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.
| Pharmacology | |||
| Calcitonin | Bisphosphonates | ||
| Role in Therapy | • • | Used to provide a transient decrease in serum calcium levels Used with aggressive fluid hydration and IV bisphosphonates | • Should be administered ASAP after diagnosis |
| Mechanism | • | Inhibits osteoclastic bone resorption and promotes renal excretion of calcium | • Deposits into bone and lowers calcium levels by inhibiting osteoclastic bone resorption |
| Dose | • | 4 IU/kg IM/SQ Q12 hours x48 hours | Zoledronic 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/PD | • • | Onset 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 Effects | • | Hypersensitivity reactions (including anaphylaxis), hypocalcemia, flushing, headache, nausea/vomiting | • Renal dysfunction, osteonecrosis of the jaw, bone and joint pain |
| Comments | • • | Consider 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 |
| Literature | |||
| Author, year | Design | Purpose | Outcome |
| Kammerman, 1970 | Case Series (n=8) | Report the efficacy of porcine calcitonin in patients with hypercalcemia | In 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, 1990 | RCT (n=34) | To assess whether a combined calcitonin and pamidronate lead to earlier normalization of the plasma calcium level than does pamidronate alone | In 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, 2001 | RCT (n= 287) | Compare the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancy | Zoledronic 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. 2014 | Open-label, single arm (n= 33) | Evaluate the efficacy of denosumab in patients with bisphosphonaterefractory HCM | Denosumab 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, 2010 | Observational, (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, 1981 | Observational (n=16) | Evaluate the efficacy of rehydration (NS) in patients with hypercalcemia | A substantial fall in serum calcium (mean decrease 0.6 mmol/l) was achieved in thirteen patients. |
| Sleeboom, 1983 | Observational (n=30) | Evaluate the effects of tumorinduced hypercalcemia management with volume repletion and intravenous pamidronate | Volume 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
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
