Malignant pleural mesothelioma: The standard of care and challenges for future management

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1 Critical Reviews in Oncology/Hematology 78 (2011) Malignant pleural mesothelioma: The standard of care and challenges for future management Jan P. van Meerbeeck a,, Arnaud Scherpereel b, Veerle F. Surmont a, Paul Baas c a Long Oncologisch Netwerk Gent (LONG), Department of Respiratory Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium b Pulmonary and Thoracic Oncology, University Hospital (CHRU) of Lille II, France c Thoracic Oncology, Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands Accepted 9 April 2010 Contents 1. Introduction Etiology and epidemiology Clinical presentation and natural history Diagnosis and staging Management of MPM Supportive treatment Prophylactic radiotherapy Palliative radiotherapy Palliative surgery Palliative chemotherapy Biological and targeted therapies Radical treatment Guidelines Discussion and areas of further research Advanced and inoperable/unresectable locally advanced early stage MPM Early and operable/borderline resectable MPM Conclusions Reviewer References Biography Abstract This review addresses the management of MPM. In an introductory section, the etiology, epidemiology, presentation, diagnosis and staging of MPM will be reviewed. The evidence was collected by a systematic analysis of the literature ( ) using the databases Medline (National Library of Medicine, USA), Embase (Elsevier, Netherlands), Cochrane Library (Great Britain), National Guideline Clearinghouse (USA), HTA Database (International Network of Agencies for Health Technology Assessment Abbreviations: CT scan, computer tomography scan; EPP, extrapleural pneumonectomy; ERS, European Respiratory Society; ESTS, European Society of Thoracic Surgery; Gy, Gray; IMRT, intensity-modulated radiotherapy; MPM, malignant pleural mesothelioma; NSCLC, non-small cell lung cancer; PET-scan, positron emission tomography scan; RCT, randomised clinical trial; VATS, video assisted thoracoscopic surgery. Corresponding author. address: jan.vanmeerbeeck@ugent.be (J.P. van Meerbeeck) /$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) INAHTA), NIH database (USA), International Pleural Mesothelioma Program WHOLIS (WHO Database) with the following keywords and filters: pleura, cancer, mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, palliation, supportive care, pleurodesis, review Elsevier Ireland Ltd. All rights reserved. Keywords: Pleura; Cancer; Mesothelioma; Guidelines; Treatment; Surgery; Chemotherapy; Radiotherapy; Palliation; Supportive care; Pleurodesis 1. Introduction 1.1. Etiology and epidemiology Mesothelioma is a rare malignant tumour originating from the cells lining the mesothelial surface of the coelomic cavities of the body: pleura, peritoneum, pericard and tunica vaginalis. Malignant pleural mesothelioma (MPM) is the commonest presentation, followed by the peritoneal localisation. Only rare pure cases of other origin have been reported. This manuscript will only address MPM. The etiology and epidemiology of MPM have recently been reviewed [1]. The background incidence of MPM is very low. Asbestos is the principal etiological agent of MPM. The first studies on the association between asbestos and MPM were published in the 1960s. Since most asbestos exposure is work-related, mesothelioma is an occupational disease in the majority of cases. This has obvious compensatory and medico-legal implications which differ among countries. Because past exposure to asbestos was more common in occupations with a predominantly male workforce, the current incidence of MPM is higher among men than among women. The risk fraction attributable to occupational asbestos exposure is higher than 80% in men, and lower than 40% in women. Over the last decades, a shift has been observed in the exposure history of mesothelioma cases, from primary asbestos workers (handling raw asbestos material) to end-users often exposed when installing asbestos products or handling asbestos materials still in place (construction workers, electricians, plumbers, heating workers, etc.). Even if the occupations with the highest risk of mesothelioma belong to the first group, the number of subjects at risk of MPM is presently much larger in the latter. Environmental mesotheliomas are linked either with a natural exposure in areas of the world where asbestos (generally tremolite) exists as a geological component of the soil or with neighbourhood exposures in people living close to asbestos mines or factories. Para-occupational cases are described in households of asbestos workers, mainly because of domestic exposure via clothes used at work. A dose effect relationship has been demonstrated, but it is impossible to define a threshold of cumulative exposure below which there is no increased risk. Therefore, all individuals who have been exposed to asbestos are considered as a population at risk. The mean latency of MPM after exposure to asbestos is around 40 years (range years). The median age at diagnosis in Western countries is 69 years with an increasing fraction of elderly patients with co-morbidities. There are prominent differences in incidence of MPM reported from different countries worldwide varying from to 7 per million (Japan) to 40 per million (Australia) inhabitants per year. In Europe the incidence is around 20 per million with large intercountry variation. It is reasonable to accept that these differences are mainly due to differences in historical asbestos import and consumption. For the future, epidemiologists expect peak incidences in the very next decades. Because of the long latency of MPM and of national differences in the timing of reduction or ban of asbestos use, the timing of the peak incidence of MPM cannot be predicted precisely and may vary from one country to another. The peak is expected between 2015 and 2020 in Europe and may already have been reached in some countries (USA, Sweden). In countries which continue to use asbestos in the 21st century, the incidence of MPM is expected to increase in the next decades. Patient distribution will be younger and more female than in the Western countries. Due to a lack of accurate tools and of a curative treatment, screening for MPM even in populations at risk is currently not recommended [2] Clinical presentation and natural history MPM typically originates from the lower parietal pleura and the costodiaphragmatic sinus. Presenting clinical symptoms are most often dyspnea and chest pain, each present in 60% of patients [3]. Pneumothorax and paraneoplastic features are classical other presenting features. The average interval between onset of symptoms and diagnosis is 2 3 months. Dyspnea is due to the accumulation of pleural fluid in the thoracic cavity with atelectasis of the underlying lung and impaired diaphragmatic movement, grafted on pulmonary co-morbidity as COPD or asbestosis. Natural history of MPM is further characterised by progressive local expansion and invasion explaining much of the symptoms and signs. Invasion of the thoracic wall with its intercostal nervous structures causes chest pain and the development of chest wall lumps. The pain is pleuritic, lateralised, dull or diffuse with nociceptive, inflammatory and neuropathic components due to entrapment of intercostal thoracic, autonomic, or brachial plexus nerves and irradiating to upper abdomen, shoulder, or arm. This pain pattern has been called the costo-pleural syndrome. Encasement of the lung results in pneumonia, dyspnea and rarely, hemoptysis. Invasion of the mediastinal structures leads to superior vena cava syndrome, hoarseness, Pancoast or Horner s syndrome by nervous invasion, or dysphagia by compression of the esophagus. Invasion of the pericard and

