Malignant mesothelioma

Transcription

1 Published Online January 4, 2010 Malignant mesothelioma R. M. Rudd * London Lung Cancer Group, 54 New Cavendish Street, London W1G 8TQ, UK Introduction: Mesothelioma is a malignant tumour of the pleura or peritoneum caused by asbestos. It is increasing in frequency and the prognosis remains grim, with average survival around 1 year. Sources of data: Medical literature and personal experience. Areas of agreement: Amphibole fibres are far more potent than chrysotile in causing mesothelioma. Areas of controversy: A minority view suggests that mesotheliomas in those exposed to chrysotile are caused only by tremolite (an amphibole) which contaminates chrysotile. There is a hypothesis, for which evidence is weakening, that Simian virus 40 may cause mesothelioma. Growing points: There is emerging evidence of genetic variation in susceptibility to fibre carcinogenesis. There are developments in treatment, particularly chemotherapy with pemetrexed and cisplatin which prolongs survival and helps symptoms. Areas timely for developing research: Targeted agents for treatment are under investigation and may improve the outlook. The role of radical and palliative surgery requires clarification. Keywords: mesothelioma/asbestos/epidemiology/chemotherapy/surgery Definition Malignant mesothelioma is a tumour which arises from mesothelial or possibly more primitive sub-mesothelial cells. It occurs most commonly in the pleura but also in the peritoneum and rarely in the pericardium or tunica vaginalis testis. Accepted: November 12, 2009 *Correspondence to: Dr R. M. Rudd, London Lung Cancer Group, 54 New Cavendish Street, London W1G 8TQ, UK. dr@robinrudd.com British Medical Bulletin 2010; 93: DOI: /bmb/ldp047 & The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 R. M. Rudd Epidemiology A very large majority of cases of mesothelioma is caused by asbestos exposure, probably of the order of 95% in industrialized countries. The annual incidence in persons with no known exposure to asbestos has been estimated at around 1 2 per million population by extrapolating backwards from epidemiological studies in several countries. 1 This translates to a lifetime risk of death from the disease of around 1 in A recent British study has suggested a higher lifetime risk of around 1 in 1000 for persons with no identified exposure but an increasing death rate in females and a substantially higher female death rate than in the USA suggest that many of these cases are due to unidentified environmental asbestos contamination. 2 Occupational asbestos exposure increases the risk greatly. In North American insulators first exposed to asbestos before the age of 20, it has been estimated that the risk of death from mesothelioma by age 80 is one in seven. 3 Mesothelioma has been increasing in incidence throughout Western Europe for several decades and is expected to continue to do so until a peak is reached between 2010 and This reflects the increasing use of asbestos in industrialized countries until the mid-1970s and the long latent period between exposure and disease. The British mesothelioma death rate is now the highest in the world, accounting for 1740 deaths in men, around 1 in 40 of all male cancer deaths below age 80, and 316 deaths in women in About 1 in 170 of all British men born in Britain in the 1940s will die of mesothelioma. The annual death rate in Great Britain is expected to peak at up to 2450 between 2011 and Cases in workers involved in industries typically associated with substantial asbestos exposure, such as insulation materials manufacture, insulation application, ship building and repair, are declining, whereas cases in construction workers are increasing. Many cases of mesothelioma have occurred in persons exposed to environmental pollution in the vicinity of asbestos mines and factories, and in persons who have shared a home with asbestos workers and who have been exposed to dust brought home on their clothing and hair. 7 There are increasing numbers of cases in persons exposed only as a result of working in buildings containing poorly maintained asbestos, constituting what has been called the third wave of the mesothelioma epidemic. Mesothelioma also occurs as a result of residence in areas where there are asbestiform minerals in the soil, e.g. parts of Greece, Cyprus and Turkey. Asbestos is still mined and exported by several countries including Canada, South Africa, Russia, China, Kazakhstan, India and Brazil. It is still used without adequate or even any precautions in many parts of 106 British Medical Bulletin 2010;93

