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Methotrexate suppresses the immune system and is often used to treat autoimmune disorders, like rheumatoid arthritis. It is sold as a generic and under the brand names Rheumatrex and Trexall. It was first approved by the U.S. Food and Drug Administration (FDA) in 1953 and was originally made by Dava Pharmaceuticals. It is now made by numerous companies and shows promise as a chemotherapeutic agent for mesothelioma.
As a chemotherapy drug, methotrexate can extend the lives of patients with mesothelioma. On the other hand, there are some serious risks from the drug, including the possibility of a life-threatening infection. More research is needed to determine how effective methotrexate may be for mesothelioma treatment and if it is worth the risk.
What is Methotrexate?
Methotrexate is a drug with dual functions. It suppresses the immune system and is used to treat autoimmune disorders like rheumatoid arthritis, in which the immune system mistakenly attacks the joints. Methotrexate is also a chemotherapeutic drug and can slow the growth of cancer cells and tumors.
First approved by the FDA in 1953, methotrexate has been tested and used since then for many indications. It is approved to treat rheumatoid arthritis and psoriasis, both immune system disorders. It is also approved for certain cancers, including gestational choriocarcinoma, acute lymphocytic leukemia, meningeal leukemia, breast cancer, head and neck cancers, lung cancer, non-metastatic osteosarcoma, and some types of lymphoma.
While it may not be approved for additional uses, doctors may sometimes prescribe methotrexate for other autoimmune disorders like Crohn’s disease and multiple sclerosis, and for other cancers. It has been tested in patients with mesothelioma, and while more work needs to be done, it has so far proven effective in improving patient outcomes.
How it Works
Methotrexate is an antimetabolite, which means that it inhibits the action of an enzyme by binding to that enzyme more effectively than the substance that normally binds to it — in this case folic acid. This antifolate action interrupts a reaction or chemical pathway in a cell and disrupts normal growth there. Methotrexate prevents DNA from being made in cancer cells, which stops cells from dividing and creating new cells, therefore slowing the growth of a tumor.
Methotrexate Side Effects
The most common side effects reported by patients being treated with methotrexate are ulcerative stomatitis, reduced white blood cell count, abdominal upset, nausea, fatigue and malaise, fever, chills, dizziness, and increased risk of infections. These symptoms are not serious or life threatening, but other potential side effects can be more serious health concerns for patients.
Severe or damaging effects include liver toxicity, hepatitis, increased liver enzymes, liver failure, low blood pressure, pericarditis or pericardial effusion, anemia, anorexia, gastrointestinal ulcers, blurred vision, blindness, speech impairment, changes in mood, severe infections, kidney damage or failure, skin damage, stress fractures, respiratory fibrosis, respiratory failure, and chronic interstitial obstructive pulmonary disease. With so many potential side effects, although they are not commonly seen, doctors must carefully weigh the benefits of methotrexate with the many risks.
Black Box Warnings
In addition to its side effects, the FDA has listed several warnings in a black box on the drug packaging, a warning used for the most severe and possibly life threatening side effects of a medication. The black box warning says methotrexate should only be used to treat severe conditions, like cancer, and those that are not responding to other drugs.
Methotrexate may suppress white blood cell production in the bone marrow. Suppressing these immune system cells could lead to serious and life threatening infections. Patients must be carefully monitored for white blood cell count and infections while on methotrexate. Caution should be taken with patients who have liver, kidney or lung damage or disease, as the drug could make these worse. Methotrexate can also increase the chance that someone will develop lymphoma.
In spite of the risks, methotrexate can help some patients. The risks may be acceptable for patients with diseases that are life threatening and difficult to treat, like mesothelioma. Clinical trials and case studies that include mesothelioma patients show methotrexate may be a useful treatment. One man with rheumatoid arthritis was also diagnosed with mesothelioma. The patient decided against traditional chemotherapy after his surgery, but remained on oral methotrexate (which is similar to the first-line treatment medication pemetrexed). The patient’s cancer didn’t worsen for many years, leading his medical team to believe that perhaps the methotrexate was helpful.
In a study with 17 mesothelioma patients, methotrexate and vinblastine were given, with some patients also receiving cisplatin or carboplatin. These patients were not candidates for surgery, so chemotherapy was their only option. Nine of the patients responded well to the treatment and two achieved complete remission. The average survival time was 14 months, results that are better than those seen with standard treatments.
In another study, 21 patients with mesothelioma received methotrexate in combination with gemcitabine. Nearly 40 percent of the patients showed a partial response to the treatment, while nearly half experienced stable disease, meaning the tumor did not grow any larger. Only three patients failed to respond to the treatment. The median survival time for these patients was 19 months, much longer than is typical for similar patients. The researchers suggest that the combination of gemcitabine and methotrexate should be considered an effective treatment and potentially as an alternative to using a platinum-based drug to which some patients respond poorly.
Methotrexate comes with some serious and concerning possible side effects. However, many patients respond well to the treatment and the side effects can often be managed through careful monitoring. For patients with mesothelioma, treatment options are limited, so even with the possible side effects and all the risks, trying methotrexate with a combination of other drugs could be a reasonable option. These small studies have shown that it could extend patients’ lives, although more studies should continue with larger groups to determine how serious the risks really are.
Page Medically Reviewed and Edited by Kyle J. Becker, PharmD, MBA, BCOP
Kyle J. Becker, PharmD is certified by the Board of Pharmacy Specialties in Oncology Pharmacy. Dr. Becker earned his pharmacy degree from Shenandoah University and he currently serves as an oncology pharmacist at Parkview Cancer Institute.