Medical Emergencies in Oncology - Turner White Communications

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ONCOLOGY BOARD REVIEW MANUAL PUBLISHING STAFF PRESIDENT, PUBLISHER

Bruce M. White

Medical Emergencies in Oncology: I

EXECUTIVE EDITOR

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Miranda J. Hughes, PhD ASSISTANT EDITOR

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Rita E. Gould SPECIAL PROGRAMS DIRECTOR

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NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine.

Endorsed by the Association for Hospital Medical Education The Association for Hospital Medical Education endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in medical education as they affect residency programs and clinical hospital practice.

Series Editor: Arthur T. Skarin, MD, FACP, FCCP Attending Physician, Department of Adult Oncology Dana-Farber Cancer Institute and Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School, Boston, MA

Contributing Author: Wolfram Goessling, MD, PhD Clinical Fellow in Hematology/Oncology Department of Adult Oncology Dana-Farber Cancer Institute and Brigham and Women’s Hospital Harvard Medical School Boston, MA

Table of Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 2 Metabolic Emergencies. . . . . . . . . . . . . . . . . 2 Neutropenic Fever . . . . . . . . . . . . . . . . . . . . 8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 10 References . . . . . . . . . . . . . . . . . . . . . . . . . 10 Cover Illustration by Christie Grams

Copyright 2000, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications, Inc. The editors are solely responsible for selecting content. Although the editors take great care to ensure accuracy, Turner White Communications, Inc., will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of the authors and do not necessarily reflect those of Turner White Communications, Inc.

Oncology Volume 5, Part 4 1

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ONCOLOGY BOARD REVIEW MANUAL

Medical Emergencies in Oncology: I Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Contributing Author: Wolfram Goessling, MD, PhD

Attending Physician Department of Adult Oncology Dana-Farber Cancer Institute and Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, MA

Clinical Fellow in Hematology/Oncology Department of Adult Oncology Dana-Farber Cancer Institute and Brigham and Women’s Hospital Harvard Medical School Boston, MA

I. INTRODUCTION Recent years have brought advances in cancer therapies, resulting in increased cure rates and survival often because of more aggressive treatment regimens. However, emergencies occur frequently in oncologic patients because of either disease progression or treatment. The morbidity and mortality of these complications is substantial. Only quick access to an emergency department, identification of the underlying pathophysiology, and rapid administration of appropriate therapy (complication specific, disease specific, or both) will prevent death or loss of quality of life. This is the first part of a 2-part review on oncologic emergencies. The first part discusses the management of metabolic emergencies and neutropenic fever. The second part discusses the management of spaceoccupying lesions and also provides sample board review questions and answers for self assessment.

II. METABOLIC EMERGENCIES A. Tumor lysis syndrome 1. Definition. The tumor lysis syndrome is a lifethreatening derangement of electrolytes

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caused by massive cytolysis of tumor cells that arises spontaneously or during treatment with chemotherapy or radiation therapy of predominantly hematologic malignancies. It is characterized by the acute development of: 1 – 3 a. Hyperkalemia b. Hyperuricemia c. Hyperphosphatemia d. Hypocalcemia, as a secondary occurrence e. Acute renal failure, as a secondary occurrence Etiology a. Massive lysis or necrosis of radiosensitive or chemosensitive tumor cells results in a sudden release of intracellular components, causing hyperkalemia, hyperphosphatemia, and hyperuricemia. Steroids have also been described as causing tumor lysis syndrome in patients with acute leukemias and non-Hodgkin’s lymphoma. b. Calcium phosphate precipitation in the tissue occurs because of acute hyperphosphatemia. c. Oxidation of hypoxanthine and xanthine by xanthine oxidase leads to accumulation of uric acid.

Medical Emergencies in Oncology: I 3.

