Emergencias Oncológicas

SYMPOSIUM ON NEOPLASTIC HEMATOLOGY AND MEDICAL ONCOLOGY
Emergencies in Hematology and Oncology

Thorvardur R. Halfdanarson, MD; William J. Hogan, MBBCh;
and Bo E. Madsen, MD, MPH
From the Division of
CME Activity Medical Oncology
(T.R.H.), Division of
Target Audience: The target audience for Mayo Clinic Proceedings is primar- Development) must ensure balance, independence, objectivity, and scientific
Hematology (W.J.H.), and
ily internal medicine physicians and other clinicians who wish to advance rigor in its educational activities. Course Director(s), Planning Committee
Department of Emer-
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of advances in medical research. of this educational activity are required to disclose all relevant financial rela- gency Medicine (B.E.M.),
Statement of Need: General internists and primary care physicians must tionships with any commercial interest related to the subject matter of the Mayo Clinic, Rochester,
maintain an extensive knowledge base on a wide variety of topics covering educational activity. Safeguards against commercial bias have been put in MN.
all body systems as well as common and uncommon disorders. Mayo Clinic place. Faculty also will disclose any off-label and/or investigational use of
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understand best practices in diagnosis and management of conditions of this information will be published in course materials so that those partic-
encountered in the clinical setting. ipants in the activity may formulate their own judgments regarding the
Accreditation: Mayo Clinic College of Medicine and Science is accredited by presentation.
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continuing medical education for physicians. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the
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Learning Objectives: On completion of this article, you should be able to Estimated Time: The estimated time to complete each article is approxi-
(1) recognize both common and uncommon hematologic and oncological emer- mately 1 hour.
gencies in patients with cancer, (2) identify which patients need emergent or Hardware/Software: PC or MAC with Internet access.
urgent initiation of therapy and admission to the hospital for an optimal outcome, Date of Release: 4/1/2017
and (3) promptly initiate the appropriate therapy for life-threatening complica- Expiration Date: 3/31/2019 (Credit can no longer be offered after it has
tions of both the cancer itself and the therapy directed against the cancer. passed the expiration date.)
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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.
ª 2017 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2017;92(4):609-641
C
ancer is expected to be diagnosed in the large number of patients with active can-
more than 1.6 million people in the cer, many practicing physicians can expect to
United States in 2017. A small per- encounter patients with a cancer-related emer-
centage of these patients will experience an gency. It is therefore imperative that practi-
emergent cancer-related complication at tioners, especially primary and emergency
some point during the disease course. For care physicians, are able to rapidly recognize
some patients, an emergent complication is and effectively manage patients with these
the first manifestation of the cancer.1 Given complications. Emergencies in hematology
Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 609

www.mayoclinicproceedings.org n ª 2017 Mayo Foundation for Medical Education and Research
MAYO CLINIC PROCEEDINGS
and oncology can be broadly classified as con- and subsequently releases calcium into the cir-
ditions resulting from the cancer itself and culation.8,10,11 The presence of elevated PTHrP
complications related to therapy directed in humoral hypercalcemia of malignancy por-
against the malignant disease, although there tends poorer prognosis and decreased response
can be some overlap between the 2 categories. to therapy with bisphosphonates.12-14 Osteol-
The emergencies can also be classified accord- ysis as a cause of hypercalcemia is commonly
ing to organ systems, which is the approach seen in patients with breast cancer, lung cancer,
taken in this review. and multiple myeloma. Several cytokines have
been implicated in the pathogenesis of cancer-
METABOLIC EMERGENCIES induced osteolysis, including tumor necrosis
factor, macrophage inflammatory protein 1a,
Hypercalcemia of Malignancy and lymphotoxin.15,16 Local production of
Hypercalcemia is common in patients with PTHrP may also result in osteolysis, which is
advanced cancer and has been reported in in part mediated through the RANKL
up to 30% of patients with cancer.2 The inci- pathway.17,18 Extrarenal production of 1,25-
dence varies greatly among cancer types, and dihydroxyvitamin D (calcitriol) can occur in
hypercalcemia is most commonly associated patients with both Hodgkin and non-Hodgkin
with multiple myeloma, nonesmall cell lung lymphomas as well as nonmalignant granulo-
cancer (especially squamous cell cancer), renal matous diseases such as sarcoidosis.19,20 Very
cell carcinoma, breast cancer, non-Hodgkin rarely, ectopic production of PTH by tumors
lymphoma, and leukemia but can also be causes hypercalcemia.21 Hypercalcemia of
seen in multiple other malignant disorders.3 malignancy can also be exacerbated by factors
The presence of hypercalcemia in a patient unrelated to the malignant disorder itself such
with cancer is an adverse prognostic factor as the intake of calcium, vitamin D, lithium, and
predicting a shorter survival, but effective ther- thiazides. Thiazides are thought to reduce
apy, both for the hypercalcemia and the un- urinary calcium excretion as a result of
derlying cancer, may improve outcomes.4-7 increased passive calcium reabsorption at the
proximal tubule and increased distal reabsorp-
Pathophysiology. The pathophysiology of hy- tion at a thiazide sensitive site.
percalcemia of malignancy can be divided into
3 major categories.8 The first category, often Clinical Presentation and Diagnosis. Hyper-
called humoral hypercalcemia of malignancy, calcemia is caused by either primary hyper-
usually results from tumor production of parathyroidism or malignant disease more
parathyroid hormoneerelated peptide (PTHrP) than 90% of the time. Therefore, it is impor-
and less commonly intact parathyroid hormone tant to distinguish between these 2 entities
(PTH). It is the most common underlying cause early on. In hypercalcemia associated with
of hypercalcemia of malignancy. The second cancer, there are frequently overt signs of
category is hypercalcemia from bone destruc- malignant disease at presentation. Hypercalce-
tion and dissolution (osteolysis) from extensive mia can cause a multitude of nonspecific
bone metastases. The third and least common symptoms. Lethargy, confusion, anorexia,
category is excess production of vitamin D nausea, constipation, polyuria, and polydipsia
analogues by the malignant cells. Humoral are all common symptoms of hypercalcemia,
hypercalcemia of malignancy accounts for up to and the severity may correlate with the
80% of hypercalcemia that occurs in patients degree of hypercalcemia and the rapidity of
with cancer and is the dominant cause in onset.22,23 Severe hypercalcemia, especially of
patients with solid tumors.2,9 Structurally, rapid onset, may cause cardiac dysrhythmias
PTHrP is closely related to PTH and exerts many such as bradycardia, shortening of the QT
of the functions of PTH itself. It binds to interval, and even cardiac arrest.24 The phys-
receptors on osteoblasts and stimulates their ical examination is generally not helpful in
activity through receptor activator of nuclear making the diagnosis but can reveal signs of
factor kB ligand (RANKL) signaling. This volume depletion and impaired cognitive
process in turn stimulates the osteoclasts, function as well as signs of the underlying
increasing their activation and proliferation cancer such as enlarged lymph nodes.
n n
610 Mayo Clin Proc. April 2017;92(4):609-641 http://dx.doi.org/10.1016/j.mayocp.2017.02.008
www.mayoclinicproceedings.org
EMERGENCIES IN HEMATOLOGY AND ONCOLOGY
TABLE 1. Treatment of Hypercalcemia

Intervention Dosage Comments
Saline 250-500 mL/h IV until euvolemic and 100-150 mL/h IV The rate of infusion should be adjusted for the cardiovascular
after volume repletion is achieved. Can start by giving status of the patient
an 1- to 2-L initial bolus over 1 h if hypovolemic
Pamidronate 60-90 mg IV over 2-4 h Use with caution in renal insufficiency. Onset of action
may take days
Zoledronic acid 4 mg IV over 15 min Use with caution in renal insufficiency. Onset of action
may take days
Calcitonin 4-8 IU/kg SC or IV every 12 h Rapid onset of action but short-lived
Glucocorticoids Prednisone, 60 mg/d PO; hydrocortisone, Useful for hypercalcemia from calcitriol overproduction and
100 mg every 6 h IV in multiple myeloma
Denosumab 120 mg SC weekly for 4 wk, then every 4 wk Safe in renal insufficiency but doses should be reduced.
Can cause severe hypocalcemia
Furosemide 20-40 mg IV Only for patients with volume overload after volume expansion
IV ¼ intravenously; PO ¼ orally; SC ¼ subcutaneously.
The diagnosis of hypercalcemia is con- while awaiting laboratory results such as

firmed by measuring the serum calcium level. PTHrP level. Not all patients with hypercal-
Ionized calcium measurement is the preferred cemia need urgent treatment, and many
method of diagnosis, if available. If total serum patients with mild hypercalcemia can be
calcium is measured, a correction needs to be managed as outpatients. Patients with more
made for the albumin level. The corrected cal- severe and symptomatic hypercalcemia are
cium level is calculated as follows: corrected usually hospitalized for inpatient therapy.
calcium ¼ measured total calcium þ [0.8 In some cases of advanced cancer, specific
(4.0 albumin)]. therapy may not be recommended if the
Intact PTH is usually low in hypercalcemia underlying malignant disease is otherwise
of malignancy and can be helpful as a diag- untreatable.6,27 The patient’s goals and wishes
nostic tool, but the results may not be avail- should always be considered before instituting
able immediately. An elevated PTH level in therapy. Best supportive care at home, often
a patient with known malignant disease sug- with the help of hospice care professionals,
gests either a coexisting hyperparathyroidism may be appropriate for patients who have no
or a PTH-producing tumor. Measurements effective treatment options remaining for their
of PTHrP are generally not needed but cancer or who do not wish to receive any
may help elucidate the etiology of the hyper- further therapy.
calcemia, and elevated levels may predict The following recommendations apply to
response to bisphosphonate therapy and pre- patients with severe hypercalcemia (calcium
dict inferior survival.12-14 One study reported level >14 mg/dL [> 3.5 mmol/L]) and/or
less response to bisphosphonates and higher very symptomatic hypercalcemia. Table 1 lists
risk of recurrent hypercalcemia in patients the treatment options for hypercalcemia. The
with PTHrP levels greater than 12 pmol/L.25 first step in the management is the administra-
A low serum chloride level (<100 mEq/L tion of intravenous (IV) fluids because patients
[to convert to mmol/L, multiply by 1.0]) can are often profoundly hypovolemic, often in
point to cancer as the underlying cause.26 All the order of 5 to 10 L. Volume expansion
patients with severe hypercalcemia should will increase the renal clearance of calcium
undergo electrocardiography. and lower calcium levels. Normal saline
(0.9% sodium chloride) is the preferred IV
Treatment. Untreated, severe hypercalcemia fluid. Patients may require large volumes of
is a life-threatening entity that calls for normal saline, and 1000 to 2000 mL should
immediate intervention for optimal results in be given in the first hour of fluid resuscitation.
patients who are candidates for active therapy. Larger volumes may be needed initially in
Physicians should not delay starting therapy hypotensive patients. After the initial bolus