3 Malignant mesothelioma the world. The mesothelioma epidemic which is currently hitting the western world can be expected to spread to more recently industrialized nations in the not too distant future. Dose and latency An increasing risk of mesothelioma with both intensity and duration of exposure has been demonstrated in various industrial cohorts. The mean latent period between first exposure to asbestos and death from mesothelioma is of the order of 40 years. 8 Latent periods of,20 years are uncommon and,15 years rare. There is no upper limit to the latent period. Asbestos fibre types There is extensive epidemiological evidence that amphiboles, of which the commercially important types are crocidolite (blue asbestos) and amosite (brown asbestos), are much more potent causes of mesothelioma than chrysotile (white asbestos). A study which calculated quantitative risks from cohorts which provided information on exposure levels suggested that the potency for the three main types of asbestos used commercially was in the ratio 1:100:500 for chrysotile, amosite and crocidolite. 9 There is a hypothesis to the effect that even those mesotheliomas which occur in persons exposed exclusively to commercial chrysotile are caused not by the chrysotile fibres but by small quantities, usually around 1% or less, of an amphibole called tremolite contaminating it, the so-called amphibole hypothesis. The evidence for this view rests largely on studies of Quebec chrysotile miners and millers in whom the incidence of mesothelioma is low but varies with the extent of tremolite contamination of the chrysotile. 10 Chrysotile is cleared from the lungs much more rapidly than amphiboles and this probably at least partly explains its lower carcinogenic potential. Animal studies suggest that fibre dimension is important in determining carcinogenicity with few mesotheliomas occurring with amosite or chrysotile fibres shorter than 5 mm. Asbestos fibres of occupational origin commonly contain a substantial proportion of longer fibres, whereas most fibres of environmental origin are shorter. Genetic factors Endemic pleural mesothelioma occurs in Karain in the Cappadocian region of Turkey where in some areas, mesothelioma is the most British Medical Bulletin 2010;93 107

4 R. M. Rudd common cause of death in adults. The very high incidence of mesothelioma is due to exposure to erionite, a type of zeolite, found in rock used by the inhabitants to build their houses. Erionite is an asbestiform mineral with a high potency to cause mesothelioma in animal experiments. Recently, it was observed that mesothelioma occurred mostly in specific homes where entire families had died from the disease, whereas others were unaffected. Moreover, in Karlik, another village where homes were built with stone from the same caves as used by inhabitants of Karain, there had been only one case and that was in a woman who had moved from Karain. These observations led to a study in which a six-generation extended pedigree was constructed. There were six families in which there was obvious clustering of mesothelioma cases. The pattern of cases suggested that mesothelioma was genetically transmitted, probably in an autosomal dominant way. 11 The findings suggest that susceptibility to the carcinogenic effects of asbestos is genetically determined. Mesothelioma and Simian virus 40 There has been interest in the possible role of an oncogenic polyoma virus, Simian virus 40, in causation of human mesothelioma. The virus can transform human cells in vitro and induce tumours, including mesothelioma, in laboratory animals. The virus is thought to have infected humans via contaminated parenteral polio vaccine used in the 1950s and early 1960s, most widely in the USA. However, the frequency with which evidence of polyoma virus has been in mesothelioma has varied widely from around 60% down to zero in different series from different countries. Recent studies suggest that its apparent presence is likely to be a result of laboratory contamination. An epidemiological study in Great Britain failed to find evidence of an increased risk of mesothelioma in cohorts likely to have received the infected vaccine. 12 Radiation There is anecdotal evidence from case series that past radiotherapy is a risk factor for the development of mesothelioma. 13 Tobacco smoking There is no evidence that tobacco smoking increases the risk of development of mesothelioma British Medical Bulletin 2010;93

