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Comprehensive Review of Mesothelioma
Sat, 06/05/2010 - 12:12
Dr Tsao

What is mesothelioma?

Mesothelioma is a unique cancer that starts from the mesothelium, the membrane lining that contains the body cavities. Mesothelioma can arise from the pleura (lining of the lungs), pericardium (sac around the heart), peritoneum (abdominal lining), and tunica vaginalis testis (lining of the male reproductive organs). The majority of mesothelioma cases originate from the pleura.

Epidemiology and Cause of Mesothelioma

Mesothelioma occurs everywhere in the world. In the United States, it is estimated that ~3000 new cases of mesothelioma occur each year. Western Europe has over 5000 new cases/year and China estimates 4000 new cases/year.

The main cause of mesothelioma is environmental and well-established; patients have often been exposed to asbestos fibers in their work or living area. Asbestos is a long thin silicate mineral and has been linked not only to mesothelioma but also to pneumoconiosis and lung cancer. Asbestos was a popular material used in insulation and construction because it had desirable properties of heat/fire and chemical resistance. The fibers are hazardous when they become airborne and are inhaled or swallowed. There are 2 main classes of asbestos: serpentine and amphibole. Serpentine minerals (chrysotile) account for 95% of the asbestos in buildings in the United States. The amphibole group consists of 5 types of asbestos - amosite, crocidolite, anthophyllite, tremolite, and actinolite. Amosite is called the brown asbestos and is found in building materials. The types of asbestos that are most carcinogenic are amosite and crocidolite. However, chrysolite also is hazardous and is linked to development of mesothelioma in people.

In more rare instances, there have been reported cases of mesothelioma that occurred from genetic inheritance (Capaddocia region of Turkey) and also potentially from exposure to simian virus 40 (SV40).

Mesothelioma has a long latency period from the time of asbestos exposure - the median time from exposure to development of mesothelioma is 32 years. Most patients develop mesothelioma between 20 to 50 years after their known exposure to asbestos.

Most patients develop mesothelioma between ages 40 to 80. As asbestos was primarily used in construction, military and manufacturing materials, there is a higher incidence of mesothelioma in men than women (3:1).

Screening and Prevention

There are currently no standardized screening tests in use. However, 2 blood tests are under investigation. Osteopontin, a glycoprotein that mediates cell matrix interactions, is elevated in mesothelioma patients' serum compared to asbestos miners who do not have the cancer. Soluble mesothelin related peptide (SMRP) assay is further along than osteopontin and may be able to identify patients who have disease recurrence of mesothelioma after surgery.

There are currently no chemoprevention agents available for mesothelioma.

Types of Pleural Mesothelioma

It is critical to make the correct diagnosis of mesothelioma as soon as possible in patients. Mesothelioma can often been mistaken for other cancer types or even benign conditions.

Many patients have symptoms of shortness of breath and cough and chest x-rays show fluid accumulation, called pleural effusions. Often, the fluid recurs even after drainage and evaluation of the fluid often does not show cancer cells and is mistaken for a benign condition. Or the fluid contains cancer cells and is confused with another cancer diagnosis of adenocarcinoma. If a patient has a potential diagnosis of mesothelioma, it is critical to be evaluated at a cancer center that treats mesothelioma patients and has the expertise to make the right diagnosis.

There are certain pathology techniques that can be done to aid in making the right diagnosis: electron microscopy and immunohistochemical markers. Immunohistochemistry uses antibodies to bind to specific proteins in the tissue. Some of the specific markers that are positive in mesothelioma are cytokeratin 5/6, calretinin, and WT-1. Mesothelioma is usually negative for CEA, Leu-M1, and TTF-1.

There are three main histologic types of mesothelioma: epitheliod, biphasic, and sarcomatoid.

The most common type is epitheliod occurs in 60-75% of cases. Biphasic occurs in 15-20% and sarcomatoid arises in 10-15% of cases. Epitheliod tumors generally have the best prognosis while sarcomatoid tumors are believed to be more aggressive. Biphasic phenotypes have characteristics of both epitheliod and sarcomatoid tumors.

Diagnostic Tests

The usual symptoms of mesothelioma include shortness of breath, cough, weight loss, loss of appetite, and fever. These symptoms are often found in other conditions and can impede making the correct diagnosis of mesothelioma. For example, recurrent pleural effusions (fluid in the pleural space) occur in benign conditions of congestive heart failure and pneumonia.

Part of the diagnostic work up for mesothelioma may include the following:

- Review of the medical history with a focus on prior asbestos exposure and occupational hazards

- Physical exam

- Chest x-ray

- Chest Computed axial tomography (CT) scan

- Positron emission tomography (PET-CT)

- Magnetic resonance imaging (MRI)

- Biopsy of tumor tissue (may include a needle biopsy or drainage of the pleural fluid)

- Thoracoscopic surgery for a biopsy

- Mediastinoscopy (biopsy of the lymph nodes in the chest)

- Laparoscopy (evaluates the abdominal cavity for transdiaphragmatic spread of mesothelioma)

- Pathologic review of tumor cells for cytology or biopsy

Staging Pleural Mesothelioma

There have been several staging systems previously used for mesothelioma. Staging is critical to determine a patient's treatment plan. The stage is determined by the radiographic images and potentially also by the surgical biopsies and evaluation of the mediastinal lymph nodes and the abdominal cavity.

The most common staging system used is from the International Mesothelioma Interest Group (IMIG) for American Joint Committee on Cancer (AJCC). This system uses the TNM (tumor, node, metastases) classification.

Stages of pleural mesothelioma

Stage 1a: Tumor involves the outermost layer of pleura (parietal pleura) but does not involve the pleura covering the lung (visceral pleura).

Stage 1b: Tumor involves the parietal as well as the visceral pleura.

Stage 2: Tumor invades into the lung or diaphragm (the thin muscle that separates the chest from the abdomen).

Stage 3: Tumor invades into the fibrous sac around the heart (pericardium), into the chest wall (in one area only) or involves the lymph glands within the chest.

Stage 4: Tumor involves multiple areas of the chest wall, extends across the diaphragm or through the pericardium, involves other organs such as the heart, windpipe or esophagus, or has spread to other organs such as the liver or opposite lung.

Types of Surgical Intervention

There are diagnostic, palliative, and definitive surgical procedures.

Diagnostic procedures:

Patients will often require a thoracic surgeon to aid in making the diagnoses of mesothelioma. Some of the procedures to both make the diagnosis and stage the patient include the following:

- Thoracentesis (needle drainage of pleural fluid)

- Core needle biopsy (larger gauge needle biopsy of the tumor)

- Video-assisted thoracoscopy (VATS) - surgery on the chest to biopsy the tumor

- Mediastinoscopy - biopsy of the lymph nodes in the center of the chest

- Endobronchial ultrasound (EBUS) guided biopsy - another method to sample biopsy the lymph nodes in the center of the chest

- Laparoscopy - operation using small cameras through tiny (0.5 - 1.5 cm) incisions in the abdomen, used to evaluate for any spread of cancer into the abdomen

Palliative Procedures:

In patients who cannot receive complete removal of the mesothelioma pleural tumor, fluid re-accumulation is a problem and leads to symptoms of shortness of breath and pain. Some of the procedures that can be done include the following:

- Placement of an indwelling chest tube or Denver catheter which allows repeated drainage of the pleural fluid

- Pleurodesis, injection of a material (often talc) into the pleural space and obliterates the cavity and prevents further fluid from accumulating.

Definitive surgical procedures:

As pleural mesothelioma is a large tumor that wraps around the lung, it is extremely difficult to remove surgically. Patients with mesothelioma should seek surgical opinions by thoracic surgeons who are trained to treat mesothelioma and have experience performing these surgeries. There are 2 main types of surgery to remove the gross tumor. It has been debated whether these procedures are curative in nature but there have been long-term survivors who have received these types of surgeries. There are several criteria beyond stage that determine whether a mesothelioma patient is a candidate for definitive surgery.

- Pleurectomy/decortication (P/D) - requires an open thoracotomy with removal of the parietal pleura, pleura over the mediastinum, pericardium, and diaphragm, and also the visceral pleura. Often, this surgery type leaves behind tumor tissue and is considered a palliative rather than curative approach. However, recent retrospective studies have shown long-term mesothelioma survivors who received P/D.

- Extrapleural pneumonectomy (EPP) - removes en bloc the parietal and visceral pleura, involved lung, mediastinal lymph nodes, diaphragm, and pericardium. The diaphragm and pericardium are then reconstructed. This surgical procedure carries significant risk with a high rate of cardiac and pulmonary complications. The 30-day mortality rate ranges between 3.4 to 8% in experienced cancer centers. In inexperienced hands, the mortality rate is rated higher around 18 to 20%. Patient selection for this type of surgery requires careful analyses and a thorough cardiopulmonary evaluation.

Types of Radiation

After surgery, radiation therapy is required to eliminate any potential microscopic disease. There are 2 main types of radiation therapy that can be administered in mesothelioma to the hemithorax: external beam and intensity-modulated radiotherapy (IMRT). Patients who have had an EPP require the full hemithorax irradiation between 4 - 8 weeks after surgery. The use of radiation after P/D or chest biopsies remain controversial. The reason for this is that patients who have had a P/D still have their lung intact and the amount of radiation that can be administered to the chest in the presence of the lung is limited. Often, radiation oncologists will limit the radiotherapy to high risk areas such as the sites where a chest wall incision was made. These sites are at high risk for tumor seeding and tracking thru the chest wall with painful results.

meso-rt (click on image to enlarge)

Types of Systemic therapy for Pleural Mesothelioma

Mesothelioma is not cured by chemotherapy but it can be stabilized for a period of time and in some cases, the tumor can be responsive to the chemotherapy or targeted agent. Historically, the most effective chemotherapies used have been given in combination. The ones most commonly used today include: platinum agents (cisplatin, carboplatin), pemetrexed (Alimta), gemcitabine (Gemzar), and vinorelbine (Navelbine). In the past, older chemotherapies used included doxorubicin, mitomycin, cyclophosphamide, and ifosfamide.

