Pulmonary toxicity
Most chemotherapy or immunosuppressive drugs can cause pulmonary toxicities ranging from minor to major as a result of treatment. These toxicities include interstitial pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), pneumonitis, radiation recall pneumonitis, and alveolar hemorrhage. The occurrence of these toxicities can vary, with case reports showing up to 20% of patients experiencing them with certain drugs.
The toxicities are primarily due to direct cytotoxic damage to the cells of the alveoli and lungs, leading to the release of cytokines from these cells and the subsequent recruitment of other inflammatory cells to the lungs. Additionally, some chemotherapy agents that induce the formation of oxygen free radicals can cause oxidative damage or trigger the systemic release of proinflammatory cytokines.
Bleomycin
Bleomycin is one of the best-known chemotherapy agents associated with pulmonary toxicity. This agent, which inhibits DNA synthesis and also causes some inhibition of some protein and RNA synthesis, is used for a number of solid tumors as well as lymphomas. Currently, the FDA labeling for bleomycin includes a black box warning regarding pulmonary toxicity.
The warning is stated as follows:
“Pulmonary fibrosis is the most severe toxicity associated with Bleomycin for Injection. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.”
Bleomycin pulmonary toxicity is potentially a combination of oxidative damage and lack of an enzyme in the lungs, bleomycin hydrolase. This enzyme breaks down bleomycin in all tissues in the body but is not usually present or is present at very low levels in the lung.
The cumulative bleomycin dosage administered is an important risk factor to the development of bleomycin pulmonary toxicity. Low doses of bleomycin (<270 units) have an estimated incidence of pulmonary toxicity of 1-2%, while higher doses of bleomycin (>360 units) are associated with an incidence of approximately 10%, though there are reports with higher rates up to 18%.
Other than cumulative dosage, age above 40 years old, use of other chemotherapies associated with pulmonary toxicity, radiation therapy, oxygen therapy, use of hematopoietic colony stimulating factors and renal function have all been identified as risk factors for bleomycin toxicity.
Signs and symptoms of bleomycin toxicity include non-productive cough, dyspnea, fever, tachypnea, and rales on chest auscultation that occur within 1-6 months after bleomycin treatment. The diagnosis of bleomycin-induced lung injury is usually made through a clinical diagnosis combining recent bleomycin therapy, exclusion of infectious or malignant causes of lung disease and clinical symptoms consistent with pneumonitis/interstitial lung disease (ILD).
Treatment of bleomycin-induced lung toxicity is to discontinue bleomycin therapy. Corticosteroids should be used in symptomatic cases as spontaneous recovery has occurred in non-symptomatic patients. The recommended dosing of prednisone is 60-100 mg/day for approximately 4 weeks based on patient response. This dose is then slowly tapered (e.g. 5 mg every week) over the next several weeks to months as the patient tolerates. Re-challenge with bleomycin is not recommended, especially with those patients who develop pulmonary fibrosis.
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