Management of oncologic emergencies

Survival in children with cancer has increased dramatically during the last five decades. This progress is due not only to advances in therapy but also to advances in supportive care and an improved ability to manage life-threatening complications. Oncologic emergencies can occur as an initial manifestation of cancer, as a side effect of therapy, or at the time of progression or recurrence of the disease.

Excellent cancer management requires mastery of the following:

metabolic emergencies, including hyperleukocytosis, tumor lysis syndrome (TLS), and associated electrolyte derangements;
cardiothoracic emergencies, including superior vena cava syndrome (SVCS) and mediastinal masses;
acute abdominal processes;
renal dysfunction and hypertension;
neurologic emergencies;
endocrine emergencies;
treatment-related emergencies;

Metabolic emergencies

Hyperleukocytosis

Hyperleukocytosis is defined as a total white cell count greater than 100,000/mm ³ . The high burden of leukemia blasts in the microcirculation leads to sludging, which interferes with oxygenation of local tissue and ultimately leads to tissue ischemia. This in turn leads to an adhesive reaction between abnormal vascular endothelium and the circulating blasts worsening leukostasis, thrombosis, and leading to secondary hemorrhage. The higher metabolic rate of the blasts and the local production of cytokines also contribute to tissue hypoxia. Thrombi in the circulation lead to vascular damage and parenchymal ischemia manifested as pulmonary or cerebrovascular hemorrhage and edema.

Myeloblasts are larger, less deformable, and more adherent to vasculature than lymphoblasts of normally maturing white blood cells. Due to these intrinsic properties, leukostasis and thrombosis are far more prevalent in acute myeloid leukemia (AML) than in acute lymphoblastic leukemia (ALL) and the threshold for clinically significant hyperleukocytosis varies by disease ( Table 31.1 ).

Table 31.1

Clinical associations of hyperleukocytosis by disease type.

	Prevalence	Disease subtypes associated with increased risk	Threshold for clinically significant hyperleukocytosis	Clinical implications
Acute lymphoblastic leukemia	9–13%	Infant leukemia T-cell Philadelphia chromosome positive and Philadelphia-like	300,000/mL	High risk of metabolic derangements and tumor lysis syndrome
Acute myeloid leukemia	5–25%	Infant leukemia French-American-British (FAB) M1, M3 (Acut promyelocytic leukemia), M4, M5 inv(16) FT3-ITD	200,000/mL	High risk of intracranial hemorrhage/thrombosis High risk of pulmonary hemorrhage
Chronic myeloid leukemia	Majority	Blast phase	300,000/mL (or higher)

Clinical features

Any patient presenting with a white blood cell count greater than 50,000/mm ³ should be evaluated closely for clinical signs and symptoms of leukostasis.

central nervous system (CNS): blurred vision, confusion, somnolence, delirium, stupor, coma, and papilledema;
pulmonary: tachypnea, dyspnea, hypoxemia;
- chest radiograph (CXR) may reveal varying degree of diffuse interstitial or alveolar infiltrates
- computed tomography (CT) may reveal hemorrhage or leukemic infiltrate
genitourinary: oliguria, anuria, rarely priapism;
hematologic: disseminated intravascular coagulation (DIC), retinal hemorrhage, myocardial infarction, renal vein thrombosis;

Treatment

Given the risk of TLS associated with hyperleukocytosis treatment is directed at decreasing the white blood cell count while preventing and treating metabolic complications of tumor lysis.

1.
Intravenous (IV) hydration (at least two times maintenance rate)
2.
Transfusion
- a.
  Transfuse platelets for platelet count less than 20,000/mL.
- b.
  Because red blood cells increase viscosity, avoid red blood cell transfusion unless hemodynamically unstable. If transfusing, should be in small aliquots of 5 cm ³ /kg at a time.
3.
Correct coagulopathy with vitamin K or fresh frozen plasma
4.
Initiate antileukemic therapy as soon as possible
5.
Leukapheresis and exchange transfusion: consider in all symptomatic patients and in asymptomatic patients if initial white cell count is greater than 200,000/mm ³ in AML or 300,000/mm ³ in ALL or chronic myeloid leukemia (CML). Definitive therapy should not be delayed to perform this procedure. Contraindicated in acute promyelocytic leukemia (APML)

Tumor lysis syndrome

TLS arises due to the rapid release of intracellular metabolites from dying tumor cells in quantities that exceed the excretory capacity of the kidneys. In patients with a high tumor burden or rapid cell proliferation, cell death and release of intracellular ions, even prior to chemotherapy initiation, may result in metabolic complications, including hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Table 31.2 lists patient stratification by risk for TLS for various types of cancer. Fig. 31.1 outlines the approach for initial management based on those risk stratifications.