5 Malignant mesothelioma Pathogenesis Fibres which have migrated directly through the visceral pleura may be reabsorbed into the parietal pleura through black spots located near lymphatic vessels. They may be transported in the lymphatics from the lungs to the abdomen where they have been found in lymph nodes and other abdominal organs. Asbestos is also transported across the mucosa of the intestinal tract after ingestion which may be relevant to peritoneal mesothelioma. Asbestos is a complete carcinogen for mesothelioma. The mechanism of malignant transformation is incompletely understood. Asbestos is an established genotoxic agent that can induce DNA damage, at least partly by evoking production of free radicals, gene transcription and protein expression important in modulating cell proliferation and cell death. 15 Mesothelioma cell lines are more resistant to apoptosis than non-transformed cells at least partly because they are more resistant to the cytotoxic effects of an oxidant stress. Pathology The right pleura is more commonly involved than the left and it has been suggested that this may be due to its greater surface area. However, if that is the explanation, it is puzzling that pleural plaques show a left-sided preponderance. In the early stages of the disease, the tumour often appears as multiple nodules on the surface of the visceral and parietal pleurae. Occasionally, a localized pleural mass may develop but more often the nodules coalesce to form a sheet of tumour which surrounds the lung, extends along the fissures and may invade the underlying parenchyma. Pericardial and diaphragmatic invasion are common. Bronchial invasion, usually by spread from the pleura near the hilum, is uncommon and may lead to diagnostic confusion if tumour is visible at bronchoscopy. Peritoneal mesothelioma has similar gross features, producing multiple peritoneal nodules and eventually encasement of abdominal organs. At post-mortem examination, distant metastases are common, occurring in about two-thirds of the cases with sarcomatoid type and one-third of the patients with the epithelioid and mixed types. 16 Histological types Diffuse malignant mesothelioma falls into three main histological types: epithelioid which is most common, sarcomatoid and mixed or British Medical Bulletin 2010;93 109

6 R. M. Rudd biphasic. The epithelial variety displays several patterns including tubulopapillary and glandular. Histochemical and immunohistochemical stains assist in differentiating epithelioid mesothelioma from adenocarcinoma, the most common and difficult differential diagnosis. Commonly used stains are shown in Table Sarcomatoid mesotheliomas occur in different patterns, most often spindle cells set in a variable amount of stroma. The desmoplastic variant consists almost entirely of collagenous stroma containing single cytologically atypical cells and this can be very difficult to distinguish from benign pleural fibrosis. Immunostains for broad-spectrum cytokeratins may assist in differentiating sarcomatoid mesotheliomas, which react positively, from sarcomas, which react negatively. Mixed or biphasic tumours show a mixture of epithelioid and sarcomatoid elements. This type is the easiest to distinguish from other tumours (Fig. 1). Occasionally, definitive pathological diagnosis may be impossible, particularly with sarcomatoid mesothelioma, and correlation with clinical and radiological features is necessary to achieve a diagnosis, on the balance of probabilities. It is important not to confuse other conditions to which the term mesothelioma has been applied with diffuse malignant mesothelioma. Localized fibrous tumour of the pleura has been known as benign or localized mesothelioma. It is unrelated to asbestos exposure and has a much better prognosis. Multicystic mesothelial proliferation is a rare condition affecting the peritoneum which has been known by various names, including multicystic mesothelioma, but it is now recognized to be a reactive rather than neoplastic lesion, unrelated to asbestos exposure. The prognosis is good though the condition tends to recur. Asbestos fibre counts Fibre counts in the lungs in cases of mesothelioma are higher, on average, than in control subjects without known asbestos exposure, but Table 1: Differentiation of mesothelioma from adenocarcinoma 17. Mesothelioma Cytoplasm contains glycogen but no diastase-resistant PAS-positive material Alcian blue-positive hyaluronic acid in glands or on tumour cell surface CEA, Leu M 1, Ber Ep4, AUA1 and TTF-1-negative Nuclear staining with calretinin present Cytokeratin 5/6, thrombomodulin and WT-1-positive Adenocarcinoma Glycogen content is small. May contain diastase-resistant PAS-positive mucin No hyaluronic acid within or on tumour cells CEA, Leu M 1, Ber Ep4, AUA1 and TTF-1-positive Nuclear staining with calretinin absent Cytokeratin 5/6, thrombomodulin and WT-1 negative 110 British Medical Bulletin 2010;93