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Risk factors a. Patients particularly at risk have the following malignancies: 1) High-grade lymphomas, especially Burkitt’s lymphoma 2) Acute and chronic leukemias, especially acute lymphocytic leukemia (ALL), most commonly subtype L3 b. Patients rarely at risk have the following solid tumors: small-cell lung cancer, breast cancer, hepatoblastoma, seminoma, and neuroblastoma.4 c. High tumor burden. An increased lactate dehydrogenase level, leukocyte count, or bulky disease on presentation is indicative of a high tumor burden and increases the likelihood of developing the tumor lysis syndrome. d. Preexisting renal insufficiency Clinical presentation. Symptoms are related to the specific metabolic abnormalities. a. Arrhythmias are the most serious consequence, generally caused by hyperkalemia or hypocalcemia. They mainly occur within the first 6 to 72 hours of initial treatment. b. Muscle cramps and weakness are most often caused by hypocalcemia and hyperkalemia. Patients may have tetany with positive Chvostek’s or Trousseau sign. c. Lethargy, nausea, or vomiting can be signs of increased uric acid levels and acute renal failure, which is caused by precipitation of uric acid and calcium phosphate crystals in the kidney.3 After prolonged periods, these crystals can also cause nephrolithiasis. d. Pruritus and arthritis may be caused by deposition of calcium phosphate in the soft tissue. Diagnosis a. Tumor lysis syndrome is diagnosed on the basis of serum electrolyte studies. Serum potassium, bicarbonate, calcium, phosphorus, uric acid, blood urea nitrogen, and creatinine levels should be checked twice daily to allow for rapid detection and correction of the metabolic abnormalities during the initial phase of chemotherapy. b. An electrocardiogram (ECG) may show signs of hyperkalemia (peaked T-waves,

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widened QRS, sine-wave pattern) or hypocalcemia (long QT). Treatment a. Prevention of this complication in patients at risk (see Section II. A. 3.) is the primary treatment goal: 1) Allopurinol inhibits xanthine oxidase, resulting in higher levels of the more water soluble xanthine while lowering the serum levels of the less soluble uric acid. This agent is the mainstay of therapy, usually given at daily doses of 600 to 900 mg. 2) Hyperuricemic agents (ie, thiazide diuretics and salicylates) should be avoided. 3) Intravenous (IV) hydration with normal saline should be given to maintain good urine output prior to the initiation of chemotherapy, normally starting 24 to 48 hours before therapy at a rate of 4 to 5 L/day.2 4) Forced diuresis using loop diuretics or mannitol may be necessary to achieve a urine output of 3 to 4 L/day. 5) Alkalinization of urine is generally not recommended on a routine basis because high urine output may be the primary mode of protection from urate nephropathy and because overly aggressive alkalinization can cause precipitation of calcium phosphate in the renal tubules.5 a) Alkalemia can also worsen the effects of hypocalcemia because it allows increased serum protein binding of calcium, thereby decreasing the ionized calcium fraction. It can also increase the risk of xanthine nephropathy by decreasing the solubility of xanthine. b) Alkalinization of urine is only recommended under certain circumstances. For patients presenting with a uric acid level more than 10 mg/dL, a urine pH more than 7.0 should be maintained by adding 50 to 100 mEq NaHCO3/L to the IV hydration fluid. Carbonic anhydrase inhibitors (acetazolamide,


Medical Emergencies in Oncology: I 250 to 500 mg/day) may be used but are contraindicated in patients with acidosis because they impair renal hydrogen excretion. b. Hyperphosphatemia is corrected with calcium given with meals (which prevents absorption of phosphate) or with aluminum-based phosphate binders. c. Hyperkalemia is treated with: 1) Insulin-glucose infusions (10 units regular insulin, 25 g 50% dextrose) to acutely lower the serum levels 2) Calcium gluconate, if arrhythmias are present on ECG 3) Potassium-wasting loop diuretics (ie, furosemide) to increase renal potassium excretion 4) Sodium polystyrene sulfonate (Kayexalate, 30 g orally, given with lactulose or as enema) to inhibit intestinal absorption d. Recent reports show that hyperuricemia can also be treated with urate oxidase, which converts uric acid into the much more soluble allantoins and is currently approved only in Italy and France.6 e. Dialysis is indicated for: 1) Hyperkalemia that is refractory to the treatment as previously described 2) Hypervolemia resulting from the combination of hyperhydration and renal failure 3) Severe uremia with altered mental status, evidence of platelet dysfunction, or pericarditis. B. Hypercalcemia of malignancy 1. Definition. Hypercalcemia is the most common metabolic complication, occurring in 10% to 20% of all cancer patients. 2. Etiology a. The condition is most commonly associated with the following: 1) Lung cancer, 25% to 35% 2) Breast cancer, 15% to 25% 3) Hematologic malignancies (multiple myeloma, lymphoma), 10% to 15% b. It occurs less frequently in head and neck, renal, prostate, and colon cancers. c. It is caused by mobilization of calcium from bone and by increased renal calcium absorption and phosphate excretion.


