Can chemotherapy (chemo) cause pulmonary fibrosis?

From the Guidelines

Yes, chemotherapy can cause pulmonary fibrosis, particularly with the use of certain drugs such as bleomycin, as evidenced by studies showing an increased risk of mortality from respiratory disease in testicular cancer survivors who received chemotherapy after 1975 1. The risk of pulmonary fibrosis associated with chemotherapy is influenced by various factors, including the specific drug used, cumulative dose, age at diagnosis, smoking, renal dysfunction, and mediastinal radiotherapy.

• Bleomycin is a well-known risk factor for pulmonary toxicity, with risk factors for bleomycin-associated pneumonitis including cumulative dose, age at diagnosis, smoking, renal dysfunction, mediastinal radiotherapy, and oxygen administration 1.
• Most patients recover with drug discontinuation or with corticosteroid treatment, and only a small percentage develop pulmonary fibrosis 1.
• Recently, it has been proposed that cisplatin-based therapy may also contribute to long-term pulmonary toxicity, with studies showing an association between cisplatin-based therapy dose and restrictive lung disease in testicular cancer survivors 1. Key considerations for patients receiving chemotherapy include:
• Monitoring with pulmonary function tests before and during treatment
• Prompt reporting of new respiratory symptoms to healthcare providers for early intervention
• Awareness of individual susceptibility to bleomycin-induced toxicity and other risk factors for impaired lung function, such as tobacco use and occupational exposures 1.

From the FDA Drug Label

The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis The microscopic tissue changes due to bleomycin toxicity include ... interstitial fibrosis

Chemotherapy with bleomycin can cause pulmonary fibrosis. The drug label states that pneumonitis can progress to pulmonary fibrosis, and approximately 1% of patients treated with bleomycin have died of pulmonary fibrosis 2. Key factors that increase the risk of pulmonary toxicity, including pulmonary fibrosis, are:

• Dose of bleomycin
• Age of the patient, with those over 70 years being more susceptible
• Combination of bleomycin with other medications such as G-CSF (filgrastim) or other cytokines, although this is still under investigation.

From the Research

Chemotherapy and Pulmonary Fibrosis

• Chemotherapy, particularly with certain drugs like bleomycin, can cause pulmonary fibrosis as a late side-effect, even in the absence of radiotherapy 3.
• Bleomycin is known to induce acute pneumonitis and lung fibrosis, and the risk of pulmonary fibrosis can occur more than five years after therapy 3, 4.
• Supplemental oxygen therapy can trigger the onset of pneumonitis and lethal pulmonary fibrosis in patients who have previously received bleomycin therapy 3.

Mechanisms of Pulmonary Fibrosis

• The mechanisms of bleomycin-induced lung fibrosis involve massive oxidative stress, alveolar epithelial cell death, proliferation of fibroblasts, and infiltration of immune cells 4.
• Chronic release of pro-inflammatory and pro-fibrotic molecules by immune cells and fibroblasts leads to pneumonitis and fibrosis 4, 5.
• Other changes such as epithelial-mesenchymal transition (EMT), oxidative stress, and the upregulation of inflammatory mediators can also potentiate lung fibrosis and pneumonitis 5.

Monitoring and Management

• Pulmonary function testing (PFT) can detect bleomycin-induced pneumonitis, but its utility is controversial, and a 25% reduction in DLCO may be too cautious a threshold for omitting bleomycin doses 6.
• Chemotherapy can be considered in the management of patients with small-cell lung cancer and idiopathic pulmonary fibrosis with poor lung function, and antifibrotic agents can be continued during the chemotherapeutic regimen 7.