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Emergencies in Hematology and Oncology

      Abstract

      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.

      Abbreviations and Acronyms:

      AML (acute myeloid leukemia), ANC (absolute neutrophil count), CNS (central nervous system), CRS (cytokine release syndrome), CT (computed tomography), IV (intravenous), MRI (magnetic resonance imaging), MSCC (malignant spinal cord compression), PTH (parathyroid hormone), PTHrP (PTH-related peptide), RANKL (receptor activator of nuclear factor κB ligand), SVC (superior vena cava), SVCS (SVC syndrome), TLS (tumor lysis syndrome), WM (Waldenström macroglobulinemia)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able to (1) recognize both common and uncommon hematologic and oncological emergencies in patients with cancer, (2) identify which patients need emergent or urgent initiation of therapy and admission to the hospital for an optimal outcome, and (3) promptly initiate the appropriate therapy for life-threatening complications of both the cancer itself and the therapy directed against the cancer.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine and Science (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation.
      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      The authors report no competing interests.
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      Date of Release: 4/1/2017
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      Questions? Contact [email protected] .
      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.
      • Savage P.
      • Sharkey R.
      • Kua T.
      • et al.
      Clinical characteristics and outcomes for patients with an initial emergency presentation of malignancy: a 15 month audit of patient level data.
      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.
      • Stewart A.F.
      Hypercalcemia associated 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.
      • Vassilopoulou-Sellin R.
      • Newman B.M.
      • Taylor S.H.
      • Guinee V.F.
      Incidence of hypercalcemia in patients with malignancy referred to a comprehensive cancer center.
      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.
      • Fahn H.J.
      • Lee Y.H.
      • Chen M.T.
      • Huang J.K.
      • Chen K.K.
      • Chang L.S.
      The incidence and prognostic significance of humoral hypercalcemia in renal cell carcinoma.
      • Ralston S.H.
      • Gallacher S.J.
      • Patel U.
      • Campbell J.
      • Boyle I.T.
      Cancer-associated hypercalcemia: morbidity and mortality; clinical experience in 126 treated patients.
      • Ling P.J.
      • A'Hern R.P.
      • Hardy J.R.
      Analysis of survival following treatment of tumour-induced hypercalcaemia with intravenous pamidronate (APD).
      • Mallik S.
      • Mallik G.
      • Macabulos S.T.
      • Dorigo A.
      Malignancy associated hypercalcaemia-responsiveness to IV bisphosphonates and prognosis in a palliative population.

      Pathophysiology

      The pathophysiology of hypercalcemia of malignancy can be divided into 3 major categories.
      • Rosner M.H.
      • Dalkin A.C.
      Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia.
      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.
      • Stewart A.F.
      Hypercalcemia associated with cancer.
      • Ratcliffe W.A.
      • Hutchesson A.C.
      • Bundred N.J.
      • Ratcliffe J.G.
      Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia.
      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.
      • Rosner M.H.
      • Dalkin A.C.
      Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia.
      • Mundy G.R.
      • Edwards J.R.
      PTH-related peptide (PTHrP) in hypercalcemia.
      • Santarpia L.
      • Koch C.A.
      • Sarlis N.J.
      Hypercalcemia in cancer patients: pathobiology and management.
      The presence of elevated PTHrP in humoral hypercalcemia of malignancy portends poorer prognosis and decreased response to therapy with bisphosphonates.
      • Wimalawansa S.J.
      Significance of plasma PTH-rp in patients with hypercalcemia of malignancy treated with bisphosphonate.
      • Pecherstorfer M.
      • Schilling T.
      • Blind E.
      • et al.
      Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients.
      • Donovan P.J.
      • Achong N.
      • Griffin K.
      • Galligan J.
      • Pretorius C.J.
      • McLeod D.S.
      PTHrP-mediated hypercalcemia: causes and survival in 138 patients.
      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.
      • Garrett I.R.
      • Durie B.G.
      • Nedwin G.E.
      • et al.
      Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells.
      • Choi S.J.
      • Cruz J.C.
      • Craig F.
      • et al.
      Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma.
      Local production of PTHrP may also result in osteolysis, which is in part mediated through the RANKL pathway.
      • Clines G.A.
      • Guise T.A.
      Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone.
      • Guise T.A.
      • Yin J.J.
      • Taylor S.D.
      • et al.
      Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis.
      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.
      • Seymour J.F.
      • Gagel R.F.
      Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas.
      • Kallas M.
      • Green F.
      • Hewison M.
      • White C.
      • Kline G.
      Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review.
      Very rarely, ectopic production of PTH by tumors causes hypercalcemia.
      • Nakajima K.
      • Tamai M.
      • Okaniwa S.
      • et al.
      Humoral hypercalcemia associated with gastric carcinoma secreting parathyroid hormone: a case report and review of the literature.
      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.
      • Bushinsky D.A.
      • Monk R.D.
      Electrolyte quintet: calcium.
      • Sternlicht H.
      • Glezerman I.G.
      Hypercalcemia of malignancy and new treatment options.
      Severe hypercalcemia, especially of rapid onset, may cause cardiac dysrhythmias such as bradycardia, shortening of the QT interval, and even cardiac arrest.
      • Wagner J.
      • Arora S.
      Oncologic metabolic emergencies.
      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.
      • Wimalawansa S.J.
      Significance of plasma PTH-rp in patients with hypercalcemia of malignancy treated with bisphosphonate.
      • Pecherstorfer M.
      • Schilling T.
      • Blind E.
      • et al.
      Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients.
      • Donovan P.J.
      • Achong N.
      • Griffin K.
      • Galligan J.
      • Pretorius C.J.
      • McLeod D.S.
      PTHrP-mediated hypercalcemia: causes and survival in 138 patients.
      One study reported less response to bisphosphonates and higher risk of recurrent hypercalcemia in patients with PTHrP levels greater than 12 pmol/L.
      • Gurney H.
      • Grill V.
      • Martin T.J.
      Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcaemia.
      A low serum chloride level (<100 mEq/L [to convert to mmol/L, multiply by 1.0]) can point to cancer as the underlying cause.
      • Mundy G.R.
      • Guise T.A.
      Hypercalcemia of malignancy.
      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.
      • Ling P.J.
      • A'Hern R.P.
      • Hardy J.R.
      Analysis of survival following treatment of tumour-induced hypercalcaemia with intravenous pamidronate (APD).
      • Penel N.
      • Berthon C.
      • Everard F.
      • et al.
      Prognosis of hypercalcemia in aerodigestive tract cancers: study of 136 recent cases.
      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
      InterventionDosageComments
      Saline250-500 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 hypovolemicThe rate of infusion should be adjusted for the cardiovascular status of the patient
      Pamidronate60-90 mg IV over 2-4 hUse with caution in renal insufficiency. Onset of action may take days
      Zoledronic acid4 mg IV over 15 minUse with caution in renal insufficiency. Onset of action may take days
      Calcitonin4-8 IU/kg SC or IV every 12 hRapid onset of action but short-lived
      GlucocorticoidsPrednisone, 60 mg/d PO; hydrocortisone, 100 mg every 6 h IVUseful for hypercalcemia from calcitriol overproduction and in multiple myeloma
      Denosumab120 mg SC weekly for 4 wk, then every 4 wkSafe in renal insufficiency but doses should be reduced. Can cause severe hypocalcemia
      Furosemide20-40 mg IVOnly for patients with volume overload after volume expansion
      IV = intravenously; PO = orally; SC = subcutaneously.
      Calcitonin can lower calcium levels by inhibiting osteoclasts and can enhance urinary excretion of calcium.
      • Deftos L.J.
      • First B.P.
      Calcitonin as a drug.
      The onset of action of calcitonin is quick, but tachyphylaxis develops within days of use.
      • Wisneski L.A.
      Salmon calcitonin in the acute management of hypercalcemia.
      • Binstock M.L.
      • Mundy G.R.
      Effect of calcitonin and glutocorticoids in combination on the hypercalcemia of malignancy.
      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.
      • Davidson T.G.
      Conventional treatment of hypercalcemia of malignancy.
      The use of loop diuretics is strongly discouraged because they may exacerbate the hypovolemia and therefore impair calcium excretion.
      • LeGrand S.B.
      • Leskuski D.
      • Zama I.
      Narrative review: furosemide for hypercalcemia; an unproven yet common practice.
      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.
      • Major P.
      • Lortholary A.
      • Hon J.
      • et al.
      Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.
      • Nussbaum S.R.
      • Younger J.
      • Vandepol C.J.
      • et al.
      Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages.
      • Gucalp R.
      • Ritch P.
      • Wiernik P.H.
      • et al.
      Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia.
      • Gucalp R.
      • Theriault R.
      • Gill I.
      • et al.
      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.
      • Major P.
      • Lortholary A.
      • Hon J.
      • et al.
      Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.
      Ibandronate is also effective but infrequently used in the United States.
      • Pecherstorfer M.
      • Herrmann Z.
      • Body J.J.
      • et al.
      Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy.
      • Pecherstorfer M.
      • Steinhauer E.U.
      • Rizzoli R.
      • Wetterwald M.
      • Bergström B.
      Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate.
      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.
      • Binstock M.L.
      • Mundy G.R.
      Effect of calcitonin and glutocorticoids in combination on the hypercalcemia of malignancy.
      • Ralston S.H.
      • Gardner M.D.
      • Dryburgh F.J.
      • Jenkins A.S.
      • Cowan R.A.
      • Boyle I.T.
      Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia.
      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.
      • Cvitkovic F.
      • Armand J.P.
      • Tubiana-Hulin M.
      • Rossi J.F.
      • Warrell Jr., R.P.
      Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia.
      • Leyland-Jones B.
      Treatment of cancer-related hypercalcemia: the role of gallium nitrate.
      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.
      • Thosani S.
      • Hu M.I.
      Denosumab: a new agent in the management of hypercalcemia of malignancy.
      • Dietzek A.
      • Connelly K.
      • Cotugno M.
      • Bartel S.
      • McDonnell A.M.
      Denosumab in hypercalcemia of malignancy: a case series.
      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.
      • Hu M.I.
      • Glezerman I.G.
      • Leboulleux S.
      • et al.
      Denosumab for treatment of hypercalcemia of malignancy.
      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.
      • Dietzek A.
      • Connelly K.
      • Cotugno M.
      • Bartel S.
      • McDonnell A.M.
      Denosumab in hypercalcemia of malignancy: a case series.
      • Hu M.I.
      • Glezerman I.G.
      • Leboulleux S.
      • et al.
      Denosumab for treatment of hypercalcemia of malignancy.
      Denosumab can safely be given to patients with renal insufficiency, but the risk of hypocalcemia may be increased.
      • Cicci J.D.
      • Buie L.
      • Bates J.
      • van Deventer H.
      Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction.
      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.
      • Cicci J.D.
      • Buie L.
      • Bates J.
      • van Deventer H.
      Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction.
      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.
      • Silverberg S.J.
      • Rubin M.R.
      • Faiman C.
      • et al.
      Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma.
      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.
      • Camus C.
      • Charasse C.
      • Jouannic-Montier I.
      • et al.
      Calcium free hemodialysis: experience in the treatment of 33 patients with severe hypercalcemia.
      • Koo W.S.
      • Jeon D.S.
      • Ahn S.J.
      • Kim Y.S.
      • Yoon Y.S.
      • Bang B.K.
      Calcium-free hemodialysis for the management of hypercalcemia.
      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.
      • Howard S.C.
      • Jones D.P.
      • Pui C.H.
      The tumor lysis syndrome.
      It is most commonly seen in patients with very aggressive hematologic cancers such as high-grade lymphomas and acute leukemias.
      • Will A.
      • Tholouli E.
      The clinical management of tumour lysis syndrome in haematological malignancies.
      • Jones G.L.
      • Will A.
      • Jackson G.H.
      • Webb N.J.
      • Rule S.
      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.
      Tumor lysis syndrome is occasionally seen in patients with aggressive solid tumors such as small cell carcinoma of the lung.
      • Gemici C.
      Tumour lysis syndrome in solid tumours.
      It usually occurs after effective therapy has begun but can also occur spontaneously.
      • Cairo M.S.
      • Coiffier B.
      • Reiter A.
      • Younes A.
      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.
      • Howard S.C.
      • Trifilio S.
      • Gregory T.K.
      • Baxter N.
      • McBride A.
      Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review.

