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<title>Nitrosoureas Toxicity - StatPearls - NCBI Bookshelf</title>
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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="StatPearls [Internet]" /><meta name="citation_title" content="Nitrosoureas Toxicity" /><meta name="citation_publisher" content="StatPearls Publishing" /><meta name="citation_date" content="2024/01/11" /><meta name="citation_author" content="James S. Jackson" /><meta name="citation_author" content="Leonard J. Harris" /><meta name="citation_pmid" content="38261709" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK599513/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Nitrosoureas Toxicity" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="StatPearls Publishing" /><meta name="DC.Contributor" content="James S. Jackson" /><meta name="DC.Contributor" content="Leonard J. Harris" /><meta name="DC.Date" content="2024/01/11" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK599513/" /><meta name="description" content="Nitrosoureas are cytotoxic chemotherapeutic drugs that cause cell death by DNA damage. They are used to treat malignancies, including malignant glioblastomas, Hodgkin's and non-Hodgkin lymphomas, and pancreatic islet cell tumors. Three of the most commonly used nitrosourea compounds are carmustine (BCNU), lomustine (CCNU), and fotemustine.[1][2] Nitrosoureas are lipophilic chemicals with antitumor and cytotoxic effects via alkylating and carbamoylating compounds; they are active in multiple cell cycle phases." /><meta name="og:title" content="Nitrosoureas Toxicity" /><meta name="og:type" content="book" /><meta name="og:description" content="Nitrosoureas are cytotoxic chemotherapeutic drugs that cause cell death by DNA damage. They are used to treat malignancies, including malignant glioblastomas, Hodgkin's and non-Hodgkin lymphomas, and pancreatic islet cell tumors. Three of the most commonly used nitrosourea compounds are carmustine (BCNU), lomustine (CCNU), and fotemustine.[1][2] Nitrosoureas are lipophilic chemicals with antitumor and cytotoxic effects via alkylating and carbamoylating compounds; they are active in multiple cell cycle phases." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK599513/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-statpearls-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/statpearls/article-148523/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK599513/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} </style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script>
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK599513_"><span class="title" itemprop="name">Nitrosoureas Toxicity</span></h1><p class="contrib-group"><h4>Authors</h4><span itemprop="author">James S. Jackson</span><sup>1</sup>; <span itemprop="author">Leonard J. Harris</span><sup>2</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> University of Tennessee</div><div class="affiliation"><sup>2</sup> Methodist University Hospital</div><p class="small">Last Update: <span itemprop="dateModified">January 11, 2024</span>.</p></div><div class="body-content whole_rhythm" itemprop="text"><div id="article-148523.s1"><h2 id="_article-148523_s1_">Continuing Education Activity</h2><p>Nitrosoureas are medications used to manage and treat high-grade gliomas and glioblastomas, as well as some lung tumors, pancreatic islet cell tumors, Hodgkin's disease, non-Hodgkin's lymphomas, and melanomas. They are classified as alkylating agents with high lipophilicity, and they treat brain cancers effectively. There is no known antidote for nitrosourea toxicity, and treatment involves drug cessation, supportive care, and, when indicated transfusions. Close monitoring for toxicity is necessary for patients on nitrosourea therapy.</p><p>This course reviews the acute and subacute toxicity of some of the most commonly used nitrosoureas. Nitrosoureas have a severe and extensive side effect profile that can cause considerable toxicity in therapeutic doses. Some of the known side effects of nitrosourea toxicity are pulmonary fibrosis leading to hypoxia and dose-dependent myelosuppression. Apparent histopathological features narrow the differential diagnosis considerably, though toxic effects are exerted on several organ systems. </p><p>Participating clinicians will learn how to work within an interdisciplinary team in identifying, evaluating, and treating patients with nitrosourea toxicity. In particular, the approach to identifying the toxic signs of an emergency versus long-term exposure is reviewed.</p><p>