of normal saline, an IV infusion of 250 to lowered the calcium levels in most patients
500 mL/h can be used until urine output and had a prolonged duration of response.44
and euvolemia are established. Denosumab was given as 120 mg subcutane-
Calcitonin can lower calcium levels by ously weekly for 4 weeks and then every 4
inhibiting osteoclasts and can enhance urinary weeks thereafter. It is well tolerated but may
excretion of calcium.28 The onset of action of result in symptomatic hypocalcemia.43,44
calcitonin is quick, but tachyphylaxis develops Denosumab can safely be given to patients
within days of use.29,30 It is therefore of most with renal insufficiency, but the risk of hypocal-
use when a prompt reduction in calcium levels cemia may be increased.45 The dose should be
is required. Calcitonin is given as a subcutane- reduced in patients with renal insufficiency, but
ous injection, and no dosage adjustment is the optimal dose has not been established. A
needed in patients with renal insufficiency.31 fixed single dose of 60 mg subcutaneously has
The use of loop diuretics is strongly dis- resulted in symptomatic hypocalcemia, and a
couraged because they may exacerbate the weight-based dose of 0.3 mg/kg may be a safer
hypovolemia and therefore impair calcium alternative followed by careful monitoring and
excretion.32 Loop diuretics should be reserved repeated administration in a week if needed.45
only for patients with clinical evidence of The calcimimetic cinacalcet has been reported
volume overload. Bisphosphonates are the to lower serum calcium levels in patients with
mainstay of the treatment and are able to con- hypercalcemia secondary to PTH production
trol the hypercalcemia in most patients.33-36 of parathyroid carcinoma but is not recommen-
Bisphosphonates block osteoclastic bone ded in hypercalcemia of other etiologies.46
resorption, but the onset of action is slow Hemodialysis can be used in refractory cases
and it may take 2 to 3 days to see a full effect. and situations in which other methods cannot
The most commonly used bisphosphonates in be used safely but should be considered as a
the United States are pamidronate (60-90 mg last-resort therapy.47,48 Effective systemic ther-
IV over 2-4 hours) and zoledronic acid apy or radiotherapy for the underlying disease,
(4 mg IV over 15 minutes), but zoledronic if available, can further help decrease the serum
acid is often preferred because it can be given calcium levels.
as a short IV infusion and may be more effec-
tive than pamidronate.33 Ibandronate is also Tumor Lysis Syndrome
effective but infrequently used in the United Tumor lysis syndrome (TLS) is a constellation
States.37,38 Bisphosphonates are potentially of metabolic derangements resulting from the
nephrotoxic and should be used with caution death of neoplastic cells which then release
in patients with renal insufficiency. their intracellular contents into the circula-
Glucocorticoids are useful in patients tion.49 It is most commonly seen in patients
whose hypercalcemia is driven by overproduc- with very aggressive hematologic cancers
tion of calcitriol because they inhibit the such as high-grade lymphomas and acute leu-
conversion of calcidiol to calcitriol.30,39 kemias.50,51 Tumor lysis syndrome is occa-
Commonly used glucocorticoids include sionally seen in patients with aggressive solid
prednisone (60 mg orally daily) and hydrocor- tumors such as small cell carcinoma of the
tisone (100 mg IV every 6 hours). Gallium lung.52 It usually occurs after effective therapy
nitrate and mithramycin (plicamycin) have has begun but can also occur spontaneously.53
been used in the past but are not readily avail- It is most commonly seen after the initiation of
able now and have been replaced by safer cytotoxic chemotherapy but can also result
agents.40,41 Denosumab, a humanized mono- from glucocorticoid therapy for lymphoma,
clonal antibody directed against the RANKL endocrine therapy for advanced breast cancer,
that inhibits osteoclast activation and function, various targeted agents, and radiotherapy for
was recently approved for use in hypercalcemia radiosensitive malignant diseases.54
of malignancy. Denosumab has been used
successfully in hypercalcemia refractory to Pathophysiology. Tumor lysis syndrome is
bisphosphonate therapy.42,43 In a single-arm caused by massive release of intracellular con-
trial in patients who remained hypercalcemic tents into the bloodstream at the time of the
after bisphosphonate therapy, denosumab death of neoplastic cells.50,55 The catabolism
n n
of nucleic acids results in hyperuricemia. High

TABLE 2. Cairo-Bishop Classification of Laboratory and Clinical Tumor Lysis
concentrations of uric acid will lead to crys-
Syndrome
tallization within renal tubules and tubular
Laboratory tumor lysis syndrome
obstruction resulting in acute kidney injury.
Uric acid 8 mg/dL (476 mmol/L) or 25% increase from baseline
The renal failure is further exacerbated by
Potassium 6.0 mEq/L (6.0 mmol/L) or 25% increase from baseline
hypovolemia leading to acute tubular necrosis. Phosphorus 4.5 mg/dL (1.45 mmol/L) or 25% increase from baseline
Elevated levels of uric acid may also lead to Calcium 7 mg/dL (1.75 mmol/L) or 25% decrease from baseline
kidney injury independently of uric acid Clinical tumor lysis syndrome
crystal formation, possibly secondary to alter- Presence of laboratory tumor lysis syndrome and one or more of the
ation in the intrarenal hemodynamics.56 following criteria
The release of organic and inorganic phos- Creatinine 1.5 times the upper limit of normal
phates from the neoplastic cells leads to Cardiac arrhythmia
Seizure
hyperphosphatemia, which in turn leads to Sudden death
hypocalcemia and precipitation of calcium
Adapted from Br J Haematol,59 with permission. Copyright ª1999-2017 John Wiley & Sons, Inc.
phosphate and nephrocalcinosis. Hyper-
All rights reserved.
kalemia is frequently the first manifestation of
TLS, may occur within a few hours after
therapy is started, and can result in life- malignant disease and patient characteristics
threatening cardiac arrhythmias.57 (Table 3).53
Clinical Presentation and Diagnosis. Patients Prevention and Treatment. Tumor lysis
with TLS can present with symptoms (clinically syndrome can often be prevented, and it is
evident TLS) or with abnormal laboratory test therefore of utmost importance to identify
results in the absence of symptoms (laboratory patients at risk and initiate prophylactic
TLS).58 The presenting symptoms of TLS are therapy because TLS is associated with
nonspecific, and a high index of suspicion increased mortality and morbidity as well as
is needed for a timely diagnosis. Decreased increased cost.51,60-63 Adequate hydration
urine output followed by symptoms of uremia and the appropriate use of uric acidelowering
and volume overload may occur. Seizures, (uricosuric) drugs can effectively reduce uric
arrhythmias, and even sudden death are known acid levels and reduce the risk of renal injury.
presentations of TLS. The choice of uricosuric drugs depends on the
Typical laboratory findings include risk of TLS for the given patient (Tables 3 and
elevated uric acid, phosphorus, potassium, 4). The most commonly used drugs are allo-
and lactate dehydrogenase levels as well as purinol and rasburicase. Allopurinol is an in-
low calcium concentrations. The diagnostic hibitor of xanthine oxidase and reduces the
criteria and definition of TLS have evolved, production of uric acid by decreasing the rate
but the most commonly used definition is of conversion of hypoxanthine to xanthine
the that of Cairo and Bishop59 (Table 2). and xanthine to uric acid. Both xanthine and
hypoxanthine are more water soluble than uric
Risk Stratification. The risk factors for devel- acid. Allopurinol does not facilitate the
opment of TLS are well known.51 The risk is breakdown of the uric acid that has already
determined by the type of cancer as well as been produced. Allopurinol is an appropriate
the treatment given and underlying condi- uricosuric drug in patients with low or inter-
tions. Tumor-specific risk factors include mediate risk of TLS. The prophylactic dose
high tumor burden, high tumor grade with of allopurinol is 200 to 400 mg/m2 daily in
rapid cell turnover, and treatment-sensitive 1 to 3 divided doses, up to a maximum of
tumor. Age, preexisting renal impairment, 800 mg daily.51 Febuxostat is a selective
and concomitant use of drugs known to in- inhibitor of xanthine oxidase that is approved
crease uric acid are patient-specific risk fac- for treatment of gout. It has fewer drug-drug
tors. Aspirin, alcohol, thiazide diuretics, and interactions than allopurinol, and dose
caffeine are known to increase uric acid adjustment is not needed in patients with
levels. The risk can be categorized on the mild to moderate renal impairment.64
basis of the characteristics of the underlying Febuxostat has been compared to allopurinol

TABLE 3. Risk Stratification of Tumor Lysis Syndrome and Recommendations for Prophylaxisa,b
Risk category Malignant disease Prophylaxis
c
Low-risk disease Solid tumor Monitoring (daily laboratory tests)
Multiple myeloma Intravenous hydration (3 L/m2 daily)
CML Consider allopurinol
CLLd
Indolent NHL
Hodgkin lymphoma
AML (WBC <25,000/mL and LDH <2 ULN)
Intermediate-risk disease AML (WBC 25,000-100,000/mL) Monitoring (laboratory tests every 8-12 h)
AML (WBC <25,000/mL and LDH 2 ULN) Intravenous hydration (3 L/m2 daily)
Intermediate-grade NHL (LDH 2 ULN) Allopurinol for up to 7 d
ALL (WBC <100,000/mL and LDH <2 ULN)
Burkitt lymphoma (LDH <2 ULN)
Lymphoblastic NHL (LDH <2 ULN)
High-risk disease ALL (WBC 100,000/mL and/or LDH 2 ULN) Monitoring (laboratory tests every 6-8 h)
Burkitt lymphoma (stages III/IV and/or LDH 2 ULN) Intravenous hydration (3 L/m2 daily)
Lymphoblastic NHL (stages III/IV and/or LDH 2 ULN) Rasburicase (consider 3 mg fixed dose)
IRD with renal dysfunction and/or renal involvement
IRD with elevated uric acid, potassium, and/or phosphate
a
ALL ¼ acute lymphoblastic leukemia; AML ¼ acute myeloid leukemia; CLL ¼ chronic lymphoid leukemia; CML ¼ chronic myeloid leukemia; IRD ¼ intermediate-risk
disease; LDH ¼ lactate dehydrogenase; NHL ¼ non-Hodgkin lymphoma; ULN ¼ upper limit of normal; WBC ¼ 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.
Adapted from Br J Haematol,53 with permission. Copyright ª1999-2017 John Wiley & Sons, Inc. All rights reserved.
for prevention of TLS. It was found to be more rasburicase is recommended in all patients
effective in lowering uric acid levels, but it is with high risk of TLS. The recommended dose
uncertain if it reduces clinically important of rasburicase is 0.2 mg/kg once daily for up to
TLS, at least when compared with high doses 5 to 7 days, but lower doses and shorter
of allopurinol, and its role in management duration of therapy are commonly used.
of TLS needs to be determined with further A single fixed dose of 3 mg has been studied
trials.65 The dose of febuxostat is 120 mg and seems to be very effective in preventing
daily. Rasburicase is a recombinant form of TLS, and the dose can be repeated later if
urate oxidase and metabolizes uric acid to needed.75-78 Recently published guidelines
allantoin, which is much more soluble than from the British Committee for Standards in
uric acid.66 The use of rasburicase is contra- Haematology have endorsed the use of a single
indicated in patients with glucose-6- fixed 3-mg dose of rasburicase as adequate
phosphate dehydrogenase (G6PD) deficiency. prophylactic therapy for TLS in the absence of
Unlike allopurinol, rasburicase also lowers established clinical or laboratory TLS.51 The
already formed uric acid. Rasburicase is dose should be repeated daily if there is any
generally reserved as prophylaxis for patients evidence of progressive TLS, and if clinical
at high risk of TLS or patients already expe- TLS develops on the fixed-dose regimen, the
riencing TLS. Rasburicase is effective as TLS treatment should be changed to the standard
prophylaxis in both adults and children.67-71 dose of 0.2 mg/kg per day. Urinary alkalin-
Despite the efficacy of rasburicase in ization is not recommended because it can
lowering uric acid levels and preventing TLS, decrease the solubility of xanthine. Normal
it has not been proven to be superior to allo- saline is recommended as the IV fluid of
purinol in preventing clinical TLS and related choice in the management of TLS.
complications.72-74 Despite the lack of data on Patients with established TLS should
hard clinical end points, treatment with receive multidisciplinary care to ensure the
n n
Mayo Clin Proc. n April 2017;92(4):609-641