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1) In patients with solid tumors, hypercalcemia is most commonly caused by tumor-related production of parathyroid hormone–related protein (PTHrP) because at least 80% of those patients with hypercalcemia have increased PTHrP levels.7 a) PTHrP, like parathyroid hormone (PTH), acts on the PTH receptor because its aminoterminal domain of 34 amino acids is homologous to PTH.7 Although PTH acts as a circulating hormone, PTHrP acts as a paracrine messenger within tissues at normal concentrations. b) The overexpression of PTHrP is best understood in adult T-cell leukemia/lymphoma patients who often present with hypercalcemia. This disease is associated with human T-cell leukemia virus type 1 [HTLV-1]) that encodes a protein, tax, which transactivates the PTHrP promoter in T-cells.8 2) Another cause of hypercalcemia, especially in myeloma, is local bone destruction involving activation of osteoclasts by cytokines such as epidermal growth factor (EGF), interleukin-1 (IL-1), IL-6, tumor growth factor–α (TGF-α) and TGF-β, and tumor necrosis factor (TNF). 3) Hypercalcemia in Hodgkin’s disease and some cases of non-Hodgkin’s lymphoma is caused by increased production of calcitriol by tumor cells.9 4) Although prostaglandin E has boneresorptive activity in vivo, prostaglandin inhibitors fail to improve serum calcium levels; thus, the pathogenetic relevance of the mechanism is not clear. Clinical presentation. Patients may present with various symptoms caused by the effects of hypercalcemia on each organ system. The severity of all of these symptoms is related to the rapidity of onset of hypercalcemia. a. Nonspecific manifestations include weight loss, anorexia, and pruritus.

Medical Emergencies in Oncology: I b.

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Renal complications. Patients may develop nephrogenic diabetes insipidus, leading to polyuria with subsequent polydipsia and dehydration. Prolonged hypercalcemia may cause nephrolithiasis. c. Neuromuscular effects include fatigue, muscle weakness, and hyporeflexia. Confusion, psychosis, seizures, and coma can occur at advanced stages. d. Effects on the gastrointestinal tract include nausea, vomiting (which further worsens the dehydration), constipation, and ileus. e. Cardiac effects are orthostasis caused by dehydration, bradycardia, prolonged PR intervals and wide T-waves, shortened QT, as well as possible J-waves otherwise only seen in hypothermia.10 Diagnosis. The differential diagnosis for hypercalcemia is broad (Table 1). a. The diagnosis of hypercalcemia is made in patients with an increased serum calcium level and with the symptoms previously mentioned (see Section II. B. 3). b. The ionized calcium fraction can be directly measured for greatest accuracy. A good approximation of the severity of the hypercalcemia can be calculated from the serum calcium and albumin levels using the following equation:

[Cacorrected] = [Cameasured]+(4.0 – [albumin])(mg/dL)

Table 1. Differential Diagnosis of Hypercalcemia Primary hyperparathyroidism Malignancy Other endocrine disorders Hyperthyroidism Pheochromocytoma Adrenal insufficiency Granulomatous diseases Sarcoidosis Tuberculosis Coccidioidomycosis Leprosy Histoplasmosis Berylliosis Crohn’s disease Wegener’s granulomatosis Ingestion Medications Calcium supplements (2–3 g elemental Ca/day) Vitamin D (> 50,000 units/wk) Vitamin A (> 150,000 units/day) Thiazide diuretics Theophylline Lithium Milk–alkali syndrome Aluminum Manganese