Table 31.2

Tumor lysis syndrome risk strata by cancer type.

Adapted from Coiffier, A., Altman, A., Pui, C.H., Younes, A., Cario, M.S., 2008. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J. Clin. Oncol. 26 (16), 2767–2778.

	ALL	AML	NHL	Other hematologic malignancies	Solid tumors
Stratification criteria	WBC	WBC	Disease type	Rate of proliferation	N/A
Low	<50,000/mm ³	<10,000	Indolent NHL	Remainder of patients	All
Intermediate	50,000–100,000/mm ³	10,000–50,000/mm ³	DLBCL	Rapid proliferation and/or expected rapid response to therapy
High	>100,000/mm ³	>50,000/mm ³	Burkitt, lymphoblastic

Abbreviations: ALL , Acute lymphoblastic leukemia; AML , acute myeloid leukemia; DLBCL , diffuse large B-cell lymphoma; NHL , non-Hodgkin’s lymphoma; WBC, white blood cell count.

If not successfully treated, TLS can result in renal insufficiency/failure, cardiac arrhythmias, seizures, DIC, and death. Recognition of risk factors, close monitoring, and appropriate preventative intervention are vital in managing TLS.

Prevention and management

Fundamental principles of prevention and management of TLS are presented in Table 31.3 .

Table 31.3

Principles of prevention and management of tumor lysis syndrome.

Objective	Management guidelines
Monitor for laboratory and clinical TLS	Strict measurement of intake and output Check electrolytes; calcium, phosphorus, potassium, uric acid, blood urea nitrogen (BUN), and creatinine every 4–12 h Complete blood counts 1–2 times per day Respiratory, CNS, and cardiac monitoring if hyperkalemia or hypocalcemia are present
Promote renal excretion of intracellular metabolites; increase GFR and renal blood flow	Urine output should be greater than 100 mL/m ² /h with a specific gravity less than 1.010 IV hydration: at least two times maintenance rate Diuretics if no hypotension or hypovolemia First line: furosemide 0.5–1 mg/kg per dose Second line: mannitol 0.5 g/kg per dose Dialysis: indicated for progressive renal failure with hyperkalemia, hyperphosphatemia, oliguria, anuria, or volume overload unresponsive to other measures
Reduce uric acid	Pharmacologic treatment based on risk. See Fig. 31.1 Allopurinol 300 mg/m ² per day or 10 mg/kg per day PO (maximum dose 800 mg/day) or 200 mg/m ² per day IV (maximum dose 600 mg/day) may be used if available Rasburicase (recombinant urate oxidase) 0.15–0.2 mg/kg per day IV, the dose can be repeated Indicated for patients at high risk of tumor lysis Assess patient’s G6PD status: in patients with G6PD deficiency, rasburicase may cause methemoglobinemia or severe hemolytic anemia Urinary alkalization: target urine pH 7–7.5 to help keep uric acid crystals from forming Discontinue at initiation of chemotherapy or with the use of rasburicase. Higher pH can cause xanthine crystal precipitation and calcium phosphate crystal formation
Reduce potassium	Potassium infusion should be avoided unless dangerously low Mild and asymptomatic hyperkalemia: Hydration and diuretics Sodium polystyrene sulfonate (Kayexalate) at dose of 1 g/kg every 6 h with sorbitol 50–150 mL will remove 1 mEq of potassium per liter per gram of resin over 24 h Moderate-to-severe hyperkalemia: Obtain an EKG Insulin (0.1 U/kg per hour) plus glucose (dextrose 0.5 g/kg per hour); in emergency cases, 50% dextrose can be used at 1 mL/kg through a central line. Monitor serum glucose closely For life-threatening arrhythmias IV calcium gluconate (100–200 mg/kg) or calcium chloride (10 mg/kg) slows IV infusion rate. The onset of action is within minutes and duration of activity lasts about 30 min (cannot be administered in the same line as NaHCO ₃ ) NaHCO ₃ to stabilize myocardial cell membrane and to reverse acidosis; 1–2 mEq/kg IV. For every increase of 0.1 pH unit, potassium is decreased about 1 mEq/L. Onset of action is within 30 min and duration of action lasts several hours Dialysis should be considered while these rescuing approaches are underway
Reduce phosphorus	IV hydration without alkalization Phosphorous binder prevents absorption of oral phosphate intake but has little direct effect on lowering serum phosphate Aluminum hydroxide 150 mg/kg per day divided into doses every 6–8 h Sevelamer hydrochloride (RenaGel), a noncalcium phosphate binder (400 mg twice daily for older children)—should be administered Low phosphate diet
Raise calcium	For symptomatic hypocalcemia (e.g., tetany) only: 10 mg/kg of elemental calcium (i.e., 0.5–1.0 mL/kg of 10% calcium gluconate). Calcium administration should be discontinued when symptoms resolve (Caution: do not administer calcium in the same line as NaHCO ₃ .)