3 94 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) of MPM. Chest CT scan is unsuitable for definitive diagnosis of MPM, but a rind-like tumour along the pleural cavity together with diffuse or nodular pleural thickening are suggestive of the disease [5,6] (Fig. 1). It is not recommended to make a diagnosis of mesothelioma based on cytology alone because of the high risk of diagnostic error. In view of the medico-legal aspects, a formal tissue diagnosis on a biopsy specimen of MPM is required to obtain compensation. The recommended way is thoracoscopy, except in cases with pleural symphysis or contraindication to thoracoscopy, when either a surgical or transthoracic needle biopsy can be substituted, albeit with a lower sensitivity. Besides light microscopy, appropriate immunohistochemistry is necessary to make the diagnosis and allow subtyping in either the epithe- Fig. 1. Interlobar fissure involvement in an 82-year-old man with MPM and a history of pleurodesis. Axial non-enhanced CT scan shows right-sided pleural thickening and a pleural mass that extends into the right major fissure (arrows) [144]. heart results in hemi-diaphragmatic paralysis, tamponade and arrhythmias. Spreading to the abdomen in ascites, constipation or even bowel obstruction; spreading to the contralateral hemithorax results in pleural effusion. Clinical lymphatic and hematogenous dissemination occurs only late in natural history but is fairly common in autopsy series. All organs can be involved, leading to case reports of unusual metastatic presentation, more often now that active treatments are applied and demise from local causes is postponed. Constitutional symptoms as fatigue, hyperhydrosis and weight loss are usually late symptoms. MPM has a dismal prognosis: median survival of untreated cases is 6 9 months with less than 5% 5-year survivors. Essential prognostic factors associated with better outcome are earlier stage and epithelioid histologic type [4]. Additional prognostic factors are the presence of symptoms, performance status, age, gender and weight loss. The prognostic value of asbestos exposure is controversial Diagnosis and staging The clinical manifestations of MPM are usually nonspecific and insidious and cannot be used alone as diagnostic criteria, even in case of previous asbestos exposure. Chest X-ray usually shows a unilateral pleural effusion or thickening. Chest X-ray alone should not be used for the diagnosis Table 1 UICC-6 staging classification of malignant pleural mesothelioma (adapted from [7,8]). Descriptor/stage T1 T1a T1b T2 T3 T4 N0 N1 N2 N3 M0 M1 Stage I Stage II Stage III Stage IV Extent of involvement Involvement of ipsilateral parietal pleura With or without mediastinal or diaphragmatic involvement but without involvement of the visceral pleura Involvement of ipsilateral parietal pleura, with focal involvement of the visceral pleura Involvement any of the ipsilateral pleural surfaces (p, m d) with at least one of the following: Involvement of diaphragmatic muscle And/or invasion from visceral pleura into underlying lung parenchyma Involvement all of the ipsilateral pleural surfaces, with at least one of the following: Invasion of the endothoracic fascia Extension into mediastinal fat Solitary focus of tumour invading the soft tissues of the chest wall Non-transmural involvement of the pericardium Involvement all of the ipsilateral pleural surfaces with at least one of the following: Extension to the internal surface of the pericardium w/wo effusion, peritoneum, mediastinal structures, contralateral pleura, spine Diffuse extension or multifocal mass in chest wall with or without rib destruction No lymph node involvement Involvement of ipsilateral bronchopulmonary, hilar lymph node Involvement of ipsilateral mediastinal and/or internal mammary and/or peri-diaphragmatic lymph node Involvement of any contralateral mediastinal and/or internal mammary and/or supraclavicular lymph node No extrathoracic metastasis Extrathoracic metastasis, hematogenous or in non-regional lymph nodes T1a N0 (IA); T1bN0 (IB) T2N0 Any T3, any N1 or any N2 Any T4, any N3 or any M1

4 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) Table 2A investigations to be considered in all patients at presentation/diagnosis (adapted from [1,12]). Investigations Including Confirmatory tests Physical examination Presence or absence of shrinking As appropriate hemithorax, cutaneous nodules, etc. Radiological investigations Chest X-ray: PA/lateral Chest X-ray: in-/expiration, pre-/post-drainage of pleural fluid Blood tests Hemoglobin, leukocytes, platelets, basic biochemistry Table 2B investigations performed in patients likely to receive any kind of active tumour directed treatment. Investigations Including Confirmatory tests Primary tumour Adequate biopsy for histology confirmation CT scan of chest and upper abdomen Spiral technique, with iv contrast, including at least level of both kidneys after drainage of pleural fluid Pulmonary function tests Forced vital capacity (FVC), forced expiratory volume 1 s (FEV1) Bone scan Brain CT/MRI Not routine, to be considered on clinical suspicion of dissemination only CT/MRI to confirm dubious findings lioid or non-epithelioid or sarcomatoid-subtype. Mixed forms occur, besides the rare desmoplastic and other variants [7]. In the absence of a uniform, robust and validated staging system, the experts advocate the use of the most recent TNMbased UICC-classification [8,9] (Table 1). Its main drawback is the inaccuracy in describing the actual T- and N-extent by the current imaging techniques with CT scan and MRI [10]. In clinical series, most patients present with locally advanced stage (stage III, 40%), followed by advanced (stage IV, 35%) and local (stages I II, 25%), respectively [11]. A three step pre-treatment staging assessment is recommended based on empirical observation, good clinical practice and the fact that the treatment intent differs between patients [1,12]. Whether a patient goes through all three steps depends strongly on the results of the procedures and the consequences for the choice of treatment with radical or palliative intent only. Step I is to be considered in all patients at presentation or diagnosis (Table 2A). Step II is to be considered in patients being candidate for any kind of active treatment (Table 2B). Step III is the final process of patient selection for combined modality or any radical loco-regional treatment (Table 2C). This last situation will be only the case in a minority of patients with pleural mesothelioma. Among the investigations to be considered in these patients are mediastinoscopy, MRI of the chest, video assisted thoracoscopy (VATS), E(B)US-FNA, FDG-PET-scan and laparoscopy. In the absence of comparative data no formal advice regarding their respective staging performance can be given. Further research should be done with regard to the comparative efficacy of different intra-thoracic techniques (mediastinoscopy, VATS, EUS-FNA) and the value of the newer ones (PET-CT, EBUS-FNA). In patients proceeding to step II or higher: (a) a diagnosis of mesothelioma should be confidently established; (b) the interval within which the pre-treatment assessment has to be finalised should be as short as possible; (c) recent (less than 1 month old) imaging studies should be available prior to invasive procedures or start of any treatment. Table 2C investigations to be considered in patients candidate for radical surgery or multimodality treatment. Area Investigation Comment Confirmatory tests Primary tumour Adequate biopsy for histological subtyping Diaphragm CT scan or MRI Extrathoracic, to exclude occult M1 FDG-PET/CT Biopsy of suspected extrathoracic lesions Mediastinum, excluding T4, N2/3 involvement Laparoscopy Cervical mediastinoscopy VATS, contralateral VATS MRI of the chest, gadolinium enhanced E(B)US-FNA According to institutional practice Investigational

5 96 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) Management of MPM Early reports of outcome in MPM have suffered from one or several of the following biases: (1) Inclusion of variable number of unproven cases of MPM, due to a lack of expertise of the pathologist with the disease. This has been addressed by a greater awareness among pathologists and the installation of central pathology panels. (2) A small sample size spread over many years of inclusion due to the rarity of the disease, restricted to a limited number of cities and institutions. With the increasing incidence, multicentre randomised trials became possible. Nevertheless, the first randomised trial in MPM was not published until 2003 [13]. (3) The use of variable inclusion criteria leading to patient groups with vastly different prognostic features. An example of a long disregarded prognostic factor is the interval between diagnosis and start of treatment [14]. (4) The difficulty of correctly addressing disease extent and clinical response in MPM, even with the advent of CT scan. This issue is now partly resolved by the use of the modified RECIST [15]. (5) The publication of (retrospective) series of operated patients in which per protocol analysis does not account in the denominator for patient selection, operative mortality and attrition in between the different steps of a multimodality treatment [16]. Prospective series should be primarily analysed as per intention to treat. (6) Retrospective series from cancer registries, attributing better outcome to treated than untreated patients, without correcting for obvious different prognostic factors between both groups [17]. The following paragraphs will review the existing solidified evidence of the management of MPM, consisting of supportive and prophylactic measures, palliative interventions and attempts of radical treatment with or without (neo-)adjuvant chemo(radio-)therapy. Ongoing and future research is addressed thereafter Supportive treatment Mesothelioma has a high symptom burden, exceeding reference scores on the EORTC quality of life questionnaire in lung cancer in the following areas: fatigue, dyspnoea, pain, insomnia, cough and anorexia [18]. Only dyspnea and pain will be discussed here in more dept, for these are frequently experienced by patients with MPM. Whenever dyspnoea is likely due to the accumulation of pleural fluid, a pleural aspiration is indicated, followed at symptomatic relapse, in good performance patients and in the absence of entrapped lung, by an early chemical pleurodesis. A thoracoscopic procedure entails visualisation of the pleural space under general anaesthetic or sedation, drainage of pleural fluid and instillation of a sclerosing agent. A bedside pleurodesis involves instillation of the sclerosant through a chest drain which has usually been inserted on the ward under local anaesthesia (thoracostomy). Pending the results of an ongoing randomised trial addressing the issue of VATS pleurectomy versus pleurodesis by either VATS or slurry [19], the conclusions of a Cochrane meta-analysis seems also applicable to MPM: (i) talc is a safe and the most effective sclerosing agent, provided low doses are used; (ii) thoracoscopic pleurodesis in comparison to bedside pleurodesis is associated with a greater likelihood of success, and in particular when comparing thoracoscopic versus bedside pleurodesis using talc [20]. This meta-analysis did however not include the largest RCT by the Cancer and Leukemia Group B (CALGB), in which in 449 patients with malignant pleural effusion no significant difference was observed in time to recurrent pleural effusion between thoracoscopic talc poudrage versus thoracic drainage with talc slurry instillation [21]. Furthermore, the thoracoscopic approach resulted in 6% toxic deaths, probably due to the higher doses of talc. Patient selection and institutional expertise are important predictive factors that should be taken into account when deciding to proceed to pleurodesis. Repeated aspiration or an indwelling chest drain may occasionally be the most practical way to manage recurrent effusions in very frail patients but should be avoidable if pleurodesis is performed early in the disease and before effusions have become loculated and/or the lung has become fixed and unable to expand fully. Indwelling chest drains can be shunted to the peritoneum (Denver TM shunt) or tunnelled externally (PleuRx TM catheter) [22]. In a randomised trial, 144 patients with a malignant pleural effusion no mesothelioma cases were allocated to either he insertion of the PleuRx TM device or to pleurodesis with doxycycline: external drainage was associated with a significant shorter duration of hospitalisation, but 13% of patients experienced a complication [23]. There is a lack of data on safety of chronic drainage during chemotherapy, making this association less appropriate. Low dose oral opioids may be useful in reducing the sensation of dyspnoea and thus also reducing associated anxiety [24]. Oxygen may be helpful but should not be used unless there is evidence of reduced oxygen saturation [25]. A simple fan that creates a cool stream of air across the face may reduce the sensation of dyspnoea via the trigeminal nerve. Self-help breathlessness management techniques, designed to increase patients sense of mastery over their breathlessness, have been shown to be effective in lung cancer but the work has not be conducted specifically in mesothelioma [26]. Pain assessment and control in mesothelioma should follow the principles of cancer pain management [27]. However, due to the complex nature of pain in mesothelioma, adjunct analgesia may frequently be required in addition to opiates. In cases of refractory pain unresponsive to the usual measures, a specialist pain management or specialist palliative medicine opinion should be sought. Occasionally neuroablative techniques may be required, depending on specialist advice, and with careful consideration of the risks and benefits [28,29].