      Pathophysiology

      Tumor lysis syndrome is caused by massive release of intracellular contents into the bloodstream at the time of the death of neoplastic cells.
      • Will A.
      • Tholouli E.
      The clinical management of tumour lysis syndrome in haematological malignancies.
      • Wilson F.P.
      • Berns J.S.
      Tumor lysis syndrome: new challenges and recent advances.
      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.
      • Shimada M.
      • Johnson R.J.
      • May Jr., W.S.
      • et al.
      A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome.
      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.
      • Locatelli F.
      • Rossi F.
      Incidence and pathogenesis of tumor lysis syndrome.

      Clinical Presentation and Diagnosis

      Patients with TLS can present with symptoms (clinically evident TLS) or with abnormal laboratory test results in the absence of symptoms (laboratory TLS).
      • Hande K.R.
      • Garrow G.C.
      Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma.
      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
      • Cairo M.S.
      • Bishop M.
      Tumour lysis syndrome: new therapeutic strategies and classification.
      (Table 2).
      Table 2Cairo-Bishop Classification of Laboratory and Clinical Tumor Lysis Syndrome
      Adapted from Br J Haematol,
      • Cairo M.S.
      • Bishop M.
      Tumour lysis syndrome: new therapeutic strategies and classification.
      with permission. Copyright ©1999-2017 John Wiley & Sons, Inc. All rights reserved.
      Laboratory tumor lysis syndrome
       Uric acid ≥8 mg/dL (≥476 μmol/L) or 25% increase from baseline
       Potassium ≥6.0 mEq/L (≥6.0 mmol/L) or 25% increase from baseline
       Phosphorus ≥4.5 mg/dL (≥1.45 mmol/L) or 25% increase from baseline
       Calcium ≤7 mg/dL (≤1.75 mmol/L) or 25% decrease from baseline
      Clinical tumor lysis syndrome
       Presence of laboratory tumor lysis syndrome and one or more of the following criteria
      Creatinine ≥1.5 times the upper limit of normal
      Cardiac arrhythmia
      Seizure
      Sudden death

      Risk Stratification

      The risk factors for development of TLS are well known.
      • Jones G.L.
      • Will A.
      • Jackson G.H.
      • Webb N.J.
      • Rule S.
      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).
      • Cairo M.S.
      • Coiffier B.
      • Reiter A.
      • Younes A.
      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.
      Table 3Risk Stratification of Tumor Lysis Syndrome and Recommendations for Prophylaxis
      ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; IRD = intermediate-risk disease; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma; ULN = upper limit of normal; WBC = white blood cell count.
      ,
      SI conversion factors: To convert WBC to ×109/L, multiply by 0.001.
      Adapted from Br J Haematol,
      • Cairo M.S.
      • Coiffier B.
      • Reiter A.
      • Younes A.
      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.
      with permission. Copyright ©1999-2017 John Wiley & Sons, Inc. All rights reserved.
      Risk categoryMalignant diseaseProphylaxis
      Low-risk diseaseSolid tumor
      Rare solid tumors such as small cell carcinoma, germ cell tumors, or others with bulky or advanced disease can be classified as IRD.


      Multiple myeloma

      CML

      CLL
      CLL treated with fludarabine and rituximab and/or those with a high WBC (≥50 × 109/L) can be classified as IRD.


