Malignant mesothelioma

1750-1172-3-34 1750-1172 Review Malignant mesothelioma Moore J Alastair a.moore@ic.ac.uk Parker J Robert robertparker@doctors.org.uk Wiggins John John.Wiggins@hwph-tr.nhs.uk

Department of Respiratory Medicine, Wexham Park Hospital, Wexham, Slough, Berkshire, SL2 4HL, UK

Orphanet Journal of Rare Diseases 1750-1172 2008 3 1 34 http://www.ojrd.com/content/3/1/34 19099560 10.1186/1750-1172-3-34 13 6 2008 19 12 2008 19 12 2008 2008 Moore et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.

Disease name and definition

Malignant mesothelioma is a cancer originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis 1. Its distribution may be uni- or multifocal or may involve the lining cells in a continuous manner.

Epidemiology and aetiology

Before 1950, malignant mesothelioma was so rare that some pathologists even questioned its existence 2. However, the increasing use of asbestos after the second world war led to the description of a causal relationship between asbestos exposure and the development of mesothelioma in 1960 3. Although its use was widely abandoned in the western world in the 1980s, the long latency period between exposure to asbestos and onset of mesothelioma, which can range from 15 to 60 years 45, meant that the mortality rates from mesothelioma have continued to rise. In the USA the annual deaths from mesothelioma peaked at 3060 in 2002 and have subsequently declined, however the incidence of mesothelioma will continue to rise in the UK until it reaches a peak in about the year 2020 6. According to data gathered in the US Surveillance Epidemiology and End Results programme for 1973–1992, there has been virtually a constant rate of mesothelioma in females but a consistently higher rate for males. In the 1960s a mesothelioma register was set up in the UK to systematically record the mortality rates from mesothelioma and to try to identify the incidence of tumour development without known occupational exposure. It is predicted that around 90,000 deaths will occur from mesothelioma by 2050, with 65,000 of these occurring from 2002 onwards 7.

Asbestos is a naturally occurring fibrous silicate, and the risk of developing mesothelioma depends on the exposure to different types of the asbestos mineral fibre. The main asbestos mineral groups are serpentine fibres, which are long and curly, or amphibole fibres which are straight and rod-like. This distinction is important as the serpentine fibre shape is more easily cleared from the respiratory tract. Epidemiologic data suggests that the amphibole, crocidolite, is associated with the highest risk of mesothelioma 8 and that the serpentine fibre, chrysotile has the lowest. The diagnosis of mesothelioma is directly attributable to occupational asbestos exposure; however there is evidence that mesothelioma may result from both para-occupational exposure (e.g.: women having laundered their husband's overalls) and non-occupational "environmental" exposure 9. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos in both animals 10 and humans 8, and a recent review suggests a spontaneous mesothelioma rate in humans of around one per million 11.

Non-asbestos mineral fibres have also been shown to induce mesothelioma, such as erionite found in certain areas of Turkey 12 or tremolite in north-western Greece 13, and whilst not specifically mined for commercial purposes, tremolite is often found as a contaminant of chrysotile asbestos and has been causally linked with an increased risk of mesothelioma 14. The role of Simian virus (SV-40) in the pathogenesis of mesothelioma is more controversial; SV-40 was found to contaminate polio vaccines in the 1950s and 60s in the UK, and although it has been suggested that it is a causative factor in the development of mesothelioma 151617, recent studies have found no link 181920.

Clinical description

Mesothelioma is primarily a disease of adults and usually presents in the fifth to seventh decades, and 70–80% of cases occur in men. Those diagnosed between the ages of 20 to 40 years usually have a history of childhood exposure 1. Typical presenting features are those of chest pain, dyspnoea or both 1121, and in one series up to a third of patients presented with breathlessness due to a pleural effusion without chest pain 22. When it occurs, the chest pain tends to be dull or boring in nature, but a pleuritic-type pain can occur in the presence of pleural effusions. Involvement of the mediastinal structures is well recognized but hoarseness of the voice and superior vena caval obstruction only rarely causes major symptoms. Dysphagia can also occur but this is a late finding. Unlike bronchogenic carcinomas, presentation with haemoptysis, lymphadenopathy and metastatic symptoms are unusual. A chest wall mass, weight loss and sweating are less common presentations, as is peritoneal mesothelioma although involvement may be found in up to one third of cases at autopsy. Presentation of peritoneal mesothelioma is with non-specific symptoms including loss of appetite, nausea and vomiting, diarrhoea or constipation and occasionally ascites. Small bowel obstruction is usually a late feature, and overall the prognosis of peritoneal mesothelioma is worse than pleural mesothelioma with a mean survival time of about 7 months 11.

Physical examination is usually unremarkable except for signs of pleural effusion and pleural thickening due to tumour infiltration. Finger clubbing is more common than in benign asbestos related pleural disease, and can occur in up to 30% of cases 23. The tumour originates mainly on the parietal pleura and spreads via the fissures, to encase the lung surfaces. Infiltration of the pericardium can result in signs of cardiac tamponade, and mesothelioma can grow along needle tracks and incisions. Blood tests can reveal an elevated erythrocyte sedimentation rate (ESR) 24, and there have been isolated case reports of mesothelioma associated with autoimmune haemolytic anaemia 25.

Diagnosis and differential diagnosis

The combination of accurate history, examination, radiology and the acquisition of pathology is essential in the diagnosis of mesothelioma. A careful history of asbestos exposure is essential, and the identification of at-risk occupations are strong markers of exposure. However, the delay between exposure and presentation may naturally preclude accurate recall of occupational exposure and working conditions which may have occurred up to 60 years previously.

In those patients with a pleural effusion, sampling of the fluid for cytological examination is the first step in confirming the diagnosis. Pleural fluid cytology is positive for malignant cells in about a third of cases 1 and if the clinical, radiological and cytological results support a diagnosis of mesothelioma then this can be accepted. However, it is uncommon for the definitive diagnosis to be made on pleural fluid cytology alone and pleural biopsy for tissue diagnosis is therefore recommended. A contrast enhanced computed tomogram (CT) scan is essential to both identify the extent of the disease, and help guide a percutaneous biopsy if the pleural fluid cytological analysis is not sufficient.

