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The development of medical emergencies related to the underlying disease or as a result of complications of therapy are common in patients with hematologic or solid tumors. These oncological emergencies can occur as an initial presentation or in a patient with an established diagnosis and are encountered in all medical care settings, ranging from primary care to the emergency department and various subspecialty environments. Therefore, it is critically important that all physicians have a working knowledge of the potential oncological emergencies that may present in their practice and how to provide the most effective care without delay. This article reviews the most common oncological emergencies and provides practical guidance for initial management of these patients.
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Cancer is expected to be diagnosed in more than 1.6 million people in the United States in 2017. A small percentage of these patients will experience an emergent cancer-related complication at some point during the disease course. For some patients, an emergent complication is the first manifestation of the cancer.
Given the large number of patients with active cancer, many practicing physicians can expect to encounter patients with a cancer-related emergency. It is therefore imperative that practitioners, especially primary and emergency care physicians, are able to rapidly recognize and effectively manage patients with these complications. Emergencies in hematology and oncology can be broadly classified as conditions resulting from the cancer itself and complications related to therapy directed against the malignant disease, although there can be some overlap between the 2 categories. The emergencies can also be classified according to organ systems, which is the approach taken in this review.
Metabolic Emergencies
Hypercalcemia of Malignancy
Hypercalcemia is common in patients with advanced cancer and has been reported in up to 30% of patients with cancer.
The incidence varies greatly among cancer types, and hypercalcemia is most commonly associated with multiple myeloma, non–small cell lung cancer (especially squamous cell cancer), renal cell carcinoma, breast cancer, non-Hodgkin lymphoma, and leukemia but can also be seen in multiple other malignant disorders.
The presence of hypercalcemia in a patient with cancer is an adverse prognostic factor predicting a shorter survival, but effective therapy, both for the hypercalcemia and the underlying cancer, may improve outcomes.
The first category, often called humoral hypercalcemia of malignancy, usually results from tumor production of parathyroid hormone–related peptide (PTHrP) and less commonly intact parathyroid hormone (PTH). It is the most common underlying cause of hypercalcemia of malignancy. The second category is hypercalcemia from bone destruction and dissolution (osteolysis) from extensive bone metastases. The third and least common category is excess production of vitamin D analogues by the malignant cells. Humoral hypercalcemia of malignancy accounts for up to 80% of hypercalcemia that occurs in patients with cancer and is the dominant cause in patients with solid tumors.
Structurally, PTHrP is closely related to PTH and exerts many of the functions of PTH itself. It binds to receptors on osteoblasts and stimulates their activity through receptor activator of nuclear factor κB ligand (RANKL) signaling. This process in turn stimulates the osteoclasts, increasing their activation and proliferation and subsequently releases calcium into the circulation.
The presence of elevated PTHrP in humoral hypercalcemia of malignancy portends poorer prognosis and decreased response to therapy with bisphosphonates.
Osteolysis as a cause of hypercalcemia is commonly seen in patients with breast cancer, lung cancer, and multiple myeloma. Several cytokines have been implicated in the pathogenesis of cancer-induced osteolysis, including tumor necrosis factor, macrophage inflammatory protein 1a, and lymphotoxin.
Extrarenal production of 1,25-dihydroxyvitamin D (calcitriol) can occur in patients with both Hodgkin and non-Hodgkin lymphomas as well as nonmalignant granulomatous diseases such as sarcoidosis.
Hypercalcemia of malignancy can also be exacerbated by factors unrelated to the malignant disorder itself such as the intake of calcium, vitamin D, lithium, and thiazides. Thiazides are thought to reduce urinary calcium excretion as a result of increased passive calcium reabsorption at the proximal tubule and increased distal reabsorption at a thiazide sensitive site.
Clinical Presentation and Diagnosis
Hypercalcemia is caused by either primary hyperparathyroidism or malignant disease more than 90% of the time. Therefore, it is important to distinguish between these 2 entities early on. In hypercalcemia associated with cancer, there are frequently overt signs of malignant disease at presentation. Hypercalcemia can cause a multitude of nonspecific symptoms. Lethargy, confusion, anorexia, nausea, constipation, polyuria, and polydipsia are all common symptoms of hypercalcemia, and the severity may correlate with the degree of hypercalcemia and the rapidity of onset.
Severe hypercalcemia, especially of rapid onset, may cause cardiac dysrhythmias such as bradycardia, shortening of the QT interval, and even cardiac arrest.
The physical examination is generally not helpful in making the diagnosis but can reveal signs of volume depletion and impaired cognitive function as well as signs of the underlying cancer such as enlarged lymph nodes.
The diagnosis of hypercalcemia is confirmed by measuring the serum calcium level. Ionized calcium measurement is the preferred method of diagnosis, if available. If total serum calcium is measured, a correction needs to be made for the albumin level. The corrected calcium level is calculated as follows: corrected calcium = measured total calcium + [0.8 × (4.0 − albumin)].
Intact PTH is usually low in hypercalcemia of malignancy and can be helpful as a diagnostic tool, but the results may not be available immediately. An elevated PTH level in a patient with known malignant disease suggests either a coexisting hyperparathyroidism or a PTH-producing tumor. Measurements of PTHrP are generally not needed but may help elucidate the etiology of the hypercalcemia, and elevated levels may predict response to bisphosphonate therapy and predict inferior survival.
All patients with severe hypercalcemia should undergo electrocardiography.
Treatment
Untreated, severe hypercalcemia is a life-threatening entity that calls for immediate intervention for optimal results in patients who are candidates for active therapy. Physicians should not delay starting therapy while awaiting laboratory results such as PTHrP level. Not all patients with hypercalcemia need urgent treatment, and many patients with mild hypercalcemia can be managed as outpatients. Patients with more severe and symptomatic hypercalcemia are usually hospitalized for inpatient therapy. In some cases of advanced cancer, specific therapy may not be recommended if the underlying malignant disease is otherwise untreatable.
The patient's goals and wishes should always be considered before instituting therapy. Best supportive care at home, often with the help of hospice care professionals, may be appropriate for patients who have no effective treatment options remaining for their cancer or who do not wish to receive any further therapy.
