Definition and etiology

Oncologic emergencies, as the term implies, are complications resulting from a cancer itself, a paraneoplastic syndrome, or from treatment of the cancer, that require immediate attention and reversal, if possible. Inpatient treatment is a must, and often these conditions require intervention in an intensive care setting.

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Types

Examples of oncologic emergencies include tumor lysis syndrome and other metabolic abnormalities, disseminated intravascular coagulopathy (DIC), hyperleukocytosis and leukostasis, fever in the setting of neutropenia, and spinal cord compression from a tumor mass.

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) is defined by a constellation of metabolic abnormalities seen in tumors with rapid cell turnover, in which the lysis of malignant cells causes release of their contents into the systemic circulation at a rate that exceeds the elimination capacity of the kidneys. TLS occurs most frequently in the acute leukemias, particularly T cell acute lymphoblastic leukemia (ALL), and in highly aggressive lymphomas, such as Burkitt’s lymphoma. Risk factors that predispose to TLS include a large tumor burden with rapid cell turnover, elevated lactate dehydrogenase (LDH) level, preexisting hyperuricemia, sensitivity of tumors to chemotherapy, and abnormal baseline renal function.¹

The sine qua non of TLS includes characteristic metabolic abnormalities, such as hyperuricemia, hyperkalemia (or, rarely, hypokalemia), hyperphosphatemia, hypocalcemia, and an elevated LDH level.

Identifying patients at risk and instituting appropriate prophylactic measures are essential. Electrolyte levels should be monitored frequently and adequate urinary output maintained in anticipation of and during TLS. Aggressive hydration should be initiated, along with urinary alkalinization and specific treatment of individual metabolic abnormalities. This includes measures that prevent uric acid formation and precipitation, and augment uric acid metabolism to allantoin. Allopurinol, which inhibits xanthine oxidase, is administered at a dosage of 300 mg/day to prevent uric acid synthesis from purines released as a result of cell lysis. Urine alkalinization is accomplished with sodium bicarbonate infusions to a target urinary pH of 7.0 or higher to prevent uric acid deposition in the renal tubules. Recombinant urate oxidase (rasburicase) has been recently approved for the treatment of hyperuricemia in pediatric patients with acute leukemia. Although it is extremely effective in reducing serum uric acid to low levels within a few hours of administration, it is reserved for severe cases that have failed traditional prophylactic methods and in which the probability of acute renal failure is very high, for cost reasons, and because it has not been shown to affect outcome.²

Disseminated Intravascular Coagulopathy

DIC can be a disorder of excessive bleeding or involving thromboembolic events. It is characterized by excess thrombin generation, usually triggered by an underlying condition, such as cancer or sepsis. DIC can accompany any type of leukemia and is most commonly observed in patients with acute promyelocytic leukemia (APL).³ The development of DIC in leukemia may be caused by several mechanisms, including release of procoagulant factors, fibrinolytic substances, and inflammatory cytokines, and mechanically via the interaction of the leukemia cell with the vascular endothelium, macrophages, and platelets. Induction chemotherapy itself may transiently worsen the coagulopathy of APL. DIC may also be a sequela of gram-negative septic shock in 30% to 50% of cases; gram-negative shock, in turn, can occur in the setting of the immunosuppression associated with leukemia, its treatment, or both. l-Asparaginase, an agent commonly used as part of induction regimens for ALL, can cause DIC as a drug-related adverse event, frequently leading to a significant drop in fibrinogen levels. This form of DIC is more often associated with episodes of thrombosis rather than bleeding.

Supportive care and treatment of the underlying cause are the cornerstones of therapy of DIC. In patients with DIC in the setting of APL, the risk of bleeding is significantly decreased by institution of differentiation therapy with all-trans retinoic acid (ATRA), cytotoxic chemotherapy, and blood product support with platelets and cryoprecipitate.⁴ Differentiation is also known to alter the clinical course of the coagulopathy of APL. Aggressive supportive care measures including platelet transfusions, clotting factor and cryoprecipitate replacement, and urgent initiation of definitive therapy; these are the key elements for management of this otherwise potentially fatal condition.