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In addition, measurement of serum PTH, PTHrP, and calcitriol levels can further clarify the diagnosis. Patients with hypercalcemia of malignancy generally have low or normal PTH levels and increased PTHrP levels. Treatment should be initiated immediately if the serum calcium level is more than 13 mg/dL or if the complications previously mentioned are present. a. Treating the underlying malignancy is the most effective treatment of hypercalcemia. However, further interventions are required in patients with severe symptoms. b. Aggressive hydration with normal saline is indicated both to correct dehydration and lower calcium levels. However, this treatment does not alter the underlying

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osteoclast activation and renal calcium handling; therefore, hydration will not substantially reduce calcium levels in most patients.11 All available agents to treat hypercalcemia of malignancy inhibit bone resorption without major effects on renal calcium excretion. 1) Bisphosphonates are now the firstline agent to treat hypercalcemia of malignancy and to reduce calcium levels in more than 90% of all patients.12 These agents bind divalent metal ions like calcium, thereby specifically targeting it to bone mineral and inhibiting bone resorption


Medical Emergencies in Oncology: I

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by acting as pyrophosphate analogues. Bisphosphonates also directly inhibit osteoclasts. In general, pamidronate is given intraveneously as a single dose of 90 mg given over 2 to 4 hours. Newer and more potent bisphosphonates will simplify administration and may improve results. Calcitonin inhibits bone resorption and increases calcium excretion by the kidney. It has a rapid onset of action—decreasing calcium levels by 2 to 3 mg/dL within 2 to 4 hours— but is much less effective than are bisphosphonates. Usually tachyphylaxis develops, diminishing the response in 2 to 3 days. Calcitonin should be given subcutaneously or preferably intramuscularly at doses of 4 to 8 units/kg every 6 to 12 hours. Gallium nitrate effectively inhibits bone resorption by inhibiting the proton pump in the ruffled membrane of osteoclasts, causing a less acidic milieu.13 It is usually given as a continuous IV infusion of 100 to 200 mg/m2 every day for up to 5 days.14 Its onset of action is 24 to 48 hours; the maximal hypocalcemic affect is achieved after the drug has been discontinued. Its use has been limited secondary to the risk of nephrotoxicity and the long infusion time. Plicamycin is an antitumor antibiotic with direct toxic effects on osteoclasts. It has a sclerosing effect on veins and therefore is usually given as a brief infusion at doses of 10 to 25 µg/kg. a) Single injections are tolerated well. b) However, repeated administration harbors the risk of renal insufficiency, hepatic toxicity, coagulopathy, and thrombocytopenia and is therefore reserved for severe hypercalcemia unresponsive to other therapies. Corticosteroids inhibit osteoclasts directly as well as intestinal absorption of calcium. They are most effective in tumors also responsive to


steroids themselves (eg, lymphoma, leukemia, multiple myeloma), especially when the hypercalcemia is induced by calcitriol. 6) Phosphate promotes deposition of calcium-phosphate complexes in bone, inhibits osteoclast activity, and decreases urinary calcium excretion. Because of severe side effects from IV application (hypotension, renal failure, tissue deposition of calciumphosphate complexes) and low efficacy of oral phosphate, it is not routinely used in the acute treatment of hypercalcemia. C. Lactic acidosis 1. Definition a. This syndrome is a complication that usually occurs in the setting of hypoperfusion and tissue hypoxia in patients with shock, sepsis, or severe anemia. b. It is a rare complication in cancer patients, usually characterized by an arterial pH of 7.35 or less and a serum lactate level of 5.0 mEq/L or more in the absence of other causes.2,15 2. Etiology a. Lactic acidosis is thought to be caused by tumor metabolism under anaerobic conditions leading to an increased production of pyruvate and subsequent conversion to lactate in order to recycle nicotinamide adenine dinucleotide (NAD). b. It is most often associated with hematologic malignancies, especially in phases of accelerated growth, or with high tumor burden. Solid tumors, especially liver metastases that impair hepatic lactate metabolism and gluconeogenesis, may also cause lactic acidosis. 3. Clinical presentation a. Patients generally present with nonspecific findings (ie, tachycardia, weakness, nausea), hyperventilation, and hypotension, which may progress to frank shock. b. In some cases, lactic acidosis may be the initial presentation of an underlying malignancy. 4. Treatment a. More common and more treatable causes of lactic acidosis should be ruled out, especially infections.