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<b>Objectives:</b>
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<ul><li class="half_rhythm"><div>Differentiate between symptoms of malignancy and toxicity from nitrosourea chemotherapy.</div></li><li class="half_rhythm"><div>Identify when nitrosourea toxicity is life-threatening, and intervention is necessary.</div></li><li class="half_rhythm"><div>Improve patient quality of life and outcomes by promptly treating symptoms of nitrosourea toxicity.</div></li><li class="half_rhythm"><div>Communicate with the interprofessional healthcare team and develop a plan for identifying and treating nitrosourea toxicity, obtaining specialist consultation if necessary.</div></li></ul>
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<a href="https://www.statpearls.com/account/trialuserreg/?articleid=148523&utm_source=pubmed&utm_campaign=reviews&utm_content=148523" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Access free multiple choice questions on this topic.</a>
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</p></div><div id="article-148523.s2"><h2 id="_article-148523_s2_">Introduction</h2><p>Nitrosoureas are cytotoxic chemotherapeutic drugs that cause cell death by DNA damage. They are used to treat malignancies, including malignant glioblastomas, Hodgkin's and non-Hodgkin lymphomas, and pancreatic islet cell tumors. Three of the most commonly used nitrosourea compounds are carmustine<b> </b>(BCNU), lomustine (CCNU), and fotemustine.<a class="bk_pop" href="#article-148523.r1">[1]</a><a class="bk_pop" href="#article-148523.r2">[2]</a> Nitrosoureas are lipophilic chemicals with antitumor and cytotoxic effects via alkylating and carbamoylating compounds; they are active in multiple cell cycle phases.</p><p>Lomustine readily crosses the blood-brain barrier and is commonly used for recurrent glioblastoma multiforme; in some European countries, fotemustine is used instead of lomustine. Carmustine was the first nitrosourea developed for public use (United States Food and Drug Administration approval in 1977). The drug has been widely discontinued due to toxicity, intravenous (IV) administration, and low availability.<a class="bk_pop" href="#article-148523.r3">[3]</a>.</p><p>Nitrosoureas are used alongside other chemotherapeutic agents (such as procarbazine, lomustine, and vincristine, a first-line regimen for oligodendroglioma) or as stand-alone chemotherapy agents.<a class="bk_pop" href="#article-148523.r4">[4]</a> Streptozocin has methylnitrosourea activity against pancreatic islet cell tumors.<a class="bk_pop" href="#article-148523.r2">[2]</a> Nitrosoureas are associated with significant and severe adverse effects, including leukoencephalopathy, pulmonary toxicity, nephrotoxicity, hepatotoxicity, neurotoxicity, myelosuppression, secondary leukemias, nausea, vomiting, stomatitis, alopecia, anemia, anorexia, and phlebitis and burning at the injection site.<a class="bk_pop" href="#article-148523.r5">[5]</a><a class="bk_pop" href="#article-148523.r6">[6]</a><a class="bk_pop" href="#article-148523.r7">[7]</a><a class="bk_pop" href="#article-148523.r8">[8]</a> Due to their severe side effect profiles, nitrosoureas are mostly used for tumor recurrence or refractory cases.<a class="bk_pop" href="#article-148523.r9">[9]</a> Nitrosourea metabolites are primarily excreted through the kidneys.<a class="bk_pop" href="#article-148523.r10">[10]</a> </p></div><div id="article-148523.s3"><h2 id="_article-148523_s3_">Etiology</h2><p>Nitrosoureas are a chemotherapeutic drug class that contains a molecule with a nitroso group and urea. They commonly treat high-grade gliomas, glioblastoma multiforme recurrence, pulmonary cancers, and pancreatic islet cell tumors. They are an important component of the BEAM (BCNU, Etoposide, Cytarabine, Melphalan) conditioning regimen commonly used for autologous hematopoietic stem cell transplantation used in lymphoma.<a class="bk_pop" href="#article-148523.r10">[10]</a> They are not widely used as first-line therapy due to their severe, dose-dependent side effects. </p></div><div id="article-148523.s4"><h2 id="_article-148523_s4_">Epidemiology</h2><p>According to the World Health Organization (WHO) Central Nervous System Tumor Classification, high-grade gliomas are grade III and IV. They account for approximately 80% of intracranial malignant tumors and are the most common intracranial primary malignancy. High-grade gliomas have a poor prognosis, with a median overall survival rate of under 2 years. Most high-grade gliomas are glioblastomas (49.1%) with a 5-year survival rate of 6.8%.