TABLE 4. Treatment of Metabolic Abnormalities Associated With Tumor Lysis Syndrome
Abnormality Intervention Dose Comments
Renal insufficiency and hypovolemia Intravenous fluids 2
NS 3 L/m /d (200 mL/kg/d) Use with caution if history of CHF
Dialysis NA Use in anuria and severe oliguria with volume
overload
Hyperuricemia Allopurinol 200-400 mg/m2/d PO in divided doses Reduce dose in renal failure
every 8-12 h Multiple drug interactions (6-mercaptopurine
Commonly used doses include 600 mg initially and azathioprine)
followed by 300 mg daily IV allopurinol should only be used in patients
IV 200-400 mg/m2/d in 2-3 divided doses unable to take medications by mouth
Does not lower uric acid already formed
n
Rasburicase Flat fixed dose of 3 mg IV Contraindicated in G6PD deficiency

http://dx.doi.org/10.1016/j.mayocp.2017.02.008
0.2 mg/kg/d IV for up to 7 d for established TLS Transfer blood samples to the laboratory on ice
Risk of sensitization and allergic reactions
Expensive
Febuxostat 120 mg PO daily Expensive
Uncertain if more effective than allopurinol
No need to adjust doses in mild to moderate
renal insufficiency
Hyperphosphatemia (phosphate Minimize phosphate intake NA Low phosphorus diet
>6.5 mg/mL [>2.1 mmol/L]) Phosphorus-free IV fluids
Phosphate binders (aluminum hydroxide) PO 50-150 mg/kg/d May interfere with drug absorption
Dialysis NA If no response to medical therapy
Hyperkalemia Insulin (regular) IV 10 U .
Dextrose (50%) IV 50-100 mL .
Calcium gluconate (10%; IV 10 mL (1000 mg) Do not give with bicarbonate
10% ¼ 100 mg/mL) Use if arrhythmias or ECG changes
Can repeat as needed
Sodium bicarbonate IV 150 mEq in 1 L of D5W over 2-4 h Use if acidosis
Can repeat in 30 min
Sodium polystyrene sulfonate PO 15-30 g every 6 h (can be used rectally) Can be given with sorbitol
Albuterol Inhaled 10-20 mg For severe hyperkalemia
Dialysis NA Severe hyperkalemia not responsive to other
measures
Renal failure
Volume overload
Hypocalcemia Calcium gluconate (10%; IV 10 mL (1000 mg) as an infusion over Only if symptomatic
10% ¼ 100 mg/mL) 10-20 minutes Repeat as necessary
Caution in patients with severe
hyperphosphatemia
CHF ¼ congestive heart failure; D5W ¼ 5% dextrose in water; ECG ¼ electrocardiogram; G6PD ¼ glucose-6-phosphate dehydrogenase; IV ¼ intravenous; NA ¼ not applicable; NaHCO3 ¼ sodium bicarbonate; NS ¼ normal
615
saline; PO ¼ orally; TLS ¼ tumor lysis syndrome.

best possible outcome. Frequent monitoring is of hyponatremia in these patients is multifac-

essential, and patients are often transferred to torial and includes the syndrome of inappro-
intensive care units for therapy. High urine priate antidiuretic hormone secretion, either
output is maintained with hydration and care- from the cancer itself or from drugs, hypovo-
ful monitoring of fluid balance. The optimal lemia, and salt-wasting nephropathy.87,88
rate of fluid replacement remains unknown, Most cases of hyponatremia in patients with
but 3 L/m2 every 24 hours is reasonable.50,79 cancer are mild to moderate and either require
Alkalinization of the urine is not recommen- no therapy or can be treated in the outpatient
ded, and diuretics should only be used for vol- setting. Symptoms of hyponatremia include
ume overload and then with extreme headache, nausea, vomiting, lethargy, confu-
caution.55 Rasburicase is the uricosuric agent sion, and seizures.89 Patients are usually hypo-
of choice in established clinical TLS and volemic or euvolemic on examination. Severe
should be used in a dose of 0.2 mg/kg daily symptomatic hyponatremia should be cor-
for up to 7 days.51 Hyperkalemia should be rected slowly with the aim of an increase in
treated aggressively. Asymptomatic hypocalce- the plasma sodium level of 4 to 6 mEq/L
mia should not be treated, but symptomatic (to convert to mmol/L, multiply by 1.0)
hypocalcemia (tetany, arrhythmia, or seizures) per day to prevent osmotic demyelination.90,91
should be treated carefully with IV calcium Patients with severe hyponatremia presenting
gluconate with the aim of controlling the with altered mental status or seizures are typi-
symptoms but not normalizing the serum cal- cally treated with hypertonic saline (3%) given
cium level. Restriction of phosphate intake as 3 mL/kg over 30 to 60 minutes, which
and phosphate binders may be used for hyper- will rapidly increase the serum sodium by
phosphatemia, but severe elevations in 4 to 6 mEq/L.
phosphate may require hemodialysis. Other
indications for dialysis are severe hyperkale- Hypoglycemia
mia, severe oliguria or anuria, and volume Hypoglycemia is a rare complication of
overload. cancers seen mainly in patients with neuroen-
docrine tumors that produce insulin (insulino-
Lactic Acidosis mas).87 Patients with metastatic malignant
Lactic acidosis is a rare complication of cancer insulinoma can have severe hypoglycemia.
and is most often seen in patients with aggres- Small, localized benign insulinomas can cause
sive hematologic cancers and less commonly intermittent symptomatic hypoglycemia and
with high-grade solid tumors.80-82 The patho- are often very difficult to diagnose. Hypoglyce-
genesis of lactic acidosis in cancer is poorly mia is rarely seen in nonneuroendocrine can-
understood and likely involves both increased cers but occasionally occurs in end-stage
lactate production by the tumor and decreased liver failure from extensive hepatic replace-
clearance by the liver. Many, but not all, ment by tumor. Typical symptoms of hypo-
patients have extensive liver metastases, glycemia are palpitations, tremulousness,
and some patients may have thiamine defi- diaphoresis, anxiety, and hunger. Further
ciency.80,81,83 Therapy for cancer-associated neuroglycopenic symptoms may follow,
lactic acidosis includes intensive supportive such as confusion, loss of consciousness,
care and therapy directed at the underlying and seizures. If tumor-induced hypoglycemia
malignant disorder but is frequently ineffec- is suspected, plasma insulin, proinsulin,
tive, and death is usually imminent. Chemo- C-peptide, and b-hydroxybutyrate levels
therapy is appropriate in patients with should be measured in addition to glucose.
chemotherapy-sensitive tumors, but long- The initial treatment of hypoglycemia in can-
term survival is rare.80,82 cer is no different than treatment of hypogly-
cemia in general. Symptomatic hypoglycemia
Hyponatremia in an alert patient can be treated with oral
Hyponatremia is the most common metabolic fast-acting carbohydrates, but severe symp-
disturbance in patients with cancer, affecting tomatic hypoglycemia requires IV administra-
up to 60% toward the end of life and associ- tion of dextrose. A common dose is 25 g
ated with inferior survival.84-86 The etiology of 50% dextrose given as a slow IV push.
n n
Patients with symptomatic hypoglycemia from HEMATOLOGIC EMERGENCIES

metastatic insulin-producing neuroendocrine
tumors usually require further therapy Hyperviscosity Due to Monoclonal Proteins
including continuous infusion of dextrose, Hyperviscosity is defined as an intrinsic resis-
diazoxide, and octreotide followed by tumor- tance of fluid to flow. It can be seen in disor-
directed therapy.92 ders in which there is increased production of
monoclonal proteins such as in multiple
Adrenal Insufficiency myeloma and Waldenström macroglobuli-
Adrenal insufficiency may result from a near- nemia (WM). Blood viscosity can be increased
complete replacement of the adrenal glands secondary to an excess of either cellular or
by malignant tumor or secondary to therapy. acellular elements.97
Despite the adrenal glands being common
sites for metastases, adrenal insufficiency Pathophysiology. Excessive production of
from tumor replacement is rare. Iatrogenic immunoglobulins can lead to increased blood
adrenal insufficiency is much more common. viscosity. Of all the dysproteinemic disorders,
Prolonged therapy with glucocorticoids will WM is the most likely to cause hyperviscosity.
result in adrenal suppression, and a sudden Earlier studies reported that up to 30% of
cessation of such therapy can lead to acute patients experienced hyperviscosity.98 The
adrenal insufficiency. Megestrol acetate, which prevalence seems to be declining because the
is commonly used for cancer cachexia, can disease is now being diagnosed at earlier
cause adrenal insufficiency while patients are stages. The IgM monoclonal protein produced
taking the drug as well as an acute exacerba- by WM is a large pentamer that is 80%
tion when it is abruptly stopped.93 Further- intravascular and can therefore profoundly
more, megestrol acetate is associated with affect the blood viscosity.99 IgG and IgA are
adrenal insufficiency in acutely ill individ- much less likely to cause hyperviscosity,
uals.94 Mitotane, a rarely used adrenolytic and hyperviscosity is uncommonly seen in
drug indicated for the management of adreno- multiple myeloma.100 The levels of mono-
cortical carcinoma, invariably results in adre- clonal protein that cause hyperviscosity sym-
nal insufficiency, and all patients taking ptoms can vary considerably between patients
mitotane also need to take replacement corti- but are relatively consistent and reproducible
costeroids.95 Typical signs and symptoms in an individual patient. In general, symptoms
of adrenal insufficiency include weakness, of hyperviscosity are unlikely with serum vis-
anorexia, nausea, vomiting, and hypotension. cosity of less than 4 cP, which usually corre-
Hyponatremia, often accompanied by hyper- sponds to IgM levels of 3 g/dL (to convert to
kalemia, is a common laboratory finding. g/L, multiply by 10).101-103 According to one
Circulatory collapse and shock may occur, study, most symptomatic patients had viscos-
especially if there is another intercurrent ity above 8 cP.104 High concentrations of
illness such as an infection. If adrenal crisis monoclonal protein result in impaired micro-
is suspected, therapy should be started circulatory blood flow and subsequent
without delay.96 Normal saline, 1 to 2 L in ischemia causing the characteristic symptoms
the first hour, followed by an infusion of hyperviscosity. Because the relationship
should be given. Hypotonic fluids should be between a monoclonal protein and symptoms
avoided because they may exacerbate the of hyperviscosity is not linear, once clinical
hyponatremia. Glucocorticoids can reverse symptoms of hyperviscosity occur, even a
the adrenal crisis and should be given once slight further increase in the concentration of
the diagnosis is suspected. Dexamethasone monoclonal protein can dramatically worsen
(4 mg IV bolus) is preferred because it does symptoms, and conversely, a modest reduc-
not interfere with cortisol assays. Hydrocorti- tion in the concentration can greatly relieve
sone at 100 mg IV can also be given but inter- symptoms.
feres with the cortisol assay. Hydrocortisone
at a dose of 50 mg IV is an appropriate Clinical Presentation and Diagnosis. The
maintenance therapy until the situation has onset of the symptoms of hyperviscosity syn-
stabilized. dromes is usually insidious. Symptoms from