7 Malignant mesothelioma Fig. 1 Histological section showing mesothelioma of mixed type, sarcomatoid in the upper part of the picture and epithelioid in the lower part. lower than in cases of asbestosis because mesothelioma can occur after much lower doses of asbestos than are necessary to cause asbestosis. There is overlap between the range of fibre counts seen in persons British Medical Bulletin 2010;93 111

8 R. M. Rudd without known exposure to asbestos in excess of background exposure from air pollution and the range found in persons who have developed mesothelioma after known low-level occupational exposure. Hence, while a fibre level clearly in the occupational range strongly supports causation of a mesothelioma by asbestos, a level within the background range is not evidence against causation of mesothelioma by welldocumented asbestos exposure. 18 Fibre analysis is thus most useful for identifying exposure when the patient has no recollection of having been exposed. Clinical presentation and course The majority of cases occur in men, reflecting their greater frequency of occupational asbestos exposure. A careful occupational history should be taken when mesothelioma is suspected or confirmed. Many patients initially answer negatively when asked if they have worked with asbestos but detailed enquiry reveals unsuspected direct or bystander exposure to asbestos used or disturbed by others in their vicinity. Median age at presentation is in the seventh decade but the disease may occur at any age. 8 Mesothelioma typically presents with rapid onset of breathlessness due to development of a pleural effusion. There is an effusion at presentation in about 70% of the cases. The other common presenting symptom is chest pain which may not be accompanied by an effusion. There may be anorexia, weight loss and general malaise. Profuse sweats, particularly at night, often occur. Usually, the effusion resolves later in the course of the disease, either because of treatment by pleurodesis or because of fusion between the lung and chest wall caused by the tumour, largely obliterating the pleural space. The affected side of the thorax becomes contracted and expands little on inspiration. Scoliosis may develop because of the contracted hemithorax. Pain often becomes progressively worse due to infiltration of nerve roots or other tissues of the chest wall, including bone. In the late stages, there may be extensive infiltration of the chest wall producing a diffuse induration which may extend subcutaneously to the upper abdomen. Subcutaneous nodules may develop, particularly at sites of previous pleural aspiration or biopsy. Other late features may include superior vena caval obstruction, pericardial tamponade due to malignant effusion or pericardial constriction due to tumour invasion of the pericardium. The tumour may spread to the abdominal cavity causing ascites. Contrary to popular belief, mesotheliomas may metastasize widely to all areas 16 including the contralateral pleura and lung, intra- and extra-thoracic lymph nodes, liver, bone and brain. 112 British Medical Bulletin 2010;93

9 Malignant mesothelioma Peritoneal mesothelioma commonly presents late, after insidious onset of ill-defined abdominal symptoms. Abdominal distension due to ascites is commonly the development which leads to the diagnosis. Eventually, irregular tumour masses may be palpable. Abdominal pain and vomiting due to subacute intestinal obstruction are common in the terminal phase. Pericardial mesothelioma presents with tamponade due to pericardial effusion or pericardial constriction by tumour. Mesothelioma of the tunica vaginalis testis presents with a testicular swelling. Investigations Imaging The chest X-ray may show a pleural effusion and/or pleural thickening. There may be evidence of other asbestos-related conditions such as pleural plaques, pleural thickening or asbestosis. The computed tomographic (CT) scan shows the changes more clearly. Pleural thickening due to mesothelioma may be uniform or only slightly irregular or it may be grossly lobulated. CT features favouring malignant over benign pleural disease are circumferential pleural thickening, nodular pleural thickening, parietal pleural thickening.1 cm, mediastinal pleural involvement and chest wall invasion 19 (Fig. 2). Magnetic resonance imaging offers little advantage unless radical surgery is under consideration. It may then help to delineate the extent of involvement of the diaphragm, mediastinum and chest wall. Positron emission tomography (PET) can identify and stage mesothelioma and help to differentiate it from benign pleural thickening which usually has low uptake of 2-fluoro-2-deoxy-D-glucose. Tissue diagnosis Although imaging can indicate a likelihood of mesothelioma, it cannot provide a definitive diagnosis. Even if the imaging leaves no doubt that the process is malignant, it is impossible to distinguish reliably between mesothelioma and metastatic carcinoma on radiological grounds. Knowledge of the histological type gives useful prognostic information. If any specific therapy is to be considered, a pathological diagnosis is essential. In the advanced case where life expectancy is short, or in patients with co-existing disease which would preclude specific British Medical Bulletin 2010;93 113

