Chapter 45: Oncologic Emergencies

As the treatments for malignancies continue to improve, so does the long-term survival and prognosis of the oncologic patient. Consequently, an increasing number of patients with cancer face complications that can lead to severe illness and require admission to the intensive care unit (ICU). As in the general population, the majority of ICU admissions for patients with malignancy are due to sepsis and respiratory failure. Intensivists should be familiar with the specific issues relevant to the critically ill oncologic patient so that adequate treatment can be offered (Table 45–1). This chapter will focus on the classic clinical syndromes that represent oncologic emergencies: superior vena cava syndrome (SVCS), cardiac tamponade, spinal cord compression, tumor lysis syndrome, hypercalcemia, and leukostasis.

Superior vena cava syndrome (SVCS) is a group of signs and symptoms that occur when there is obstruction of the SVC. Currently more than 85% to 90% of SVCS cases are associated with malignancy.¹ Ninety percent of malignant causes are due to lung cancer (nonsmall cell lung carcinoma—50%, small cell lung carcinoma—25%) and lymphoma (non-Hodgkin's lymphoma—10%).^2,3 Once SVCS is present in the oncologic patient, life expectancy is not greater than 9 months, although these numbers can vary widely according to the type of malignancy.³

Findings on physical exam include facial plethora, neck and superficial chest vein distention, upper extremity edema, dyspnea, orthopnea, and presyncope. In the past, SVCS was considered a medical emergency; however, current data suggests that immediate death is only observed when there is airway compromise (laryngeal or vocal cord edema) or cerebral edema.^2,4

The diagnosis of SVCS is made clinically with support of imaging studies such as computed tomographic (CT) scan with contrast, magnetic resonance imaging (MRI), or venography. Imaging is used to evaluate the extent of obstruction, possible associated thrombosis, and vascular anatomy in case of any planned interventions.^1,3

Management of SVCS should be directed toward restoring the patency of flow in the SVC; all other treatments are considered supportive. Management of airway compromise requires oxygenation and rapid stabilization of the airway. Use of corticosteroids has been described but there are no randomized controlled trials suggesting that their use is beneficial.⁵ Moreover, the use of corticosteroids prior to any biopsy can alter the yield of pathologic diagnosis, especially if lymphoma is suspected.^1,3 In patients with brain edema, quick restoration of vascular flow should be attempted because morbidity and mortality in these cases is extremely high. Diuretics to decrease edema should not be regularly used; intravascular depletion can adversely affect hemodynamics in these patients; and there is no data to support the effectiveness of diuretics.^2,4

In recent years, the use of intravascular stents for SVCS treatment has increased significantly. Stenting improves symptoms in the first 24 to 72 hours, making it the treatment of choice for patients with severe SVCS.^5,6 Multiple studies have shown stenting to be efficient, safe, and cost-effective.^5,6 Complications such as stent migration, stenosis, pericardial tamponade, and pulmonary embolism (PE) have been reported in less than 8% of cases.⁶ Prolonged use of anticoagulants for this population is controversial. Evidence of PE and risk for stent occlusion have made routine anticoagulation an appealing choice.⁷ However, bleeding complications are high and current data do not suggest improved outcomes when using routine anticoagulation.³

After stent placement, final treatment for SVCS should be guided toward management of the malignancy. Initiating treatment prior to diagnosis can obscure biopsy results in up to 48% of cases.³ Therefore, tissue biopsy, pathologic evaluation, and staging should be performed to define adequate treatment. Response to radiation and chemotherapy occurs only after 2 to 3 weeks of initiating treatment and symptoms improve in only 50% to 70% of cases.^1,3 All treatments should be reviewed and their intent, either palliative or curative, should be clear to the clinicians.