The only therapeutic option is to treat the primary malignancy. Correcting the blood pH with bicarbonate has not shown any survival benefit.16 D. Hyperleukocytic syndrome 1. Definition a. Hyperleukocytic or leukostasis syndrome is one of the most dangerous complications of leukemias. This syndrome occurs when small blood vessels are occluded by extremely high number of leukocytes and blasts adhering to and damaging the endothelium.17 b. If left untreated, it is rapidly fatal. Lungs and brain are most commonly involved, but any organ system as well as peripheral vessels can be affected. 2. Etiology a. Leukostasis generally occurs in patients with leukemia whose blast count is more than 100,000/mm3. b. It is found more commonly and at lower leukocyte counts in patients with myeloblastic leukemias, with up to 15% of chronic myelogenous leukemia (CML) and 5% to 13% of acute myelogenous leukemia (AML) with a higher incidence in the pediatric population. It is found less frequently in patients with ALL (4%) and rarely in chronic lymphocytic leukemia (CLL) (1%). c. With increasing leukocyte count, the blood viscosity increases because of the decreased deformability of the large and more rigid blast cells. 1) The cells obstruct the circulation by aggregation. Leukocytes also damage the endothelium (which is mediated by cytokine release) with subsequent migration of blasts in the perivascular space, resulting in bleeding. 2) Patients with AML who present with leukostasis have a worse prognosis than those without because they have a lower likelihood of achieving remission and a markedly decreased overall survival.18 3. Clinical presentation. The symptoms depend on which organ system is affected by leukostasis. a. Pulmonary involvement manifests as: 1) Dyspnea 2) Tachypnea

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3) Hypoxia 4) Cyanosis b. Neurologic symptoms include: 1) Headaches 2) Dizziness 3) Blurred vision with papilledema and retinal vein distention on funduscopy 4) Cerebellar deficits like intention tremor, ataxia, hypotonia, and dysdiadochokinesis 5) Motor and sensory deficits 6) Altered mental state: confusion, somnolence, stupor, coma c. Cardiac involvement is rare (ie, congestive heart failure, angina, and myocardial infarction). d. Renal failure e. Priapism f. Fever Diagnosis a. With pulmonary involvement, hypoxemia can be demonstrated by analyzing peripheral oxygen saturation and arterial blood gas measurements. Chest radiograph may reveal infiltrates, and ventilation/perfsion (V/Q) scan can show a ventilation/ diffusion mismatch. However, radiographic data and autopsy findings rarely correlate.19 b. Computed tomographic or magnetic resonance imaging scans of the head are indicated with neurologic symptoms to exclude the presence of an intracranial hemorrhage. Treatment options for leukostasis have not been studied in a prospective, randomized trial. The following treatments are generally used when appropriate and appear to be effective. a. Aggressive hydration, alkalinization, and allopurinol are given to improve blood rheology and to prevent tumor lysis syndrome. b. Leukapheresis before the initiation of chemotherapy is indicated to rapidly lower the leukocyte count by 20% to 60% and has been shown to improve symptoms in up to 66% of the patients. Transient hypotension may occur in approximately 10% of patients. c. Hydroxyurea (given twice daily at 50 to


Medical Emergencies in Oncology: I 100 mg/kg per day) is also used to rapidly lower the leukocyte count within 24 to 48 hours, either in conjunction with leukapheresis or instead of, if the former is not available.20 d. Brain irradiation has been previously used to reduce the likelihood of intracerebral hemorrhage. However, its efficacy is doubtful and it is not generally recommended.21 e. Antileukemic therapy should be initiated as soon as the patient is clinically stabilized.

