Felip, E.

Lievens, Y.

Stahel, R. A.

Weder, W.

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Annals of Oncology 21 (Supplement 5): v126–v128, 2010doi:10.1093/annonc/mdq173clinical practice guidelinesMalignant pleural mesothelioma: ESMO ClinicalPractice Guidelines for diagnosis, treatment andfollow-upR. A. Stahel1, W. Weder2, Y. Lievens3 & E. Felip4On behalf of the ESMO Guidelines Working Group*1Clinic and Policlinic of Oncology; 2Department of Thoracic Surgery, University Hospital of Zu¨rich, Zu¨rich, Switzerland; 3Radiation Oncology Department, LeuvenUniversity Hospitals, Leuven, Belgium; 4Medical Oncology Service, Vall d’Hebron University Hospital, Barcelona, SpainincidenceMalignant pleural mesothelioma (MPM) is a rare tumour.The incidence is 1.25/100 000 in Great Britain and 1.1/100 000in Germany. Within the next 20 years the incidence isestimated to double in many countries. Exposure to asbestos isa well-established aetiological factor for MPM, withoccupational exposure being documented in 70%–80% of thoseaffected.diagnosisPatients typically present with shortness of breath due topleural effusion or chest pain in a more advanced stage. Thediagnosis is usually suggested by imaging studies (unilateralpleural thickening; pleural effusion). An occupational historymust be obtained.Cytological examination of the effusion can be diagnostic,but often shows equivocal results. Therefore, histology,including immunohistochemistry, is the gold standard.Pleuroscopy, a video-assisted surgical procedure or openpleural biopsy in a fused pleural space may be necessary toprovide sufficient material for accurate histological diagnosis.There are three main histological types (epithelial, sarcomatousand mixed) with 60% being epithelial.Data suggest the possible contribution of serum mesothelin-related proteins and osteopontin as useful markers to supportthe diagnosis of mesothelioma; however, the precise role ofthese markers is yet to be defined.staging and risk assessmentClinical staging is based on the CT scan of the chest. However,the translation of the images into TNM stages is often notconclusive. Mediastinoscopy and video-assisted thoracoscopymay be useful in determining the stage. Accurate initial stagingis essential to provide both prognostic information andguidance on the most appropriate therapeutic options. Severaldifferent staging systems exist, among them the internationalIMIG staging system for MPM which emphasizes the extent ofdisease post-surgery in a traditional TNM system and stratifiespatients into prognostic categories similar to those shown inTable 1.The European Organization for Research and Treatment ofCancer prognostic scores may be used. They includeperformance status, gender, certainty of histology, histologicaltype and white blood count.MPM rarely metastasizes to distant sites but most patientspresent with locally advanced disease. The use of PET scan torule out extra-thoracic metastasis in patients considered forradical treatment is under investigation and findings seempromising.treatmentsurgeryVarious surgical procedures have been studied with varyingdegrees of success.Extra-pleural pneumonectomy (EPP) with resection of thehemi-diaphragm and the pericardium en bloc has thepotential for a radical treatment and this approach isgenerally combined with neoadjuvant or adjuvantchemotherapy and/or adjuvant radiotherapy. Surgery, theappropriateness of which is still under consideration, shouldonly be performed on selected patients by experienced thoracicsurgeons in the context of a multidisciplinary team andpreferably as part of a clinical trial [III, A]. Selection criteriainclude good performance status, and earlier stage disease withnot more than localized involvement of the thoracic wall,and adequate cardiopulmonary function. The inclusion of*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.Taddei 4, CH-6962 Viganello-Lugano, Switzerland;E-mail: clinicalrecommendations@esmo.orgApproved by the ESMO Guidelines Working Group: December 2004, last update March2010. This publication supercedes the previously published version—Ann Oncol 2009;20 (Suppl 4): iv73–iv75.Conflict of interest: Professor Lievens and Dr Felip have reported no conflicts of interest.Prof Stahel has reported that he has received honoraria from Eli Lilly for advisory boardsand speaker activity; Prof Weder has not reported any conflicts of interest.ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.orgpatients with N2 or sarcomatoid disease is controversial.Pleurectomy/decortication may be indicated for elderlypatients, at early stages or when EPP would leave macroscopictumour behind.To optimally palliate patients from dyspnea and pain, localprocedures to control pleural effusion include parietalpleurectomy or talc pleurodesis.radiotherapyThe use of curative intent hemithoracic radiotherapy has beenlimited because of the difficulty of irradiating such a largetarget volume to high doses without exceeding the tolerance ofthe adjacent normal tissues, especially the (homolateral)lung. The exact role of definitive radiotherapy in the multi-modality approach of MPM is currently underinvestigation. Nevertheless, in an attempt to improve localcontrol after EPP, it has been shown feasible to deliverradiotherapy doses of >45 Gy with both 3D conformal(3D-CRT) and intensity-modulated radiotherapy (IMRT).However, caution must be exercised regarding the exposure ofthe contralateral lung to low-dose irradiation, especially whenusing IMRT [III, B].In the palliative setting, radiotherapy can be delivered locallyin view of pain control or prevention of obstructive symptoms[IV, C]. As mesothelioma invades the tracts made by chestinstrumentation, prophylactic irradiation to the interventiontracts (PIT) has been advocated to reduce the incidence of portmetastases. In the absence of unambiguous prospectivedata—the consequence of randomized trials with small patientnumbers, different results according to histology and highlyvariable RT techniques—however, it remains impossible todraw definitive conclusions regarding its efficacy [II, C].chemotherapyPlatinum analogues, doxorubicin and some antimetabolites(methotrexate, raltitrexed, pemetrexed) have shown modestsingle-agent activity [III, B].The combinations of both pemetrexed/cisplatin, and toa smaller extent raltitrexed/cisplatin, have been shown toimprove survival as well as lung function and symptom controlin comparison with cisplatin alone in randomized trials [II, A].The combination of pemetrexed/carboplatin is an alternativeeffective therapy [III, A]A phase III trial evaluated second-line pemetrexed versus bestsupportive care in patients not previously exposed to this agentand found a longer time to disease progression in thechemotherapy arm. Since vinorelbine or gemcitabine have first-line activity they might be a reasonable choice in second-linetherapy. One study on 63 patients treated with vinorelbinereported a 16% response rate and median survival of 9.6months [III, A].If extrapleural pneumonectomy is planned, platinum-basedneoadjuvant or adjuvant combination chemotherapy should beconsidered.response evaluationResponse evaluation using CT scan is recommended after twoto three chemotherapy cycles and the modified RECIST criteriashould be applied. Volumetric measurements are underinvestigation.follow-upFollow-up consists of clinical evaluation, with particularattention to symptoms or chest wall recurrence, and chest CTas needed.noteLevels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the American Society of Clinical Oncology aregiven in square brackets. Statements without grading wereconsidered justified standard clinical practice by the expertauthors and the ESMO faculty.literature1. Peto J, Decarli A, La Vecchia C et al. The European mesothelioma epidemic. Br JCancer 1999; 86: 1970–1971.2. Pelucchi C, Malvezzi M, La Vecchia C et al. The mesothelioma epidemic inWestern Europe: an update. Br J Cancer 2004; 90: 1022–1024.3. Robinson BW, Creaney J, Lake R et al. Mesothelin-family proteins and diagnosisof mesothelioma. Lancet 2003; 362: 1612–1616.4. Pass HI, Wali A, Tang N et al. Soluble mesothelin-related peptide level elevationin mesothelioma serum and pleural effusions. Ann Thorac Surg 2008; 85(1008):265–272.Table 1. TNM staging system for MPMStage TNM CommentsIa T1a N0 M0 Primary tumour limited toipsilateral parietal