Nitrosoureas Toxicity

Etiology

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.[10] They are not widely used as first-line therapy due to their severe, dose-dependent side effects. 

Epidemiology

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%.[11]  

Pathophysiology

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.[1] 

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.[12]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. 

Neurotoxicity 

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.[13] 

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.[14] 

Cardiotoxicity 

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.[15] 

Pulmonary Toxicity 

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%.[16] Symptoms begin with pulmonary edema and pulmonary infiltrates, followed by progressive fibrosis.[17] Irreversible and progressive pulmonary insufficiency may result, leading to hypoxemia and death.[17]

Nephrotoxicity 

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.[18]

Hepatotoxicity 

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.[19] 

Myelosuppression 

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.[20] The platelet nadir occurs about 27 days after drug administration, and the leukocyte count nadir occurs later, about 35 days after therapy.[8] 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.[21][22]

Histopathology

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.[16] 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.[16] 

Renal biopsies of patients with nitrosourea toxicity demonstrate tubular atrophy, interstitial fibrosis, and glomerular sclerosis.[5] 

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.[19] 

Toxicokinetics

The pharmacological effects of lomustine when administered at therapeutic doses have been studied. Following oral lomustine administration at doses ranging from 30 mg/m² to 100 mg/m², 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.[10]  

History and Physical

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.

Patients may report nausea, vomiting, and diarrhea in the acute setting. Long-term complaints include dyspnea, dry cough, and fluid retention. 

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.[16] 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.[14]

Evaluation

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. 

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.[23] Carbon monoxide diffusion abnormalities may be the earliest indicator of pulmonary damage.[16] 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.[16] 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.[16] 

Treatment / Management

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.[8] Many blood products, such as platelets, can take around 51 days after chemotherapy to rise spontaneously.[8] (B3)

Erythropoietic agents can reduce the need for transfusions and are recommended in adults and children with non-myeloid malignancies.[24][25] 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.[26] Prophylactic antibiotics such as quinolones for patients with neutropenia or leukopenia reduce mortality, and neutropenic precautions should be exercised.[27] Antibiotic selection should be based on local epidemiology and sensitivities.[28] (A1)

Patients experiencing nephrotoxicity require clinical monitoring and adequate hydration. Protein and metabolic disorders should be corrected to maximize renal protection.[29] Corticosteroids treat and prevent nitrosourea-induced pulmonary fibrosis, but studies have failed to show a benefit in patients prescribed steroids during nitrosourea therapy.[16][30] Pulmonary fibrosis can progress after nitrosourea therapy cessation.[16] (B2)

Differential Diagnosis

The differential diagnoses of nitrosourea toxicity:

• Pulmonary causes include restrictive lung diseases such as pulmonary fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, or, pneumonia.
• Rheumatological causes include dermatomyositis, polymyositis, mixed connective tissue disease, pneumoconiosis, systemic lupus erythematosus, rheumatoid arthritis, scleroderma.
• Hepatological causes such as infectious hepatitis, chemical hepatitis, cirrhosis, and tumor metastasis.
• Hematological causes due to effects of myelosuppression such as malignancy-associated myelofibrosis, autoimmune disorders, aplastic anemia, and anemia of chronic disease.
• Nephrological causes such as prerenal azotemia, acute tubular necrosis, and other causes of acute kidney injury.
• Neurological causes such as intoxication, tumor recurrence, and delirium. 

Prognosis

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.[31]

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.[31] However, patients with BCNU-induced pulmonary fibrosis have a mortality rate of 30% to 40%.[16] Pre-existing pulmonary disease and a history of smoking are risk factors for developing pulmonary fibrosis following nitrosourea therapy.[30]  

Complications

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.

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/m² 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.