Accumulation of fluid in the pericardial sac leads to elevated intrapericardial pressures, impaired ventricular filling, decreased preload, low cardiac output, and shock, a clinical syndrome known as cardiac tamponade. Pericardial effusions secondary to malignancy usually accumulate slowly giving time for compensatory mechanisms against the elevated intrapericardial pressures. Thus, in the case of malignancy, cardiac tamponade usually occurs in the setting of large pericardial effusions. The most common malignancies associated with pericardial effusions are lung, breast, melanoma, and lymphoma.⁸ Primary malignancies of the pericardium, such as mesothelioma, are rare.⁸ In addition, treatment for malignancy—including radiation and some chemotherapy agents (eg, cytarabine, daunorubicin)—can cause pericarditis and secondary pericardial effusions.⁸ Prognosis of patients with malignant pericardial effusions is poor; at 6 months the survival rate is 45% and at 1 year the survival rate is 10% to 26%.⁹ Poor prognostic factors include the presence of primary adenocarcinoma of the lung, positive fluid cytology, and advanced malignancy.^9,10

The most common symptoms associated with cardiac tamponade are dyspnea, chest discomfort, and chest pain. Beck's triad—pulsus paradoxus, distant heart sounds, and jugular venous distention—is pathognomonic; however, it is present only in a minority of patients.¹¹ Electrocardiography (EKG) has always been used in the diagnosis of cardiac tamponade. Most specific (86%-99%) EKG signs of cardiac tamponade are low voltage, PR depression, and electric alternans; their sensitivity, however, can be as low as 8% to 42%.¹² Echocardiogram is the gold standard for the diagnosis of cardiac tamponade and should be performed emergently. Signs of tamponade include right ventricular collapse during diastole, exaggerated contraction of the right atrium during atrial systole, swinging motion of the heart, and mitral and tricuspid valve inflow variation with respiration.^8,13

Emergent drainage by either pericardiocentesis (guided by echocardiogram, fluoroscopy, or CT) or pericardial window is the treatment of choice. Pericardial window is recommended for patients who have a higher risk of recurrence such as those with adenocarcinoma of the lung.^14,15 There is, however, no difference in overall survival or safety when performing any of these 2 procedures.¹⁵ Pericardial radiation and instillation of chemotherapy agents for recurrent effusions have been used safely; however, no survival benefit has been demonstrated with these techniques.^8,14

After drainage of the effusion, symptoms and hemodynamic instability should improve dramatically. In a small percentage of patients, however, there can be persistent shock due to what is described as a “low cardiac output syndrome.”¹⁰ Management should be supportive as resolution is usually gradual; however, it has been associated with a poor prognosis in some studies.¹⁰

Spinal lesions occur in 50% of patients with osseous metastasis.¹⁶ Of these, almost 10% of patients develop malignant spinal cord compression (MSCC).^16,17 Hematologic spread is the most common mechanism of spinal cord involvement. Metastatic solid tumors of the lung, breast, and prostate cancer are the most common malignancies associated with MSCC.¹⁸ Non-Hodgkin's lymphoma, multiple myeloma, renal cancer, sarcomas, and unknown primary tumors are less common causes.^18,19

Early recognition of MSCC is vital because restoration of neurologic function and prognosis is directly related to the degree of initial neurologic damage.^17,19 Pain is the first symptom in 83% to 90% of cases and studies suggest that 60% of cancer patients complaining of back pain have compression of the epidural space.^18,20,21 Thus, in the setting of metastatic disease and back pain, there should be a high suspicion for MSCC. Motor deficits, ranging from weakness to paralysis, are present in 35% to 68% of cases.^17,20 Sensory deficits are usually not recognized by the patients but are present on physical exam in 70% of cases.²⁰ Autonomic dysfunction and loss of sphincter tone is a poor prognostic factor for recovery as this presents late in the progression of the disease.^17,18,20

The gold standard and most cost-effective method for diagnosis of MSCC is MRI.¹⁸ Metastatic lesions to the spine are usually widespread, therefore, a whole spine MRI should be performed in all patients with suspected MSCC.¹⁸ Angiography is useful for hypervascular tumors (sarcoma, melanoma, thyroid, and renal cancer) in which presurgical embolization can be considered.^19,21

Prognosis after MSCC is poor and survival after diagnosis of MSCC is usually 3 to 6 months.^16,17 The goal of treatment is to decrease pain and preserve neurologic function; therefore, a high suspicion and early recognition is important to improve outcomes.^18,19 Scoring systems that include functional status, type of tumor, number of bone and visceral metastases, degree of neurologic dysfunction, and response to radiotherapy are intended to evaluate prognosis and guide therapy.^17,18 Due to the wide variety of available scores, it is important that treatment is guided by a multidisciplinary team that can assess risks and benefits in an individual manner.