Measurements of immunoglobulin levels will

TABLE 5. Clinical Manifestations of Hyperviscosity
likely be more available in real time and can
Central nervous system guide therapy. In patients with typical symp-
Headache
toms and clinical findings, especially those
Dizziness and vertigo
with a known dysproteinemic disorder, treat-
Seizures
Concentrating difficulties
ment can start urgently without laboratory
Impaired level of consciousness confirmation of hyperviscosity.
Tinnitus and deafness
Ophthalmologic Treatment. Therapy should be started without
Blurry vision or loss of vision delay in symptomatic patients. Severely symp-
Diplopia tomatic patients with a known WM diagnosis
Retinal vein occlusion
can be treated with phlebotomy and normal
Papilledema
Retinal hemorrhage saline replacement while arranging for emer-
Mucocutaneous gent plasmapheresis. Red blood cell transfu-
Epistaxis sions should be avoided before initiating
Gingival bleeding therapy to prevent exacerbation of the hyper-
Cutaneous bleeding viscosity. Plasmapheresis is an effective
Gastrointestinal bleeding method to lower serum viscosity, especially
Other in patients with WM because 80% of the
Shortness of breath
IgM monoclonal protein is intravascular.99,105
Congestive heart failure
Priapism 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
the central nervous system (CNS) and eyes systemic therapy is always needed for durable
predominate (Table 5).99,102 Common symp- control of the disease.
toms include blurred vision, headache, ver-
tigo, dizziness, hearing loss, and impaired
Hyperleukocytosis and Leukostasis
mental status. Shortness of breath, chest pain
Hyperleukocytosis is often defined as a total
from myocardial ischemia, peripheral arterial
leukocyte count of 100 109/L or more,
occlusion, and venous thromboembolism
but symptoms of leukostasis can occur at
have been reported. The physical examination
lower leukocyte counts.106 Hyperleukocytosis
often reveals retinal venous engorgement
can cause microvascular obstruction leading
(sausaging), retinal hemorrhages, papilledema,
and retinal vein occlusion at later stages
(Figure 1). The patient can also have devel-
opment of localized serous detachments of the
fovea, which are thought to be secondary to
accumulations of the immunoglobulin and
resolve with plasmapheresis. Bleeding com-
plications can be seen, especially purpura and
petechiae due to hemostatic defects.
The diagnosis of hyperviscosity requires a
high index of suspicion. Most patients have a
known diagnosis of a dysproteinemic disor-
der, but some may present with hyperviscosity
as the initial manifestation. The blood smear
may reveal rouleaux formation of the red FIGURE 1. Retinal photograph of a patient with
hyperviscosity showing dilated and tortuous
blood cells, in which they stack up like coins
retinal veins, intraretinal hemorrhages, and a
(Figure 2). Measurements of serum viscosity
cotton wool spot (infarction) by the optic disc.
may be difficult or impossible to perform Image courtesy of Dr Jose Pulido, Department
in many hospitals, especially if urgently of Ophthalmology, Mayo Clinic.
requested outside the usual office hours.
n n
Pathophysiology. Rapid proliferation and dis-

rupted cell adhesion result in the release of a
large number of leukemic blasts from the
bone marrow into the circulation.107 This
process can lead to microvascular occlusion
resulting in tissue ischemia and infarction.111
In addition, patients with hyperleukocytosis
are at risk for development of TLS and
disseminated intravascular coagulation. Two
FIGURE 2. Red blood cell rouleaux formation
main mechanisms are thought to explain
in a patient with Waldenström macroglobuli-
nemia (peripheral blood, Wright-Giemsa, orig-
leukostasis.107 First, the sheer quantity of
inal magnification 600). Image courtesy of Dr immature leukocytes (Figure 3), which are
Phuong Nguyen, Department of Laboratory frequently larger and less deformable than
Medicine and Pathology, Mayo Clinic. mature leukocytes, can lead to microvascular
occlusion. Frequently, there is no clear corre-
lation between the leukocyte count and the
occurrence of leukostasis, likely due in part to
to tissue hypoxia and infarction (leukostasis). a second important mechanism of abnormal
Hyperleukocytosis and leukostasis are most interaction between the leukemic blasts and
commonly seen in acute leukemias, especially the endothelium. This abnormal interaction
acute myeloid leukemia (AML) (5%-20% of may be secondary to aberrant expression of
patients).107-109 Hyperleukocytosis secondary adhesion molecules by the blasts.106,112
to AML is more common in children
than adults. Acute lymphoblastic leukemia Clinical Presentation and Diagnosis. The
is less likely to cause leukostasis than symptoms and signs of leukostasis can
AML. Chronic lymphocytic leukemia and resemble the presentation of hyperviscosity
chronic myeloid leukemia rarely cause symp- secondary to dysproteinemia (Table 6).
tomatic leukostasis, even despite extreme Symptoms from the respiratory system and
elevations in the white blood cell counts. CNS including the eyes are common but can
Symptomatic hyperviscosity can also occur be difficult to distinguish from infectious and
in patients with severe erythrocytosis and hemorrhagic complications.109 Patients may
thrombocytosis.110 present with fever, dyspnea, and pulmonary
FIGURE 3. Photomicrographs 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.

leukemic blasts and reduce the likelihood of

TABLE 6. Clinical Manifestations of Leukostasis
complications, but the effect of leukapheresis
Central nervous system on early mortality is uncertain.115-117 Despite
Headache
the uncertainties, it should be strongly
Dizziness and vertigo
considered for all patients presenting with
Seizures
Confusion and delirium
symptomatic leukostasis. The goal of leuka-
Impaired level of consciousness and coma pheresis should be resolution of symptoms,
Focal neurologic deficits typically with reduction of the blast count
Intracranial hemorrhage to less than 100 109/L in AML.106,118,119
Ophthalmologic Hydroxyurea is commonly used to provide
Blurry vision or loss of vision additional control by preventing rapid reac-
Visual field defect cumulation of blasts in the initial stages of
Papilledema
Retinal hemorrhage
therapy, again with an uncertain effect on
Retinal vein thrombosis mortality in isolation.115 Rapid initiation of
Pulmonary standard induction therapy with curative
Dyspnea and tachypnea intent is therefore recommended in all patients
Hypoxia in whom intensive therapy is appropriate.
Auscultatory crackles Hydroxyurea can be considered as a bridging
Respiratory failure strategy while awaiting the results of diag-
Pulmonary infiltrates nostic tests. Cranial radiation is no longer
Cardiovascular
routinely recommended. Patients with leuko-
Chest pain
Myocardial ischemia/infarction stasis are at greater risk for TLS and should
Other receive prophylactic therapy.
Fever
Renal failure
NEUROLOGIC EMERGENCIES
Priapism
Extremity ischemia Malignant Spinal Cord Compression
Venous thrombosis Malignant spinal cord compression (MSCC) is
Disseminated intravascular coagulation
a true oncological emergency. Up to 6% of pa-
Tumor lysis syndrome
tients with cancer are expected to experience
MSCC at some time during the course of
their illness, and the annual incidence of
infiltrates resembling symptoms of pneumonia hospitalizations secondary to MSCC among
or volume overload. Fever with neurologic patients with advanced cancer is 3.4%.120-122
symptoms can be difficult to distinguish from All cancers can cause MSCC, but the most
CNS infections. There is no single diagnostic often implicated malignant diseases are breast,
test for leukostasis, but the diagnosis should lung, and prostate cancer, which account for
be considered in all patients with extreme almost two-thirds of all cases, but multiple
leukocytosis and typical symptoms. myeloma and non-Hodgkin lymphoma have
the highest cancer-specific incidence.121-123
Treatment. Hyperleukocytosis and leukosta- The prognosis of patients with MSCC is
sis in patients with acute leukemia are asso- poor, especially if the presenting features
ciated with an inferior prognosis with an include paralysis or if there is no response
increase in early deaths compared with pa- to therapy.121,124 Slower onset of symptoms
tients without these complications, and ther- and the absence of neurologic deficits at diag-
apy should be started without unnecessary nosis predict a better functional outcome after
delay.107,113 Red blood cell transfusions therapy.125,126
should be administered with caution and
preferably after control of the symptoms of Pathophysiology. Most cases of MSCC are
leukostasis given the concern of increasing secondary to metastases to vertebral bodies
viscosity.114 Leukapheresis, a mechanical that erode into the spinal canal and encroach
separation and removal of leukocytes from on the spinal cord. Paravertebral tumors can
the blood, can rapidly reduce the number of extend through the neural foramina, resulting
n n
in cord compression.127 Intramedullary and usually occur later in the course of