Radiological findings

Radiological imaging is essential for the diagnosis, staging and management of mesothelioma. X-ray, CT, magnetic resonance imaging (MRI) and positron emission tomography (PET) have all been used to evaluate the disease.

Intravenous contrast-enhanced CT is the primary imaging modality for suspected pleural malignant disease. CT allows visualisation of the whole pleural surface and diaphragm and use of a 45–60 second scan delay enables the pleural surfaces to be studied whilst still allowing assessment of the mediastinal nodes 26. A standard protocol should include the liver and adrenal glands, but in cases where there is a past history of abdominal or pelvic malignancy, the scan should also include the lower abdomen and pelvis 11.

Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement 27. The specificities of these findings were 100%, 94%, 94% and 88% respectively. The sensitivities were 41%, 51%, 36% and 56% respectively. The presence of bilateral pleural calcification on CT is uncommon in malignant mesothelioma 27. A significant reduction in thoracic volume seen on CT is more common, however, occurring in up to 73% of cases according to some series 28. Whilst these features have a high positive predictive value, absence of these signs does not reliably exclude the diagnosis of pleural malignancy.

MRI

MRI screening is not used routinely in the assessment of malignant mesothelioma, however in patients with potentially resectable disease, MRI can help to provide additional staging information over and above CT. Using gadolinium enhancement, MRI can improve the identification of tumour extension into the diaphragm or chest wall, allowing better assessment of the individual for surgical treatment. MRI also is the imaging modality of choice in those in whom intravenous iodinated contrast is contraindicated 29.

PET

The standardized uptake value (SUV) in PET is a semi-quantitative measure of the metabolic activity of a lesion and the SUV is significantly higher in mesothelioma than in other benign pleural diseases such as pleural plaques or inflammatory pleuritis 2930, and one study found PET scanning to have a 96.8% sensitivity and an 88.5% specificity at distinguishing benign from malignant pleural disease 31. PET scanning has also increased the accuracy in diagnosing mediastinal nodal metastases 30 and therefore the combination of metabolic and anatomical information provided by PET makes it useful in the staging and preoperative evaluation of mesothelioma. PET may also help as a guide to the optimal site for CT guided pleural biopsy, and there is evidence that changes in the fluorodeoxyglucose (FDG) uptake within the tumour might indicate response to treatment suggesting its role in the assessment of response to both chemotherapy and chemo-radiotherapy 32.

Staging and assessment of disease response

At least six different staging systems have been suggested for malignant mesothelioma, but none have been accurately shown to predict survival. Currently, a TNM staging system (Table 1) similar to that used in non-small cell lung carcinoma has been proposed by the International Mesothelioma Interest Group (IMIG) 33.

Table 1

IMIG TNM staging system

Primary tumour (T)

T1a

Tumour limited to the ipsilateral parietal including mediastinal and diaphragmatic pleura, no involvement of the visceral pleura

T1b

Tumour involving the ipsilateral parietal including mediastinal and diaphragmatic pleura, scattered foci of tumour also involving the visceral pleura

Tumour involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral pleura) with at least one of the following features:

• involvement of diaphragmatic muscle

• confluent visceral pleural tumour (including the fissures)

• extension of tumour from visceral pleura into the underlying pulmonary parenchyma

Locally advanced but potentially resectable tumour; tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral pleura) with at least one of the following features:

• involvement of the endothoracic fascia

• extension into the mediastinal fat

• solitary, completely resectable focus of tumour extending into the soft tissues of the chest wall

• non transmural involvement of the pericardium

Locally advanced technically unresectable tumour; tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral) with at least one of the following features:

• diffuse extension or multifocal masses of tumour in the chest wall with or without associated rib destruction

• direct transdiaphragmatic extension of tumour to the peritoneum

• direct extension of tumour to the contralateral pleura

• direct extension of tumour to one or more mediastinal organs

• direct extension of tumour into the spine: tumour extending through to the internal surface of the pericardium with or without a pericardial effusion

• tumour involving the myocardium

Lymph nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastases

Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes

Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes including the ipsilateral internal mammary nodes

Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral or contralateral supraclavicular lymph nodes

Metastases (M)

Presence of distant metastases cannot be assessed

No distant metastasis

Distant metastasis present

Tumour response to treatment is an important surrogate for patient benefit. The World Health Organization (WHO) criteria for tumour response were most useful for measuring bi-dimensional lesions, whereas the irregular growth pattern of mesothelioma as a rind around the chest wall makes these criteria poorly applicable 34. More recently, the Response Evaluation Criteria in Solid Tumours (RECIST) 35 uses a uni-dimensional measurement of tumour size to assess response, but this is based on the assumption that tumours are largely spherical, so again there are limitations to the applicability of this technique in the assessment of malignant mesothelioma.

A modified RECIST criteria has now been published, however, with particular reference to malignant mesothelioma 36. Assessment of response to treatment is now made by measuring uni-dimensional tumour thickness perpendicular to the chest wall in 2 sites at three different levels on CT.

Pathological findings

According to the WHO classification, malignant mesothelioma can be classified as epithelioid, sarcomatoid, or biphasic based on tissue obtained by biopsy. The pathological diagnosis is reached with the aid of immunohistochemistry to demonstrate the presence of mesothelial, epithelial, or true sarcomatous differentiation in the malignant cells 37. The reported diagnostic yield from CT guided biopsy varies from 60% with a single attempt up to 85% with multiple attempts 38. Ultimately, however, the highest yields are obtained with open or thoracoscopic pleural biopsy.

There is currently no individual immunohistochemical mesothelial marker that provides 100% specificity and high sensitivity for the diagnosis of malignant mesothelioma 37 and so a number of mesothelial and epithelial markers have been developed. Clearly, distinguishing a malignant pleural process from an inflammatory process is a priority and immunohistochemistry has demonstrated that mesothelioma frequently shows immunoreactivity for keratin, p53 and epithelial membrane antigen (EMA) which is unusual for benign pleural disease.