6 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) The reader is referred to articles and textbooks of palliative medicine for a comprehensive review of the management of other common symptoms. Sweating may improve with avoidance of restrictive clothing, use of a fan, and medication such as cimetidine. Stenting of the oesophagus may be effective in reducing dysphagia due to external compression. Ascites usually develops due to tumour extension through the diaphragm into the peritoneal cavity. Paracentesis may reduce discomfort due to large volume ascites but may need to be repeated. Patients with mesothelioma may exhibit anger, depression or stoicism and resigned acceptance. Reports from specific mesothelioma telephone help-lines demonstrate that patients and their families request accurate information about the illness, treatment options, state benefits and medico-legal issues. Support may be offered by specialist nurses, psychological or psychiatric services and asbestos support groups Prophylactic radiotherapy In 1995, Boutin et al. suggested that an irradiation with a 7 Gray (Gy) fractionation for three consecutive days, in the four weeks following drainage or thoracoscopy, prevented the occurrence of subcutaneous metastasis developing along drainage tracts or thoracocentesis tracts of MPM patients [30]. An Australian series randomised patients to a 10-Gy treatment with 9-MeV electrons, following invasive thoracic procedures or not [31]. There was no statistically significant difference in tract metastasis and a single fraction electron treatment hence seems ineffective. A recent randomised trial compared immediate drain site radiotherapy to 21 Gy in three fractions to best supportive care in 61 patients treated between 1998 and 2004, with no difference in terms of tract metastatic recurrence between the 2 arms [32]. The authors concluded that prophylactic drain site radiotherapy in MPM did not reduce the incidence of tumour seeding as indicated by previous studies. They came to the same conclusion as a systematic review [33]. Different techniques of radiotherapy may explain the discrepancy of these results, as well as the advent of effective systemic therapies, reducing or delaying the parietal seeding along the drainage channels. Whether prophylactic tract irradiation is a wasted resource remains controversial [34] Palliative radiotherapy Palliative radiotherapy aimed at pain relief may be considered in cases of painful chest wall infiltration or nodules [33]. Responses of over 60% have been seen, although the duration of response a median of 2 3 months is often disappointing. The optimum dose has not been shown and many of the series were small and retrospective. As for other palliative indications, hypofractionation with 4 G fractions is currently advocated, for a total dose bio-equivalence of Gy. Palliative radiotherapy is more effective if a bone erosion or subcutaneous masses are present and less for diffuse pain, dyspnea, superior vena cava syndrome or for retreatment. An improved response has been seen in several studies where hyperthermia was added to radiotherapy. However, further investigation of this technique, which is not widely available, is required. There has not been any comparison of radiotherapy with chemotherapy in the palliation of patients with MPM Palliative surgery Debulking pleurectomy/decortication can be defined as significant but incomplete macroscopic clearance of pleural tumour. The objective of the operation is to relieve an entrapped lung by removing the visceral tumour cortex. Removal of the parietal tumour cortex may relieve a restrictive ventilatory deficit and reduce chest wall pain. The operative procedure needs to be further standardised and may be performed by either open thoracotomy, but the closed video assisted thoracoscopic surgery (VATS) is preferred. There are a small series of retrospective studies which provide low grade evidence for debulking pleurectomy [35 38]. The associated morbidity of thoracotomy may diminish the benefits [39], however there is limited but emerging evidence that VATS can provide good symptom control and may have a beneficial effect on survival [37] Palliative chemotherapy In the past decades many phase II studies have been performed to select drugs with a potential activity against MPM. Unfortunately this approach did not result in a significant breakthrough and only a limited group of drugs were identified that exerted some activity. Doxorubicin, cisplatin and methotrexate were considered the most effective single agents [40]. A 3-armed randomised study was initiated in the UK that compared the efficacy of 2 different chemotherapy regimens one platinum combination and one single agent 3rd generation drug with best supportive care [41]. The study was prematurely stopped due to a slow accrual and was hence insufficiently powered to show a survival difference, even after pooling the results of both chemotherapy arms, but a positive trend favouring the vinorelbine single agent treatment was observed. Based on other reviews [40,42], the choice of the comparative chemotherapy cannot be considered to be optimal in this study. The decision to administer chemotherapy should be discussed with the patients and relatives, because of its palliative intent. In an individual patient meta-analysis of 1205 patients with landmark correction at 62 days, response to chemotherapy was found to be predictive for survival, irrespective of whether therapy contains platinum or not [43]. Two international randomised studies [13,44] suggested that a combination chemotherapy including cisplatin and an antifolate, either pemetrexed or raltitrexed, increases survival compared to single agent cisplatin. The median survival observed in both studies showed an improvement of