Hyperleukocytosis and Leukostasis

Approximately 5% to 30% of adult patients with acute leukemia will present with a high leukocyte count, usually higher than 100,000/mm³. This leukocytosis can cause leukostasis, or sludging of the microcirculation with leukemic blasts. This phenomenon occurs more frequently in acute myelogenous leukemia (AML), in which the myeloid blast is larger and has impaired deformability characteristics as compared with a mature granulocyte. Leukemic blasts can also form microaggregates and white bland thrombi in small vessels, leading to impairment in flow, local hypoxemia (exacerbated by the high metabolic activity of the dividing malignant cells), and resultant direct endothelial damage and bleeding. The pulmonary and cerebral vascular beds are the most clinically relevant targets of leukostasis, although the coronary circulation can also be affected. Cerebral involvement can range from subtle confusion and somnolence to frank intracerebral bleeding and coma. Early pulmonary involvement is signaled by mild dyspnea and respiratory alkalosis. Typical chest x-ray findings include diffuse interstitial or alveolar infiltrates, but can be normal in early stages.⁵

The management of hyperleukocytosis and leukostasis is centered on cytoreduction and maximizing vascular flow through supportive measures. In patients with AML, hydroxyurea should be started, 1 to 3 g orally every 6 hours, in combination with emergent leukapheresis for patients presenting with white blood cell (WBC) counts higher than 100,000/mm³ or signs or symptoms indicative of leukostasis. In ALL, the threshold to initiate leukapheresis is higher, usually higher than 200,000/mm³, and patients may be treated with vincristine, steroids, or both. The replacement of fresh-frozen plasma that occurs in conjunction with leukapheresis may improve the coagulopathy that may be present in these patients, thereby reducing the risk of hemorrhage. However, leukapheresis has never been shown convincingly to reduce the risk of developing leukostasis or to reduce early mortality.⁶ The most definitive therapy for this condition, naturally, involves urgent institution of induction chemotherapy.

Fever and Neutropenia

Patients with malignancies, and particularly those with acute leukemias, in which the cancer involves the immune system directly, often have neutropenia associated with their disease (commonly defined as an absolute neutrophil count lower than 500/mm³) or with the immunosuppressive chemotherapy used to treat their disease. In particular, they are susceptible to infections with gram-negative organisms, staphylococci, and fungi. The most common sites of infection include the oropharynx, lungs, perirectum, and skin, particularly at IV catheter sites. Broad-spectrum antibiotics should be instituted immediately in the settings of fever and neutropenia to prevent these infections from becoming life threatening.⁷ Antibiotics, which must include adequate coverage for Pseudomonas aeruginosa and other gram-negative organisms, should be continued until the absolute neutrophil count is higher than 500/mm³. Antifungal therapy should be instituted if fever persists despite initial broad-spectrum antibiotics, usually 48 to 72 hours after failure of other antibiotics. Although the use of hematopoietic growth factors may reduce the length of hospital stay, they do not improve survival.⁸

Spinal Cord Compression

Compression of the spinal cord from a rapidly growing mass can result in neurologic compromise. Patients will often present with symptoms of back pain and neurologic complaints specific to the dermatome affected by the mass. In patients with cord compression in the lumbosacral area, this can include incontinence of the bowel or bladder or urinary retention, or leg pain or numbness. Without rapid reversal, these neurologic sequelae will become permanent. Malignant causes include liquid tumors, particularly aggressive lymphomas or multiple myeloma, and solid tumors, particularly those with a predilection for bone metastases, such as prostate, lung, or breast cancer. If at all possible, it is imperative first to establish a diagnosis of cancer in a patient previously undiagnosed who presents with cord compression; this can be accomplished through surgical decompression with a biopsy of the culprit lesion. In patients with known cancer diagnoses, nonsurgical interventions can also be used. These include treatment with high-dose steroids and local radiation therapy.

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Summary

• Oncologic emergencies include tumor lysis syndrome and other metabolic abnormalities, disseminated intravascular coagulopathy, hyperleukocytosis and leukostasis, fever in the setting of neutropenia, and spinal cord compression from a tumor mass.
• Immediate institution of aggressive supportive measures is warranted, followed quickly by definitive treatment of the underlying malignancy.
• Monitoring electrolyte levels, complete blood cell counts, vital signs, and measures of coagulation are crucial for detecting these abnormalities and quickly initiating appropriate therapy.

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