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Methotrexate is a drug that suppresses the immune system and that 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 It was first approved by the U.S. Food and Drug Administration (FDA) in 1953 and was originally made by Dava Pharmaceuticals.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 is beginning to show promise as a chemotherapeutic agent for mesothelioma.

As a chemotherapy drug, methotrexate is proving in studies to extend the lives of patients with mesothelioma. On the other hand, there are some serious risks of taking this drug, including the possibility of developing 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 of complications.

What is Methotrexate?

Methotrexate is a drug with a dual function. It suppresses the immune system and can be used to treat autoimmune disorders. These are disorders in which the immune system mistakenly attacks part of the body, such as the joints in rheumatoid arthritis. It is also a chemotherapeutic drug and slows the growth of cancer cells and tumors.

First approved by the FDA in 1953, methotrexate has been in use for decades. It is currently approved for treating rheumatoid arthritis and psoriasis, both immune system disorders. It is also approved for treating certain types of 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.

Although it is not approved for other uses, doctors may prescribe methotrexate for other autoimmune disorders like Crohn’s disease and multiple sclerosis, and for other types of cancer. It has been tested in patients with mesothelioma, and while more work needs to be done, it has so far proven to be effective in improving patient outcomes.

How it Works

Methotrexate is a type of drug known as an antimetabolite. This 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 prevents a reaction or chemical pathway from proceeding in a cell and disrupts the normal activity of the cell. In the case of methotrexate and cancer cells, it prevents DNA from being made and that prevents cells from dividing to create new cells, therefore slowing the growth of the 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 decreased infection resistance. These symptoms are mostly not serious or life threatening, but there are other potential side effects that can be more serious and that can be major health concerns for patients.

Some of the other potential side effects that can be more severe or damaging 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 all the side effects that methotrexate can cause, the FDA has listed several warnings in a black box on the drug packaging. This level of warning is for the most severe and possibly life threatening side effects of a medication. The black box warning states that because of these risks, methotrexate should only be used to treat sever conditions, like cancer, and those that are not responding to other drugs.

One serious risk of methotrexate is severe suppression of white blood cell production in the bone marrow. These are cells of the immune system and suppression can lead to serious and life threatening infections. Patients must be carefully monitored for white blood cell count and infections while on methotrexate. The warnings also state that caution should be taken with patients who have liver, kidney or lung damage or disease, as the drug can make these worse. Methotrexate can also increase the chance that someone will develop lymphoma.

Mesothelioma Studies

In spite of all the serious risks that come with taking methotrexate, this drug can also have great benefits for some patients. The risks are often considered to be acceptable for patients with diseases that are life threatening and difficult to treat, like mesothelioma. Both case studies and studies with multiple mesothelioma patients have shown that methotrexate may be a useful treatment. In one case study, for instance, a man with rheumatoid arthritis was also treated for mesothelioma. He was on methotrexate for the arthritis, but his doctors discovered that he surpassed the life expectancy for mesothelioma patients, an outcome they attributed to the methotrexate.

In a study with 17 mesothelioma patients, methotrexate, cisplatin, and one other chemotherapy drug was administered. These patients were not candidates for surgery and chemotherapy was their only option. The researchers found that nine of the patients responded well to the treatment and two achieved remission. The median survival time was 14 months, results that are better than those seen with more standard treatments.

In another study, 21 patients with mesothelioma were given methotrexate in combination with gemcitabine. Nearly 40 percent of the patients showed a partial response to the treatment, while nearly half experienced stability in the disease, meaning the tumor did not grow any larger. Only three patients experienced disease progression in spite of the treatment. The median survival time for these patients was 19 months, much longer that what is expected with mesothelioma patients. The researchers suggest that the combination of gemcitabine and methotrexate should be considered an effective treatment and an alternative to using a platinum-based drug to which some patients respond poorly.

Methotrexate is a drug that comes with some serious and scary potential side effects and complications. However, many patients respond well to it and never experience any of the worst side effects. They may also be given a chemoprotective drug, leucovorin, which is designed to counteract some of the complications of methotrexate. For patients with mesothelioma, treatments options are limited, so even with the possible side effects and all the risks, trying methotrexate with a combination of other drugs is a valid and reasonable option. These small studies have shown that it can extend patients’ lives, although more work needs to be done with larger groups and to determine how serious the risks really are.

Page edited by Dave Foster

Dave has been a mesothelioma Patient Advocate for over 10 years. He consistently attends all major national and international mesothelioma meetings. In doing so, he is able to stay on top of the latest treatments, clinical trials, and research results. He also personally meets with mesothelioma patients and their families and connects them with the best medical specialists and legal representatives available.

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