Treatment of Stage IV/Recurrent Malignant Pleural 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^® (cisplatin), has demonstrated anticancer activity in some patients with malignant pleural mesothelioma.

The following is a general overview of treatment for stage IV or recurrent malignant pleural mesothelioma. Treatment may consist of surgery, radiation, chemotherapy, or a combination of these treatment techniques. In some cases, participation in a clinical trial using new, innovative therapies may provide the most promising treatment.

It is important for patients with stage IV or recurrent malignant pleural mesothelioma to understand their treatment options, which may include:

• Chemotherapy
• Surgery
• Radiation therapy
• Strategies to improve treatment

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 pemetrexed, when administered in combination with cisplatin, is the only drug specifically approved by the U.S. Food and Drug Administration for the treatment of inoperable mesothelioma. Other drugs that have produced response rates of 20 percent or less include 5-fluorouracil, cisplatin, Paraplatin^® (carboplatin), Eloxatin^® (oxaliplatin), Tomudex^® (raltitrexed), Adriamycin^® (doxorubicin), interferon, Navelbine^® (vinorelbine), Taxotere^® (docetaxel), methotrexate, and Onconase^® (ranpirnase). Until the development of pemetrexed, the standard single agent for the treatment of mesothelioma was cisplatin 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 pemetrexed and cisplatin appears to be the most promising new regimen, but there is still room for development of new agents or combinations of agents.

Pemetrexed and cisplatin: The combination of pemetrexed and cisplatin 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 cisplatin and pemetrexed to cisplatin alone.

Patients treated with pemetrexed/cisplatin lived longer and experienced a longer time before their cancer progressed compared to those treated with cisplatin alone. Vitamin supplementation with B₁₂ and folic acid further improved average survival and time to cancer progression (Table 1).

Table 1. Alimta plus Platinol vs. Platinol alone in mesothelioma

Of additional importance, lung function was improved and pain was reduced in patients following treatment with pemetrexed and cisplatin compared to cisplatin alone. In addition to greater anticancer activity and improved survival, the pemetrexed and cisplatin combination was also associated with a significant and lasting improvement in the quality of life and symptom relief (including pain, shortness of breath, fatigue, anorexia, and cough).

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.

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of stage IV malignant pleural mesothelioma will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active exploration to improve the treatment of stage IV malignant pleural mesothelioma include the following:

Chemotherapy combinations - Since the combination of pemetrexed and cisplatin 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. Data from patients treated with pemetrexed and cisplatin with folic acid and vitamin B₁₂ supplementation is presented for reference (Table 2).

Table 2. Result from studies of combination chemotherapy in pleural mesothelioma

New chemotherapy drugs - There is a need to develop more effective chemotherapy drugs for the treatment of mesothelioma.

One of the new drugs being studied is Onconase^® (ranpirnase). Ranpirnase, a ribonuclease, is a novel therapeutic agent that is entering the final phases of clinical trials before 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 percent of patients lived 1 year or more and 27 percent lived 2 years or more. Importantly, the 41 patients who responded to therapy lived longer; 61 percent of these patients lived 1 year or more and 41 percent lived 2 years or more.

Gene therapy - Currently, there are no gene therapies approved for the treatment of mesothelioma. Gene therapy is defined as the transfer of new genetic material into a cell for therapeutic benefit. This is accomplished by replacing or inactivating a dysfunctional gene, by replacing or adding a functional gene, or by inserting a gene into a cell to induce an immune or cytotoxic response. Although promising, current gene therapy approaches have had only modest clinical success and this modality requires further research.

Immunotherapy with interferon - The administration of alpha interferon in addition to other chemotherapy drugs has shown promise in phase II studies, but there are no randomized trials to document this. The combination of cisplatin, doxorubicin, and interferon has shown activity in the treatment of mesothelioma. Italian researchers used this drug combination to treat 34 patients with previously untreated malignant mesothelioma. The overall response rate was approximately 30 percent. At 1 year following treatment, 45 percent of patients were alive and 34 percent were alive at 2 years following treatment. Low blood counts and/or fatigue were the most common side effects and were experienced by a majority of patients.

Immunotherapy with interleukin-2 (IL-2) - IL-2 appears to be an active agent for the treatment of mesothelioma, but the optimal dose, duration, and route of administration remain to be determined. Two studies have found that patients with mesothelioma do respond to IL-2 that is administered directly into the pleural lung cavity.

Italian researchers administered IL-2 into the pleural cavity, followed by low-dose IF-2 subcutaneously (under the skin). Among the 31 patients involved in this study, accumulation of fluid in the pleura was prevented in 90 percent. Overall, 22 percent of patients responded to treatment. There was one complete response and six partial responses, and 10 patients had stabilization of disease. On average the patients in this study lived 15 months.

When French researchers treated 22 cases of malignant pleural mesothelioma with intrapleural IL-2 alone, 12 patients responded to treatment and patients lived approximately 18 months (median survival time). Patients that responded to treatment lived longer; the median survival time for responders was 28 months, compared to 8 months for nonresponders.

Intrapleural chemotherapy - Chemotherapy directly infused into the pleural lung cavity has produced responses in patients with pleural mesothelioma. Researchers believe that administering chemotherapy drugs in this way delivers a higher concentration of drug to the cancer than intravenous (into a vein) administration. However, there is currently no evidence that chemotherapy given directly into the pleura is better than the same drugs given intravenously.

Managing side effects (supportive care) - Supportive care is treatment designed to prevent or control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the delivery of therapy at its planned dose and schedule. To achieve optimal outcomes from treatment and improve quality of life, it is imperative that treatment be delivered as planned and that side effects resulting from cancer and its treatment are appropriately managed.