Differentiating malignant mesothelioma from other malignancies, however, can be more difficult as mesotheliomas, especially those of the epithelioid type, can mimic several other tumours. Again, immunohistochemistry can help in the differentiation of mesothelioma and markers such as mesothelin, cytokeratin 5/6, calretinin, thrombomodulin and WT-1 have been used. The most specific and sensitive markers for mesothelioma are mesothelin (in epithelioid mesothelioma), calretinin and cytokeratin 5/6. However, according to a recent review article, mesothelin is positive in 27% of squamous cell carcinomas, and calretinin and cytokeratin 5/6 can be raised in both squamous cell carcinoma of the lung and adenocarcinoma of both the lung and other sites 37. Clearly there can be difficulty in making the diagnosis, and so usually a panel of two positive and two negative markers will be sufficient to confirm the presence of malignant mesothelioma.

Serum markers in the diagnosis of mesothelioma

Reliably diagnosing malignant mesothelioma early in the disease is notoriously difficult due to the variability in time to presentation from exposure in the disease. Recently there has been much interest in the use of serum markers for the diagnosis of the disease. The ideal serum marker would be one that is able to offer: 1) early diagnosis, 2) identification of all the subtypes, 3) differentiation of malignant mesothelioma from benign pleural disease and other metastatic pleural malignancies, and 4) be able to track response to therapy and predict survival. As yet no such ideal marker exists, but studies have suggested the use of osteopontin, mesothelin or megakaryocyte potentiating factor in this role.

Osteopontin is a glycoprotein that is over-expressed in lung, breast, colorectal, gastric and ovarian carcinomas and in melanoma. Increased levels correlate with tumour progression, invasion and metastases. Although increased levels do not exclude other malignancies, recent data suggest that osteopontin has great potential use as a marker for mesothelioma 39 and has a positive predictive power for mesothelioma equivalent to Ca-125 for ovarian cancer. Studies have suggested a sensitivity and specificity for mesothelioma of 77% and 85% respectively 40.

Mesothelin is a membrane bound glycoprotein expressed by mesothelial cells and over expressed in malignancy, especially mesothelioma 41. Soluble mesothelin related proteins (SMRP) are serum proteins thought to be released by alternative splicing of the mesothelin protein and thereby preventing adherence to cell membranes. Serum concentrations are increased in malignant mesothelioma, and therefore this protein is a potential serum marker for the disease 42. However, although most patients with mesothelioma have raised serum levels of SMRP, giving a sensitivity of between 80–83% and specificity between 80–100% 434445, it is mostly associated with the epithelioid sub-type, leading to difficulties in identifying the other sub-types of mesothelioma, especially sarcomatoid, using this marker alone 46. Nevertheless a commercially available FDA-approved assay, MESOMARK (Fujirebio Diagnostics Inc, Malvern, PA, USA), has been recently approved for use in the monitoring of disease in epithelioid and biphasic mesothelioma, and data seems to support its usefulness 47.

Megakaryocyte Potentiating Factor (MPF) is secreted by cells of several mesothelioma cell lines. In recent studies, MPF was elevated in 91% of 56 malignant mesothelioma patients compared with controls, and levels returned to normal after surgery in patients with peritoneal mesothelioma 4648. This might make MPF useful in the monitoring of treatment response in mesothelioma.

Management

Because there can be difficulty reaching a diagnosis of mesothelioma despite radiology, cytology and biopsy, the general management of patients with mesothelioma should be under a multidisciplinary team including respiratory physicians, oncologists, radiologists, palliative care physicians and lung cancer specialist nurses. In addition, once the diagnosis has been reached, there should be close liaison with the patient's primary care physician, and both the primary care physician and family should be warned that, at least in the UK, a post mortem examination will usually be required after the death of a patient with mesothelioma.

The general treatment strategy of mesothelioma should cover the following areas:

• Management of pleural effusions

• Radiotherapy to intervention sites

• Suitability for radical surgery

• Suitability for clinical trial entry and chemotherapy

• Compensation issues

• Palliation of symptoms and end-of-life care

Management of pleural effusions

Management of malignant pleural effusions begins with therapeutic thoracocentesis, which assesses the response of dyspnoea to fluid removal. If symptoms do not respond to thoracocentesis, alternative causes of dyspnoea should be sought such as pulmonary thromboembolic disease, or lymphangitis carcinomatosis. Early, successful management on pleural effusions with pleurodesis is essential for the palliation of symptoms and the prevention of a trapped lung. However with repeated thoracocentesis, the pleural fluid may undergo loculation making it difficult to drain subsequently and also the risk of pleural infection increases. If a conclusive diagnosis has been made, chemical pleurodesis can be performed via a small bore intercostal chest drain (9–14F), which has equivalent success rates to larger bore chest drains with the added benefit of patient comfort 4950. The ideal sclerosing agent is sterile talc, with success rates between 70 and 96% 505152, although care must be taken to ensure the talc particles are of the optimal calibration to prevent the rare risk of adult respiratory distress syndrome (ARDS) 53.

If a firm diagnosis is yet to be made, and the patient is fit enough for surgery, then thoracoscopy is an extremely useful technique in the management of suspected malignant pleural effusions. This procedure allows visualisation of the pleural surface, enables histological sampling for diagnosis and allows complete drainage of the effusion followed by pleurodesis via talc poudrage.

In patients with a trapped lung, or in whom pleurodesis has failed, a pleuro-peritoneal shunt can be considered. Whilst symptoms can improve in over 90% of patients, complications (including shunt occlusion and infection) occur in 15% and therefore their use is diminishing 54. More recently, an ambulatory pleural drainage system (Pleur_xPleural Catheter, Denver Biomedical Inc, USA) has been developed. This system enables the patient to control the pleural effusion at home by means of a long-term drainage catheter and vacuum bottles. This might help patients with trapped lungs as it both avoids the need for surgical intervention, and palliates dyspnoea 55.

Radiotherapy

Palliative radiotherapy

Radiotherapy can be used to control local tumour growth and occasionally causes regression of disease, but there is no evidence that radiotherapy alone affects survival 56. It has, however, been shown to be helpful in the palliation of pain 57, and approximately half the patients treated with palliative radiotherapy derive some benefit 58. It also appears that short courses of radiotherapy (for example 20 Gy in 5 fractions) are as effective as longer courses such as 30 Gy in 10+ fractions 59, although there is a total dose response effect 60. Unfortunately, radiotherapy is rarely helpful in either the palliation of dyspnoea or the management of symptoms of mediastinal infiltration such as superior vena caval obstruction (SVCO), and alternative methods of treatment such as SVC stenting should be sought 1161.