7 98 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) Fig. 2. Overall survival curves of patients with MPM treated with cisplatin with/without pemetrexed and vitamins (A) [13] or raltitrexed (B) [44]. months for the combination therapy arm (Fig. 2A). The results of the median survival in patients treated with cisplatin only are also above those usually reported in the literature (7 9 months) for active supportive care, confirming a modest single agent activity of cisplatin. Both trials showed a significant increase in response rate and no deleterious impact on quality of life. Based on these two randomised phase III trials, it is now generally accepted to treat patients with MPM with a combination of an antifolate with platinum. When pemetrexed is used, folic acid and vitamin B12 supplementation are required to reduce the haematological toxicity. Unfortunately about 80% of the patients have recurrent disease within 2 years of follow-up. Other cisplatin-based combinations have also produced interesting response rates of 20 30% in phase 2 studies: etoposide, epirubicin, gemcitabine, vinorelbine or methotrexate [40,42]. As in non-small cell lung cancer (NSCLC), opinions differ as to the interchangeability of cisplatin and carboplatin, the combination of the latter drug with pemetrexed showing outcome data similar to the ones obtained with the former [45,46]. Only one study has addressed the question when to start chemotherapy treatment in patients with MPM. O Brien et al. investigated if early administration was better than waiting until symptoms progression urged both the patient and clinician to start treatment with chemotherapy [47]. When a treatment with chemotherapy was started immediately, the median survival increased from 10 to 14 months with a 1- year survival of 66% versus 36%. The limited sample size of the study precluded a statistical significance. However, taking into account the data from numerous other tumour types, it is now considered not to be of any benefit for the patient to delay the start of treatment until progression of symptoms, unless the patient or other reasons indicate so. The duration of treatment has attracted attention in MPM as soon as pemetrexed containing combination chemotherapy was introduced. In a few cases a delayed response to treatment was observed and the relatively low toxicity has allowed to treat patient beyond 4 6 courses. Ongoing responses have been the reason for a study showing that the number of courses of chemotherapy could be extended up to 12 in selected patients [48]. Not all patients received cisplatin in these cases but pemetrexed was well tolerated as single agent. Unfortunately, the study was neither designed nor powered for a change in practice and selection of patients could have influenced the outcome. In retrospect, 53% of patients in the cisplatin-pemetrexed arm of the registration trial received 6 cycles, whilst in the EORTC trial, the median number of cisplatin-raltitrexed cycles was 5. As in NSCLC, it is now recommended to consider prolonged treatment with the antifolate and platinum for a minimum of 4 courses and in case of delayed responses to continue to 6 or more courses, whenever tolerance is kept. In case disease stabilisation is observed as best response, a maximum of 6 courses is recommended. Patients progressing early should be switched to another (palliative) treatment. After failure of first line chemotherapy, no randomised study has yet demonstrated any gain in overall survival or quality of life. In the last two decades, only 7 phase II studies [49 55] have addressed this question but failed to come to any recommendation. Chemotherapies consisting in doxorubicin, doxorubicin plus cyclophosphamide, oxaliplatin-raltitrexed or a platinum analogue appeared ineffective. Some promising activity was noted with pemetrexed alone [54], and a combination of cisplatin, irinotecan and mitomycine [52]. In a phase III study, patients with progressive disease were randomised to best supportive care (BSC) or second line pemetrexed single agent [56]. Time to progression was significantly longer in the pemetrexed arm but there was no improvement in overall survival. This might be due to significantly more patients in the BSC arm receiving postdiscontinuation chemotherapy with pemetrexed compared with patients randomised in the pemetrexed arm. In the case of recurrence of the disease it

8 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) Fig. 3. Patient with biopsy proven MPM obtaining near complete response with cycles carboplatin and pemetrexed, and successfully rechallenged at symptomatic relapse 6 months later. is recommended to include patients in clinical studies whenever their performance allows this. Patients showing a durable objective and symptomatic response can be rechallenged with pemetrexed (Fig. 3) Biological and targeted therapies Interferons and interleukins are the principal drugs being tested in the treatment of malignant mesothelioma. Dose, method of administration (intrapleural, subcutaneous, intramuscular, intravenous), type of drug and disease stage varied between the reported studies and do not allow to compare these easily. Interferon or interleukin-2 treatment has been tested but seems not to be effective and is only indicated as part of a clinical trial. Ranpirnase, a ribonuclease, which breaks down RNA, has been tested in a randomised phase III study with doxorubicin versus doxorubicin alone but failed to improve overall survival [57]. In a preplanned analysis including 130 pretreated patients a small but significant advantage in survival in favour of doxorubicin plus ranpirnase was found. The safety profile for both treatment arms was similar. Whether this small advantage is of enough clinical value to continue further research with this drug remains presently unclear. Recent pharmaceutical developments have focused on the identification and inhibition of molecular pathways involved in the growth and progression of MPM. A number of novel agents have been or are being evaluated, including drugs targeted against the epidermal growth factor, platelet derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteosome and mesothelin. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is over-expressed in a variety of malignancies. Signalling through EGFR is associated with resistance to chemotherapy, inhibition of apoptosis and metastases. EGFR was also observed to be over-expressed on immunohistochemistry (IHC) in a majority of epithelioid mesothelioma specimens [58]. Based on these data, the CALGB conducted a phase II trial that evaluated the role of gefitinib for the treatment of MPM [59]. No objective responses were noted and the regimen was not deemed suitable for further evaluation. Erlotinib, another EGFR inhibitor, was also evaluated in a phase II study for patients with MPM [60]. No objective responses were seen despite a high rate of patients with EGFR-expressing tumours in the study. A possible explanation of absence of significant benefit from using EGFR-TKIs could be due to the absence of activating somatic mutation in EGFR-TKI domain that is strongly predictive of response to EGFR-TKIs [61]. Cetuximab, a monoclonal antibody against the EGF receptor is currently investigated in a phase II study in combination with platinum and pemetrexed [62]. Another Her-family member, ErbB-2 or Her2/neu is expressed in 97% of mesothelioma specimens on IHC. However, the ErbB-2 gene does not appear to be amplified and data from breast cancer studies suggest that specific ErbB-2 inhibitors may not be effective in the absence of amplification.