III. NEUTROPENIC FEVER A. Definition 1. Neutropenia is defined in most sources as an absolute neutrophil count (ANC) less than 500/mm3. It may be intrinsic to the malignant disease (as in leukemia) or a consequence of chemotherapy.22 – 24 2. In general, a single temperature spike of more than 38.5 °C is considered a medical emergency in patients with cancer; however, repeated episodes (> 2) of low-grade temperatures (> 38.0 °C) within a 12-hour period should be evaluated and treated in the same fashion because the patient may not be able to mount a stronger immune response. B. Etiology 1. ANCs of less than 1000/mm3 increase the risk of infection. Patients with less than 100 neutrophils/mm3 are at even higher risk; 25% develop infections within a week and 100% develop them within 6 weeks.25 2. The duration of neutropenia is important. If the patient is neutropenic for less than 7 to 10 days, the risk of infection is generally low. However, if neutropenia persists for more than 10 days, the risk of infection markedly increases.25 3. Chemotherapy also changes the mucosa of the alimentary and respiratory tracts, thereby weakening the natural mucosal barrier. Patients often have indwelling catheters for the administration of chemotherapy, opening another portal of entry. 4. Four groups of patients have been identified according to their risk from febrile neutropenia. The first 3 groups are at high risk for


complications (36%) and mortality (20%). In the low-risk group, however, the complication rate is minimal (2%) and the mortality rate is 0%. This low-risk group comprises 70% of all outpatients presenting with fever and neutropenia.26,27 a. Patients with hematologic malignancies or those who have had bone marrow transplantation b. Outpatients with concurrent symptoms (hypotension, dehydration, bleeding, respiratory failure) c. Outpatients without concurrent symptoms but progressive cancer d. Outpatients without concurrent symptoms and treatment-responsive malignancies 5. Bacteremia can be detected in 40% of all patients, and an organism can be identified in 60% of these patients. 6. The spectrum of infectious organisms in these patients has changed during the last 2 decades: gram-positive organisms are now most frequent and often arise from endogenous flora. The most frequent causes of bacteremia are: a. Aerobic gram-positive cocci (Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus viridans) b. Aerobic gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) c. Fungi (especially Aspergillus, less commonly Candida albicans) often occur in patients after treatment with broadspectrum antibiotics. d. Viral infections with herpes simplex virus are commonly seen in patients with neutropenia. C. Clinical presentation. Infection might be difficult to ascertain because patients may not be able to mount an appropriate immune response. 1. Typical signs of infection—pulmonary infiltrates, sputum production, or pus collection— may be absent because of the low number of neutrophils. 2. Fever, pain, and erythema or subtle changes like tachycardia and a widened pulse pressure might be the only findings in some patients. D. Diagnosis 1. Because clinical findings are rare or nonspecific, a careful physical examination should be

Medical Emergencies in Oncology: I performed, with inspection of the mucosal surfaces (including perineal area and teeth), fundi, and skin with special attention to the site of indwelling catheters. 2. A detailed neurologic examination should also be performed. 3. Digital rectal examination is generally contraindicated because it may cause bacteremia. 4. Blood, urine, and sputum specimens should be obtained routinely for gram stain and culture before the initiation of antimicrobial therapy. Cerebrospinal fluid and other body fluids should also be tested if localizing symptoms exist. If patients have indwelling catheters, cultures should be taken from each lumen. 5. Chest radiograph is indicated in high-risk patients or if symptoms exist. E. Treatment 1. Rapid administration of appropriate antibiotics is essential and the only way to decrease the substantial morbidity and mortality in high-risk patients. 2. Close clinical observation and reassessment of the patient is equally important in improving outcome. 3. Initial treatment consists of broad-spectrum coverage against gram-positive cocci and gram-negative organisms, including Pseudomonas. The following options for initial treatment are widely accepted.22,23,28 a. Monotherapy 1) Broad spectrum third-generation cephalosporin: ceftazidime or cefepime 2) Carbapenem (imipenem, meropenem) plus an aminoglycoside if Pseudomonas is suspected b. Combination therapy: antipseudomonal penicillin and aminoglycoside 4. Vancomycin a. Many infections are now caused by grampositive cocci, many of which are resistant to multiple antibiotics. Several studies have included vancomycin as an initial agent and have shown a high response rate. b. However, prolonged use of this antibiotic is also associated with increased occurrence of vancomycin-resistant, untreatable enterococci. Therefore, initial treatment with vancomycin is generally

