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Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

2015; Elsevier BV; Volume: 26; Linguagem: Inglês

10.1093/annonc/mdv199

1569-8041

Paul Baas, Dean A. Fennell, Keith M. Kerr, Paul E. Van Schil, Rick L. Haas, Solange Peters,

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Malignant pleural mesothelioma (MPM) is considered to be a relatively rare tumour. In Great Britain, the incidence in males is 3.4/100 000, in France it is 2.3/100 000 and in the Netherlands it is 3.2/100 000. In the last 10 years, the incidence of MPM has increased slightly, mainly due to the lag time of 30–50 years after exposure to asbestos and the banning of handling and importing this product in the late twentieth century. The World Health Organisation (WHO) estimates asbestos-related disease (ARD) accounts for 92 250 deaths per year globally [1.Delgermaa V. Takahashi K. Park E.K. et al.Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008.Bull World Health Organ. 2011; 89: 716-724Crossref PubMed Scopus (304) Google Scholar]. Occupational exposure to asbestos accounts for more than 80% of the cases and makes MPM a preventable disease. Although the Western world is moving towards a levelling-off of ARD incidence, the continued use of asbestos in the developing world could lead to a global epidemic of MPM. Even though asbestos is banned in Europe, other developed countries have only controlled the import, but not abolished handling of asbestos products. Recently, a germline mutation in the BAP1 gene has been linked to predisposition in some cases of MPM [2.Testa J.R. Cheung M. Pei J. et al.Germline BAP1 mutations predispose to malignant mesothelioma.Nat Genet. 2011; 43: 1022-1025Crossref PubMed Scopus (797) Google Scholar]. Somatic mutations may also play a role in the development of MPM. Patients typically present with complaints of shortness of breath, pain and weight loss. These symptoms can occur over a period of many months. During physical examination, unilateral effusions are often observed. It is of great importance that a detailed occupational history is obtained. Standard work-up includes:•Chest X-ray•Computed tomography (CT) scan of chest and upper abdomen•Thoracentesis, with examination of the pleural effusion•General laboratory blood tests Plain chest radiography lacks sufficient sensitivity for routine staging. Significant volumes of pleural effusions can mask pleural/chest lesions and make small malignant pleural effusions undetectable. When an occupational history indicates considerable asbestos exposure, or the radiology is suggestive of mesothelioma, cytology can be used to detect malignant cells but histological specimens must often be obtained (see 'pathology' section). A thoracoscopy is recommended to obtain adequate histology, to optimally stage, and to allow pleural fluid evacuation (with or without pleurodesis) [3.Maskell N.A. Gleeson F.V. Davies R.J. Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial.Lancet. 2003; 361: 1326-1330Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 4.Greillier L. Cavailles A. Fraticelli A. et al.Accuracy of pleural biopsy using thoracoscopy for the diagnosis of histologic subtype in patients with malignant pleural mesothelioma.Cancer. 2007; 110: 2248-2252Crossref PubMed Scopus (53) Google Scholar]. This can be performed as a pleuroscopy or as video-assisted thoracic surgery (VATS). MPM can be difficult to identify and it is therefore recommended to obtain biopsies from tissue of both abnormal and normal appearance. When a thoracoscopy is not feasible or contra-indicated, ultrasound-guided true-cut biopsies are a good alternative. Besides a clinical reason to obtain a diagnosis, there are medico-legal reasons to confirm the diagnosis of MPM. In Europe, the requirements for this vary between countries. To date, there are no studies that recommend screening of patients who have had any (occupational) history of asbestos exposure. Circulating tumour markers have been tested to a great extent and only a few have been able to facilitate the diagnostic process: cyfra 21.1, Fibulin-3 and Mesothelin all lack specificity and should not be used as specific markers for mesothelioma [5.Greillier L. Baas P. Welch J.J. et al.Biomarkers for malignant pleural mesothelioma: current status.Mol Diagn Ther. 2008; 12: 375-390Crossref PubMed Google Scholar, 6.Creaney J. Dick I.M. Meniawy T.M. et al.Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma.Thorax. 