemia associated with malignancy which are as follows ^{6, 11}:
1. Excessive secretion of parathyroid hormone-related protein (PTHrP)
2. Osteolysis by bony metastases with the release of osteoclast activating factors
3. Production of 1,25-dihydroxy vitamin D (calcitriol)
4. Others such as excessive PTH secretion, ectopic or primary, multiple concurrent aetiologies

Among all the above mechanisms, the commonest cause is excessive secretion of PTHrP (a paraneoplastic syndrome) and accounting for approximately 80% of cases. This is also known as humoral hypercalcemia of malignancy. Structure of PTHrP resembles to parathyroid hormone (PTH) in the sequences of first 13 amino acid. Because of its structural similarity, PTHrP binds to the same receptor as PTH, triggering bone resorption, increased excretion of phosphate in the proximal tubules, and reabsorption of calcium in the distal tubules in kidney³. However, the production of 1,25-dihydroxy vitamin D is not affected. Biochemical results show high PTHrP, low to normal PTH, and normal 1,25-dihydroxy vitamin D levels. Treatment response can be assessed by monitoring PTHrP levels. Usually, patients with this type of hypercalcemia tend to have advanced disease, and it points to a poor prognosis ^{1, 11, 4}. The types of cancer most frequently linked with this mechanism of hypercalcaemia include squamous cell carcinomas of lung, oesophagus, head and neck, skin, cervix, breast, kidney, prostate, and bladder cancer.

Fig 1. Effects of parathyroid hormone (PTH) and vitamin D. From “How to Approach Hypercalcemia,” by R. Crowley and N. Gittoes, 2013, Clinical Medicine, Vol. 13, Issue 3, pp. 287–290

However, unlike PTH, PTHrP does not stimulate the production of 1, 25(OH)2D, and therefore does not increase the intestinal absorption of calcium and phosphorus. PTHrP interacts with osteoblasts, promoting the increased synthesis of RANKL ¹¹.

Osteolytic hypercalcemia due to bony metastases cause releasing osteoclast activating factor which account for 20% of cases ⁶. This type of hypercalcemia is commonly associated with multiple myeloma, metastatic breast cancer and less occurs in leukaemia and lymphoma. Classical findings involve skeletal metastasis with low to low-normal PTH, PTHrP and calcitriol levels. The release of local cytokines from the tumour leads to excess osteoclast activation which enhance resorption of bone via RANK/RANKL ^1,5. Other humoral factors related with increased bone remodelling and hypercalcemia involve interleukin 1, 3 and 6 (IL1, IL3, IL6), tumour necrotic factor (TNF), transforming growth factor a and b (TGF a, b), prostaglandins, lymphotoxin and macrophage inflammatory protein 1a ¹¹.

Other uncommon mechanisms for hypercalcaemia due to malignancy include increased ectopic extra-renal production of the active metabolite of Vitamin D (usually by lymphomas) and ectopic PTH secretion ⁴.

Assessment and investigations

Thorough clinical history and physical examination as a mandatory initial step direct clinician to a prompt suspicion of diagnosis. Patients present with a wide spectrum of symptoms. Depending on the severity, patients can either be asymptomatic or significant symptomatic due to involving multiple organ systems as below ^{1, 2}:

• Gastrointestinal tract (GI): anorexia, nausea and constipation
• Renal involvement: polydipsia, polyuria, acute kidney injury (AKI)
• Central nervous system (CNS): lethargy, confusion, or even coma (more common in elderly patients)
• Psychiatric disturbances: anxiety, depression, or cognitive disturbances.
• Cardiovascular system (CVS): are subtle, short QTc interval and ST segment, rare cases of arrythmias, heart block
• Musculoskeletal system: muscle weakness and bone pain

Low-normal or low levels of PTH (lower than 20 pg/mL) should suspect non-PTH related hypercalcemia. As a next step, PTHrP and vitamin D metabolites such as 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D levels should be checked. If PTHrP is elevated, it suggests humoral hypercalcemia of malignancy.

Vitamin D intoxication causes raised 25-hydroxy vitamin D levels. Elevated 1,25-dihydroxy vitamin D levels should be raised suspicion of Lymphoma and granulomatous diseases. If vitamin D levels are noted within normal limit, serum and urine electrophoresis with immunofixation, and serum-free light chains should be checked to rule out multiple myeloma.