9 100 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) Proteins involved in regulating the angiogenic process have been implicated in the prognosis of MPM and can be indirectly assessed using immunohistochemistry and micro-vessel counting. Studies have indicated that increased micro-vessel density is associated with a poor outcome [63]. VEGF, the VEGF receptors (VEGFRs) flt1 (VEGFR1), KDR (VEGFR2), and VEGFC and its cognate receptor VEGFR3 have been shown to be co-expressed in MPM [64,65]. Both VEGF and VEGFC function as autocrine growth factors for the development of MPM. Bevacizumab, a monoclonal antibody against the VEGF, is approved for the treatment of colon and nonsquamous non-small cell lung cancer, in combination with chemotherapy. A randomised phase II study was conducted in patients with advanced MPM to evaluate whether the addition of bevacizumab can enhance the efficacy of chemotherapy [66]. Patients were treated with cisplatin and gemcitabine with or without bevacizumab. The treatment was tolerated well without any major toxicity. Nevertheless, there was no suggestion of improved outcome with the addition of bevacizumab. The median progression free survival with and without the addition of bevacizumab, were 6.9 and 6.0 months, respectively. Though the overall median survival was numerically superior for bevacizumab + chemotherapy (15.6 versus 14.7 months), this difference was not statistically significant. An exploratory subset analysis noted improved survival with bevacizumab-chemotherapy regimen in patients with low circulating levels of VEGF. Ongoing phase 2 studies are addressing the activity of bevacizumab added to a pemetrexed platinum combination in first line or to erlotinib in second line [67,68]. Several small molecule inhibitors of the VEGF receptor tyrosine kinase have been tested in phase II studies. The multikinase inhibitor sorafenib inhibits the Ras/Raf/MEK/ERK and p38 signaling pathways, VEGFR2 and VEGFR3, and members of the PDGF receptor family, PDGFR and c- Kit. Sorafenib was evaluated as monotherapy for recurrent MPM in a phase II study by the CALGB [69]. Treatment was tolerated well, but the response rate of 4% did not meet the criteria for further evaluation of this agent as monotherapy. In a phase I study, one patient with MPM reported a partial response when sorafenib was combined with doxorubicin [70]. This combination is currently under evaluation in a phase II study in MPM [71]. Vatalanib, another VEGF tyrosine kinase inhibitor has also been studied in this setting [72]. In a study of 47 patients, this agent was associated with an objective response in five patients and a median survival of 10 months. However, the study did not meet the prespecified end point of 3-month PFS rate to warrant further investigation. Other VEGF tyrosine kinase inhibitors that are currently under evaluation include cediranib and pazopanib. Sunitinib a receptor tyrosine kinase inhibitor that acts on several targets, such as VEGFRs, PDGFR and c-kit is under evaluation in MPM in a phase II study [73] and in a phase I study in association with pemetrexed, cisplatin and pemetrexed/carboplatin and pemetrexed [74]. Thalidomide inhibits angiogenesis mediated by VEGF, basic fibroblast growth factor and TGF-. A Phase II study evaluated the efficacy of these inhibitors in 40 patients who have mesothelioma, of whom 50% had received previous chemotherapy. Disease stabilisation for longer than 6 months was observed in 27.5% of the patients [75]. Pavlakis et al. evaluated thalidomide alone or in combination with gemcitabine/cisplatin in two parallel non-randomised phase II studies [76]. Single agent thalidomide was administered to 22 patients who were not considered suitable for chemotherapy nor progressed during treatment with antiblastic drugs, whereas gemcitabine plus cisplatin was given with thalidomide to 16 chemotherapy-naive patients. Disease stabilisation for longer than 6 months was observed in 25% of the patients who received single agent thalidomide, while in the combination arm, a partial response rate of 14% was reported, and 32% of these patients achieved disease stabilisation for longer than 6 months. Moreover, a nonsignificant trend suggested that higher baseline levels of VEGF correlated with a shorter survival in both arms. Other angiogenic growth factors expressed in this disease include transforming growth factor, fibroblast growth factor (FGF) 1, FGF2, thrombospondin 1, methionine aminopeptidases, interleukin (IL)-6 and IL-8. High levels of VEGF and FGF2 or co-expression of TGF, VEGF, FGF1 and FGF2 have been found to be associated with a poor outcome [77]. MPM exhibits high levels of expression of the surrogate marker of hypoxia, hypoxia-inducible factor 1 [78]. Imatinib is a highly selective inhibitor of the bcr/abl mutated tyrosine kinase, as well as of both c-kit and PDGFRs. Several Phase II studies have been conducted with imatinib mesylate in MPM refractory to chemotherapy or chemonaive patients, but negative results were reported [79 82]. In vitro and in vivo experiments demonstrated that STI-571 can cause MPM cell apoptosis and death through inhibition of the AKT/PI3K pathway and that it can also enhances MPM sensitivity to gemcitabine or pemetrexed [83]. Patients with MPM are currently being enrolled in a Phase I study of imatinib combined with cisplatin and pemetrexed [84] and in a phase II study in association with gemcitabine to evaluate the efficacy of these compounds [85]. Rapamycin, a natural macrolide approved as immunosuppressor, was found to exert anti-proliferative effects by inhibition of serine/threonine kinase, which in mammals is called mammalian target of rapamycin (m-tor). Synthetic derivatives or rapalogs have been developed to improve the pharmacological properties of rapamycin: everolimus, temsirolimus and deforolimus. Temsirolimus was evaluated in a phase I study of dose escalation and did not induce tumour response in patients with MPM [86]. Histone deacetylase (HDAC) inhibitors are novel anticancer agents that act by a variety of mechanisms. Histones are the core-proteins in the centre of the DNA double helix. The histone proteins exist in either a non-acetylated transcriptional inactive configuration or an acetylated state that is open to gene transcription. The dynamic equilibrium between