      Indolent NHL

      Hodgkin lymphoma

      AML (WBC <25,000/μL and LDH <2 × ULN)
      Monitoring (daily laboratory tests)

      Intravenous hydration (3 L/m2 daily)

      Consider allopurinol
      Intermediate-risk diseaseAML (WBC 25,000-100,000/μL)

      AML (WBC <25,000/μL and LDH ≥2 × ULN)

      Intermediate-grade NHL (LDH ≥2 × ULN)

      ALL (WBC <100,000/μL and LDH <2 × ULN)

      Burkitt lymphoma (LDH <2 × ULN)

      Lymphoblastic NHL (LDH <2 × ULN)
      Monitoring (laboratory tests every 8-12 h)

      Intravenous hydration (3 L/m2 daily)

      Allopurinol for up to 7 d
      High-risk diseaseALL (WBC ≥100,000/μL and/or LDH ≥2 × ULN)

      Burkitt lymphoma (stages III/IV and/or LDH ≥2 × ULN)

      Lymphoblastic NHL (stages III/IV and/or LDH ≥2 × ULN)

      IRD with renal dysfunction and/or renal involvement

      IRD with elevated uric acid, potassium, and/or phosphate
      Monitoring (laboratory tests every 6-8 h)

      Intravenous hydration (3 L/m2 daily)

      Rasburicase (consider 3 mg fixed dose)
      a ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; IRD = intermediate-risk disease; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma; ULN = upper limit of normal; WBC = white blood cell count.
      b SI conversion factors: To convert WBC to ×109/L, multiply by 0.001.
      c Rare solid tumors such as small cell carcinoma, germ cell tumors, or others with bulky or advanced disease can be classified as IRD.
      d CLL treated with fludarabine and rituximab and/or those with a high WBC (≥50 × 109/L) can be classified as IRD.

      Prevention and Treatment

      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.
      • Jones G.L.
      • Will A.
      • Jackson G.H.
      • Webb N.J.
      • Rule S.
      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.
      • Annemans L.
      • Moeremans K.
      • Lamotte M.
      • et al.
      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.
      • Canet E.
      • Zafrani L.
      • Lambert J.
      • et al.
      Acute kidney injury in patients with newly diagnosed high-grade hematological malignancies: impact on remission and survival.
      • Coiffier B.
      • Altman A.
      • Pui C.H.
      • Younes A.
      • Cairo M.S.
      Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review.
      • Montesinos P.
      • Lorenzo I.
      • Martín G.
      • et al.
      Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model.
      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.
      • Jones G.L.
      • Will A.
      • Jackson G.H.
      • Webb N.J.
      • Rule S.
      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.
      • Mayer M.D.
      • Khosravan R.
      • Vernillet L.
      • Wu J.T.
      • Joseph-Ridge N.
      • Mulford D.J.
      Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with 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.
      • Spina M.
      • Nagy Z.
      • Ribera J.M.
      • et al.
      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.
      • Oldfield V.
      • Perry C.M.
      Rasburicase: a review of its use in the management of anticancer therapy-induced hyperuricaemia.
      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.
      • Coiffier B.
      • Mounier N.
      • Bologna S.
      • et al.
      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.
      • Jeha S.
      • Kantarjian H.
      • Irwin D.
      • et al.
      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.
      • Goldman S.C.
      • Holcenberg J.S.
      • Finklestein J.Z.
      • et al.
      A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis.
      • Cortes J.
      • Moore J.O.
      • Maziarz R.T.
      • et al.
      Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone—results of a multicenter phase III study.
      • Galardy P.J.
      • Hochberg J.
      • Perkins S.L.
      • Harrison L.
      • Goldman S.
      • Cairo M.S.
      Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children's Oncology Group Report.
      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.
      • Lopez-Olivo M.A.
      • Pratt G.
      • Palla S.L.
      • Salahudeen A.
      Rasburicase in tumor lysis syndrome of the adult: a systematic review and meta-analysis.
      • Dinnel J.
      • Moore B.L.
      • Skiver B.M.
      • Bose P.
      Rasburicase in the management of tumor lysis: an evidence-based review of its place in therapy.
      • Cheuk D.K.
      • Chiang A.K.
      • Chan G.C.
      • Ha S.Y.
      Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer.
      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.
      • Trifilio S.
      • Gordon L.
      • Singhal S.
      • et al.
      Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer patients with hyperuricemia.
      • Trifilio S.M.
      • Pi J.
      • Zook J.
      • et al.
      Effectiveness of a single 3-mg rasburicase dose for the management of hyperuricemia in patients with hematological malignancies.
      • Coutsouvelis J.
      • Wiseman M.
      • Hui L.
      • et al.
      Effectiveness of a single fixed dose of rasburicase 3 mg in the management of tumour lysis syndrome.
      • Feng X.
      • Dong K.
      • Pham D.
      • Pence S.
      • Inciardi J.
      • Bhutada N.S.
      Efficacy and cost of single-dose rasburicase in prevention and treatment of adult tumour lysis syndrome: a meta-analysis.
      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.
      • Jones G.L.
      • Will A.
      • Jackson G.H.
      • Webb N.J.
      • Rule S.
      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
      AbnormalityInterventionDoseComments
      Renal insufficiency and hypovolemiaIntravenous fluidsNS 3 L/m2/d (200 mL/kg/d)Use with caution if history of CHF
      DialysisNAUse in anuria and severe oliguria with volume overload
      HyperuricemiaAllopurinol200-400 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
      RasburicaseFlat 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
      Febuxostat120 mg PO dailyExpensive

      Uncertain if more effective than allopurinol

      No need to adjust doses in mild to moderate renal insufficiency
      Hyperphosphatemia (phosphate >6.5 mg/mL [>2.1 mmol/L])Minimize phosphate intakeNALow phosphorus diet

      Phosphorus-free IV fluids
      Phosphate binders (aluminum hydroxide)PO 50-150 mg/kg/dMay interfere with drug absorption
      DialysisNAIf no response to medical therapy
      HyperkalemiaInsulin (regular)

      Dextrose (50%)
      IV 10 U

      IV 50-100 mL


      Calcium gluconate (10%; 10% = 100 mg/mL)IV 10 mL (1000 mg)Do not give with bicarbonate

      Use if arrhythmias or ECG changes

      Can repeat as needed
      Sodium bicarbonateIV 150 mEq in 1 L of D5W over 2-4 hUse if acidosis

      Can repeat in 30 min
      Sodium polystyrene sulfonatePO 15-30 g every 6 h (can be used rectally)Can be given with sorbitol
      AlbuterolInhaled 10-20 mgFor severe hyperkalemia
      DialysisNASevere hyperkalemia not responsive to other measures

      Renal failure

      Volume overload
      HypocalcemiaCalcium gluconate (10%; 10% = 100 mg/mL)IV 10 mL (1000 mg) as an infusion over 10-20 minutesOnly if symptomatic

      Repeat as necessary

      Caution in patients with severe hyperphosphatemia
      CHF = congestive heart failure; D5W = 5% dextrose in water; ECG = electrocardiogram; G6PD = glucose-6-phosphate dehydrogenase; IV = intravenous; NA = not applicable; NaHCO3 = sodium bicarbonate; NS = normal saline; PO = orally; TLS = tumor lysis syndrome.
      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.
      • Will A.
      • Tholouli E.
      The clinical management of tumour lysis syndrome in haematological malignancies.
      • Tosi P.
      • Barosi G.
      • Lazzaro C.
      • et al.
      Consensus conference on the management of tumor lysis syndrome.
      Alkalinization of the urine is not recommended, and diuretics should only be used for volume overload and then with extreme caution.
      • Wilson F.P.
      • Berns J.S.
      Tumor lysis syndrome: new challenges and recent advances.
      Rasburicase is the uricosuric agent of choice in established clinical TLS and should be used in a dose of 0.2 mg/kg daily for up to 7 days.
      • Jones G.L.
      • Will A.
      • Jackson G.H.
      • Webb N.J.
      • Rule S.
      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.
      • Sillos E.M.
      • Shenep J.L.
      • Burghen G.A.
      • Pui C.H.
      • Behm F.G.
      • Sandlund J.T.
      Lactic acidosis: a metabolic complication of hematologic malignancies; case report and review of the literature.
      • Friedenberg A.S.
      • Brandoff D.E.
      • Schiffman F.J.
      Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: a case series from a single institution and literature review.
      • de Groot R.
      • Sprenger R.A.
      • Imholz A.L.
      • Gerding M.N.
      Type B lactic acidosis in solid malignancies.
      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.
      • Sillos E.M.
      • Shenep J.L.
      • Burghen G.A.
      • Pui C.H.
      • Behm F.G.
      • Sandlund J.T.
      Lactic acidosis: a metabolic complication of hematologic malignancies; case report and review of the literature.
      • Friedenberg A.S.
      • Brandoff D.E.
      • Schiffman F.J.
      Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: a case series from a single institution and literature review.
      • Kuba H.
      • Inamura T.
      • Ikezaki K.
      • Kawashima M.
      • Fukui M.
      Thiamine-deficient lactic acidosis with brain tumor treatment: report of three cases.
      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.
      • Sillos E.M.
      • Shenep J.L.
      • Burghen G.A.
      • Pui C.H.
      • Behm F.G.
      • Sandlund J.T.
      Lactic acidosis: a metabolic complication of hematologic malignancies; case report and review of the literature.
      • de Groot R.
      • Sprenger R.A.
      • Imholz A.L.
      • Gerding M.N.
      Type B lactic acidosis in solid malignancies.