Radical radiotherapy as a single modality

Whilst hemithorax irradiation may provide symptomatic benefit, no studies have shown that it prolongs survival 61. Mesothelioma can involve large areas of the pleural cavity and use of radical radiotherapy over large fields places a range of organs such as lungs, liver, spinal cord or heart at a significant risk of dose related damage. As a result, a recent Cochrane review found no randomised clinical trial evidence to support the use of radical radiotherapy alone (or in combination with other treatment modalities) in mesothelioma 62, and this treatment option has been shown to confer a significant mortality, with rates as high as 17% in one series 59.

Radiotherapy as part of multimodality treatment

Failure to increase survival using single treatment modalities has led to a multimodality approach to treatment in mesothelioma. Combining debulking surgery with radiotherapy is the cornerstone of this approach and can both reduce systemic recurrence and influence the natural history of the disease 6364. Typically, hemithorax radiotherapy is combined with extra pleural pneumonectomy (EPP – see later) and correctly staged patients with epithelioid mesothelioma can have median survival rates of 33 months 65. Due to the large, irregular nature of malignant mesothelioma along with the close proximity of other organs, a more directed modality of irradiation which could help improve local tumour control whilst limiting exposure to surrounding organs has been developed, known as intensity modulated radiotherapy (IMRT) 66. Despite the possibilities for improved tumour control, however, IMRT still carries a potential risk of fatal pulmonary toxicity in mesothelioma 6768.

Prophylactic radiotherapy

Mesothelioma may seed malignant cells in procedure scars. Whilst pain from these metastases is rare, they can become uncomfortable, and evidence has suggested that radiotherapy to intervention sites can prevent this complication 6970. Whilst this practice is recommended in current guidelines 11, evidence is emerging that it should only be offered to those patients who are symptomatic from these subcutaneous tumours as the radiotherapy itself may have side effects 7172.

Surgery

The role of surgery in the treatment of malignant mesothelioma is still uncertain. The three most common surgical procedures are surgical pleurodesis via video assisted thoracoscopic surgery (VATS), debulking surgery (also known as cytoreductive surgery or pleurectomy/decortication (P/D)) and extra pleural pneumonectomy (EPP). This comprises en-bloc resection of the parietal pleura, lung, pericardium and diaphragm and mediastinal nodes 56. P/D allows the removal of the visceral, parietal and pericardial pleura as well as debulking the tumour and is therefore less demanding, with mortality rates < 5% 73. P/D has limitations, however, as it does not remove the tumour completely, and the preservation of the ipsilateral lung makes postoperative radiotherapy difficult due to the risk of pulmonary side effects 74. The impact of P/D on overall survival is contentious, with some evidence suggesting that P/D surgery via a VATS approach may provide a survival benefit in patients with advanced disease not suitable for EPP 75, whilst other studies do not clearly distinguish the benefit of P/D over EPP 76.

EPP is a much more demanding procedure with morbidity rates as high as 60% 77 and mortality rates of 4–9% 117879. However, the pneumonectomy in EPP allows the use of high dose hemithoracic radiotherapy, and this combined treatment has been shown to reduce local recurrence and prolong survival in early disease 65. As a result, as part of the trimodality approach to treatment with surgery chemotherapy and radiotherapy, EPP has arisen as the surgical treatment of choice, albeit without clear randomised controlled trial evidence 78. In order to clarify this issue, a large randomized trial (Mesothelioma And Radical Surgery (MARS)) is underway 80. In this trial, EPP is sandwiched between induction chemotherapy and radical radiotherapy. The control arm offers full active tri-modality therapy, although the surgery is limited to debulking surgery. In addition patients receive the same induction chemotherapy and are given radiotherapy to any drain or port sites.

Chemotherapy

The use of chemotherapy in malignant mesothelioma aims to lengthen survival, improve quality of life and provide symptomatic relief. Currently, there is no single drug or combination therapy that could be considered as standard treatment for mesothelioma. A variety of single agent and combination regimens have been tried in clinical trials with response rates of between 0% and 45% 81.

A review of studies by Berghmans et al 82 revealed that cisplatin was the most effective single agent for mesothelioma, with carboplatin having similar activity, and in combination with doxorubicin provided a response rate superior to other regimens studied, although there was no clear benefit in terms of survival. Single agent vinorelbine and combination treatment MVP (mitomycin C, vinblastine and cisplatin) have also been shown to provide good symptom relief with acceptable toxicity 838485.

Recently, there has been much interest in the use of the antifolate pemetrexed (Alimta; Eli Lilly). Pemetrexed exerts its effect by interrupting folate dependent metabolic synthesis of purines and pyrimidines (the building blocks of DNA and RNA), and a Cochrane review of the effectiveness of combination treatment with cisplatin/pemetrexed 81 suggests a survival benefit, albeit with increased toxicity which is reduced by the co-administration of vitamin B12 and folate supplements. Much of the evidence supporting the use of pemetrexed comes from a single study 86 in which 331 patients, fully supplemented with vitamin B12, demonstrated a median survival of 13.3 months with combination pemetrexed/cisplatin compared to 10.0 months with cisplatin alone (p = 0.05). This was associated with a significant improvement in quality of life and symptom relief compared to cisplatin alone 87. Combination with carboplatin instead of cisplatin, however, may be an alternative regimen which provides similar efficacies and reduced side effects 88. An alternative antifolate agent, raltitrexed, has also been shown to confer a survival benefit in combination with cisplatin, with median overall survival increasing from 8.8 months (CI 7.8–10.8) with cisplatin alone to 11.4 months (CI 10.1 to 15) with combination cisplatin-raltitrexed (p = 0.05) 89. Although this study only demonstrated borderline significance, likely as a result of sample size, the results of these trials mean that combination cisplatin and an antifolate should be the reference regimen in mesothelioma. Recent advances now favour the use of neoadjuvant chemotherapy followed by EPP and radiation for malignant mesothelioma; Weder et al recently published their experience of a prospective trial of neoadjuvant chemotherapy consisting of cisplatin and gemcitabine followed by EPP, demonstrating a median survival of 23 months 90. Similarly, Flores et al prospectively studied patients given induction gemcitabine and cisplatin followed by EPP. Median survival of all patients in the study was 19 months, but those patients who completed induction chemotherapy and subsequently underwent EPP had a median survival of 33.5 months 91.