10 R. M. Rudd Fig. 2 CT scan showing mesothelioma invading the chest wall. treatment, it is sometimes acceptable to make a diagnosis on the basis of typical clinical and radiological features. Histological diagnosis is more useful than cytology of pleural fluid because of its greater sensitivity and specificity and its ability to identify subtype. Blind pleural biopsy using an Abrams needle has a very low sensitivity of around 20%. If there is a suitable target lesion, ultrasound or CT-guided cutting-needle biopsy gives a diagnostic sensitivity of around 80 85%. 17 If there is no suitable target for percutaneous biopsy, thoracoscopic biopsy yields a diagnosis in most cases. Open biopsy is occasionally necessary when the pleural space is obliterated so that thoracoscopy is not possible and a percutaneous biopsy has failed to give the diagnosis. Even after open biopsy, the diagnosis may remain elusive because of sampling error and may only be confirmed at post-mortem examination. Staging The most widely used system is that devised by the International Mesothelioma Interest Group (IMIG) based upon a TNM (tumour, node, metastasis) system 20 (Tables 2 and 3). It is often impossible to apply this fully without information from thoracoscopy to assess the 114 British Medical Bulletin 2010;93

11 Malignant mesothelioma Table 2: New International Staging System for Malignant Pleural Mesothelioma (IMIG): TNM staging (Rusch). T1 T1a Tumour limited to the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura. No involvement of the visceral pleura T1b Tumour involving the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura. Scattered foci of tumour also involving the visceral pleura T2 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) or extension of tumour from visceral pleura into the underlying pulmonary parenchyma T3 Describes locally advanced but potentially resectable tumour. Tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral) 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 T4 Describes 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, or tumour involving the myocardium N Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes N2 Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes including the ipsilateral internal mammary nodes N3 Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral or contralateral supraclavicular lymph nodes M Metastases MX Presence of distant metastases cannot be assessed M0 No distant metastasis M1 Distant metastasis present degree of visceral and parietal pleural involvement. Such information may well have been obtained in the course of the diagnostic process but if not an approximation can be attempted from the CT scan. Serological tests There is increasing interest in identifying a blood-based marker for mesothelioma. Three potential markers are mesothelin, British Medical Bulletin 2010;93 115

