Aim of the guideline

The key aim of this guideline is to provide detailed, evidence-based guidance for the investigation of suspected MPM and the subsequent care and management of individuals with proven MPM. MPM is a rare cancer where the malignancy affects the pleura, a thin membrane of lubricating cells that lines the lungs and chest wall. The focus of this guideline is MPM as it is far more common than mesothelioma occurring in the abdomen. The 2016 Mesothelioma Audit data reported that in the UK in 2014 pleural mesothelioma accounted for 2179 cases (97%), with 70 peritoneal cases (approximately 3%).¹

In 2007, the British Thoracic Society (BTS) statement on mesothelioma was published in response to a request from the National Health Executive in England.² The BTS has reviewed this statement and is of the opinion that the publication is no longer fit for purpose as an up-to-date reference guide for healthcare professionals. The 2007 statement did not attempt to provide a comprehensive review of all relevant published literature and since the publication of the statement the BTS has achieved NICE accreditation for its guideline production process. The Standards of Care Committee (SOCC) of the BTS established a guideline development working group in 2014, chaired by Professor Nick Maskell and Dr Ian Woolhouse.

The main cause of mesothelioma is breathing in asbestos dust-approximately 85% of all mesotheliomas in males are attributable to occupational asbestos exposures. The use of products containing asbestos was banned in the UK in 1999. The latency period between first exposure and development of the disease is very long, typically 30–40 years.

Cases of mesothelioma were recorded systematically from the late 1960s. The incidence of mesothelioma has been increasing steadily since then, and current predictions suggest there will continue to be approximately 2500 deaths per year for the rest of this decade, before numbers begin to fall. (HSE http://www.hse.gov.uk/Statistics/causdis/mesothelioma/mesothelioma.pdf).

The largest dataset of MPM in the UK comes from the National Lung Cancer Audit report, which described 8740 cases seen in hospitals in England and Wales between 2008 and 2012.³ Eighty-three per cent of patients were male and the median age at diagnosis was 73 years. Sixty-seven per cent of patients received active anticancer treatment (chemotherapy, radiotherapy and surgery) and overall median survival was 9.5 months, with 1-year and 3-year survival rates of 41% and 12%, respectively. The report identified significant variation in treatment and outcomes across the UK which further highlights the need for an evidence-based guideline to facilitate the highest standards of care for all patients with mesothelioma in the UK.

Intended users of the guideline and target patient populations

The guideline will be primarily of interest to healthcare professionals working within the National Health Service (NHS), but the aim is to make the guideline as applicable to international practice as possible so that it may be used across Europe and America as appropriate. Given the nature of MPM, the majority of the guideline will be relevant to secondary care-based specialists; however, symptom recognition, management and follow-up are all relevant to community-based specialties.

Intended users

• Primary care–general practitioners (GPs) and practice nurses;

• Hospital specialist teams in respiratory medicine, oncology, thoracic surgery and palliative care;

• Hospices/community teams;

• Specialist nurses (including lung cancer and palliative care);

• Radiologists;

• Pathologists.

Areas covered by the guideline

Inclusion

• The epidemiology and incidence of mesothelioma in the UK and worldwide;

• The preferred investigation pathway of suspected cases of MPM;

• Consider special situations including:

  • Imaging;

  • Histology/cytology;

  • Frail patient not fit for invasive tests.

• Biomarkers;

• Role of mesothelioma MDTs;

• Outline best practice in oncological management:

• Role of chemotherapy;

• Place for radiotherapy;

• Role of surgery.

• Guidance on palliation in MPM;

• Guidance on providing patients with relevant disease-specific information, including medicolegal/compensation issues;

• Summary of future therapeutic agents that might be available within next 5 years;

• Summary of major MPM recommendations.

Areas not covered by the guideline

Non-pleural mesothelioma is excluded from this guideline.

Limitations of the guideline

Healthcare providers need to use clinical judgement, knowledge and expertise when deciding whether it is appropriate to apply recommendations for the management of patients. The recommendations cited here are a guide and may not be appropriate for use in all situations. The guidance provided does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of each patient, in consultation with the patient and/or their guardian or carer.

Members of the guideline development group

The guideline development group (GDG) was chaired by two respiratory consultants–Dr Ian Woolhouse and Professor Nick Maskell. The GDG had a wide membership with representation from respiratory medicine, thoracic surgery, medical oncology, radiotherapy, pathology and primary care. A patient representative was on the group for the duration of the process. Those on the group were not required to be BTS members.

Representation

Professor Dean Fennell and Dr Jeremy Steel represented the Association of Cancer Physicians. Dr Anthony Edey represented the British Society of Thoracic Imaging. Professor Corinne Faivre-Finn represented the British Thoracic Oncology Group. Professor Keith Kerr represented the Royal College of Pathologists. Dr Ian Woolhouse represented the Royal College of Physicians. Mr John Edwards and Mr Apostolos Nakas represented the Society of Cardiothoracic Surgeons. Dr Corinne-Faivre-Finn and Dr Anthony Edey represented the Royal College of Radiologists. Dr Tim Peel represented the Association for Palliative Medicine. Dr Steve Holmes represented the Primary Care Respiratory Society UK. Ms Liz Darlison represented the Royal College of Nursing. Dr Graham Abbott, Mr Paul Astle and Mr John Gillies were the patient representatives on the group.

Establishment of guideline development group

The GDG was convened in June 2014, with the first meeting taking place in October 2014. The full GDG met six times during the development of the guideline and kept in close contact by teleconference and email throughout the process. The BTS SOCC reviewed the draft guideline in November 2016. The draft guideline was made available online from 22 March 2017 until 24 April 2017 for public consultation and circulated to all relevant stakeholders. The BTS SOCC reviewed the revised draft in June 2017 and final SOCC approval was granted in September 2017.

