Oncologic Emergencies and Urgencies A Comprehensive Review

CA CANCER J CLIN 2022;0:1–24
Oncologic emergencies and urgencies:

A comprehensive review
1
Bonnie E. Gould Rothberg, MD, PhD, MPH ; Tammie E. Quest, MD2; Sai-Ching J. Yeung, MD, PhD3; Lorraine C. Pelosof, MD, PhD4;
David E. Gerber, MD ; Justin A. Seltzer, MD6; Jason J. Bischof, MD7; Charles R. Thomas, Jr, MD8; Nausheen Akhter, MD9;
5
Mira Mamtani, MD, MSEd10; Robin E. Stutman, MD11; Christopher W. Baugh, MD, MBA12;
Venkataraman Anantharaman, MBBS, FRCP Edin.13; Nicholas R. Pettit, DO, PhD14; Adam D. Klotz, MD11; Michael A. Gibbs, MD15;
Demetrios N. Kyriacou, MD, PhD16,17
1
Yale Cancer Center Innovations
Laboratory, Yale Comprehensive Cancer Abstract: Patients with advanced cancer generate 4 million visits annually to emer-
Center, New Haven, Connecticut;
2 gency departments (EDs) and other dedicated, high-acuity oncology urgent care
Department of Emergency Medicine,
Emory University, Atlanta, Georgia; centers. Because of both the increasing complexity of systemic treatments overall
3
Department of Emergency Medicine, and the higher rates of active therapy in the geriatric population, many patients expe-
The University of Texas MD Anderson riencing acute decompensations are frail and acutely ill. This article comprehensively
Cancer Center, Houston, Texas; reviews the spectrum of oncologic emergencies and urgencies typically encountered
4
Office of Oncologic Diseases, US Food in acute care settings. Presentation, underlying etiology, and up-to-date clinical path-
and Drug Administration, Silver Spring, ways are discussed. Criteria for either a safe discharge to home or a transition of
Maryland; 5 Division of Hematology-
care to the inpatient oncology hospitalist team are emphasized. This review extends
Oncology, Harold C. Simmons
Comprehensive Cancer Center, University beyond familiar conditions such as febrile neutropenia, hypercalcemia, tumor lysis
of Texas Southwestern Medical School, syndrome, malignant spinal cord compression, mechanical bowel obstruction, and
Dallas, Texas; 6 Department of Emergency breakthrough pain crises to include a broader spectrum of topics encompassing the
Medicine, University of California syndrome of inappropriate antidiuretic hormone secretion, venous thromboembolism
San Diego, San Diego, California; and malignant effusions, as well as chemotherapy-induced mucositis, cardiomyopa-
7
thy, nausea, vomiting, and diarrhea. Emergent and urgent complications associated
The Ohio State University Wexner
Medical Center, Columbus, Ohio;
with targeted therapeutics, including small molecules, naked and drug-conjugated
8
Department of Radiation monoclonal antibodies, as well as immune checkpoint inhibitors and chimeric an-
Oncology, Geisel School of Medicine tigen receptor T-cells, are summarized. Finally, strategies for facilitating same-day
at Dartmouth, Norris Cotton Cancer direct admission to hospice from the ED are discussed. This article not only can
Center, Lebanon, New Hampshire; serve as a point-of-care reference for the ED physician but also can assist outpatient
9
Department of Medicine, Division of oncologists as well as inpatient hospitalists in coordinating care around the ED visit.
Cardiology, Northwestern University
Feinberg School of Medicine, Chicago,
Illinois; 10 Department of Emergency
Keywords: emergency medicine, hematology/medical oncology, internal medicine,
Medicine, University of Pennsylvania palliative care
Perelman School of Medicine,
Philadelphia, Pennsylvania;
11
Department of Medicine, Division of
Urgent Care Services, Memorial Sloan
Kettering Cancer Center, New York,
New York; 12 Department of Emergency Introduction
Medicine, Brigham and Women’s There are currently 16 million Americans living with cancer who account for
Hospital, Harvard Medical School,
approximately 4 million visits to emergency departments (EDs) each year.1 Patients
Boston, Massachusetts;
13
Department of Emergency with advanced cancer, especially those older than 65 years, exhibit a comparatively
Medicine, Singapore General Hospital, high frailty index characterized by the prevalence of disability, multiple medical
SingHealth Duke–National University of comorbidities, and ensuing polypharmacy such that the level of acuity among pa-
Singapore Academic Medical Center,
Singapore, Singapore; 14 Department of tients with cancer who are seeking emergency care is substantial.2 As oncology care
Emergency Medicine, Indiana University delivery has largely shifted to the outpatient clinic, complications are most likely
School of Medicine, Indianapolis, Indiana;
15
to arise outside of the hospital to require a separate acute care visit.3 These emer-
Atrium Health-Carolinas Medical Center,
gencies represent a wide spectrum of disorders resulting from initial manifestations
Charlotte, North Carolina; of malignancy, progression of known disease, recurrence of a previous cancer, and
16
Department of Emergency Medicine, adverse effects from therapy, and some can be life-threatening. Although growing
Northwestern University Feinberg School
numbers of large community oncology practices and tertiary cancer centers have
of Medicine, Chicago, Illinois;
17
Department of Preventive established dedicated, high-acuity, same-day oncology urgent care centers, many
Medicine, Northwestern University patients still require general ED care for acute symptom management.4,5 Here, we
Feinberg School of Medicine, Chicago, present a comprehensive review of the clinical aspects of oncologic urgencies and
Illinois.
VOLUME 0 | NUMBER 0 | MONTH 2022 1

Oncologic emergencies and urgencies
emergencies, including sections discussing paraneoplas- Table 1 enumerates 15 common primary cancers frequently
tic syndromes, structural complications, and adverse events diagnosed in the ED7 along with their expected number of
associated with chemotherapy, radiotherapy, and targeted new cases in 2021, 5-year survival rates when diagnosed at
therapies, with the latter including each of small-molecule, advanced stage, and presenting signs and symptoms likely
monoclonal antibody, and cell-based therapeutics. We also encountered in the ED.11-14
include sections that discuss the management of previously
undiagnosed cancers that present emergently, pain crisis, and Paraneoplastic Syndromes
end-of-life care in the ED as well as discuss areas of future Paraneoplastic syndromes occur in up to 15% of patients
research (Fig. 1). with cancer. The vast majority of paraneoplastic syndromes
are endocrine-mediated and involve the secretion of bioac-
Cancer Presentation as an Emergent Diagnosis tive substances. Syndrome of inappropriate antidiuretic hor-
Emergently diagnosed cancers account for 11% to 29% of mone (SIADH) is a hallmark of small cell lung cancer with
newly diagnosed cancers and are associated with lower 1- 10% to 15% of patients affected and otherwise is most com-
year survival rates, increased hospitalization rates, and poorer monly observed across a broad spectrum of aerodigestive tract
quality of life compared with cancers diagnosed during rou- tumors, in particular nonsmall cell lung cancer, as well as in
tine primary care.6 Lower socioeconomic status, older age, breast cancer and lymphomas.15 SIADH can also arise as a
race, underlying comorbidities, and, depending on the spe- physiologic response to extreme cancer pain. Eight percent
cific cancer, sex correlate with increased prevalence of ED- of patients with cancer develop paraneoplastic hypercalcemia
based cancer diagnoses.7 Decreased access to primary care because of tumor-based parathyroid hormone-related protein
and established screening schedules as well as more frequent secretion. This is most frequently observed in squamous cell
use of the ED for urgent care likely contribute.8 Thirty per- cancers, renal cell cancer, gynecologic malignancies, breast
cent of cancers that present emergently will already demon- cancer, and some lymphomas.16 Secretion of ectopic vitamin
strate distant metastases compared with 14% of electively D or parathyroid hormone rarely occurs. Hypercalcemia can
diagnosed cancers.9 Even among cancers for which robust, additionally present with local osteolytic metastases, such as
validated screening is available, those diagnosed as emer- in breast cancer and multiple myeloma, accounting for 20%
gencies are more likely to be higher grade and have arisen of malignancy-related hypercalcemia. Ectopic adrenocortico-
de novo between screening intervals.10 The most common tropic hormone syndrome is rare and difficult to treat. Most
emergently diagnosed malignancies are those in which commonly observed in small cell lung cancer (1%-6% of
patients present either with nonspecific symptoms (eg, cases) and bronchial carcinoids (1% of all cases), it can present
intra-abdominal malignancies that present with diffuse gas- in other tumors with neuroendocrine differentiation such as
trointestinal discomfort) or with minimal symptoms until a small cell prostate tumors.17,18 Up to 40% of upper gastro-
dramatic event occurs (eg, generalized seizure as the sentinel intestinal neuroendocrine tumors produce a broad spectrum
event for primary brain tumor or new cerebral metastases).6 of paraneoplastic syndromes, each determined according to
Corresponding Author: Bonnie E. Gould Rothberg, MD, PhD, MPH, Yale Cancer Center Innovations Laboratory, Yale Comprehensive Cancer Center, 35 Park Street
15th Floor, New Haven, CT 06510 (bonnie.gouldrothberg@gmail.com).
DISCLOSURES: No external funding sources were used to support the writing of this article. Bonnie E. Gould Rothberg reports stock or stock options in Butterfly
Networks Inc, Quantum Si, Hyperfine Research, AI Therapeutics, Detect Labs, Tesseract, Protein Evolution Inc, and Electric Futures outside the submitted work; in
addition, her children have been employed by 4 Catalyzer; her spouse has a leadership or fiduciary role in Butterfly Networks Inc, Quantum Si, Hyperfine Research,
AI Therapeutics, Detect Labs, and Tesseract; has patents planned, issued, or pending at ThermoFisher, Butterfly Networks Inc, Quantum Si, Hyperfine Research,
AI Therapeutics, Detect Labs, and Tesseract; and owns stock or stock options in Butterfly Networks Inc, Quantum Si, Hyperfine Research, AI Therapeutics,
Detect Labs, Tesseract, Protein Evolution Inc, Electric Futures, AbbVie, Amgen, Biocryst Pharma, Gilead, Regeneron, and Roche Holdings. Sai-Ching J. Yeung
reports research funding from Bausch Health, Bristol-Myers Squibb, and DepoMed, Inc; personal fees from Celgene, Inc; and honoraria from Medscape outside
the submitted work. David E. Gerber reports institutional grants from AstraZeneca, BerGenBio ASA, Karyopharm Pharmaceuticals, and Novocure; personal fees
from Adjuvant Genomics, Regeneron Pharmaceuticals, Catalyst Pharmaceuticals, Sanofi, BeiGene LtD, Mirati Therapeutics Inc, and Janssen Scientific Affairs LLC;
royalties from Oxford University Press; participation on a data safety monitoring board or advisory board for Janssen Pharmaceuticals, Regeneron, and Sanofi
Aventis; and stock ownership in Gilead all outside the submitted work. Justin A. Seltzer reports long-term stock ownership in Pfizer, Inc, outside the submitted
work and is a PEER Section Editor for the American College of Emergency Physicians. Charles R. Thomas, Jr, is Deputy Editor of JAMA Oncology and CA: A Cancer
Journal for Clinicians. Christopher W. Baugh reports grants/research support from Visby Medical, Inc; personal fees from AcelRx Pharmaceuticals, Inc, Lucia Health
Guidelines, LLC, Nabriva Therapeutics, Roche Diagnostics, and Salix Pharmaceuticals; and honoraria from Roche Diagnostics all outside the submitted work.
Demetrios N. Kyriacou reports personal fees from Wellstat Therapeutics, Genetesis, and Remagine Ventures outside the submitted work. The remaining authors
report no conflicts of interest.
The views contained in this article represent those of the authors and not necessarily those of the US Food and Drug Administration.
CA Cancer J Clin 2022;0:2-24 © 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer
Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
doi: 10.3322/caac.21727. Available online at cacancerjournal.com
2 CA: A Cancer Journal for Clinicians