12 R. M. Rudd Table 3: New International Staging System for Malignant Pleural Mesothelioma (IMIG): Clinical staging (Rusch). Stage Stage I Ia Ib Stage II Stage III Stage IV Description T1aN0M0 T1bN0M0 T2N0M0 Any T3M0 Any N1M0 Any N2M0 Any T4 Any N3 Any M1 megakaryocyte-potentiating factor and osteopontin. A comparison of the three markers found that diagnostic sensitivity was not improved by adding the latter two markers to mesothelin for which sensitivity was 73% with a specificity compared with healthy controls of 95%. 21 The specificity is far too low for serum mesothelin to be used as a screening test for mesothelioma among asbestos exposed persons because many false positives would occur leading to unnecessary investigations and anxiety. Prognostic factors Unless radical surgery is being considered, other prognostic factors predict outcome more usefully than tumour stage. Factors predicting poor prognosis include poor performance status, non-epithelioid histology, low haemoglobin, high white count and high platelet count. 22 Those with sarcomatoid and mixed histology tend to die within about 12 months of diagnosis, whereas those with epithelioid histology tend to survive a few months longer. 8 Treatment Until fairly recently, it was widely felt that mesothelioma is an untreatable disease and that only palliative measures are appropriate. Some still hold this view but there has been increasing interest in the possibilities of anti-tumour therapy. This has been fuelled at least partly by patient demand, as numbers affected continue to rise and public expectations for cancer treatment increase. On the basis of recent data, it appears that a small minority of patients is suitable for potentially curative therapy and many others may be considered for anti-tumour 116 British Medical Bulletin 2010;93

13 Malignant mesothelioma chemotherapy or targeted therapy. The British Thoracic Society Statement on Mesothelioma highlighted the importance of the multidisciplinary team and discussed palliative measures in management of mesothelioma. 17 Extra-pleural pneumonectomy and trimodality therapy Pleural mesothelioma can be radically excised by extra-pleural pneumonectomy (EPP), i.e. removal of the whole lung and both layers of pleura, taking also any involved pericardium and diaphragm which are reconstituted with synthetic materials. Sites of previous pleural biopsy or drainage are also excised, in case there has been seeding with tumour. Intra- and extra-pleural lymph nodes are sampled for accurate pathological staging. Following surgery, radiotherapy to the thorax and chemotherapy are commonly used, referred to as trimodality therapy. 23 Among 183 patients treated in a large series, there were seven perioperative deaths (3.8%). 23 For the rest, the median survival was 19 months, with 38% surviving 2 years and 15% surviving 5 years. These rather disappointing figures for the whole group reflect a broad spectrum of outcomes according to different prognostic variables. The important variables predicting a better outcome were epithelioid tumour type, lack of extra-pleural lymph node involvement and negative resection margins. Among a subset of 31 patients with all these features, the median survival was 51 months, with 68% surviving 2 years and 46% surviving 5 years. The poor outcome in patients with extra-pleural node involvement suggests that pre-operative node staging by mediastinoscopy or PET scan may be worthwhile. Similar results from EPP have been reported from elsewhere with median survivals between 10 and 24 months In a series which compared in a non-randomized manner, EPP and pleurectomy median survival in patients after EPP was 10 months compared with 18 months after pleurectomy, but this may have reflected earlier tumour stage in those undergoing pleurectomy. 24 The site of relapse differed according to the type of surgery, local relapse being more common after pleurectomy and distant relapse, particularly in the contralateral pleura and abdomen occurring more commonly after EPP. On the basis of these data, it is reasonable to consider radical surgery for highly selected patients with early-stage disease, i.e. IMIG stages I and perhaps II without extra-pleural node involvement, with epithelioid histology and good performance status. The outcome in patients with sarcomatoid and biphasic tumours, or with extra-pleural node involvement, is very poor and radical surgery should not be offered to these patients. It is important to appreciate that EPP has not been British Medical Bulletin 2010;93 117

