US Pharm. 2015;40(5)(Specialty&Oncology suppl):3-7.

ABSTRACT: An oncologic emergency is a clinical condition resulting from a structural or metabolic change caused by cancer or its treatment and requiring immediate medical intervention. An oncologic emergency can occur at any time during the course of a malignancy, from the presenting symptom to end-stage disease. Although some of these conditions are related to cancer therapy, they are not confined to the period of initial diagnosis and active treatment. Two oncologic emergencies are hypercalcemia of malignancy and tumor lysis syndrome. Pharmacists play an essential role in appropriately managing the pharmacotherapeutic agents used for prevention and treatment of oncologic emergencies in order to improve quality of life, even in the setting of terminal illness.

An oncologic emergency is a clinical condition resulting from a structural or metabolic change caused by cancer or its treatment that requires immediate medical intervention.¹ Although oncologic emergencies are typically classified as either metabolic or structural, subclassifications (metabolic, neurologic, cardiovascular, hematologic, and infectious) may be used. An oncologic emergency can occur at any time during the course of a malignancy, from the presenting symptom to end-stage disease. In the case of recurrent malignancy, these events can take place years after the surveillance of a cancer patient has been appropriately transferred from a medical oncologist to a primary care provider. As such, awareness of a patient’s cancer history and its possible complications forms an important part of any clinician’s knowledge base. Prompt identification of and intervention in oncologic emergencies can prolong survival and improve quality of life, even in the setting of terminal illness.²

Two major oncologic emergencies, hypercalcemia of malignancy (HCM) and tumor lysis syndrome (TLS), will be discussed in this article. HCM is experienced by 20% to 30% of cancer patients at some point during the course of the disease.³ It is more common in patients with tumors associated with bone metastasis, such as breast and lung cancer, multiple myeloma (MM), and hematologic malignancies (non-Hodgkin lymphoma [NHL] and leukemia).⁴ The detection of hypercalcemia in patients with cancer signifies a very poor prognosis; approximately 50% of such patients die within 30 days.⁴

TLS is a serious and sometimes life-threatening complication that may occur in patients with malignancies before or after starting antineoplastic therapy.⁵ The incidence of TLS remains ill-defined.⁶ The most frequently referenced percentages are from Hande and Garrow’s 1993 retrospective analysis, which found a 42% incidence of laboratory TLS and a 6% incidence of clinically significant TLS in 102 adult NHL patients.⁷ TLS has been reported most commonly in acute lymphoblastic leukemia (ALL) (5%-26%), acute myelogenous leukemia (3%-17%), and Burkitt lymphoma (BL; 27%).⁷

PATHOPHYSIOLOGY

HCM

HCM can be segmented into four categories: local osteolytic; humoral; HCM associated with 1,25-dihydroxyvitamin D (1,25(OH)₂D)–secreting lymphomas; and HCM associated with ectopic hyperparathyroidism (TABLE 1).³

Local osteolytic hypercalcemia, which occurs in approximately 20% of HCM cases, results from increased osteoclastic bone resorption in areas surrounding the malignant cells within the marrow space. Although the bone destruction is mediated primarily by osteoclasts, tumor cells also produce factors that induce osteoclast activity.^8,9

Humoral hypercalcemia of malignancy (HHM), which is by far the most common, is caused by the release of parathyroid hormone (PTH)–related protein (PTHrP) by cancerous tumors. HHM is often seen in squamous cell cancer (e.g., of head and neck, esophagus, cervix, or lung) and in renal, ovarian, endometrial, and breast cancer. The homology of PTHrP is similar to that of PTH; accordingly, PTHrP is able to bind to the same receptors. The effects of PTHrP represent a true paraneoplastic syndrome (i.e., systemic signs and symptoms caused by a tumor, but not confined to the area proximal to the tumor), with circulating PTHrP causing bone resorption and renal calcium retention.²

