Many antineoplastic drugs can cause damage to the lungs, airways, pleura, and pulmonary circulation. Pulmonary toxicities induced by antineoplastic drugs can vary in severity ranging from minor to life threatening. For some antineoplastic drugs such as bleomycin, pulmonary toxicity is the most common dose limiting toxicity.rr
Several pathophysiologic mechanisms have been proposed for antineoplastic drug induced pulmonary toxicity:rr
- direct chemical injury to pneumocytes or alveolar capillary endothelium, with subsequent cytokine release and inflammatory cell recruitment
- capillary leak and pulmonary oedema due to systemic release of cytokines by antineoplastic agents (e.g. gemcitabine)
- oxidative injury secondary to free oxygen radicals (e.g. bleomycin, mitomycin)
- EGFR-mediated disruption to alveolar repair mechanisms potentiating lung injury from other causes such as sepsis and radiotherapy (e.g. EGFR tyrosine kinase inhibitors)
- activation of lymphocytes causing cell-mediated lung injury (e.g. idiosyncratic drug-induced hypersensitivity, mTOR inhibitors, immunotherapy with antiPD-1 and anti-CTLA4 checkpoint inhibitors).rrr
The most common pattern of antineoplastic drug induced pulmonary toxicity is interstitial lung disease (ILD).r Clinical syndromes can be categorised based on either clinical criteria or pathologic findings, and may include acute, subacute or chronic presentation with ILD.
The specific ILD patterns which are seen associated with antineoplastic drugs are varied, and include chronic and progressive interstitial pneumonia, diffuse alveolar damage, organising pneumonia, pulmonary eosinophilia, non-cardiogenic pulmonary oedema, pulmonary haemorrhage, vascular thrombosis and pulmonary veno-occlusive disease. rrr
Some of the above presentations, including organising pneumonia, may progress to pulmonary fibrosis.r Pulmonary fibrosis is a disorder characterised by the replacement of the lung tissue by connective tissue, leading to progressive dyspnoea, respiratory failure or right heart failure.r
The incidence of antineoplastic drug induced pulmonary toxicity according to the literature has been reported as high as 20%, dependent on the antineoplastic agent. However, in practice clinical toxicity is uncommon for most antineoplastic drugs.rrr The cytotoxic drugs with the highest reported incidence of pulmonary toxicities are bleomycin, carmustine, methotrexate, busulfan, and mitomycin.rr Everolimus is associated with non-infectious pneumonitis in about 10% (range 2-36%) of patients.r Ipilimumab is rarely associated with symptomatic pneumonitis (1%).r For anti-PD1 checkpoint inhibitors such as pembrolizumab and nivolumab, symptomatic pneumonitis is more common for patients with non-small-cell lung cancer compared to other non-lung malignancies (7% vs 2%).r
Time of onset can vary from immediately after the first treatment, to several months or years after completion of treatment.r There have been reported cases of pulmonary toxicity developing decades after completion of treatment with carmustine.rr The most common manifestation that occurs months to years after treatment is pulmonary fibrosis.r
Risk factors for developing antineoplastic drug induced pulmonary toxicity may include:
- age (bleomycin, methotrexate)*
- female sex (carmustine)rr
- history of smoking (bleomycin)**
- pre-existing lung diseaserrr
- reduced renal function (bleomycin)rrrr
- cumulative drug dose (bleomycin, carmustine)***
- concomitant chemotherapy with known lung toxicityrr
- concomitant or previous radiation therapyrrr
- high fraction of inspired oxygen (bleomycin, cyclophosphamide, carmustine)****
- colony stimulating factors (bleomycin, cyclophosphamide)*****
* The risk of bleomycin and methotrexate induced pulmonary toxicity appears higher in older patients; for bleomycin the risk appears to be increased in those over 40 years.rrr
** There is some data to suggest cigarette smoking increases the risk of bleomycin induced pulmonary toxicity.rr
*** Cumulative dose of bleomycin greater than 300,000 international units has been associated with higher rates of pulmonary toxicity.rrr Pulmonary toxicity can however occur with bleomycin cumulative doses less than 50,000 international units.rrr Cumulative dose of carmustine greater than 1400 mg/m2 has been associated with higher rates of pulmonary toxicity.rr
**** High concentrations of inspired oxygen may increase the risk of pulmonary toxicity in patients treated with bleomycin, cyclophosphamide or carmustine.rrrr Available evidence is inconsistent, and is largely anecdotal.
***** It has been reported that the risk of bleomycin and cyclophosphamide induced pulmonary toxicity is increased when used in combination with colony stimulating factors.rrr Available data is conflicting, and has not been confirmed in randomised clinical trials.
Pulmonary toxicity can be unpredictable; development in young patients and those treated with low doses has been observed.