FIGURE 1. Spectrum of Oncologic Urgencies and Emergencies. Oncologic emergencies can be caused by either the malignancy itself or the applied
treatments. Disease-based emergencies include those precipitated by paraneoplastic syndromes or because of structurally based complications that arise
from compressive, expansive, space-occupying, or erosive effects of the malignancy. Emergent de novo presentations of previously undiagnosed cancers also
contribute. At the treatment level, complications can be subdivided according to systemic, generally cytotoxic chemotherapies; radiotherapy; and the newer
classes of small-molecule, antibody-based, and cellular targeted therapies as well as immunotherapeutics. Finally, both pain and palliative care reflect the
convergence of both cancer-related and treatment-related adverse events and require emergent consideration throughout the disease trajectory to culminate
in addressing end of life and goals of care in the emergency care setting.
its secreted hormone. Insulinomas form the largest subset of antibodies; <1%)36 are most commonly observed although
functional pancreatic neuroendocrine tumors, representing case reports have been noted in other malignancies. Because
50% of all such lesions, with gastrinomas occurring in 35%. these rare neurologic conditions may be the first sign of an
The remaining 15% are comprised of a mixture of glucagono- occult malignancy, evaluation must extend beyond a standard
mas, somatostatinomas, vasoactive intestinal peptide- omas neurologic workup to include serologic testing of both the pe-
and pancreatic polypeptide-omas, each producing a unique ripheral blood and the cerebrospinal fluid for onconeural au-
metabolic derangement that requires appropriate electrolyte toantibodies. If found, these should prompt a thorough search
and nutritional repletion.19 Bronchopulmonary and jejuno- for an underlying tumor.37 At the same time, onconeural an-
ileal carcinoids arise from enterochromaffin cells and with tibodies are neither sensitive nor specific because only 60%
a subset being functional tumors that secrete serotonin and of Lambert–Eaton myasthenic syndrome cases and <25%
other vasogenic amines. Carcinoid syndrome only occurs when of dermatomyositis cases are paraneoplastic.38,39 Immune
monoamines are injected into the systemic circulation, either modulation is the mainstay of therapy and includes cortico-
directly through the pulmonary circulation or from hepatic steroids, corticosteroid-sparing agents like cyclophosphamide,
or retroperitoneal metastases of the bowel lesions.20 Table 2 anti-CD20 monoclonal antibodies, intravenous immunoglob-
describes the presentations and management strategies of the ulins, and plasmapheresis.40,41 Acetylcholinesterase inhibitors
most common endocrine paraneoplastic syndromes.19,21-32 for myasthenia gravis and potassium channel blockers for
Humoral paraneoplastic syndromes result when an im- Lambert–Eaton myasthenic syndrome may be useful.
mune response occurs to tumor antigens that also yields au-
toantibodies against normal cellular components to trigger
corresponding autoimmune syndromes. Autoimmune para- Cancer-Related Structural Complications
neoplasias are altogether rare, affecting <1% of patients with Major oncologic structural complications are related to pro-
cancer, and most commonly present as neurologic, rheumato- voked impingement of adjacent end organs through external
logic, and dermatologic syndromes. Thymomas causing myas- compression, internal expansion, or space occupation as well
thenia gravis and myositis (antiacetylcholine receptor, antititin, as erosion through mucosae by the primary tumor or its me-
antiryanodine receptor antibodies; 50% of cases),33 small cell tastases. Although these complications can be the initial pre-
lung cancer causing paraneoplastic cerebellar degeneration senting symptom, many occur in the setting of progression
(anti-Hu antibodies; 5%-15%),34 Hodgkin and non-Hodgkin of disease or as a consequence of treatment (Table 3).42-69
lymphomas causing a spectrum of central or peripheral nervous Vascular complications include venous thromboembolism
system and neuromuscular junction syndromes (multiple35; (VTE), superior vena cava syndrome, carotid blowout syn-
1%), and testicular cancers causing encephalitis (anti-Ma2 drome, pulmonary hemorrhage, and gastrointestinal bleeding.

TABLE 1. Fifteen Common Cancers Frequently Diagnosed as Emergencies and Associated Typical Presenting Signs and
Symptoms
5-Y RELATIVE SURVIVAL FOR
% CASES DIAGNOSED NO. OF CASES EXPECTED CANCERS DIAGNOSED AT TYPICAL EMERGENT SIGNS AND
CANCER TYPE EMERGENTLYa IN US, 2021b ADVANCED STAGE: 2021,% SYMPTOMS
Acute myelogenous 31.0 20,240 26.0 (adults)c Pancytopenias with or without blasts on
leukemia peripheral smear, mucosal bleeding,
bruising, petechiae, bone pain, fatigue.
Acute lymphocytic 28.9 5690 38.0 (adults)c
leukemia
Chronic myelogenous 26.4 9110 72.0c Extreme granulocytosis with or without
leukemia blasts, tumor lysis syndrome, throm-
botic events after leukostasis, fatigue.
Multiple myeloma 24.2 34,920 54.0c Hypercalcemia, diffuse bony achiness,
acute kidney injury, hyperviscosity,
spinal cord compression.
Lymphoma (Hodgkin and 26.0 90,390 66.0b Lymphadenopathy, fever, night sweats,
non-Hodgkin) weight loss anorexia, seizures (CNS
lymphoma), visceral organ obstruction.
Esophageal cancer 26.3 19,260 5.0b Hematemesis, anorexia, weight loss,
midepigastric pain, dysphagia to liquids
Stomach cancer 24.7 26,560 38.0d
and solids, odynophagia, vomiting
without nausea.
Pancreatic cancer 30.9 60,430 3.0b Painless jaundice, ascites, pruritus,
anorexia, weight loss, epigastric pain,
Gallbladder/liver/biliary 27.8 54,210 3.0b
steatorrhea, back pain.
cancer
Colon cancer 27.2 104,270 14.0b Iron deficiency, rectal bleeding, change
in bowel habits, abdominal pain.
Cancer of unknown 26.3 32,880 11.0 at 1 ye General malaise, fatigue, focal discom-
primary fort that maps to the anatomic location
of the mass.
Ovarian cancer 28.5 21,410 30.0b Bloating, ascites, lower abdominal
pain, flank pain, lower extremity deep
venous thrombosis.
Renal cancer 21.0 76,080 13.0b Painless hematuria, flank pain.
b
Bladder cancer 20.2 83,730 6.0 Acute kidney injury (because of ureteral
obstruction), irritation with voiding,
urinary frequency, and urgency.
Lung cancer 20.9 235,760 6.0b Cough, dyspnea, chest pain, hemoptysis.
Abbreviation: CNS, central nervous system.

a
Data from Herbert 2019.7
b
Data from Seigel 2021.11
c
Data from American Society of Clinical Oncology 2021.12
d
Data from Kao 2019.13
e
Data from Lee & Sanoff 2020.14
From 2% to 15% of patients with cancer, especially those and pericardial effusions, intracranial bleeding, seizures, and
with aerodigestive and genitourinary cancers, develop VTE death.73 The intercalation of tumor tissue with the struc-
(15-fold greater than the general population) to represent a tural matrix of large-caliber blood vessels risks significant
significant cause of associated morbidity and mortality.70,71 and potentially catastrophic hemorrhage after tumor necro-
Recurrent VTE occurs in 4% to 6% of patients after comple- sis or treatment-based erosion of the vascular wall. Carotid
tion of initial therapy.72 Superior vena cava syndrome results blowout syndrome (CBO) is an infrequent consequence of
from partial or complete obstruction of blood return from the either postsurgical wound breakdown or reirradiation of re-
head and neck to the right heart either by mechanical com- current head and neck cancer.74 Patients with impending
pression or by thromboembolic occlusion of the superior vena CBO who present with a self-resolving sentinel hemorrhage
cava, and most cases are attributed to regionally advanced require prompt referral to vascular surgeons. Acute CBO is
lung cancer and non-Hodgkin B-cell lymphoma with the usually fatal. Pulmonary hemorrhage can result from either
subsequent risk for edema of the brain and trachea, pleural radiotherapy-driven erosion of the pulmonary vasculature or