meningeal metastases are rare causes of spinal MSCC.120,130 Ataxia is an unusual manifesta-
cord compression.128,129 The thoracic spine is tion of MSCC.138 Other presenting symptoms
the most common location for metastases, of MSCC include radicular pain and gait
followed by the lumbar spine and cervical disturbance.120,127,130,132
spine.120,128,130 Injury to the spinal cord can The diagnostic method of choice is mag-
occur secondary to direct compression of netic resonance imaging (MRI) because it is
the cord or from cord ischemia from vascular both sensitive and specific (Figure 4).139-143
occlusion secondary to the tumor. Both It is important to image the entire spine
mechanisms will eventually lead to irreversible because up to 40% of patients may have
neuronal damage resulting in neurologic def- multiple levels of compression or cord
icits if untreated. impingement.144-147 If imaging of the entire
spine is not feasible on initial evaluation,
Clinical Presentation and Diagnosis. The focused MRI of the suspected area should be
literature on the natural history and early performed emergently with a more complete
identification of MSCC is limited, but known MRI evaluation of the entire spine as soon
bone metastases, high tumor burden, and as possible.142 Computed tomography (CT),
recent onset of symptoms are suggestive of with or without myelography, can be used
MSCC in patients with cancer who have when MRI is contraindicated or not available.
back pain.131 Most patients have back pain Plain bone radiographs and radionuclide bone
at diagnosis, but in 5% to 15% the pain is scans are insensitive for spinal cord compres-
either absent or mild.120,130,132-134 The pain sion. Positron emission tomography with CT
can be localized to the spine, radicular, or both imaging is a useful modality to identify meta-
and is usually progressive.130 The back pain is statis to the spine but lacks anatomic detail
often nocturnal and can be worsened by for diagnosis of MSCC.148
certain movements as well as with increase in
intra-abdominal pressure such as the Valsalva Treatment. Therapy should be initiated
maneuver. Guidelines for evaluation of back without delay in all patients with suspected
pain have recommended looking for “red MSCC to help preserve neurologic function,
flags” suggestive of malignant disease, but preferentially after imaging studies have been
there is limited evidence that such red flags are performed. Pretreatment motor function is
useful in identifying cancer as the underlying an important predictor of functional outcome
source of back pain.135,136 Twenty percent of after therapy for MSCC.124,125,149,150 If there
patients do not have a known cancer diagnosis is a delay in obtaining imaging studies, corti-
at the time the MSCC is diagnosed.133,134,137 costeroid therapy may be initiated without
Back pain in patients with cancer, especially confirmation of the diagnosis. Dexamethasone
pain of recent onset and worsening pain, is the most commonly used glucocorticoid. A
should be taken very seriously and considered typical initial dose is 10 to 16 mg IV followed
to be secondary to MSCC until proven by 4 mg every 4 to 6 hours. The use of higher
otherwise. A careful history and a thorough doses of dexamethasone (up to 100 mg) may
physical examination including a neurologic result in a slightly better neurologic outcome
examination are critical when evaluating but is associated with a higher risk of adverse
back pain in patients with cancer. Weakness is events and is not universally supported in the
the second most common presenting feature literature.151-155 High-dose dexamethasone
of MSCC, and patients may report heaviness can be considered in patients with severe and
or clumsiness of an extremity, which on progressive neurologic deficits in whom the
examination is secondary to motor weakness. small potential gain may outweigh the risks.
Up to 70% of patients are unable to walk at Almost all patients with MSCC should
the time of presentation.120,127,132 Sensory be evaluated urgently for a decompressive
deficits usually occur after motor deficits, surgical procedure. A randomized clinical trial
and up to 70% of patients will have sensory evaluated surgical intervention in addition
deficits at diagnosis.127 Autonomic symptoms to high-dose dexamethasone and radiation
such as loss of bladder and bowel function therapy.156 The trial was stopped early

FIGURE 4. Metastatic 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.
because the predetermined criteria were met, Radiation therapy remains the mainstay of
with surgical patients more likely to be able the treatment for most patients with MSCC,
to walk after therapy compared with those whether they do or do not undergo a decom-
who received radiation and dexamethasone pressive surgical procedure. Multiple radiation
alone (84% vs 57%; P¼.003). Furthermore, regimens are in use, but none has emerged as
patients in the surgical group remained ambu- the standard.155,160,161 Shorter courses of radi-
latory for a longer period (122 days vs 13 ation therapy may be as effective as longer
days) and had better survival. An unplanned courses, especially for patients with poor
subgroup analysis suggested that the benefit prognosis.162-164 Stereotactic radiosurgical
was related to age, with younger patients being procedures may be considered in selected
more likely to benefit.157 Other researchers cases, especially after resection.165-167
have questioned the generalizability of the
results of the trial to a broader cohort of Brain Metastases
patients because the study patients were high- Brain metastases are a common complication
ly selected. Moreover, the outcome in the in cancer, occurring in up to 20% of pa-
nonsurgical group was inferior to that found tients.168 The incidence of symptomatic brain
in other studies. A matched pair analysis metastases is not well known, but autopsy
comparing patients who underwent surgical studies have found that the prevalence of brain
intervention plus radiotherapy with patients metastases is higher than clinically appreciated
receiving radiotherapy alone did not show a antemortem.169,170 The cancers most likely to
benefit from surgical intervention.158 Until metastasize to the brain are lung cancer (both
more data become available, it is appropriate nonesmall cell and small cell), breast cancer,
to have most patients evaluated for a decom- renal cell cancer, and malignant mela-
pressive surgical procedure, especially younger noma.171,172 About 50% of brain metastases
patients and those with better performance are solitary.171
status, evidence of spinal instability, or rapidly
progressive symptoms. A scoring system has Pathophysiology. Brain metastases arise sec-
been proposed to predict the prognosis of ondary to hematogenous dissemination of tu-
patients with MSCC, and those in the poorest mor cells to the brain. The biology of brain
prognosis group may best be served with cor- metastases is complex.173 The distribution
ticosteroids, short-course radiation therapy, within the brain reflects the distribution of
and best supportive care.159 blood flow, with 80% of brain metastases
n n
into a brain metastasis can result in sudden

and severe symptoms.
Contrast-enhanced MRI is the most sensi-
tive imaging modality for brain metastases
(Figure 5).178,179 Contrast-enhanced CT can
be used when MRI is either unavailable or
contraindicated but is less sensitive for smaller
tumors and posterior fossa tumors. Noncon-
trast CT is helpful when an intracranial hem-
orrhage is suspected.
Treatment. The prognosis of most patients

with brain metastases is poor, and other fac-
tors in addition to the presence of brain metas-
tases determine the prognosis. Those factors
include the tumor type, age at diagnosis, the
FIGURE 5. Contrast-enhanced T2-weighted performance score, and the presence of extra-
magnetic resonance image showing symptom- cranial disease. Several scoring systems have
atic cerebellar metastasis with associated cere- been proposed, and one useful and accurate
bellar edema and distortion of the fourth system is the Graded Prognostic Assessment,
ventricle in a patient with esophageal
which is easily applied in clinical practice.180
adenocarcinoma.
Patients with poor performance may be best
served with supportive care alone. Table 7 lists
treatment options for intracranial hyperten-
sion and seizures. Glucocorticoids are indi-
occurring in the cerebral hemispheres,169 15% cated in all symptomatic patients with cerebral
in the cerebellum, and 3% in the brain stem. edema secondary to metastases, and the effect
Brain metastases are frequently located in the of therapy occurs within several hours.175 A
watershed areas of the arterial circulation and commonly used glucocorticoid is dexametha-
at the junction of gray and white matter.174 sone, but others are likely as effective as long
Brain metastases frequently result in cerebral as they are given in equipotent doses.181
edema and subsequently elevated intracranial Dexamethasone is generally preferred
pressure. The etiology of the edema is com- because it has a long half-life and less miner-
plex and includes vasogenic edema secondary alocorticoid activity.181 The optimal dose is
to leaky capillaries, stasis from impaired unknown, but one trial reported no benefit of
venous drainage, and obstruction of cerebro- higher doses of dexamethasone (16 mg/d) vs
spinal fluid by the tumor.175 lower doses (4-8 mg/d) in patients with no
signs of impending brain herniation.182
Clinical Presentation and Diagnosis. Most Therefore, a reasonable starting dose is 4 to
patients presenting with brain metastases 8 mg/d unless the patient has severe symp-
have a known diagnosis of cancer, and the toms, in which case 16 mg/d can be consid-
highest incidence is in patients with advanced ered.183 Dexamethasone has excellent oral
malignant disease.176 Brain metastases can also bioavailability and can therefore be given
be the first presentation of a malignant disor- orally in patients with intact mentation and a
der. The presenting features of brain metasta- functioning gastrointestinal tract. The dexa-
ses are variable, but headache is the most methasone should be tapered over 3 to 4
common symptom.174,177 Other symptoms weeks after more definitive therapy. Patients
depend on the location of the lesion within the with asymptomatic brain metastases and
brain. Common symptoms include motor and minimal edema do not need glucocorticoids.
sensory deficits, speech disturbance, unstead- Seizures occur in 10% to 20% of patients and
iness, and cognitive decline. Up to 10% of should be treated aggressively.184 Prophylactic
patients have seizures, usually when there are anticonvulsant therapy is not recommended
multiple brain metastases.174 A hemorrhage for patients who have not had seizures.185-188