10 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) the acetylated and non-acetylated forms is mediated by histone acetyltransferase and HDAC [87]. Agents that inhibit HDAC have recently demonstrated promising anticancer activity in early phase clinical trials. Vorinostat is a small molecule inhibitor of HDAC that is approved by the FDA for the treatment of advanced, relapsed, or refractory cutaneous T-cell lymphoma. In addition to its inhibitory effect on HDAC, vorinostat also acetylates several key cell signalling proteins that play a role in regulating normal cell differentiation, apoptosis, and proliferation. Therefore, both histone and non-histone protein-mediated effects of HDAC inhibitors are thought to be responsible for their anticancer effects [88]. Initial studies of vorinostat have demonstrated objective responses in patients with MPM. In the initial phase I studies with the oral formulation of vorinostat, 13 patients with advanced MPM were included [89]. Twelve out of these patients had received prior systemic chemotherapy for MPM. Two objective partial responses were noted and four patients received six or more cycles of therapy. The treatment regimen was tolerated well. These data form the basis for a large randomised clinical trial to compare vorinostat to placebo in pretreated patients. The primary end point is the determination of overall survival [90]. The mechanistic aspects of the efficacy noted with vorinostat in MPM are unclear. Because inhibitors of thymidilate synthase (TS) have demonstrated activity in MPM, it is conceivable that repression of TS and cytidine triphosphate synthetase by HDAC inhibitors could play a role. Another mechanism may be the induction of apoptosis, which has been demonstrated with preclinical studies of sodium butyrate, a HDAC inhibitor, in mesothelioma cell lines. HDAC inhibitors have also been shown to block angiogenic signalling by inhibiting VEGF-induced expression of VEGF receptors. Another HDAC inhibitor, belinostat, is being evaluated in a Phase II study as a second line therapy [91]. The proteosome inhibitor bortezomib inhibits nuclear factor-kappa B and upregulates proapoptotic BH3 proteins [92]. Proteosome inhibition induces apoptosis of mesothelioma cells in vivo and in vitro [93,94]. On the basis of promising preclinical data, two phase II trials of bortezomib have been initiated in Europe. One trial is exploring single agent activity in the second line setting and in patients with a performance status of 2 in the first line setting [95]. The second trial, conducted by the EORTC, is exploring the use of this agent in a combination regimen with cisplatin in the first line setting [96]. 3. Radical treatment a: The use of radiation therapy to the full hemithorax is limited by critical organs such as the lung, the liver and heart most particularly, but also the spinal cord and the esophagus. Therefore it is difficult to administer a total dose more than 54 Gy to such a large volume, so that sophisticated treatment techniques, oriented by surgeon s and pathologist s findings, are needed [97,98]. As radical radiotherapy has never been compared to chemotherapy or surgery or to best supportive care (as part of combination therapy) in a prospective, randomised trial, no data exist supporting one or the other treatment as a better option for patients with malignant pleural mesothelioma [99]. Four non-comparative retrospective studies have shown that hemithoracic irradiation alone resulted in significant toxicity, including radiation-induced pulmonary fibrosis, radiation pneumonitis, and bronchopleural fistula, without any survival benefit [33]. Few of the identified studies reported on symptom control, and no studies included formal measures of quality of life. Retrospective studies seem to show a radiation dose effect that should be further studied with conformal radiation technique. b: Radical surgery may be defined as an attempt to remove all macroscopic tumour from the hemithorax. These objectives are usually achieved by extrapleural pneumonectomy (EPP) with an en bloc resection of lung, visceral and parietal pleura and ipsilateral hemi-pericardium and hemi-diaphragm, followed by pericardial and diaphragmatic reconstruction with prosthetic material (usually Goretex TM ). The goal is ideally to remove the entire mesothelial lining respecting a safe macroscopic margin. Operative mortality has fallen to an acceptable level of around 5% in experienced centres, but morbidity remains high at around 50% [100,101]. As is the case with all surgical interventions, indications for this technique rely on both disease- and patient-related variables (see f ). Older literature indicates that surgery alone for MPM is not curative since no oncological resection margins can be obtained. The pleural lining, especially on the pericardium and mediastinum cannot be resected with a 1 2 cm margin. Therefore all surgical procedures are considered R1 resections [102]. This observation is therefore the rationale for combined therapy, as high local recurrence rates more than 50% are the rule [103]. c: Postoperative radiotherapy (PORT) with 54 Gy to the hemithorax after EPP resulted in a local recurrence rate of 13%, and a 4% local-only recurrence rate [104]. The ability to cover fully all the areas at risk, limited by the surrounding normal structures (heart and liver, particularly), the total dose given and radiotherapy technique contribute to explain these discrepancies. Preliminary results of intensity-modulated radiotherapy (IMRT) in the adjuvant setting after EPP seemed particularly promising as they could provide good local control and protect organs at risk such as heart or liver [105]. However, severe pulmonary toxicity has been reported in recent studies so that it should not be recommended outside of clinical trials [106,107]. The most frequent side effects reported (up to 80% of cases) are fatigue, anorexia, nausea and vomiting. In case of left pneumonectomy, the spleen receives an important radiation dose and a prophylaxis for pneumococcal infections can be indicated. As the ipsilateral kidney is largely included in the radiation field, it is necessary to check the regional kidney function before the treatment. The contralateral kidney should in fact contribute to the entire