TABLE 2. Paraneoplastic Syndromes: Common Presentations and Management Strategies
SYNDROME PRESENTATION MANAGEMENT
Syndrome of inappropri- • Urine osmolarity >100 mOsm coincident with euvolemic hypo- • In the ED, symptomatic hyponatremia requires 100 mL 3%
ate antidiuretic hormone tonic hyponatremia. normal saline bolus to acutely raise serum sodium by 2-3
(SIADH) • Corresponding serum sodium levels: mEq/L.
◦ Mild: 130 mEq/dL –134 mEq/dL • Total increase of serum sodium by no more than 4-6 mEq/L
◦ Moderate: 125 mEq/dL –129 mEq/dL in 24 hrs to avoid central pontine myelinolysis.
◦ Severe: <125 mEq/dL (Ellison & Berl21).
• Acute hyponatremia associated with headaches and neurocogni- • Free water restriction and sodium chloride tablets are
tive slowing. preferred for correcting chronic hyponatremia.
• Severe hyponatremia can be associated with seizures and death. • Correction of hyponatremia is usually necessary prior to
• Must be distinguished from hypovolemic hyponatremia due to initiating systemic therapy.
excessive gastrointestinal losses where urine osmolarity >300
mOsm but urine sodium < 20 mEq/L. (Raftopoulos 201722)
Hypercalcemia • Corresponding serum calcium levels: • Immediate aggressive intravenous hydration with normal
◦ Mild: 10.5 mg/dL –11.9 mg/dL saline, typically 1-2 L in the first hour followed by 2 L at
◦ Moderate: 12.0 mg/dL –13.9 mg/dL 200 mL/hr with close monitoring of volume status.
◦ Severe: ≥14.0 mg/dL • Early intravenous bisphosphonate administration (most
• In patients with hypoalbuminemia, observed serum calcium must commonly zolendronic acid). (Stewart 200523)
be further increased by 0.8*(4.0 –serum albumin) mg/dL. • Supplemental calcitonin can be administered during the
• Presents with altered mental status, generalized muscle weakness first 48 hours while the bisphosphonate is not yet at peak
and constipation due to generalized slowing of central, peripheral efficacy. (Khan 202124)
and autonomic nervous systems. • Denosumab (monoclonal antibody inhibitor of osteoclast
• Dehydration with ensuing acute kidney injury. activity) is alternatively administered in bisphosphonate-
• Urolithiasis can be observed with subacute presentations. refractory cases. (Fizazi 201125)
• Loop diuretics are generally now avoided as they can
exacerbate hypercalcemia and kidney injury in inadequately
hydrated patients. (LeGrand 200826)
Ectopic ACTH Syndrome • Hypertensive urgency/emergency. • Acute management of electrolyte disturbances and hyper-
• Hypokalemia and associated muscle weakness. tensive crisis.
• Generalized edema. (Fanous 202028) • Ketoconazole and metyrapone, agents that inhibit steroido-
genesis are often used. (Toivanen 202127)
Insulinoma • Fasting hypoglycemia in the absence of diabetes associated with • Oral and parenteral dextrose to maintain glucose levels.
diaphoresis, anxiety and altered mental status. • Diazoxide or streptozocin can inhibit insulin secretion from
β-islet cells. (Giannis 202029)
Gastrinoma • Extensive and pervasive peptic ulcers. • Proton pump inhibitors or histamine-2 receptor blockers,
initially at maximal twice-daily parenteral dosing. (Krampitz
& Norton 201330)
Carcinoid syndrome • Acute watery diarrhea, flushing, bronchospasm, hypotension from • Definitive therapy requires complete surgical resection.
excess serotonin secretion. • When curative-intent surgery is not possible, systemic
• Elevated urinary hydroxy-indoleacetic acid. therapy using long-acting somatostatin receptor inhibitors,
• Right heart disease including valvular compromise. (Oronsky peptide receptor radioligand therapy or hepatic artery
201719) embolization is performed. (Tella 202131)
• Niacin deficiency and hypoproteinemia from preferential tryptophan • Antidiarrheals, bronchodilators and vasoconstrictors can
diversion towards serotonin production. (Castiello & Lynch 197232) provide acute symptomatic relief.
necrosis of a large tumor, most frequently squamous cell car- also develop if increased intracranial pressure is not promptly
cinoma, with high morbidity and mortality owing to interfer- identified.77 Malignant spinal cord compression occurs in 20%
ence with alveolar gas exchange.75 Gastrointestinal bleeding of patients with spinal metastases and is most commonly as-
is most frequent with either erosive gastrointestinal tumors or sociated with breast, lung, prostate, and kidney cancers as well
the concurrent use of anticoagulants. as lymphoma and multiple myeloma.78 This occurs either by
Neurologic compromise can arise from tumor mass effect hematogenous spread into a vertebral-body mass, by patho-
on the brain or spinal cord. Increased intracranial pressure logic fractures resulting in epidural compression, or by direct
results from vasogenic edema associated with primary brain tumor extension into the vertebral column. Compression of
tumors, discrete foci of intraparenchymal solid tumor metas- the thecal sac and epidural venous plexus precipitates va-
tases, disseminated leptomeningeal metastases or postradia- sogenic edema of the white matter and demyelination.79
tion necrosis of previously treated lesions which then critically Major viscus obstruction in the thorax, abdomen, and
exceed the capacity of the nonexpendable cranium or precip- pelvis results from primary tumor- derived endoluminal
itate hydrocephalus.76 The most immediate emergent threat filling defects or external compression from either solid
is a herniation syndrome. Irreversible neurologic deficits can tumor regional disease or lymphomas. Overall, management

TABLE 3. Cancer-Related Structural Complications: Common Presentations and Management Strategies
Vascular complications
Venous thromboembolism • Chief complaints of shortness of breath, unilateral leg • Computed tomographic (CT) angiography of the chest is the
swelling, or reduced oxygenation on pulse oximetry. definitive study because it not only can rule out other processes
but also can confirm right ventricular strain.
• D-dimer levels are not informative because they can • When IV contrast is contraindicated, a ventilation-perfusion
be elevated generally in patients with cancer (Moore scan along with cardiac echography is appropriate.
201842).
• Systemic thrombolysis is indicated for massive PE with hemo-
dynamic compromise except in patients with a high risk of
bleeding for whom catheter-assisted thrombectomy is indicated
(Kearon 201843).
• Factor Xa inhibitors have been shown to be noninferior to low-
molecular-weight heparin with apixaban demonstrating fewer
major bleeding events (Agnelli 202044).
• Patients without risk of bleeding can be immediately started on
long-acting agents; those at increased risk are first given a trial
of IV heparin.
• Patients with small, incidental PEs and no functional or vital
sign compromise are eligible to initiate anticoagulation in the
ED then be safely discharged home with close follow-up.
• Resumption of anticoagulation is recommended for recurrent VTE.
• The benefit of thromboprophylaxis has not been demonstrated
(Khorana 201945).
Superior vena cava syndrome • Facial edema and subcutaneous vein engorgement in • Elevate the head to minimize venous congestion.
the head, neck, and chest regions.
• Complete obstructions additionally present with • Diuretic use should be minimized (Sonavane 201547).
plethora, dyspnea, orthopnea, cough, hoarseness,
cyanosis, headache, seizures, and coma (Thomas &
Edmondson 199146).
• Mediastinal widening (66%) or pleural effusions • IV corticosteroids decrease extrinsic pressure on the vena cava.
(25%) on chest x-ray.
• CT with contrast venography is the gold standard for • Urgent thrombolysis, thrombectomy, or placement of a venous
measuring vena cava patency. stent may alleviate stridor, altered mental status, and hemody-
namic compromise although vascular intervention risks luminal
perforation (Friedman 201748).
• Fibrinolytic therapy can reduce the risk of thromboembolism
(Kee 199849).
• Medical and radiation oncology consultation should be expe-
dited to initiate systemic therapy because reducing tumor bulk
is definitive.
Gastrointestinal bleeding • Frank hematemesis or hematochezia. • Emergent gastroenterology consultation.
• Melena or coffee-ground emesis. • Volume repletion using crystalloid and blood products, as
determined by hemodynamics and hemoglobin levels.
• Reversal of anticoagulation where appropriate.
• Endoscopic administration of hemostatic powders provides the
lowest rebleeding rates (Tjwa 199850).
Neurologic complications
Malignant spinal cord • A gradual onset may only be demonstrated by back • Comprehensive neurologic examination followed by total spine
compression pain and weakness. MRI is the gold standard.
• Acute sensory loss, urinary retention, constipation, • For patients unable to tolerate MRI, a CT scan with and without
perineal numbness, or sudden inability to walk may IV contrast can be attempted, but the diagnostic yield because
suggest irreversible vascular injury and spinal cord of inferior imaging resolution is limited.
infarction.
(Continued)

TABLE 3. (Continued)
Malignant spinal cord • Opiate pain control and dexamethasone 10 mg IV loading dose
compression (Continued) followed by 4 mg every 6 h are initiated along with urgent
neurosurgical and radiation oncology consultation (Barzilai
201851).
• If surgery is not indicated, palliative stereotactic body radio-
therapy of 16-24 Gy in 1 fraction or 24-30 Gy in 3 fractions is
administered (Eckstein 202152).
Increased intracranial pressure • Intractable headaches or nausea and vomiting are • An expedited noncontrast CT scan to evaluate for midline shift
most common; vomiting is significantly correlated is then followed by a nonurgent brain MRI with and without
with infratentorial lesions that risk brainstem contrast to further characterize the posterior fossa and deline-
impingement. ate smaller lesions (Schellinger 199953).
• Altered mental status, focal neurologic deficits, • Dexamethasone dosing as above is recommended except
vision changes or seizures are less frequent but more when lymphoma is suspected because this can compromise the
concerning (Esquenazi 201754). diagnostic biopsy by shrinking the mass (Ryken 201055).
• Hemorrhagic metastases are most likely to cause • Nonenzyme-inducing anticonvulsants (eg, levetiracetam) are
stroke-like focal deficits (Achrol 201956). typically administered in oncology patients because the risk of
drug-drug interactions is minimized, although there are mixed
data supporting their use (Kong 201557).
• Although hypertonic (3%) saline or mannitol can be
used emergently to create an osmotic gradient across the
blood-brain barrier, the priority is alleviating the mass effect
(Prabhakar 201458).
• Gamma Knife stereotactic radiosurgery has emerged as the pre-
ferred modality for managing solid intracranial masses because
of its favorable risk/benefit ratio; surgical approaches may be
necessary for addressing radiation necrosis (Brown 201659).
• Lumbar puncture increases the risk for herniation and is
contraindicated.
Thoracoabdominopelvic viscus
obstructions
Airway obstruction • Symptoms range from mild, subjective shortness of • Tracheal or bronchial stenting is the least invasive and pre-
breath to stridor and severe respiratory compromise. ferred intervention; laser therapy, balloon bronchoplasty, and
mechanical debulking are alternatives (Varadharajan 201660).
• Intubation, cricothyroidotomy, or tracheotomy may be required
to establish an emergency airway.
• The anatomical distortion in patients with previously resected
head and neck cancers may require otolaryngology consulta-
tion if airway management is needed.
• Postobstructive pneumonia requires broad-spectrum antibiotics
that cover both Pseudomonas spp. and methicillin-resistant
Staphylococcus aureus (Rolston & Nesher 201861).
• Interventional management of multiple small-airway obstruc-
tions from excessive tumor burden is not recommended.
Bowel obstruction • Vomiting, occasionally in the absence of nausea, is • Intractable vomiting is relieved by gastric decompression in
ubiquitous. combination with anticholinergics and octreotide to reduce
secretions (Franke 201762).
• Vomitus with upper tract obstructions often includes • Following decompression, complete bowel rest should be initi-
undigested food and liquids and occurs a short time ated with diet advancement, as tolerated.
after eating; lower tract obstructions are associated
with bilious or feculent vomiting (Alese 201563).
• Unrelenting abdominal pain. • Adynamic ileus additionally requires motility agents.
• Dilated loops of bowel on plain and cross-sectional • For esophageal, gastric outlet and rectosigmoid obstructions,
radiography. Mechanical obstruction has a transition consultation with interventional gastroenterology can deter-
point whereas, in functional obstructions, the bowel mine whether stenting is feasible.
is dilated throughout (Vilz 201764).
(Continued)