TABLE 7. Management of Intracranial Hypertension and Seizures

Disorder Intervention Dosage and comments
Intracranial Dexamethasone 4-8 mg/d in divided doses; a higher dose can be used with severe
hypertension symptoms (10-16 mg IV followed by 4 mg IV every 6 h)
Seizures Lorazepam 2-4 mg IV (or 0.1 mg/kg up to 4 mg maximum) at 2 mg/min; total dose
capped at 4 mg
Phenytoin 20 mg/kg IV at 50 mg/min (25 mg/min in elderly patients and patients
with cardiovascular disorders)
Fosphenytoin 20 mg/kg PE at 150 mg/min
IV ¼ intravenous; PE ¼ phenytoin equivalent.
The treatment of refractory seizures in patients Typical symptoms of large or rapidly accumu-
with cancer is no different than that in patients lating effusions include dyspnea, cough, and
without cancer.189 More definitive therapy for chest pain. A physical examination may reveal
brain metastases, including resection, radia- tachycardia, hypotension, distant heart
tion, and chemotherapy, is offered to patients sounds, fixed jugular venous distention, pe-
with good performance status and more ripheral edema, and pulsus paradoxus. In
favorable prognosis.168,190 Surgical resection addition, patients with tamponade can have
can rapidly decrease the intracranial pressure, hypotension and shock.193,194 Electrocardi-
especially in patients with tumors in the pos- ography frequently reveals low-voltage and
terior fossa. A neurosurgeon should be con- nonspecific ST-T changes. Electrical alternans
sulted for all cases in which an operative (beat-to-beat variations in the QRS complex
intervention may be indicated. size and shape) is thought to be caused by the
heart moving within the enlarged and fluid-
CARDIOVASCULAR EMERGENCIES filled pericardium but can be seen in other
cardiac conditions (Figure 6).195 The diagnosis
Malignant Pericardial Effusion and Cardiac of pericardial effusions and tamponade is best
Tamponade made by echocardiography, which confirms
Pericardial effusions are commonly seen in pa- the presence of the effusion but also provides
tients with advanced and metastatic malignant hemodynamic information (Figure 7).196
diseases, but most patients are asymptomatic Computed tomography and MRI can also
and do not require urgent therapy. Pericardial provide valuable information, especially
effusions in patients with cancer are not regarding tumor invasion and metastases to
always related to the malignant disease itself the pericardium.197 Cytological examination
and may also be secondary to cancer therapy, of the pericardial fluid may reveal malignant
especially radiotherapy, or a manifestation cells, but occasionally a pericardial biopsy is
of either an infection or an autoimmune needed to establish the diagnosis.
process.191,192
Treatment. Small and asymptomatic pericar-
Pathophysiology. Pericardial effusions in pa- dial effusions do not need to be treated. Pa-
tients with cancer can be secondary to metas- tients with symptomatic effusions, especially
tases to the pericardium, tumor invasion of the with rapidly developing symptoms and hemo-
pericardium, or treatment related. Large effu- dynamic instability, may need urgent interven-
sions, especially if they accumulate rapidly, tions. Therapeutic echocardiographically
can impair ventricular filling and reduce car- guided pericardiocentesis is a safe procedure
diac output.193 Patients with slowly accumu- that can immediately relieve symptoms and
lating effusions are frequently asymptomatic improve hemodynamics, but a more durable
despite large effusions. treatment is usually needed.198 A pericardial
drain can be placed for drainage, and in
Clinical Presentation and Diagnosis. Small selected cases, surgical procedures or instilla-
pericardial effusions are often asymptomatic. tion of a sclerosing agent may be used.199,200
n n
FIGURE 6. Electrocardiogram 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.
Systemic chemotherapy and/or radiotherapy compression below the azygos vein can result
may prevent reaccumulation in some in more severe symptoms, highlighting the
patients.192 importance of the azygos vein as a collateral
vessel.205
Superior Vena Cava Syndrome
Superior vena cava syndrome (SVCS) occurs Clinical Presentation and Diagnosis. Superior
in the setting of an extrinsic compression or vena cava syndrome can be acute, subacute, or
other occlusion of the superior vena cava more insidious and sometimes occurs with
(SVC). It is a common complication of cancer, minimal symptoms. Very highly proliferative
and thoracic malignant disorders are the most tumors and SVC thrombosis can result in a
common cause of SVCS.201,202 Superior vena rapid onset of symptoms. Common symptoms
cava syndrome can also be seen as a complica- include dyspnea, orthopnea, cough, sensation
tion of benign conditions such as SVC throm- of fullness in the head and face, and headache,
bosis secondary to indwelling venous lines or often exacerbated by stooping. Less common
pacemaker leads as well as a complication of symptoms are chest pain, hemoptysis, hoarse-
fibrosing mediastinitis and histoplasma ness, dizziness, light-headedness, and even
infection.201,203,204 syncope. The most common physical findings
are facial and neck swelling, arm swelling, and
Pathophysiology. The thin-walled SVC can dilated veins in the chest (Figure 8, A), neck,
easily be compressed by tumors outside of the and proximal part of the arms. Stridor and
vessel, resulting in impaired venous drainage mental status changes are worrisome signs
from the head, neck, and upper extremities. and indicate laryngeal edema and increased
The compressing tumors are frequently in the intracranial pressure, respectively. A grading
middle or anterior mediastinum and the right system for SVCS has been proposed that can
paratracheal and precarinal nodal regions. The easily be applied in clinical practice
compression results in the formation of (Table 8).206 Computed tomography with IV
venous collaterals, including the azygos vein. contrast is the most useful method of diag-
Superior vena cava syndrome secondary to a nosing SVCS (Figure 8, B).202,207 A plain chest

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 sec-
ondary to lymphoma relieve symptoms
but should typically not be given until the
diagnosis has been established with a biopsy
FIGURE 7. Transthoracic echocardiographic because corticosteroids may obscure the
subcostal 4-chamber view showing a large pathologic diagnosis. Corticosteroids have
circumferential pericardial effusion. Image little or no role in SVCS secondary to lung
courtesy of Dr S. Allen Luis, Division of Car- cancer.212 Anticoagulation should be reserved
diovascular Diseases, Mayo Clinic. for patients with evidence of an SVC thrombus
or other venous thromboembolic complica-
tions and considered for patients who undergo
radiograph may suggest SVCS, usually by a stent placement. Catheter-directed throm-
showing a right hilar mass. Magnetic reso- bolysis can be useful in SVCS secondary to a
nance imaging is particularly helpful in cases thrombus.213 More definitive therapy, such
in which the administration of IV contrast is as systemic therapy and radiation therapy,
contraindicated. is dictated by the underlying cancer, which
also is the primary determinant of the patient’s
Treatment. Although SVCS is commonly prognosis.
considered an oncological emergency, most
cases are not.206,208,209 Patients with symp- PULMONARY EMERGENCIES
toms and signs concerning for cerebral and/or
airway edema and circulatory instability need Acute Airway Obstruction
urgent initiation of therapy (Table 8). In cases Malignant thoracic and mediastinal tumors
in which the etiology is not yet known, there can erode into the major airways or cause
is usually time to establish a diagnosis extrinsic compression leading to airway
before starting therapy. Endovascular stenting obstruction. The most common cause of
of the SVC can promptly relieve symptoms cancer-related airway obstruction is lung
of SVCS and is the treatment of choice in cancer, and up to one-third of patients
very symptomatic patients (Figure 9).210,211 may experience airway obstruction during
Radiation therapy is effective for many pa- the course of the illness.214 Other cancers,
tients, but the relief of symptoms may be slow. including anaplastic thyroid cancer,
FIGURE 8. Superior 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.
n n
TABLE 8. Grading of Superior Vena Cava Syndrome

Grade Category Definition Urgent treatment needed
0 Asymptomatic Radiographic superior vena cava obstruction in the absence of symptoms No
1 Mild Edema of the head or neck (vascular distention), cyanosis, plethora No
2 Moderate Facial and neck edema with functional impairment (mild dysphagia, cough, mild No
or moderate impairment of head, jaw, or eyelid movements, visual
disturbances caused by ocular edema)
3 Severe Mild or moderate cerebral edema (headache, dizziness) or mild/moderate Yes
laryngeal edema or diminished cardiac reserve (syncope after bending)
4 Life-threatening Severe cerebral edema (confusion, obtundation), laryngeal edema (stridor), Yes
or hemodynamic compromise (syncope without precipitating factors,
hypotension, renal insufficiency)
5 Fatal Death Not applicable
206
Adapted from J Thorac Oncol, with permission from the International Association for the Study of Lung Cancer.
squamous cell cancers of the head and neck, Airway stenting, laser therapy, argon plasma
and mediastinal malignant diseases such coagulation, photodynamic therapy, and
as lymphoma and germ cell tumor, can brachytherapy have all been used in the
also cause airway obstruction. Primary management of central airway obstruction and
tracheal tumors are a rare cause of airway result in substantial relief of symptoms in most
obstruction. patients.218,219 Interventions such as stent
placement can have severe negative conse-
Clinical Presentation and Diagnosis. The quences such as subsequent airway in-
most common symptoms include dyspnea, fections.220,221 External beam radiation
cough, wheezing, hemoptysis, and stridor, therapy and systemic chemotherapy play an
and the manifestations depend on the severity important role in the subsequent management
and location of the obstruction.215,216 The of malignant airway occlusion.
symptoms of airway obstruction can resemble
symptoms of worsening chronic obstructive Acute Airway Hemorrhage
pulmonary disease, which is a common co- The etiologies of hemoptysis are diverse and
morbidity in patients with lung cancer. The vary with anatomic location. Malignant disease
physical examination frequently reveals focal is among the most common causes of hemop-
wheezing on auscultation and inspiratory tysis. Tumors eroding into the airways can
stridor. Computed tomography is the cause hemoptysis, which usually is not an
preferred method of evaluation and provides emergency. Substantial airway hemorrhage
information on the extent of the cancer as well leads to hypoxemia and can be fatal.222,223
as the airway involvement. The obstruction The definition of massive hemoptysis is not
can be visualized with bronchoscopy, and bi- well established, and definitions of 100 to
opsies can be performed at the same time if 600 mL of bloody expectoration over 24 hours
needed. have been used.224 Airway hemorrhage is
commonly divided into proximal and distal
Treatment. The treatment of airway obstruc- airway bleeding, and the causes and manage-
tion requires good visualization of the larger ment differ according to the anatomic loca-
airways, which usually necessitates the use of tion.225 Lung cancer is the most common
rigid bronchoscopy.216 The goal of therapy is cause of massive hemoptysis, but other can-
to restore airway patency, which can be ach- cers, especially squamous cell carcinoma of
ieved with a variety of modalities.217 Supple- the head and neck, can bleed profusely into
mental oxygen should be given to patients the airways.
awaiting interventions, and bronchodilator
therapy may be indicated in patients with Clinical Presentation and Diagnosis. Patients
coexisting obstructive small airways disease. usually present with expectoration of bloody

FIGURE 9. Insertion 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.
mucus or frank blood. Other symptoms and in the unaffected lung. If the patient is intu-
signs include dyspnea, respiratory distress, bated, the bronchial main stem of the affected
hypoxia, and hemodynamic instability. It is side can also be selectively intubated to avoid
important to promptly identify the source of bleeding into the unaffected side. Administra-
bleeding in patients with hemoptysis who are tion of IV fluids and blood products may be
considered for more aggressive therapy. needed for stabilization, especially in patients
Computed tomography, especially CT angiog- with hemodynamic instability or thrombocyto-
raphy, can provide important information penia. Coagulation abnormalities should
regarding the location of the bleeding and be corrected as indicated with blood products
may help select an appropriate treatment strat- and reversal of anticoagulants if needed.
egy.226,227 Bronchial artery angiography Recombinant factor VII has been used to
frequently reveals the bleeding location, and treat massive hemoptysis in patients with
therapeutic embolization can be performed at cancer and can be considered when other mea-
the same time. sures fail.228,229 Rigid bronchoscopy is the
preferred method for control of airway hemor-
Treatment. As with acute airway obstruction, rhage, but other treatments are frequently
securing the airway is of utmost importance. needed.225 Bronchial artery angiography can
The patient should be positioned in the lateral identify the bleeding vessel(s), and embolization
decubitus position with the bleeding side can be performed during the procedure, often
down, if known, to preserve alveolar exchange with successful control of the bleeding.230-232
n n
Massive hemoptysis is extremely distress- substantial variations depending on the regi-