Abbreviations: CNS , Central nervous system; GFR , glomerular filtration rate; IV , intravenous; TLS , tumor lysis syndrome.

Renal dysfunction from tumor lysis

Multiple mechanisms contribute to kidney injury in TLS, including:

precipitation of uric acid in the renal tubules,
precipitation of xanthine when the urine pH exceeds 7.5 and after initiation of allopurinol,
precipitation of calcium phosphate in renal microvasculature and renal tubules when the product of serum calcium and phosphate values exceeds 60, and
cytokine release leading to inflammation and hypotension.

Hemodialysis or hemofiltration should be used when renal failure occurs. Specific indications for dialysis include:

presence of hyperphosphatemia (>6 mg/dL) and hypercalcemia, which promotes deposition in renal interstitium and tubular system, exacerbating kidney damage,
an estimated glomerular filtration rate less than 50%,
persistent hyperkalemia with QRS interval widening and/or level exceeding 6 mEq/L,
severe metabolic acidosis,
volume overload unresponsive to diuretic therapy,
anuria and overt uremic symptoms (i.e., encephalopathy),
severe symptomatic hypocalcemia,
hypertension [blood pressure (BP)>150/90] and inadequate urine output at 10 hours from the start of treatment, and
congestive heart failure.

Cardiothoracic emergencies

Superior vena cava syndrome and superior mediastinal syndrome

SVCS consists of the signs and symptoms of SVC obstruction due to compression or thrombosis. This condition is frequently due to a large anterior mediastinal mass compressing the SVC. The rapid growth of the mediastinal mass does not permit the development of effective collateral circulation to compensate and results in the signs and symptoms of compression of the SVC. Superior mediastinal syndrome (SMS) consists of SVCS with tracheal compression. The trachea and main stem bronchus are more compressible in children, making them more susceptible to SMS and the terms SVCS and SMS are often used synonymously.

Etiology

1.
Intrinsic causes: vascular thrombosis following the introduction of a catheter, intravascular tumor thrombosis (Wilms, lymphoma)
2.
Extrinsic causes: malignant anterior mediastinal tumors
- a.
  Hodgkin lymphoma
- b.
  non-Hodgkin lymphoma
- c.
  T-cell ALL (rarely B-cell ALL)
- d.
  teratoma or other germ cell tumor
- e.
  thyroid cancer
- f.
  thymoma

Clinical features

1.
Respiratory symptoms: cough, hoarseness, dyspnea, orthopnea, wheezing, and stridor. Supine position worsens symptoms
2.
swelling, plethora, and cyanosis of the face, neck, and upper extremities
3.
dysphagia
4.
chest pain
5.
suffusion of the conjunctiva
6.
engorgement of collateral veins
7.
altered mental status, syncope

Management

1.
Extreme care is required in handling the patient. The following may precipitate respiratory arrest:
- a.
  supine or recumbent position (as for CT or operative procedures),
- b.
  medications that cause intercostal muscle relaxation (anxiolytics, sedatives),
- c.
  sedation (moderate sedation, general anesthesia). Patients cannot always be intubated due to mass location, extracorporeal membrane oxygenation may be required if intubation is not possible,
- d.
  anxiety/stress.
2.
Diagnosis should be made quickly in the least invasive manner possible.
- a.
  Screening blood work such as a complete blood count (CBC) with manual differential, peripheral blood flow cytometry, lactate dehydrogenase, uric acid, α-fetoprotein, and Beta human chorionic gonadotropin (β-hCG) (screening for leukemia, lymphoma, and germ cell tumors),
- b.
  CXR and CT imaging (if tolerated),
- c.
  echocardiogram, to assess anesthesia risk, cardiac function and for possible intravascular thrombus if no evidence of mass on CXR, and
- d.
  determine anesthesia risk
  - i.
    If high risk, perform the least invasive technique with local anesthesia preferably in an operating room setting with an anesthesiologist present (bone marrow aspirate, pleurocentesis, pericardiocentesis, lymph node biopsy, or fine-needle aspirate).
  - ii.
    If low risk, use moderate sedation or anesthesia and monitor closely.
3.
Cancer treatment
- a.
  Patients may need empiric treatment as a lifesaving measure. First-line treatment in emergent situations is high-dose steroids. IV methylprednisolone 1 mg/kg per dose up to every 6 hours. This will treat hematologic malignancies and decrease airway edema. The patient should undergo biopsy as soon as the mass shrinks and the patient is stable.
- b.
  Steroids should be initiated pending pathologic diagnosis once diagnostic tissue is obtained.
- c.
  If poor response to steroids, chemotherapy such as vincristine, cyclophosphamide with or without an anthracycline can be added.
- d.
  Tumor-specific chemotherapy should be instituted as soon as a diagnosis is made.
- e.
  If a solid tumor not responsive to steroids or chemotherapy, emergent radiation can be performed.
4.
Thrombosis treatment—see Chapter 13 , Disorders of Coagulation.