2014; 69: 895-902Crossref PubMed Scopus (117) Google Scholar]. Carcinoembryonic antigen (CEA) is a negative marker and is not increased in MPM [7.van den Heuvel M.M. Korse C.M. Bonfrer J.M. Baas P. Non-invasive diagnosis of pleural malignancies: the role of tumour markers.Lung Cancer. 2008; 59: 350-354Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. It can therefore be used to rule out MPM if cytological/histological analysis is inconclusive.Recommendation 1Diagnostic procedures in MPM should encompass at least•Occupational history with emphasis on asbestos exposure [II, A]•CT scanning of the thorax [II, A]•In all patients who have a unilateral pleural thickening, with or without fluid and/or calcified asbestos plaques, efforts should be made to obtain a pathological specimen, as there are no specific clinical features of MPM [II, A]•There is no place for screening of persons exposed to asbestos [IV, B]•Tumour markers cannot distinguish MPM [II, B] Recommendation 1 Diagnostic procedures in MPM should encompass at least•Occupational history with emphasis on asbestos exposure [II, A]•CT scanning of the thorax [II, A]•In all patients who have a unilateral pleural thickening, with or without fluid and/or calcified asbestos plaques, efforts should be made to obtain a pathological specimen, as there are no specific clinical features of MPM [II, A]•There is no place for screening of persons exposed to asbestos [IV, B]•Tumour markers cannot distinguish MPM [II, B] The pathological diagnosis of MPM may be difficult for a number of reasons:•MPMs are a heterogeneous group of tumours, with the ability to mimic almost any other form of malignant tumour.•The three main subtypes (epithelioid, biphasic and sarcomatoid) have numerous variants, as described in the 2004 WHO classification [8.Churg A. Roggli V.L. Galateau-Salle F. et al.Tumours of the pleura: mesothelial tumours.in: Travis W.D. Brambilla E. Muller-Hermelink H.K. Harris C.C. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC, Lyon, France2004Google Scholar].•The pleura is a common site for metastatic disease and reactive changes in the pleura may be confused with MPM.•There are other uncommon benign and malignant pleural tumours. Samples for diagnosis may vary widely: pleural effusions, small (closed) pleural biopsies, image-guided needle core biopsies, larger open or VATS surgical biopsy samples or debulking specimens. Surgical resection (extrapleural pneumonectomy) is rarely performed. In some cases, samples may also be obtained through autopsy. Significant sampling errors can occur in effusion cytology and small biopsy samples, but also with larger surgical samples (though less common). Blind biopsies are not recommended because of risk of complications and are no longer indicated since the introduction of thoracic ultrasonography. Cytological features in effusions may permit a diagnosis of malignancy but reported sensitivities vary widely. When a biopsy is not possible, appropriate clinical and radiological features may assist in suggesting a diagnosis of MPM. Many mesotheliomas lack significant cytological atypia and it is impossible to distinguish between benign, reactive mesothelial proliferations and MPM. Cytology sample cells may show variable atypia (usually low grade) and exhibit a mesothelial immune phenotype, but malignancy cannot be confirmed. The term 'atypical mesothelial proliferation' is useful in this context, but is insufficient for a diagnosis of MPM. This does not confirm the diagnosis of MPM, but leaves the possibility open [see below for fluorescence in situ hybridisation (FISH) testing]. In the vast majority of cases, it is necessary to have adequate tissue biopsies and the use of appropriate immunohistochemistry (IHC) for definitive, primary diagnosis of MPM. Consequently, definitive diagnosis of mesothelioma by frozen section is not recommended. Tissue biopsy samples the abnormal (mesothelial) cell population and permits micro-anatomical assessment of the location of these cells. This is crucial to identify the extent of invasion. IHC is pivotal in confirming the mesothelial nature of cells, but cannot confirm their biological potential (see below). The larger the tissue biopsy and the more targeted the sampling approach [radiological or surgical (VATS or open procedure)], the more reliable and definitive the diagnosis. Invasion may be difficult to recognise, especially when tissue sampling is limited, but identification may be assisted by IHC (see below). Early invasive mesothelioma is particularly difficult, often disguised by cutting artefacts or the malorientation of sections, but may be suspected if there is nodular mesothelial cell proliferation. If definitive invasion cannot be recognised, the diagnosis of 'atypical mesothelial proliferation' is appropriate, and further sampling may be indicated. Distinguishing MPM from organising fibrinous exudates (fibrinous/fibrous pleurisy) requires a full-thickness biopsy sample, with correct orientation of histological sections, perpendicular to the pleural surface. Pathological details of these differential diagnoses are discussed elsewhere [9.Husain A.N. Colby T. Ordonez N. et al.Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group.Arch Pathol Lab Med. 2013; 137: 647-667Crossref PubMed Scopus (374) Google Scholar, 10.Henderson D.W. Reid G. Kao S.C. et al.Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers.J Clin Pathol. 2013; 66: 847-853Crossref PubMed Scopus (98) Google Scholar]. The most commonly used mesothelial markers are calretinin, cytokeratin 5/6, WT1 and podoplanin (D240). For (adeno)carcinoma, the most useful markers are TTF1, CEA and EP4 [9.Husain A.N. Colby T. Ordonez N. et al.Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group.Arch Pathol Lab Med. 2013; 137: 647-667Crossref PubMed Scopus (374) Google Scholar, 10.Henderson D.W. Reid G. Kao S.C. et al.Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers.J Clin Pathol. 2013; 66: 847-853Crossref PubMed Scopus (98) Google Scholar]. Some markers have been advocated for, due to their distinction of benign (desmin) versus malignant mesothelial cells (EMA, p53, GLUT1, IMP3), but these methods lack reliability and are generally not recommended. Other immunohistochemical markers may be appropriate, depending on the differential diagnosis in a particular case. It is worth noting that although pan-cytokeratin markers are not specific in any way for mesothelial cells, or malignancy, in the appropriate context, they can be extremely useful in the diagnosis of sarcomatoid mesothelioma, which often does not express the usual markers mentioned above. The use of in situ hybridisation (e.g., FISH) to detect homozygous deletion of p16 is strongly associated with malignancy; it is not specific to MPM, but may aid diagnosis [11.King J. Thatcher N. Pickering C. Hasleton P. Sensitivity and specificity of immunohistochemical antibodies used to distinguish between benign and malignant pleural disease: a systematic review of published reports.Histopathology. 2006; 49: 561-568Crossref PubMed Scopus (80) Google Scholar, 12.Chiosea S. Krasinskas A. Cagle P.T. et al.Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas.Mod Pathol. 2008; 21: 742-747Crossref PubMed Scopus (177) Google Scholar]. The role of this technique has yet to be defined and established. Comprehensive analysis of the genomic landscape of mesothelioma has not yet been completely defined, however the Tumour Genome Atlas study is currently underway (www.cancergenome.nih.gov).Recommendation 2A. Definitive diagnosis of MPM on effusion cytology specimens•Effusion cytology for definitive diagnosis of MPM remains a controversial topic and is still generally not recommended [IV, C].•If effusion cytology is frankly malignant, the diagnosis may be strongly suggested but confirmation by biopsy, if possible, is recommended [A, no level of evidence].•IHC is invaluable to characterise the nature of atypical effusion cells and sample preparation to facilitate IHC should be carried out if at all possible [A, no level of evidence].B. Definitive diagnosis of MPM on tissue biopsy specimens•The recognition of tissue invasion is required for definitive diagnosis of MPM [IV, A].•Larger and directly targeted biopsy samples facilitate definitive diagnosis. Surgical-type samples are preferred for diagnosis [IV, A].•A major subtype diagnosis (epithelioid, biphasic, sarcomatoid) should be given in all cases of MPM [IV, A].C. IHC in the diagnosis of MPM•IHC is recommended for all primary diagnoses of MPM [IV, A].•At least two 'mesothelial' markers and at least two '(adeno)carcinoma' markers should be used [V, A].•Sarcomatoid MPM often does not express usual 'mesothelial' markers [IV, A]. Recommendation 2 A. Definitive diagnosis of MPM on effusion cytology specimens•Effusion cytology for definitive diagnosis of MPM remains a controversial topic and is still generally not recommended [IV, C].•If effusion cytology is frankly malignant, the diagnosis may be strongly suggested but confirmation by biopsy, if possible, is recommended [A, no level of evidence].•IHC is invaluable to characterise the nature of atypical effusion cells and sample preparation to facilitate IHC should be carried out if at all possible [A, no level of evidence]. B. Definitive diagnosis of MPM on tissue biopsy specimens•The recognition of tissue invasion is required for definitive diagnosis of MPM [IV, A].