Less commonly, some lymphomas produce the active form of vitamin D, resulting in increased renal calcium retention and bone resorption. Nearly one-half of all hypercalcemic patients with lymphoma present with inappropriately elevated circulating concentrations of the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)₂D3).¹⁰ Finally, ectopic hyperparathyroidism production can cause HCM, but this is a rare occurrence, with only a few well-documented cases reported to date.¹¹

TLS

TLS is most commonly observed following chemotherapy (ChT) for high-grade lymphoproliferative malignancies such as ALL and BL.⁶ This oncologic emergency is characterized by the rupture of cells, which leads to severe electrolyte abnormalities and, frequently, acute renal failure.⁶ Either spontaneously or following antineoplastic therapy, malignant cells release their contents into the bloodstream (FIGURE 1).¹² Hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia may occur suddenly and lead to life-threatening end-organ damage of the myocardium, kidneys, and central nervous system.^1,13

Hyperkalemia may occur 6 to 72 hours after initiation of ChT, and serum potassium levels may rise from 3 mEq/L to 7 mEq/L.¹ Arrhythmias and electrocardiographic changes may occur. Hyperuricemia occurs within 48 to 72 hours following treatment initiation and the liberation of large amounts of purine nucleic acid. The purine nucleic acids adenosine and guanine are converted into uric acid, resulting in the precipitation of uric acid crystals in the kidney, which causes renal failure. Hyperphosphatemia may develop 24 to 48 hours following ChT initiation. Precipitation of calcium phosphate occurs when the solubility product of calcium and phosphate is exceeded, possibly leading to hypocalcemia.^6,14

Hyperphosphatemia and hyperuricemia will further potentiate the kidney damage that occurs during TLS. Evidence of tumor lysis with renal failure is seen in up to two-thirds of patients before treatment; furthermore, ChT may accelerate or precipitate acute renal failure. Acute renal failure is caused by the varying degrees of preexisting volume depletion coupled with the precipitation of uric acid and calcium phosphate complexes in the renal tissue.¹⁵

HCM

Clinical Manifestations and Laboratory Findings

Approximately 50% of total serum calcium is bound to proteins, primarily albumin, and a small proportion is complexed to anions such as phosphate and citrate. The remaining 45% to 50% is ionized, which is the only biologically active form.¹⁶ The ionized calcium becomes a disproportionately greater fraction of the total calcium concentration if the serum albumin is reduced. Therefore, in hypoalbuminemic states, the measured calcium level tends to underestimate the degree of hypercalcemia. One formula for calculating total serum calcium for alterations in plasma protein concentrations is as follows: corrected calcium (mg/dL) = measured total calcium (mg/dL) + 0.8[4 – measured albumin in (g/dL)].^2,17 Hypercalcemia is classified according to severity, and measurements of serum calcium levels may differ between laboratories. The corrected serum calcium concentration of mild hypercalcemia is approximately 10.5 to 11.9 mg/dL; that for moderate hypercalcemia, 12.0 to 13.9 mg/dL; and that for severe hypercalcemia, ≥14.0 mg/dL.³

A mildly elevated serum calcium concentration tends to evoke no symptoms, whereas moderate elevations can cause anorexia, polyuria, polydipsia, nausea, vomiting, and constipation. Further elevations can result in more severe symptoms, including weakness, difficulty concentrating, confusion, stupor, and coma.¹⁸ HCM usually is rapidly progressive; therefore, the presence of rapidly rising calcium levels should signal the possibility of malignancy.

Treatment

Definitive treatment of the underlying malignancy with surgery or ChT is the most effective way to manage HCM. Until this object is achieved, however, treatment strategies are aimed at restoring intravascular volume, enhancing renal excretion of calcium, and inhibiting bone resorption.¹⁹ The agents currently available to treat HCM include normal saline, pamidronate, zoledronic acid, denosumab, calcitonin, and corticosteroids (TABLE 2).