14 R. M. Rudd demonstrated to prolong survival in a randomized trial. A recent pilot trial which randomly allocated patients to EPP or no surgery, known as the MARS trial, closed after 50 patients were recruited over a period of 3 years. 28 Results are awaited but the trial does not have the power to determine whether there is any survival benefit from surgery. It is doubtful that any trial large enough to answer this question will be performed in future and careful standardized data collection may be a more realistic option for increasing knowledge in this area. Palliative surgery It is important for quality of life to obtain effective pleurodesis. Talc in slurry administered through a chest drain at the bedside is usually successful. 17 If an initial attempt at pleurodesis with talc in suspension fails, it is worth going on to thoracoscopic talc poudrage which is more effective. Some surgeons advocate so-called cytoreductive surgery, i.e. removal of as much as possible of the tumour, usually by means of video-assisted thoracoscopy. 29 There is a significant morbidity from complications such as chronic infection and air leak requiring prolonged chest drainage. A randomized trial is currently in progress comparing quality of life comparing thoracoscopic resection with bedside pleurodesis. When the lung is bound down by visceral pleural tumour so that pleurodesis cannot be achieved, a tunnelled indwelling chest drain may be used so that the patient or a carer can drain fluid into a bag periodically. 30 Radiotherapy Radiotherapy may be helpful for reducing the size of chest wall masses and alleviating localized pain in more than half the patients treated but responses are usually short-lived. 31 Radiotherapy seldom produces a partial response of intra-thoracic disease, as assessed by radiological criteria, and it has not been found to improve survival. The lack of response of intra-thoracic disease is probably related at least partly to the difficulty in administering a sufficient dose to disease spread over a large area. There is interest in possible utility of sophisticated computerized planning techniques to target all the tumours without damaging neighbouring structures. There is conflicting evidence as to whether prophylactic radiation of biopsy and drain sites reduces the frequency of tumour seeding. A recent review noted that of three randomized controlled trials, two did 118 British Medical Bulletin 2010;93

15 Malignant mesothelioma not support the use of radiation and none of those trials included patients who had received chemotherapy. 32 The randomized studies used different schedules and timing of radiation. Some non-randomized studies reported low rates of track seeding after radiotherapy. About 75% of UK centres which responded to a survey were currently using radiotherapy. A clear evidence-based recommendation cannot be given on present evidence and a further large trial is needed. An argument for radiotherapy is that it is of relatively low toxicity and may be helpful. If used, radiotherapy should be administered within 4 weeks and preferably within 15 days of the biopsy or drainage procedure, and all sites which have been used should be irradiated. Chemotherapy There have been important recent developments in chemotherapy for mesothelioma. The largest randomized trial of chemotherapy in mesothelioma yet carried out compared a combination of pemetrexed, a multi-targeted anti-folate, and cisplatin (PC) with cisplatin (C) alone in 456 patients with mesothelioma. 33 Part way through the trial, vitamin B12 and folate supplementation was introduced to reduce toxicity from pemetrexed. Median survival with pemetrexed was 12.1 months, significantly.9.3 months with cisplatin alone, and in vitamin supplemented patients, median survivals were 13.2 and 10.0 months, respectively. Symptom relief was greater with pemetrexed also, although full quality of life data have not been published. Similar results were achieved in a randomized trial comparing raltitrexed, another anti-folate, plus cisplatin with cisplatin alone in 250 patients. 34 A UK three-arm randomized trial compared active supportive care with two chemotherapy regimes, single-agent vinorelbine and the combination of mitomycin, vinblastine and cisplatin (MVP). 35 Both regimes have shown tumour response rates of around 20% and symptomatic benefit in phase II studies. Because of slow recruitment, the study was closed with 409 of an intended total of 840 patients entered. The chemotherapy arms were combined for analysis which did not show a significant survival advantage, median 8.5 months compared with 7.6 months for supportive care. Exploratory analyses showed that patients on vinorelbine had longer survival than ASC patients, median 9.4 months, but there was no suggestion of any survival benefit with MVP. There was no difference between the arms in overall quality of life. Further studies with pemetrexed have shown that similar results may be obtained by combining it with carboplatin rather than cisplatin, with reduced toxicity and greater convenience of adminstration. 36 British Medical Bulletin 2010;93 119