<a class="bk_pop" href="#article-148523.r11">[11]</a>  </p></div><div id="article-148523.s5"><h2 id="_article-148523_s5_">Pathophysiology</h2><p>Nitrosoureas break down in water to produce 2 reactive intermediates. The first is a chloroethyl carbonium ion that can create adducts and cross-link DNA strands. The second is isocyanate, which decreases glutathione levels and is responsible for repairing DNA damage and RNA maturation. This aqueous dissolution leads to cell damage and, eventually, death.<a class="bk_pop" href="#article-148523.r1">[1]</a> </p><p>Nitrosoureas are highly lipophilic and can cross the blood-brain barrier, making them effective for central nervous system tumors. Lomustine can reach up to 30% concentration in the brain. The toxic effects of the nitrosoureas affect nearly every organ system. Patients with intrinsic or acquired high levels of O6-methyl guanine methyltransferase (MGMT) are resistant to the cytotoxic effects of alkylating agents, rendering these chemotherapeutic agents ineffective.<a class="bk_pop" href="#article-148523.r12">[12]</a>The most common presenting symptom of nitrosourea toxicity is nausea and vomiting, which can occur within a few hours after treatment initiation. Most of the other symptoms of toxicity present in weeks to months after initial exposure. </p><p>
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<b>Neurotoxicity </b>
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</p><p>The neurotoxic effects of nitrosourea compounds have led to usage in animal experiments to induce neurotoxicity and simulate Alzheimer disease. Streptozotocin causes memory impairment, decreased antioxidant capacity, and deposition of amyloid β plaques.<a class="bk_pop" href="#article-148523.r13">[13]</a> </p><p>1-(4-amino-2-methylpyrimidin-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and Ranimustine (MCNU) were found to cause brain edema, headache, nuchal stiffness, vomiting, motor weakness, and cranial nerve palsies. Pathologic changes include capsule formation, spongy degeneration, reactive gliosis of adjacent white matter, occlusion of neighboring arteries, and demyelination of cranial nerves. Focal brain necrosis was seen in patients treated with MCNU.<a class="bk_pop" href="#article-148523.r14">[14]</a> </p><p>
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<b>Cardiotoxicity </b>
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</p><p>Carmustine is found to cause systolic dysfunction associated with decreased ejection fraction, decreased cardiac output, and an increase in left ventricular internal dimension and left ventricular volume in systole by echocardiography.<a class="bk_pop" href="#article-148523.r15">[15]</a> </p><p>
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<b>Pulmonary Toxicity </b>
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</p><p>Nitrosourea compounds have been determined to cause dose-dependent pulmonary toxicity, resulting in pulmonary fibrosis, as is seen in similar alkylating agents. The rate of pulmonary fibrosis in patients treated with carmustine is estimated to be 10% to 30%.<a class="bk_pop" href="#article-148523.r16">[16]</a> Symptoms begin with pulmonary edema and pulmonary infiltrates, followed by progressive fibrosis.<a class="bk_pop" href="#article-148523.r17">[17]</a> Irreversible and progressive pulmonary insufficiency may result, leading to hypoxemia and death.<a class="bk_pop" href="#article-148523.r17">[17]</a></p><p>
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<b>Nephrotoxicity </b>
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</p><p>Carmustine and semustine have demonstrated nephrotoxic effects on patients receiving therapy for malignant brain tumors. The nephrotoxicity appears to be dose-dependent and causes patients to develop impaired renal function, measured by the elevation of blood urea nitrogen and/or serum creatinine or a decrease in filtration rate determined by inulin clearance. The damage occurs without a phase of acute renal failure or urinary abnormalities. In some patients, the nephrotoxicity is severe enough to cause uremia. The hepatic metabolism of nitrosoureas is hypothesized to create a nephrotoxic metabolite that causes renal tissue damage.<a class="bk_pop" href="#article-148523.r18">[18]</a></p><p>
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<b>Hepatotoxicity </b>