First-line treatment of MSCC are corticosteroids as they have been shown to reduce pain and improve neurologic function.²² Corticosteroids should be administered promptly to decrease spinal cord edema and in some cases, such as lymphoma, to reduce tumor burden.¹⁸ Administration should be prior to radiotherapy, for a total of 10 days, and low doses seem to be as efficacious as megadoses.²²

Radiation therapy is also widely used for the treatment of MSCC. It is recommended for patients who are unable to tolerate surgical procedures, have a short life expectancy, have diffuse spinal disease, symptoms present for longer than 48 hours, or those with a known tumor sensitivity to radiotherapy.^17,20 This mode of treatment is known to reduce pain, tumor size, and preserve neurologic function.¹⁷

Surgical decompression is indicated in patients with progression of tumor and symptoms while undergoing radiation, significant cord compression, medically intractable pain, radioresistant tumors, and evidence of spinal instability.²⁰ Published meta-analysis and randomized controlled trials (RCTs) have shown that surgical intervention in combination with radiotherapy improves neurologic function, pain control, and survival when compared to radiation alone.^16,18,21 Despite these encouraging results, it is important to take into account the patient's overall status and prognosis before undergoing any surgical procedure.^17,18

Spinal stereotactic radiosurgery, percutaneous vertebroplasty, and kyphoplasty are being considered as more localized and less invasive methods of treatment of MSCC. Although some studies have shown promising results, they are still not widely used and are still considered experimental.^18,19,21

Overall, MSCC should be readily recognized in the oncologic population. Management and diagnosis should be immediate, multidisciplinary, and tailored to every patient's diagnosis and overall prognosis.

Malignancy-associated hypercalcemia (MAH) occurs in approximately 20% to 30% of patients and is more common in solid tumors such as breast and lung cancer.^23,24,25 Patients with hematologic malignancies such as Hodgkins disease, non-Hodgkins lymphoma, adult T-cell leukemia/lymphoma, and multiple myeloma can also rarely present with MAH.^23,24,26 MAH can be divided into humoral, osteolytic, and calcitriol-associated hypercalcemia. Humoral hypercalcemia is the most common presentation of MAH. The main mediator is parathyroid hormone–related protein (PTHrP) which is mostly released by solid tumors but has also been described in cases of non-Hodgkins lymphoma and multiple myeloma.^23,24,26 Osteolytic MAH, observed in 20% of cases, is associated with increased osteoclastic activity secondary to bone metastasis.^24,26 Less than 1% of MAH is mediated by calcitriol production in hematologic malignancies such as lymphomas.^24,27 While these distinctions exist, many cases of MAH are multifactorial. MAH is a marker of poor prognosis and median survival time after its presentation is less than 35 days.^25,28

Symptoms of hypercalcemia include muscular cramping, constipation, dehydration, polyuria, changes in mental status, and cardiac dysrhythmias. The severity of symptoms is usually associated with the degree of hypercalcemia, and central nervous system symptoms are usually present with calcium levels above 14 mg/dL.²⁴ Initial workup for hypercalcemia should include measurements of ionized calcium, PTH, PTHrP, and 25-hydroxy vitamin D levels.²⁵

Volume repletion should be the initial goal of hypercalcemia as hydration decreases tubular reabsorption of calcium by the renal tubules.²³ Loop diuretics to promote calciuresis are no longer recommended because they do not consistently decrease calcium levels and are associated with further volume depletion and electrolyte disorders.²⁹ Glucocorticoids, which inhibit calcitriol production, are effective in the treatment of lymphoma-related hypercalcemia.^25,27

