MALIGNANT PLEURAL MESOTHELIOMA

Introduction

Prognosis in this disease is difficult to assess consistently because there is great variability in the time before diagnosis and the rate of disease progression. In large studies of pleural mesothelioma patients, important prognostic factors were found to be stage, age, performance status, and histology. Histology means the specific type of mesothelioma cancer cells that are found. Various surgical procedures may be possible in selected patients. They typically provide long-term survival without cure. For patients treated with aggressive surgical approaches, factors associated with improved long-term survival include epithelial histology, no cancer found in the lymph nodes, and negative surgical margins. That means that the surgeons were able to remove all of the cancer, as far as they can tell, and there is a margin of healthy tissue around the tumor that they removed. For those patients treated with aggressive surgical approaches, nodal status is an important prognostic factor. In other words, if you had cancer in your lymph nodes your prognosis is worse than if no cancer was found in the nodes.

Median survival has been reported as 16 months from date of diagnosis for patients with malignant pleural disease confined to the pleura, and 5 months from date of diagnosis for patients with extensive disease. In some instances the tumor grows through the diaphragm making the site of origin difficult to assess. The diaphragm is the thin muscle that separates the lungs from the abdomen. The diaphragm helps you breathe. Cautious interpretation of treatment results with this disease is important because of the selection differences among series. Patient selection can influence the outcomes of clinic trials. Effusions, both pleural and peritoneal, represent major symptomatic problems for at least two-thirds of patients (the National Cancer Institute has a statement on Cardiopulmonary Syndromes for more information on this subject).

Cellular Classification

Histologically (by cell type), these tumors are composed of fibrous or epithelial elements or both. The epithelial form occasionally causes confusion with peripheral anaplastic lung carcinomas or metastatic carcinomas (cancers that had spread from somewhere else). Attempts at diagnosis by removing effusions and looking for cancer cells, or by needle biopsy of the pleura are often unsuccessful. It can be especially difficult to differentiate mesothelioma from adenocarcinoma on small tissue specimens. Thoracoscopy can be helpful in obtaining enough tissue for diagnostic purposes. Thoracoscopy is the examination of the inside of the chest using a thoracoscope. A thoracoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue to be checked under a microscope for signs of disease.) Examination of the gross tumor (visible by eye) at surgery, and use of special stains or using an electron microscope by the pathologist can often help. The special stains reported to be most useful include periodic acid-Schiff diastase, hyaluronic acid, mucicarmine, CEA, and Leu M1. Histologic appearance (the appearance of the cell under the microscope) seems to be of prognostic value, and most clinical studies show that patients with epithelial mesotheliomas have a better prognosis than those with sarcomatous or mixed histology mesotheliomas.

Staging

Patients with stage I disease have a significantly better prognosis than those with more advanced stages. Because of the relative rarity of this disease, exact survival information based upon stage is limited. A proposed staging system based upon thoracic surgery principles and clinical data is shown below. It is a modification of an older system. Other staging systems that have been employed include the current international TNM staging system.

Stage I: Disease confined within the capsule of the parietal pleura (i.e., ipsilateral (on the same side) pleura, lung, pericardium, and diaphragm).

Stage II: All of stage I with positive intrathoracic (N1 or N2) lymph nodes.

Stage III: Local extension of disease into the following areas, e.g., chest wall or mediastinum, heart or through the diaphragm or peritoneum, with or without extrathoracic (outside of the thorax) or contralateral (on the opposite side of) (N3) lymph node involvement.

Stage IV: Distant metastatic disease, meaning spread of the cancer to distant sites.

These stages are then put into two groups: Localized malignant mesothelioma, which is defined as stage I described above; and advanced malignant mesothelioma which includes stages II, III, and IV above. In practice, mesothelioma is generally categorized as either localized or advanced and the stage numbers like stage II or III are not used.

Treatment Option Overview

Standard treatment for all but localized mesothelioma is generally not curative. Although some patients will experience long-term survival with aggressive treatment approaches, it remains unclear if overall survival has been significantly altered by the different treatment modalities or by combinations of modalities. Surgery and chemotherapy are examples of different treatment modalities. Extrapleural pneumonectomy in selected patients with early stage disease may improve recurrence-free survival, but its impact on overall survival is unknown. Extrapleural pneumonectomy is surgery to remove a diseased lung, part of the pericardium (membrane covering the heart), part of the diaphragm (muscle between the lungs and the abdomen), and part of the parietal pleura (membrane lining the chest). Pleurectomy (removing the pleura) and decortication (removal of part or all of the external surface of an organ) can provide relief from symptomatic effusions, discomfort caused by tumor burden, and pain caused by invasive tumor. Operative mortality from pleurectomy/decortication is less than 2%, while mortality from extrapleural pneumonectomy has ranged from 6% to 30%. Given the high mortality rate from a pneumonectomy, it is important to find a surgeon who has significant experience in doing such an operation. See our list of mesothelioma specialists to find experienced surgeons (http://www.mesorfa.org/specialist.htm).