As a result, all patients who are fit enough (ECOG performance status 0–2) should have the opportunity to discuss the merits of chemotherapy in mesothelioma with an oncologist 11, in the knowledge that there are no published data which compares survival or symptom control in patients treated with chemotherapy or best supportive care only. The first such trial (MSO-1) 92 is complete, and the preliminary results were published in abstract form in 2007 93. These results suggest that the addition of chemotherapy to active symptom control with best supportive care did not infer a significant survival benefit in mesothelioma, however this trial was started before the emergence of pemetrexed.

Supportive and palliative care

Given that malignant mesothelioma has a poor overall prognosis, referral of patients to specialist palliative care services will be appropriate at some time in the disease course. Most patients need palliation of symptoms early on in the course of the disease and recognition of this by the patient, family and primary care physician is essential in the management of the patient with mesothelioma. The use of a central lung cancer nurse specialist provides a means by which the patient can gain access to the delivery of care needed for this disease, through the following core elements 11:

• Communication

• Information

• Coordinated care between respiratory physicians, oncologists, radiologist and palliative care specialists

• Nursing care

• Accessibility

• Support

Prognosis and survival

Life expectancy in malignant mesothelioma is poor, with median survival varying between 8 and 14 months 11. The Cancer and Leukaemia Group B, and the European Organization for Research and Treatment of Cancer have analysed large numbers of patients enrolled in treatment trials for mesothelioma and have identified the following poor prognostic factors:

• Non-epithelioid histology

• Poor performance status

• Chest pain

• Age older than 75

• Male gender

• White blood cell count 8.3 × 10⁹/L or greater

• Platelets greater than 400,000 μL

• LDH greater than 500 IU/L

The majority of patients who survive for more than 2 years have epithelioid histology and death from mesothelioma tends to be due to respiratory failure.

Compensation issues

Eligibility for compensation for mesothelioma may vary from country to country. In the UK for example, a diagnosis of mesothelioma allows compensation via the Industrial Injuries Disablement Benefit, War Pensions Scheme or through a Common Law claim from the firm/firms where the asbestos exposure occurred. Patients who cannot identify occupational exposure to asbestos are not entitled for compensation, however pathological confirmation of the diagnosis is not mandatory; establishing the diagnosis and causation on the balance of probability is sufficient, although an unequivocal diagnosis obviously removes any cause for debate. Earlier this year, a new legislation was made in the UK Child Maintenance and Other Payments Act whereby dependants of persons with mesothelioma became eligible to claim for lump-sum compensation after death http://www.opsi.gov.uk/acts/acts2008a.

Abbreviations

ESR: erythrocyte sedimentation rate; CT: computed tomogram; MRI: magnetic resonance imaging; PET: positron emission tomography; SUV: standardized uptake value; FDG: fluorodeoxyglucose; IMIG: International Mesothelioma Interest Group; WHO: World Health Organization; RECIST: Response Evaluation Criteria in Solid Tumours; EMA: epithelial membrane antigen; SMRP: Soluble mesothelin related proteins; ARDS: adult respiratory distress syndrome; MPF: Megakaryocyte Potentiating Factor; SVCO: superior vena caval obstruction; IMRT: intensity modulated radiotherapy; VATS: video assisted thoracoscopic surgery; P/D: pleurectomy/decortication; EPP: extra pleural pneumonectomy; MARS: Mesothelioma And Radical Surgery.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All authors contributed to this review article.