The following recommendations apply to patients with severe hypercalcemia (calcium level >14 mg/dL [> 3.5 mmol/L]) and/or very symptomatic hypercalcemia. Table 1 lists the treatment options for hypercalcemia. The first step in the management is the administration of intravenous (IV) fluids because patients are often profoundly hypovolemic, often in the order of 5 to 10 L. Volume expansion will increase the renal clearance of calcium and lower calcium levels. Normal saline (0.9% sodium chloride) is the preferred IV fluid. Patients may require large volumes of normal saline, and 1000 to 2000 mL should be given in the first hour of fluid resuscitation. Larger volumes may be needed initially in hypotensive patients. After the initial bolus of normal saline, an IV infusion of 250 to 500 mL/h can be used until urine output and euvolemia are established.
Table 1Treatment of Hypercalcemia
Intervention
Dosage
Comments
Saline
250-500 mL/h IV until euvolemic and 100-150 mL/h IV after volume repletion is achieved. Can start by giving an 1- to 2-L initial bolus over 1 h if hypovolemic
The rate of infusion should be adjusted for the cardiovascular status of the patient
Pamidronate
60-90 mg IV over 2-4 h
Use with caution in renal insufficiency. Onset of action may take days
Zoledronic acid
4 mg IV over 15 min
Use with caution in renal insufficiency. Onset of action may take days
Calcitonin
4-8 IU/kg SC or IV every 12 h
Rapid onset of action but short-lived
Glucocorticoids
Prednisone, 60 mg/d PO; hydrocortisone, 100 mg every 6 h IV
Useful for hypercalcemia from calcitriol overproduction and in multiple myeloma
Denosumab
120 mg SC weekly for 4 wk, then every 4 wk
Safe in renal insufficiency but doses should be reduced. Can cause severe hypocalcemia
Furosemide
20-40 mg IV
Only for patients with volume overload after volume expansion
IV = intravenously; PO = orally; SC = subcutaneously.
It is therefore of most use when a prompt reduction in calcium levels is required. Calcitonin is given as a subcutaneous injection, and no dosage adjustment is needed in patients with renal insufficiency.
Loop diuretics should be reserved only for patients with clinical evidence of volume overload. Bisphosphonates are the mainstay of the treatment and are able to control the hypercalcemia in most patients.
Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.
Treatment of cancer-associated hypercalcemia: double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone.
Bisphosphonates block osteoclastic bone resorption, but the onset of action is slow and it may take 2 to 3 days to see a full effect. The most commonly used bisphosphonates in the United States are pamidronate (60-90 mg IV over 2-4 hours) and zoledronic acid (4 mg IV over 15 minutes), but zoledronic acid is often preferred because it can be given as a short IV infusion and may be more effective than pamidronate.
Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.
Bisphosphonates are potentially nephrotoxic and should be used with caution in patients with renal insufficiency.
Glucocorticoids are useful in patients whose hypercalcemia is driven by overproduction of calcitriol because they inhibit the conversion of calcidiol to calcitriol.
Commonly used glucocorticoids include prednisone (60 mg orally daily) and hydrocortisone (100 mg IV every 6 hours). Gallium nitrate and mithramycin (plicamycin) have been used in the past but are not readily available now and have been replaced by safer agents.
Denosumab, a humanized monoclonal antibody directed against the RANKL that inhibits osteoclast activation and function, was recently approved for use in hypercalcemia of malignancy. Denosumab has been used successfully in hypercalcemia refractory to bisphosphonate therapy.
In a single-arm trial in patients who remained hypercalcemic after bisphosphonate therapy, denosumab lowered the calcium levels in most patients and had a prolonged duration of response.
Denosumab was given as 120 mg subcutaneously weekly for 4 weeks and then every 4 weeks thereafter. It is well tolerated but may result in symptomatic hypocalcemia.
The dose should be reduced in patients with renal insufficiency, but the optimal dose has not been established. A fixed single dose of 60 mg subcutaneously has resulted in symptomatic hypocalcemia, and a weight-based dose of 0.3 mg/kg may be a safer alternative followed by careful monitoring and repeated administration in a week if needed.
The calcimimetic cinacalcet has been reported to lower serum calcium levels in patients with hypercalcemia secondary to PTH production of parathyroid carcinoma but is not recommended in hypercalcemia of other etiologies.
Hemodialysis can be used in refractory cases and situations in which other methods cannot be used safely but should be considered as a last-resort therapy.
Effective systemic therapy or radiotherapy for the underlying disease, if available, can further help decrease the serum calcium levels.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is a constellation of metabolic derangements resulting from the death of neoplastic cells which then release their intracellular contents into the circulation.
British Committee for Standards in Haematology Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.
TLS Expert Panel Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus.
It is most commonly seen after the initiation of cytotoxic chemotherapy but can also result from glucocorticoid therapy for lymphoma, endocrine therapy for advanced breast cancer, various targeted agents, and radiotherapy for radiosensitive malignant diseases.
The catabolism of nucleic acids results in hyperuricemia. High concentrations of uric acid will lead to crystallization within renal tubules and tubular obstruction resulting in acute kidney injury. The renal failure is further exacerbated by hypovolemia leading to acute tubular necrosis. Elevated levels of uric acid may also lead to kidney injury independently of uric acid crystal formation, possibly secondary to alteration in the intrarenal hemodynamics.
The release of organic and inorganic phosphates from the neoplastic cells leads to hyperphosphatemia, which in turn leads to hypocalcemia and precipitation of calcium phosphate and nephrocalcinosis. Hyperkalemia is frequently the first manifestation of TLS, may occur within a few hours after therapy is started, and can result in life-threatening cardiac arrhythmias.
Patients with TLS can present with symptoms (clinically evident TLS) or with abnormal laboratory test results in the absence of symptoms (laboratory TLS).
The presenting symptoms of TLS are nonspecific, and a high index of suspicion is needed for a timely diagnosis. Decreased urine output followed by symptoms of uremia and volume overload may occur. Seizures, arrhythmias, and even sudden death are known presentations of TLS.
Typical laboratory findings include elevated uric acid, phosphorus, potassium, and lactate dehydrogenase levels as well as low calcium concentrations. The diagnostic criteria and definition of TLS have evolved, but the most commonly used definition is the that of Cairo and Bishop
British Committee for Standards in Haematology Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.
The risk is determined by the type of cancer as well as the treatment given and underlying conditions. Tumor-specific risk factors include high tumor burden, high tumor grade with rapid cell turnover, and treatment-sensitive tumor. Age, preexisting renal impairment, and concomitant use of drugs known to increase uric acid are patient-specific risk factors. Aspirin, alcohol, thiazide diuretics, and caffeine are known to increase uric acid levels. The risk can be categorized on the basis of the characteristics of the underlying malignant disease and patient characteristics (Table 3).