      Hyponatremia

      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.
      • Yoon J.
      • Ahn S.H.
      • Lee Y.J.
      • Kim C.M.
      Hyponatremia as an independent prognostic factor in patients with terminal cancer.
      • Berghmans T.
      • Paesmans M.
      • Body J.J.
      A prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis.
      • Doshi S.M.
      • Shah P.
      • Lei X.
      • Lahoti A.
      • Salahudeen A.K.
      Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes.
      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.
      • Spinazzé S.
      • Schrijvers D.
      Metabolic emergencies.
      • Flombaum C.D.
      Metabolic emergencies in the cancer patient.
      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.
      • Adrogué H.J.
      • Madias N.E.
      Hyponatremia.
      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.
      • Sterns R.H.
      • Silver S.M.
      Complications and management of hyponatremia.
      • Verbalis J.G.
      • Goldsmith S.R.
      • Greenberg A.
      • et al.
      Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.
      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).
      • Spinazzé S.
      • Schrijvers D.
      Metabolic emergencies.
      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.
      • Mathur A.
      • Gorden P.
      • Libutti S.K.
      Insulinoma.

      Adrenal Insufficiency

      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.
      • Delitala A.P.
      • Fanciulli G.
      • Maioli M.
      • Piga G.
      • Delitala G.
      Primary symptomatic adrenal insufficiency induced by megestrol acetate.
      Furthermore, megestrol acetate is associated with adrenal insufficiency in acutely ill individuals.
      • Chidakel A.R.
      • Zweig S.B.
      • Schlosser J.R.
      • Homel P.
      • Schappert J.W.
      • Fleckman A.M.
      High prevalence of adrenal suppression during acute illness in hospitalized patients receiving megestrol acetate.
      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.
      • Terzolo M.
      • Ardito A.
      • Zaggia B.
      • et al.
      Management of adjuvant mitotane therapy following resection of adrenal cancer.
      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.
      • Puar T.H.
      • Stikkelbroeck N.M.
      • Smans L.C.
      • Zelissen P.M.
      • Hermus A.R.
      Adrenal crisis: still a deadly event in the 21st century.
      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.
      • Baskurt O.K.
      • Meiselman H.J.
      Blood rheology and hemodynamics.

      Pathophysiology

      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.
      • García-Sanz R.
      • Montoto S.
      • Torrequebrada A.
      • et al.
      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.
      • Stone M.J.
      • Bogen S.A.
      Evidence-based focused review of management of hyperviscosity syndrome.
      IgG and IgA are much less likely to cause hyperviscosity, and hyperviscosity is uncommonly seen in multiple myeloma.
      • Kyle R.A.
      • Gertz M.A.
      • Witzig T.E.
      • et al.
      Review of 1027 patients with newly diagnosed multiple myeloma.
      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).
      • Mehta J.
      • Singhal S.
      Hyperviscosity syndrome in plasma cell dyscrasias.
      • Kwaan H.C.
      Hyperviscosity in plasma cell dyscrasias.
      • Crawford J.
      • Cox E.B.
      • Cohen H.J.
      Evaluation of hyperviscosity in monoclonal gammopathies.
      According to one study, most symptomatic patients had viscosity above 8 cP.
      • MacKenzie M.R.
      • Lee T.K.
      Blood viscosity in Waldenström macroglobulinemia.
      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).
      • Stone M.J.
      • Bogen S.A.
      Evidence-based focused review of management of hyperviscosity syndrome.
      • Kwaan H.C.
      Hyperviscosity in plasma cell dyscrasias.
      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.
      Table 5Clinical Manifestations of Hyperviscosity
      Central nervous system
       Headache
       Dizziness and vertigo
       Seizures
       Concentrating difficulties
       Impaired level of consciousness
       Tinnitus and deafness
      Ophthalmologic
       Blurry vision or loss of vision
       Diplopia
       Retinal vein occlusion
       Papilledema
       Retinal hemorrhage
      Mucocutaneous
       Epistaxis
       Gingival bleeding
       Cutaneous bleeding
       Gastrointestinal bleeding
      Other
       Shortness of breath
       Congestive heart failure
       Priapism
      Figure thumbnail gr1
      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 thumbnail gr2
      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.

      Treatment

      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.
      • Stone M.J.
      • Bogen S.A.
      Evidence-based focused review of management of hyperviscosity syndrome.
      • Zarkovic M.
      • Kwaan H.C.
      Correction of hyperviscosity by apheresis.
      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.
      • Ganzel C.
      • Becker J.
      • Mintz P.D.
      • Lazarus H.M.
      • Rowe J.M.
      Hyperleukocytosis, leukostasis and leukapheresis: practice management.
      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).
      • Röllig C.
      • Ehninger G.
      How I treat hyperleukocytosis in acute myeloid leukemia.
      • Ruggiero A.
      • Rizzo D.
      • Amato M.
      • Riccardi R.
      Management of hyperleukocytosis.
      • Porcu P.
      • Cripe L.D.
      • Ng E.W.
      • et al.
      Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management.
      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.
      • Adams B.D.
      • Baker R.
      • Lopez J.A.
      • Spencer S.
      Myeloproliferative disorders and the hyperviscosity syndrome.

      Pathophysiology

      Rapid proliferation and disrupted cell adhesion result in the release of a large number of leukemic blasts from the bone marrow into the circulation.
      • Röllig C.
      • Ehninger G.
      How I treat hyperleukocytosis in acute myeloid leukemia.
      This process can lead to microvascular occlusion resulting in tissue ischemia and infarction.
      • McKee Jr., L.C.
      • Collins R.D.
      Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia.
      In addition, patients with hyperleukocytosis are at risk for development of TLS and disseminated intravascular coagulation. Two main mechanisms are thought to explain leukostasis.
      • Röllig C.
      • Ehninger G.
      How I treat hyperleukocytosis in acute myeloid leukemia.
      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.
      • Ganzel C.
      • Becker J.
      • Mintz P.D.
      • Lazarus H.M.
      • Rowe J.M.
      Hyperleukocytosis, leukostasis and leukapheresis: practice management.
      • Stucki A.
      • Rivier A.S.
      • Gikic M.
      • Monai N.
      • Schapira M.
      • Spertini O.
      Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination.
      Figure thumbnail gr3
      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.

      Clinical Presentation and Diagnosis

      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.
      • Porcu P.
      • Cripe L.D.
      • Ng E.W.
      • et al.
      Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management.
      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.
      Table 6Clinical Manifestations of Leukostasis
      Central nervous system
       Headache
       Dizziness and vertigo
       Seizures
       Confusion and delirium
       Impaired level of consciousness and coma
       Focal neurologic deficits
       Intracranial hemorrhage
      Ophthalmologic
       Blurry vision or loss of vision
       Visual field defect
       Papilledema
       Retinal hemorrhage
       Retinal vein thrombosis
      Pulmonary
       Dyspnea and tachypnea
       Hypoxia
       Auscultatory crackles
       Respiratory failure
       Pulmonary infiltrates
      Cardiovascular
       Chest pain
       Myocardial ischemia/infarction
      Other
       Fever
       Renal failure
       Priapism
       Extremity ischemia
       Venous thrombosis
       Disseminated intravascular coagulation
       Tumor lysis syndrome

