Stage IV/Recurrent

of Malignant Mesothelioma

Patients with stage IV malignant pleural mesothelioma have cancer that is considered inoperable and has spread to the opposite side of the chest or to distant sites. Patients with recurrent or refractory malignant pleural mesothelioma have cancer that has failed primary treatment or recurred after an initial response.

The primary treatment for patients with stage IV or recurrent malignant pleural mesothelioma is chemotherapy or supportive care to alleviate uncomfortable symptoms. Historically, chemotherapy has been ineffective. However, the newly approved chemotherapy drug Alimta® (pemetrexed), when administered in combination with Platinol®, has demonstrated anti-cancer activity in some patients with malignant pleural mesothelioma.

The following is a general overview of treatment for stage IV or recurrent malignant pleural mesothelioma. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

Chemotherapy for Stage IV/Recurrent Malignant Pleural Mesothelioma

Chemotherapy is treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, and is typically administered through a vein or delivered orally in the form of a pill. Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancer cells at sites great distances from the original cancer. As a result, chemotherapy is considered a systemic treatment.

Several chemotherapy drugs have been evaluated for the treatment of malignant pleural mesothelioma, but Alimta®, when administered in combination with Platinol®, is the only drug specifically approved by the U.S. Food and Drug Administration for the treatment of inoperable mesothelioma.1 Other drugs that have produced response rates of 20% or less include 5-fluorouracil, Platinol®, Paraplatin®, Eloxatin®, raltitrexed, Adriamycin®, interferon, Navelbine®, Taxotere®, methotrexate and ranpirnase.2,3,4,5 Until the development of Alimta®, the standard single agent for the treatment of mesothelioma was Platinol® or doxorubicin.

While many chemotherapy regimens (combinations of chemotherapy drugs) are being tested for the treatment of mesothelioma, the gains in survival with the best therapies are still very modest. The combination of Alimta® and Platinol® appears to be the most promising new regimen, but there is still room for development of new agents or combinations of agents.

Alimta® and Platinol®: The combination of Alimta® and Platinol® has emerged as the most active and best studied drug combination for the treatment of mesothelioma and will probably be adopted as a “standard” by which other treatments are compared. A large clinical trial was performed that directly compared Platinol®and Alimta® to Platinol® alone.6

Patients treated with Alimta®/Platinol® lived longer and experienced a longer time before their cancer progressed compared to those treated with Platinol® alone. Vitamin supplementation with B12 and folic acid further improved average survival and time to cancer progression.

Surgery for Stage IV/Recurrent Malignant Pleural Mesothelioma

For patients diagnosed with stage IV malignant pleural mesothelioma, surgery is not typically part of the treatment regimen. However, there may be situations where surgical removal of the involved pleura may improve breathing. There are also researchers who think that removal of as much tumor as possible (debulking) will improve the results of chemotherapy.

Radiation Therapy for Stage IV/Recurrent Mesothelioma

Radiation therapy uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Similar to surgery, radiation therapy is a local treatment used to eliminate or eradicate cancer in a defined area. Radiation therapy is not typically useful in eradicating cancer cells that have already spread to other parts of the body. Radiation may be used to cure or control cancer, or to ease some of the symptoms caused by cancer. Radiation therapy has not had a prominent role in the treatment of stage IV mesothelioma, except for the alleviation of some symptoms caused by the cancer.

For more information, go to Radiation Therapy for Malignant Pleural Mesothelioma.

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Areas of active exploration to improve the treatment of stage IV malignant pleural mesothelioma include the following:

Keytruda (pembrolizumab), an antibody drug already used to treat other forms of cancer, can be effective in the treatment of the most common form of mesothelioma, according to a new study led by investigators from the Perelman School of Medicine at the University of Pennsylvania. The study, published in The Lancet Oncology, is the first to show a positive impact from checkpoint inhibitor immunotherapy drugs on this disease.7

Chemotherapy combinations: Since the combination of Alimta® and Platinol® is the new “standard” regimen for treatment of mesothelioma, other promising chemotherapy regimens will be compared to this drug regimen. The following table summarizes some of the most recently performed clinical trials evaluating new drug combinations in mesothelioma. Most of these studies present preliminary results with a short follow-up time and include only small numbers of patients.