TLS Expert Panel Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus.
TLS Expert Panel Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus.
Tumor lysis syndrome can often be prevented, and it is therefore of utmost importance to identify patients at risk and initiate prophylactic therapy because TLS is associated with increased mortality and morbidity as well as increased cost.
British Committee for Standards in Haematology Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.
Incidence, medical resource utilisation and costs of hyperuricemia and tumour lysis syndrome in patients with acute leukaemia and non-Hodgkin's lymphoma in four European countries.
Adequate hydration and the appropriate use of uric acid–lowering (uricosuric) drugs can effectively reduce uric acid levels and reduce the risk of renal injury. The choice of uricosuric drugs depends on the risk of TLS for the given patient (Table 3, Table 4). The most commonly used drugs are allopurinol and rasburicase. Allopurinol is an inhibitor of xanthine oxidase and reduces the production of uric acid by decreasing the rate of conversion of hypoxanthine to xanthine and xanthine to uric acid. Both xanthine and hypoxanthine are more water soluble than uric acid. Allopurinol does not facilitate the breakdown of the uric acid that has already been produced. Allopurinol is an appropriate uricosuric drug in patients with low or intermediate risk of TLS. The prophylactic dose of allopurinol is 200 to 400 mg/m2 daily in 1 to 3 divided doses, up to a maximum of 800 mg daily.
British Committee for Standards in Haematology Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.
Febuxostat is a selective inhibitor of xanthine oxidase that is approved for treatment of gout. It has fewer drug-drug interactions than allopurinol, and dose adjustment is not needed in patients with mild to moderate renal impairment.
Febuxostat has been compared to allopurinol for prevention of TLS. It was found to be more effective in lowering uric acid levels, but it is uncertain if it reduces clinically important TLS, at least when compared with high doses of allopurinol, and its role in management of TLS needs to be determined with further trials.
FLORENCE Study Group FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk.
The dose of febuxostat is 120 mg daily. Rasburicase is a recombinant form of urate oxidase and metabolizes uric acid to allantoin, which is much more soluble than uric acid.
The use of rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Unlike allopurinol, rasburicase also lowers already formed uric acid. Rasburicase is generally reserved as prophylaxis for patients at high risk of TLS or patients already experiencing TLS. Rasburicase is effective as TLS prophylaxis in both adults and children.
Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study.
Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial.
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.
Despite the efficacy of rasburicase in lowering uric acid levels and preventing TLS, it has not been proven to be superior to allopurinol in preventing clinical TLS and related complications.
Despite the lack of data on hard clinical end points, treatment with rasburicase is recommended in all patients with high risk of TLS. The recommended dose of rasburicase is 0.2 mg/kg once daily for up to 5 to 7 days, but lower doses and shorter duration of therapy are commonly used. A single fixed dose of 3 mg has been studied and seems to be very effective in preventing TLS, and the dose can be repeated later if needed.
Recently published guidelines from the British Committee for Standards in Haematology have endorsed the use of a single fixed 3-mg dose of rasburicase as adequate prophylactic therapy for TLS in the absence of established clinical or laboratory TLS.
British Committee for Standards in Haematology Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.
The dose should be repeated daily if there is any evidence of progressive TLS, and if clinical TLS develops on the fixed-dose regimen, the treatment should be changed to the standard dose of 0.2 mg/kg per day. Urinary alkalinization is not recommended because it can decrease the solubility of xanthine. Normal saline is recommended as the IV fluid of choice in the management of TLS.
Table 4Treatment of Metabolic Abnormalities Associated With Tumor Lysis Syndrome
Abnormality
Intervention
Dose
Comments
Renal insufficiency and hypovolemia
Intravenous fluids
NS 3 L/m2/d (200 mL/kg/d)
Use with caution if history of CHF
Dialysis
NA
Use in anuria and severe oliguria with volume overload
Hyperuricemia
Allopurinol
200-400 mg/m2/d PO in divided doses every 8-12 h Commonly used doses include 600 mg initially followed by 300 mg daily IV 200-400 mg/m2/d in 2-3 divided doses
Reduce dose in renal failure Multiple drug interactions (6-mercaptopurine and azathioprine) IV allopurinol should only be used in patients unable to take medications by mouth Does not lower uric acid already formed
Rasburicase
Flat fixed dose of 3 mg IV 0.2 mg/kg/d IV for up to 7 d for established TLS
Contraindicated in G6PD deficiency Transfer blood samples to the laboratory on ice Risk of sensitization and allergic reactions Expensive
Febuxostat
120 mg PO daily
Expensive Uncertain if more effective than allopurinol No need to adjust doses in mild to moderate renal insufficiency
Patients with established TLS should receive multidisciplinary care to ensure the best possible outcome. Frequent monitoring is essential, and patients are often transferred to intensive care units for therapy. High urine output is maintained with hydration and careful monitoring of fluid balance. The optimal rate of fluid replacement remains unknown, but 3 L/m2 every 24 hours is reasonable.
British Committee for Standards in Haematology Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.
Hyperkalemia should be treated aggressively. Asymptomatic hypocalcemia should not be treated, but symptomatic hypocalcemia (tetany, arrhythmia, or seizures) should be treated carefully with IV calcium gluconate with the aim of controlling the symptoms but not normalizing the serum calcium level. Restriction of phosphate intake and phosphate binders may be used for hyperphosphatemia, but severe elevations in phosphate may require hemodialysis. Other indications for dialysis are severe hyperkalemia, severe oliguria or anuria, and volume overload.
Lactic Acidosis
Lactic acidosis is a rare complication of cancer and is most often seen in patients with aggressive hematologic cancers and less commonly with high-grade solid tumors.
The pathogenesis of lactic acidosis in cancer is poorly understood and likely involves both increased lactate production by the tumor and decreased clearance by the liver. Many, but not all, patients have extensive liver metastases, and some patients may have thiamine deficiency.
Therapy for cancer-associated lactic acidosis includes intensive supportive care and therapy directed at the underlying malignant disorder but is frequently ineffective, and death is usually imminent. Chemotherapy is appropriate in patients with chemotherapy-sensitive tumors, but long-term survival is rare.