Normal Saline and Furosemide: The cornerstone of initial management of HCM is hydration with IV normal saline (NaCl 0.9%), since almost all patients with hypercalcemia have intravascular volume depletion.² The infusion rate depends upon the patient’s degree of dehydration, severity of hypercalcemia, and cardiovascular status. A reasonable approach should begin with NaCl 0.9% at 200 to 500 mL/h, with frequent monitoring of serum calcium levels and volume status.²⁰ The use of furosemide is controversial because there is minimal evidence supporting the use of this drug, and it may lead to additional volume depletion, hypokalemia, and worsening hypercalcemia.²¹

Bisphosphonates: Highly effective in the management of HCM, bisphosphonates exert several effects on osteoclasts, including inhibiting their recruitment, activity, and adhesion to bone matrix.²² Additionally, bisphosphonates can cause apoptosis in osteoclasts through inhibition of the enzyme squalene synthase, which interferes with cholesterol biosynthesis.²³ The bisphosphonates FDA-approved for the treatment of HCM are pamidronate and zoledronic acid.

Pamidronate or zoledronic acid should be initiated immediately upon diagnosis, since the maximum effect occurs in 2 to 4 days.³ Zoledronic acid is proven to be more efficacious than pamidronate, making it the agent of choice.^24,25 Zoledronic acid also has the advantage of shorter administration times at a dosage of 4 mg compared with pamidronate dosages of 60 to 90 mg (15 minutes vs. 2 hours). A limitation of zoledronic acid is that it is relatively contraindicated in patients with severe renal insufficiency.² Osteonecrosis of the jaw is a recognized complication of bisphosphonate therapy. This condition can be prevented through good dental hygiene and avoidance of invasive dental procedures during bisphosphonate therapy.²⁰

Calcitonin: Calcitonin has been shown to transiently lower serum calcium levels, often producing normocalcemia within 12 to 24 hours.²⁶ However, it rapidly loses efficacy through tachyphylaxis, which typically occurs after 48 hours because repeated administration of calcitonin results in downregulation of its receptors on osteoclasts.^24,26 Calcitonin may be administered IV or SC at a dosage of 4 to 8 IU/kg every 12 hours; however, intranasal administration is ineffective.²

Denosumab: This agent has been approved for HCM that is refractory to bisphosphonate therapy. FDA approval was based on an open-label study of 33 patients with advanced cancer and persistent HCM after recent bisphosphonate treatment, 63.6% of whom demonstrated a response (albumin-corrected serum calcium level of ≤11.5 mg/dL within 10 days after first dose).²⁷ Denosumab is administered SC at 120 mg every 4 weeks, with additional doses on days 8 and 15 of therapy month 1.²⁷ This drug does not require dosage adjustments for renal impairment; however, it has been associated with an incidence of osteonecrosis of the jaw similar to that of zoledronic acid.²⁰

Corticosteroids: Corticosteroids may help lower calcium levels in patients with steroid-sensitive malignancies (i.e., MM, lymphoma, and sarcoidosis), but they are generally ineffective for treating HCM associated with solid tumors.²⁶ These agents combat HCM by effecting an increase in urinary calcium excretion and a decrease in intestinal calcium absorption through inhibition of 1-alpha-hydroxylase.^24,26 Corticosteroids are administered as hydrocortisone dose-equivalents of 200 to 400 mg/day IV for 3 to 5 days.²⁶ Their onset of action is not well established and may not occur for days to weeks.

TLS

Clinical Manifestations and Laboratory Findings

Clinical signs and symptoms associated with TLS occur as a result of abnormalities in electrolyte levels of potassium, phosphate, uric acid, and calcium. They may include nausea, vomiting, lethargy, cardiac dysrhythmias, seizures, muscle cramps, and renal failure.^28,29 Although symptoms may occur before the start of ChT, they are more commonly observed within 12 to 72 hours after initiation of cytotoxic therapy.²⁹

TLS may be categorized as laboratory (LTLS) or clinical (CTLS) based on Cairo and Bishop’s current classification system (TABLE 3).^28,29 In LTLS, two or more metabolic abnormalities, including uric acid, potassium, phosphorus, or calcium, occur within 3 days before or 7 days after treatment initiation. CTLS occurs when LTLS is accompanied by one or more of the following: increased creatinine level, cardiac arrhythmias/sudden death, and seizures.^28,29

Prevention and Treatment

The mainstays of TLS prophylaxis and treatment are aggressive hydration and diuresis, control of hyperuricemia with allopurinol and rasburicase, and monitoring of electrolyte abnormalities.²⁸ Urine alkalization is controversial.