•Larger and directly targeted biopsy samples facilitate definitive diagnosis. Surgical-type samples are preferred for diagnosis [IV, A].•A major subtype diagnosis (epithelioid, biphasic, sarcomatoid) should be given in all cases of MPM [IV, A]. C. IHC in the diagnosis of MPM•IHC is recommended for all primary diagnoses of MPM [IV, A].•At least two 'mesothelial' markers and at least two '(adeno)carcinoma' markers should be used [V, A].•Sarcomatoid MPM often does not express usual 'mesothelial' markers [IV, A]. Staging procedures are standard in all tumours. Staging not only describes the anatomical extent of a tumour, but it also correlates with prognosis and helps in treatment decision-making. At least five staging systems for MPM have been reported. The first staging system was introduced by Butchart, consisted of four stages and was based on observations from only 29 patients [13.Butchart E.G. Gibbs A.R. Pleural mesothelioma.Curr Opin Oncol. 1990; 2: 352-358Crossref PubMed Scopus (9) Google Scholar]. This system was succeeded by others developed by Mattson, Boutin and Sugarbaker who based their system on their own experiences. Most of these staging systems had limitations, being based on small numbers of patients. The most recent system was developed in 1995; it was presented by the International Mesothelioma Interest Group (IMIG) and is approved by the Union for International Cancer Control (UICC) (Table 1) [14.Rusch V.W. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group.Chest. 1995; 108: 1122-1128Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. The limitation of most classifications is their inaccuracy in describing tumour (T-) and node (N-)extent. Most staging systems are based on surgical interventions, as current imaging techniques have limited resolution. The IMIG is currently validating a new tumour-node-metastases (TNM) staging system, using a large retrospective dataset obtained from centres all over the world.Table 1TNM staging according to the International Mesothelioma Interest Group (IMIG)/Union for International Cancer Control (UICC) [14.Rusch V.W. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group.Chest. 1995; 108: 1122-1128Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]StageTNMCommentsIaT1a N0 M0Primary tumour limited to ipsilateral parietal pleuraIbT1b N0 M0As stage Ia plus focal involvement of visceral pleuraIIT2 N0 M0As stage Ia or Ib plus confluent involvement of diaphragm or visceral pleura or involvement of the lungIIIAny T3 M0Locally advanced tumourAny N1 M0Ipsilateral, bronchopulmonary or hilar lymph node involvementAny N2 M0Subcarinal or ipsilateral mediastinal lymph node involvementIVAny T4Locally advanced, technically unresectable tumourAny N3Contralateral mediastinal, internal mammary, and ipsilateral or contralateral supraclavicular lymph node involvementAny M1Distant metastasesReproduced with permission from the American College of Chest Physicians. Open table in a new tab Reproduced with permission from the American College of Chest Physicians. Although the IMIG staging system could predict prognosis [15.Nowak A.K. Armato III, S.G. Ceresoli G.L. et al.Imaging in pleural mesothelioma: a review of imaging research presented at the 9th International Meeting of the International Mesothelioma Interest Group.Lung Cancer. 2010; 70: 1-6Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar], it failed to be an independent prognostic factor when analysed in the clinical setting using multivariate analysis [16.Tammilehto L. Kivisaari L. Salminen U.S. et al.Evaluation of the clinical TNM staging system for malignant pleural mesothelioma: an assessment in 88 patients.Lung Cancer. 1995; 12: 25-34Abstract Full Text PDF PubMed Scopus (29) Google Scholar]. After the first analysis of an IMIG/International Association for the Study of Lung Cancer (IASLC) database with data from 3101 patients with MPM, several areas of the current staging system have been defined as requiring modification [17.Rusch V.W. Giroux D. Kennedy C. et al.Initial analysis of the International Association for the Study of Lung Cancer Mesothelioma Database.J Thorac Oncol. 