Hyponatremia is the most common metabolic disturbance in patients with cancer, affecting up to 60% toward the end of life and associated with inferior survival.
The etiology of hyponatremia in these patients is multifactorial and includes the syndrome of inappropriate antidiuretic hormone secretion, either from the cancer itself or from drugs, hypovolemia, and salt-wasting nephropathy.
Most cases of hyponatremia in patients with cancer are mild to moderate and either require no therapy or can be treated in the outpatient setting. Symptoms of hyponatremia include headache, nausea, vomiting, lethargy, confusion, and seizures.
Patients are usually hypovolemic or euvolemic on examination. Severe symptomatic hyponatremia should be corrected slowly with the aim of an increase in the plasma sodium level of 4 to 6 mEq/L (to convert to mmol/L, multiply by 1.0) per day to prevent osmotic demyelination.
Patients with severe hyponatremia presenting with altered mental status or seizures are typically treated with hypertonic saline (3%) given as 3 mL/kg over 30 to 60 minutes, which will rapidly increase the serum sodium by 4 to 6 mEq/L.
Hypoglycemia
Hypoglycemia is a rare complication of cancers seen mainly in patients with neuroendocrine tumors that produce insulin (insulinomas).
Patients with metastatic malignant insulinoma can have severe hypoglycemia. Small, localized benign insulinomas can cause intermittent symptomatic hypoglycemia and are often very difficult to diagnose. Hypoglycemia is rarely seen in nonneuroendocrine cancers but occasionally occurs in end-stage liver failure from extensive hepatic replacement by tumor. Typical symptoms of hypoglycemia are palpitations, tremulousness, diaphoresis, anxiety, and hunger. Further neuroglycopenic symptoms may follow, such as confusion, loss of consciousness, and seizures. If tumor-induced hypoglycemia is suspected, plasma insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels should be measured in addition to glucose. The initial treatment of hypoglycemia in cancer is no different than treatment of hypoglycemia in general. Symptomatic hypoglycemia in an alert patient can be treated with oral fast-acting carbohydrates, but severe symptomatic hypoglycemia requires IV administration of dextrose. A common dose is 25 g of 50% dextrose given as a slow IV push. Patients with symptomatic hypoglycemia from metastatic insulin-producing neuroendocrine tumors usually require further therapy including continuous infusion of dextrose, diazoxide, and octreotide followed by tumor-directed therapy.
Adrenal insufficiency may result from a near-complete replacement of the adrenal glands by malignant tumor or secondary to therapy. Despite the adrenal glands being common sites for metastases, adrenal insufficiency from tumor replacement is rare. Iatrogenic adrenal insufficiency is much more common. Prolonged therapy with glucocorticoids will result in adrenal suppression, and a sudden cessation of such therapy can lead to acute adrenal insufficiency. Megestrol acetate, which is commonly used for cancer cachexia, can cause adrenal insufficiency while patients are taking the drug as well as an acute exacerbation when it is abruptly stopped.
Mitotane, a rarely used adrenolytic drug indicated for the management of adrenocortical carcinoma, invariably results in adrenal insufficiency, and all patients taking mitotane also need to take replacement corticosteroids.
Typical signs and symptoms of adrenal insufficiency include weakness, anorexia, nausea, vomiting, and hypotension. Hyponatremia, often accompanied by hyperkalemia, is a common laboratory finding. Circulatory collapse and shock may occur, especially if there is another intercurrent illness such as an infection. If adrenal crisis is suspected, therapy should be started without delay.
Normal saline, 1 to 2 L in the first hour, followed by an infusion should be given. Hypotonic fluids should be avoided because they may exacerbate the hyponatremia. Glucocorticoids can reverse the adrenal crisis and should be given once the diagnosis is suspected. Dexamethasone (4 mg IV bolus) is preferred because it does not interfere with cortisol assays. Hydrocortisone at 100 mg IV can also be given but interferes with the cortisol assay. Hydrocortisone at a dose of 50 mg IV is an appropriate maintenance therapy until the situation has stabilized.
Hematologic Emergencies
Hyperviscosity Due to Monoclonal Proteins
Hyperviscosity is defined as an intrinsic resistance of fluid to flow. It can be seen in disorders in which there is increased production of monoclonal proteins such as in multiple myeloma and Waldenström macroglobulinemia (WM). Blood viscosity can be increased secondary to an excess of either cellular or acellular elements.
Excessive production of immunoglobulins can lead to increased blood viscosity. Of all the dysproteinemic disorders, WM is the most likely to cause hyperviscosity. Earlier studies reported that up to 30% of patients experienced hyperviscosity.
Spanish Group for the Study of Waldenström Macroglobulinaemia and PETHEMA (Programme for the Study and Treatment of Haematological Malignancies) Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases.
The prevalence seems to be declining because the disease is now being diagnosed at earlier stages. The IgM monoclonal protein produced by WM is a large pentamer that is 80% intravascular and can therefore profoundly affect the blood viscosity.
The levels of monoclonal protein that cause hyperviscosity symptoms can vary considerably between patients but are relatively consistent and reproducible in an individual patient. In general, symptoms of hyperviscosity are unlikely with serum viscosity of less than 4 cP, which usually corresponds to IgM levels of 3 g/dL (to convert to g/L, multiply by 10).
High concentrations of monoclonal protein result in impaired microcirculatory blood flow and subsequent ischemia causing the characteristic symptoms of hyperviscosity. Because the relationship between a monoclonal protein and symptoms of hyperviscosity is not linear, once clinical symptoms of hyperviscosity occur, even a slight further increase in the concentration of monoclonal protein can dramatically worsen symptoms, and conversely, a modest reduction in the concentration can greatly relieve symptoms.
Clinical Presentation and Diagnosis
The onset of the symptoms of hyperviscosity syndromes is usually insidious. Symptoms from the central nervous system (CNS) and eyes predominate (Table 5).
Common symptoms include blurred vision, headache, vertigo, dizziness, hearing loss, and impaired mental status. Shortness of breath, chest pain from myocardial ischemia, peripheral arterial occlusion, and venous thromboembolism have been reported. The physical examination often reveals retinal venous engorgement (sausaging), retinal hemorrhages, papilledema, and retinal vein occlusion at later stages (Figure 1). The patient can also have development of localized serous detachments of the fovea, which are thought to be secondary to accumulations of the immunoglobulin and resolve with plasmapheresis. Bleeding complications can be seen, especially purpura and petechiae due to hemostatic defects.