      Treatment

      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.
      • Röllig C.
      • Ehninger G.
      How I treat hyperleukocytosis in acute myeloid leukemia.
      • Marbello L.
      • Ricci F.
      • Nosari A.M.
      • et al.
      Outcome of hyperleukocytic adult acute myeloid leukaemia: a single-center retrospective study and review of literature.
      Red blood cell transfusions should be administered with caution and preferably after control of the symptoms of leukostasis given the concern of increasing viscosity.
      • Harris A.L.
      Leukostasis associated with blood transfusion in acute myeloid leukaemia.
      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.
      • Oberoi S.
      • Lehrnbecher T.
      • Phillips B.
      • et al.
      Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: a systematic review and meta-analysis.
      • Pastore F.
      • Pastore A.
      • Wittmann G.
      • Hiddemann W.
      • Spiekermann K.
      The role of therapeutic leukapheresis in hyperleukocytotic AML.
      • Aqui N.
      • O'Doherty U.
      Leukocytapheresis for the treatment of hyperleukocytosis secondary to acute leukemia.
      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.
      • Ganzel C.
      • Becker J.
      • Mintz P.D.
      • Lazarus H.M.
      • Rowe J.M.
      Hyperleukocytosis, leukostasis and leukapheresis: practice management.
      • Pham H.P.
      • Schwartz J.
      How we approach a patient with symptoms of leukostasis requiring emergent leukocytapheresis.
      • Schwartz J.
      • Winters J.L.
      • Padmanabhan A.
      • et al.
      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.
      • Oberoi S.
      • Lehrnbecher T.
      • Phillips B.
      • et al.
      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%.
      • Bach F.
      • Larsen B.H.
      • Rohde K.
      • et al.
      Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression.
      • Loblaw D.A.
      • Laperriere N.J.
      • Mackillop W.J.
      A population-based study of malignant spinal cord compression in Ontario.
      • Mak K.S.
      • Lee L.K.
      • Mak R.H.
      • et al.
      Incidence and treatment patterns in hospitalizations for malignant spinal cord compression in the United States, 1998-2006.
      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.
      • Loblaw D.A.
      • Laperriere N.J.
      • Mackillop W.J.
      A population-based study of malignant spinal cord compression in Ontario.
      • Mak K.S.
      • Lee L.K.
      • Mak R.H.
      • et al.
      Incidence and treatment patterns in hospitalizations for malignant spinal cord compression in the United States, 1998-2006.
      • Loblaw D.A.
      • Smith K.
      • Lockwood G.
      • Laperriere N.
      The Princess Margaret Hospital experience of malignant spinal cord compression.
      The prognosis of patients with MSCC is poor, especially if the presenting features include paralysis or if there is no response to therapy.
      • Loblaw D.A.
      • Laperriere N.J.
      • Mackillop W.J.
      A population-based study of malignant spinal cord compression in Ontario.
      • Helweg-Larsen S.
      • Sørensen P.S.
      • Kreiner S.
      Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients.
      Slower onset of symptoms and the absence of neurologic deficits at diagnosis predict a better functional outcome after therapy.
      • Kim R.Y.
      • Spencer S.A.
      • Meredith R.F.
      • et al.
      Extradural spinal cord compression: analysis of factors determining functional prognosis—prospective study.
      • Rades D.
      • Heidenreich F.
      • Karstens J.H.
      Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression.

      Pathophysiology

      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.
      • Cole J.S.
      • Patchell R.A.
      Metastatic epidural spinal cord compression.
      Intramedullary and meningeal metastases are rare causes of spinal cord compression.
      • Constans J.P.
      • de Divitiis E.
      • Donzelli R.
      • Spaziante R.
      • Meder J.F.
      • Haye C.
      Spinal metastases with neurological manifestations: review of 600 cases.
      • Wasserstrom W.R.
      • Glass J.P.
      • Posner J.B.
      Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients.
      The thoracic spine is the most common location for metastases, followed by the lumbar spine and cervical spine.
      • Bach F.
      • Larsen B.H.
      • Rohde K.
      • et al.
      Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression.
      • Constans J.P.
      • de Divitiis E.
      • Donzelli R.
      • Spaziante R.
      • Meder J.F.
      • Haye C.
      Spinal metastases with neurological manifestations: review of 600 cases.
      • Gilbert R.W.
      • Kim J.H.
      • Posner J.B.
      Epidural spinal cord compression from metastatic tumor: diagnosis and treatment.
      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.
      • Sutcliffe P.
      • Connock M.
      • Shyangdan D.
      • Court R.
      • Kandala N.B.
      • Clarke A.
      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.
      Most patients have back pain at diagnosis, but in 5% to 15% the pain is either absent or mild.
      • Bach F.
      • Larsen B.H.
      • Rohde K.
      • et al.
      Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression.
      • Gilbert R.W.
      • Kim J.H.
      • Posner J.B.
      Epidural spinal cord compression from metastatic tumor: diagnosis and treatment.
      • Helweg-Larsen S.
      • Sørensen P.S.
      Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients.
      • Levack P.
      • Graham J.
      • Collie D.
      • et al.
      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.
      • Schiff D.
      • O'Neill B.P.
      • Suman V.J.
      Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach.
      The pain can be localized to the spine, radicular, or both and is usually progressive.
      • Gilbert R.W.
      • Kim J.H.
      • Posner J.B.
      Epidural spinal cord compression from metastatic tumor: diagnosis and treatment.
      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.
      • Downie A.
      • Williams C.M.
      • Henschke N.
      • et al.
      Red flags to screen for malignancy and fracture in patients with low back pain: systematic review.
      • Henschke N.
      • Maher C.G.
      • Ostelo R.W.
      • de Vet H.C.
      • Macaskill P.
      • Irwig L.
      Red flags to screen for malignancy in patients with low-back pain.
      Twenty percent of patients do not have a known cancer diagnosis at the time the MSCC is diagnosed.
      • Levack P.
      • Graham J.
      • Collie D.
      • et al.
      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.
      • Schiff D.
      • O'Neill B.P.
      • Suman V.J.
      Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach.
      • Savage P.
      • Sharkey R.
      • Kua T.
      • et al.
      Malignant spinal cord compression: NICE guidance, improvements and challenges.
      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.
      • Bach F.
      • Larsen B.H.
      • Rohde K.
      • et al.
      Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression.
      • Cole J.S.
      • Patchell R.A.
      Metastatic epidural spinal cord compression.
      • Helweg-Larsen S.
      • Sørensen P.S.
      Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients.
      Sensory deficits usually occur after motor deficits, and up to 70% of patients will have sensory deficits at diagnosis.
      • Cole J.S.
      • Patchell R.A.
      Metastatic epidural spinal cord compression.
      Autonomic symptoms such as loss of bladder and bowel function usually occur later in the course of MSCC.
      • Bach F.
      • Larsen B.H.
      • Rohde K.
      • et al.
      Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression.
      • Gilbert R.W.
      • Kim J.H.
      • Posner J.B.
      Epidural spinal cord compression from metastatic tumor: diagnosis and treatment.
      Ataxia is an unusual manifestation of MSCC.
      • Hainline B.
      • Tuszynski M.H.
      • Posner J.B.
      Ataxia in epidural spinal cord compression.
      Other presenting symptoms of MSCC include radicular pain and gait disturbance.
      • Bach F.
      • Larsen B.H.
      • Rohde K.
      • et al.
      Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression.
      • Cole J.S.
      • Patchell R.A.
      Metastatic epidural spinal cord compression.
      • Gilbert R.W.
      • Kim J.H.
      • Posner J.B.
      Epidural spinal cord compression from metastatic tumor: diagnosis and treatment.
      • Helweg-Larsen S.
      • Sørensen P.S.
      Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients.
      The diagnostic method of choice is magnetic resonance imaging (MRI) because it is both sensitive and specific (Figure 4).
      • Li K.C.
      • Poon P.Y.
      Sensitivity and specificity of MRI in detecting malignant spinal cord compression and in distinguishing malignant from benign compression fractures of vertebrae.
      • Loughrey G.J.
      • Collins C.D.
      • Todd S.M.
      • Brown N.M.
      • Johnson R.J.
      Magnetic resonance imaging in the management of suspected spinal canal disease in patients with known malignancy.
      • Loblaw D.A.
      • Perry J.
      • Chambers A.
      • Laperriere N.J.
      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.