ing to both patients and their caregivers and mens used and the patient characteristics.
is often a terminal event in the disease course. Preexisting comorbidities such as liver or
Best supportive care without further interven- kidney dysfunction as well as concurrent use
tions may be appropriate in selected cases. of certain drugs can increase the severity and
Intravenous administration of opioids and duration of the neutropenia (Table 9). Patients
benzodiazepines may provide substantial relief with bone marrow dysfunction, especially
but with the risk of suppressing respiratory acute leukemia, myelodysplastic syndromes,
drive. Darkly colored bed sheets, pillowcases, and aplastic anemia, as well as drug- or
and towels may decrease the psychological radiation-induced neutropenia can present
trauma associated with massive hemoptysis. with febrile neutropenia in the absence of
cytotoxic chemotherapy. Factors other than
INFECTIOUS EMERGENCIES the neutropenia itself play a role in the path-
ogenesis of febrile neutropenia. Chemotherapy
Febrile Neutropenia can disrupt mucosal barriers, making the risk
Infections are common in patients with cancer of gram-negative sepsis greater. Indwelling
and a major contribution to both morbidity vascular devices can serve as the port of entry
and mortality. Most infections in patients for organisms that colonize the skin such as
with cancer are not emergencies and can be gram-positive cocci. Hematologic cancers are
treated in the outpatient setting. Febrile neu- often associated with defects in both humoral
tropenia is a common complication in patients and cellular immunity, further adding to the
undergoing therapy for malignant disease. immunosuppressive effects of the cancer-
Prompt diagnosis and initiation of therapy directed therapy.
are of key importance in decreasing morbidity
and mortality and can also decrease costly hos- Microbiology. Most patients with febrile neu-
pitalizations. For the purpose of this review, tropenia will not have a specific microbial
we use the definitions of the Infectious Dis- pathogen isolated during their illness, and a
eases Society of America. Fever is defined as focus of an infection may not be identified.
a single oral temperature higher than 38.3 C A bacterial pathogen is isolated in less than
or a temperature higher than 38.0 C sustained 30% of patients during an episode of febrile
for more than 1 hour.233 Neutropenia is neutropenia and is more common in patients
defined as an absolute neutrophil count with prolonged or profound neutropenia.233
(ANC) of less than 0.5 109/L or an ANC The epidemiology of bacterial infections dur-
that is expected to decrease to less than ing neutropenia has changed markedly in
0.5 109/L during the next 48 hours.233,234 recent decades. Gram-negative bacteria were
An ANC level of less than 0.1 109/L is the most commonly identified cause of febrile
defined as profound neutropenia.233 neutropenia in the past, but more recently, the
incidence of gram-positive infections has sur-
Pathophysiology. Febrile neutropenia is most passed those caused by gram-negative bacte-
common in patients receiving cytotoxic ria.236,237 In recent years, an increase in the
chemotherapy, especially patients with acute incidence of gram-negative bacteria has been
leukemia. Febrile neutropenia is much less observed, but infections with gram-positive
common in patients undergoing therapy for bacteria are still in the majority.238,239 The
solid tumors given the less intensive therapy. most common gram-positive bacteria are
Some malignant disorders, especially sarcomas coagulase-negative staphylococci. Among the
and germ cell tumors, require high-intensity gram-negative bacteria, Escherichia coli, Kleb-
chemotherapy, which increases the risk of siella, and Pseudomonas aeruginosa are the
febrile neutropenia (Table 9).235 The risk of most commonly isolated. Fungal and viral
febrile neutropenia depends on both the infections are also frequently encountered.
severity and duration of neutropenia. The The risk of fungal infections increases with the
neutrophil nadir usually occurs 5 to 10 days duration and severity of the neutropenia and is
from initiation of therapy, and neutrophil re- a common etiology of persistent neutropenic
covery begins about 5 days later, but there are fever in patients treated empirically with

TABLE 9. Risk Factors for Febrile Neutropenic Episodes

Risk factors Effect on risk Reported febrile neutropenia rate
Patient characteristics
Advanced age Increased risk if age 65 y NA
ECOG performance status Increased risk if 2 NA
Nutritional status Increased risk if albumin <35 g/L (3.5 g/dL) NA
Prior febrile neutropenia Increased risk if FN during the first cycle NA
Comorbidities FN odds increase by 27%, 67%, and 125%, NA
respectively, for 1, 2, or 3 comorbidities
Underlying malignant disorder
Acute leukemia/MDS NA 85%-95%
Soft tissue sarcoma NA 27%
NHL/myeloma NA 26%
Germ cell tumors NA 23%
Hodgkin lymphoma NA 15%
Ovarian carcinoma NA 12%
Lung cancer NA 10%
Colorectal cancer NA 5%
Breast cancer NA 5%
Prostate cancer NA 1%
Cancer stage Increased risk if stage II or higher NA
Remission status Increased risk if not in remission NA
Treatment response Increased risk in patients not responding to therapy NA
Treatment characteristics
Cytotoxic regimen Increased risk with higher doses of chemotherapy NA
Degree and duration of mucositis Higher risk with more severe mucositis NA
Neutropenia Absolute neutrophil count <0.5 109/L for 7 d NA
Lymphopenia Absolute lymphocyte count <0.7 109/L NA
Monocytopenia Absolute monocyte count <0.15 109/L NA
Prophylactic use of growth factors Reduces the risk in selected populations NA
ECOG ¼ Eastern Cooperative Oncology Group; FN ¼ febrile neutropenia; MDS ¼ myelodysplastic syndrome; NA ¼ not available; NHL ¼ non-Hodgkin lymphoma.
Adapted from Flowers CR et al. J Clin Oncol. 2013;31(6):794-810.235 Reprinted with permission. ª2013 American Society of Clinical Oncology. All rights reserved.
broad-spectrum antibiotics. A more detailed soft tissue infection may be erythema. The
review of the microbiology of febrile neu- oral cavity should be examined for the presence
tropenia is outside the scope of this review, of mucosal ulcers and periodontal disease. The
but it is important to understand that there are skin should be carefully evaluated. All sites of
substantial geographic variations, both in the indwelling venous devices should be thor-
type of pathogens implicated and in their oughly examined for erythema and tenderness.
resistance patterns regarding antimicrobial For example, port sites and line exit sites should
therapy. be gently palpated and all dressings removed if
needed for better visualization. Abdominal
Clinical Presentation and Diagnosis. The examination may reveal tenderness suggestive
predominant sign at diagnosis is fever, but of enterocolitis, and examination of the lungs
patients may also present with localizing symp- can identify focal abnormalities or tachypnea.
toms and signs. A thorough history and phys- The perianal region should be examined for
ical examination are essential in the initial erythema and tenderness, but a digital rectal
evaluation of patients with febrile neutropenia, examination should be avoided. Central ner-
even though a focus of infection is frequently vous system infections may present with
not found. Emphasis should be placed on the nonspecific symptoms of confusion or subtle
oral cavity and oropharynx, skin, lungs, focal findings. Patients should undergo risk
abdomen, and perianal area. Because of the assessment at presentation, as factors such as
lack of neutrophils, clinical and laboratory find- advanced age, poor performance status, and
ings may be atypical. Purulence and swelling comorbidities may increase the risk of serious
are frequently absent, and the only sign of a complications.
n n
A complete blood count with differential, Patients with low risk can be considered
liver chemistry tests, electrolyte panels, lactic for outpatient IV or possibly oral antibiotic
acid measurements, coagulation tests, and therapy assuming they meet certain
creatinine measurements should be performed criteria.234,235,247 A useful risk stratification
at presentation. At least 2 sets of blood spec- tool is the Multinational Association for Sup-
imens should be collected for cultures, with portive Care in Cancer risk index score
one from a peripheral vein. If the patient (Table 10).248 Other risk stratification models
has an indwelling venous access device, spec- exist, such as the National Comprehensive
imens for culture should be obtained from Cancer Network guidelines for management
each lumen in addition to a culture specimen of cancer-related infections249 and the Clinical
from a peripheral vein. Other samples should Index of Stable Febrile Neutropenia.250 Pa-
be collected as clinically indicated, such as tients with anticipated longer duration and
urine and stool samples. Very neutropenic pa- greater severity of neutropenia (>7 days,
tients may not have pyuria, pulmonary infil- ANC <0.5 109/L) as well as patients with
trates, or cerebrospinal fluid leukocytosis. major comorbidities are considered to be at
Samples should be obtained from skin lesions high risk and should be hospitalized for ther-
and sent for cultures, fungal stains, and viro- apy. Other indications for an admission
logic examation as indicated. Discharge from include the presence of renal or hepatic insuf-
any line exit sites should be submitted for ficiency, hypotension, severe mucositis, pneu-
bacterial cultures. A lumbar puncture should monia, hypoxia, new-onset abdominal pain,
be performed in patients with suspected neurologic changes including mental status
meningitis, but platelet transfusion should abnormalities, and suspected line infections.
be administered to patients with a platelet Patients with afebrile neutropenia who have
count of less than 50 109/L before the pro- new or worsening signs and symptoms of an
cedure. Chest radiography should be done in infection should be evaluated and treated as
all patients with respiratory signs and symp- being at high risk and be admitted to the hos-
toms, and CT imaging should be considered pital. For outpatient antibiotic therapy to be
in patients with high risk of complications. successful, the patient must have prompt ac-
Given its greater sensitivity, high-resolution cess to health care professionals for evaluation
CT should be performed in patients with sus- as needed; have reliable transportation and
pected respiratory infection but no abnormal- access to a telephone; and have a reliable
ities on chest radiography.240 The role of caregiver who is with them all the time. If
circulating blood markers such as C-reactive there are any doubts regarding the safety of
protein and procalcitonin is unclear. Procalci- outpatient therapy, the patient should be
tonin may have a role when used with other hospitalized. A recommended outpatient oral
predictors in risk stratification of patients regimen is a combination of amoxicillin/
with febrile neutropenia.241,242 clavulanic acid and ciprofloxacin, but this
regimen will depend on many factors includ-
Treatment. Early recognition and treatment ing clinical presentation, absence of comorbid-
of febrile neutropenia are key to successful ities, access to rapid advanced health care,
management (Figure 10). Not all patients antimicrobial prophylaxis, and resistance pat-
with neutropenic fever need to be admitted to terns.251,252 Patients previously taking a pro-
the hospital. Empirical antibiotic therapy phylactic fluoroquinolone antibiotic should
should be initiated without delay once sam- not receive fluoroquinolone-based empirical
ples for microbial cultures have been obtained. antibiotic therapy.234 Low-risk patients with
Delays in the initiation of antimicrobial ther- hematologic cancers can be treated as outpa-
apy have been associated with inferior out- tients with IV chemotherapy, often in a
comes in patients admitted to the hospital hospital-based outpatient environment.
with sepsis.243,244 A systemic and algorithmic Monotherapy with a broad-spectrum
method to identify patients with febrile neu- cephalosporin such as cefepime, a carbape-
tropenia and start appropriate therapy has nem, or an antipseudomonal b-lactam such
been found to reduce the time from triage to as piperacillin/tazobactam is recommended as
initiation of antibiotics.245,246 initial therapy by the Infectious Diseases

Temperature ≥38.3ºC and ANC ≤0.5×109/L
Calculate MASCC score
Low risk (≥21) High risk (<21)
Are there
contraindications to Yes
Admit to hospital
outpatient therapy
(see text for details)?
No
Contact primary or on-call Empiric inpatient antibiotic therapy

hematologist/oncologist • Piperacillin/tazobactam
• Cefepime
• Carbapenem
• Ceftazidime
Does consultant agree with No
outpatient therapy?
Yes
Is there need for additional
Ciprofloxacin +
gram-positive coverage (Table 11)?
amoxicillin/clavulanic acid
If yes, add an appropriate antibiotic
for gram-positive bacteria such as
vancomycin as indicated
Daily follow-up by a
health care professional
Continue outpatient therapy

