Treatment of Stage I-III Malignant Pleural Mesothelioma

Patients with stage I-III malignant pleural mesothelioma have cancer limited to one side of the chest. In these cases, it may be possible to remove the cancer surgically. However, in stage III disease there can be extensive local spread, which means spread to other tissues or organs near where the cancer originated. This spread may include the regional lymph nodes, lungs, and soft tissues, but there is no spread to the opposite lung.

Until recently, the primary treatments for patients with stage I-III pleural mesothelioma were surgery (often extensive) and radiation therapy. Historically, chemotherapy was ineffective, but newer agents appear more promising. Treatment with radiation therapy and chemotherapy following surgery, called adjuvant therapy, is becoming a more common practice and may improve patient outcomes.

The following is a general overview of treatment for malignant pleural mesothelioma. Treatment may consist of surgery, radiation, chemotherapy, or a combination of these treatment techniques. Multimodality treatment is treatment using two or more techniques and is increasingly recognized as an important approach for improving a patient's chance of a cure or prolonging survival.

In some cases, participation in a clinical trial using new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied and which treatment a patient decides to receive. The potential benefits of multimodality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks.

It is important for patients with stage I-III mesothelioma to understand their treatment options, which may include the following:

• Multimodality treatment
• Surgery
  • Extrapleural pneumonectomy
  • Pleurectomy
• Radiation therapy
• Chemotherapy
• Strategies to improve treatment

Multimodality Treatment: Surgery, Radiation, and Chemotherapy

The lack of any single consistently curative treatment modality for malignant pleural mesothelioma has led to the development of multimodality therapy, which may include surgery, radiation therapy, and/or chemotherapy. Current research suggests that patients in good condition with stage I-III malignant pleural mesothelioma should be treated with adjuvant chemotherapy and radiation therapy following surgery. However, not all patients will be eligible for multimodality treatment.

Researchers from the Dana Farber Cancer Center in Boston have reported that among 120 patients with malignant pleural mesothelioma who underwent surgery (extrapleural pneumonectomy), chemotherapy, and radiotherapy, 22 percent survived 5 years or longer. Patients with epithelial type cancer and those with no lymph node involvement lived the longest (Table 1). On average, patients with stage I disease survived 22 months, compared to 17 months for stage II disease and 11 months for stage III disease.

Table 1. Survival of patients treated with surgery, radiation, and chemotherapy

	2-year survival	5-year survival
Epithelial type	65%	27%
Sarcomatous type	20%	0%
No lymph node involvement	74%	39%

 

Surgery for Stage I-III Pleural Mesothelioma

For patients diagnosed with stage I-III malignant pleural mesothelioma, the mainstay of treatment is surgical removal of the cancer in the pleura and areas of local spread. Mesothelioma is often located in many different places within the pleura (multifocal), often involves lymph nodes, and is usually associated with local pleural spread. These characteristics mean that a lot of tissue must be removed for complete eradication of the cancer. One of the following two surgical procedures is typically performed for operable mesothelioma:

• Removal of the pleura (pleurectomy/decortication)
• Removal of the entire lung (extrapleural pneumonectomy)

The choice of surgery will depend on the extent the cancer has spread outside the pleura and the overall health of the patient.

At the time of diagnosis, many patients with stage I-III mesothelioma are not in suitable clinical condition to withstand major surgery. Many patients that suffer from chronic lung disease due to asbestosis (fibrosis) would not survive surgery or would be left with marginal lung function. To determine if a patient is appropriate for surgery, pulmonary (lung) function tests are performed. Patients unable to undergo surgery are typically treated with radiation therapy and/or chemotherapy to relieve symptoms of their disease.

Pleurectomy (decortication) - Pleurectomy involves surgical removal of the entire pleura containing the cancer without resecting a major part of the underlying lung. In this procedure, the cancer is removed from the lung, diaphragm, and blood vessels. The mortality of pleurectomy is 1.5 percent to 5 percent when performed by an experienced surgeon. When performed at an early stage, pleurectomy can be just as effective in removing all cancer as the extrapleural pneumonectomy. 

