Guideline sources The following summarized guidelines for the evaluation and management of malignant pleural mesothelioma (MPM) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2022), the Spanish Association of Medical Oncology (SEOM 2021), the European Society for Radiotherapy and Oncology (ESTRO/EACTS/ERS/ESTS 2020), the British Thoracic Society (BTS 2018), and the American Society of Clinical Oncology (ASCO 2018). 1 2 3 4 5 Calculator Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s TNM class https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 1/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway Guidelines 1. Screening and diagnosis Indications for screening: As per ESMO 2022 guidelines, insufficient evidence to recommend screening for early diagnosis of MPM in patients exposed to asbestos. I As per BTS 2018 guidelines, do not obtain biomarker testing to screen for MPM. D Diagnosis: As per SEOM 2021 guidelines, diagnose MPM based on biopsy results correlated with appropriate clinical, radiologic, and surgical findings. B As per BTS 2018 guidelines, do not rule out MPM based on symptoms and examination findings alone. D 2. Classification and risk stratification Staging: As per ESMO 2022 guidelines, use the 8th revision of the UICC TNM staging system for clinical and pathological staging. A Show 3 more As per SEOM 2021 guidelines, use the 8th edition of AJCC/UICC TNM staging system for staging MPMs. Define the level of intervention (curative or palliative intent) based on the clinical stage and other factors (patient fitness, comorbidities, tumor histology). As per ASCO 2018 guidelines, recognize that the current AJCC/UICC staging classification remains difficult to apply to clinical staging with respect to both T and N components and thus may be imprecise in predicting prognosis. Recognize that upstaging may occur at surgery in patients with clinical stage I/II disease. A As per BTS 2018 guidelines, stage MPM according to the IASLC staging proposals. B Prognosis: consider calculating a prognostic score in patients with MPM at diagnosis. Consider calculating prognostic scores to obtain survival information but do not for treatment decision- making. C Show 2 more 3. Diagnostic investigations Occupational history: As per ESMO 2022 guidelines, elicit occupational history with emphasis on asbestos exposure in patients with suspected MPM. B https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 2/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway As per BTS 2018 guidelines, elicit a thorough occupational history to cover all occupations throughout life. Elicit para exposure by exploring details of relative and/or partner occupations. B Diagnostic imaging: As per ESMO 2022 guidelines, obtain contrast-enhanced CT of the thorax and upper abdomen in patients with suspected MPM. B As per SEOM 2021 guidelines: Obtain contrast-enhanced chest CT for initial evaluation of patients with suspected MPM. B Use the modified RECIST criteria version 1.1 (requires the expertise of a radiologist) for the assessment of tumor lesions and tumor response on CT. B As per BTS 2018 guidelines, obtain an urgent CXR to assess for mesothelioma in 40 years old patients with 2 of the following unexplained symptoms, or 1 in case of history of smoking or asbestos exposure: cough fatigue shortness of breath chest pain weight loss appetite loss. B Show 5 more Imaging for staging: obtain contrast-enhanced CT of the chest and upper abdomen for the initial staging in patients with mesothelioma. B Show 7 more Molecular testing: As per ESMO 2022 guidelines, do not obtain PD-L1 expression and immune microenvironment analyses or assessment of tumor mutational burden to select patients for treatment with immune checkpoint inhibitors. D Show 2 more As per SEOM 2021 guidelines: Do not obtain routine genomic studies in patients with MPM. D Consider obtaining genetic testing in selected patients with MPM, especially in young patients and those having a family history of cancer. B As per ASCO 2018 guidelines, do not obtain tumor genomic sequencing in patients with MPM. D Biomarkers: As per ASCO 2018 guidelines, do not obtain non-tissue-based biomarkers to predict outcomes or monitor tumor response. D As per BTS 2018 guidelines, do not obtain biomarker testing to screen for MPM. D https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 3/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway Show 2 more Biomarkers (EMSO): do not obtain circulating tumor markers for distinguishing MPM. D 4. Diagnostic procedures Histopathology: As per ESMO 2022 guidelines, use the current WHO criteria for classifying mesotheliomas, including major subtype and documentation of architectural patterns, grading of epithelioid subtypes and stromal and cytologic features refining prognostication. B Show 6 more As per SEOM 2021 guidelines, include histological subtype in the pathological report of patients with MPM. A As per ASCO 2018 guidelines, report mesothelioma subtype (epithelial, sarcomatoid, or biphasic) for prognostic significance. A Show 2 more As per BTS 2018 guidelines, obtain immunohistochemistry for the differential diagnosis of MPM in both biopsy and cytology-type specimens. B Show 4 more Thoracentesis: Perform an initial thoracentesis in patients presenting with symptomatic pleural effusions and send pleural fluid for cytologic examination as an initial assessment for possible mesothelioma. B Consider obtaining a cytologic evaluation of pleural fluid as an