16 R. M. Rudd There is preliminary evidence from open rather than randomized studies that second-line chemotherapy 37 and maintenance chemotherapy with pemetrexed 38 may be of benefit to selected patients fit enough to receive it. There is uncertainty regarding the optimal timing of chemotherapy. There is a common tendency to defer treatment while the patient feels relatively well, after initial effective management of a pleural effusion by pleurodesis. The drawback is that the transition from too well for chemotherapy to too ill for chemotherapy can be unexpectedly rapid, so many patients miss the opportunity to benefit from chemotherapy. A small randomized study using relatively ineffective chemotherapy found a survival advantage from early rather than delayed chemotherapy. 39 Further studies with more effective regimes are needed. In the current state of knowledge, all patients who would be fit enough to receive chemotherapy should be given accurate information about it and should have the opportunity to receive it if they wish. The benefits are modest but not dissimilar to those obtained with chemotherapy in advanced non-small cell lung cancer. Pemetrexed with a platinum agent is the regime of first choice. Pemetrexed is now, after an initial delay, approved by NICE for the treatment of pleural mesothelioma in the UK. Other systemic treatments Increasing knowledge of carcinogenesis has led to the discovery of many ways in which tumour cells differ from normal cells and so-called targeted therapies try to exploit these to inhibit and kill tumour cells without damaging normal cells. Various angiogenesis inhibitors and cell cycle pathway inhibitors have shown minor activity in phase II trials, including vatalanib which inhibits all vascular endothelial growth factor tyrosine kinases 40 and sunitinib 41 which is an oral multitargeted receptor tyrosine kinase inhibitor which has useful activity in renal carcinoma. Epithelial growth factor inhibitors such as gefitinib 42 and erlotinib 43 which have proved useful in lung cancer have disappointingly proved ineffective in mesothelioma. Many studies of new agents are in progress. Initial reports of tumour responses with interleukin-2 and interferon did not lead to useful treatment. There has been considerable interest in the possibility of gene therapy for mesothelioma but work is at an early stage and it is not yet a practical treatment option. 120 British Medical Bulletin 2010;93

17 Malignant mesothelioma Pain relief Thoracic pain is a common and difficult problem in pleural mesothelioma. Radiotherapy may help, particularly if the pain is localized and due to chest wall invasion. Transdermal fentanyl is a useful alternative to opiates for severe pain. If pain is intractable to analgesics, percutaneous cervical cordotomy is a valuable last resort which is usually successful and can transform quality of life. 44 Treatment of mesothelioma at other sites Peritoneal mesothelioma is generally regarded as resistant to treatment by any means but there are advocates of an aggressive approach analogous to that used for early-stage pleural mesothelioma. 45 Chemotherapy has not been demonstrated to be beneficial in a randomized trial but may reasonably be attempted in fitter patients. Compensation Most patients with mesothelioma will be eligible to apply for compensation. In the UK, there are two routes. All patients can claim statutory compensation from the government. Those who can identify one or more sources of asbestos exposure can also pursue a claim at common law. They have to prove that exposure was negligent in the light of knowledge at the time it occurred as well as causation of their disease by the exposure. References 1 McDonald JC, McDonald AD (1996) The epidemiology of mesothelioma in historical context. Eur Respir J, 9, Rake C, Gilham C, Hatch J, Darnton A, Hodgson J, Peto J (2009) Occupational, domestic and environmental mesothelioma risks in the British population: a case control study. Br J Cancer, 100, Peto J, Seidman H, Selikoff IJ (1982) Mesothelioma mortality in asbestos workers: implications for models of carcinogenesis and risk assessment. Br J Cancer, 45, Peto J, Decarli A, La Vecchia C, Levi F, Negri E (1999) The European mesothelioma epidemic. Br J Cancer, 79, Peto J, Rake C, Gilham C, Hatch J (2009) Occupational, Domestic and Environmental Mesothelioma Risks in Britain. Norwich: Health and Safety Executive. 6 Hodgson JT, McElvenny DM, Darnton AJ, Price MJ, Peto J (2005) The expected burden of mesothelioma mortality in Great Britain from 2002 to Br J Cancer, 92, Newhouse ML, Thompson H (1965) Mesothelioma of the pleura and peritoneum following exposure to asbestos in the London area. Br J Ind Med, 22, British Medical Bulletin 2010;93 121

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