Extrapleural pneumonectomy (pleuropneumonectomy) - Extrapleural pneumonectomy is a more extensive surgery than pleurectomy and involves the surgical removal of the lung, pleura, and cancer as a whole. When a pleurectomy is not an option due to spread of the cancer into the lung, extrapleural pneumonectomy may be considered. Surgery is associated with risk but with newer anesthetic and surgical techniques, fewer patients experience complications and fatality occurs in less than 5 percent of patients.

Extrapleural pneumonectomy alone is usually not curative, even in early-stage disease, but does provide varying degrees of relief from symptoms. Currently, the most common use of surgery is as a component of a multimodality treatment approach to reduce the amount of cancer and then to administer adjuvant chemotherapy and/or radiation therapy, as described below.

Although no clinical trials have directly compared pleurectomy to extrapleural pneumonectomy, noncomparative studies do suggest a significant improvement in survival without cancer recurrence for patients treated with extrapleural pneumonectomy versus pleurectomy. 

Radiation Therapy for 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 alone may be used for the treatment of stage I-III malignant pleural mesothelioma to relieve signs and symptoms of disease in patients who cannot undergo surgery or more aggressive adjuvant treatment.

One of the problems with radiation therapy for malignant pleural mesothelioma is that the cancer is usually widespread, requiring a large area to be radiated. The high doses of radiation necessary for eradication of the disease may damage normal tissues in the lung and chest. Complications of radiation therapy for malignant pleural mesothelioma can include inflammation of the lungs (pneumonitis), inflammation of the sack around the heart (pericarditis), and compression of the heart (cardiac tamponade).

Adjuvant radiation therapy - Adjuvant therapy is therapy given following surgical treatment. Researchers from the Memorial Sloan-Kettering Cancer Center in New York have shown that adjuvant radiation therapy can reduce the risk of local recurrence in patients with malignant mesothelioma and may prolong survival in patients with early-stage disease.

Research also indicates that progress has been made in decreasing side effects of radiation by using modern radiation therapy techniques. For example, intensity modulated radiation therapy (IMRT) may decrease the damage to normal tissues and allow increased doses of radiation to be delivered to the cancer. Researchers from the MD Anderson Cancer Center in Texas concluded that this was a promising and feasible approach. They reported that with a median follow-up time of 9 months, there were no local recurrences in 28 patients treated with IMRT. However, metastasis became more frequent, suggesting the need for chemotherapy.

Chemotherapy for Stage I-III 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.

Chemotherapy may be given to patients unable to undergo major surgery or it may be administered as an adjuvant therapy after surgery. There have been no systematic evaluations of adjuvant chemotherapy in patients with stage I-III pleural mesothelioma who have had all of their cancer removed with surgery.  However, due to the high rate of cancer recurrence after treatment with surgery alone, the general consensus is that patients with early-stage disease should consider adjuvant treatment with radiation therapy and/or chemotherapy.

A variety of chemotherapy drugs have been evaluated for the treatment of malignant pleural mesothelioma, but Alimta^® (pemetrexed) in combination with Platinol^® (cisplatin) is the only drug specifically approved by the U.S. Food and Drug Administration for the treatment of inoperable mesothelioma.

Strategies to Improve Treatment

The development of more effective cancer treatment 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 malignant 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 malignant mesothelioma include the following:

Chemotherapy Combinations 

Pemetrexed and cisplatin - Development of the chemotherapy drug pemetrexed has constituted a major step forward in the treatment of mesothelioma. Pemetrexed was evaluated as a single drug treatment for mesothelioma in a clinical trial carried out in the U.S., Germany, and Italy. Researchers reported that 16 percent of patients responded to treatment.

The combination of pemetrexed and cisplatin has emerged as the most active and best studied drug combination for the treatment of inoperable mesothelioma and will be adopted as a “standard” by which other regimens are compared. The largest phase III randomized study of chemotherapy for inoperable mesothelioma ever performed was the comparison of cisplatin and pemetrexed to cisplatin alone. A total of 456 patients were enrolled from April 1999 to March 2001.

On average, 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 improved average survival and time to cancer progression even further (Table 2).