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</p><p>Hepatotoxicity may occur in up to 26% of patients treated with nitrosourea analogs, causing reversible serum liver enzyme elevations, hepatomegaly, hepatocyte necrosis, and jaundice. It usually takes at least 2 weeks after initiation of treatment for the clinical signs of hepatotoxicity to manifest, and it resolves spontaneously. However, hepatocyte necrosis may persist up to 4 months after exposure.<a class="bk_pop" href="#article-148523.r19">[19]</a> </p><p>
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<b>Myelosuppression </b>
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</p><p>The nitrosoureas have been shown to cause delayed and cumulative bone marrow toxicity, with a nadir occurring at around 4 to 6 weeks after administration.<a class="bk_pop" href="#article-148523.r20">[20]</a> The platelet nadir occurs about 27 days after drug administration, and the leukocyte count nadir occurs later, about 35 days after therapy.<a class="bk_pop" href="#article-148523.r8">[8]</a> High doses have been shown to cause permanent marrow damage. Studies have failed to show that lithium administration with nitrosoureas can counteract myelosuppression as it does in vinblastine treatment.<a class="bk_pop" href="#article-148523.r21">[21]</a><a class="bk_pop" href="#article-148523.r22">[22]</a></p></div><div id="article-148523.s6"><h2 id="_article-148523_s6_">Histopathology</h2><p>The histology of pulmonary toxicity due to nitrosoureas resembles that of pulmonary disease caused by other chemotherapeutic agents. Lung biopsy and autopsy reveal end-stage pulmonary disease characterized by edema, desquamation of alveolar type I cells and hyperplasia, hypertrophy of alveolar type II cells, and diffuse interstitial fibrosis.<a class="bk_pop" href="#article-148523.r16">[16]</a> There is a pronounced increase in collagen bundles, fibroblasts, and plasma cells in the alveolar septa and bronchial and capillary walls. Typical histological features include hyperplasia in the bronchiolar epithelium, early squamous metaplasia, and peribronchiolar granulomatous lesions.<a class="bk_pop" href="#article-148523.r16">[16]</a> </p><p>Renal biopsies of patients with nitrosourea toxicity demonstrate tubular atrophy, interstitial fibrosis, and glomerular sclerosis.<a class="bk_pop" href="#article-148523.r5">[5]</a> </p><p>Hematoxylin and eosin stains of post-mortem liver samples of patients who received nitrosourea therapy reveal bands of fibrosis with nodules of acute and subacute necrosis.<a class="bk_pop" href="#article-148523.r19">[19]</a> </p></div><div id="article-148523.s7"><h2 id="_article-148523_s7_">Toxicokinetics</h2><p>The pharmacological effects of lomustine when administered at therapeutic doses have been studied. Following oral lomustine administration at doses ranging from 30 mg/m<sup>2</sup> to 100 mg/m<sup>2</sup>, about half is excreted in the urine as degradation products within 24 hours. While lomustine serum's half-life is approximately 90 minutes, metabolite serum's half-life is 16 to 48 hours.<a class="bk_pop" href="#article-148523.r10">[10]</a>  </p></div><div id="article-148523.s8"><h2 id="_article-148523_s8_">History and Physical</h2><p>Patients with a history of high-grade malignant gliomas, glioblastoma multiforme, and other metastatic cancers undergoing chemotherapy with nitrosoureas are at high risk of nitrosourea toxicity. In patients who have a family member currently undergoing chemotherapy with nitrosoureas, drug toxicity should be considered among the differential diagnoses due to accidental or intentional ingestion.</p><p>Patients may report nausea, vomiting, and diarrhea in the acute setting. Long-term complaints include dyspnea, dry cough, and fluid retention. </p><p>On physical exam, patients with nitrosourea toxicity may exhibit a petechial rash, fever, scleral icterus, and bleeding gums from the myelosuppression. Pulmonary exam may reveal diffuse fine crackles, tachypnea, and dry cough. Gastrointestinal physical exam findings include guarding, jaundice, abdominal tenderness, and pain.<a class="bk_pop" href="#article-148523.r16">[16]</a> The neurologic examination is challenging if the provider is not familiar with the patient's baseline neurologic status due to deficits caused by the malignancy, radiation therapy, or tumor resection. Neuro exam may reveal cranial nerve palsy, motor weakness, and cognitive slowing.<a class="bk_pop" href="#article-148523.r14">[14]</a></p></div><div id="article-148523.s9"><h2 id="_article-148523_s9_">Evaluation</h2><p>Complete blood count (CBC) with differential is a key laboratory test because of delayed myelosuppression. A comprehensive metabolic panel should be obtained to assess for electrolyte abnormalities, uremia, or elevated creatinine due to renal dysfunction, as well as gastric function tests, such as AST, ALT, ALP, and bilirubin, to assess for hepatotoxicity. </p><p>Chest x-rays may demonstrate pulmonary infiltrates, and chest CT may show features of honeycombing, traction bronchiectasis, lung architectural distortion, reticulation, and interlobular septal thickening.