Bowel obstruction (Continued) • Persistent obstructions may require venting gastrostomy

tubes for permanent decompression of gastrointestinal
secretions.
• Although parenteral nutrition can be considered for highly
functioning patients with persistent obstructions, the evidence
for improved quality of life or survival is equivocal (Sowerbutts
201865).
Biliary tract obstruction • Painless jaundice or cholangitis-related febrile sepsis. • Hemodynamic stabilization followed by broad spectrum
antibiotics to cover enteral Enterobacteriaceae species and
anaerobes (Gomi 201866).
• Evaluation by endoscopic retrograde cholangiopancreatogram
to reestablish bile duct patency through stenting (Perone
201667).
• If the obstruction cannot be stented, transhepatic biliary drain-
age should be performed (Duan 201768).
Obstructive uropathy • Flank pain, oliguria, or an asymptomatic elevation of • Ultrasonography can identify hydronephrosis with a subsequent
serum creatinine on routine examination. CT scan to identify the location of the obstruction.
• Prolonged obstruction can precipitate permanent • Ureteral stents or percutaneous nephrostomy tubes can be
kidney injury. placed to decompress the obstruction (Tan 201969).
Abbreviations: ED, emergency department; Gy, grays; IV, intravenous; MRI, magnetic resonance imaging; PE, pulmonary embolism; VTE, venous
thromboembolism.
involves minimally invasive attempts at stenting the ob- represents 25% of malignant ascites cases.84 Pleural effusions
structed viscus and, if that is impossible, placing an exter- can also occur after poor cardiopulmonary circulation from
nal vent or drain to decompress the blockage. Patients with pulmonary emboli or external vascular compression, whereas
anaplastic thyroid cancer as well as head and neck cancers, pericardial effusions are also adverse effects of cyclophos-
in particular laryngeal cancer, are at risk for tracheal ob- phamide, cytarabine, dasatinib, doxorubicin, and gemcit-
struction with impending airway collapse.80 Lower airway abine treatment.85 Malignant effusions typically accumulate
obstruction is defined as ≥50% luminal narrowing of the insidiously over weeks to months, with the most common
mainstem bronchi, bronchus intermedius, or lobar bronchi. symptoms being pain and shortness of breath or nausea and
Concurrent postobstructive pneumonia significantly in- vomiting due to compression of visceral organs. In patients
creases morbidity and mortality. Obstructions of the gastro- with pericardial effusion, the classically described syndrome
intestinal tract can manifest from the most proximal regions of Beck triad (hypotension, jugular venous distention, and
of the esophagus through to the rectum. Upper gastrointes- muffled heart sounds) is rarely seen.86 Overall management
tinal tract obstructions can be caused not only by intrinsic involves initially draining the effusion, with hemodynamic
esophageal and gastric malignancies but also by pancreatic stability dictating the timing, coadministration of volume
cancer and locoregional lymphomas.81 Primary gastrointes- expanders (eg, albumin) as necessary, evaluation for locu-
tinal, genitourinary, and gynecologic cancers, in addition to lation and infection, and monitoring for re-accumulation.
metastatic peritoneal carcinomatosis, can cause small bowel Recurrent effusions may require membrane decortication
and large bowel obstructions. Postsurgical adhesions also or placement of indwelling drainage catheters to eliminate
contribute. Biliary tract obstruction is often the presenting the need for frequent instrumentation. The median survival
symptom associated with pancreatic, periampullary, and ex- after positive cytology is <12 months.87
trahepatic cholangiocarcinomas and with hepatic metasta-
ses. Obstructive uropathy is most common with pelvic or Cytotoxic Chemotherapy and Radiotherapy
retroperitoneal malignancies. Complications
Malignant effusions can occupy the pleural, pericardial, Classical cytotoxic chemotherapeutics and radiotherapy
and intraabdominal spaces and are largely precipitated by largely mediate their antineoplastic effects through affect-
tumor implants to the cavity membranes. Greater than 90% ing DNA replication. Substantial numbers of recognized
of pleural effusions are unilateral, and 56% to 65% arise from side effects, including tumor lysis syndrome (TLS), febrile
either breast or lung cancers.82 Similarly, malignant pericar- neutropenia, severe anemia, oral mucositis and esophagi-
dial effusions are most prevalent in breast and lung cancers tis, and chemotherapy-induced diarrhea (CID), are direct
in addition to melanoma and lymphoma.83 Ovarian cancer consequences. TLS results when a large volume of cells

simultaneously releases its contents into the blood stream distress that negatively affects performance status, and aggres-
faster than their corresponding renal excretion rates to yield sive prophylaxis with loperamide and diphenoxylate/atropine
hyperkalemia and, from metabolism of the excess nucleo- combinations is standard.99 Breakthrough CID is commonly
tides, hyperphosphatemia and hyperuricemia.88 Although observed among patients receiving fluoropyrimidines, irino-
TLS can occur spontaneously with any tumor type, it is tecan, and tyrosine kinase inhibitors and those who have
more likely with treatment for high-grade lymphomas, acute incomplete compliance with prophylactic antidiarrheals.100
leukemias, and other rapidly proliferating tumors, such as Additional diarrheal etiologies, including graft- versus-
host
germ cell tumors.89 Seven days immediately after therapy disease and Clostridioides difficile, must also be entertained in
initiation reflects the highest vulnerability.90 the appropriate host. C. difficile colonization in patients with
Febrile neutropenia (FN) is a potentially life-threatening cancer is common due to frequent clinical touchpoints and
condition and is defined as a single oral temperature mea- gut microbiome depletion with either antibiotic use or cyto-
surement of ≥38.3 °C (101 °F) or a temperature of ≥38.0 toxic chemotherapy treatment can activate dormant spores to
°C (100.4 °F) sustained over a 1-hour period, combined trigger infection.101 Gastrointestinal graft-versus-host disease,
with severe neutropenia, defined as an absolute neutrophil characterized by a profuse secretory watery diarrhea, can occur
count (ANC) <500 cells/mm3 or an ANC that is expected as either an acute or chronic complication of allogeneic HSCT
to decrease to <500 cells/mm3 during the next 48 hours.91 and is a significant adverse prognostic factor.102
FN is a complication in up to 50% of patients with solid Radiotherapy and anthracyclines can cause late effects
tumors and in >80% of patients with hematologic malig- of tissue remodeling and subsequent fibrosis that can com-
nancies on active chemotherapy or after hematopoietic stem promise the cardiopulmonary system. Thoracic radiation
cell transplantation (HSCT) and most frequently occurs as a is a mainstay for locoregional lung cancer management. It
consequence of gut bacterial translocation in the absence of
is also common in patients being treated for breast, thy-
neutrophil-precipitated direct antimicrobiosis and immune-
mic, esophageal, and hematologic malignancies. Radiation
effector responses.92 Risk factors for FN include an ANC
pneumonitis, which is observed in up to 60% of patients
<100 cells/mm3 for >7 days, older age, poor performance
receiving intensity- modulated radiation therapy, can be
status, the presence of comorbid conditions, and advanced-
the dose- limiting toxicity.103 Incidence is substantially
stage disease.93 FN is considered a medical emergency, with
lower in patients receiving stereotactic beam radiotherapy.
an overall mortality of 5% to 20%, which can rise to 50%
Cardiomyopathy as a consequence of cardiac myofibril drop-
among patients with shock.94
out with subsequent necrosis and ensuing fibrosis can result
Although mild anemia (serum hemoglobin < 11.0 g/dL)
from a broad range of cytotoxic chemotherapies (primarily
is present in the majority of patients with cancer, severe ane-
anthracyclines), newer targeted therapies, and external-beam
mia (serum hemoglobin < 7.0 g/dL) occurs in 1 % to 7% of
radiotherapy to the chest, each in a dose-dependent fash-
patients and is associated with poor outcomes and decreased
quality of life.95 Severe anemia is usually a complication of ion usually after a latency period of ≥1 year after therapy.104
systemic therapy but can also occur from bone marrow in- Because early detection of presymptomatic heart failure can
filtration, gastrointestinal or genitourinary bleeding, poor improve outcomes,105 echocardiographic surveillance is rec-
overall nutrition or specific vitamin/mineral deficiency, as ommended in patients who receive high-dose anthracycline,
well as chronic infection. Tumor-provoked or treatment- ≥30 Gy of mediastinal radiation, the combination of a low-
provoked inflammatory cytokines may additionally precip- dose anthracycline and low-dose radiation, or a low-dose
itate chronic kidney disease and subsequent erythropoietin anthracycline and 2 cardiovascular risk factors within 6 to
deficiency. Profound anemia can delay chemotherapy cycles 12 months of completing therapy.106 The role of advanced
to further negatively affect prognosis.96 cardiac imaging for surveillance and early detection is being
Gastrointestinal distress is ubiquitous with standard che- explored.
motherapy and radiotherapy. Whereas chemotherapy can affect Reactive oxygen species are the acute irritants that un-
the entire gastrointestinal tract, radiotherapy selectively affects derlie hemorrhagic cystitis. Radiotherapy and chemotherapy
those regions within the field of radiation. Oropharyngeal and with select agents, including cyclophosphamide, ifosfamide,
esophageal mucositis can result not only from direct radia- busulfan, idarubicin and carboplatin, as well as intravesicular
tion damage to or high-dose chemotherapy effects on basal treatment with a broader range of chemotherapeutics and
epithelial cells but also from the release of reactive oxygen HSCT conditioning regimens are causative.107 Cessation of
species that triggers a proinflammatory cascade.97 Treatment chemotherapeutic therapy usually resolves the bleeding in a
with the mammalian target of rapamycin inhibitor everolimus few weeks once the bladder epithelium is restored. However,
also yields oral mucositis, with approximately 50% of patients radiotherapy-induced hemorrhagic cystitis can persist for
affected.98 CID contributes to physical and psychological years due to scarring and fibrosis of the bladder lining.108