Table 2. Alimta plus Platinol vs. Platinol alone in inoperable mesothelioma

	Alimta/Platinol	Platinol alone
Median survival (MS)	12.1 months	9.3 months
MS w/vitamin supplementation	13.3 months	10 months
Time to tumor progression (TTP)	5.7 months	3.9 months
TTP w/vitamin supplementation	6.1 months	3.9 months
Response rate	46%	29%

 

In addition to greater anticancer activity and greater survival time, the pemetrexed and cisplatin combination was also associated with a significant and lasting improvement in quality of life and symptom relief, including pain, shortness of breath, fatigue, anorexia, and cough when compared with cisplatin alone. Researchers have also documented that lung function improved in patients who either respond or have stable disease following treatment with pemetrexed.

Other chemotherapy combinations - Since it appears that the combination of pemetrexed and cisplatin will be the new “standard” regimen for the treatment of inoperable mesothelioma, other promising chemotherapy regimens will probably be compared to this drug regimen. The following table summarizes the results of some of the more recently performed clinical trials evaluating chemotherapy in mesothelioma. Data from patients treated with pemetrexed and cisplatin with folic acid and vitamin B₁₂ supplementation is presented for reference (Table 3).

Table 3. Result from studies of combination chemotherapy in pleural mesothelioma

Regimen	Number of patients	Response rate (%)	Time to cancer progression (months)	Median survival (months)
Alimta/Platinol	168	46	6.1	13.3
Doxil/Paraplatin/Gemzar	64	31	6	>12.0
Platinol/Gemzar/Novantrone	53	28	8	NR
Platinol/Gemzar	35	26	8	13
Gemzar/Oxaliplatin	25	40	7	13
Gemzar/Paraplatin	50	16	10	16
Raltitrexed/Oxaliplatin	70	20	4.5	9.0

Onconase ^® - Onconase (ranpirnase), a ribonuclease, is a novel therapeutic agent that is entering the final phases of clinical trials before FDA approval for the 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. Out of the 81 patients involved in this study, 35 patients experienced a stabilization of their cancer and six patients had a regression of their cancer. Forty-two percent of patients survived 1 year or more and 27 percent lived 2 years or more from the initiation of treatment. 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 approach requires further research.

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.

Hyperthermia - High temperature makes cancer cells more susceptible to chemotherapy and radiation therapy. Researchers are evaluating the effects of cytoreductive surgery combined with intraoperative hyperthermia and instillation of chemotherapy directly into the pleural cavity. In a phase I study using cisplatin and Adriamycin^® (doxorubicin), researchers reported that hyperthermia plus intrathoracic instillation of chemotherapy was feasible and resulted in high concentrations of the drug.

Whole body hyperthermia and chemotherapy was evaluated in a phase II clinical trial by German researchers. Chemotherapy included Ifex^® (ifosfamide), Paraplatin® (carboplatin), and etoposide. All patients had stage I-III disease. The overall response rate was 20 percent with an average survival of 1.5 years. Time to progression of disease averaged 30 weeks. The 2-year survival was 20 percent. These researchers thought that these results warranted a phase III trial.

Photodynamic therapy - Photodynamic therapy involves using protoporphyrin dye given intravenously, which is taken up by the tumor cells and absorbs a laser light administered into the pleural cavity. The dye is activated to produce singlet oxygen radicals. These oxygen radicals cause subsequent cell death. Depth of penetration of the dye is limited, and the ratio of uptake in normal and tumor tissue is poor. It is unclear at the present time whether or not this form of therapy offers any advantage over other treatments for mesothelioma.

Only one study has evaluated photodynamic therapy for adjuvant therapy in mesothelioma and the results were negative. Researchers randomly allocated 48 patients who had received aggressive surgery and adjuvant chemotherapy to receive or not receive intraoperative photodynamic therapy. The average survival was 14 months, with no difference between those receiving and not receiving photodynamic therapy. At the present time, it appears that this form of therapy is limited.

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 interleukin-2 (IL-2) into the pleura, followed by low-dose IL-2 subcutaneously (under the skin). Among the 31 patients involved in this study, the 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 these patients 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). Patients that responded to treatment lived longer; the median survival for responders was 28 months, compared to 8 months for nonresponders.

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.