initial screening test for mesothelioma, recognizing that it is not a sufficiently sensitive diagnostic test. B Biopsy: As per ESMO 2022 guidelines, attempt obtaining a pathological specimen, preferably via thoracoscopy B , in patients with unilateral pleural thickening, with or without fluid and/or pleural plaques. B Show 3 more As per SEOM 2021 guidelines, perform mediastinal biopsy by mediastinoscopy or endobronchial ultrasound in patients with MPM suitable for surgery. B As per ASCO 2018 guidelines, perform biopsies via thoracoscopy or CT guidance over thoracocentesis with cytological analysis for a better opportunity to reach a definitive diagnosis whenever a definitive histologic diagnosis is needed. B Show 4 more Contralateral thoracoscopy: consider performing a contralateral thoracoscopy to exclude contralateral disease in the presence of contralateral pleural abnormalities detected on initial positron emission tomography/CT or chest CT. C https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 4/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway Laparoscopy: perform a laparoscopy in patients with suspicious findings for intra-abdominal disease on imaging and no other contraindications to surgery. B 5. Medical management General principles: consider referring patients with MPM to a regional mesothelioma multidisciplinary team. C Show 4 more Expectant management: consider offering a trial of expectant observation before initiating systemic therapy in asymptomatic patients with epithelial mesothelioma and a low disease burden unsuitable for surgery. C First-line systemic therapy: As per ESMO 2022 guidelines, offer the following regimens as first-line systemic therapy options in patients with MPM: pemetrexed combined with cisplatin (or alternatively carboplatin), and vitamin supplementation, up to 6 cycles bevacizumab with platinum-pemetrexed nivolumab plus ipilimumab, given up to 2 years equivalent dosing, regardless of histologies or PD-L1 status for unresectable MPM. A Show 2 more As per SEOM 2021 guidelines, offer platinum-based chemotherapy as first-line therapy for patients with MPM not suitable for surgery, after a multidisciplinary assessment in the thoracic tumor board. A Show 2 more As per ERS 2020 guidelines: Offer first-line combination chemotherapy consisting of platinum and pemetrexed (with folic acid and vitamin B12 supplementation) in patients with MPM suitable for chemotherapy (good performance status, ECOG performance status 0-2, no contraindications). B Consider offering bevacizumab, if available, in combination with cisplatin/pemetrexed as first- line therapy in patients with MPM suitable for bevazucimab and cisplatin, but not for macroscopic complete resection. C As per BTS 2018 guidelines: Offer cisplatin and pemetrexed as first-line therapy in patients with MPM with good performance status (WHO 0-1). Add bevacizumab to this regime where licensed. Offer raltitrexed as an alternative to pemetrexed. A Offer carboplatin in combination with pemetrexed where cisplatin is contraindicated or has adverse risk. E Second-line systemic therapy: As per ESMO 2022 guidelines, consider offering single-agent pembrolizumab (which has similar outcomes to single-agent chemotherapy) as a second-line therapy option in immunotherapy- https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 5/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway na ve patients. C Show 4 more As per SEOM 2021 guidelines, encourage participation in clinical trials due to the limited efficacy of second-line therapy. B Show 2 more As per BTS 2018 guidelines: Do not offer pemetrexed or vorinostat as second-line therapy in patients with MPM. D Offer first-line clinical trials over any other option as second-line therapy, providing the patient is of adequate performance status. E 6. Therapeutic procedures Radiotherapy: As per ESMO 2022 guidelines, consider offering radiotherapy for palliation of pain related to local infiltration of thoracic structures. C Show 3 more As per SEOM 2021 guidelines, do not offer routine prophylactic radiotherapy of chest wall procedure tracts in patients with MPM. D As per ERS 2020 guidelines: Consider offering palliative radiotherapy in patients with MPM for pain relief in cases of painful sites of disease caused by local infiltration of normal structures. C Do not offer routine prophylactic radiotherapy of the drain site. D As per BTS 2018 guidelines, do not offer preoperative or postoperative radiotherapy in patients with MPM. D Show 3 more Pleurodesis: As per ESMO 2022 guidelines: Perform talc poudrage via thoracoscopy over video-assisted thoracoscopic partial pleurectomy as the first surgical procedure of choice for pleurodesis. A Recognize that pleurodesis helps to prevent recurrent effusions. A As per SEOM 2021 guidelines, perform talc pleurodesis rather than video-assisted thoracoscopic partial pleurectomy (partial removal of parietal and/or visceral pleura for diagnostic or palliative purposes) for the management of pleural effusions in symptomatic patients with MPM, as the latter procedure has no effect on overall survival and results in increased complications and longer hospital stay. A As per ERS 2020 guidelines, perform talc poudrage via thoracoscopy to control a recurrent MPM-related pleural effusion as first-line procedure to achieve pleurodesis in patients with expanded lungs. B https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 6/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway As per BTS 2018 guidelines, perform talc (via slurry or thoracoscopic poudrage) for symptomatic pleural effusion in MPM, informed by patient choice. Perform talc pleurodesis in preference to a video-assisted thoracoscopic partial pleurectomy for fluid control in patients with MPM. A Indwelling pleural catheter: As per ESMO 2022 guidelines: Consider offering an indwelling pleural catheter in patients with recurrent pleural effusions. B Do not perform aggressive draining over symptomatic drainage to control breathlessness in patients with indwelling pleural catheters. D As per BTS 2018 guidelines, offer an indwelling pleural catheter for symptomatic pleural effusion in MPM, informed by patient choice. A 7. Surgical interventions Macroscopic complete resection: as per ESMO 2022 guidelines, perform macroscopic complete resection in combination with other modalities in selected patients with MPM at experienced centers, discussed with a multidisciplinary team involving thoracic surgeons, pulmonologists, medical and radiation oncologists. B Extended pleural decortication: As per ESMO 2022 guidelines, prefer extended pleural decortication as a lung-preserving procedure over extrapleural pneumonectomy. B As per BTS 2018 guidelines, do not perform extended pleurectomy decortication outside of a clinical trial. D Palliation of pleural effusion: As per ESMO 2022 guidelines, perform surgery for palliation of pleural effusions when chest tube drainage is unsuccessful. B As per ERS 2020 guidelines, consider performing palliative video-assisted video-assisted thoracoscopic partial pleurectomy to control pleural effusion in symptomatic patients with MPM suitable for surgery and not able to benefit from (or after the failure of) chemical pleurodesis or indwelling catheter. C As per ASCO 2018 guidelines, offer palliative approaches, such as a tunneled permanent catheter placement or thoracoscopic exploration with partial resection and/or pleurodesis, in patients with symptomatic pleural effusion and performance status 2, or if a maximal cytoreduction cannot be performed due to disease extent or comorbid conditions. Perform additional biopsy to confirm pathologic diagnosis during the procedure in the latter case. Obtain material for additional studies (such as molecular and/or immunologic profiling) if the patient is being evaluated for investigational therapy. B As per BTS 2018 guidelines: https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 7/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway Do not perform video-assisted thoracoscopic partial pleurectomy over talc pleurodesis in patients with MPM. D Do not perform extra-pleural pneumonectomy in patients with MPM. D 8. Patient education General counseling: Provide accurate and understandable information to patients and carers about compensation for MPM. B Provide patients with MPM and their carers the opportunity to discuss concerns regarding their disease. B 9. Follow-up and surveillance Assessment of treatment response: As per ESMO 2022 guidelines, obtain contrast-enhanced CT for the assessment of treatment response. B As per ASCO 2018 guidelines: Do not obtain non-tissue-based biomarkers to predict outcomes or monitor tumor response. D Assess tumor response classification based on the RECIST criteria by comparing the sums across serial CT. B As per BTS 2018 guidelines, do not obtain routine biomarker testing to predict treatment response or survival. D Clinical findings Symptoms Past medical history Chest pain Autoimmune hemolytic anemia Cough Head and neck exam Dysphagia Fatigue Neck mass Hemoptysis Respiratory exam Hoarseness Loss of appetite Chest wall mass Neck swelling Dullness to percussion Shortness of breath breath sounds Sweating Weight loss Integument exam https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 8/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway Digital clubbing Social history Hematological findings Exposure to asbestos blood platelet count Cardiac exam Jugular venous distention Pulsus paradoxus Lymphatic exam Supraclavicular lymphadenopathy Lab findings Hypergammaglobulinemia Hypoalbuminemia ESR soluble mesothelin-related peptide Imaging findings Hemithorax Hilar lymphadenopathy Internal mammary lymphadenopathy Lung mass Mediastinal lymphadenopathy Pericardial effusion Pleaural plaques Pleural calcifications Pleural effusion Pleural thickening T h l d i ti References 1. Ian Woolhouse, Lesley Bishop, Liz Darlison et al. British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma. Thorax. 2018 Mar;73 Suppl 1):i1-i30. Open 2. Hedy L Kindler, Nofisat Ismaila, Samuel G Armato rd et al. Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018 May 1;36 13 1343 1373. Open 3. S Popat, P Baas, C Faivre-Finn et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2022 Feb;33 2 129 142. Open https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 9/10 6/30/23, 1:00 AM Malignant pleural mesothelioma Pathway 4. E Nadal, J Bosch-Barrera, S Cedr s et al. SEOM clinical guidelines for the treatment of malignant pleural mesothelioma 2020 . Clin Transl Oncol. 2021 Feb 4. Open 5. Isabelle Opitz, Arnaud Scherpereel, Thierry Berghmans et al. ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma. Eur J Cardiothorac Surg. 2020 Jul 1;58 1 1 24. Open 6. Lawek Berzenji, Paul E Van Schil, Laurens Carp. The eighth TNM classification for malignant pleural mesothelioma. Transl Lung Cancer Res. 2018 Oct;7 5 543 549. Open https://web.pathway.md/diseases/recGZQsqc7jCc4Aqz 10/10