The addition of radiation therapy and/or chemotherapy following surgical intervention has not demonstrated improved survival. The use of radiation therapy in pleural mesothelioma has been shown to alleviate pain in the majority of patients treated; however, the duration of symptom control is short-lived. Single-agent and combination chemotherapy have been evaluated in single and combined modality studies. The most studied agent is doxorubicin, which has produced partial responses in approximately 15% to 20% of patients studied. Some combination chemotherapy regimens have been reported to have higher response rates in small phase II trials; however, the toxic effects reported are also higher, and there is no evidence that combination regimens result in longer survival or longer control of symptoms. Recurrent pleural effusions may be treated with pleural sclerosing procedures. However, the efficacy of these procedures depends on the bulk of the tumor. If the tumor is too large they may not be helpful.

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Localized Malignant Mesothelioma (Stage I)

Standard treatment options:

1. Solitary mesotheliomas: Surgical resection en bloc (as a whole, or in one large piece) including contiguous structures to ensure wide disease-free margins. Sessile polypoid lesions (tumors sticking up from the pleura) should be treated with surgical resection to maximize the potential for cure.

2. Intracavitary mesothelioma:

  • Palliative surgery (i.e., pleurectomy and decortication) with or without postoperative radiation therapy. Palliation means treatment to lessen side effects rather than treatment to try to cure the patient.
  • Extrapleural pneumonectomy (removing the affected lung)
  • Palliative radiation therapy. Palliation means treatment to lessen side effects rather than treatment to try to cure the patient.

Treatment options under clinical evaluation:

1. Intracavitary chemotherapy (putting chemotherapy directly into the space around the lungs) following surgery to remove the cancer.

2. Multimodality therapy (using more than one mode of treatment).

3. Other clinical trials. See our clinical trials page for more information (http://www.mesorfa.org/clinicalTrials.htm).

Treatment for Advanced Malignant Mesothelioma (Stages II, III, and IV)

Standard treatment options:

  1. Treatment of symptoms including drainage of effusions, chest tube pleurodesis, or thoracoscopic pleurodesis. Pleurodesis is a medical procedure that uses chemicals or drugs to cause inflammation and adhesion between the layers of the pleura (the tissue that covers the lungs and lines the interior wall of the chest cavity). This prevents the buildup of fluid in the pleural cavity. It is used as a treatment for severe pleural effusion.
  2. Palliative surgical resection in selected patients. Palliation means treatment to lessen side effects rather than treatment to try to cure the patient.
  3. Palliative radiation therapy.
  4. Single-agent chemotherapy. Partial responses have been reported with doxorubicin, epirubicin, mitomycin, cyclophosphamide, cisplatin, carboplatin, and ifosfamide.
  5. Combination chemotherapy (under clinical evaluation). Information about ongoing clinical trials is available from our clinical trials page (http://www.mesorfa.org/clinicalTrials.htm).
  6. Multimodality clinical trials.
  7. Intracavitary therapy. Intrapleural administration of chemotherapeutic agents (e.g., cisplatin, mitomycin, and cytarabine) has been reported to produce transient reduction in the size of tumor masses and temporary control of effusions in small clinical studies. Additional studies are needed to define the role of intracavitary therapy.

Treatment of Recurrent Malignant Mesothelioma

Treatment of recurrent mesothelioma uses procedures and/or agents (drugs) not previously employed in the initial treatment attempt. No standard treatment approaches have been proven to improve survival or control symptoms for a prolonged period of time. These patients should be considered candidates for phase I and II clinical trials evaluating new biologicals , chemotherapeutic agents, or physical approaches (new surgeries or radiation therapy approaches.) Biological therapies use the body's immune system to fight cancer or to lessen the side effects that may be caused by some cancer treatments. Information about ongoing clinical trials is available from our clinical trials page (http://www.mesorfa.org/clinicalTrials.htm) or at the NCI clinical trials web site.

New treatments for malignant peritoneal mesothelioma

Because malignant peritoneal mesothelioma is hard to control, the National Cancer Institute is sponsoring 14 clinical trials (research studies with people) that are designed to find new treatments and better ways to use current treatments. Before any new treatment can be recommended for general use, doctors conduct clinical trials to find out whether the treatment is safe for patients and effective against the disease. Clinical trials are an important treatment option for many patients with pleural mesothelioma.