      • Husband D.J.
      • Grant K.A.
      • Romaniuk C.S.
      MRI in the diagnosis and treatment of suspected malignant spinal cord compression.
      It is important to image the entire spine because up to 40% of patients may have multiple levels of compression or cord impingement.
      • Cook A.M.
      • Lau T.N.
      • Tomlinson M.J.
      • Vaidya M.
      • Wakeley C.J.
      • Goddard P.
      Magnetic resonance imaging of the whole spine in suspected malignant spinal cord compression: impact on management.
      • Helweg-Larsen S.
      • Hansen S.W.
      • Sørensen P.S.
      Second occurrence of symptomatic metastatic spinal cord compression and findings of multiple spinal epidural metastases.
      • Schiff D.
      • O'Neill B.P.
      • Wang C.H.
      • O'Fallon J.R.
      Neuroimaging and treatment implications of patients with multiple epidural spinal metastases.
      • van der Sande J.J.
      • Kröger R.
      • Boogerd W.
      Multiple spinal epidural metastases: an unexpectedly frequent finding.
      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.
      • Metser U.
      • Lerman H.
      • Blank A.
      • Lievshitz G.
      • Bokstein F.
      • Even-Sapir E.
      Malignant involvement of the spine: assessment by 18F-FDG PET/CT.
      Figure thumbnail gr4
      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.

      Treatment

      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.
      • Helweg-Larsen S.
      • Sørensen P.S.
      • Kreiner S.
      Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients.
      • Kim R.Y.
      • Spencer S.A.
      • Meredith R.F.
      • et al.
      Extradural spinal cord compression: analysis of factors determining functional prognosis—prospective study.
      • Maranzano E.
      • Latini P.
      Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial.
      • Rades D.
      • Fehlauer F.
      • Schulte R.
      • et al.
      Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression.
      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.
      • Sørensen S.
      • Helweg-Larsen S.
      • Mouridsen H.
      • Hansen H.H.
      Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial.
      • Vecht C.J.
      • Haaxma-Reiche H.
      • van Putten W.L.
      • de Visser M.
      • Vries E.P.
      • Twijnstra A.
      Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression.
      • Graham P.H.
      • Capp A.
      • Delaney G.
      • et al.
      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.
      • Heimdal K.
      • Hirschberg H.
      • Slettebø H.
      • Watne K.
      • Nome O.
      High incidence of serious side effects of high-dose dexamethasone treatment in patients with epidural spinal cord compression.
      • George R.
      • Jeba J.
      • Ramkumar G.
      • Chacko A.G.
      • Tharyan P.
      Interventions for the treatment of metastatic extradural spinal cord compression in adults.
      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.
      • Patchell R.A.
      • Tibbs P.A.
      • Regine W.F.
      • et al.
      Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.
      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.
      • Chi J.H.
      • Gokaslan Z.
      • McCormick P.
      • Tibbs P.A.
      • Kryscio R.J.
      • Patchell R.A.
      Selecting treatment for patients with malignant epidural spinal cord compression—does age matter? results from a randomized clinical trial.
      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.
      • Rades D.
      • Huttenlocher S.
      • Dunst J.
      • et al.
      Matched pair analysis comparing surgery followed by radiotherapy and radiotherapy alone for metastatic spinal cord compression.
      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.
      • Rades D.
      • Rudat V.
      • Veninga T.
      • et al.
      A score predicting posttreatment ambulatory status in patients irradiated for metastatic spinal cord compression.
      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.
      • George R.
      • Jeba J.
      • Ramkumar G.
      • Chacko A.G.
      • Tharyan P.
      Interventions for the treatment of metastatic extradural spinal cord compression in adults.
      • Rades D.
      • Stalpers L.J.
      • Veninga T.
      • et al.
      Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression.
      • Prewett S.
      • Venkitaraman R.
      Metastatic spinal cord compression: review of the evidence for a radiotherapy dose fractionation schedule.
      Shorter courses of radiation therapy may be as effective as longer courses, especially for patients with poor prognosis.
      • Rades D.
      • Lange M.
      • Veninga T.
      • et al.
      Final results of a prospective study comparing the local control of short-course and long-course radiotherapy for metastatic spinal cord compression.
      • Maranzano E.
      • Trippa F.
      • Casale M.
      • et al.
      8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial.
      • Maranzano E.
      • Bellavita R.
      • Rossi R.
      • et al.
      Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial.
      Stereotactic radiosurgical procedures may be considered in selected cases, especially after resection.
      • Laufer I.
      • Iorgulescu J.B.
      • Chapman T.
      • et al.
      Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients.
      • Ryu S.
      • Rock J.
      • Jain R.
      • et al.
      Radiosurgical decompression of metastatic epidural compression.
      • Ryu S.
      • Yoon H.
      • Stessin A.
      • Gutman F.
      • Rosiello A.
      • Davis R.
      Contemporary treatment with radiosurgery for spine metastasis and spinal cord compression in 2015.

      Brain Metastases

      Brain metastases are a common complication in cancer, occurring in up to 20% of patients.
      • Lin X.
      • DeAngelis L.M.
      Treatment of brain metastases.
      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.
      • Gavrilovic I.T.
      • Posner J.B.
      Brain metastases: epidemiology and pathophysiology.
      • Fox B.D.
      • Cheung V.J.
      • Patel A.J.
      • Suki D.
      • Rao G.
      Epidemiology of metastatic brain tumors.
      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.
      • Nussbaum E.S.
      • Djalilian H.R.
      • Cho K.H.
      • Hall W.A.
      Brain metastases: histology, multiplicity, surgery, and survival.
      • Barnholtz-Sloan J.S.
      • Sloan A.E.
      • Davis F.G.
      • Vigneau F.D.
      • Lai P.
      • Sawaya R.E.
      Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.
      About 50% of brain metastases are solitary.
      • Nussbaum E.S.
      • Djalilian H.R.
      • Cho K.H.
      • Hall W.A.
      Brain metastases: histology, multiplicity, surgery, and survival.

      Pathophysiology

      Brain metastases arise secondary to hematogenous dissemination of tumor cells to the brain. The biology of brain metastases is complex.
      • Eichler A.F.
      • Chung E.
      • Kodack D.P.
      • Loeffler J.S.
      • Fukumura D.
      • Jain R.K.
      The biology of brain metastases—translation to new therapies.
      The distribution within the brain reflects the distribution of blood flow, with 80% of brain metastases occurring in the cerebral hemispheres,
      • Gavrilovic I.T.
      • Posner J.B.
      Brain metastases: epidemiology and pathophysiology.
      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.
      • Tosoni A.
      • Ermani M.
      • Brandes A.A.
      The pathogenesis and treatment of brain metastases: a comprehensive review.
      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.
      • Kaal E.C.
      • Vecht C.J.
      The management of brain edema in brain tumors.

      Clinical Presentation and Diagnosis

      Most patients presenting with brain metastases have a known diagnosis of cancer, and the highest incidence is in patients with advanced malignant disease.
      • Tabouret E.
      • Chinot O.
      • Metellus P.
      • Tallet A.
      • Viens P.
      • Gonçalves A.
      Recent trends in epidemiology of brain metastases: an overview.
      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.
      • Tosoni A.
      • Ermani M.
      • Brandes A.A.
      The pathogenesis and treatment of brain metastases: a comprehensive review.
      • Forsyth P.A.
      • Posner J.B.
      Headaches in patients with brain tumors: a study of 111 patients.
      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.
      • Tosoni A.
      • Ermani M.
      • Brandes A.A.
      The pathogenesis and treatment of brain metastases: a comprehensive review.
      A hemorrhage into a brain metastasis can result in sudden and severe symptoms.
      Contrast-enhanced MRI is the most sensitive imaging modality for brain metastases (Figure 5).
      • Schaefer P.W.
      • Budzik Jr., R.F.
      • Gonzalez R.G.
      Imaging of cerebral metastases.
      • Sze G.
      • Milano E.
      • Johnson C.
      • Heier L.
      Detection of brain metastases: comparison of contrast-enhanced MR with unenhanced MR and enhanced CT.
      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 thumbnail gr5
      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.