<a class="bk_pop" href="#article-148523.r23">[23]</a> Carbon monoxide diffusion abnormalities may be the earliest indicator of pulmonary damage.<a class="bk_pop" href="#article-148523.r16">[16]</a> Pulmonary function tests can be used to track the severity of pulmonary tissue damage. Hydroxyproline levels are used to quantify pulmonary fibrosis, but the usefulness of measuring levels in patients with nitrosourea-induced pulmonary fibrosis is uncertain.<a class="bk_pop" href="#article-148523.r16">[16]</a> Carmustine inhibits fatty acid synthesis in pulmonary alveolar type II cells in a dose-dependent manner, and the rate of fatty acid biosynthesis is a sensitive marker for carmustine-induced lung toxicity.<a class="bk_pop" href="#article-148523.r16">[16]</a> </p></div><div id="article-148523.s10"><h2 id="_article-148523_s10_">Treatment / Management</h2><p>The treatment of nitrosourea toxicity involves supportive care and discontinuation of the offending agent since there is no known antidote or reversal agent. Patients with significant myelosuppression should be admitted to the hospital for transfusion of packed platelets to maintain a platelet count of over 15,000/mm³ and packed red blood cells to maintain a hemoglobin over 7 g/dL.<a class="bk_pop" href="#article-148523.r8">[8]</a> Many blood products, such as platelets, can take around 51 days after chemotherapy to rise spontaneously.<a class="bk_pop" href="#article-148523.r8">[8]</a> </p><p>Erythropoietic agents can reduce the need for transfusions and are recommended in adults and children with non-myeloid malignancies.<a class="bk_pop" href="#article-148523.r24">[24]</a><a class="bk_pop" href="#article-148523.r25">[25]</a> A hemoglobin under 10 g/dL indicates a need for erythropoiesis-stimulating agents, and the FDA recommends a goal hemoglobin between 10 g/dL to 12 g/dL.<a class="bk_pop" href="#article-148523.r26">[26]</a> Prophylactic antibiotics such as quinolones for patients with neutropenia or leukopenia reduce mortality, and neutropenic precautions should be exercised.<a class="bk_pop" href="#article-148523.r27">[27]</a> Antibiotic selection should be based on local epidemiology and sensitivities.<a class="bk_pop" href="#article-148523.r28">[28]</a> </p><p>Patients experiencing nephrotoxicity require clinical monitoring and adequate hydration. Protein and metabolic disorders should be corrected to maximize renal protection.<a class="bk_pop" href="#article-148523.r29">[29]</a> Corticosteroids treat and prevent nitrosourea-induced pulmonary fibrosis, but studies have failed to show a benefit in patients prescribed steroids during nitrosourea therapy.<a class="bk_pop" href="#article-148523.r16">[16]</a><a class="bk_pop" href="#article-148523.r30">[30]</a> Pulmonary fibrosis can progress after nitrosourea therapy cessation.<a class="bk_pop" href="#article-148523.r16">[16]</a> </p></div><div id="article-148523.s11"><h2 id="_article-148523_s11_">Differential Diagnosis</h2><p>The differential diagnoses of nitrosourea toxicity:</p><ul><li class="half_rhythm"><div>Pulmonary causes include restrictive lung diseases such as pulmonary fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, or, pneumonia.</div></li><li class="half_rhythm"><div>Rheumatological causes include dermatomyositis, polymyositis, mixed connective tissue disease, pneumoconiosis, systemic lupus erythematosus, rheumatoid arthritis, scleroderma.</div></li><li class="half_rhythm"><div>Hepatological causes such as infectious hepatitis, chemical hepatitis, cirrhosis, and tumor metastasis.</div></li><li class="half_rhythm"><div>Hematological causes due to effects of myelosuppression such as malignancy-associated myelofibrosis, autoimmune disorders, aplastic anemia, and anemia of chronic disease.</div></li><li class="half_rhythm"><div>Nephrological causes such as prerenal azotemia, acute tubular necrosis, and other causes of acute kidney injury.</div></li><li class="half_rhythm"><div>Neurological causes such as intoxication, tumor recurrence, and delirium. </div></li></ul></div><div id="article-148523.s12"><h2 id="_article-148523_s12_">Prognosis</h2><p>Patients who are receiving nitrosourea therapy have a poor prognosis before the start of treatment. High-grade gliomas have a median overall survival rate of less than 2 years. The mean overall survival of patients with glioblastoma multiforme and anaplastic astrocytoma was 14.1 months.