One example of a new approach is a drug called Veglin being studied by Dr. Gill at the USC/Norris Comprehensive Cancer Center. Veglin is one of several newly developed non-chemotherapy drugs being tested in the ongoing struggle to combat malignant mesothelioma. It is an anti-angiogenesis agent that works by cutting off the blood supply the cancer needs in order to grow. A phase I trial has already been completed and a phase II trial is underway. More information on Veglin and the trial can be found at http://www.mesorfa.org/treatments/veglin.php . Patients interested in taking part in a clinical trial should talk with their doctor.

The safety and efficacy of pemetrexed and cisplatin in chemotherapy-naive patients (patients who have never had chemo) with malignant mesothelioma who were not eligible for curative surgery was demonstrated in a large phase III randomized trial. This trial compared pemetrexed (500 mg/m2) and cisplatin (75 mg/m2 on day 1) with cisplatin alone (75 mg/m2 on day 1 intravenously every 21 days). With a total of 456 enrolled patients in the trial, 226 patients received pemetrexed plus cisplatin, 222 patients received cisplatin alone, and 8 patients did not receive therapy. After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxic effects. Folic acid (350-1,000 µg orally) was given daily, beginning 1 to 3 weeks before the first chemotherapy dose and continuing daily until 1 to 3 weeks after treatment ended. A vitamin B12 injection (1,000 µg intramuscularly) was administered 1 to 3 weeks before the first chemotherapy dose and was repeated approximately every 9 weeks until treatment ended. Dexamethasone (4 mg) or an equivalent corticosteroid was administered orally twice daily for skin rash prophylaxis (prevention) to all patients 1 day before, on the day of, and 1 day after each pemetrexed dose.

In an analysis of all patients who were randomized and treated, the combination of pemetrexed and cisplatin was associated with a statistically significant improvement in survival compared with cisplatin alone; the median survivals were 12.1 versus 9.3 months, respectively. Median time-to-progression was significantly longer in the pemetrexed plus cisplatin arm (5.7 months vs. 3.9 months). This superiority in the combination arm was also demonstrated in the vitamin-supplemented subgroup. The median survivals were 13.3 and 10.0 months in the combination group and cisplatin alone group, respectively. The principal adverse effects of the pemetrexed plus cisplatin regimen were myelosuppression, fatigue, nausea, vomiting, and dyspnea (difficulty breathing). Most adverse effects were significantly reduced by vitamin supplementation without any decrease in efficacy of the treatment.

Information about Veglin and other clinical trials is also available by speaking to a Cancer Information Specialist from the Mesothelioma Research Foundation of America at: 800 909-MESO (6376).

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Useful medical journal article references for malignant peritoneal mesothelioma

Search PubMed http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed to find additional articles that apply to your situation. Most will have an abstract, which is a brief description of the article. Many articles have a link to the full text of the article. You can also see the full text at a medical library assuming they have the particular journal you are looking for. The articles below are review articles that have full text and are free to read, unlike many medical journal articles.

1. Steele JP, Klabatsa A.
Chemotherapy options and new advances in malignant pleural mesothelioma.
Ann Oncol. 2005 Mar;16(3):345-51. Epub 2005 Jan 27. Review.
PMID: 15677623

2: Pistolesi M, Rusthoven J.
Malignant pleural mesothelioma: update, current management, and newer therapeutic strategies.
Chest. 2004 Oct;126(4):1318-29. Review.
PMID: 15486399

3: Hazarika M, White RM, Johnson JR, Pazdur R.
FDA drug approval summaries: pemetrexed (Alimta).
Oncologist. 2004;9(5):482-8. Review.
PMID: 15477632

4: Sharma A, Fidias P, Hayman LA, Loomis SL, Taber KH, Aquino SL.
Patterns of lymphadenopathy in thoracic malignancies.
Radiographics. 2004 Mar-Apr;24(2):419-34. Review.
PMID: 15026591

5: Wang ZJ, Reddy GP, Gotway MB, Higgins CB, Jablons DM, Ramaswamy M, Hawkins RA, Webb WR.
Malignant pleural mesothelioma: evaluation with CT, MR imaging, and PET.
Radiographics. 2004 Jan-Feb;24(1):105-19. Review.
PMID: 14730040

6: Antony VB.
Immunological mechanisms in pleural disease.
Eur Respir J. 2003 Mar;21(3):539-44. Review.
PMID: 12662014

7: van Ruth S, Baas P, Zoetmulder FA.
Surgical treatment of malignant pleural mesothelioma: a review.
Chest. 2003 Feb;123(2):551-61. Review.
PMID: 12576380

8: Antoniou KM, Ferdoutsis E, Bouros D.
Interferons and their application in the diseases of the lung.
Chest. 2003 Jan;123(1):209-16. Review.
PMID: 12527624

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