Malignant Pleural Mesothelioma Jett J Aubry M Clinical Respiratory Medicine. Mosby Albert, Spiro, Jett 2 735 741 The pathogenesis of mesothelioma Carbone M Bedrossian CW Semin Diagn Pathol 2006 23 56 60 10.1053/j.semdp.2006.08.002 17044196 Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province Wagner JC Sleggs CA Marchand P Br J Ind Med 1960 17 260 271 1038078 13782506 Latency periods in asbestos-related mesothelioma of the pleura Bianchi C Giarelli L Grandi G Brollo A Ramani L Zuch C Eur J Cancer Prev 1997 6 162 166 9237066 Mesothelioma mortality in Great Britain from 1968 to 2001 McElvenny DM Darnton AJ Price MJ Hodgson JT Occup Med (Lond) 2005 55 79 87 10.1093/occmed/kqi034 15757980 Continuing increase in mesothelioma mortality in Britain Peto J Hodgson JT Matthews FE Jones JR Lancet 1995 345 535 539 10.1016/S0140-6736(95)90462-X 7776771 The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050 Hodgson JT McElvenny DM Darnton AJ Price MJ Peto J Br J Cancer 2005 92 587 593 15668716 Current controversies regarding the role of asbestos exposure in the causation of malignant mesothelioma: the need for an evidence-based approach to develop medicolegal guidelines Marchevsky AM Wick MR Ann Diagn Pathol 2003 7 321 332 10.1016/S1092-9134(03)00078-9 14571437 Mineral fibre analysis and routes of exposure to asbestos in the development of mesothelioma in an English region Howel D Gibbs A Arblaster L Swinburne L Schweiger M Renvoize E Hatton P Pooley F Occup Environ Med 1999 56 51 58 1757652 10341747 10.1136/oem.56.1.51 Spontaneous peritoneal malignant mesothelioma in a geriatric japanese macaque (Macaca fuscata) Yamate J Tomita A Kuwamura M Mitsunaga F Nakamura S Exp Anim 2007 56 155 159 10.1538/expanim.56.155 17460361 BTS statement on malignant mesothelioma in the UK, 2007 Wiggins J Thorax 2007 62 Suppl 2 ii1 ii19 17965072 Lung diseases due to environmental exposures to erionite and asbestos in Turkey Emri S Demir A Dogan M Akay H Bozkurt B Carbone M Baris I Toxicol Lett 2002 127 251 257 10.1016/S0378-4274(01)00507-0 12052665 Malignant pleural mesothelioma from nonoccupational asbestos exposure in Metsovo (north-west Greece): slow end of an epidemic? Sakellariou K Malamou-Mitsi V Haritou A Koumpaniou C Stachouli C Dimoliatis ID Constantopoulos SH Eur Respir J 1996 9 1206 1210 10.1183/09031936.96.09061206 8804939 Mesothelioma and asbestos Gibbs GW Berry G Regul Toxicol Pharmacol 2008 52 1 Suppl S223 31 10.1016/j.yrtph.2007.10.003 18022298 A multi-institutional study confirms the presence and expression of simian virus 40 in human malignant mesotheliomas Testa JR Carbone M Hirvonen A Khalili K Krynska B Linnainmaa K Pooley FD Rizzo P Rusch V Xiao GH Cancer Res 1998 58 4505 4509 9788590 Simian virus 40 and mesothelioma in Great Britain Price MJ Darnton AJ McElvenny DM Hodgson JT Occup Med (Lond) 2007 57 564 568 10.1093/occmed/kqm079 17675661 Asbestos, Simian virus 40 and malignant mesothelioma Stenton SC Thorax 1997 52 Suppl 3 S52 57 1765882 9381428 Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids Lopez-Rios F Illei PB Rusch V Ladanyi M Lancet 2004 364 1157 1166 10.1016/S0140-6736(04)17102-X 15451223 Evidence against a role for SV40 in human mesothelioma Manfredi JJ Dong J Liu WJ Resnick-Silverman L Qiao R Chahinian P Saric M Gibbs AR Phillips JI Murray J Axten CW Nolan RP Aaronson SA Cancer Res 2005 65 2602 2609 10.1158/0008-5472.CAN-04-2461 15805256 Mesothelioma mortality in Europe: impact of asbestos consumption and simian virus 40 Leithner K Leithner A Clar H Weinhaeusel A Radl R Krippl P Rehak P Windhager R Haas OA Olschewski H Orphanet J Rare Dis 2006 1 44 1664552 17090323 10.1186/1750-1172-1-44 Malignant pleural mesothelioma – an update Stewart DJ Edwards JG Smythe WR Waller DA O'Byrne KJ Int J Occup Environ Health 2004 10 26 39 15070023 Malignant mesothelioma in south east England: clinicopathological experience of 272 cases Yates DH Corrin B Stidolph PN Browne K Thorax 1997 52 507 512 1758573 9227715 Finger clubbing in malignant mesothelioma and benign asbestos pleural disease McGavin C Hughes P Respir Med 1998 92 691 692 10.1016/S0954-6111(98)90519-4 9659538 The clinical aspects of mesothelioma Elmes PC Simpson JC Q J Med 1976 45 427 449 948545 Autoimmune haemolytic anaemia associated with malignant peritoneal mesothelioma Selleslag DL Geraghty RJ Ganesan TS Slevin ML Wrigley PF Brown R Acta Clin Belg 1989 44 199 201 2816228 Current state and future directions of pleural mesothelioma imaging Armato SG 3rd Entwisle J Truong MT Nowak AK Ceresoli GL Zhao B Misri R Kindler HL Lung Cancer 2008 59 411 420 10.1016/j.lungcan.2007.09.027 18061303 CT in differential diagnosis of diffuse pleural disease Leung AN Muller NL Miller RR AJR Am J Roentgenol 1990 154 487 492 2106209 Computed tomography findings in 66 patients with malignant pleural mesothelioma due to environmental exposure to asbestos Okten F Koksal D Onal M Ozcan A Simsek C Erturk H Clin Imaging 2006 30 177 180 10.1016/j.clinimag.2005.12.027 16632152 Malignant pleural mesothelioma: evaluation with CT, MR imaging, and PET Wang ZJ Reddy GP Gotway MB Higgins CB Jablons DM Ramaswamy M Hawkins RA Webb WR Radiographics 2004 24 105 119 10.1148/rg.241035058 14730040 Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography Benard F Sterman D Smith RJ Kaiser LR Albelda SM Alavi A Chest 1998 114 713 722 10.1378/chest.114.3.713 9743156 Evaluation of pleural disease with 18-fluorodeoxyglucose positron emission tomography imaging Duysinx B Nguyen D Louis R Cataldo D Belhocine T Bartsch P Bury T Chest 2004 125 489 493 10.1378/chest.125.2.489 14769729 Malignant mesothelioma 2008 Zervos MD Bizekis C Pass HI Curr Opin Pulm Med 2008 14 303 309 10.1097/MCP.0b013e328302851d 18520263 A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group Rusch VW Chest 1995 108 1122 1128 10.1378/chest.108.4.1122 7555126 CT, RECIST, and malignant pleural mesothelioma Nowak AK Lung