New Chemotherapy Drugs: There is a need to develop more effective chemotherapy drugs for the treatment of mesothelioma.8,9,10,11,12,13,14

One of the new drugs being studied is ranpirnase (Onconase®). Ranpirnase, a ribonuclease, is a novel therapeutic agent that is entering the final phases of clinical trials prior to FDA approval for treatment of malignant mesothelioma. Ranpirnase is a small protein that is isolated from the eggs of Rana pipiens – a leopard frog. Ranpirnase initially binds to the surface of cells in the body and becomes internalized into the cells. It works by degrading a protein (tRNA) that is produced more readily when cells are growing and replicating. The irreparable degradation of tRNA can directly kill a cell or can signal a cell to stop replicating. Since cancer cells replicate more frequently and tend to have higher levels of tRNA than normal cells in the body, they are more susceptible to the effects of ranpirnase.

A multi-institutional clinical trial that evaluated ranpirnase in patients with malignant mesothelioma showed that this drug appears to be an effective and safe treatment option. Of the 81 patients involved in this study, 35 experienced a stabilization of their cancer and six patients had a regression of their cancer. On average, 42% of patients lived one year or more and 27% lived two years or more. Importantly, the 41 patients who responded to therapy lived longer; 61% of these patients lived one year or more and 41% lived two years or more.15

Next: Radiation Therapy for Mesothelioma

Next: Precision Cancer Medicine


1 Scagliotti G, Shin DM, Kindler H, et al. Phase II Study of Pemetrexed with and without Folic Acid and Vitamin B12 as Front-line Therapy in Malignant Pleural Mesothelioma. J Clin Oncol 2003;21:1556-1561.

2 Taub, Robert N. & Antman, Karen H. Chemotherapy for Malignant Mesothelioma. Seminars in Thoracic and Cardiovascular Surgery 1997; 9:361-66.

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5 Baas P, Ardizzoni A, Grossi F, et al. The Activity of Raltitrexed (Tomudex) in Malignant Pleural Mesothelioma: An EORTC Phase II Study (08992). Eur J Cancer 2003;39:353-357.

6 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Journal of Clinical Oncology 2003;15;21:2636-44.


8 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Journal of Clinical Oncology 2003;15;21:2636-44.

9 Hillerdal G, Sundstrom S, Sorensen JB, et al. Malignant pleural mesothelioma treated with a combination of pegylated liposomal doxorubicin, carboplatin and gemcitabine: The CCG study. Proc Amer Soc Clin Oncol 39; 2003, Abstract #2534.

10 Pinto C, Marino A, De Pangher Manzini V, et al. Sequential chemotherapy with Platinol/gemcitabine (CG) followed by mitoxantrone /methotrexate /mitomycin (MMM) in untreated malignant pleural mesothelioma (MPM): A multicentric italian phase II study (SITMP1). Proc Amer Soc Clin Oncol 39; 2003, Abstract #2613.

11 Castagneto B, Zai S, Dongiovanni V, et al. Platinol and gemcitabine in malignant pleural mesothelioma: A phase II study. Proc Amer Soc Clin Oncol 39; 2003, Abstract #2637.

12 Schutte W, Blankenburg T, Lauerwald K, et al. A Multicenter Phase II Study of Gemcitabine and Oxaliplatin for Malignant Pleura Mesothelioma. Clin Lung Cancer 2003;4:294-297.

13 Favaretto AG, Aversa AML, Paccagnella A, et al. Gemcitabine Combined with Carboplatin in Patients with Malignant Pleural Mesothelioma: A Multicenter Phase II Study. Cancer 2003;97:2791-2797.

14 Fizazi K, Doubre H, Le-Chevalier T, et al. Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study. Journal of Clinical Oncology 2003;21: 349-354.

15 Mikulski S, Costanzi J, Vogelzang N, et al. Phase II trial of single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma Journal of Clinical Oncology 2002;20:274-281.