Treatment of hypercalcaemia of malignancy in adults

Abstract

Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2–30%, depending on cancer type and disease stage. HCM is associated with impaired quality of life, increased risk of hospitalisation and limited survival. Evidence-based guidelines for management of HCM have been lacking to date, despite its prevalence and detrimental impact. This concise guidance highlights key recommendations from the recent Endocrine Society Clinical Practice Guidelines on Treatment of Hypercalcaemia of Malignancy in Adults, published in December 2022. A systematic review and meta-analysis was commissioned to support the guideline development process. Key suggestions include the use of denosumab in preference to intravenous bisphosphonates as first-line treatment for HCM and the use of denosumab in cases of recurrent or refractory HCM in patients previously treated with intravenous bisphosphonates. The guideline also identifies priority areas for future research.

Introduction

Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies, with a prevalence rate of 2–30% depending on cancer type and disease stage.^1,2 HCM has been reported in almost all cancers, but most commonly occurs in breast cancer, lung cancer, renal cancer and multiple myeloma. Clinical manifestations are dependent on hypercalcaemia severity, acuity of onset and nature of the underlying malignancy. HCM can be classified as mild (serum calcium (sCa) <3.0 mmol/L), moderate (sCa 3.0–3.5 mmol/L) or severe (sCa >3.5 mmol/L).³ Mild hypercalcaemia can cause fatigue, constipation and cognitive dysfunction. More severe or rapidly increasing hypercalcaemia can induce nephrogenic diabetes insipidus, resulting in significant dehydration and renal failure. HCM has been shown to impair quality of life and increase the risk of hospitalisation.^4,5 The reported adverse prognosis associated with HCM (median survival of 52 days in those with solid malignancies)⁶ has improved noticeably with the introduction of more effective anticancer treatments. Humoral HCM, mediated by parathyroid hormone-related protein, is the most common cause (80%), followed by osteolytic bone metastases (20%).¹ Less common causes include calcitriol-mediated hypercalcaemia and parathyroid carcinoma. Increased osteoclastic bone resorption is the common pathway responsible for the development of HCM. Treatment is aimed at initially lowering serum calcium concentrations followed by treating the underlying cancer. The authors of this concise guidance are not aware of any other previously published guidelines on the management of HCM.

Scope and purpose

The Endocrine Society recently published a Clinical Practice Guideline on the Treatment of Hypercalcaemia of Malignancy in Adults.⁷ A systematic review and meta-analysis was commissioned to examine eight clinical questions on which the guideline then issued recommendations.⁸ This concise guidance highlights key recommendations from the guideline and is aimed at a general medical audience (Table 1). It also contains a workflow outlining the management of HCM based on pathophysiology and hypercalcaemia severity (Fig 1).

Table 1.

Summary of recommendations^a

	Recommendations	Strength of recommendation	Certainty of evidence
1	Recommend treating HCM with IV BP or Dmab rather than no treatment	Strong	Very low (⊕OOO)
2	Suggest treatment of HCM with Dmab over IV BP	Conditional	Very low (⊕OOO)
3	Suggest combination of calcitonin and antiresorptive agent (IV BP or Dmab) in treatment of severe HCM	Conditional	Very low (⊕OOO)
4	Suggest Dmab in refractory/recurrent HCM already treated with IV bisphosphonate	Conditional	Very low (⊕OOO)
5	Suggest adding antiresorptive agent if sCa is inadequately controlled despite glucocorticoids in HCM because of high calcitriol levels	Conditional	Very low (⊕OOO)
6	Suggest treatment with either calcimimetic or antiresorptive agent in HCM resulting from parathyroid carcinoma	Conditional	Very low (⊕OOO)
7	Suggest adding antiresorptive agent if sCa is inadequately controlled with calcimimetic in HCM resulting from parathyroid carcinoma	Conditional	Very low (⊕OOO)
8	Suggest adding calcimimetic if sCa is inadequately controlled with an antiresorptive agent in HCM resulting from parathyroid carcinoma	Conditional	Very low (⊕OOO)

^aGrading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to develop the guideline, including strength of recommendations (weak, strong) and grading the certainty of evidence (good, fair, low, very low).⁹

BP = bisphosphonate; Dmab = denosumab; HCM = hypercalcaemia of malignancy; IV = intravenous; sCa = serum calcium.

Fig 1.

Suggested workflow for the management of hypercalcaemia of malignancy. The therapeutic approach depends on both the pathophysiology and severity of hypercalcaemia. Reproduced, with permission, from Oxford University Press.⁷ BP = bisphosphonate; Dmab = denosumab; HCM = hypercalcaemia of malignancy.

Good practice statements

The guideline development group additionally issued ungraded good practice statements that represent accepted best practices, but which were not examined in the systematic review (Table 2).

Table 2.