Cancer 2005 49 Suppl 1 S37 40 10.1016/j.lungcan.2005.03.030 15950799 New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L Verweij J van Glabbeke M van Oosterom AT Christian MC Gwyther SG J Natl Cancer Inst 2000 92 205 216 10.1093/jnci/92.3.205 10655437 Modified RECIST criteria for assessment of response in malignant pleural mesothelioma Byrne MJ Nowak AK Ann Oncol 2004 15 257 260 10.1093/annonc/mdh059 14760119 Application of immunohistochemistry to the diagnosis of malignant mesothelioma Marchevsky AM Arch Pathol Lab Med 2008 132 397 401 18318582 CT-guided pleural needle biopsy in the diagnosis of malignant mesothelioma Metintas M Ozdemir N Isiksoy S Kaya T Ekici M Erginel S Harmanci E Erdinc P Ulgey N Alatas F J Comput Assist Tomogr 1995 19 370 374 7790544 Utility of osteopontin and serum mesothelin in malignant pleural mesothelioma diagnosis and prognosis assessment Grigoriu BD Scherpereel A Devos P Chahine B Letourneux M Lebailly P Gregoire M Porte H Copin MC Lassalle P Clin Cancer Res 2007 13 2928 2935 10.1158/1078-0432.CCR-06-2144 17504993 Asbestos exposure, pleural mesothelioma, and serum osteopontin levels Pass HI Lott D Lonardo F Harbut M Liu Z Tang N Carbone M Webb C Wali A N Engl J Med 2005 353 1564 1573 10.1056/NEJMoa051185 16221779 Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers Chang K Pastan I Proc Natl Acad Sci USA 1996 93 136 140 40193 8552591 10.1073/pnas.93.1.136 Mesothelin-family proteins and diagnosis of mesothelioma Robinson BW Creaney J Lake R Nowak A Musk AW de Klerk N Winzell P Hellstrom KE Hellstrom I Lancet 2003 362 1612 1616 10.1016/S0140-6736(03)14794-0 14630441 Soluble mesothelin-related peptides in the diagnosis of malignant pleural mesothelioma Scherpereel A Grigoriu B Conti M Gey T Gregoire M Copin MC Devos P Chahine B Porte H Lassalle P Am J Respir Crit Care Med 2006 173 1155 1160 10.1164/rccm.200511-1789OC 16456138 Soluble mesothelin-related protein – a blood test for mesothelioma Robinson BW Creaney J Lake R Nowak A Musk AW de Klerk N Winzell P Hellstrom KE Hellstrom I Lung Cancer 2005 49 Suppl 1 S109 111 10.1016/j.lungcan.2005.03.020 15950789 Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions Pass HI Wali A Tang N Ivanova A Ivanov S Harbut M Carbone M Allard J Ann Thorac Surg 2008 85 265 272 discussion 272 10.1016/j.athoracsur.2007.07.042 18154821 Biomarkers for mesothelioma Scherpereel A Lee YC Curr Opin Pulm Med 2007 13 339 443 10.1097/MCP.0b013e32812144bb 17534183 MESOMARK: a potential test for malignant pleural mesothelioma Beyer HL Geschwindt RD Glover CL Tran L Hellstrom I Hellstrom KE Miller MC Verch T Allard WJ Pass HI Sardesai NY Clin Chem 2007 53 666 672 10.1373/clinchem.2006.079327 17289801 Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma Onda M Nagata S Ho M Bera TK Hassan R Alexander RH Pastan I Clin Cancer Res 2006 12 4225 4231 10.1158/1078-0432.CCR-06-0472 16857795 BTS guidelines for the management of malignant pleural effusions Antunes G Neville E Duffy J Ali N Thorax 2003 58 Suppl 2 ii29 38 1766015 12728148 Recent advances in the diagnosis and management of malignant pleural effusions Heffner JE Klein JS Mayo Clin Proc 2008 83 235 250 18241636 Pleurodesis for malignant pleural effusions Shaw P Agarwal R Cochrane Database Syst Rev 2004 CD002916 14973997 Malignant pleural effusions: treatment with small-bore-catheter thoracostomy and talc pleurodesis Marom EM Patz EF Jr Erasmus JJ McAdams HP Goodman PC Herndon JE Radiology 1999 210 277 281 9885620 Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size Maskell NA Lee YC Gleeson FV Hedley EL Pengelly G Davies RJ Am J Respir Crit Care Med 2004 170 377 382 10.1164/rccm.200311-1579OC 15142871 The long-term morbidity of pleuroperitoneal shunts in the management of recurrent malignant effusions Genc O Petrou M Ladas G Goldstraw P Eur J Cardiothorac Surg 2000 18 143 146 10.1016/S1010-7940(00)00422-X 10925221 Management of malignant pleural effusions using the Pleur(x) catheter Warren WH Kalimi R Khodadadian LM Kim AW Ann Thorac Surg 2008 85 1049 1055 10.1016/j.athoracsur.2007.11.039 18291195 Multidisciplinary treatment of malignant pleural mesothelioma Ceresoli GL Gridelli C Santoro A Oncologist 2007 12 850 863 10.1634/theoncologist.12-7-850 17673616 Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation Davis SR Tan L Ball DL Australas Radiol 1994 38 212 214 10.1111/j.1440-1673.1994.tb00177.x 7524472 The role of palliative radiotherapy in malignant mesothelioma Bissett D Macbeth FR Cram I Clin Oncol (R Coll Radiol) 1991 3 315 317 1720658 The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy Ball DL Cruickshank DG Am J Clin Oncol 1990 13 4 9 10.1097/00000421-199002000-00002 1689538 Radiation therapy in the management of patients with mesothelioma Gordon W Jr Antman KH Greenberger JS Weichselbaum RR Chaffey JT Int J Radiat Oncol Biol Phys 1982 8 19 25 6174494 The role of radiotherapy in the treatment of malignant pleural mesothelioma Waite K Gilligan D Clin Oncol (R Coll Radiol) 2007 19 182 187 17359904 Radiotherapy for malignant pleural mesothelioma Chapman E Berenstein EG Dieguez M Ortiz Z Cochrane Database Syst Rev 2006 3 CD003880 16856023 Influence of radiotherapy technique and dose on patterns of failure for mesothelioma patients after extrapleural pneumonectomy Allen AM Den R Wong JS Zurakowski D Soto R Janne PA Zellos L Bueno R Sugarbaker DJ Baldini EH Int J Radiat Oncol Biol Phys 2007 68 1366 1374 17674974 Multimodality approach in management of malignant pleural mesothelioma Neragi-Miandoab S Eur J Cardiothorac Surg 2006 29 14 19 10.1016/j.ejcts.2005.10.008 16343925 A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma Rusch VW Rosenzweig K Venkatraman E Leon L Raben A Harrison L Bains MS Downey RJ Ginsberg RJ J Thorac Cardiovasc Surg 2001 122 788 795 10.1067/mtc.2001.116560 11581615 Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation Forster KM Smythe WR Starkschall G Liao