Figure 1Retinal photograph of a patient with hyperviscosity showing dilated and tortuous retinal veins, intraretinal hemorrhages, and a cotton wool spot (infarction) by the optic disc.
Image courtesy of Dr Jose Pulido, Department of Ophthalmology, Mayo Clinic.
The diagnosis of hyperviscosity requires a high index of suspicion. Most patients have a known diagnosis of a dysproteinemic disorder, but some may present with hyperviscosity as the initial manifestation. The blood smear may reveal rouleaux formation of the red blood cells, in which they stack up like coins (Figure 2). Measurements of serum viscosity may be difficult or impossible to perform in many hospitals, especially if urgently requested outside the usual office hours. Measurements of immunoglobulin levels will likely be more available in real time and can guide therapy. In patients with typical symptoms and clinical findings, especially those with a known dysproteinemic disorder, treatment can start urgently without laboratory confirmation of hyperviscosity.
Figure 2Red blood cell rouleaux formation in a patient with Waldenström macroglobulinemia (peripheral blood, Wright-Giemsa, original magnification ×600).
Image courtesy of Dr Phuong Nguyen, Department of Laboratory Medicine and Pathology, Mayo Clinic.
Therapy should be started without delay in symptomatic patients. Severely symptomatic patients with a known WM diagnosis can be treated with phlebotomy and normal saline replacement while arranging for emergent plasmapheresis. Red blood cell transfusions should be avoided before initiating therapy to prevent exacerbation of the hyperviscosity. Plasmapheresis is an effective method to lower serum viscosity, especially in patients with WM because 80% of the IgM monoclonal protein is intravascular.
Even a small reduction in the monoclonal protein concentration can have a major effect on the symptoms. Plasmapheresis does not affect the underlying disease process, and systemic therapy is always needed for durable control of the disease.
Hyperleukocytosis and Leukostasis
Hyperleukocytosis is often defined as a total leukocyte count of 100 × 109/L or more, but symptoms of leukostasis can occur at lower leukocyte counts.
Hyperleukocytosis can cause microvascular obstruction leading to tissue hypoxia and infarction (leukostasis). Hyperleukocytosis and leukostasis are most commonly seen in acute leukemias, especially acute myeloid leukemia (AML) (5%-20% of patients).
Hyperleukocytosis secondary to AML is more common in children than adults. Acute lymphoblastic leukemia is less likely to cause leukostasis than AML. Chronic lymphocytic leukemia and chronic myeloid leukemia rarely cause symptomatic leukostasis, even despite extreme elevations in the white blood cell counts. Symptomatic hyperviscosity can also occur in patients with severe erythrocytosis and thrombocytosis.
In addition, patients with hyperleukocytosis are at risk for development of TLS and disseminated intravascular coagulation. Two main mechanisms are thought to explain leukostasis.
First, the sheer quantity of immature leukocytes (Figure 3), which are frequently larger and less deformable than mature leukocytes, can lead to microvascular occlusion. Frequently, there is no clear correlation between the leukocyte count and the occurrence of leukostasis, likely due in part to a second important mechanism of abnormal interaction between the leukemic blasts and the endothelium. This abnormal interaction may be secondary to aberrant expression of adhesion molecules by the blasts.
Figure 3Photomicrographs showing hyperleukocytosis in a patient with chronic myeloid leukemia (A) and a blood smear from a normal individual (B) as a comparison (both peripheral blood, Wright-Giemsa, original magnification ×400).
Images courtesy of Dr Phuong Nguyen, Department of Laboratory Medicine and Pathology, Mayo Clinic.
The symptoms and signs of leukostasis can resemble the presentation of hyperviscosity secondary to dysproteinemia (Table 6). Symptoms from the respiratory system and CNS including the eyes are common but can be difficult to distinguish from infectious and hemorrhagic complications.
Patients may present with fever, dyspnea, and pulmonary infiltrates resembling symptoms of pneumonia or volume overload. Fever with neurologic symptoms can be difficult to distinguish from CNS infections. There is no single diagnostic test for leukostasis, but the diagnosis should be considered in all patients with extreme leukocytosis and typical symptoms.
Hyperleukocytosis and leukostasis in patients with acute leukemia are associated with an inferior prognosis with an increase in early deaths compared with patients without these complications, and therapy should be started without unnecessary delay.
Red blood cell transfusions should be administered with caution and preferably after control of the symptoms of leukostasis given the concern of increasing viscosity.
Leukapheresis, a mechanical separation and removal of leukocytes from the blood, can rapidly reduce the number of leukemic blasts and reduce the likelihood of complications, but the effect of leukapheresis on early mortality is uncertain.
Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: a systematic review and meta-analysis.
Despite the uncertainties, it should be strongly considered for all patients presenting with symptomatic leukostasis. The goal of leukapheresis should be resolution of symptoms, typically with reduction of the blast count to less than 100 × 109/L in AML.
Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue.
Hydroxyurea is commonly used to provide additional control by preventing rapid reaccumulation of blasts in the initial stages of therapy, again with an uncertain effect on mortality in isolation.
Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: a systematic review and meta-analysis.
Rapid initiation of standard induction therapy with curative intent is therefore recommended in all patients in whom intensive therapy is appropriate. Hydroxyurea can be considered as a bridging strategy while awaiting the results of diagnostic tests. Cranial radiation is no longer routinely recommended. Patients with leukostasis are at greater risk for TLS and should receive prophylactic therapy.
Neurologic Emergencies
Malignant Spinal Cord Compression
Malignant spinal cord compression (MSCC) is a true oncological emergency. Up to 6% of patients with cancer are expected to experience MSCC at some time during the course of their illness, and the annual incidence of hospitalizations secondary to MSCC among patients with advanced cancer is 3.4%.
All cancers can cause MSCC, but the most often implicated malignant diseases are breast, lung, and prostate cancer, which account for almost two-thirds of all cases, but multiple myeloma and non-Hodgkin lymphoma have the highest cancer-specific incidence.
Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients.
Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression.
Most cases of MSCC are secondary to metastases to vertebral bodies that erode into the spinal canal and encroach on the spinal cord. Paravertebral tumors can extend through the neural foramina, resulting in cord compression.