2012; 7: 1631-1639Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar]. Multivariable analyses showed significant differences in overall survival (OS) for most T stages, but not for T2 versus T1. Although a negative node status was of prognostic importance, no difference between N1 and N2 was noted. Disease stage according to the TNM system, when assessed by surgical staging, is an important predictor of prognosis in patients with mesothelioma, and the TNM system is therefore the preferred system. For decision-making, magnetic resonance imaging (MRI), using gadolinium, may improve delineation of the tumour with regard to the surrounding tissues, especially when surgical resection is considered to be a part of the treatment plan. This will also help to visualise foci that may be present in the diaphragm, pericardium or chest wall [18.Heelan R.T. Rusch V.W. Begg C.B. et al.Staging of malignant pleural mesothelioma: comparison of CT and MR imaging.AJR Am J Roentgenol. 1999; 172: 1039-1047Crossref PubMed Scopus (234) Google Scholar]. The use of positron emission tomography (PET) scanning is still under debate because MPM tends to only grow locally and metastases occur solely in patients with advanced disease. Discrimination of involved lymph nodes is difficult, due to anatomy and the limited spatial resolution of current PET scans [19.Armato III, S.G. Labby Z.E. Coolen J. et al.Imaging in pleural mesothelioma: a review of the 11th International Conference of the International Mesothelioma Interest Group.Lung Cancer. 2013; 82: 190-196Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. PET scanning can be used in the diagnostic work-up when PET-avid sites in the thoracic cavity need to be identified to obtain representative tissue. Some studies use repeated PET scanning as a response criterion in addition to the CT scan. However, no randomised prospective studies have yet been published on this. One of the caveats in the evaluation of PET scanning is the false-positive outcome after pleurodesis. This can result in high activity for a period of more than 6 months after pleurodesis.Recommendation 3Staging for every patient with a confirmed diagnosis of MPM•In the absence of a uniform, robust and validated staging system, experts advocate the use of the most recent TNM-based IMIG/UICC classification [III, B].•The use of MRI is only recommended in special situations when tumour delineation is necessary [II, B].•The use of PET scanning is limited and can be used for localisation of tumour sites, distant metastases or early response to treatment, as part of a study protocol [III, B]. Recommendation 3 Staging for every patient with a confirmed diagnosis of MPM•In the absence of a uniform, robust and validated staging system, experts advocate the use of the most recent TNM-based IMIG/UICC classification [III, B].•The use of MRI is only recommended in special situations when tumour delineation is necessary [II, B].•The use of PET scanning is limited and can be used for localisation of tumour sites, distant metastases or early response to treatment, as part of a study protocol [III, B]. Front-line chemotherapy improves survival of patients with unresectable MPM. Combination doublet chemotherapy of cisplatin, with either pemetrexed or raltitrexed, has shown a longer survival compared with cisplatin alone in randomised phase III trials [20.Vogelzang N.J. Rusthoven J.J. Symanowski J. et al.Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.J Clin Oncol. 2003; 21: 2636-2644Crossref PubMed Scopus (2539) Google Scholar, 21.van Meerbeeck J.P. Gaafar R. Manegold C. et al.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.J Clin Oncol. 2005; 23: 6881-6889Crossref PubMed Scopus (547) Google Scholar]. Carboplatin is an acceptable alternative to cisplatin and may be better tolerated in the elderly population [22.Santoro A. O'Brien M.E. Stahel R.A. et al.Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program.J Thorac Oncol. 2008; 3: 756-763Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 23.Ceresoli G.L. Castagneto B. Zucali P.A. et al.Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials.Br J Cancer. 2008; 99: 51-56Crossref PubMed Scopus (96) Google Scholar]. Several phase II clinical trials are investigating the addition of novel agents to pemetrexed/cisplatin therapy. To date, no agent has demonstrated superior efficacy. Although the agent CBP501 (a G2 checkpoint abrogator) met its primary end point, it was not considered to improve upon the efficacy of standard chemotherapy. Trials of anti-angiogenic agents such as bevacizumab or sunitinib [24.Kindler H.L. Karrison T.G. Gandara D.R. et al.Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma.J Clin Oncol. 2012; 30: 2509-2515Crossref PubMed Scopus (170) Google Scholar, 25.Nowak A.K. Millward M.J. Creaney J. et al.A phase II trial of intermittent sunitinib maleate as second-line therapy in progressive malignant pleural mesothelioma.J Thorac Oncol. 