Prognosis

The prognosis for malignancy related hypercalcemia patients with concurrent hyperparathyroidism is anticipated in years, whereas true hypercalcemia of malignancy typically has a median survival of 2 -4 months. Hypercalcemia that is resistant to treatment is linked to a very poor prognosis ^{4, 5}. While the symptoms of hypercalcemia of malignancy are often mild and nonspecific depending on disease burden, the consequence of metabolic disturbances can develop significant morbidity and mortality. It is estimated that mortality rate of cancer patients with hypercalcemia within 30 days is about 50% ⁶.

Fig.2 Median overall survival after hypercalcemia. Patients admitted with symptomatic hypercalcemia experienced a short overall survival of 40 days.

JGO–Journal of Global Oncology, Volume3, Issue6, December2017 ¹⁴

Management

Initial Treatment

First most important steps of treatment is IV hydration with 0.9% sodium chloride 3-4L in the first 24 hours (the rate of 200 to 300 mL/hr) and maintaining an adequate urine output of more than 100 mL/hr is crucial for restoring intravascular volume and increasing urinary calcium excretion. Patients with heart or renal failure should be given IV hydration with caution and strict monitoring of intake/output fluid balance is necessary. It is very important that loop diuretics should be administered following adequate IV fluid resuscitation. Loop diuretics promote urinary calcium excretion by blocking calcium reabsorption at the loop of Henle. Blood test for urea and electrolytes, Ca2+, magnesium and phosphate should be monitored daily.

Soon after patients have been rehydrated and established urine output within first 24 hours, either IV bisphosphonates, such as zoledronic acid (ZA) (dose of 4mg) over 15 to 30 minutes or IV pamidronate (dose of 60 to 90 mg) over 2 hours, are recommended for patients without renal dysfunction. Zoledronic acid is preferred choice of hypercalcemia associated with malignancy as it is more potent and can be administered over a shorter course of time. Bisphosphonates are also commenced regularly to patients with bone metastases to reduce the risk of later skeletal complications. The most important serious side effects of bisphosphonate are osteonecrosis of jaw and nephrotoxicity. Formal dental check up by dentist is recommended before starting this treatment as a regular basis.

Treatment in Renal Impairment

It is essential that caution needs to be taken in treating high calcium in renal impairment patients and continuous monitoring of fluid balance and renal function is important since there is significant risk of renal tubular damage and renal failure. Bisphosphonate dose must be adjusted in mild to moderate renal insufficiency. Dose adjustments as per BNF/NICE guidelines ²⁰:

• Creatinine clearance 50–60 mL/minute reduce dose to 3.5 mg
• Creatinine clearance 40–50 mL/minute reduce dose to 3.3 mg
• Creatinine clearance 30–40 mL/minute reduce dose to 3 mg

If renal function deteriorates in patients with bone metastases, withhold dose until serum creatinine returns to within 10% of baseline value.

Pamidronate is relatively safer in mild to moderate renal dysfunction, however, must not exceed a rate of 90mg/4hr ⁵.

If creatinine clearance is less than 30ml/min (GFR <10), bisphosphonate is not recommended and seek advice from endocrinology team.

Treatment Resistant and/or Recurrent Hypercalcemia

After 7-10 days of bisphosphonate, the level of corrected calcium is higher than 3 mmol/L and/or persistent hypercalcemia symptoms, another dose of bisphosphonate infusion can be considered. It is very important that bisphosphonate must not be given further dose until at least 4-7 after previous dose ¹⁹.

If there is no response to bisphosphonate, Denosumab should be considered which inhibiting RANKL or in those with kidney insufficiency since it is not excreted by kidneys ²¹.

Glucocorticoid therapy is another option of treatment especially in patients with high 1, 25-dihydroxy vitamin D production, particularly in lymphomas or granulomatous diseases, since this encourage to decrease vitamin D production and intestinal absorption of calcium.

Cinacalcet, which is Calcimimetic agent, is preferred choice of treatment in patients who are having haemodialysis and hypercalcemia due to parathyroid cancer.

Fig.3 Acute Oncology Initial Management Guidelines ¹⁹, www.ukacuteoncology.co.uk

Fig 4. Osteoclast formation, activity, and pharmacologic inhibition.

Conclusion

Overall, although dramatic improvement of oncology treatment and effective management, patients with symptomatic cancer related hypercalcemia still have poor prognosis and hypercalcemia one of the strong predictor of mortality in malignant patients.

References

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Author Information

Su Lei Yin
M.B., B.S, MRCP (UK), MSc Oncology (The University of Nottingham)
Specialty Trainee Registrar in Medical Oncology at Department of Oncology, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK