Broaddus-Robinson
V. Courtney Broaddus, M.D. and Bruce W. S. Robinson, M.D.
Incidence and etiology
Genetic characteristics
Clinical features
Radiographic evaluation
Diagnosis
Pathologic features
Prognosis and staging
Therapy and palliation:
- Surgical therapy
- Chemotherapy
- Radiation therapy
- Immunotherapy
- Gene therapy
- Palliative therapy
- Chemoprevention & Screening
Malignant pleural mesothelioma is uncommon but can no longer be considered rare with almost 3000 cases per year diagnosed in the United States alone. The number of cases is anticipated to continue to increase in the United States and Western Europe until approximately 2020 1 due to the increase in occupational exposures to asbestos and asbestos containing products that occurred after World War II. During the heyday of excitement about asbestos, asbestos was viewed as a modern innovation and was even used in such products as toothpaste 2 and cigarette filters! 3 Unfortunately, after extensive use in industry and in building materials, asbestos fibers were discovered to be harmful. It appears that their mechanisms of action are multiple.4 (see below)
After 2020, the number of cases is anticipated to plateau and then gradually decline in these countries due to the reduction in occupational exposures caused by restrictions on asbestos use, worker protection, and asbestos abatement efforts that were instituted from the mid 1970s to 1990s; nonetheless, many individuals will continue to be exposed incidentally e.g. while performing home renovations. In those industrialized countries where the control of asbestos was delayed by several decades, as in Japan, the ‘epidemic’ of mesothelioma will also be delayed by several decades. Unfortunately, asbestos continues to be mined, and its use is actually increasing in many developing countries. 5 Of Asian countries, only Japan and Singapore have adopted a ban on asbestos.6 As a consequence, the incidence of malignant mesothelioma in these countries is expected to reach high levels in the future. Asbestos-induced lung cancer will also increase in those countries because of the multiplicative effects of asbestos inhalation (including chrysotile) and cigarette smoking. 7
Those with significant asbestos exposure and increased rates of mesotheliomas include: workers in the asbestos industry, insulators, pipefitters, shipyard workers, brake mechanics, railroad workers, construction trades, carpenters plumbers, electricians, painters, non-asbestos miners, welders, machinists, manufactures of mineral products, and workers who perform maintenance and repair in buildings with asbestos insulation.8 In addition, it is not uncommon to see women with asbestos-induced mesothelioma whose only clear asbestos exposure was from exposure to their spouses’ contaminated clothing. Children who have been incidentally exposed can develop mesothelioma in early adult life. Incidence may rise due to recent population exposures such as from the dust that settled after the collapse of the World Trade Center. 9 In addition, recent use of nanoparticles and nanotubes raises concerns for unforeseen toxic effects analogous to those of asbestos. 10
Other causes of mesothelioma have been postulated. Recently, there has been a great deal of controversy as to whether a simian virus (SV40) that contaminated the polio vaccine administered from 1955 through 1961 may be contributing to the development of mesotheliomas in the United States and other countries. SV40 is an intriguing candidate because it can immortalize cells by binding and inactivating both the retinoblastoma (Rb) protein and p53, key control steps for proliferation and apoptosis, respectively. In a review of 15 studies, mesothelioma tissues were 17 times more likely to have evidence of SV40 compared to control tissues.11 In cell and animal studies, SV40 may cooperate with asbestos in inducing damage and generating mesothelioma. 12 However, in humans, a causal relationship has not been established and epidemiological studies to date have not shown an increase in the incidence of mesotheliomas in populations exposed to this virus 13, 14. Further complicating the analysis is the recognition that the presence of SV40 DNA sequences alone does not prove its role in tumor development. Viral proteins must be expressed and impair the function of cell proteins necessary for normal cell function. At this time, SV40 is still a subject of intense discussion, more as a possible co-carcinogen with asbestos than as a primary cause of mesothelioma. See arguments addressing the evidence for 15 and against 16SV40 as a cause of mesothelioma.
Cigarette smoking is not associated with an increased incidence of mesotheliomas. 17 Silica or man-made vitreous fibers (rock/slag wool and fiberglass) have not been found to be associated with occupational mesotheliomas. 18, 19 Excess cases of mesotheliomas have been identified in oil refinery workers; this risk was once thought to be due to exposure to petroleum oil and its products, but is now attributed to occupational asbestos exposure. 20 Ionizing radiation may be a cause as well with a small increased risk in patients exposed to the contrast medium Thorotrast, to radiation therapy and to low level radiation as atomic energy workers. 21
Environmental asbestos exposures have been associated with the development of mesothelioma. Low dose exposure in large populations may produce only ‘background’ levels of asbestos in lung tissue but, because of the number of individuals exposed in that way, lead to an increase in the number of mesothelioma cases (similar to widespread exposure to sunlight and melanoma development). Studies of household contacts of asbestos workers who develop mesothelioma have shown that these patients often have pulmonary asbestos concentrations similar to occupationally exposed individuals.22 Exposure of occupants in buildings with asbestos-containing materials is generally not associated with increased asbestos fiber burden in the lung or an increase in mesothelioma incidence. In Turkey, an extraordinarily high incidence of mesothelioma is found in certain villages in central Turkey with exposure to erionite dust, a non-asbestos crystalline fibrous form of the mineral zeolite. Finally, chronic inflammation of the pleura as in familial Mediterranean fever has been postulated to cause mesothelioma. At least four cases of mesothelioma have been reported in patients with this disease, presumedly due to recurrent serositis. 23 Asbestos may still be an underlying cause or contributing factor in patients without a clear occupational exposure given that fiber burden studies suggest that most urban dwellers have some asbestos fibers in their lungs. 24
Although millions of workers have been exposed to significant amounts of asbestos, only a few develop mesothelioma making it likely that there are genetic factors that increase susceptibility. Supporting the notion of genetic susceptibility is the identification of multiple clusters of this disease in families 25, although clusters may also be explained by common environmental exposure to asbestos. Nonetheless, in the Cappadocian region of Turkey, where exposure to erionite is widespread, the susceptibility to mesothelioma appears to be inherited in an autosomal dominant pattern. 26
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Mesothelioma is characterized by a high degree of aneuploidy, but there is no one oncogene or tumor suppressor gene that has yet been found to underly the tumor. The tumor suppressor genes most frequently implicated in mesothelioma are p16INK4A-p14ARF(9p21) and the neurofibromatosis type 2 (NF2) gene (22q12).27 p53, a tumor suppressor mutated in most lung cancers and other solid tumors, is not frequently mutated in mesothelioma. 28 Nonetheless, abnormalities in the pathway that controls p53 function may still be present. Kras, a protooncogene frequently activated in lung cancer, is also not found to be abnormal in mesothelioma. 29 Studies of cytogenetics and loss of heterozygosity show consistent losses of chromosomal regions suggesting that these regions may contain genes for key tumor suppressors. Losses are consistently found in regions 1p, 3p, 6q, 9p, 13q, 15q and 22q. Oncogenes or growth promoting genes suspected to play a role in mesothelioma include those coding for c-myc and for growth factors or growth factor receptors (e.g. platelet derived growth factor, epidermal growth factor receptor). Gene expression profiling may provide additional insights into genetic abnormalities critical for mesothelioma and, in so doing, may also provide prognostic information, help with diagnosis, guide therapy and suggest future therapeutic approaches. 30, 31
The long latency period between exposure to asbestos and development of mesothelioma suggests that multiple genetic abnormalities are required. Unlike the situation for bronchogenic carcinoma where the natural history can be studied by repeatedly accessing the bronchial epithelium, the pleural space is not easily sampled, making the natural history of mesothelioma more opaque. From cell and animal studies, it appears that asbestos can injure the chromosomes both by generating reactive oxygen species that damage DNA and by mechanical breakage of chromosomes. 32 Due to their long thin shape, asbestos fibers are inhaled deep into the lung and translocate from the lung to the pleural space and accumulate at the parietal pleura, where they can interact with mesothelial cells over decades. Along the way, the fibers are ingested by macrophages, inducing a chronic inflammation. The fibers may also be internalized by mesothelial cells where they can both interfere with chromosome segregation leading to chromosome damage and generate reactive oxygen species via their iron content leading to oxidant injury to DNA.33 In the process, the cells develop unregulated proliferation and an increased resistance to apoptosis.34 The combination of chronic inflammation, chromosomal and DNA damage may explain their potent carcinogenic effect. Loss of key genetic areas containing tumor suppressors may be critical steps in generating mesothelioma. If SV40 contributes to this process, it may be by binding and inactivating key regulators of cell growth and survival, Rb and p53 proteins.
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The mean age at presentation is 60 years because of the long latency (usually 30 to 40 years) from the time of first exposure to asbestos to the development of clinically evident disease. 1 The incidence is higher in men, presumably because more men have worked in asbestos-related trades.
Symptoms and physical findings are generally not specific for the disease. Most patients present with non-pleuritic chest pain or dyspnea. 35 Compared to that of metastatic pleural diseases, the pain from mesothelioma can be severe, aching, and often very difficult to control. Less common complaints are cough, fevers, chills, sweats, and fatigue. Fatigue, cachexia and pain are common in advanced disease. Physical examination is usually only remarkable for signs related to the presence of a pleural effusion or mass. Later in the course of disease one can often appreciate volume loss and decreased mobility of the chest wall on the side of the primary tumor. Occasionally, the tumor may extend directly into the chest wall, and be detected as a tender or non-tender chest wall mass.
Laboratory findings are also nonspecific, and include anemia and thrombocytosis. Thrombocytosis (platelets > 400,000/mm3) can be seen in 40% of patients, may be due to production by the tumor of interleukin-6 and augurs a poor prognosis 36, 37 Measurement of mesothelin-family proteins in serum shows future promise for the diagnosis of mesothelioma and for monitoring of disease progression 38.
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Figure 1 - Axial thoracic CT scan shows diffuse right pleural thickening (arrows) associated with marked volume loss in the right thorax. Note the presence of mediastinal pleural involvement (arrowhead).
The most common findings on chest radiograph are a moderate to large unilateral pleural effusion or unilateral pleural thickening (nodular or smooth) 35 (Figure 1). In a study of 99 patients with malignant mesothelioma, the most common finding on computed tomography (CT) was a rind-like extension of tumor on the pleural surfaces (70%) 39.
Other findings included: circumferential lung encasement by multiple nodules (28%), pleural thickening with an irregular margin between the lung and pleura (26%), and pleural thickening with pleural-based nodules (20%). Invasion of soft tissues and the chest wall with rib destruction may also be seen.
Figure 2 - MRI of the same patient as in Figure 2 with malignant mesothelioma showing invasion across the diaphragm by tumor. (see arrow)
As the disease progresses and the lung becomes more encased with tumor there is often volume loss with a shift of the mediastinum toward the side of the primary tumor (see Figure 1). Signs of lymphatic metastasis may be seen, but are more commonly evident late in the course of disease. Further tumor progression may lead to invasion into the contralateral chest. It is important to note that pleural plaques are often not visible; only 28% have radiographically apparent plaques 40. Large mediastinal lymph nodes are more consistent with metastatic disease than with mesothelioma.
Mediastinal adenopathy on chest radiographs or CT as the initial presentation of mesothelioma has been reported, but is exceedingly rare 41, although PET scanning often identifies active nodes that are normal in size and shape on imaging.42
Figure 3 - Axial CT scan showing mesothelioma of the right chest with effusion and thickened visceral pleura with underlying pulmonary atelectasis (see arrowheads)
Radiographic features that favor the diagnosis of malignant mesothelioma over metastatic pleural disease were found by multivariate analysis to include: rind-like pleural involvement, mediastinal pleural involvement, and pleural thickness more than 1 cm. 39 Some clinicians prefer MRI over CT for staging and preoperative evaluation because, as reported in one study, MRI may demonstrate extent of disease and in particular chest wall and diaphragmatic invasion better than CT. 43 (Figure 2-3) However, this has not yet been shown to confer an important clinical advantage. In an earlier study, Heelan and co-workers also found MRI superior in detection of tissue invasion in these areas, nonetheless, they found no improvement in staging and no alteration in therapy due to its use 44.
Figure 4 - Axial PET scan image indicates high activity in area of thickened pleura, indicating likely involvement by tumor, suggesting at least a T2 lesion by IMIG staging (see arrowheads). The bright central uptake appears to indicate malignant involvement, either of a mediastinal lymph node or mediastinal pleura
Fluorodeoxyglucose positron emission tomography (PET) and particularly PET/CT shows promise as a tool to differentiate benign from malignant disease and as an adjunctive tool for staging (Figure 4-5).
In a comparison of different diagnostic imaging techniques in patients with mesothelioma who then underwent surgery, PET/CT was more accurate than either PET, CT or MRI alone. 45
It is hoped that functional assessment by PET may also be useful for monitoring response to therapy. 46
In patients being considered for an extensive debulking procedure such as extrapleural pneumonectomy, every effort should be made to define the extent of disease, in particular to exclude patients with unsuspected extension beyond the pleura.
Figure 5 - Coronal view of PET also showing high activity of visceral pleura in fissure (see arrow)
A combination of the imaging techniques may be necessary for determining the best approach to the patient 47. Imaging alone may not be sufficient; in patients being evaluated for surgery, even with negative imaging, many patients undergo pre-operative endoscopic ultrasound with biopsy of suspicious nodes or thoracoscopic visualization of the contralateral pleura or peritoneum. (see Surgical Therapy below) 48
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The only serum biomarker that is clinically useful is serum mesothelin which, in the serum, has a high specificity (over 90%) but only a 50% sensitivity for the diagnosis.49 The role of pleural fluid cytology in establishing a diagnosis is controversial, with some groups demonstrating a high level of diagnostic specificity and others demanding tissue histopathology. 50, 51 Patterns of gene expression by microarray in cytological samples may also help with diagnosis.52Mesothelin biomarker levels in pleural fluid are also useful in diagnosis.53
Closed pleural biopsy often misses malignant tissue though it may be improved using CT guidance. In one study in which patients were randomly assigned to closed pleural biopsy or CT-guided biopsy, mesothelioma was diagnosed by closed pleural biopsy with a sensitivity of 55% (6/11) and by CT-guided biopsy with a sensitivity of 88% (8/9); although the difference was not significant because of small numbers, a similar diagnostic advantage of CT-guided biopsy was found for other pleural malignancies.54 With current immunohistochemical stains, mesothelioma can usually, though not always, be differentiated from metastatic adenocarcinoma. It is often harder to differentiate mesothelioma from the benign mesothelial cell hyperplasias that often accompany inflammatory processes in the pleura. In uncertain cases, surgical biopsy is required to establish a definitive diagnosis. A surgical biopsy not only provides larger specimens for immunohistochemistry and electron microscopy, but also provides critical information about the biologic behavior of the tumor. The behavior of mesotheliomas is unique in that they usually start on the parietal pleural surface with multiple colonies of cells that coalesce and spread to the visceral pleura. Distant metastases are generally a very late finding. In contrast, metastatic adenocarcinomas are usually more prominent on the visceral pleural surface and often associated with distant metastasis. Benign inflammation lacks the surface irregularity usually (but not always) seen with malignant disease.
The preferred technique for surgical biopsy is pleuroscopic biopsy. Not only does pleuroscopy have the advantage of obtaining large samples, but also it permits the drainage of effusions and the freeing up of a trapped lung 55. In addition, if the lung is not trapped, talc can be insufflated at the end of the procedure to achieve a pleurodesis. The insertion site of the thoracoscope is an important consideration if tumor debulking is attempted in the future due to the tendency of mesotheliomas to seed biopsy and chest tube sites 50. Misdiagnosis with thoracosopy has rarely been reported and in those cases was thought due to adhesions preventing access to the primary tumor 56. If thoracoscopy cannot be performed due to the absence of at least a small pleural effusion, an incisional biopsy has an equally high diagnostic yield.
Intraoperative talc insufflation has been reported to have a greater than 95% success rate of preventing recurrent pleural effusion in this setting 57. Talc pleurodesis does not apparently interfere with later attempts at surgical debulking. Talc pleurodesis does interfere with any intrapleural therapy that might be considered, as in clinical trials of gene therapy, so this should be considered before pursuing pleurodesis. Talc pleurodesis can also confound interpretation of PET which can show increased activity in areas of talc deposition for long periods of time following pleurodesis. 58 In such cases, PET/CT may be helpful by localizing the increased activity to areas of increased attenuation due to talc. 58Back to index
The dilemma for the pathologist can be in differentiating mesothelioma from metastatic adenocarcinoma or reactive mesothelium. Because of the difficulties in establishing the diagnosis in some cases, an expert panel of pathologists from the United States and Canada was formed. 59 In their statement, they stressed the need for the pathologist to have information about the biologic behavior of the tumor from the radiographic and intraoperative observations. In addition, they stressed the need to obtain larger specimens to permit multiple immunohistochemical stains and electron microscopy. Ultrastructural features seen with electron microscopy that are typical of mesothelioma include cytoplasmic tonofilaments and long, sinuous, branching microvilli. 60 In contrast, the microvilli of adenocarcinomas are relatively short, wide, and straight. For electron microscopy, some biopsy material must be preserved in glutaraldehyde, while formalin-fixed specimens can be analyzed by immunohistochemistry. Although a variety of immunohistochemical stains have been used to differentiate adenocarcinoma of the lung and mesothelioma, none is specific, especially with less well-differentiated tumors. Use of a panel of immunohistochemical stains is recommended, with calretinin and cytokeratin 5/6 (or WT1) (favoring mesothelioma) and CEA and MOC-31 (or B72.3, Ber-EP4, or BG-8) (favoring adenocarcinoma). 61 Sarcomatous and biphasic mesothelioma raise special issues, usually in differentiating from other sarcomatous tumors. 61
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The median survival for patients with malignant mesothelioma is between 4 and 12 months from the time of diagnosis. 62 Regardless of therapy, patients with the epithelial cell type do best and those with the sarcomatous cell type the worst, with mixed or biphasic falling between the two other types. 62 In two separate studies, age, male gender, performance status, leukocytosis, and presence of chest pain were associated with a worse prognosis.63, 64 Pathologic findings of microvessel density and tumor necrosis, which was found to correlate with vessel density, are poor prognostic factors. 65, 66
Table 1 - IMIG Staging System for Malignant Pleural Mesothelioma.
Staging is an issue for those patients in whom surgery is contemplated and continues to be controversial. Prior to the proposal of a TNM-based staging system by the International Mesothelioma Interest Group 67, there had been at least six other systems proposed for staging of mesotheliomas. None of the six was clearly shown to predict survival, including the most widely used Butchart staging system. 68 The TNM-based staging system is organized in a manner similar to the system currently in use for non-small cell carcinoma of the lung (Table 1). Further surgical studies at the Memorial Sloan Kettering supported the prognostic value of this system 69, 70. For example, patients with stage I disease had a median survival of 30 months and those with stage IV had a median survival of 8 months 70. However, the Brigham group found it less useful for determination of surgical resectability, and have proposed yet another staging system that is also widely used 71. (Table 2) It should be noted that this staging system requires resection to determine the involvement of surgical margins, limiting its applicability mostly to post-surgical staging. A new staging system is being devised by the
Table 2- The Brigham Staging System for Malignant Pleural Mesothelioma.
Staging systems may be supplemented by prognostic scoring systems that do not require surgical staging. Prognostic scoring systems proposed by the European Organisation for Research and Treatment of Cancer (EORTC) and by the Cancer and Leukaemia Group B (CALGB) incorporate performance status, histopathology, and other laboratory studies. 37
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The two potential goals of surgical therapy for mesothelioma are palliation of symptoms and debulking of tumor with therapeutic intent. Many believe that therapy should follow the paradigm of treatment developed for ovarian cancer because of the similarities in biologic behavior of the cancer and similar embryologic origin of the cells of the primary tumor. 72 In both diseases, surgical resection alone does not prevent disease recurrence. However the approach of surgical debulking followed by systemic chemotherapy has shown significant success for the treatment of ovarian cancer. For surgical debulking of mesotheliomas, two surgical approaches are commonly employed, pleurectomy with decortication (P/D) or extrapleural pneumonectomy (EPP). Pleurectomy with decortication (P/D) removes all gross disease from all pleural surfaces and preserves the underlying lung. Extrapleural pneumonectomy (EPP) entails en bloc removal of the lung along with surrounding parietal pleura, pericardium, and diaphragm, with the pericardium and diaphragm then replaced by synthetic grafts. These are both technically challenging procedures and should be performed only by surgeons with extensive experience. EPP is especially difficult, and was originally associated with an unacceptably high morbidity of 30%. However, with advances in surgical, anesthetic, and critical care techniques, and more exacting patient selection, experienced centers now report mortality rates of < 4%, a rate comparable to standard pneumonectomy. 73 Both P/D and EPP are accomplished through an extended posterolateral thoracotomy and, as mentioned above, previous talc pleurodesis is not a contraindication to either procedure and may actually facilitate the separation of the pleura from the chest wall.
Preoperative evaluation of patients considered for surgery includes a thorough assessment of tumor stage, cardiac function, and pulmonary function. Most surgery is confined to those with the epithelial cell morphology. If debulking surgery is to be of benefit, it is essential that tumor is early stage and confined to one hemithorax. Chest CT or MRI are the usual first steps in staging. MRI is preferred by some centers for assessment of transdiaphragmatic extension of tumor (see Figure 2), and many now request PET or PET/CT as well (see Figure 3). Recognition that mediastinal lymph node involvement is a poor prognostic sign has prompted centers to require either cervical mediastinoscopy or endoscopic ultrasound with biopsy of suspicious nodes prior to EPP. Even with negative imaging studies, some groups perform extensive surgical staging with mediastinosopy and including laparoscopy because mesothelioma often spreads through the diaphragm to the peritoneum. 48
For patients who successfully complete such extensive screening, a few large series suggest that surgical debulking procedures may provide a survival advantage. In the first studies in which both surgeries were performed, it appeared as if pleurectomy was superior, with better survival than extrapleural pneumonectomy 69, 74. However, in a follow-up report, the same investigators found that there was no difference in median survival between the two surgical debulking procedures 70. Both series showed that failure after pleurectomy is more often local, while failure after extrapleural pneumonectomy is more often extrathoracic. These results underscore the difficulty in eradicating mesothelioma with surgery alone.
Based on such studies showing that surgery alone is insufficient to cure mesothelioma, Sugarbaker and colleagues at the Brigham and Women’s Hospital have developed a strategy of tumor debulking using extrapleural pneumonectomy followed by chemotherapy and high-dose radiation therapy to destroy residual tumor cells. This strategy was reported to yield a median survival of 19 months and five year survival of 15%. 73 However, patients with all three positive variables (an epithelial cell type, clean margins after resection, and negative lymph nodes) had a median survival of 51 months and a 5-year survival of 46%. Of note, patients with sarcomatous cell type did especially poorly. These results, while exciting, have been criticized for selection bias. Given the lack of prospective randomized studies comparing surgery with or without adjuvant therapy to medical management or supportive care, the therapeutic or even palliative benefit of surgical debulking followed by chemotherapy and radiation therapy remains unknown. Some critics point out that there are some long term survivors without treatment and that surgery may actually harm patients without improving survival.75 For example, in one unrandomized prospective study, 52 patients receiving surgery and other treatments (chemotherapy or radiotherapy) were compared to 64 patients without treatment. Although the treatments were felt to provide palliation, there was no significant difference in survival between treated and untreated patients.76 Until randomized studies are performed, the best treatment plan for patients with mesothelioma will remain unknown.
Surgical debulking has been combined with a variety of other cytoreductive approaches to destroy residual tumor cells on the surface of the thoracic cavity including hyperthermia and photodynamic therapy, without convincing success. At this time the value of surgical debulking and adjunctive measures such as hyperthermia, photodynamic therapy, chemotherapy, immunotherapy and radiation therapy are not known. It may be that an approach of debulking followed by some modality to eradicate residual tumor will improve outcome. However, until randomized trials are undertaken and a consensus is reached on staging, this will not be known with confidence.
Most patients with mesothelioma are not candidates for surgical or radiotherapy treatment and chemotherapy is their main option. There are two main regimens that are used in mesothelioma. The most commonly used now includes the multitargeted antifolate drug pemetrexed with a platinum drug such as cisplatinum. The use of this combination has been compared to cisplatin alone in a large Phase III study of 456 patients. 77 Response rates were significantly better in the pemetrexed/cisplatin arm than in the cisplatin-alone arm (41.3% vs. 16.7%), and survival was significantly better as well (median survival 12.1 months versus 9.3 months). Importantly, the addition of folic acid and vitamin B12 significantly reduced toxicity without altering survival benefit. 77 The other regimen used commonly is the false nucleotide gemcitabine with a platinum agent. Nearly half of the patients on this doublet regimen noted symptom improvement, 33% had a partial response, and 60% had stable disease; no survival benefit was demonstrated compared to historical controls. 78 Similarly, treatment with the combination of gemcitabine and oxaliplatin has been reported to improve symptoms, but not significantly improve survival (median survival of 13 months). 79
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Studies of the molecular biology of mesothelioma and the cellular mechanisms leading to a malignant phenotype have led to the identification of several possible therapeutic targets for treatment of this disease. Some of these are already under investigation in clinical trials (see www.clinicaltrials.gov). For example, several receptor tyrosine kinases are aberrantly expressed in these tumors, including the epidermal growth factor receptor. 80 Inhibitors of these proteins are now available in oral form and are being evaluated in patients with mesothelioma. Drugs blocking EGF or PDGF receptor signaling such as gefitinib and imatinib, have not proven to be of benefit when used as single agents. Other novel agents targeting growth factors found to be overexpressed in mesothelioma, e.g. vascular endothelial growth factor and its receptor, are under investigation. Other agents under study include anti-angiogenic agents, e.g AZD2171, thalidomide and PTK/ZK787, inhibitors of histone deacetylase superoylanilide and hydroxamic acid (SAHA), proteasome inhibitors, and histone deacetylase inhibitors (PXD101). Monoclonal antibodies labeled with toxins targeted to the mesothelioma cells are also underway in immunotoxin trials. 81
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Although in vitro studies suggest that mesothelioma is more sensitive to radiation than non-small cell lung cancer 82, the clinical experience reported by radiation oncologists suggests that it is an especially radioresistant tumor. In addition, radiation of the involved chest is limited by the presence of radiosensitive organs and the extensive nature of the tumor. As a consequence, its use appears limited to adjunctive therapy for patients who have undergone EPP, and to palliative treatment of painful chest wall lesions.. Prophylactic chest wall irradiation may reduce the incidence of chest wall recurrences at incision sites but there is no consensus on its use and randomized controlled trials are needed. 83 An area of active ongoing research is the role of high-dose hemithorax irradiation after extrapleural pneumonectomy for early stage disease. In carefully staged patients, this approach has resulted in a marked reduction in local tumor recurrences, although nearly one half of patients subsequently developed isolated distant metastases. 84
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It is known that an immune response is induced by mesothelioma, but it is weak.85 This knowledge has prompted a number of investigators to study different ways of strengthening that response. The intrapleural instillation of cytokines is limited by the short half-life of most cytokines, necessitating repeated injections or continuous infusion via a pleural catheter. Intrapleural interferon-gamma twice weekly for 2 months was reported to induce response rate of 56% in early stage disease.86 A continuous intrapleural infusion of interleukin-2 induced a partial response in four of 21 patients and an overall survival of 16 months. 87 In both cases, side effects were minimal and consisted primarily of fever and constitutional symptoms. Studies in animals suggest that interferons have an antiproliferative effect on mesothelioma cells and enhance the cytotoxic effect of cisplatin. The results from these studies led to the development of a Phase II trial of cisplatin-doxorubicin and interferon alpha-2b in advanced maligant mesothelioma. 88 The overall response rate was 29% and the median survival was 9.3 months with a one year survival of 45% and two year of 34%. However, severe myelosuppression was seen in 60% of patients limiting the application of this treatment. 88