Abdominal emergencies

Abdominal pain is a very common complaint in oncology patients, both as the presentation of a new intraabdominal malignancy or due to toxicity from therapy. For patients on therapy the differential diagnosis is very broad so a focus on history, concomitant symptoms, medication, physical examination, and imaging is often necessary to pinpoint and treat the etiology.

Table 31.4 provides a detailed evaluation and management of common causes of abdominal pain.

Table 31.4

Evaluation and management of common causes of abdominal pain.

Diagnosis	Signs and symptoms	Clinical risk factors	Evaluation	Management
Bowel obstruction	Pain Decreased bowel sounds Distended abdomen	Tumor Intussusception Adhesions	Examination, Abdominal radiograph, US or CT	Bowel rest/NG Surgical consultation
Constipation/ileus	Hard stools or no stool Pain Distended abdomen	Narcotics Postoperative Vincristine Dehydration	Examination Abdominal radiograph	Stool motility agents Stool softeners, Hydration
Gastritis/esophagitis	Gastric/throat pain Metallic taste	Chemotherapy Steroids Candida	Oral examination	Oral or IV antacid Antifungal
Gastrointestinal hemorrhage (upper)	Hematemesis	Chemotherapy Steroids Epistaxis Emesis	Oral examination Endoscopy	IV antacid Antiemetics
Gastrointestinal hemorrhage (lower)	Dark tarry stools Bright red blood per rectum Bloody diarrhea	Prolonged neutropenia Tumor mass causing intussusception Hemorrhoids	Abdominal and perirectal examination abdominal imaging (CT or US) Tagged RBC scan PET scan	Bowel rest/NG Broad-spectrum antibiotics Surgical consultation
Hepatic enlargement	RUQ mass	Neuroblastoma stage 4S HLH Intrahepatic tumor hemorrhage SOS/VOD	CT, urine VMA/HVA	Chemotherapy
Pancreatitis	RUQ pain Emesis	Asparaginase Steroids	Amylase, lipase US/CT for hemorrhage or pseudocyst	Bowel rest/NG
Perirectal abscess	Erythema Induration Pain with defecation	Severe myelosuppression prolonged neutropenia	Perirectal examination	Broad-spectrum antibiotics (Gram-negatives and anaerobes) Sitz baths (four times a day)
Sinusoidal obstructive syndrome/veno-occlusive disease	RUQ mass Edema Weight gain Ascites Jaundice	Peri-transplant Thiopurines Inotuzumab Actinomycin Gemtuzumab	Hepatic US for reversal of flow Bilirubin Weight checks	Stop inciting agents Defibrotide Fluid management
Typhlitis/colitis	Acute abdomen P/RLQ pain Diarrhea Hypotension Bloody diarrhea	Severe myelosuppression Acute leukemia Peri-HSCT	Abdominal radiograph or CT (free air or thickened bowel wall) Stool cultures	Bowel rest/NG Surgical consultation Broad-spectrum antibiotics (Gram-negatives and anaerobes) antifungals

Abbreviations: CT , Computed tomography; HLH , Hemophagocytic Lymphohistiocytosis; HSCT , Hematopoietic Stem Cell Transplant; IV , intravenous; NG , nasogastric tube suctioning; PET , Positron Emission Tomography; RBC , Red Blood Cell; RLQ , right lower quadrant of abdomen; RUQ , right upper quadrant of abdomen; SOS/VOD ; Sinusoidal obstructive syndrome/veno-occlusive disease; US , ultrasound; VMA/HVA , Vanillylmandelic Acid/Homovanillic Acid.