Good Practice statements^a

1	Isotonic intravenous fluids to correct intravascular volume depletion (eg 0.9% saline) are first-line treatment in HCM. IV fluids have an immediate onset of action while awaiting antiresorptive treatments to take effect. Rates of 200–500 mL/h might be required Additional advice: patients receiving high rates of IV fluids should be monitored for volume overload. Loop diuretics (eg furosemide) are not recommended for the routine treatment of HCM, but can be considered in patients at risk of volume overload (eg cardiac or renal impairment)
2	Review dental heath in all patients before administering antiresorptive therapy
3	Vitamin D levels should be checked and supplemented (in accordance with the Endocrine Society Vitamin D Guidelines) to reduce risk of hypocalcaemia following antiresorptive treatment10
4	Assess renal function before administering IV bisphosphonates
5	Consider need for renal dose adjustment for bisphosphonates
6	Serum magnesium and phosphate levels should be monitored and replaced as necessary
7	Oncology consultation for treatment of underlying malignancy should be undertaken; anti-cancer therapy is crucial in the management of HCM where clinically appropriate
8	Surgical consultation for definitive treatment should be sought in all patients with HCM resulting from parathyroid carcinoma

^aReproduced, with permission, from Oxford University Press.⁷

HCM = hypercalcaemia of malignancy; IV = intravenous.

Antiresorptive treatment versus placebo

The guideline authors recommend either intravenous (IV) bisphosphonate or denosumab over placebo in the treatment of HCM (Recommendation 1). A pooled analysis of four studies demonstrated that normalisation of sCa was twice as likely with bisphosphonates compared with placebo.⁸ Zoledronic acid is the bisphosphonate of choice for treating HCM. A randomised controlled trial (RCT) reported that zoledronic acid had a higher response rate and longer duration of response compared with pamidronate.¹¹ Monitoring of renal function is required to identify bisphosphonate-induced kidney injuries; however, the optimal timing of monitoring is unclear. Bisphosphonate dosing adjustments are required in stage 3 chronic kidney disease (CKD) and are contraindicated in stages 4+5 CKD (Table 2). Denosumab is accepted as an effective treatment for HCM. The systematic review supporting the guideline did not identify any studies comparing denosumab with placebo in treating HCM, because withholding IV bisphosphonate (as approved for this indication) would be unethical.⁸

Choice of antiresorptive agent

The guideline authors suggest using denosumab in preference to IV bisphosphonates as first-line pharmacological treatment in HCM (Recommendation 2). Comparative studies of IV bisphosphonates and denosumab do not report treatment of HCM as an endpoint. The guideline development group based their recommendation on surrogate endpoints from RCTs including the risk of, and time to, skeletal-related events, development of HCM and hypocalcaemia risk.^12–14 The combined results of these trials indicate that denosumab is a more potent suppressor of bone turnover and, therefore, is expected to be more effective for HCM treatment.⁸ The guideline development group also considered the side-effect profiles of both antiresorptive agents and noted that infusion reactions and renal injuries are more common with IV bisphosphonates than with denosumab. Denosumab has additional advantages in that it can be administered subcutaneously in community settings and can be used in stage 4+5 CKD, albeit with a higher risk of hypocalcaemia.¹⁵

Management of severe hypercalcaemia

The guideline authors suggest using calcitonin in combination with either IV bisphosphonates or denosumab in patients with severe HCM (Recommendation 3). Only indirect evidence of very low certainty was available to support this recommendation. The potential advantage of calcitonin is that it has a rapid onset of action, and can reduce calcium levels by 0.25–0.5 mmol/L while awaiting antiresorptive therapies to take maximal effect.¹⁶ Calcitonin might be useful in patients with cardiac or renal impairment who are unable to tolerate rapid infusions of IV fluids. Calcitonin should not be prescribed for longer than 48–72 h because tachyphylaxis can develop.

Management of refractory and recurrent HCM

The guideline suggests using denosumab to treat refractory or recurrent HCM in patients previously treated with IV bisphosphonates (Recommendation 4). This recommendation was based on meta-analysis findings that denosumab normalised sCa levels in 67% of patients with bisphosphonate-refractory HCM.⁸ The number of previous bisphosphonate treatments required to define refractory HCM has not yet been established. The systematic review did not identify any literature to support the use of IV bisphosphonates for HCM refractory to denosumab.⁸

Management of calcitriol-mediated hypercalcaemia

Lymphomas can cause hypercalcaemia through ectopic production of calcitriol (activated vitamin D), which increases intestinal calcium absorption and osteoclastic bone resorption. First-line treatment of calcitriol-mediated hypercalcaemia is high-dose glucocorticoids (Table 3). Persistent and rebound hypercalcaemia are common in calcitriol-associated malignancy after initial glucocorticoid treatment.¹⁷ The guideline authors suggest adding either an IV bisphosphonate or denosumab in patients who continue to experience severe or symptomatic hypercalcaemia despite initial glucocorticoid treatment (Recommendation 5). Indirect evidence that both antiresorptive agents are effective at inhibiting osteoclastic bone resorption was used to support this recommendation. It is important to counsel patients that the risk of serious adverse effects, including osteonecrosis of the jaw and atypical femoral fractures, although low, is increased by concomitant prescribing of antiresorptive agents and high-dose glucocorticoids.¹⁸

Table 3.