Bisphosphonates, which block bone resorption by osteoclasts, are recommended for long-term treatment of hypercalcemia.²⁵ While one study showed zoledronic acid to be more efficient than pamidronate in immediate reduction of calcium levels, the difference seemed to dissipate after 1 week.^24,30 Due to these findings any of the 2 medications can be used according to availability. However, if hypercalcemia is causing severe neurologic and cardiac symptoms, zoledronic acid should be considered as it is more effective in the short term. Renal failure can rarely occur when using bisphosphonates; administration should be avoided, or after discussion or risk benefits, if the glomerular filtration rate is less than 30 mg/dL.^23,25,30

Because bisphosphonates are effective only after 48 hours and hydration can only aid with calciuresis to a certain degree, other immediate measures such as calcitonin administration should be taken. Calcitonin decreases calcium levels by inhibiting osteoclasts and inducing calciuresis 2 hours after administration.^23,30 Administration should be limited to 2 doses due to resistance and downregulation of its receptors.²⁸ Cinacalcet, a calcimimetic, rapidly decreases calcium levels in the setting of benign hyperparathyroidism; it's role in MAH, however, is limited only to occasional case reports.²⁵ Denosumab, a monoclonal antibody that inhibits osteoclast activity, is used in patients with refractory MAH as long-term treatment; its use in the acute setting is also limited and it is not recommended on a regular basis.²⁵

As previously mentioned, alhough hypercalcemia can be reversible and treated with current medications, it is usually associated with poor long-term prognosis. Palliation and goals of care should be discussed with these patients even if their outcome after ICU admission is excellent.

Tumor lysis syndrome (TLS) is characterized by electrolyte and metabolic derangements which occur after rapid breakdown of proliferating malignant cells. TLS can be spontaneous in rapidly growing tumors or present after treatment with chemotherapy, corticosteroids, or radiation.^31,32 TLS has an incidence of 5% to 10% and is typically associated with acute leukemias particularly acute lymphoblastic leukemia (ALL) and highly aggressive lymphomas, such as Burkitt's lymphoma.^31,32 TLS can also rarely occurs with solid malignancies and usually occurs weeks after chemotherapy treatment is initiated.³²

Electrolyte abnormalities associated with TLS include hyperkalemia, hyperphosphatemia, hypocalcemia (due to binding of phosphorus to calcium), and hyperuricemia. Clinical findings include vomiting, diarrhea, cramping, lethargy, seizures, cardiac arrhythmias, and shock. Acute kidney injury (AKI) in TLS is caused by deposition of uric acid and calcium phosphate crystals in the kidney tubules.³¹ Early recognition and prevention are extremely important as all of these symptoms and complications progress rapidly and can lead to death.

Recognition of high-risk patients and early detection should be the foundation of TLS management. Common risk factors for TLS include: pre-existing hyperuricemia, large tumor burden, rapidly growing malignancies, fluid depletion, and renal dysfunction.^32,33,34 Patients can be characterized into low, intermediate, and high risk for TLS according to their malignancy, laboratory findings, and presence of pre-existing kidney disease.^31,33 This stratification improves early recognition and serves as a guide for treatment. Moreover, laboratory criteria developed by Cairo and Bishop have helped with the diagnosis and classification according to severity of TLS.^34,35 In their definition, elevations above 25% from baseline of uric acid, potassium, phosphorus, and calcium were included. When 2 or more laboratory abnormalities, 2 days before or 7 days after cytotoxic treatment are present, this is indication of TLS.³⁵ In addition to these laboratory abnormalities, the presence of AKI, seizures, or arrhythmias classifies the disorder as clinical TLS which carries a higher mortality and should be treated aggressively.^31,34

