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Introduction

  • Hypercalcemia of Malignancy (HCM) is an oncologic emergency typically seen in patients with advanced stage

    • cancers

  • HCM is more common in patients with tumors that are associated with bone metastases (breast, lung, multiple

    • myeloma, renal cell carcinoma and colorectal cancer)

  • Hypercalcemia is defined as a corrected calcium level > 10.5 mg/dL
  • Symptoms occur slowly (or may be absent) and can include nephrolithiasis, polyuria, polydipsia, gout, ventricular

    • tachyarrhythmias, fatigue, anorexia, cognitive dysfunction, etc.

  • Management of hypercalcemia is traditionally with aggressive IV fluids, calcitonin, and bisphosphonates. Loop

    • diuretics and steroids have a limited role in treatment for most patients.

Clinical Detail

CalcitoninBisphosphonates
Role in TherapyUsed to provide a transient decrease in serum calcium levels
Used with aggressive fluid hydration and IV bisphosphonates		Should be administered ASAP after diagnosis
MechanismInhibits osteoclastic bone resorption and promotes renal excretion of calciumDeposits into bone and lowers calcium levels by inhibiting osteoclastic bone resorption
Dose4 IU/kg IM/SQ Q12 hours x48 hoursZoledronic Acid (Zometa)
4mg IV over 15-30 minutes (NO dose adjustments needed for HCM indication)
SCr must be < 4.5 mg/dL

Pamidronate
90 mg IV over 4 hours
May use if SCr > 4.5 mg/dL
PK/PDOnset of action: 4-6 hours
Efficacy limited to 48 hours due to tachyphylaxis		Onset of action: 48 hours (maximal effect: 2-4 days)
Duration of action: 3-4 weeks
Adverse EffectsHypersensitivity reactions (including anaphylaxis), hypocalcemia, flushing, headache, nausea/vomitingRenal dysfunction, osteonecrosis of the jaw, bone and joint pain
CommentsConsider administering if corrected Ca ≥ 14 mg/dL and/or neurologic or cardiac symptoms
Must administer IVF x4-6 hours and recheck Ca PRIOR to ordering		Zoledronic is more efficacious with regards to time to normalization of calcium and duration of complete response

May repeat bisphosphonate dose in 7 days if needed

Evidence

Author, YearDesignPurposeOutcome
Kammerman, 1970Case Series (n=8)Report the efficacy of porcine calcitonin in patients with hypercalcemiaIn the 7 patients given a uniform dose of 4 MRC U/kg body weight, a mean change in serum calcium concentration of −1.97 mg/dL

The calcium-lowering effect was measurable at 2 hr and maximal at 6–9 hr; by 20–24 hr the serum calcium had begun to rise.
Thiébaud, 1990RCT (n=34)To assess whether a combined calcitonin and pamidronate lead to earlier normalization of the plasma calcium level than does pamidronate aloneIn the group receiving calcitonin, the mean plasma calcium level decreased from 3.22 ±0.09 mmol/L to 2.29 ±0.03 mmol/L by day 9 (P<.001) and was normalized by day 3.

There was a significant difference the groups in the plasma calcium level from day 2 to day 4, reflecting the earlier drop in calcium level in the group receiving calcitonin.
Major, 2001RCT (n=287)Compare the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancyZoledronic acid is superior to pamidronate with a complete response rate by day 10 (88.4% vs. 69.7%) and longer median duration of complete response (32 days vs. 18 days)
Hu, 2014Open-label, single arm (n=33)Evaluate the efficacy of denosumab in patients with bisphosphonate-refractory HCMDenosumab lowered calcium in 64% of patients within 10 days, with an estimated median time to response of 9 days.
FDA-approved denosumab for HCM
Sabry, 2010Observational (n=80)Evaluate the difference in efficacy and safety of zoledronic acid and clodronate in malignant hypercalcemia secondary to bone metastases.The calcium level significantly decreased in both groups.

At least one skeletal-related event occurred in 15 (37.5%) patients receiving zoledronic acid and 32 (80%) patients receiving clodronate.
Hosking, 1981Observational (n=16)Evaluate the efficacy of rehydration (NS) in patients with hypercalcemiaA substantial fall in serum calcium (mean decrease 0.6 mmol/l) was achieved in thirteen patients.
Sleeboom, 1983Observational (n=30)Evaluate the effects of tumor-induced hypercalcemia management with volume repletion and intravenous pamidronateVolume repletion was only partially effective in lowering serum calcium and raising glomerular filtration rate and it increased the tendency towards hypomagnesaemia.

In twenty-nine of the patient’s serum calcium, serum magnesium, and glomerular filtration rate were rapidly restored to normal by intravenous pamidronate, in doses of 1.75-30 mg/day.

Conclusions

  • Reported in 20 – 30% of cancer patients and is a poor prognostic indicator
  • Primarily associated with lung and breast cancer, as well as myeloma and lymphoma
  • Presentation can range from asymptomatic to progressive mental impairment, arrhythmias,

    • and renal failure

  • Cornerstones of therapy include aggressive hydration, calcitonin, and IV bisphosphonates

    • [email protected];

References

    Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 6, 2020, from

    http://www.micromedexsolutions.com/

    Goldner, W. Cancer-Related Hypercalcemia. Journal of Oncology Practice. 2016; 12:5, 426-432.

    Stewart AF. Hypercalcemia of Malignancy. N Engl J Med 2005; 352:373-9.

    Feldenzer, K, Sarno J. Hypercalcemia of Malignancy. J Adv Pract Oncol. 2018; 9(5):496-504.

    Major P, et al. J Clin Oncol. 2001;19(2):558-567.

    Hu MI, et al. J Clin Endocrinol Metab. 2014 Sep; 99(9): 3144-3152.

    Kammerman S, et al. J Clin Endocrinol Metab. 1970 Jul;31(1):70-5.

    Thiébaud D, et al P. Arch Intern Med. 1990 Oct;150(10):2125-8.

    Sabry NA, et al. Med Oncol. 2011 Jun;28(2):584-90.

  • Sleeboom HP, et al. Lancet. 1983 Jul 30;2(8344):239-43.
  • Hosking DJ, et al.. Q J Med. 1981 Autumn;50(200):473-81.
  • Thiébaud D, et al. Arch Intern Med. 1990 Oct;150(10):2125-8
Tags:hypercalcemia malignancy bisphosphonate calcitonin

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