11 102 J.P. van Meerbeeck et al. / Critical Reviews in Oncology/Hematology 78 (2011) Table 3 Prospective multicentre phase 2 trials of radical multimodality treatment in early stage mesothelioma. Variable SAKK-trial [112] US- trial [113] EORTC trial [114] N/n institutions 61/6 77/9 59/11 Induction regimen Cis-gem 3 Cis-pem 4 Cis-pem 3 Compliance to induction chemotherapy 95% 83% 93% EPP 45 (74%) 54 (70%) 42 (74%) Operative mortality 2.2% 7% 6.5% PORT completed 36 (59%) 40 (52%) 37 (65%) Median OS (ITT) (range) 19.8 m 16.8 m 18.4 m Median OS (PP) 23 m 29.1 m NA Local relapse (% PP) NS 11 (28%) 6 (16%) Median PFS (ITT) 13.5 m 10.1 m 13.9 m Median overall treatment time (days) (range) NS NS 184 NS: not stated; PORT: postoperative radiotherapy; ITT: intentionto treat; PP: per protocol; EPP: extrapleural pneumonectomy; OS: overall survival; PFS: progression free survival. renal perfusion for more than 40%, in order to sustain possible radiation-induced damage to the ipsilateral kidney. Patients with a large V20 (volume of both lungs minus the primary target volume (PTV) that receives more than 20 Gy) or mean lung dose (MLD) are at risk of lethal lung toxicity. To predict the risk of pneumonitis, the following pulmonary dosimetric values (V20, V5 and MLD) should be specified. The V20 should be less than 15%, and the MLD should be less than 10 Gy. Furthermore, dose volume histograms (DVH) of all target volumes (CTV and PTV) and of all critical organs (contralateral lung, cardiac volume, spinal cord, oesophagus, liver, right and left kidney) should be clearly stated. d: Among resected mesothelioma patients, the only published long-term survivors have undergone radical surgery (EPP) as part of a multimodality program including postoperative chemotherapy with or without PORT. Sugarbaker et al. treated 183 patients over nearly two decades with EPP and adjuvant platinum-based chemotherapy and radiotherapy [108]. The median survival was 19 months and the 2-year survival rate was 38%, with 15% of patients surviving at 5 years. Epithelioid subtype, extrapleural nodal and resection margin involvement are predictive of a better outcome after surgery. Flores et al. reported data on 633 patients with MPM treated at 3 institutions, 56% of who received adjuvant treatment (chemotherapy, radiotherapy or both) [109]. In this large retrospective analysis, postoperative treatment demonstrated some benefits in respect to surgery alone in disease-free and overall survival. Toxicity was high and compliance to adjuvant treatment low. These series are particularly prone to one or several of the abovementioned biases. e: The preference for neoadjuvant chemotherapy is justified by its better compliance, lower rate of surgical morbidity, high rate of objective response, good rate of radical resections and the possibility to select the optimal patients to be submitted to surgery. This approach was explored first in a number of single institutional phase 2 studies with promising results [110,111], after which a number of multicentre prospective phase 2 trials exploring the feasibility of a multimodality approach in highly selected patients, combining neoadjuvant chemotherapy, followed by EPP and PORT, were conducted, which have demonstrated a similar median survival of months (Table 3). In the Swiss trial, 58 of 61 patients completed three cycles of chemotherapy and 45 patients (74%) underwent EPP, with 37 resected completely and 36 treated with postoperative irradiation [112]. The median survival of all patients was 19.8 months, with 23 months for subgroup treated with EPP. Psychological distress was most impaired among the four global quality of life dimensions. It showed only minor variation over time despite the aggressiveness of the therapeutic approach and a full recovery after a period of 6 months after surgery which was longer than expected. In the North American trial, 83% of patients completed the four cycles of cisplatin-pemetrexed planned, 54 patients (70%) were underwent to EPP and 40 completed irradiation [113]. The median survival of all patients was 16.8 months, while for patients completing all therapy was 29.1 months. In the EORTC trial, 93% of 59 patients complete their 3 cycles of induction with cisplatin and pemetrexed, 74% proceeded to EPP and 65% completed PORT [114]. Median overall treatment time was 184 days. At least 2 more multicentric phase 2 trials addressing the same issues are ongoing. f: Due to the extent of surgery and combination treatment, patients need to undergo a thorough work-up before embarking on any multimodality treatment. For potential patients the work-up should consist of (i) the functional examinations to assess the fitness for radical therapy [115], (ii) the absence at physical examination of shrinkage of the afflicted hemithorax, growth through the ribs or in the abdominal cavity, all considered a sign of inoperable disease, and (iii) the staging examinations as shown in Tables 2B and 2C. 4. Guidelines Several international cancer organisations have issued guidelines and recommendations for the management of MPM: the British Thoracic Society [116], the Société de Pneumologie de Langue Française (SPLF) [117], the provincial Lung Cancer Disease Site Group of Ontario (CDN) [118], the European Society of Medical Oncology (ESMO)