2012; 7: 1449-1456Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar] have so far failed to demonstrate improvement over standard treatment. The use of continuation or switch maintenance therapy with pemetrexed monotherapy has changed practice in the management of non-small-cell lung cancer, but is yet to be evaluated in the mesothelioma setting. However, a phase II trial addressing this question [NCT01085630], led by the Cancer and Leukemia Group B (CALGB), is currently underway. Switch maintenance, with the focal adhesion kinase inhibitor defactinib (VS6063) versus placebo, is currently under evaluation in the COMMAND trial [NCT01870609]. Another phase III, switch maintenance, study of gemcitabine versus observation is currently on-going in the Netherlands (NVALT 19). A recent phase III study evaluating switch maintenance to thalidomide was negative [26.Buikhuisen W.A. Burgers J.A. Vincent A.D. et al.Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study.Lancet Oncol. 2013; 14: 543-551Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. There is currently no second-line standard of care. Phase III evaluation of pemetrexed monotherapy in previously treated patients was not associated with longer survival when compared with best supportive care (BSC). Post-study chemotherapy has been shown to be associated with significantly longer survival, with an adjusted hazard ratio of 0.56 [27.Manegold C. Symanowski J. Gatzemeier U. et al.Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.Ann Oncol. 2005; 16: 923-927Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar]. Single agent vinorelbine has shown useful activity in phase II trials [28.Stebbing J. Powles T. McPherson K. et al.The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma.Lung Cancer. 2009; 63: 94-97Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 29.Zauderer M.G. Kass S.L. Woo K. et al.Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma.Lung Cancer. 2014; 84: 271-274Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar], demonstrating a trend towards longer survival as was seen in the first-line study (MSO1) [30.Muers M.F. Stephens R.J. Fisher P. et al.Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial.Lancet. 2008; 371: 1685-1694Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar]. There are promising developments in the novel agent arena, for example, anti-mesothelin immunotoxin [31.Hassan R. Miller A.C. Sharon E. et al.Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression.Sci Transl Med. 2013; 5: 208ra147Crossref PubMed Scopus (186) Google Scholar]. Immunotherapy targeting CTLA4 with tremelimumab [32.Calabro L. Morra A. Fonsatti E. et al.Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.Lancet Oncol. 2013; 14: 1104-1111Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar] is under evaluation in a large global phase III trial [NCT01843374]. Recent data suggest that the PDL1, a putative biomarker for PD1/PDL1 therapy, is significantly expressed in mesotheliomas, particularly the sarcomatoid subtype. In the absence of standard second-line or further-line therapy, it is recommended that patients are enrolled into clinical trials. Individual patient meta-analyses have shown that response to chemotherapy or progression-free survival (PFS) [33.Blayney J.K. Ceresoli G.L. Castagneto B. et al.Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma.Eur J Cancer. 2012; 48: 2983-2992Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar] is correlated with a longer survival. Personalised therapy is therefore warranted, although currently it is in its infancy. Mesotheliomas harbouring epigenetically silenced argininosuccinate synthase (AS) are sensitive to arginine-degrading enzymes pre-clinically. Open label, randomised clinical evaluation of ADI-PEG 30, in AS-negative patients, has confirmed efficacy with increased PFS compared with BSC alone. A study to evaluate ADI-PEG20, in combination with chemotherapy, in AS-negative mesothelioma [NCT02029690] is underway. Mutation of NF2 occurs in around 50% of mesotheliomas, sensitising inhibition of FAK [34.Hasan B. Greillier L. Pallis A. et al.Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation.Eur J Cancer. 2014; 50: 2771-2782Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 35.Poulikakos P.I. Xiao G.H. Gallagher R. et al.Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK.Oncogene. 2006; 25: 5960-5968Crossref PubMed Scopus (142) Google Scholar, 36.Shapiro I.M. Kolev V.N. Vidal C.