Chemotherapy-induced nausea and vomiting (CINV) inhibitor-induced dermatologic adverse events, and hand-
and peripheral neuropathy are mediated through diverse foot skin reaction (HFSR).
neurologic mechanisms, which include cell death and disrup- QTc prolongation with subsequent risk for ventricular
tion of synaptic vesicle transport with subsequent discharge. arrythmias has been observed among each of the subclasses
CINV results from discharge of gut enterochromaffin cell of small-molecule agents. Both tyrosine kinase inhibitors
serotonin.109 Depending on the emetogenic potential of and HDAC inhibitors can prolong QTc, with a mean in-
the chemotherapeutic or radiation regimen, prevention of crease of 15 msec and the largest effects observed from van-
CINV can include up to a 4-drug combination, compris- detanib, ibrutinib, and ribociclib.104 EGFR inhibitors induce
ing a 5-HT3 receptor antagonist, a neurokinin-1 antagonist, a spectrum of dermatologic complications, including pap-
dexamethasone, and, olanzapine.110 Topics regarding the ulopustular acneiform rash, dry skin, itching, and hair and
development, diagnosis, and management of peripheral neu- periungual alterations.137 Although these are rarely severe,
ropathy are discussed elsewhere in this review. they cause significant psychological distress, with the rash
Finally, infusion reactions to both classical chemothera- having the greatest negative impact on quality of life.138
pies and biologic therapies are common. Although they are HFSR is a dermatologic complication of the multityrosine
most frequently observed with platinum-based compounds kinase inhibitors sorafenib and regorafenib (60%) and the
(12%-24%),111 taxanes (30%),111 ofatumumab (60%),112 vascular edothelial growth factor (VEGF) inhibitors suni-
obinutuzumab (60%),113 and rituximab (70%-80%),114 they tinib and axitinib (30%), resulting from the simultaneous
can occur after any systemic therapy. Both IgE-mediated disruption of epithelial and vascular remodeling necessary
allergic and anaphylactoid mechanisms are noted. Table 4 after routine touch-induced microtrauma. Although mecha-
summarizes the most common complications observed with nistically different, HFSR is similar to hand-foot syndrome
these therapeutic modalities and the current standards for or palmar-plantar erythrodysesthesia, an epidermal irritation
their management.90,91,110,115-132 seen with certain cytotoxic chemotherapies (eg, capecitabine,
liposomal doxorubicin, docetaxel, and continuously infused
Targeted Therapeutic-Related Complications 5-fluorouracil).139 The significant pain associated with rou-
Targeted therapies represent the subclass of antineoplastic tinely applied pressure to eroded surfaces adversely affects
140
agents deliberately engineered to interfere with oncogenic quality of life and is often a dose-limiting toxicity.
signal transduction pathways and are divided into small- Monoclonal antibodies are subdivided into naked
molecule inhibitors, monoclonal antibody-based pharma- monoclonal antibodies, which halt signal transduction by
ceuticals, and cell-based agents. In general, targeted agents inhibiting ligand- receptor interactions (eg, trastuzumab,
are less toxic than nonspecific cytotoxic chemotherapeutics; bevacizumab, and pembrolizumab); antibody-drug/radiola-
however, because many agents require long-term use, both bel conjugates, which deliver cytotoxic agents specifically to
acute and chronic treatment- related toxicities should be malignant cells (eg, gemtuzumab ozogamicin, brentuximab
133
considered (Fig. 2). Finally, certain adverse events reflect vedotin, and sacituzumab govitecan); and bispecific anti-
an on-target effect to nonneoplastic tissues.134 bodies, which recruit immune cells to the immediate can-
Small- molecule compounds represent an increasingly cer microenvironment (eg, blinatumomab). Antiangiogenic
prevalent class of antineoplastic agents, with a total of 89 therapy is a frequently used modality that includes mono-
novel antineoplastic small molecules having been approved clonal antibodies that bind circulating VEGF-A (beva-
through 2020.135 The largest group of small-molecule anti- cizumab) or the VEGF receptor-2 extracellular domain
neoplastics are kinase inhibitors, but additional targets in- (ramucirumab and alacizumab pegol) in addition to small
clude epigenetic regulatory proteins (eg, histone deacylase molecules that bind the VEGF receptor intracellular tyro-
(HDAC) inhibitors), DNA damage- repair enzymes (eg, sine kinase domain (eg, axitinib, sunitinib). Because VEGF
poly- [ADP- ribose] polymerase inhibitors), and protea- signaling plays an important role in vascular homeostasis,
somes. These agents can also cause cytopenias (eg, olaparib, patients receiving antiangiogenic therapy may develop hy-
niraparib, and, entrectinib), nausea, vomiting and diarrhea pertensive urgency or emergency, hemorrhagic stroke, un-
(eg, ribociclib, palbociclib, vemurafenib, and dabrafenib), and stable angina, or myocardial infarction as well as venous
cardiomyopathy (eg, cobimetinib, trametinib, sunitinib, and thromboembolism, atherosclerosis, and platelet activa-
pazopanib).104,136 Management of these complications par- tion.141 Antiangiogenic drugs can also trigger posterior re-
allels previously described algorithms. Cataloguing the spe- versible encephalopathy syndrome (PRES) which involves
cific toxicities associated with each approved small-molecule direct injury to the cerebrovascular endothelium with an
agent can be accessed in the reviews cited above. Three ensuing inflammatory response and cytokine release that
toxicities unique to these small-molecule agents are QTc triggers vasogenic edema. This is mediated through break-
prolongation, epidermal growth factor receptor (EGFR) down of the blood- brain barrier, which preferentially

TABLE 4. Cytotoxic Chemotherapy and Radiotherapy Complications: Common Presentations and Management Strategies
Tumor lysis syndrome • Laboratory tumor lysis syndrome is defined according to serum • Aggressive hydration with crystalloid improves renal perfusion
levels of uric acid, potassium, phosphorus, and calcium and and glomerular filtration as well as reduces uric acid or calcium
requires either a 25% change in value or ≥2 abnormal values phosphate crystallization and tubular deposition.
among these (Cairo & Bishop 2004115).
• Hyperkalemia destabilizes myocardial and other muscular con- • Continuous cardiac monitoring and re-evaluation of serum
ductivity and can trigger nausea, numbness, heart palpitations, electrolytes, creatinine, and uric acid every 4-6 h track the clini-
arrythmias, seizures, and possible sudden death. cal course.
• Both uric acid and calcium phosphate can precipitate in the • In patients with urine output <2 mL/kg per h, a loop diuretic
renal tubules to trigger an intrarenal acute kidney injury. may be considered.
• Flank pain raises concern for ureteral stones. • Allopurinol reduces the formation of uric acid and is prophylac-
tically administered to at-risk patients.
• Rasburicase metabolizes uric acid and is the preferred
medication for extreme hyperuricemia; 0.2 mg/kg is initially
administered with repeated dosing as necessary but should be
avoided in patients with G6PD deficiency because it can lead
to methemoglobinemia and hemolysis (Bosly 2003116).
• Renal replacement therapy may be required for severe kidney
injury or persistent electrolyte abnormalities (Jones 201590).
Febrile neutropenia • A single oral temperature measured at ≥38.3 °C (101 °F) or • The current door-to-antibiotics guideline is <1 h after ED pres-
a temperature of ≥38.0 °C (100.4 °F) sustained over a 1-h entation, although recent research has shown that delays up to
period combined with severe neutropenia, defined as an abso- 3 h do not substantially affect outcomes (Daniel 2019117).
lute neutrophil count (ANC) <500 cells/mm3 or an ANC that is
expected to decrease to <500 cells/mm3 during the next 48 h
(Zimmer & Freifeld 201991).
• Presentation can bridge the spectrum from otherwise asympto- • Blood cultures, both peripheral and from in-dwelling lines,
matic to moribund with florid hemodynamic collapse. should be universally collected because the established rate of
bacteremia is 10%-25%.
• Empiric monotherapy with an antipseudomonal β-lactam is
recommended with the following exceptions:
◦ Carbapenems for patients with a high risk of infection by an
extended-spectrum β-lactamase-expressing organism
◦ Polymyxin-colistin in patients at high risk for a
carbapenemase-producing Klebsiella
◦ Aztreonam, fluoroquinolones, or aminoglycosides for
patients with an anaphylactic β-lactam allergy (Zimmer &
Freifeld 201991).
• Vancomycin, linezolid, or daptomycin should be given only
when either methicillin-resistant Staphylococcus aureus or
indwelling catheter infections are likely and should be discon-
tinued once these are ruled out (Niessen 2020118).
• Empiric antifungal coverage is not recommended at the time
of presentation; however, in patients with prolonged, profound
neutropenia, invasive fungal disease markers should be assayed
and empiric therapy begun after 4-7 d of persistent fevers and
no apparent bacterial source with echinocandins being the
preferred choice (Chen 2017119).
• The MASCC criteria defines patients with scores ≥21 as low-
risk patients safe for ED discharge and outpatient management
(Klastersky & Paesmans 2013120) with appropriate regimens
comprised of broad-spectrum β-lactams combined with a
fluoroquinolone (Klastersky 2006121).
Severe anemia • Because of decreased oxygen-carrying capacity, debilitating • Reticulocyte count and haptoglobin, iron studies, serum vitamin
fatigue and dyspnea, initially with exertion then at rest, are the B12 and folate levels, liver function tests (including albumin,
predominant presenting symptoms. prealbumin, total and direct bilirubin), and lactate dehydroge-
nase concentrations as well as a peripheral blood smear should
be obtained in addition to the complete blood count.
(Continued)

