Stage I-III of Malignant Mesothelioma
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
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 and precision cancer medicines 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. The information on this Web site 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.
It is important for patients with stage I-III mesothelioma to understand their treatment options which may include the following:
Multi-modality Treatment: Surgery, Radiation, and Chemotherapy
The lack of any single consistently curative treatment modality for malignant pleural mesothelioma has led to the development of multi-modality 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 multi-modality treatment.
Researchers from the Dana Farber Cancer Center in Boston, MA have reported that among 120 patients with malignant pleural mesothelioma who underwent surgery (extrapleural pneumonectomy), chemotherapy, and radiotherapy, 22% survived 5 years or longer. Patients with epithelial type cancer and those with no lymph node involvement lived 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.1
Table 1 Survival of patients treated with surgery, radiation, and chemotherapy
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) or
- 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. In order 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.2
Pleurectomy (decortication): Pleurectomy involves surgical removal of the entire pleura containing the cancer without resecting a major part of the underlying lung.3 In this procedure, the cancer is removed from the lung, diaphragm, and blood vessels. The mortality of pleurectomy is 1.5%-5% 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 anesthesia and surgical techniques, fewer patients experience complications and fatality occurs in less than 5% of patients.4,5
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 multi-modality 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, non-comparative 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 in order to relieve signs and symptoms of disease in patients who cannot undergo surgery or more aggressive adjuvant treatment.6
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, and the high doses of radiation necessary for eradication of 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).7
Adjuvant radiation therapy: Adjuvant therapy is therapy given following surgical treatment. Researchers from 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.8
Research also indicates that progress has been made in decreasing side effects of radiation by utilizing modern radiation therapy techniques.9 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 MD Anderson Cancer Center in Texas concluded that this was a promising and feasible approach. They reported that with a median follow-up of 9 months there were no local recurrences in 28 patients treated with IMRT. However, metastasis became more frequent, suggesting the need for chemotherapy.10
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® is the only drug specifically approved by the U.S. Food and Drug Administration for the treatment of inoperable mesothelioma.11
Strategies to Improve Treatment
The development of more effective cancer treatment requires that new and innovative therapies be evaluated with cancer patients. Areas of active exploration to improve the treatment of malignant 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.12
Alimta® and Platinol®: Development of the chemotherapy drug Alimta® has constituted a major step forward in the treatment of mesothelioma. Alimta® 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% of patients responded to treatment.13
The combination of Alimta® and Platinol® has emerged as one of 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.14 On average, 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 improved average survival and time to cancer progression even further.
Ranpirnase: Ranpirnase (Onconase®), a ribonuclease, is a novel therapeutic agent that is entering the final phases of clinical trials prior to FDA approval for the treatment of malignant mesothelioma.24 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.24 Out of the 81 patients involved in this study, 35 patients experienced a stabilization of their cancer and 6 patients had a regression of their cancer. Forty-two percent of patients survived one year or more and 27% lived two years or more from the initiation of treatment. 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.
8 Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122:788-95.
10 Ahamad A, stevens CW, Smythe WR, et al. Promising Early Local Control of Malignant Pleural Mesothelioma Following Postoperative Intensity Modulated Radiotherapy (IMRT) to the Chest. Cancer J 2003;9:476-484.
11 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.
13 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.
14 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.
15 Gralla RJ, Hollen PJ, Liepa AM, et al. Improving quality of life in patients with malignant pleural mesothelioma: Results of the randomized Alimta + Platinol vs. Platinol trial using the LCSS-meso instrument. Proc Amer Soc Clin Oncol 39; 2003, Abstract # 2496.
16 Paoletti P, Pistolesi M, Rusthoven JJ, et al. Correlation of pulmonary function tests with best tumor response status: Results from the phase III study of Alimta + Platinol vs. Platinol in malignant pleural mesothelioma. Proc Amer Soc Clin Oncol 39; 2003, Abstract #265.
17 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.
18 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.
19 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.
23 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.
24 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.