<a class="bk_pop" href="#article-148523.r31">[31]</a></p><p>The efficacy of nitrosoureas in treating high-grade gliomas is beneficial. Patients treated with CCNU have a survival gain of 5.3 months, and patients treated with ACNU have a survival gain of 8.9 months.<a class="bk_pop" href="#article-148523.r31">[31]</a> However, patients with BCNU-induced pulmonary fibrosis have a mortality rate of 30% to 40%.<a class="bk_pop" href="#article-148523.r16">[16]</a> Pre-existing pulmonary disease and a history of smoking are risk factors for developing pulmonary fibrosis following nitrosourea therapy.<a class="bk_pop" href="#article-148523.r30">[30]</a>  </p></div><div id="article-148523.s13"><h2 id="_article-148523_s13_">Complications</h2><p>Complications from nitrosourea toxicity include irreversible bone marrow suppression and fibrosis, irreversible pulmonary fibrosis and diminished pulmonary function, renal failure, leukemias, and systolic heart failure.</p><p>Clinical signs of hepatotoxicity resolve within a couple of weeks, but biopsies may demonstrate evidence of hepatic necrosis for months. Patients who receive doses over 1400 mg/m<sup>2</sup> are at a significantly higher risk of pulmonary fibrosis. According to 2022 FDA guidelines, pulmonary toxicity may manifest years after treatment and can result in death, especially if treated in childhood. </p></div><div id="article-148523.s14"><h2 id="_article-148523_s14_">Deterrence and Patient Education</h2><p>Patients taking nitrosourea chemotherapy should be educated on the signs and symptoms of nitrosourea toxicity and instructed to go to the emergency room if symptoms are severe. Nitrosoureas should be kept in a safe location out of reach of children to avoid accidental ingestion. </p></div><div id="article-148523.s15"><h2 id="_article-148523_s15_">Pearls and Other Issues</h2><p>Nitrosoureas are a class of highly toxic and highly effective chemotherapy drugs used to treat certain forms of brain cancer and metastatic cancers. The most common side effect is a delayed and dose-dependent myelosuppression. Another severe side effect is diffuse pulmonary fibrosis, found in up to 20% of patients. Nitrosoureas can damage virtually every organ system, and patients experiencing significant toxicity should stop therapy. There is no known antidote for nitrosourea toxicity, and treatment consists of supportive care, transfusions, and prophylactic antibiotics.</p></div><div id="article-148523.s16"><h2 id="_article-148523_s16_">Enhancing Healthcare Team Outcomes </h2><p>Adverse effects of nitrosurea chemotherapy are common due to their potent cytotoxicity. The management of nitrosourea toxicity requires a team of healthcare professionals, including laboratory technicians, radiology technicians, blood bank technologists, and clinicians in various specialties.</p><p>Several specialists may be involved in treating nitrosourea toxicity depending on the organ systems affected. The emergency medicine clinician may be the first provider to identify the toxicity, or it may occur during a clinic visit with a primary care provider or the patient's oncology team.</p><p>A hospitalist and hematologist manage patients who require admission to the hospital, and oncology should be consulted, especially when there is evidence of myelosuppression. Depending on the organ systems affected, nephrology, hepatology, gastroenterology, neurology, pulmonology, and cardiology may also be involved.</p><p>Current guidelines recommend antibiotic treatment for patients with neutropenic fever classified as high risk, as well as neutropenic contact precautions. The risk stratification is based on the length of expected neutropenia, with at least 8 days making the patient high risk.<a class="bk_pop" href="#article-148523.r28">[28]</a> Erythropoietic agents and blood transfusions are recommended for myelosuppression resulting in anemia or thrombocytopenia.<a class="bk_pop" href="#article-148523.r24">[24]</a><a class="bk_pop" href="#article-148523.r26">[26]</a> </p></div><div id="article-148523.s17"><h2 id="_article-148523_s17_">Review Questions</h2><ul><li class="half_rhythm"><div>
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<b>Disclosure: </b>James Jackson declares no relevant financial relationships with ineligible companies.</p></div></dd><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Leonard Harris declares no relevant financial relationships with ineligible companies.</p></div></dd></dl></div></div></div>
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