No Yes until the neutropenia has
Clinical deterioration? Continue monitoring? Clinical improvement?
resolved and patient afebrile
for 3-4 days
Yes No
Admit to hospital
FIGURE 10. Algorithm for initial management of febrile neutropenia. ANC ¼ absolute neutrophil count; MASCC ¼ Multinational
Association for Supportive Care in Cancer.
Society of America.233 Gram-positive coverage there is a high risk for or suspicion of a fungal
should be considered in selected patients and or viral infection. The role of myeloid growth
not employed routinely for all patients. Pa- factors is uncertain. They may reduce the
tients with hypotension, sepsis, or suspected duration of hospital stay but do not seem to
catheter-related infection should receive an improve mortality.253 Myeloid growth factors
antibiotic with adequate gram-positive activity can be considered in patients with neutropenic
such as vancomycin. Table 11 lists other indi- fever who are at risk of severe complications.
cations for gram-positive coverage. Knowledge Such patients include those with expected
of the susceptibility patterns in the community prolonged (>10 days) and profound neutro-
and within institutions and hospitals is impor- penia, pneumonia, hypotension, uncontrolled
tant when selecting the appropriate initial primary cancer and multiorgan dysfunction,
therapy. Empirical antifungal or antiviral ther- or sepsis and those who are older than
apy is not routinely recommended unless 65 years.254
n n
UNIQUE EMERGENCIES RELATED TO

TABLE 10. MASCC Scoring System for Patients
SYSTEMIC TUMOR-DIRECTED THERAPY
With Neutropenic Fevera,b
Cytotoxic chemotherapy has a relatively pre-
Characteristic Score
dictable range of toxicities, most commonly
Burden of febrile neutropenia: no or 5 associated with the dose-related cytotoxic ef-
mild symptomsc fect on normal cells. Cytotoxic chemotherapy
No hypotension 5
can result in life-threatening complications
No chronic obstructive pulmonary disease 4
that can present as emergencies, such as
Solid tumor or no previous fungal infection 4
No dehydration 3
thrombotic microangiopathy with mitomycin
Burden of illness: moderate symptoms 3 C and gemcitabine, pulmonary toxicity with
Outpatient status 3 bleomycin and gemcitabine, and coronary va-
Age <60 y 2 sospasms from fluoropyrimidines. Many of the
newer targeted agents and immunotherapeutic
a
MASCC ¼ Multinational Association for Supportive Care in
Cancer. drugs are associated with unique and some-
b
Patients with a total score of 21 have a low risk of having times life-threatening toxicities.260 Cardiotox-
serious medical complications. icity of targeted therapies is increasingly
c
Burden of neutropenia reflects the clinical status of the patient being recognized as a major clinical problem,
and is scored on the following scale: no or mild symptoms,
often with acute presentations.261 With the
score of 5; moderate symptoms, score of 3; severe symptoms
or moribund, score of 0. Points attributed to the variable increasing use of immunotherapy for cancer,
“burden of febrile neutropenia” are not cumulative. There- we are likely to encounter more patients
fore, the maximum theoretical score is 26. with unusual complications of such therapy.
Adapted from Klastersky J et al. J Clin Oncol. 2000;18(16):3038- Immunotherapy can adversely affect multiple
3051.248 Reprinted with permission. Copyright ª2017
organs, most commonly the skin, gastrointes-
American Society of Clinical Oncology. All rights reserved.
tinal tract, endocrine system, and lungs,
and patients may present in an emergent
mannerdfor example, with adrenal insuffi-
Fever in Patients Without a Functional ciency or severe diarrhea leading to hypovole-
Spleen mia and shock.262 Newer immunologic
Patients who have either undergone a splenec- technologies such as bispecific antibodies
tomy or have functional asplenia are at (blinatumomab) or chimeric antigen receptor
increased risk of fulminant infections with T cells are frequently associated with serious
encapsulated bacteria such as Streptococcus or life-threatening cytokine release syndrome
pneumoniae, Haemophilus influenzae, and (CRS).263 A CRS grading system has been
Neisseria meningitidis.255,256 The risk of severe described by Lee et al.263 Specific therapies
infections in asplenic patients is the highest in such as tocilizumab, an antieinterleukin 6
the first few years after splenectomy when it receptor inhibitor, have efficacy in treating
may be as high as one infection per 14 CRS but require experience and judgment
patient-years, but the risk persists for de- as to timing of use to minimize the impair-
cades.257,258 Sepsis in asplenic patients has a ment of efficacy while maximizing safety.
high risk of mortality.259 Asplenic and hypo-
splenic patients with fever should be evaluated
immediately, and empirical antibiotic therapy TABLE 11. Indications for the Addition of a Gram-Positive Antibiotic in the
should be initiated once blood has been drawn Empirical Management of Febrile Neutropenia
for cultures. Patients who are not acutely ill Hypotension or hemodynamic instability
can be treated with ceftriaxone or cefotaxime. Sepsis syndrome
More severely ill patients should receive dual Radiographically documented or strongly suggested pneumonia
therapy with a combination of ceftriaxone or Known colonization with methicillin-resistant Staphylococcus aureus, vancomycin-
cefotaxime and vancomycin because of con- resistant enterococcus, or penicillin-resistant streptococci
cerns for penicillin-resistant pneumococci or Blood cultures positive for gram-positive bacteria
b-lactamaseeproducing H influenzae. A com- Skin or soft tissue infections
Severe mucositis
bination of moxifloxacin or levofloxacin and
Previous use of fluoroquinolones as prophylactic therapy
vancomycin can be used in patients with
Suspected catheter-related infection
allergy to b-lactam antibiotics.

TABLE 12. Emergencies and Other Urgent Adverse Events Related to Targeted Cancer Therapies
Organ system affected Class of drug Example
Cardiovascular
Congestive heart failure HER2-directed therapy Trastuzumab, pertuzumab
Immunotherapy Ipilimumab, nivolumab, pembrolizumab
Arterial thromboembolism VEGF-directed therapy Bevacizumab, aflibercept, ramucirumab
Kinase inhibitors Ponatinib, pazopanib
Venous thromboembolism Immunomodulatory drugs Thalidomide, lenalidomide
Arrhythmia Kinase inhibitors Dasatinib, vandetanib, ibrutinib, lenvatinib
Antiemetics Ondansetron, metoclopramide
Protesome inhibitors Bortezomib, carfilzomib
Pulmonary
Pneumonitis mTOR inhibitors Everolimus, temsirolimus
Kinase inhibitors Erlotinib, gefitinib, crizotinib, idelalisib
Pleural effusions Kinase inhibitors Dasatinib
Gastrointestinal
Bowel perforation VEGF inhibitors Bevacizumab
Diarrhea Kinase inhibitors Multiple TKIs
Immunotherapy Ipilimumab, nivolumab, pembrolizumab
Acute liver failure Multiple targeted agents
Endocrine
Adrenal insufficiency Immunotherapy Ipilimumab, nivolumab, pembrolizumab
Hypophysitis Immunotherapy Ipilimumab, nivolumab, pembrolizumab
Hyperglycemia mTOR inhibitors Everolimus, temsirolimus
Hematologic
Hemorrhage VEGF inhibitors Bevacizumab, aflibercept, ramucirumab
Neutropenia Multiple targeted agents
Thrombocytopenia Multiple targeted agents
HER2 ¼ human epidermal growth factor receptor 2; mTOR ¼ mammalian target of rapamycin; TKI ¼ tyrosine kinase inhibitor; VEGF ¼
vascular endothelial growth factor.
A detailed discussion of the emergent toxic- Abbreviations and Acronyms: AML = acute myeloid
ities secondary to noncytotoxic systemic leukemia; ANC = absolute neutrophil count; CNS = central
nervous system; CRS = cytokine release syndrome; CT =
therapy is outside the scope of this review.
computed tomography; IV = intravenous; MRI = magnetic
Table 12 lists examples of targeted therapies resonance imaging; MSCC = malignant spinal cord
associated with acute and life-threatening compression; PTH = parathyroid hormone; PTHrP = PTH-
complications. related peptide; RANKL = receptor activator of nuclear
factor kB ligand; SVC = superior vena cava; SVCS = SVC
syndrome; TLS = tumor lysis syndrome; WM = Walden-
CONCLUSION ström macroglobulinemia
Patients with cancer commonly present with Correspondence: Address to Thorvardur R. Halfdanarson,
emergent complications of either the malignant MD, Division of Medical Oncology, Mayo Clinic, 200 First
disease itself or the therapy they are receiving. St SW, Rochester, MN 55905 (halfdanarson.thorvardur@
Practicing clinicians can therefore expect to mayo.edu). Individual reprints of this article and a bound
encounter such patients in emergency depart- reprint of the entire Symposium on Neoplastic Hematology
and Medical Oncology will be available for purchase from
ments or outpatient offices. Prompt evaluation our website www.mayoclinicproceedings.org.
and accurate diagnosis followed by the institu-
tion of appropriate therapy can be lifesaving The Symposium on Neoplastic Hematology and Medical
and may prevent irreversible loss of organ func- Oncology will continue in an upcoming issue.
tion. A sound knowledge of oncological and
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SYMPOSIUM ON NEOPLASTIC HEMATOLOGY AND MEDICAL ONCOLOGY

Emergencies in Hematology and Oncology

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 609

TABLE 1. Treatment of Hypercalcemia

The diagnosis of hypercalcemia is con- while awaiting laboratory results such as

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 611

of nucleic acids results in hyperuricemia. High

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 613

EMERGENCIES IN HEMATOLOGY AND ONCOLOGY

Rasburicase Flat ﬁxed dose of 3 mg IV Contraindicated in G6PD deﬁciency

saline; PO ¼ orally; TLS ¼ tumor lysis syndrome.

best possible outcome. Frequent monitoring is of hyponatremia in these patients is multifac-

Patients with symptomatic hypoglycemia from HEMATOLOGIC EMERGENCIES

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 617

Measurements of immunoglobulin levels will

Pathophysiology. Rapid proliferation and dis-

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 619

leukemic blasts and reduce the likelihood of

in cord compression.127 Intramedullary and usually occur later in the course of

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 621

into a brain metastasis can result in sudden

Treatment. The prognosis of most patients

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 623

TABLE 7. Management of Intracranial Hypertension and Seizures

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 625

Tissue diagnosis should be established

TABLE 8. Grading of Superior Vena Cava Syndrome

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 627

Massive hemoptysis is extremely distress- substantial variations depending on the regi-

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 629

TABLE 9. Risk Factors for Febrile Neutropenic Episodes

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 631

Temperature ≥38.3ºC and ANC ≤0.5×109/L

Calculate MASCC score

Low risk (≥21) High risk (<21)

Contact primary or on-call Empiric inpatient antibiotic therapy

Continue outpatient therapy

UNIQUE EMERGENCIES RELATED TO

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 633

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 635

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 637

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 639

Mayo Clin Proc. n April 2017;92(4):609-641 n http://dx.doi.org/10.1016/j.mayocp.2017.02.008 641

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