      Treatment

      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.
      • Sperduto P.W.
      • Kased N.
      • Roberge D.
      • et al.
      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.
      • Kaal E.C.
      • Vecht C.J.
      The management of brain edema in brain tumors.
      A commonly used glucocorticoid is dexamethasone, but others are likely as effective as long as they are given in equipotent doses.
      • Soffietti R.
      • Cornu P.
      • Delattre J.Y.
      • et al.
      EFNS guidelines on diagnosis and treatment of brain metastases: report of an EFNS task force.
      Dexamethasone is generally preferred because it has a long half-life and less mineralocorticoid activity.
      • Soffietti R.
      • Cornu P.
      • Delattre J.Y.
      • et al.
      EFNS guidelines on diagnosis and treatment of brain metastases: report of an EFNS task force.
      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.
      • Vecht C.J.
      • Hovestadt A.
      • Verbiest H.B.
      • van Vliet J.J.
      • van Putten W.L.
      Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per day.
      Therefore, a reasonable starting dose is 4 to 8 mg/d unless the patient has severe symptoms, in which case 16 mg/d can be considered.
      • Ryken T.C.
      • McDermott M.
      • Robinson P.D.
      • et al.
      The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline.
      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.
      • Cohen N.
      • Strauss G.
      • Lew R.
      • Silver D.
      • Recht L.
      Should prophylactic anticonvulsants be administered to patients with newly-diagnosed cerebral metastases? a retrospective analysis.
      Prophylactic anticonvulsant therapy is not recommended for patients who have not had seizures.
      • Mikkelsen T.
      • Paleologos N.A.
      • Robinson P.D.
      • et al.
      The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline.
      • Glantz M.J.
      • Cole B.F.
      • Forsyth P.A.
      • et al.
      Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: report of the Quality Standards Subcommittee of the American Academy of Neurology.
      • Tremont-Lukats I.W.
      • Ratilal B.O.
      • Armstrong T.
      • Gilbert M.R.
      Antiepileptic drugs for preventing seizures in people with brain tumors.
      • Sirven J.I.
      • Wingerchuk D.M.
      • Drazkowski J.F.
      • Lyons M.K.
      • Zimmerman R.S.
      Seizure prophylaxis in patients with brain tumors: a meta-analysis.
      The treatment of refractory seizures in patients with cancer is no different than that in patients without cancer.
      • Betjemann J.P.
      • Lowenstein D.H.
      Status epilepticus in adults.
      More definitive therapy for brain metastases, including resection, radiation, and chemotherapy, is offered to patients with good performance status and more favorable prognosis.
      • Lin X.
      • DeAngelis L.M.
      Treatment of brain metastases.
      • Jenkinson M.D.
      • Haylock B.
      • Shenoy A.
      • Husband D.
      • Javadpour M.
      Management of cerebral metastasis: evidence-based approach for surgery, stereotactic radiosurgery and radiotherapy.
      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
      DisorderInterventionDosage and comments
      Intracranial hypertensionDexamethasone4-8 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)
      SeizuresLorazepam2-4 mg IV (or 0.1 mg/kg up to 4 mg maximum) at 2 mg/min; total dose capped at 4 mg
      Phenytoin20 mg/kg IV at 50 mg/min (25 mg/min in elderly patients and patients with cardiovascular disorders)
      Fosphenytoin20 mg/kg PE at 150 mg/min
      IV = intravenous; PE = phenytoin equivalent.

      Cardiovascular Emergencies

      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.
      • Maisch B.
      • Ristic A.
      • Pankuweit S.
      Evaluation and management of pericardial effusion in patients with neoplastic disease.
      • Lestuzzi C.
      • Berretta M.
      • Tomkowski W.
      2015 Update on the diagnosis and management of neoplastic pericardial disease.

      Pathophysiology

      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.
      • Spodick D.H.
      Acute cardiac tamponade.
      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.
      • Spodick D.H.
      Acute cardiac tamponade.
      • Roy C.L.
      • Minor M.A.
      • Brookhart M.A.
      • Choudhry N.K.
      Does this patient with a pericardial effusion have cardiac tamponade?.
      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).
      • Goyal M.
      • Woods K.M.
      • Atwood J.E.
      Electrical alternans: a sign, not a diagnosis.
      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).
      • Wann S.
      • Passen E.
      Echocardiography in pericardial disease.
      Computed tomography and MRI can also provide valuable information, especially regarding tumor invasion and metastases to the pericardium.
      • Lopez Costa I.
      • Bhalla S.
      Computed tomography and magnetic resonance imaging of the pericardium.
      Cytological examination of the pericardial fluid may reveal malignant cells, but occasionally a pericardial biopsy is needed to establish the diagnosis.
      Figure thumbnail gr6
      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.
      Figure thumbnail gr7
      Figure 7Transthoracic echocardiographic subcostal 4-chamber view showing a large circumferential pericardial effusion.
      Image courtesy of Dr S. Allen Luis, Division of Cardiovascular Diseases, Mayo Clinic.

      Treatment

      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.
      • Tsang T.S.
      • Enriquez-Sarano M.
      • Freeman W.K.
      • et al.
      Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes spanning 21 years.
      A pericardial drain can be placed for drainage, and in selected cases, surgical procedures or instillation of a sclerosing agent may be used.
      • Virk S.A.
      • Chandrakumar D.
      • Villanueva C.
      • Wolfenden H.
      • Liou K.
      • Cao C.
      Systematic review of percutaneous interventions for malignant pericardial effusion.
      • Jama G.M.
      • Scarci M.
      • Bowden J.
      • Marciniak S.J.
      Palliative treatment for symptomatic malignant pericardial effusion.
      Systemic chemotherapy and/or radiotherapy may prevent reaccumulation in some patients.
      • Lestuzzi C.
      • Berretta M.
      • Tomkowski W.
      2015 Update on the diagnosis and management of neoplastic pericardial disease.

      Superior Vena Cava Syndrome

      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.
      • Lepper P.M.
      • Ott S.R.
      • Hoppe H.
      • et al.
      Superior vena cava syndrome in thoracic malignancies.
      • Wilson L.D.
      • Detterbeck F.C.
      • Yahalom J.
      Superior vena cava syndrome with malignant causes.
      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.
      • Lepper P.M.
      • Ott S.R.
      • Hoppe H.
      • et al.
      Superior vena cava syndrome in thoracic malignancies.
      • Rice T.W.
      • Rodriguez R.M.
      • Light R.W.
      The superior vena cava syndrome: clinical characteristics and evolving etiology.
      • Bertrand M.
      • Presant C.A.
      • Klein L.
      • Scott E.
      Iatrogenic superior vena cava syndrome: a new entity.

      Pathophysiology

      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.
      • Stanford W.
      • Jolles H.
      • Ell S.
      • Chiu L.C.
      Superior vena cava obstruction: a venographic classification.

      Clinical Presentation and Diagnosis

      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).
      • Yu J.B.
      • Wilson L.D.
      • Detterbeck F.C.
      Superior vena cava syndrome—a proposed classification system and algorithm for management.
      Computed tomography with IV contrast is the most useful method of diagnosing SVCS (Figure 8, B).
      • Wilson L.D.
      • Detterbeck F.C.
      • Yahalom J.
      Superior vena cava syndrome with malignant causes.
      • Wan J.F.
      • Bezjak A.
      Superior vena cava syndrome.
      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 thumbnail gr8
      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.
      Table 8Grading of Superior Vena Cava Syndrome
      Adapted from J Thorac Oncol,
      • Yu J.B.
      • Wilson L.D.
      • Detterbeck F.C.
      Superior vena cava syndrome—a proposed classification system and algorithm for management.
      with permission from the International Association for the Study of Lung Cancer.
      GradeCategoryDefinitionUrgent treatment needed
      0AsymptomaticRadiographic superior vena cava obstruction in the absence of symptomsNo
      1MildEdema of the head or neck (vascular distention), cyanosis, plethoraNo
      2ModerateFacial 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
      3SevereMild or moderate cerebral edema (headache, dizziness) or mild/moderate laryngeal edema or diminished cardiac reserve (syncope after bending)Yes
      4Life-threateningSevere cerebral edema (confusion, obtundation), laryngeal edema (stridor), or hemodynamic compromise (syncope without precipitating factors, hypotension, renal insufficiency)Yes
      5FatalDeathNot applicable

      Treatment

      Although SVCS is commonly considered an oncological emergency, most cases are not.
      • Yu J.B.
      • Wilson L.D.
      • Detterbeck F.C.
      Superior vena cava syndrome—a proposed classification system and algorithm for management.
      • Schraufnagel D.E.
      • Hill R.
      • Leech J.A.
      • Pare J.A.
      Superior vena caval obstruction: is it a medical emergency?.
      • Yellin A.
      • Rosen A.
      • Reichert N.
      • Lieberman Y.
      Superior vena cava syndrome: the myth—the facts.
      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).
      • Rachapalli V.
      • Boucher L.M.
      Superior vena cava syndrome: role of the interventionalist.
      • Ganeshan A.
      • Hon L.Q.
      • Warakaulle D.R.
      • Morgan R.
      • Uberoi R.
      Superior vena caval stenting for SVC obstruction: current status.
      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.
      • Rowell N.P.
      • Gleeson F.V.
      Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review.
      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.
      • Kee S.T.
      • Kinoshita L.
      • Razavi M.K.
      • Nyman U.R.
      • Semba C.P.
      • Dake M.D.
      Superior vena cava syndrome: treatment with catheter-directed thrombolysis and endovascular stent placement.
      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 thumbnail gr9
      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.