Injury to the spinal cord can occur secondary to direct compression of the cord or from cord ischemia from vascular occlusion secondary to the tumor. Both mechanisms will eventually lead to irreversible neuronal damage resulting in neurologic deficits if untreated.
Clinical Presentation and Diagnosis
The literature on the natural history and early identification of MSCC is limited, but known bone metastases, high tumor burden, and recent onset of symptoms are suggestive of MSCC in patients with cancer who have back pain.
A systematic review of evidence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression.
Scottish Cord Compression Study Group Don't wait for a sensory level—listen to the symptoms: a prospective audit of the delays in diagnosis of malignant cord compression.
The back pain is often nocturnal and can be worsened by certain movements as well as with increase in intra-abdominal pressure such as the Valsalva maneuver. Guidelines for evaluation of back pain have recommended looking for “red flags” suggestive of malignant disease, but there is limited evidence that such red flags are useful in identifying cancer as the underlying source of back pain.
Scottish Cord Compression Study Group Don't wait for a sensory level—listen to the symptoms: a prospective audit of the delays in diagnosis of malignant cord compression.
Back pain in patients with cancer, especially pain of recent onset and worsening pain, should be taken very seriously and considered to be secondary to MSCC until proven otherwise. A careful history and a thorough physical examination including a neurologic examination are critical when evaluating back pain in patients with cancer. Weakness is the second most common presenting feature of MSCC, and patients may report heaviness or clumsiness of an extremity, which on examination is secondary to motor weakness. Up to 70% of patients are unable to walk at the time of presentation.
Sensitivity and specificity of MRI in detecting malignant spinal cord compression and in distinguishing malignant from benign compression fractures of vertebrae.
Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group.
National Institute for Health and Clinical Excellence. Metastatic spinal cord compression in adults: risk assessment, diagnosis, and management, Clinical Guideline 75. National Institute for Health and Clinical Excellence website. www.nice.org.uk/CG75. Published November 2008. Accessed February 7, 2016.
If imaging of the entire spine is not feasible on initial evaluation, focused MRI of the suspected area should be performed emergently with a more complete MRI evaluation of the entire spine as soon as possible.
National Institute for Health and Clinical Excellence. Metastatic spinal cord compression in adults: risk assessment, diagnosis, and management, Clinical Guideline 75. National Institute for Health and Clinical Excellence website. www.nice.org.uk/CG75. Published November 2008. Accessed February 7, 2016.
Computed tomography (CT), with or without myelography, can be used when MRI is contraindicated or not available. Plain bone radiographs and radionuclide bone scans are insensitive for spinal cord compression. Positron emission tomography with CT imaging is a useful modality to identify metastatis to the spine but lacks anatomic detail for diagnosis of MSCC.
Figure 4Metastatic spinal cord compression. Sagittal (A) and cross-sectional (B) views show metastasis to the thoracic spine in a patient with lung cancer resulting in symptomatic cord compression.
Therapy should be initiated without delay in all patients with suspected MSCC to help preserve neurologic function, preferentially after imaging studies have been performed. Pretreatment motor function is an important predictor of functional outcome after therapy for MSCC.
Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients.
If there is a delay in obtaining imaging studies, corticosteroid therapy may be initiated without confirmation of the diagnosis. Dexamethasone is the most commonly used glucocorticoid. A typical initial dose is 10 to 16 mg IV followed by 4 mg every 4 to 6 hours. The use of higher doses of dexamethasone (up to 100 mg) may result in a slightly better neurologic outcome but is associated with a higher risk of adverse events and is not universally supported in the literature.
A pilot randomised comparison of dexamethasone 96 mg vs 16 mg per day for malignant spinal-cord compression treated by radiotherapy: TROG 01.05 Superdex study.
High-dose dexamethasone can be considered in patients with severe and progressive neurologic deficits in whom the small potential gain may outweigh the risks.
Almost all patients with MSCC should be evaluated urgently for a decompressive surgical procedure. A randomized clinical trial evaluated surgical intervention in addition to high-dose dexamethasone and radiation therapy.
The trial was stopped early because the predetermined criteria were met, with surgical patients more likely to be able to walk after therapy compared with those who received radiation and dexamethasone alone (84% vs 57%; P=.003). Furthermore, patients in the surgical group remained ambulatory for a longer period (122 days vs 13 days) and had better survival. An unplanned subgroup analysis suggested that the benefit was related to age, with younger patients being more likely to benefit.
Other researchers have questioned the generalizability of the results of the trial to a broader cohort of patients because the study patients were highly selected. Moreover, the outcome in the nonsurgical group was inferior to that found in other studies. A matched pair analysis comparing patients who underwent surgical intervention plus radiotherapy with patients receiving radiotherapy alone did not show a benefit from surgical intervention.
Until more data become available, it is appropriate to have most patients evaluated for a decompressive surgical procedure, especially younger patients and those with better performance status, evidence of spinal instability, or rapidly progressive symptoms. A scoring system has been proposed to predict the prognosis of patients with MSCC, and those in the poorest prognosis group may best be served with corticosteroids, short-course radiation therapy, and best supportive care.
Radiation therapy remains the mainstay of the treatment for most patients with MSCC, whether they do or do not undergo a decompressive surgical procedure. Multiple radiation regimens are in use, but none has emerged as the standard.
Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients.
The incidence of symptomatic brain metastases is not well known, but autopsy studies have found that the prevalence of brain metastases is higher than clinically appreciated antemortem.
The cancers most likely to metastasize to the brain are lung cancer (both non–small cell and small cell), breast cancer, renal cell cancer, and malignant melanoma.
15% in the cerebellum, and 3% in the brain stem. Brain metastases are frequently located in the watershed areas of the arterial circulation and at the junction of gray and white matter.
Brain metastases frequently result in cerebral edema and subsequently elevated intracranial pressure. The etiology of the edema is complex and includes vasogenic edema secondary to leaky capillaries, stasis from impaired venous drainage, and obstruction of cerebrospinal fluid by the tumor.
Most patients presenting with brain metastases have a known diagnosis of cancer, and the highest incidence is in patients with advanced malignant disease.
Brain metastases can also be the first presentation of a malignant disorder. The presenting features of brain metastases are variable, but headache is the most common symptom.
Other symptoms depend on the location of the lesion within the brain. Common symptoms include motor and sensory deficits, speech disturbance, unsteadiness, and cognitive decline. Up to 10% of patients have seizures, usually when there are multiple brain metastases.