pleuraIb T1b N0 M0 As stage Ia plus focalinvolvement of visceralpleuraII T2 N0 M0 As stage Ia or Ib plusconfluent involvement ofdiaphragm or visceralpleura or involvement ofthe lungIII Any T3 M0 Locally advanced tumourAny N1 M0 Ipsilateral,bronchopulmonary orhilar lymph nodeinvolvementAny N2 M0 Subcarinal or ipsilateralmediastinal lymph nodeinvolvementIV Any T4 Locally advanced technicallyunresectable tumourAny N3 Contralateral mediastinal,internal mammary, andipsilateral or contralateralsupraclavicular lymphnode involvementAny M1 Distant metastasesAnnals of Oncology clinical practice guidelinesVolume 21 | Supplement 5 | May 2010 doi:10.1093/annonc/mdq173 | v1275. Fennell DA, Parmar A, Shamash J et al. Statistical validation of the EORTCprognostic model for malignant pleural mesothelioma based on threeconsecutive phase II trials. J Clin Oncol 2005; 23: 184–189.6. Edwards JG, Abrams KR, Leverment JN et al. Prognostic factors for malignantmesothelioma in 142 patients: validation of CALGB and EORTC prognosticscoring systems. Thorax 2000; 55: 731–735.7. Weder W, Stahel RA, Bernhard J et al. Multicenter trial of neoadjuvantchemotherapy followed by extrapleural pneumonectomy in malignant pleuralmesothelioma. Ann Oncol 2007; 18: 1196–1202.8. Krug LM, Pass HI, Rusch V et al. Multicenter trial of neoadjuvant pemetrexedplus cisplatin followed by exptrapleural pneumonectomy and radiation formalignant pleural mesothelioma. J Clin Oncol 27 2009; 27: 3007–3013.9. De Perrot M, Feld R, Cho J et al. Trimodality therapy with inductionchemotherapy followed by extrapleural pneumonectomy and adjuvant high-dosehemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27: 1413–1418.10. McAleer MF, Tsao AS, Liao Z. Radiotherapy in malignant pleural mesothelioma.Int J Radiat Oncol Biol Phys 2009; 75: 326–337.11. Nakas A, Ucar M, Edwards JG, Waller DA. The role of video-assistedthoracoscopic pleurectomy/decortication in the therapeutic management ofmalignant pleural mesothelioma. Eur J Cardiothorac Surg 2008; 33: 83–88.12. Rice DC, Stevens CW, Correa AM et al. Outcomes after extrapleuralpneumonectomy and intensity-modulated radioation therapy for malignantpleural mesothelioma. Ann Thorac Surg 2007; 84: 1685–1692.13. O’Rourke N, Garcia JC, Paul J et al. A randomized controlled trial of interventionsite radiotherapy in malignant pleural mesothelioma. Radiother Oncol 2007; 84:18–22.14. Lee C, Bayman N, Swindell R, Faivre-Finn C. Prophylactic radiotherapy tointervention sites in mesothelioma: A systematic review and survey of UKpractice. Lung Cancer 2009; 66: 150–156.15. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study ofpemetrexed in combination with cisplatin versus cisplatin alone inpatients with malignant pleural mesothelioma. J Clin Oncol 2003; 21:2636–2644.16. van Meerbeeck JP, Gaafar R, Manegold C et al. Randomized phase III study ofcisplatin with or without raltitrexed in patients with malignant pleuralmesothelioma: an intergroup study of the European Organisation for Researchand Treatment of Cancer Lung Cancer Group and the National Cancer Institute ofCanada. J Clin Oncol 2005; 23: 6881–6889.17. Castagneto B, Bota M, Aitini E et al. Phase II study of pemetrexed in combinationwith carboplatin in patients with malignant pleural mesothelioma. Ann Oncol2008; 19: 370–373.18. Ceresoli GL, Zucali PA, Favaretto AG et al. Phase II study of pemetrexed pluscarboplatin in malignant pleural mesothelioma. J Clin Oncol 2006; 24:1443–1448.19. Jassem J, Ramlau R, Santoro A et al. Phase III trial of pemetrexed plus bestsupportive care campared with best supportive care in previously treated patientswith advanced malignant pleural mesothelioma. J Clin Oncol 2008; 26:1698–1704.20. Stebbing J, Powles T, McPherson K et al. The efficacy and safety of weeklyvinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009; 63:94–97.21. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response inmalignant pleural mesothelioma. Ann Oncol 2004; 15: 257–260.clinical practice guidelines Annals of Oncologyv128 | Stahel et al. Volume 21 | Supplement 5 | May 2010

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

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