Z Takanaka T Kelly JF Vaporciyan A Ahamad A Dong L Salehpour M Komaki R Stevens CW Int J Radiat Oncol Biol Phys 2003 55 606 616 12573747 Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma Rice DC Smythe WR Liao Z Guerrero T Chang JY McAleer MF Jeter MD Correa A Vaporciyan AA Liu HH Komaki R Forster KM Stevens CW Int J Radiat Oncol Biol Phys 2007 69 350 357 17467922 Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma Allen AM Czerminska M Janne PA Sugarbaker DJ Bueno R Harris JR Court L Baldini EH Int J Radiat Oncol Biol Phys 2006 65 640 645 16751058 Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy Boutin C Rey F Viallat JR Chest 1995 108 754 758 10.1378/chest.108.3.754 7656629 Prevention of tumour seeding following thoracoscopy in mesothelioma by prophylactic radiotherapy Low EM Khoury GG Matthews AW Neville E Clin Oncol (R Coll Radiol) 1995 7 317 318 8580058 Drain site radiotherapy in malignant pleural mesothelioma: a wasted resource Muirhead R O'Rourke N Eur Respir J 2007 30 1021 10.1183/09031936.00079407 17978160 A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma O'Rourke N Garcia JC Paul J Lawless C McMenemin R Hill J Radiother Oncol 2007 84 18 22 10.1016/j.radonc.2007.05.022 17588698 Pleurectomy/decortication in the setting of multimodality treatment for diffuse malignant pleural mesothelioma Rusch VW Semin Thorac Cardiovasc Surg 1997 9 367 372 9352954 Deterioration in lung function following hemithorax irradiation for pleural mesothelioma Maasilta P Int J Radiat Oncol Biol Phys 1991 20 433 438 1995528 Improved survival with VATS pleurectomy-decortication in advanced malignant mesothelioma Halstead JC Lim E Venkateswaran RM Charman SC Goddard M Ritchie AJ Eur J Surg Oncol 2005 31 314 320 10.1016/j.ejso.2004.08.014 15780570 Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients Flores RM Pass HI Seshan VE Dycoco J Zakowski M Carbone M Bains MS Rusch VW J Thorac Cardiovasc Surg 2008 135 620 626 10.1016/j.jtcvs.2007.10.054 18329481 Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies Sugarbaker DJ Jaklitsch MT Bueno R Richards W Lukanich J Mentzer SJ Colson Y Linden P Chang M Capalbo L Oldread E Neragi-Miandoab S Swanson SJ Zellos LS J Thorac Cardiovasc Surg 2004 128 138 146 10.1016/j.jtcvs.2004.02.021 15224033 Pleural mesothelioma: little evidence, still time to do trials Treasure T Sedrakyan A Lancet 2004 364 1183 1185 10.1016/S0140-6736(04)17108-0 15451229 Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients Sugarbaker DJ Garcia JP Richards WG Harpole DH Jr Healy-Baldini E DeCamp MM Jr Mentzer SJ Liptay MJ Strauss GM Swanson SJ Ann Surg 1996 224 288 294 discussion 294–286 1235368 8813257 10.1097/00000658-199609000-00005 The MARS trial: mesothelioma and radical surgery Treasure T Tan C Lang-Lazdunski L Waller D Interact Cardiovasc Thorac Surg 2006 5 58 59 10.1510/icvts.2005.123430 17670513 Pemetrexed disodium in combination with cisplatin versus other cytotoxic agents or supportive care for the treatment of malignant pleural mesothelioma Green J Dundar Y Dodd S Dickson R Walley T Cochrane Database Syst Rev 2007 CD005574 17253564 Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis Berghmans T Paesmans M Lalami Y Louviaux I Luce S Mascaux C Meert AP Sculier JP Lung Cancer 2002 38 111 121 10.1016/S0169-5002(02)00180-0 12399121 Good symptom relief with palliative MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in malignant mesothelioma Middleton GW Smith IE O'Brien ME Norton A Hickish T Priest K Spencer L Ashley S Ann Oncol 1998 9 269 273 10.1023/A:1008236010868 9602260 The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma Andreopoulou E Ross PJ O'Brien ME Ford HE Priest K Eisen T Norton A Ashley S Smith IE Ann Oncol 2004 15 1406 1412 10.1093/annonc/mdh356 15319247 Phase II study of vinorelbine in patients with malignant pleural mesothelioma Steele JP Shamash J Evans MT Gower NH Tischkowitz MD Rudd RM J Clin Oncol 2000 18 3912 3917 11099320 Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma Vogelzang NJ Rusthoven JJ Symanowski J Denham C Kaukel E Ruffie P Gatzemeier U Boyer M Emri S Manegold C Niyikiza C Paoletti P J Clin Oncol 2003 21 2636 2644 10.1200/JCO.2003.11.136 12860938 Improving quality of life in patients with malignant pleural mesothelioma: results of the randomised pemetrexed + cisplatin trial using the LCSS-meso instrument (abstract) Gralla R Hollen P Liepa Aea Proc Am Soc Clin Oncol 2003 22 621 Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM) Castagneto B Botta M Aitini E Spigno F Degiovanni D Alabiso O Serra M Muzio A Carbone R Buosi R Galbusera V Piccolini E Giaretto L Rebella L Mencoboni M Ann Oncol 2008 19 370 373 10.1093/annonc/mdm501 18156144 Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada van Meerbeeck JP Gaafar R Manegold C van Klaveren RJ van Marck EA Vincent M Legrand C Bottomley A Debruyne C Giaccone G J Clin Oncol 2005 23 6881 6889 10.1200/JCO.20005.14.589 16192580 Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma Weder W Stahel RA Bernhard J Bodis S Vogt P Ballabeni P Lardinois D Betticher D Schmid R Stupp R Ris HB Jermann M Mingrone W Roth AD Spiliopoulos A Ann Oncol 2007 18 1196 1202 10.1093/annonc/mdm093 17429100 Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial Flores RM Krug LM Rosenzweig KE Venkatraman E Vincent A Heelan R Akhurst T Rusch VW J Thorac Oncol 2006 1 289 295 10.1097/01243894-200605000-00004 17409872 BTS randomised feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma: ISRCTN 54469112 Muers MF Rudd RM O'Brien ME Qian W Hodson A Parmar MK Girling DJ Thorax 2004 59 144 148 1746929 14760156 10.1136/thorax.2003.009290 A randomised Phase III trial of active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma. The Medical Research Council/British Thoracic Society MSO 1 Trial [abstract] Muers M Fisher P O'Brien ME Peake M Rudd RM Snee M Steele JP Nankivell M Pugh C Stephens R Thorax 2007 62 A49