Pulmonary toxicity
Methotrexate
Methotrexate, a dihydrofolate reductase inhibitor, is used for various hematologic malignancies and rheumatologic disorders. Its toxicities include potential pulmonary toxicity, such as pneumonitis, with recent estimates of methotrexate-induced pneumonitis ranging between 2-5%. Methotrexate is also linked to bronchiolitis obliterans with organizing pneumonia (BOOP), pulmonary fibrosis, bronchitis, and acute lung injury (ALI) with pulmonary edema.
Identified risk factors for methotrexate-induced pulmonary toxicity include being over 60 years old, having diabetes mellitus, hypoalbuminemia, rheumatoid pleuropulmonary involvement, and prior use of disease-modifying antirheumatic drugs. Criteria for diagnosing methotrexate-induced pulmonary toxicity, initially developed for research, have not been clinically validated but may serve as useful guidelines for clinicians. These criteria are categorized into major and minor criteria.
Major criteria
- Hypersensitivity pneumonitis by histopathology without evidence of pathogenic organisms.
- Radiologic evidence of pulmonary interstitial or alveolar infiltrates.
- Blood cultures (if febrile) and initial sputum cultures (if sputum is produced) that are negative for pathogenic organisms.
Minor criteria
- Shortness of breath for less than 8 weeks.
- Nonproductive cough.
- O2 saturation below 90% at the time of initial evaluation on room air.
- DLCO below 70% that predicted for age.
- Leukocyte count below 15,000 cells/mm3.
Definite methotrexate pneumonitis is defined as major criteria 1 alone or major criteria 2 and 3 plus 3 of the 5 minor criteria. Probable methotrexate pneumonitis is defined as major criteria 2 and 3 plus 2 of the 5 minor criteria.
Methotrexate pneumonitis typically manifests within the first year of treatment, although it can occur years later, even after discontinuing the drug. The primary treatment involves stopping the drug if it hasn’t been already, and re-challenge is generally advised against. Symptoms are expected to improve within days to weeks following discontinuation. Corticosteroids have been reported as a treatment in cases where toxicity develops long after stopping the drug. Before initiating corticosteroids, it is crucial to rule out any infectious causes.
References
- Cassandra B, Amanda B. Life threatening toxicities of chemo-therapies and immunomodulating medications. Critical Care Medicine. Decision Support in Medicine.
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- Schiff, D, Wen, P. “Central Nervous System Toxicity from Cancer Therapies”. Hematol Oncol Clin N Am. vol. 20. 2006. pp. 1377-98.(Brief review of most common neutrologic complications from standard chemotherapy.)
- Patel, PN. “Methylene Blue for Management of Ifosfamide-Induced Encephalopathy”. Ann Pharmacother. vol. 40. 2006. pp. 299-303.(Review of methylene blue for ifosfamide neurotoxicity including any clinical studies and case reports.)
- Sul, JK, DeAngelis, LM. “Neurologic Complications of Cancer Chemotherapy”. Semin Oncol. vol. 33. 2006. pp. 324-32.(Expanded review of neurologic complications including mention of treatment.)
- Lee, MS, McKinney, AM, Brace, JR. “Clinical and Imaging Features of Fludarabine Neurotoxicity”. Journal of Neuro-Ophthalmology. vol. 30. 2010. pp. 37-41.(Discussion of two case reports of fludarabine neurotoxicity including managment suggestions.)
- Cheson, BD, Vena, DA, Foss, FM. “Neurotoxicity of Purine Analogs: A Review”. J Clin Oncol. vol. 12. 1994. pp. 2216-28.(Older comprehensive review of fludarine neurotoxicity patient cases.)
- Dietrich, J, Marienhagen, J, Schalke, B. “Vascular Neurotoxicity Following Chemotherapy with Cisplatin, Ifosfamide, and Etoposide”. Ann Pharmacother. vol. 38. 2004. pp. 242-6.(Case report describing the increasing incidence of vascular toxicity seen in patients receiving cisplatin therapy.)
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