Overview of tumor lysis syndrome

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Seminars in Oncology Nursing. Vol 18, No 3 (August), 2002: pp 2-5

OBJECTIVES:

To pror.'iele a generctl o'Verview q{ tumor lysis syndmme (TLS) focusing on the incidence. epidemiology. and patient outcome~ associated with the syndrome; review the role q{ the oncology 1t1irSe in impactin.~ patie1H 01ltcomes and identify e'Vol'Ving issues relating £0 TLS.

OVERVIEW OF TUMOR LYSIS SYNDROME

D.\TA SOURCE,:

Primw)' and tertiwy literature related £0 TL cmd clinical practice e:'(peJience.

LOIS DOANE

CONCLUSIONS:

[ssu£s relateel £0 TLS cOlltimle to C'OOI'Ve (mel the 011 !Ologv nurse pl!),s a key role in patient mWlcl:!!cmenL \s wid1 om 'r neoplastic di:,;ease-I-elued complications (eg, /xlin, nau. eal'1.xJmiting). Imowledge ofT!.}) and attention and intervention, wher appropliate, can po. 'i[i'Vely impact patiem outcome. RSING

The oncology nurse play' a clitical role in impacting patiem outcomes with respect to TL ranging }rom collaboration 'with other disciplin . to identif.>,ing patients at lis/~, through asses 'ments, igilant monitorin." and implementing optimal treatment regimens.

UMOR lysis syndrome (TLS) is a well-documented oncologic emergency, Originally described in 1980,1 the incidence, epidemiology, pathophysiology, and effective management of TLS have been further defined throughout the years,2-4 The proliferation of information and published case reports/studies has proVided nurses with the appropriate knowledge to effectively identify patients at risk and ultimately to prevent or minimize TLS. Despite this enhanced awareness, many patients remain susceptible to the consequences of this syndrome, either from a lack of vigilant patient monitoring and identification or simply because of unpredictable patient responses to cytotoxic drug regimens. For these reasons, the nursing professional serves a vital role in the recognition of patients who may be at risk to assure the implementation of timely and effective prophylactic strategies. Additionally, intense monitoring of all patients for initial clinical signs and symptoms, even those considered low risk, may prove useful in minimizing the onset and diminishing the severity of this disorder. OVERVIEW OF PATHOPHYSIOLOGY AND CLINICAL

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umor lysis syndrome is a constellation of symptoms ranging from life-threatening hyperkalemia, hypocalcemialhyperphosphatemia, and hyperuricemia-induced acute renal failure, s These symptoms most commonly occur as a result of chemotherapyinduced electrolyte and metabolic disturbances. 6 ,7 Changes in electrolyte and uric acid concentrations are precipitated by the treatment of malignancies associated with large tumor burdens and/or rapidly proliferating cells, FollOWing chemotherapy administration for these neoplasms, cells are lysed, which release significant amounts of intracellular potassium and phosphate into the extracellular circulation, If not corrected promptly, serious and sometimes fatal arrhythmias can occur. 8 Additionally, large quantities of nucleic acids are also "deployed" that further break down

OVERVIEW OF TUMOR LYSIS SYNDROME

into uric acid. The ability of the patient to excrete uric acid may often be superceded by excessive urate plasma concentrations, resulting in hyperuricemia, precipitation of urate crystals in the kidney, and acute renal failure. If not adequately treated, the syndrome intensifies and patients may require dialysis.