Severe anemia • In the appropriate situations, hemagglutinins can be assessed

(Continued) to rule out hemolysis.
• Ensuring adequate nutrition can partially remediate chronic
causes.
• Transfusion should be used as sparingly as possible and should
target a hemoglobin level of 7.0 mg/dL unless the patient has
established cardiac disease or continues to be overtly sympto-
matic where 8.0 mg/dL is appropriate (Watkins 2015122).
• Completing transfusions in the ED can offset the additional
financial toxicity of an inpatient admission.
• Erythropoiesis-stimulating agents are no longer indicated for
cancer-related anemia (Schoen 2020123).
Oral mucositis and • Intractable breakthrough pain with multiple open mouth sores. • Pain control often requires opiate analgesia in addition to topi-
esophagitis cal anti-inflammatory, lidocaine-containing mouthwashes.
• Severe dehydration and failure to thrive because of inadequate • Nystatin is indicated for thrush.
oral intake.
• When mucositis is expected to persist for several wks (eg,
in patients with head and neck cancers requiring extended
courses of radiotherapy), placement of a percutaneous feeding
tube may be required.
Chemotherapy-induced • Multiple, frequent, liquid bowel movements per d, typically as- • Intravenous hydration with deliberate potassium and magne-
diarrhea sociated with urgency, which can be provoked by or independ- sium supplementation to offset gastrointestinal losses.
ent of meals or with nocturnal arousal.
• Superinfections with Escherichia coli or Salmonella species
whose virulence is accentuated in patients with cancer must
also be considered (Chao 2017,124 Ku 2012125).
• Clostridioides difficile is ruled out through toxin enzyme
immunoassays combined with nucleic acid amplification tests.
• Oral vancomycin or fidaxomicin for 10 d is the first-line therapy
for mild-to-moderate C. difficile infections; intravenous met-
ronidazole is added in more severe cases characterized by signs
of peritonitis, leukemoid reaction, toxic megacolon, or severe
sepsis (Guh & Kutty 2018126).
• Graft-versus-host disease is treated with aggressive hydration
and electrolyte repletion along with systemic steroids dosed at
2 mg/kg with supplemental oral budesonide; ibrutinib, ruxoli-
tinib, belumosidil, and basiliximab are useful secondary agents
in refractory cases (Ruutu 2014,127 Waller 2019,128 Zeiser
2021,129 Jagasia 2021,130 Liu 2020131).
Radiation pneumonitis • Radiation pneumonitis is a diagnosis of exclusion that typically • Initiation of a slow steroid taper and optimization of
presents 3-12 wks after completion of radiotherapy. oxygenation.
• Characterized by a low-grade fever, shortness of breath, • Patients with a new oxygen requirement may benefit from brief
nonproductive cough, crackles on physical examination. inpatient observation.
• Cross-sectional imaging is notable for fibrosis in the field of
radiation.
Cardiomyopathy • Patients present with asymptomatic or symptomatic left • Management is consistent with standard heart failure protocols
ventricular dysfunction. that include admission to telemetry and escalation to intensive
care, as appropriate.
• Increased susceptibility in patients with prior history of heart
failure.
• Patients with cancer and survivors must be surveyed for prior
anthracycline or radiation exposure.
Hemorrhagic cystitis • Bleeding is primarily microscopic, but persistent bleeding can • Blood transfusion to correct ensuing anemia.
precipitate intravesicular blood clot formation with subsequent
urinary tract obstruction (Manikandan 2010132).
(Continued)

Hemorrhagic cystitis • Continuous bladder irrigation using a large-bore, 3-way

(Continued) catheter with saline infusion may be necessary to evacuate a
substantial clot burden.
Chemotherapy-induced • Weakness and dehydration from decreased oral intake because • Intravenous hydration corrects volume deficits.
nausea and vomiting of ongoing symptoms.
• Breakthrough episodes are treated with short-acting antiemet-
ics (eg, ondansetron, lorazepam, prochlorperazine, or olanzap-
ine) prioritized to complement the patient’s existing outpatient
regimen (Hesketh 2017110).
• Inpatient admission is required for patients unable to tolerate
enteral nutrition.
Hypersensitivity • Common clinical manifestations include: • The infusion should be terminated immediately if not already
reactions ◦ Fatigue, myalgia, fever, headache finished.
◦ Rash, urticaria, pruritus, flushing • Respiration and hemodynamics must first be stabilized.
◦ Nausea, vomiting, abdominal pain
◦ Dyspnea, throat irritation, pharyngeal or laryngeal edema, • If severe anaphylaxis or angioedema is suspected, intramuscular
bronchospasm epinephrine should be administered immediately.
◦ Dizziness, hypotension, tachycardia. • For milder reactions, use of H1 and H2 receptor antagonists and
glucocorticoids may be sufficient.
• Symptomatic wheezing additionally requires nebulized β-
agonist bronchodilators.
Abbreviations: C. difficile, Clostridioides difficile; ED, emergency department; MASCC, Multinational Association for Supportive Care in Cancer.
affects the bilateral parieto-occipital region because of the HER2-targeting agents (pertuzumab, neratinib, and lapa-
paucity of sympathetic innervation of the posterior fossa.142 tinib) are substantially less cardiotoxic.146
Nearly one-half of patients with PRES have autoimmune Administration of ozogamicin-conjugated gemtuzumab
disorders; patients who have cancer with these comor- or inotuzumab monoclonal antibodies can lead to hepatic
bidities are at increased risk.143 Trastuzumab-associated sinusoid occlusion syndrome/venous occlusive disease, an
cardiomyopathy arises from and occurs concurrently with obliterative terminal hepatic venulitis caused by a prothrom-
ongoing therapy.144 Because it is mediated through HER2 botic, hypofibrinolytic state which can also be observed in
signal-transduction pathways within endocardial cells, left the first 60 days after allogeneic HSCT.147 In the presence
ventricular function improves when therapy is withdrawn of multiorgan failure, the mortality rate of sinusoid occlusion
although 25% of patients never fully recover.145 Other syndrome may reach 80%.
FIGURE 2. Mechanisms of Targeted Therapeutics Toxicities. Targeted therapies can be subdivided into small molecules, cell-based therapies (eg, chimeric
antigen receptor [CAR] T-cells), and antibody-based therapies, with the latter including the specific subclasses of antibody-drug conjugates and immune
checkpoint inhibitors. Although some toxicities, such as immune-related adverse events, QTc prolongation, and sinusoidal occlusion syndrome, are class-
specific, angiogenesis-related toxicities and cytokine release syndrome are demonstrated with multiple classes.

Immune checkpoint inhibitors (ICIs) represent a sub- workup occurring in the ED.163 The spectrum of targeted
class of naked monoclonal antibodies that undermine a therapeutic toxicities is presented in Table 5.137,142,152,163-185
tumor cell’s ability to evade detection by the patient’s im-
mune system by abrogating the patient’s natural antitumor Cancer Pain Management
T-cell response.148 To date, 3 immune checkpoint targets Cancer-related pain results from either the malignancy itself
(cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), or its treatment and it affects both patients on active treat-
programmed cell death 1 (PD-1), and programmed cell ment and long-term cancer survivors alike. Pain is the most
death ligand 1 (PD-L1)) have agents approved as first- common chief complaint upon ED presentation for patients
line, standard-of-care treatment for a broad spectrum of with end-stage disease. Severe pain correlates with increased
solid and liquid tumors.149,150 Relatlimab, an anti-L AG3 hospital readmissions, morbidity, and mortality.186 Among
monoclonal antibody, is in late-stage clinical trials.151 By survivors, approximately 40% will experience chronic pain
interfering with this immunologic balance of self-tolerance, posttreatment, and 5% to 10% will have pain that interferes
the primary adverse events associated with ICIs mimic au- with daily living.187 Acute pain crises can be triggered by
toimmune disorders.152 Altogether, the incidence rate of disease progression, tolerance to prescribed therapy, and sub-
immune- related adverse events (irAEs) of any intensity optimal use of a prescribed regimen or can be provoked by
exceeds 80%, and that for severe toxicities leading to hospi- ongoing systemic chemotherapy/radiotherapy. Nociceptive
talization or death approaches 30% across all classes of med- (visceral or somatic) and neuropathic pain mechanisms can
ications.153 Toxicities peak at 12 to 16 weeks after initiation present either independently or in combination.
(around the fourth dose) but have been reported to occur Algorithms for evaluating cancer- related pain are de-
even after the first dose, after many months of treatment, termined by the patient’s primary cancer, prior and ongoing
or even after stopping treatment.154 Combination therapy treatments, as well as established locations for known disease.
with 2 ICIs precipitates irAEs earlier than monotherapy.155 Skeletal surveys should be considered for patients in whom
The presence of irAEs correlates with overall response, lytic or sclerotic bony lesions are suspected. In patients at risk
and improved survival has been observed among patients for peritoneal carcinomatosis, a computed tomographic scan of
with multisystem, mild-to-moderate irAEs after adjusting the abdomen and pelvis should be obtained. Comparison with
for treatment duration. Most irAEs respond to high-dose prior imaging can corroborate progression of disease as the
glucocorticoids (1-2 mg/kg daily), and acute management etiology of observed breakthrough pain. The physical relation-
involves urgently starting therapy in consultation with the ship between a tumor and proximate nerve trunks and plexuses
primary oncologist.156 should be considered because this may suggest the likelihood
Chimeric antigen receptor (CAR) T- cells are a cell- of mixed pain syndromes and the possible need for advanced,
based therapy in which the patient’s T-cells are extracted multimodal interventions that combine both pharmacologic
using leukapheresis and then are genetically modified in and nonpharmacologic strategies. Cancer-related pain must
the laboratory through the insertion of DNA encoding a also be discriminated from both chronic pain that predated the
recombinant CAR whose extracellular domain recognizes malignancy and acute pain episodes from comorbid pathol-
a cancer-specific antigen, whereas the intracellular domain ogies, such as gallstones, renal stones, and headaches, each of
contains signaling components to activate the T-cell im- which requires management according to standard practices.
munogenic, antineoplastic response.157,158 The cells are Opioids are the first-line treatment for cancer-related
subsequently reinfused into the patient and can persist for nociceptive pain. Standard outpatient regimens include
>2 years.159 There are currently 2 approved CD19-specific scheduled short-acting and extended-release oral formula-
CAR T-cells treatments: tisagenlecleucel for patients with tions, breakthrough as-needed oral agents, and transdermal
relapsed or refractory B-cell acute lymphoblastic leukemia160 fentanyl. Tolerance (ie, muted therapeutic response) to a
and axicabtagene ciloleucel for patients with relapsed or re- previously effective dose frequently develops, such that dose
fractory diffuse large B-cell lymphoma.161 Antigens useful escalation is necessary to maintain adequate pain control.
for multiple myeloma, chronic lymphocytic leukemia, me- Patients who are receiving a daily oral morphine equiva-
sothelioma, ovarian cancer, pancreatic cancer, and prostate lency >200 mg per day may be at higher risk for under-
cancer are currently under investigation.162 Severe adverse treatment of their cancer pain.188 Because it is common for
reactions are seen in up to 88% of treated patients. Although patients to either underuse an as-needed prescription or to
myelosuppression after conditioning regimens and cytokine develop confusion regarding their correct schedule, confirm-
release syndrome is typically observed in the inpatient set- ing compliance with the prescribed regimen coupled with
ting 24 to 72 hours immediately after CAR T-cells infusion, ED-facilitated re-education and supervised administration
immune cell-associated neurologic syndrome (ICANS) can of scheduled oral pain medications can promote a straight-
first manifest up to 12 weeks after infusion, with the initial forward, same-day safe discharge to home.