Aggressive Hydration/Forced Diuresis: Aggressive fluid hydration has been recommended in patients at risk for TLS, excepting those who are at risk for volume overload, such as elderly patients and those with heart failure.³⁰ TLS may be present prior to ChT or develop during treatment. Accordingly, IV hydration should be initiated 24 to 48 hours prior to ChT and continue for up to 72 hours after treatment completion.³⁰ Patients should receive 2 to 3 L/m²/day IV of a solution consisting of one-quarter of normal saline/5% dextrose, with a urine output goal of 80 to 100 mL/h (2-3 mL/kg/h for pediatric patients).²⁹

Aggressive IV hydration increases intravascular volume and helps correct electrolyte disturbances by diluting extracellular fluid, thereby reducing serum potassium, uric acid, and phosphate concentrations.³⁰ Despite adequate hydration, diuretics may be required if adequate urine output cannot be achieved solely through IV hydration. The two diuretics commonly used are furosemide and mannitol. Renal excretion of potassium can be facilitated by diuretics, but furosemide is not very effective if the renal tubules are affected by urate precipitation. In these instances, mannitol may be used.³⁰

Urinary Alkalinization: The role of urinary alkalinization remains controversial. This approach historically has been used for patients with hyperuricemia in an attempt to increase uric acid solubility, thereby diminishing the likelihood of uric acid precipitation in the tubules.³¹ However, urinary alkalinization has fallen out of favor because no data demonstrate its efficacy, and alkalinization may increase precipitation of calcium phosphate crystals, further damaging the kidneys.³¹

Allopurinol: Allopurinol, a structural analogue of hypoxanthine, acts as a competitive inhibitor of xanthine oxidase. When converted to its active metabolite, oxypurinol, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid.²⁹ Allopurinol treatment is generally initiated 24 to 48 hours prior to the initiation of induction ChT and administered at a dosage of 100 mg/m² orally every 8 hours (maximum daily dose 800 mg).²⁹ Because allopurinol is excreted by the kidneys, a dosage reduction of 50% is recommended in patients with renal insufficiency. In patients unable to tolerate oral therapy, allopurinol 200 to 400 mg/m²/day IV (maximum daily dose 600 mg) may be administered.²⁹ The most frequent adverse effects of allopurinol are skin rashes and hypersensitivity.

Allopurinol has several limitations that should be considered. This agent acts by decreasing the formation of uric acid, so it is ineffective for reducing levels of uric acid developed prior to treatment.²⁹ Allopurinol also can cause an increase in serum levels of the purine precursors xanthine and hypoxanthine. Accordingly, the lower solubility of xanthine in the urine may confer a risk of xanthine crystal deposition in the renal tubules, resulting in xanthine nephropathy.²⁸ Allopurinol also reduces the degradation of other purines, so a dosage reduction of 50% to 70% is required when used concomitantly in patients being treated with 6-mercaptopurine or azathioprine.²⁸

Rasburicase: Rasburicase is a recombinant urate oxidase that converts uric acid into water-soluble allantoin. Unlike allopurinol, it does not cause accumulation of xanthine and hypoxanthine, which demonstrate poor water solubility and can worsen renal function.² In a phase III randomized trial, Cortes and colleagues demonstrated that, compared with allopurinol, rasburicase normalized serum uric acid (≤7.5 mg/dL) in a significantly higher percentage of patients.³² Rasburicase is contraindicated in pregnancy and in patients with glucose-6-phosphate dehydrogenase deficiency; this is based on reports of hemolytic anemia, which may occur because of the inability to metabolize the hydrogen peroxide produced during allantoin formation.⁶ Rasburicase is approved at a dosage of 0.15 to 0.2 mg/kg IV once daily in 50 mL of normal saline infused over 30 minutes for 5 days; it does not require adjustment for decreased renal function.^6,29 Adverse effects include fever, headache, nausea, and vomiting.^6,29 Because of its high cost, rasburicase should be used judiciously in the appropriate population.