Contrast-enhanced CT can be used when MRI is either unavailable or contraindicated but is less sensitive for smaller tumors and posterior fossa tumors. Noncontrast CT is helpful when an intracranial hemorrhage is suspected.
Figure 5Contrast-enhanced T2-weighted magnetic resonance image showing symptomatic cerebellar metastasis with associated cerebellar edema and distortion of the fourth ventricle in a patient with esophageal adenocarcinoma.
The prognosis of most patients with brain metastases is poor, and other factors in addition to the presence of brain metastases determine the prognosis. Those factors include the tumor type, age at diagnosis, the performance score, and the presence of extracranial disease. Several scoring systems have been proposed, and one useful and accurate system is the Graded Prognostic Assessment, which is easily applied in clinical practice.
Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases.
Patients with poor performance may be best served with supportive care alone. Table 7 lists treatment options for intracranial hypertension and seizures. Glucocorticoids are indicated in all symptomatic patients with cerebral edema secondary to metastases, and the effect of therapy occurs within several hours.
The optimal dose is unknown, but one trial reported no benefit of higher doses of dexamethasone (16 mg/d) vs lower doses (4-8 mg/d) in patients with no signs of impending brain herniation.
Dexamethasone has excellent oral bioavailability and can therefore be given orally in patients with intact mentation and a functioning gastrointestinal tract. The dexamethasone should be tapered over 3 to 4 weeks after more definitive therapy. Patients with asymptomatic brain metastases and minimal edema do not need glucocorticoids. Seizures occur in 10% to 20% of patients and should be treated aggressively.
Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: report of the Quality Standards Subcommittee of the American Academy of Neurology.
More definitive therapy for brain metastases, including resection, radiation, and chemotherapy, is offered to patients with good performance status and more favorable prognosis.
Surgical resection can rapidly decrease the intracranial pressure, especially in patients with tumors in the posterior fossa. A neurosurgeon should be consulted for all cases in which an operative intervention may be indicated.
Table 7Management of Intracranial Hypertension and Seizures
Disorder
Intervention
Dosage and comments
Intracranial hypertension
Dexamethasone
4-8 mg/d in divided doses; a higher dose can be used with severe symptoms (10-16 mg IV followed by 4 mg IV every 6 h)
Seizures
Lorazepam
2-4 mg IV (or 0.1 mg/kg up to 4 mg maximum) at 2 mg/min; total dose capped at 4 mg
Phenytoin
20 mg/kg IV at 50 mg/min (25 mg/min in elderly patients and patients with cardiovascular disorders)
Malignant Pericardial Effusion and Cardiac Tamponade
Pericardial effusions are commonly seen in patients with advanced and metastatic malignant diseases, but most patients are asymptomatic and do not require urgent therapy. Pericardial effusions in patients with cancer are not always related to the malignant disease itself and may also be secondary to cancer therapy, especially radiotherapy, or a manifestation of either an infection or an autoimmune process.
Pericardial effusions in patients with cancer can be secondary to metastases to the pericardium, tumor invasion of the pericardium, or treatment related. Large effusions, especially if they accumulate rapidly, can impair ventricular filling and reduce cardiac output.
Patients with slowly accumulating effusions are frequently asymptomatic despite large effusions.
Clinical Presentation and Diagnosis
Small pericardial effusions are often asymptomatic. Typical symptoms of large or rapidly accumulating effusions include dyspnea, cough, and chest pain. A physical examination may reveal tachycardia, hypotension, distant heart sounds, fixed jugular venous distention, peripheral edema, and pulsus paradoxus. In addition, patients with tamponade can have hypotension and shock.
Electrocardiography frequently reveals low-voltage and nonspecific ST-T changes. Electrical alternans (beat-to-beat variations in the QRS complex size and shape) is thought to be caused by the heart moving within the enlarged and fluid-filled pericardium but can be seen in other cardiac conditions (Figure 6).
The diagnosis of pericardial effusions and tamponade is best made by echocardiography, which confirms the presence of the effusion but also provides hemodynamic information (Figure 7).
Cytological examination of the pericardial fluid may reveal malignant cells, but occasionally a pericardial biopsy is needed to establish the diagnosis.
Figure 6Electrocardiogram showing electrical alternans in a patient with malignant pericardial effusion.
Image courtesy of Dr Donald Brown, Division of Cardiology, University of Iowa Hospitals and Clinics.
Small and asymptomatic pericardial effusions do not need to be treated. Patients with symptomatic effusions, especially with rapidly developing symptoms and hemodynamic instability, may need urgent interventions. Therapeutic echocardiographically guided pericardiocentesis is a safe procedure that can immediately relieve symptoms and improve hemodynamics, but a more durable treatment is usually needed.
Superior vena cava syndrome (SVCS) occurs in the setting of an extrinsic compression or other occlusion of the superior vena cava (SVC). It is a common complication of cancer, and thoracic malignant disorders are the most common cause of SVCS.
Superior vena cava syndrome can also be seen as a complication of benign conditions such as SVC thrombosis secondary to indwelling venous lines or pacemaker leads as well as a complication of fibrosing mediastinitis and histoplasma infection.
The thin-walled SVC can easily be compressed by tumors outside of the vessel, resulting in impaired venous drainage from the head, neck, and upper extremities. The compressing tumors are frequently in the middle or anterior mediastinum and the right paratracheal and precarinal nodal regions. The compression results in the formation of venous collaterals, including the azygos vein. Superior vena cava syndrome secondary to a compression below the azygos vein can result in more severe symptoms, highlighting the importance of the azygos vein as a collateral vessel.
Superior vena cava syndrome can be acute, subacute, or more insidious and sometimes occurs with minimal symptoms. Very highly proliferative tumors and SVC thrombosis can result in a rapid onset of symptoms. Common symptoms include dyspnea, orthopnea, cough, sensation of fullness in the head and face, and headache, often exacerbated by stooping. Less common symptoms are chest pain, hemoptysis, hoarseness, dizziness, light-headedness, and even syncope. The most common physical findings are facial and neck swelling, arm swelling, and dilated veins in the chest (Figure 8, A), neck, and proximal part of the arms. Stridor and mental status changes are worrisome signs and indicate laryngeal edema and increased intracranial pressure, respectively. A grading system for SVCS has been proposed that can easily be applied in clinical practice (Table 8).
