Can methotrexate (MTX) cause lung cancer?

From the Guidelines

There is no clear evidence that methotrexate (MTX) directly causes lung cancer. Methotrexate is an immunosuppressive and anti-inflammatory medication commonly used to treat conditions like rheumatoid arthritis, psoriasis, and certain cancers. While MTX can cause lung toxicity in the form of pneumonitis or fibrosis in some patients (occurring in approximately 1-5% of users) 1, current medical research has not established a direct causal relationship between methotrexate use and the development of lung cancer.

Key Points to Consider

• Patients taking methotrexate should be aware that the medication can cause other pulmonary complications that require monitoring, including shortness of breath, dry cough, and fever.
• Regular follow-up with healthcare providers is important for patients on methotrexate therapy, and chest X-rays or pulmonary function tests may be recommended periodically 1.
• The theoretical cancer risk must be balanced against the known benefits of controlling inflammatory diseases, which themselves can lead to complications if left untreated.
• If you're concerned about lung risks while taking methotrexate, discuss these concerns with your healthcare provider rather than discontinuing the medication on your own.

Monitoring and Safety

• Monitoring for methotrexate includes complete blood count, hepatic transaminases, and creatinine, although there is no consensus regarding a particular monitoring protocol 1.
• Proper timing of the laboratory evaluation is imperative to accurately interpret the data.
• Monitoring for latent infections such as tuberculosis, hepatitis, or HIV should be considered before therapy based on individual circumstances and local epidemiology.

Recommendation

Methotrexate should be used under the guidance of a healthcare provider, with careful monitoring for potential side effects and consideration of the benefits and risks for each individual patient 1.

From the Research

Methotrexate and Lung Cancer

• Methotrexate (MTX) is used to treat various types of cancer, including lung cancer, as evidenced by a study published in 1981 2.
• The study found that MTX was an active agent in both non-small cell and small cell anaplastic lung cancer, with a 26% partial response rate in patients with squamous cell bronchogenic tumors.
• However, there is no direct evidence to suggest that MTX causes lung cancer.

Methotrexate Toxicity and Lung Disease

• A comprehensive literature review published in 2022 found that MTX can produce toxicity and side effects, including pulmonary toxicity 3.
• The review noted that higher doses of MTX can increase the risk of pulmonary toxicity, as well as other side effects such as bone marrow suppression and nephrotoxicity.
• A meta-analysis of randomized controlled trials published in 2014 found that MTX was associated with an increased risk of adverse respiratory events, including respiratory infection, in patients with rheumatoid arthritis (RA) 4.
• Another study published in 2017 discussed the complex relationship between MTX and lung disease in RA, highlighting the need for a correct understanding of pulmonary disease processes in RA to improve outcomes 5.

Immune Checkpoint Inhibitors and Lung Cancer

• A review published in 2025 discussed the use of immune checkpoint inhibitors (ICIs) in lung cancer patients with pre-existing autoimmune diseases, including rheumatoid arthritis 6.
• The review highlighted the challenges of using ICIs in this population and the need for further studies to establish guidelines for their use.
• However, this study does not provide direct evidence on the relationship between MTX and lung cancer.