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Gene therapy strategies that have been investigated for the treatment of mesothelioma include: mutation compensation, molecular chemotherapy, and genetic immunopotentiation. Mutation compensation attempts to block or replace abnormally expressed genes. The best example of this in mesothelioma is compensation for the absence of p16 gene expression, a consistent abnormality in mesothelioma. Re-expression of p16INK using an adenoviral vector improved survival in a murine model of mesothelioma. 89 Molecular chemotherapy is a technique of genetically modifying cells to make them susceptible to a drug. For example, an adenoviral vector containing the herpes simplex thymidine kinase (HSVtk) gene has been injected into the pleural space of patients; the virus is taken up by mesothelial cells and the (HSVtk) gene product makes the cells metabolize ganciclovir to a toxic byproduct. In humans, such approaches have been limited by patchy viral uptake and the development of immunity to the virus. 90 Genetic immunopotentiation employs the genetic induction of an inflammatory anti-tumor response. For example, vaccinia virus carrying the gene for interleukin-2 has been studied in patients to determine toxicity 91. Intratumoral injection was not only well tolerated, but 50% of tumors were found to have T-cell infiltration. However, no tumor regression was seen. Recent gene therapy trials are focusing on the use of the interferon beta gene to enhance immunity.92
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Pain is common and often disabling. Invasion of the chest wall can cause localized somatic pain, intercostal nerve invasion or vertebral invasion can cause neuropathic pain, and lung invasion may cause diffuse visceral pain. Opioids, such as liquid morphine plus sustained release morphine, are the mainstay of pain control. Somatic pain responds to non-steroidal anti-inflammatory drugs and neuropathic pain requires an anti-convulsant such as carbamazepine or sodium valproate. Some patients require procedural pain relief as from intrathecal analgesia or nerve block.
Dyspnea and cough are often due to large pleural effusions or from tumor spread. Effusions due to mesothelioma can usually be controlled with pleurodesis or placement of an indwelling tunneled catheter. Pleurodesis with talc is an option if a patent pleural space is not needed as for intrapleural therapy within clinical trials. Talc pleurodesis is reasonably effective and relatively inexpensive agent for this task. As described earlier, it can be administered as a slurry through a chest tube or as an aerosol during thoracoscopy with equal effect. Regardless, with either technique, the affected lung must be capable of expanding so that the visceral and parietal pleura are in contact. Placement of a tunneled pleural catheter for chronic pleural drainage is another option for these patients, as described for Malignant Pleural Effusions earlier.
Psychosocial care is also very important in palliation given the fear, anger and suffering associated with the disease. 93, 94
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The existence of populations with known exposure to asbestos suggests that an effective chemoprevention strategy could reduce the incidence of mesothelioma. In one such study, former workers of the Wittenoom asbestos mines of Australia were assigned randomly to daily use of vitamin A (retinol) or beta-carotene, without a placebo group. 95 While not definitive, studies of retinol are continuing because of some early promising data. Such approaches have the potential of preventing a disease for which curative therapies do not yet exist.
Screening of high risk populations has the potential of detecting early lesions that could respond better to therapy. Screening trials of high risk populations are ongoing to determine the value of routine low dose CT scanning.96 The sensitivity of serum mesothelin is not sufficient for use as a marker for early stage mesothelioma; biomarkers with greater sensitivity are needed. 53
Additional information on clinical and basic research concerning mesothelioma can be found in reports of biannual meetings plus the website of the International Mesothelioma Interest Group. 97 (www.imig.org) Other independent web sites are the National Cancer Institute (www.nci.nih.gov), Oncolink (Abramson Cancer Center, University of Pennsylvania)(www.oncolink.com) and, for referral of patients for ongoing NIH-sponsored studies, www.clinicaltrials.gov.
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