      Pulmonary Emergencies

      Acute Airway Obstruction

      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.
      • Chhajed P.N.
      • Baty F.
      • Pless M.
      • Somandin S.
      • Tamm M.
      • Brutsche M.H.
      Outcome of treated advanced non-small cell lung cancer with and without central airway obstruction.
      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.
      • Chen K.
      • Varon J.
      • Wenker O.C.
      Malignant airway obstruction: recognition and management.
      • Theodore P.R.
      Emergent management of malignancy-related acute airway 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.
      • Theodore P.R.
      Emergent management of malignancy-related acute airway obstruction.
      The goal of therapy is to restore airway patency, which can be achieved with a variety of modalities.
      • Murgu S.
      • Egressy K.
      • Laxmanan B.
      • Doblare G.
      • Ortiz-Comino R.
      • Hogarth D.K.
      Central airway obstruction: benign strictures, tracheobronchomalacia and malignancy-related obstruction.
      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.
      • Gorden J.A.
      • Ernst A.
      Endoscopic management of central airway obstruction.
      • Ost D.E.
      • Ernst A.
      • Grosu H.B.
      • et al.
      AQuIRE Bronchoscopy Registry
      Therapeutic bronchoscopy for malignant central airway obstruction: success rates and impact on dyspnea and quality of life.
      Interventions such as stent placement can have severe negative consequences such as subsequent airway infections.
      • Grosu H.B.
      • Eapen G.A.
      • Morice R.C.
      • et al.
      Stents are associated with increased risk of respiratory infections in patients undergoing airway interventions for malignant airways disease.
      • Agrafiotis M.
      • Siempos I.I.
      • Falagas M.E.
      Infections related to airway stenting: a systematic review.
      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.
      • Crocco J.A.
      • Rooney J.J.
      • Fankushen D.S.
      • DiBenedetto R.J.
      • Lyons H.A.
      Massive hemoptysis.
      • Hirshberg B.
      • Biran I.
      • Glazer M.
      • Kramer M.R.
      Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital.
      The definition of massive hemoptysis is not well established, and definitions of 100 to 600 mL of bloody expectoration over 24 hours have been used.
      • Jean-Baptiste E.
      Clinical assessment and management of massive hemoptysis.
      Airway hemorrhage is commonly divided into proximal and distal airway bleeding, and the causes and management differ according to the anatomic location.
      • Yendamuri S.
      Massive airway hemorrhage.
      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.
      • Noë G.D.
      • Jaffé S.M.
      • Molan M.P.
      CT and CT angiography in massive haemoptysis with emphasis on pre-embolization assessment.
      • Khalil A.
      • Parrot A.
      • Nedelcu C.
      • Fartoukh M.
      • Marsault C.
      • Carette M.F.
      Severe hemoptysis of pulmonary arterial origin: signs and role of multidetector row CT angiography.
      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.
      • Meijer K.
      • de Graaff W.E.
      • Daenen S.M.
      • van der Meer J.
      Successful treatment of massive hemoptysis in acute leukemia with recombinant factor VIIa.
      • Wheater M.J.
      • Mead G.M.
      • Bhandari S.
      • Fennell J.
      Recombinant factor VIIa in the management of pulmonary hemorrhage associated with metastatic choriocarcinoma.
      Rigid bronchoscopy is the preferred method for control of airway hemorrhage, but other treatments are frequently needed.
      • Yendamuri S.
      Massive airway hemorrhage.
      Bronchial artery angiography can identify the bleeding vessel(s), and embolization can be performed during the procedure, often with successful control of the bleeding.
      • Chun J.Y.
      • Morgan R.
      • Belli A.M.
      Radiological management of hemoptysis: a comprehensive review of diagnostic imaging and bronchial arterial embolization.
      • Fruchter O.
      • Schneer S.
      • Rusanov V.
      • Belenky A.
      • Kramer M.R.
      Bronchial artery embolization for massive hemoptysis: long-term follow-up.
      • Cremaschi P.
      • Nascimbene C.
      • Vitulo P.
      • et al.
      Therapeutic embolization of bronchial artery: a successful treatment in 209 cases of relapse hemoptysis.
      Massive hemoptysis is extremely distressing to both patients and their caregivers and is often a terminal event in the disease course. Best supportive care without further interventions may be appropriate in selected cases. Intravenous administration of opioids and benzodiazepines may provide substantial relief but with the risk of suppressing respiratory drive. Darkly colored bed sheets, pillowcases, and towels may decrease the psychological trauma associated with massive hemoptysis.

      Infectious Emergencies

      Febrile Neutropenia

      Infections are common in patients with cancer and a major contribution to both morbidity and mortality. Most infections in patients with cancer are not emergencies and can be treated in the outpatient setting. Febrile neutropenia is a common complication in patients undergoing therapy for malignant disease. Prompt diagnosis and initiation of therapy are of key importance in decreasing morbidity and mortality and can also decrease costly hospitalizations. For the purpose of this review, we use the definitions of the Infectious Diseases Society of America. Fever is defined as a single oral temperature higher than 38.3°C or a temperature higher than 38.0°C sustained for more than 1 hour.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
      Neutropenia is defined as an absolute neutrophil count (ANC) of less than 0.5 × 109/L or an ANC that is expected to decrease to less than 0.5 × 109/L during the next 48 hours.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
      • Klastersky J.
      • de Naurois J.
      • Rolston K.
      • et al.
      ESMO Guidelines Committee
      Management of febrile neutropaenia: ESMO Clinical Practice Guidelines.
      An ANC level of less than 0.1 × 109/L is defined as profound neutropenia.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.

      Pathophysiology

      Febrile neutropenia is most common in patients receiving cytotoxic chemotherapy, especially patients with acute leukemia. Febrile neutropenia is much less common in patients undergoing therapy for solid tumors given the less intensive therapy. Some malignant disorders, especially sarcomas and germ cell tumors, require high-intensity chemotherapy, which increases the risk of febrile neutropenia (Table 9).
      • Flowers C.R.
      • Seidenfeld J.
      • Bow E.J.
      • et al.
      Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline.
      The risk of febrile neutropenia depends on both the severity and duration of neutropenia. The neutrophil nadir usually occurs 5 to 10 days from initiation of therapy, and neutrophil recovery begins about 5 days later, but there are substantial variations depending on the regimens used and the patient characteristics. Preexisting comorbidities such as liver or kidney dysfunction as well as concurrent use of certain drugs can increase the severity and duration of the neutropenia (Table 9). Patients with bone marrow dysfunction, especially acute leukemia, myelodysplastic syndromes, and aplastic anemia, as well as drug- or radiation-induced neutropenia can present with febrile neutropenia in the absence of cytotoxic chemotherapy. Factors other than the neutropenia itself play a role in the pathogenesis of febrile neutropenia. Chemotherapy can disrupt mucosal barriers, making the risk of gram-negative sepsis greater. Indwelling vascular devices can serve as the port of entry for organisms that colonize the skin such as gram-positive cocci. Hematologic cancers are often associated with defects in both humoral and cellular immunity, further adding to the immunosuppressive effects of the cancer-directed therapy.
      Table 9Risk Factors for Febrile Neutropenic Episodes
      Adapted from Flowers CR et al. J Clin Oncol. 2013;31(6):794-810.
      • Flowers C.R.
      • Seidenfeld J.
      • Bow E.J.
      • et al.
      Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline.
      Reprinted with permission. ©2013 American Society of Clinical Oncology. All rights reserved.
      Risk factorsEffect on riskReported febrile neutropenia rate
      Patient characteristics
       Advanced ageIncreased risk if age ≥65 yNA
       ECOG performance statusIncreased risk if ≥2NA
       Nutritional statusIncreased risk if albumin <35 g/L (3.5 g/dL)NA
       Prior febrile neutropeniaIncreased ri