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recommended only in patients with: 1) Colonization with methicillinresistant S. aureus 2) Presence of severe mucositis 3) Previous use of prophylactic fluoroquinolones 4) Evidence of line infection 5) No identified source of infection in addition to fever that persists for 3 days while taking the previously mentioned antibiotics Aggressive antibacterial treatment leads to selection of fungal infections, causing major mortality and morbidity in cancer patients. a. If the fever persists for 5 to 7 days without recovery in leukocyte count, amphotericin B (1.0 to 1.5 mg/kg) is initiated. b. Liposomal formulations of amphotericin B have been shown to have less nephrotoxicity and infusion-related toxicity, and they are equally effective.29 Discontinuation of antibiotics a. In patients with documented infections, antibiotics are continued for a full course of treatment and can be discontinued at day 14 if all symptoms have resolved or when the neutropenia has resolved. b. In patients without evidence of infection and resolved fever, it is considered safe to stop antibiotics once the ANC is greater than 500/mm3. Oral antibiotics a. In recent studies, oral ciprofloxacin and amoxicillin-clavulanate have been found to be as safe as IV ceftriaxone or ceftazidime in selected low-risk patients in whom the projected duration of neutropenia is less than 10 days.30 – 32 b. However, outpatient treatment of febrile neutropenia is not recommended until larger-scale studies have shown its safety because close clinical observation and ready access to emergency treatment are not guaranteed for every patient.33 Use of growth factors a. Treatment with granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF) reduces the duration and severity of neutropenia after chemotherapy, although overall survival is not significantly improved.34



Therefore, these agents are useful in patients with expected prolonged episodes of neutropenia to decrease the risk of complications but are not recommended in low-risk patients.

REFERENCES 1. Arrambide K, Toto RD: Tumor lysis syndrome. Semin Nephrol 1993;13:273–280. 2. Flombaum CD: Metabolic emergencies in the cancer patient. Semin Oncol 2000;27:322–334.

IV. SUMMARY A. Tumor lysis syndrome is a life-threatening complication and is characterized by hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute renal failure. This syndrome mainly occurs in patients with high-grade lymphomas and acute leukemias. It can be best prevented by aggressive hydration, allopurinol, and alkalinization (but only if indicated). B. Hypercalcemia is the most common metabolic complication of malignancy and is characterized by polyuria, polydipsia, constipation, and dehydration. It is associated especially with lung and breast cancer as well as hematologic malignancies. In patients with solid tumors, it is generally caused by tumor-related production of parathyroid hormone–related protein. Hypercalcemia is most commonly treated with rehydration and bisphosphonates as well as treatment of the primary disease. C. Although it rarely occurs, lactic acidosis is a complication of cancer, especially hematologic malignancies. Lactic acidosis is characterized by a pH of 7.35 or less and by lactic acid levels of 5.0 mEq/L or more. Exclusion of other causes of (lactic) acidosis is most important, especially infections. D. Hyperleukocytic syndrome occurs as a complication of leukemia when high numbers of blasts obstruct blood vessels and damage the endothelium; this syndrome most commonly involves the lung and brain. Initial therapy consists of hydration, alkalinization, allopurinol, and hydroxyurea as well as leukapheresis if indicated. If left untreated, it is rapidly fatal. E. Neutropenic fever is defined as a temperature of 38 °C in a patient with an absolute neutrophil count of 500/mm3 or less. Management should include blood and urine cultures as well as further testing that is guided by symptoms. Rapid administration of broad-spectrum antibiotics (thirdgeneration cephalosporin or carbapenem and if necessary, an aminoglycoside) is indicated. Vancomycin is used initially only if gram-negative cocci are suspected.


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