Evaluation and diagnosis of abdominal emergencies

1.
history regarding onset, timing, location, and radiation of pain;
2.
observation and gentle examination, including mouth and perirectal area in particular;
3.
the classic signs of an acute abdomen may be muted in a neutropenic patient or a patient on steroids;
4.
vital signs monitoring;
5.
serial blood counts to evaluate for hemorrhage, neutropenia, infection;
6.
blood, stool, and urine cultures as indicated;
7.
laboratory tests, liver enzymes, bilirubin, amylase, lipase, electrolytes; and
8.
abdominal radiography: US, CT, and magnetic resonance imaging (MRI) as indicated.

Typhlitis

Typhlitis, a necrotizing colitis often localized in the cecum, occurs in the setting of severe neutropenia, particularly in patients with leukemia and in stem cell transplant recipients. It should be strongly suspected in patients with right lower quadrant pain, fever, and diarrhea. Typhlitis is the result of bacterial or fungal invasion of the mucosa and can quickly progress from inflammation to full-thickness infarction to perforation, peritonitis, and septic shock.

Etiology

1.
Gram-negative bacteria are the most common pathogens, including Pseudomonas species, Escherichia coli , and Clostridium , but it can also be caused by Staphylococcus , Streptococcus , and Enterococcus species. Fungal etiologies include Candida and Aspergillus .
2.
Typhlitis in patients receiving chemotherapy is linked to mucosal injury caused by cytotoxic chemotherapeutic agents.

Diagnosis

Typhlitis is usually diagnosed clinically when a neutropenic patient presents with:

1.
right lower quadrant pain
2.
Physical examination may reveal an absence of bowel sounds, bowel distention, tenderness on deep palpation, or a palpable mass in the right lower quadrant. Serial abdominal examinations are required.
3.
Imaging studies may aid in the diagnosis of typhlitis:
- a.
  Radiograph of the abdomen may reveal pneumatosis intestinalis, free air in the peritoneum, or bowel wall thickening.
- b.
  US may reveal thickening of the bowel wall in the region of the cecum and is becoming a more commonly used nonradiation modality to image for typhlitis.
- c.
  CT scan is the definitive imaging study and may demonstrate diffuse thickening of the bowel wall.

Treatment

1.
Medical management is the preferred treatment when possible, consisting of:
- a.
  discontinuation of oral intake
- b.
  nasogastric tube to suction
- c.
  broad-spectrum antibiotics (Gram-negative, anaerobic, and antifungal coverage)
- d.
  IV fluid and electrolytes
- e.
  packed red cell and platelet transfusions, as indicated
- f.
  vasopressors, as needed (hypotension is associated with a poor outcome)
2.
Indications for surgical intervention:
- a.
  persistent gastrointestinal (GI) bleeding despite resolution of neutropenia and thrombocytopenia,
- b.
  evidence of free air in the abdomen on abdominal radiograph (indicating perforation),
- c.
  necrotic bowel causing sepsis/hypotension,
- d.
  surgery consists of removing necrotic portions of the bowel and diversion via colostomy, and
- e.
  mortality is related to bowel perforation, bowel necrosis, and sepsis.

Perirectal abscess/fistula

Inflammation and infection of the rectum and perirectal tissue occur commonly in patients receiving chemotherapy or radiation therapy, especially in patients with prolonged neutropenia. Most abscesses are caused not by a single organism but rather by a combination of aerobic organisms, such as Staphylococcus, Streptococcus , E. coli , Pseudomonas , and fecal anaerobes.

Presentation includes anorectal pain, tenderness, and painful bowel movements. An abscess or draining fistula may be present; however, in the neutropenic patient, pus will be absent and the patient will present with a brawny edema and dense cellulitis.

Management

1.
Broad-spectrum antibiotics to cover Gram-positive and -negative organisms and anaerobes,
2.
granulocyte colony-stimulating factor to shorten period of neutropenia,
3.
sitz baths multiple times a day, and meticulous attention to perirectal hygiene, and
4.
surgical incision and drainage of obviously fluctuant areas or draining fistulas that do not resolve with medical management.

Renal emergencies

Renal complications can be caused by the tumor itself (urinary tract obstruction and renal vein thrombosis) or as a result of cancer therapy (hemorrhagic cystitis, acute renal failure, or hypertension).

Oliguria/anuria

Differential diagnoses

1.
Prerenal: sepsis, shock, dehydration, emesis, diarrhea, decreased fluid intake;
2.
Postrenal: bulky abdominopelvic tumors with obstruction, hemorrhagic cystitis; and
3.
Renal insufficiency: TLS, chemotherapy agents, contrast dyes, antiinfectives.

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