CONCLUSION

HCM and TLS are two common oncologic emergencies that can occur in almost any patient with a malignancy. Identification of at-risk patients is critical to managing and preventing both HCM and TLS. A variety of pharmacotherapeutic options are available, so the appropriate selection of agents is a key role for the pharmacist.

References

1. Tan SJ. Recognition and treatment of oncologic emergencies. J Infus Nurs. 2002;25:182-188.
2. Lewis MA, Hendrickson AW, Moynihan TJ. Oncologic emergencies: pathophysiology, presentation, diagnosis, and treatment. CA Cancer J Clin. 2011;61:287-314.
3. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373-379.
4. Ralston SH, Gallacher SJ, Patel U, et al. Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med. 1990;112:499-504.
5. Locatelli F, Rossi F. Incidence and pathogenesis of tumor lysis syndrome. Contrib Nephrol. 2005;147:61-68.
6. Davidson MB, Thakkar S, Hix JK, et al. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004;116:546-554.
7. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med. 1993;94:133-139.
8. Quinn JM, Matsumura Y, Tarin D, et al. Cellular and hormonal mechanisms associated with malignant bone resorption. Lab Invest. 1994;71:465-471.
9. Taube T, Elomaa I, Blomqvist C, et al. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone. 1994;15:161-166.
10. Hewison M, Kantorovich V, Liker HR, et al. Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. J Bone Miner Res. 2003;18:579-582.
11. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl J Med. 1990;323:1324-1328.
12. Pession A, Melchionda F, Castellini C. Pitfalls, prevention, and treatment of hyperuricemia during tumor lysis syndrome in the era of rasburicase (recombinant urate oxidase). Biologics. 2008;2:129-141.
13. Tufan A, Unal N, Koca E, et al. Spontaneous tumor lysis syndrome in a patient with diffuse large B cell lymphoma and Richter syndrome. Ann Hematol. 2006;85:183-184.
14. Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol. 2000;27:322-334.
15. Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol. 1993;13:273-280.
16. Maier JD, Levine SN. Hypercalcemia in the intensive care unit: a review of pathophysiology, diagnosis, and modern therapy. J Intensive Care Med. 2013 [epub ahead of print].
17. Bajorunas DR. Clinical manifestations of cancer-related hypercalcemia. Semin Oncol. 1990;17(2 suppl 5):16-25.
18. Inzucchi SE. Understanding hypercalcemia. Its metabolic basis, signs, and symptoms. Postgrad Med. 2004;115:69-70,73-76.
19. Ritch PS. Treatment of cancer-related hypercalcemia. Semin Oncol. 1990;17(2 suppl 5):26-33.
20. Rosner MH, Dalkin AC. Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol. 2012;7:1722-1729.
21. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149:259-263.
22. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998;19:80-100.
23. Amin D, Cornell SA, Gustafson SK, et al. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res. 1992;33:1657-1663.
24. Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011;18:339-346.
25. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19:558-567.
26. Davidson TG. Conventional treatment of hypercalcemia of malignancy. Am J Health Syst Pharm. 2001;58(suppl 3):S8-S15.
27. Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014;99:3144-3152.
28. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.
29. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-2778.
30. Rampello E, Fricia T, Malaguarnera M. The management of tumor lysis syndrome. Nat Clin Pract Oncol. 2006;3:438-447.
31. Wagner J, Arora S. Oncologic metabolic emergencies. Emerg Med Clin North Am. 2014;32:509-525.
32. Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone—results of a multicenter phase III study. J Clin Oncol. 2010;28:4207-4213.

To comment on this article, contact rdavidson@uspharmacist.com.