TABLE 2. Nonmalignancy-Related Causes of Tumor Lysis Syndrome Chemotherapy Immunotherapy Corticosteroids Hormonal therapy Radiation Surgery Spontaneous

INCIDENCE AND EPIDEMIOLOGY

T

he precise incidence of TLS is not known. It is thought that early recognition and prophylactic strategies have contributed throughout the years to a decrease in the incidence and severity of the disorder. Tumor lysis syndrome tends to occur more frequently in. hematologic malignancies with high proliferative fractions and large bulky tumors such as Burkitt's lymphoma, acute lymphoblastic lymphoma, and acute and chronic lymphocytic leukemias (Table 1).3,5 Given the types of hematologic malignancies linked to TLS, it is not surprising that this syndrome has a greater prevalence in the pediatric population. In general, TLS is less likely to occur in patients with solid tumors; however, it has been associated with small cell lung cancer, neuroblastoma, and breast cancer. 9 Descriptions of solid-tumor induced TLS are typically limited to a hand full of case reports in the literature with additional tumor types reported as single case series only. While it is clearly documented that cytotoxic therapy of highly proliferative tumors is the primary cause (Table 2), specific chemotherapeutic agents have been more closely associated with TLS than others. Most notably, cisplatin, cytosine arabinoside, etopo-

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Data from refs 7, 10, 13.

side, intrathecal methotrexate, and paclitaxel have been reported. 7 ,10,11 Also, biologic agents such as the interferons and interleukins, tumor necrosis factor, and monoclonal antibody therapies, including rituximab, gemtuzumab, and alemtuzumab have been associated with this syndrome. 12 - 16 Radiation-, surgery- and spontaneousinduced TLS have been documented as well:' It is theorized that as more sophisticated forms of cytotoxic therapy and other specific cell-directed regimens for hematologic and oncologic malignancies are developed to manage previously untreatable diseases, the incidence of TLS may begin to rise. Therefore, it is prudent to closely monitor patients for potential signs and symptoms of this syndrome, even in those individuals who are not traditionally considered at high risk of TLS. PATIENT OUTCOMES AsSOCIATED WITH TUMOR LYSIS SYNDROME: CLINICAL, ECONOMIC AND PATIENT SATISFACTION

TABLE 1. Malignancies Associated With Tumor Lysis Syndrome (in Order of Decreasing Frequency) Burkitt's lymphoma Lymphoblastic lymphoma Acute lymphocytic leukemia Chronic lymphocytic leukemia Other leukemias and lymphomas Small cell lung cancer Breast cancer Neuroblastoma Metastatic medulloblastoma Other solid tumors (case reports) Data from refs 3-5.

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nother impo~tant facet of TLS is .to appreciate the devastatmg consequences of the disorder including and beyond the immediate clinical features of the disease. Certainly a first priority is to maintain electrolyte and uric acid concentrations within normal limits to prevent cardiac toxicities, renal compromise, and ultimately, fatalities. Tumor lysis syndrome should also be of concern to the health care profeSSional given the potential for significant increases in health care costs related to its management. Care related to drug therapies, hemodialysis, intensified laboratory and clinical monitoring, and extended lengths of stay, including ICU admissions, all contribute to increased costs and adverse economic outcomes. Inpatient

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LOIS DOANE

management of metabolic disorders has been estimated on average to cost an additional $4,000. The treatment cost for hemodialysis ranges from $900 to $11,000 per inpatient stayY In general, the acquisition cost of preventative therapies for TLS is quite low. Urinary alkalinization, hydration, and oral allopurinol can be administered for less than $100 per day. On average, the hospital price for intravenous allopurinol is $420 per 500 mg. On initial glance, this may appear high, however, if oral absorption is impaired, the additional cost associated with intravenous allopurinol is reasonable compared with the overall cost involved with the treatment of complications of hyperuricemia and TLS. Finally, patient/family satisfaction outcomes are compromised as a function of increased length of stay, morbidity and mortality, and decreased quality of life. One can anticipate the potential for patient dissatisfaction when a predicted short-term patient stay for chemotherapy administration is profoundly prolonged because of complications of TLS.