Treatment regimens for hypercalcaemia of malignancy^a

Medication	Dosing	Adverse effects
Intravenous bisphosphonates
Zoledronic acid	4 mg IV infusion over 15–30 min. Can be repeated after 7 days if required and every 3–4 weeks thereafter Renal dosing: 3 mg over 30 min if CrCl 30–60 mL/min; C/I if CrCl <30 mL/min	Infusion reaction Renal impairment Hypocalcaemia ONJ and AFF (rare)
Pamidronate	90 mg IV infusion over 2 h. Can be repeated every 2–3 weeks Renal dosing: 60 mg over 4 h if CrCl 30–60 mL/min; C/I if CrCl <30 mL/min	Infusion reaction Renal impairment Hypocalcaemia ONJ and AFF (rare)
RANKL monoclonal antibody
Denosumab	120 mg SC injection; repeat after 1, 2 and 4 weeks; monthly thereafter	Injection site reactions Hypocalcaemia ONJ and AFF (rare)
Other treatments
Salmon calcitonin	4–8 units/kg SC TDS or QDS for 2–3 days	Tachyphylaxis after 2–3 days
Hydrocortisone (HC) Prednisolone (P)	HC: 200–400 mg/day for 3–5 days P: 60 mg/day for 10 days	Hyperglycaemia Hypertension Mood alterations
Cinacalcet	30 mg BD initially, titrate to maximum dose 90 mg TDS or QDS	Nausea/vomiting Headaches

^aReproduced, with permission, from Oxford University Press.⁷

AFF = atypical femoral fracture; BD = twice daily; C/I = contraindicated; CrCl = creatinine clearance; IV = intravenous; ONJ = osteonecrosis of the jaw; QDS = 4 times/day; RANKL = receptor activator of nuclear factor kappa-B ligand; SC = subcutaneous; TDS = 3 times/day.

Management of hypercalcaemia resulting from parathyroid carcinoma

Parathyroid carcinoma is a rare form of cancer and an uncommon cause of HCM.¹⁹ Definitive treatment of parathyroid carcinoma is surgical excision. Recurrent and metastatic disease are unlikely to be resectable. The guideline suggests cinacalcet as first-line treatment in patients with mild hypercalcaemia resulting from parathyroid carcinoma (Recommendation 6). Cinacalcet reduces mean sCa by 0.43 mmol/L, with the greatest reduction in those with the highest sCa levels.²⁰ Dose titration of cinacalcet is limited by gastrointestinal side effects. In patients with moderate to severe hypercalcaemia, antiresorptive therapy with either IV bisphosphonates or denosumab is the suggested first-line treatment (Recommendation 6). Antiresorptive agents have a quicker onset of action and better gastrointestinal tolerability compared with cinacalcet. Persistent hypercalcaemia despite treatment with either cinacalcet or an antiresorptive agent is common in parathyroid carcinoma.⁸ Therefore, the guideline recommends combination therapy with addition of either an antiresorptive agent (IV bisphosphonate or denosumab) or cinacalcet in those with persistent hypercalcaemia receiving a single agent (Recommendations 7 and 8). The guideline relied on indirect evidence from studies of patients with benign primary hyperparathyroidism and parathyroid carcinoma to support these recommendations.

Limitations

With the exception of Recommendation 1, the strength of guideline recommendations was assessed as weak and based on very low certainty of evidence. Although there is an urgent need for well-designed, prospective studies (in particular, head-to-head studies comparing the efficacy of denosumab and IV bisphosphonates in the initial treatment of HCM), the situational and ethical challenges of conducting such studies are recognised, given the nature of HCM and its negative prognosis. The guideline also relies on indirect evidence when making some recommendations, such as using adverse skeletal events as a surrogate for HCM resolution and benign primary hyperparathyroidism treatment as a surrogate for parathyroid carcinoma treatment. Such indirect evidence was based on case series and/or small single-arm studies with short follow-up periods.

Implication for clinical practice

Denosumab is licenced for the treatment of bisphosphonate-refractory HCM but not as first-line treatment for HCM by the US Food and Drug Administration (FDA). It is not licenced for HCM treatment in the UK or European Union. Patients should be informed that denosumab is an off-label treatment for HCM, but that limited available evidence supports its use for first-line and bisphosphonate-refractory HCM. The guideline authors' suggestion of calcitonin in combination with antiresorptive agents in severe hypercalcaemia has significant budgetary implications. Calcitonin cost, affordability and marketing status vary significantly between countries and, therefore, it might not be feasible for some healthcare systems to follow this recommendation.

Statement on conflicting interests

Guideline Development Panel Members for the original full guideline were identified by the Endocrine Society Board of Directors and the Clinical Guidelines Committee (CGC) and were vetted according to the Endocrine Society conflict-of-interest policy for Clinical Practice Guidelines.