Supportive care of patients at risk for TLS should be initiated with aggressive hydration to maintain a urine output of 100 mL/h. Close monitoring of electrolytes, lactate dehydrogenase, and uric acid levels are necessary on days prior and after cytoreduction. Alkalinization of urinary pH has been shown to increase phosphate and xanthine (a uric acid metabolite) precipitation in the renal tubules, therefore, administration of sodium bicarbonate is no longer recommended.^31,34 Diuretics in the setting of oliguria can be administered, however, there is no evidence of improved outcome after its use.³² Indications for hemodialysis in TLS include signs of uremia, volume overload, persistent hyperkalemia, and acidosis. It is also recommended that patients with severe hyperphosphatemia and symptomatic hypocalcemia be initiated on hemodialysis.^31,34 Prophylactic or early hemodialysis, however, has not been studied for TLS.³⁴

Two agents are used in the management of TLS: allopurinol (a xanthine oxidase inhibitor that blocks uric acid production) and rasburicase (a recombinant urate oxidase that degrades formed uric acid into allantoin which is easily excreted in urine).³⁶ Allopurinol should be started 2 days prior to initiation of cytotoxic treatment in patients at risk for TLS and can be administered both orally and intravenously with the same effectiveness.^31,32 Studies have shown that rasburicase can reduce uric acid levels as fast as 4 hours after the initial dose and treatment required averages 3 days.³⁶ However, due to its costs and availability, the decision to administer rasburicase should probably be limited to high-risk or severe cases and after further discussion with the oncologist. Secondary effects reported with rasburicase include hypersensitivity, methemoglobinemia, and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.^32,36

Current guidelines on management of TLS are based on the risks and severity of the syndrome.^31,33,34 Although there are no studies comparing outcomes of these different guidelines, they all facilitate early recognition of high-risk patients and initiation of early aggressive treatment.

Hyperleukocytosis (WBC > 50,000-100,000/mm³), common in chronic leukemias, is considered a medical emergency and a sign of poor prognosis when found in acute leukemias.^37,38 Leukostasis occurs when blasts aggregate in the microvasculature leading to endovascular damage, hypoperfusion, cytokine release, and secondary organ dysfunction.^39,40 Incidence of leukostasis is 10% to 30% and is more common in patients with acute myelogenous leukemia (AML) than ALL.³⁹ Mortality can be as high as 60% and independent risk factors such as age, creatinine, total bilirubin, and lactic dehydrogenase (LDH) levels have been associated with early death.^37,41

The diagnosis of leukostasis is challenging as its clinical presentation and radiologic findings cannot be differentiated from common infectious and hemorrhagic complications which affect patients with leukemia. Moreover, some cases have been diagnosed with WBC less than 100,000/mm³, making this diagnosis even more challenging.⁴¹ Most common symptoms associated to leukostasis are respiratory (hypoxemia, dyspnea, and hemoptysis) and neurologic (dizziness, headache, blurry vision, confusion, and stroke or intracranial hemorrhage). Other clinical findings may include extremity, bowel and cardiac ischemia, renal vein thrombosis, heart failure, and priapism.^40,41 It is important to recognize that in the presence of both respiratory failure and neurologic symptoms, mortality can be as high as 90%.⁴⁰

For the past 2 decades there has been very little progress in the treatment of leukostasis. Current available treatment consists of cytoreduction with leukapheresis, hydroxyurea, and chemotherapy. Leukapheresis is initiated in cases of AML if WBC is more than 50,000/mm³, and in ALL if WBC is more than 250,000/mm³.^39,41 Although leukapheresis is still used in many institutions, its timing, number of treatments, and target WBC are not well defined. Reasons for this include the fact that the effectiveness of leukapheresis is not associated with WBC reduction, and its use continues to be based mainly on case reports and retrospective studies.^39,41 Hydroxyurea has comparable efficiency and outcomes to leukapheresis and should be used in all patients with leukostasis.³⁹

Early chemotherapy is the only treatment that has shown to improve mortality in the short term.⁴² Cranial irradiation was used in the past for neurologic symptoms and as prophylaxis to reduce intracranial hemorrhage; however, this is no longer recommended due to lack of effectiveness.⁴² Dexamethasone, which decreases cytokine production and suppresses adhesion markers, has been shown to be effective in acute promyelocytic leukemia; nevertheless, additional studies to look at its role in other hematologic malignancies is necessary.⁴⁰