TABLE 5. Targeted Therapy Complications: Common Presentations and Management Strategies
Small-molecule
therapeutic-related
toxicities
QTc prolongation • QTc >450 msec in males or >470 msec in females. • Routine electrolyte assessment to ensure serum K+ >4.0 and Mg2+
• Tyrosine kinase inhibitors display a mean increase of 15 msec; >2.0.
the largest QTc prolongation occurs with vandetanib, ibrutinib, • Routine serial EKG monitoring.
and ribociclib. • Ventricular arrythmias are managed according to advanced cardiac
• Crizotinib, dasatinib, lapatinib, nilotinib, pazopanib, sunitinib, life support algorithms.
sorafenib and vemurafenib, as well as romedepsin should
be administered cautiously in patients with preexisting QTc
prolongation.
EGFR inhibitor skin • Rash typically presents within 2 wks after initiating treatment • Topical calcineurin inhibitors which should be prescribed with
toxicities and forms around hair follicles, therefore is densest on the dermatologic consultation (Lacouture 2006137).
scalp, face, and upper torso which correlates with hair follicle
density (Tsimboukis 2009164).
• Most frequent with erlotinib, afatinib, cetuximab, and
panitumumab; among these, presence of the rash positively
correlates with survival (Chu 2018,165 Petrelli 2013166).
Hand-foot skin • Most commonly observed with regorafenib, sorafenib, axitinib, • A cocktail of topical high-dose steroids, a nonsteroidal anti-
reaction and sunitinib. inflammatory, and an emollient is effective.
• Characterized by palmar-plantar numbness, tingling or burning • Ultimately, dose reduction or switching to an alternate regimen is
pain alongside yellowish, hyperkeratotic plaques in high- required.
pressure areas of the hands and feet (Nikolaou 2016167).
Monoclonal antibody-
related toxicities
Sinusoid occlusion • Elevated liver function tests, and hyperbilirubinemia in a • High-dose glucocorticoids for moderate-to-severe disease (Al
syndrome patient treated with ozogamicin-conjugated monoclonal Beihany 2008168).
antibodies, or after allo-HSCT. • Defibrotide, an anti-inflammatory, antithrombotic, profibrinolytic
• Tender hepatomegaly and ascites. agent, can be administered in severe cases after normalization of
platelet count, fibrinogen, and prothrombin time with appropriate
blood products (Ho 2008169).
Angiogenesis-related • Hypertensive urgency or emergency. • Acute hemodynamic stabilization with advanced cardiac life support,
toxicities • Altered mental status. as indicated.
• Unstable angina or myocardial infarction from atherosclerosis • Noncontrast head CT to evaluate for hemorrhagic stroke in patients
and platelet activation. with altered mental status.
• PRES presents with nonspecific neurologic findings including • If posterior reversible encephalopathy syndrome (PRES) is suspected,
headache (50%), seizures (65%-70%), encephalopathy (up to an MRI should be obtained to evaluate for vasogenic edema in the
80%), visual disturbances (33%), and focal neurologic defects parieto-occipital region bilaterally on T2-weighted images, which is
(15%) (Fugate & Rabinstein 2015142). diagnostic.
• There is no specific treatment for PRES, and care is usually
supportive.
• Optimal preventive strategies for cardiac and cerebrovascular events
are still under investigation, but current standards include high-
dose statins, aspirin, and aggressive blood pressure control (Touyz
2018170).
(Continued)

Immune-related adverse General management across all irAEs:

events (irAEs)a
Dermatitis • Rash, pruritis, or bullous dermatitis occurs in 50% and typically • First-line therapy for all irAEs is high-dose glucocorticoids
appears in the first 2 cycles. (1-2 mg/kg), either oral or parenteral as clinically indicated.
• Niklosky sign, Stevens-Johnson syndrome, toxic epidermal • With mild reactions, trend abnormal laboratory values (eg, serum
necrolysis, and drug rash with eosinophilia and systemic lipase, liver function tests, troponin, or creatinine).
symptoms can occur (Belum 2016171).
• Severe reactions require hospitalization.
• After severe events, urgent subspecialty consultation may be
required.
• Second-line immunosuppressants for steroid-refractory patients
include:
◦ Infliximab (antitumor necrosis factor-α)
◦ Mycophenolate mofetil (nucleic acid depletion)
◦ Antithymocyte globulin (T-cell depletion)
◦ Tocilizumab (anti-interleukin-6)
Colitis • Colitis typically occurs within 5-8 wks of initiating therapy in ◦ Vedolizumab (anti-α4β7 integrin; regulates T-cell trafficking)
the absence of comorbid infections. ◦ Intravenous immunoglobulin (broad immunosuppression)
• It is a dose-limiting toxicity with severe disease present in 10% ◦ Rituximab (anti-CD20; B-cell depletion)
(Rajha 2020172). ◦ Tacrolimus (calcineurin inhibitor) (Sullivan & Weber 2021152).
Hepatitis and • Hepatitis occurs in about 5% of patients and is defined as
pancreatitis serum transaminase or serum bilirubin levels >1 times the
upper limit of normal (ULN); severe disease is noted at serum
transaminase levels >3 times or bilirubin >5 times the ULN.
• Exocrine pancreatitis, noted by isolated levels of serum lipase,
is rare.
• Most cases are asymptomatic, but severe cases may warrant Organ-specific considerations in irAEs:
discontinuation (Dougan 20211173).
Hypophysitis • Mild presentations include headache, fatigue, and general • High-grade pruritis requires supplemental gabapentin or pregabalin
weakness that can be misattributed to the malignancy itself (Wu & Lacouture 2018175).
(Faje 2016174). • Administer levothyroxine for patients who have hypophysitis and
• Central adrenal insufficiency represents a significant source of thyroiditis; mineralocorticoid is additionally required for hypophysitis.
morbidity and mortality. • Adrenal crisis-driven hypotension and hyponatremia require emer-
• Subtherapeutic TSH levels with concomitant low thyroid func- gent intervention.
tion tests in the absence of supplementation can corroborate • Severe thyrotoxicosis can be treated with methimazole or
the diagnosis. propylthiouracil.
• Patients with diabetes mellitus will require initiation of subcutane-
ous insulin following ketoacidosis resolution.
• MRI without contrast is the preferred imaging modality to evaluate for
encephalitis and can demonstrate T2 hyperintensities in 25% of cases.
• Supplemental oxygen may be required for pneumonitis; antibiotics
should be withheld unless infection is strongly suspected.
• Aggressive hydration and monitoring of renal function are necessary
with myositis-induced rhabdomyolysis.
• Mild ophthalmic involvement requires ophthalmologic consultation
for intraocular steroid administration.
Thyroiditis • Occurs in up to 20% of patients.
• Can initially present as thyrotoxicosis but ultimately manifests
as hypothyroidism.
• Myxedema with altered mental status, bradycardia, and hypo-
thermia can occur in severe cases (de Filette 2016176).
Islet cell-mediated • New-onset diabetes mellitus has been reported in 1% and
diabetes mellitus most frequently presents as acute-onset diabetic ketoacidosis
(Maamari 2019177).
Encephalitis • Mild and nonspecific neurologic findings (eg, headaches, dizzi-
ness, and sensory impairment) are reported in 6%-12%.
• Severe encephalitis, manifested by confusion, ataxia, abnormal
behavior, altered mental status, and seizures occurs in 0.1%.
(Continued)

Pneumonitis • Occurs in only 3%-5% of patients, but severe cases can be

fatal.
• Presents with new persistent cough or shortness of breath
along with new ground-glass opacities or interlobular septal
thickening on CT scan in the absence of infection or tumor
progression (Suresh 2018178).
Arthritis, parotitis, and • Rheumatologic irAEs occur in 5%-11%, with myositis being
myositis the most severe (Steven & Fisher 2019179).
• Myositis presents with myalgias and proximal muscle weak-
ness concurrent with elevations in serum muscle enzymes (cre-
atine phosphokinase, aldolase, and, occasionally, troponins).
Nephritis • Intrinsic nephrotoxicity occurs in 2%-5%; most commonly as
acute interstitial nephritis with or without tubular injury or
glomerular disease (Cortazar 2016180).
• Serum creatinine can peak as high as 3-4 g/dL and may not re-
turn to baseline after adequate therapy, even among patients
with no prior renal disease.
Uveitis • Occurs in 1%. Although most cases are mild nongranuloma-
tous anterior inflammation, panuveitis can lead to impaired
visual acuity (Cunningham 2020181).
Myocarditis • Occurs in <1% but can present with decompensated heart
failure or with highly morbid arrhythmias, including ventricular
tachycardia or complete atrioventricular block (Eschudier
2017182).
Hemophagocytic • Rare but potentially fatal.
lymphohistiocytosis
• Presents with fever, cytopenias, splenomegaly and elevated
serum triglycerides, fibrinogen, ferritin,
C-reactive protein, and soluble interleukin-2 (Sadaat & Jang
2018183).
CAR T-cell therapy
toxicities
Cytokine release • Clinical and pathologic variant of sepsis marked by fever and • Hemodynamic stabilization and respiratory support may require ag-
syndrome fatigue along with elevated levels of serum C-reactive protein, gressive IV fluid support, vasopressors, and mechanical ventilation.
ferritin, and interleukin-6 (Lee 2014184). • If supportive care measures are insufficient, patients first receive to-
• Hemodynamic collapse occurs in 27%-43%. cilizumab, then corticosteroids, concurrently or sequentially (Reigler
2019185).
• Up to 95% of cases will resolve with supportive measures, although
high-dose IV corticosteroids are given for severe ICANS.
• Tocilizumab is not effective in preventing or managing neurotoxicity.
Immune cell-associated • ICANS manifests as confusion, dysarthria, ataxia, tremors,
neurologic syndrome expressive aphasia, somnolence, memory problems, seizures, or
(ICANS) obtundation and occurs in 21%-38% of patients (Santomasso
2019163).
a
Abbreviations: allo-HSCT, allogenic hematopoietic stem cell transplantation; CAR T-cells, chimeric antigen receptor T cells; CT, computed tomography; EKG, elec-
trocardiogram; IV, intravenous; MRI, magnetic resonance imaging; TSH, thyroid-stimulating hormone.
When breakthrough therapy is necessary, intravenous opi- intravenous opioids; 2-6 hours for short-acting oral medica-
oids are indicated. Optimal initial breakthrough dosing for tions).190 In cases of moderate-to-severe hepatic capsulitis or
adults is 10% of the total daily opiate dose (5% in the elderly). bony pain, steroids or nonsteroidal anti-inflammatory agents
Converting between different opiates and intravenous and oral can be useful as adjunctive therapies.191 Patients in whom sus-
formulations of the same opiate is conducted using calibration tained analgesia is achieved using combinations of oral and
against morphine-equivalents (Table 6).189 Redosing should be transdermal formulations can discharge to home. Hospital ad-
conducted if the pain is still not adequately managed at the mission is required for those experiencing ongoing, intractable
expected peak pharmacokinetic concentration (15 minutes for pain despite repeated intravenous dosing.