TABLE 3. Role of the Oncology Nurse in Impacting Positive Patient Outcomes Related to Tumor Lysis Syndrome

OUTCOMES

• Identify patients at risk for proactive management • Malignancies commonly associated with TLS • Drug-induced causes of TLS • Clinical conditions such as renal impairment predisposing to TLS • Ensure implementation of preventative regimens and risk reduction strategies • Institute prophylactic measures prior to cytotoxic treatment of malignancies known to induce TLS • Optimize renal function for urinary excretion of uric acid • Eliminate factors that may aggravate this syndrome such as excess exogenous potassium or drugs that compromise renal function • Judiciously monitor patients for early recognition of TLS before, during, and after chemotherapy • Electrolyte imbalances • Electrocardiogram changes • Uric acid level • Renal function • Monitor therapeutic regimens to ensure the appropriateness based on clinical status of patient • Hydration status • Acid-base balance • Oral versus intravenous drug regimens throughout entire patient stay

ursing plays a vital role in positively impacting the clinical, economic, and patient satisfaction outcomes associated with TLS (Table 3). Clearly, proactive identification of patients at risk and potential candidates for prophylactic therapy is a key strategy in preventing TLS. Familiarizing oneself with malignancies commonly associated with TLS and other key patient parameters predisposing to TLS is of critical importance. Once identified, the oncology nurse collaborates with the physician to aggressively promote the addition of prophylactic regimens and risk-reduction strategies for at-risk patients. Also, diligent monitoring of and prompt attention to key parameters associated with TLS, particularly in those patient populations not thought to be predisposed, can facilitate better outcomes. For example, careful potassium monitoring with close attention to eliminating exogenous sources through dietary supplements and drug therapies may diminish the clinical impact of excess intracellular stores of potassium released into the circulation. Adequate hydration and maintenance of urinary output will assist in the effective urinary excretion of uric acid. Attention to optimal treatment regimens based on the clinical status of the patient is an-

other key management strategy. The standard of care for prophylaxis and treatment of TLS has been hydration, urinary alkalinization, and allopurinol. The prescriber often does not consider factors that can diminish the effectiveness of oral allopurinol therapy. Difficulty or painful swallowing, nausea and/or vomiting delaying oral administration of drug therapy, and an inability to ingest large oral tablets, especially in the pediatric population, can result in missed oral doses and/or decreased intake of oral drug. Of additional relevance, recent gastrointestinal surgery or rapid gastrointestinal transit disorders can result in compromised bioavailability of allopurinol when given orally. Knowledge of alternative routes of therapy, such as intravenous allopurinol,18 and prompt intervention can significantly impact outcome because it assures delivery of effective plasma concentrations of allopurinol. Also, awareness of newer therapies for selected patients unable to tolerate allopurinol is of benefit. A recombinant form of urate oxidase, an investigational agent, has also been shown to be effective in the prophylaxis and treatment of hyperuricemia in

ROLE OF NURSING IN IMPACTING PATIENT

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OVERVIEW OF TUlvlOR LYSIS SYNDROME

patients with hematologic disorders.I 9 Finally, once therapy is initiated, monitoring for changes in the clinical status of the patient is vital to ensure continued effectiveness of drug therapy. Often, orders for medications are written without continuous assessment of appropriateness. Changes in the level of consciousness of the patient or a new episode of nausea ancllor vomiting, as well as worsening of mucositis, may necessitate a change in the form of allopurinol administration. Typically, acute patient care needs are addressed, whereas other considerations for optimal drug therapy may be overlooked. Tumor lysis syndrome has been delineated and managed over the years. However, issues related to the syndrome continue to evolve and the oncology nurse plays a key role in the prevention and early recognition of TLS as well as the identification of appropriate interventions for the patient at risk of TLS. As with most neoplastic diseases, the primary focus of care is inducing remission or debulking tumor load with the most currently effective cytotoxic therapy. However, the oncology nurse is in a key position to assess, monitor, and intervene with