A plain chest radiograph may suggest SVCS, usually by showing a right hilar mass. Magnetic resonance imaging is particularly helpful in cases in which the administration of IV contrast is contraindicated.
Figure 8Superior vena cava syndrome in a patient with a large malignant mediastinal mass. A, Extensive venous collaterals can be seen on the right side of the chest wall and the right arm. B, Computed tomogram shows dilated superficial veins in the anterior chest wall.
with permission from the International Association for the Study of Lung Cancer.
Grade
Category
Definition
Urgent treatment needed
0
Asymptomatic
Radiographic superior vena cava obstruction in the absence of symptoms
No
1
Mild
Edema of the head or neck (vascular distention), cyanosis, plethora
No
2
Moderate
Facial and neck edema with functional impairment (mild dysphagia, cough, mild or moderate impairment of head, jaw, or eyelid movements, visual disturbances caused by ocular edema)
No
3
Severe
Mild or moderate cerebral edema (headache, dizziness) or mild/moderate laryngeal edema or diminished cardiac reserve (syncope after bending)
Yes
4
Life-threatening
Severe cerebral edema (confusion, obtundation), laryngeal edema (stridor), or hemodynamic compromise (syncope without precipitating factors, hypotension, renal insufficiency)
Patients with symptoms and signs concerning for cerebral and/or airway edema and circulatory instability need urgent initiation of therapy (Table 8). In cases in which the etiology is not yet known, there is usually time to establish a diagnosis before starting therapy. Endovascular stenting of the SVC can promptly relieve symptoms of SVCS and is the treatment of choice in very symptomatic patients (Figure 9).
Radiation therapy is effective for many patients, but the relief of symptoms may be slow. Tissue diagnosis should be established before initiating radiation therapy. Adjunctive supportive therapy may be useful, such as elevation of the head of the bed, supplemental oxygen, and cautious use of diuretics and glucocorticoids in cases of laryngeal edema. Glucocorticoids administered for SVCS secondary to lymphoma relieve symptoms but should typically not be given until the diagnosis has been established with a biopsy because corticosteroids may obscure the pathologic diagnosis. Corticosteroids have little or no role in SVCS secondary to lung cancer.
Anticoagulation should be reserved for patients with evidence of an SVC thrombus or other venous thromboembolic complications and considered for patients who undergo a stent placement. Catheter-directed thrombolysis can be useful in SVCS secondary to a thrombus.
More definitive therapy, such as systemic therapy and radiation therapy, is dictated by the underlying cancer, which also is the primary determinant of the patient's prognosis.
Figure 9Insertion of a stent in the SVC can promptly improve the symptoms of superior vena cava syndrome.
Images courtesy of Dr Haraldur Bjarnason, Department of Radiology, Mayo Clinic.
Malignant thoracic and mediastinal tumors can erode into the major airways or cause extrinsic compression leading to airway obstruction. The most common cause of cancer-related airway obstruction is lung cancer, and up to one-third of patients may experience airway obstruction during the course of the illness.
Other cancers, including anaplastic thyroid cancer, squamous cell cancers of the head and neck, and mediastinal malignant diseases such as lymphoma and germ cell tumor, can also cause airway obstruction. Primary tracheal tumors are a rare cause of airway obstruction.
Clinical Presentation and Diagnosis
The most common symptoms include dyspnea, cough, wheezing, hemoptysis, and stridor, and the manifestations depend on the severity and location of the obstruction.
The symptoms of airway obstruction can resemble symptoms of worsening chronic obstructive pulmonary disease, which is a common comorbidity in patients with lung cancer. The physical examination frequently reveals focal wheezing on auscultation and inspiratory stridor. Computed tomography is the preferred method of evaluation and provides information on the extent of the cancer as well as the airway involvement. The obstruction can be visualized with bronchoscopy, and biopsies can be performed at the same time if needed.
Treatment
The treatment of airway obstruction requires good visualization of the larger airways, which usually necessitates the use of rigid bronchoscopy.
Supplemental oxygen should be given to patients awaiting interventions, and bronchodilator therapy may be indicated in patients with coexisting obstructive small airways disease. Airway stenting, laser therapy, argon plasma coagulation, photodynamic therapy, and brachytherapy have all been used in the management of central airway obstruction and result in substantial relief of symptoms in most patients.
AQuIRE Bronchoscopy Registry Therapeutic bronchoscopy for malignant central airway obstruction: success rates and impact on dyspnea and quality of life.
External beam radiation therapy and systemic chemotherapy play an important role in the subsequent management of malignant airway occlusion.
Acute Airway Hemorrhage
The etiologies of hemoptysis are diverse and vary with anatomic location. Malignant disease is among the most common causes of hemoptysis. Tumors eroding into the airways can cause hemoptysis, which usually is not an emergency. Substantial airway hemorrhage leads to hypoxemia and can be fatal.
Airway hemorrhage is commonly divided into proximal and distal airway bleeding, and the causes and management differ according to the anatomic location.
Lung cancer is the most common cause of massive hemoptysis, but other cancers, especially squamous cell carcinoma of the head and neck, can bleed profusely into the airways.
Clinical Presentation and Diagnosis
Patients usually present with expectoration of bloody mucus or frank blood. Other symptoms and signs include dyspnea, respiratory distress, hypoxia, and hemodynamic instability. It is important to promptly identify the source of bleeding in patients with hemoptysis who are considered for more aggressive therapy. Computed tomography, especially CT angiography, can provide important information regarding the location of the bleeding and may help select an appropriate treatment strategy.
Bronchial artery angiography frequently reveals the bleeding location, and therapeutic embolization can be performed at the same time.
Treatment
As with acute airway obstruction, securing the airway is of utmost importance. The patient should be positioned in the lateral decubitus position with the bleeding side down, if known, to preserve alveolar exchange in the unaffected lung. If the patient is intubated, the bronchial main stem of the affected side can also be selectively intubated to avoid bleeding into the unaffected side. Administration of IV fluids and blood products may be needed for stabilization, especially in patients with hemodynamic instability or thrombocytopenia. Coagulation abnormalities should be corrected as indicated with blood products and reversal of anticoagulants if needed. Recombinant factor VII has been used to treat massive hemoptysis in patients with cancer and can be considered when other measures fail.
Bronchial artery angiography can identify the bleeding vessel(s), and embolization can be performed during the procedure, often with successful control of the bleeding.
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