Patients who are tolerant to extremely high daily mor- TABLE 6. Equianalgesic Dosing Among Opiate Agonists
phine equivalents are at risk for acute neurotoxic effects EQUIANALGESIC DOSEa
such as confusion, hallucination, respiratory depression, and
PO (ONSET
constipation. Patients at highest risk include those who are MEDICATION IM/IV (ONSET 15-30 MIN) 30-60 MIN)
relatively opioid-naive, are elderly, have a comorbid mood
Morphine 10 mg 30 mg
disorder, or are concurrently requiring sedative-hypnotics.192
Oxycodone — 20 mg
Moreover, because opioids are metabolized by the liver and
cleared by the kidney, both chronic and breakthrough dosing Codeine 130 mg 200 mg
should be adjusted in patients with hepatic or renal dysfunc- Hydrocodone — 30 mg
tion.193,194 Morphine should be generally avoided in patients Hydromorphone 1.5 mg 7.5 mg

with an acute kidney injury. To guard against constipation, all Fentanyl 12.5 mcg/h patch = 30-59 mg oral morphine 24 h dose
patients should concurrently initiate a daily bowel regimen 25 mcg/h patch = 60-134 mg oral morphine 24 h dose
using guidelines that recommend a tiered approach with the 50 mcg/h patch = 135-224 mg oral morphine 24 h dose
initial introduction of stool softeners (eg, docusate) in com- 75 mcg/h patch = 225-314 mg oral morphine 24 h dose
bination with stimulant laxatives (eg, bisacodyl, senna) and 100 mcg/h patch = 315-404 mg oral morphine 24 h dose
the subsequent addition of osmotic agents (eg, polyethylene Abbreviations: IM, intramuscular; IV, intravenous; PO, per os (oral).
glycol, magnesium citrate, lactulose).195 Opioid-induced
a
Data are from Quill 2019.189
constipation that is refractory to ≥2 traditional laxatives is

eligible for peripherally acting μ-opioid receptor antagonists aggressive end-of-life care, oncologists’ hesitation to directly
(eg, nadelmidine, naloxegol).196 For respiratory depression in and clearly discuss transitions of care with patients also con-
which urgent reversal is required, 1 mL of low-dose nalox- tributes.205 Consequently, some patients are first confronted
one (0.4 mg naloxone in 10 mL normal saline) is admin- with end-of-life decision making when they present to the
istered every 5 minutes until a satisfactory respiratory rate ED for acute management of terminal cancer complications.
is restored. More aggressive treatment with naloxone may Moreover, when de-escalated goals of care are not previ-
cause a traumatic return of severe, uncontrollable pain.197 ously documented in the medical record, ED clinicians are
Neuropathic pain is most often characterized as numb- defaulted into initiating an aggressive treatment plan that
ness, either hot or cold prickling, or electric sensations, with may be contrary to the patient’s underlying preferences.206
or without muscle weakness. It can be tumor-related, such as To avoid this gap, the American College of Emergency
with invasion of the celiac plexus in pancreatic cancer,198 or, Physicians Choosing Wisely Campaign expressly states that,
more commonly, a consequence of certain chemotherapies, in the absence of advance directives, goals-of-care discussions
such as platinum-based compounds.199 Neuropathic pain should begin in the ED.207 These conversations should use
syndromes respond variably to opioids.200 Gabapentin, pre- strategies such as SPIKES208 or EMAP,209 which are rubrics
gabalin, duloxetine, and glucocorticoids are commonly used for breaking bad news, to align care escalation plans with
but typically require several weeks to attain maximal ther- near-term prognosis while accounting for patient preference
apeutic impact and many patients are nonetheless refrac- and addressing their spiritual, psychological, and social care
tory. For patients with major nerve plexus invasion, referral needs.210 Care coordination for any home care services and
to chronic pain specialists for procedural interventions (eg, durable medical equipment required to support a safe dis-
nerve block or neurolysis201) may also be indicated. charge to home directly from the ED should be facilitated.
Finally, completing a same-day transfer to inpatient or home
End-of-Life Care in the ED hospice that circumvents an inpatient transition of care is
Aggressive active cancer therapy at the end of life care leads favorable. Although many systems- based barriers persist,
to poor patient outcomes and quality of life. Early referral including ED time constraints, timely access to care coor-
to palliative care services while the patient is still undergo- dination, and the uneasiness of initiating an intimate goals-
ing active disease management has been shown to minimize of-care conversation with a new patient, Quality- driven
acute care use during the last months of life.202,203 Current programs that develop this infrastructure will ameliorate
statistics indicate that >50% of patients experience at least overall management of the oncology patient in the ED.211
one acute care inpatient admission in the last 30 days of
life, with close to 60% of these admissions requiring trans- Conclusion
fer to the intensive care unit. Many of these end-stage ad- Acute care use represents a major contributor to the cost of
missions are triaged through the ED.204 Although patient oncology care and accounts for a substantial portion of the re-
factors, including strong preference for active therapy and gional variation in the cost of cancer care. Optimizing the ur-
denial of current disease state, do account for the majority of gent and emergent care of patients with cancer through timely

symptom recognition and initiation of recommended clinical neurofilament light chain as a marker of neuronal injury212)
algorithms, including the effective triage of patients who are and the use of immunomodulators (eg, anakinra213) in the hy-
safe for discharge home, is essential for improving the quality peracute setting. Quality-based research focuses on optimiz-
and value of oncology care. Active areas of research include the ing ED-driven care coordination to facilitate direct discharge
ongoing optimization of FN clinical pathways with a focus on to hospice and improving transitions of care between the ED
refining criteria to identify patients who are sufficiently stable and the oncology hospitalist. Together, these provide a unique
for outpatient management, developing active pain-control resource for the ED physician, the outpatient oncologist, the
interventions within a 24-hour or 48-hour timeframe to man- primary care physician, and the oncology hospitalist, with the
age acute pain crises in the ED, and approaches to identify potential for improving the management of oncology patients
targeted therapeutic-related complications in the ED to de- who require urgent or emergent care. ■
velop protocols for their early management. Within the lat-
ter, efforts to improve the management of ICANS include the Acknowledgments: We acknowledge the Comprehensive Oncologic Emergency
identification of early serum-based diagnostic markers (eg, Research Network (CONCERN) consortium for their support of this article.
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Oncologic Emergencies and Urgencies A Comprehensive Review

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Oncologic Emergencies and Urgencies A Comprehensive Review

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CA CANCER J CLIN 2022;0:1–24

Oncologic emergencies and urgencies:

VOLUME 0 | NUMBER 0 | MONTH 2022 1

doi: 10.3322/caac.21727. Available online at cacancerjournal.com

2 CA: A Cancer Journal for Clinicians

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Abbreviation: CNS, central nervous system.

4 CA: A Cancer Journal for Clinicians

TABLE 2. Paraneoplastic Syndromes: Common Presentations and Management Strategies

SYNDROME PRESENTATION MANAGEMENT

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SYNDROME PRESENTATION MANAGEMENT

6 CA: A Cancer Journal for Clinicians

SYNDROME PRESENTATION MANAGEMENT

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SYNDROME PRESENTATION MANAGEMENT

Bowel obstruction (Continued) • Persistent obstructions may require venting gastrostomy

8 CA: A Cancer Journal for Clinicians

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10 CA: A Cancer Journal for Clinicians

SYNDROME PRESENTATION MANAGEMENT

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SYNDROME PRESENTATION MANAGEMENT

Severe anemia • In the appropriate situations, hemagglutinins can be assessed

12 CA: A Cancer Journal for Clinicians

SYNDROME PRESENTATION MANAGEMENT

Hemorrhagic cystitis • Continuous bladder irrigation using a large-­bore, 3-­way

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14 CA: A Cancer Journal for Clinicians

SYNDROME PRESENTATION MANAGEMENT

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SYNDROME PRESENTATION MANAGEMENT

Immune-­related adverse General management across all irAEs:

16 CA: A Cancer Journal for Clinicians

Pneumonitis • Occurs in only 3%-­5% of patients, but severe cases can be

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should be adjusted in patients with hepatic or renal dysfunc- Hydrocodone —­ 30 mg

tion.193,194 Morphine should be generally avoided in patients Hydromorphone 1.5 mg 7.5 mg

constipation that is refractory to ≥2 traditional laxatives is

18 CA: A Cancer Journal for Clinicians

References A longitudinal data-­ linkage study in 19. Oronsky B, Ma PC, Morgensztern D,

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20 CA: A Cancer Journal for Clinicians

VOLUME 0 | NUMBER 0 | MONTH 2022 21

22 CA: A Cancer Journal for Clinicians

VOLUME 0 | NUMBER 0 | MONTH 2022 23

24 CA: A Cancer Journal for Clinicians

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Hemorrhagic cystitis • Continuous bladder irrigation using a large-bore, 3-way

Immune-related adverse General management across all irAEs:

Pneumonitis • Occurs in only 3%-5% of patients, but severe cases can be

should be adjusted in patients with hepatic or renal dysfunc- Hydrocodone — 30 mg

References A longitudinal data- linkage study in 19. Oronsky B, Ma PC, Morgensztern D,