For resectable disease:

Neoadjuvant (before surgery) chemotherapy has been investigated in several clinical trials. These trials have used platinum doublets with either gemcitabine or pemetrexed. Response rates (defined as tumor shrinkage) between 26 to 33% have been reported. However, the median survival for all patients with neoadjuvant chemotherapy, surgery, and radiation still remains low at ~17 months. In the subgroup analysis from the largest of these clinical trials, the median survival in patient who had a response to neoadjuvant chemotherapy was higher at 23 months. This indicates that finding more effective systemic therapies can improve survival for mesothelioma patients.

There are ongoing clinical trials for patients with resectable mesothelioma that bring in novel oral targeted agents (see below) in addition to the surgery, chemotherapy and radiation. Patients with mesothelioma are encouraged to participate in clinical trials.

For unresectable disease:

The current standard front-line chemotherapy regimen in the United States is cisplatin-pemetrexed (cisplatin 75 mg/m2 and pemetrexed 500 mg/m2). This chemotherapy regimen is given with vitamin supplementation (vitamin B12 and folic acid) and improves the median survival for mesothelioma patients to 1 year. The main side effects experienced with this regimen are neutropenia (low white count), anemia (low red blood cells), nausea, vomiting, fatigue, and stromatitis/rash. At times, carboplatin (another platinum agent) can be substituted for cisplatin if a patient has allergies or intolerance to cisplatin. Several clinical trials are currently underway that combine novel targeted agents with platinum-pemetrexed.

When a patient's mesothelioma develops progression or is refractory to platinum-pemetrexed, the next step would be to switch agents. There is currently no established standard of care for the next treatment regimen. Medical oncologists may consider treatment with single agent gemcitabine, vinorelbine or pemetrexed (if the patient did not receive pemetrexed in the frontline setting). Clinical trials in this setting are highly encouraged.

Novel agents and clinical trials

There are several classes of novel targeted agents under investigation. One class targets the angiogenesis pathway. Angiogenesis is the formation of new blood vessels and therefore, targeting the angiogenesis pathway potentially starves the tumor. There are several agents under active investigation. To determine if you are a candidate for a clinical trial, consult with your medical oncologist.

List of novel agents under investigation:

Bevacizumab - a monoclonal antibody that targets vascular endothelial growth factor (VEGF). This is given intravenously and is combined with other chemotherapy agents, usually every 3 weeks. Mesothelioma has the highest expression levels of VEGF of the solid tumors. Bevacizumab is FDA approved for non-small cell lung cancer, breast cancer, colorectal cancer, gastrointestinal cancer, and glioblastoma.

Cediranib - an oral VEGF receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) inhibitor. This is taken every day. Clinical trials are underway combining this agent with chemotherapy or by itself.

Sorafenib - an oral VEGFR, PDGFR, Raf inhibitor. Sorafenib is FDA approved for use in renal and hepatocellular cancer.

Sunitinib - an oral VEGFR, PDGFR, KIT inhibitor. Sunitinib is FDA approved for use in renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor (GIST).

Imatinib mesylate - an oral bcr-abl, KIT, and PDGFR inhibitor. Imatinib is FDA approved for use in CML and GIST.

Dastinib - a multitargeted inhibitor of Src kinase, PDGFR, ephrin kinases, KIT is FDA approved for use in imatinib-refractory CML.

Pazopanib - a VEGFR, PDGFR, and KIT inhibitor.

Vatalanib - a VEGFR, PDGFR and KIT inhibitor.

Other agents under investigation:

Vorinostat - a histone deactylase inhibitor. Vorinostat is FDA approved for use in T-cell lymphoma. A large phase III trial is underway evaluating vorinostat in the second- and third-line setting.

Everolimus - a mTor inhibitor. Everolimus is used as an immunosuppressant to prevent organ transplant rejection.

Bortezomib - a proteosome inhibitor. Bortezomib is FDA approved for use in multiple myeloma and mantle cell lymphoma.

Gene therapy (IFN-b HSV-thymidine kinase adenoviral vectors) - injected directly into the pleural space.

Anti-mesothelin antibodies (SS-1) - mesothelin is a protein present on mesothelial cells and is overexpressed on mesothelioma tumors. SS-1 targets mesothelin.

Additional Reading for details

Pass et al. NEJM 353:1564-1473
Robinson et al. Lancet 362:1612-1616
Rice et al. Annals of Thoracic Surgery 80: 1988-1992, 2005
Rusch et al. Chest 108: 1122-1128, 1995
Rusch et al. JCO 12: 1156-1163, 1994
Sugarbaker et al. Journal of Thoracic and Cardiovascular Surgery 128: 138-146, 2004
Ahamed et al. The Cancer Journal 9:476-484, 2003
Krug et al. JCO 27: 3007-3013, 2009
Tsao et al. JCO 27:2081-2090, 2009
Vogelzang et al. JCO 21:2636-2644, 2003

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