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appropriate nursing strategies to optimize the care of these patients. The nurse also plays a pivotal role in educating the patient and family about the risk factors and clinical manifestations of TLS. In addition, educating the patient about possible treatment measures and when to seek medical care is important. Should TLS develop, the nurse also proVides emotional support to the patient and family. In identifying patients at risk, recognition of the increased potential for TLS secondary to cytotoxic therapies is of extreme importance and key in preventing TLS. Knowledge of alternative routes of administration for various prophylactic/therapeutic regimens for TLS (eg, intravenous 'V oral allopUrinol) as well as awareness of newer therapies will contribute to greater efficacy in patient management. Therefore, just as the oncology nurse has contributed to improved cancer care and has a well-established role in the care of oncology patients, caring for the patient with TLS is no exception. With early recognition of TLS and prompt intervention, the oncology nurse plays a major role in preventing this serious oncologic emergency.

REFERENCES 1. Cohen LF, Ballow JE, Magrath IT, et al: Acute tumor lysis syndrome: Review of 37 patients with Burkitt's lymphoma. Am J Med 68:486-491,1980 2. Razis E, Arlin ZA, Ahmed T, et al: Incidence and treatment of tumor lysis syndrome in patients with acute leukemia. Act IIaematol 91:171-174, 1994 3. Jones DP, Mahmoud H, Chesney RW: Tumor lysis syndrome: Pathogenesis and management. Pediatr Nephrol 9:206212, 1995 4. Altman A: Acute tumor lysis syndrome. Semin Oncol 28:3-8, 2001 (suppl 5) 5. Flombaum CD: Metabolic emergencies in the cancer patient. Semin Oncol 27:322-334, 2000 6. Ettinger DS, Harker WG, Gerry HW, et al: Hyperphosphatemia, hypocalcemia and transient renal failure. JAMA 239:2472-2473, 1978 7. McCroskey RD, Mosher DF, Spencer CD, et at Acute tumor lysis syndrome and treatment response in patients treated for refractory chronic Iymphocyctic leukemia with short-course, high-dose cytosine arabinoside, cisplatin and etoposide. Cancer 66:246-250, 1990 8. VanDer Klooster JM, Van Der \Viel HE, Van Saase JL, et al: Asystole during combination chemotherapy for nonHodgkin's lymphoma: The acute tumor lysis syndrome. Neth J Med 56:147-152, 2000 9. Kalemkerian GP, Darwish B, Varterasian ML: Tumor lysis syndrome in small cell carcinoma and other solid tumors. Am J YIed 103:363-367, 1997

10. Cech P, Block JF, Cone LA: Tumor lysis syndrome after tamoxifen flare. N Engl J Med 315:263-265, 1986 (suppl) 11. Ustundag Y, Boyacioglu S, Haznedaroglu IC, et al: Acute tumor lysis syndrome associated with paclitlLxel (letter). Ann Pharmacother 31:1548-1549, 1997 12. Castro MP, VanAuken J, Spencer-Cisak P, et al: Acute tumor lysis syndrome associated with concurrent biochemotherapy of metastatic melanoma. Cancer 85:1055-1059, 1999 13. Yang H, Rosove MH, FigIin RA: Tumor lysis syndrome occurring after the administration of rituximab in Iymphoproliferative disorders: High-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Am J HematoI62:247-250, 1999 14. Rituxan product label information. IDEC Pharmaceuticals (San Diego, CAl and Genentech, Inc (San Francisco, CAl, 1999 15. Mylotarg product label information. Wyeth Pharmaceuticals (Philadelphia, PAl, 2001 16. Campath product label information. Berlex (Richmonda, CAl, 2001 17. Farber MS: Pharmacoeconomic considerations in the management of acute tumor lysis syndrome. Semin Oncol 28:19-22,2001 (suppl 5) 18. Smalley RV, Guaspari A, Haase-Statz S, et al: Allopurinol: Intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol 18:1758-1763, 2000 19. Pui CH, Mahmoud HH, Wiley JM, et al: Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol 19:697-704, 2001