Methodology

This guideline is based on the best available evidence and follows the NICE-accredited BTS guideline production process. The methodology used to write the guideline adheres strictly to the criteria as set by the Appraisal of Guidelines, Research and Evaluation (AGREE) II collaboration, which is available online www.agreetrust.org/resource-centre/agree-ii/. The BTS SOCC guideline production manual is available at: https://www.brit-thoracic.org.uk/guidelines-and-quality-standards/

Summary of key questions and literature search

Clinical questions were gathered in the Patient, Intervention, Comparison, Outcome and Time (PICOT) format. The key questions are summarised below.

• Which clinical features predict the presence of MPM?

• In patients with suspected MPM (post chest X-ray), which imaging modality is best for diagnosis/staging and what technical factors are important?

• Should biomarkers (serum/fluid) be measured in MPM?

• Is there a staging system for MPM that determines management and predicts outcome?

• What factors determine prognosis and timing of treatment in MPM?

• What are the appropriate cytopathological approaches which allow diagnosis and subtyping of MPM?

• Is the care of patients with suspected/proven MPM improved by discussion at a specialist MDT?

• Where histological confirmation is either not possible or not definite, what are criteria for a clinical diagnosis of MPM?

• What is the optimum strategy for the management of pleural fluid in MPM?

• Is there a role for surgery in the management and treatment of patients with MPM?

• Is there a role for systemic anticancer treatment in MPM?

• Is there a role for radiotherapy in MPM?

• What treatment/interventions are effective for symptom control in MPM?

• What are the nursing care and information needs for patients with suspected and proven MPM?

• What is the most effective follow-up strategy of patients with MPM?

The PICOT framework was used to define the scope of the guideline and formed the basis of the literature search. The literature search was conducted in December 2014 by York University. Systematic electronic database searches were conducted in order to identify all papers which may potentially be included in the guideline. For each question, the following databases were searched: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In-Process, EMBASE and PUBMED (see online supplementary appendix 1).

The search was limited to papers published in English. The searches identified a total of 6173 abstracts. The full list of abstracts was retained and is kept in an archive. A second search was completed in July 2016 to search for relevant papers published between 2014 and 2016, yielding a further 1038 potentially relevant references. Additional references were included from personal collections as appropriate.

Appraisal of the evidence

An initial screen was completed to remove letters, conference papers and news articles. Dr Woolhouse and Professor Maskell read the remaining abstracts (5129), marked those considered relevant to the scope of the guideline and allocated each relevant abstract to a clinical question(s). 950 abstracts were allocated to clinical question(s). For the second search, the initial screen reduced the abstracts to 582. These were all read by Dr Woolhouse and Professor Maskell and 44 were allocated to clinical question(s). GDG members were allocated to work on the questions in small groups.

Each abstract was read and at least two members agreed whether the paper was relevant to the particular guideline section. Papers were excluded if the following applied:

• If the paper did not answer the clinical question concerned.

• If it was a case report of fewer than 20 patients; however, this was not an absolute cut-off. Professional judgement was applied and some smaller case reports were considered, and indeed some case reports of more than 20 patients were excluded.

• If the language of the full paper was not English.

At least two members of each small group independently appraised each paper using the SIGN critical appraisal checklists. An evidence level was assigned to each study using the SIGN methodology (table 1 and 2).

Full papers were obtained for all relevant, or possibly relevant, abstracts.

Each relevant paper was read in full by at least two members of the GDG and an evidence table entry was completed for each paper used to support a recommendation/good practice point. The full GDG reviewed each section during the regular meetings and consensus was reached. Evidence tables are available in the online supplementary appendix 2.

From the outset, it was acknowledged that there would be little high-quality evidence for some of the clinical questions identified. In this instance, low-grade evidence was considered, along with expert opinion via consensus at the meetings.

The following parameters were used by the GDG to appraise the evidence:

• How applicable the obtained evidence was in making recommendations for the defined target audience of this guideline.

• Whether the evidence was generalisable and relevant to the target population for the guideline.

• Whether there was a clear consistency in the evidence obtained to support recommendations.

• What the implications of recommendations would be on clinical practice in terms of resources and skilled expertise.

Cost-effectiveness was not considered in detail as in-depth economic analysis of recommendations falls outside of the BTS guideline production process. However, the GDG were asked to be mindful of any barriers to implementing the recommendations and good practice points (GPPs).

Recommendations were graded from A to D as indicated by the strength of the evidence as shown in table 2. In line with SIGN guidance, ‘minus’ evidence was considered where necessary, but only in such instances when there were no published ‘plus’ papers. In this context, any recommendation based on this evidence was made Grade D. GPPs were included where research evidence was lacking, but the GDG felt it was important to highlight practical points which could improve the care of patients. Research recommendations were also highlighted and passed to the Chair of the SOCC on publication of the guideline.

Planned review and updating of the guideline

In line with BTS policy, this guideline will be reviewed by the SOCC within 5 years of publication.

Declaration of interest

BTS Declarations of Interest forms have been completed by all members for each year they were part of the GDG. Details of these forms can be obtained from BTS Head Office. Declarations of Interest was a standing item at each GDG meeting.

Stakeholders

Stakeholders were identified at the start of the process and where appropriate societies and organisations were contacted and asked to nominate a specific person to join the GDG. All stakeholder organisations were notified when the guideline was available for public consultation.

Symptoms

Chest pain and dyspnoea are the most common presenting symptoms, but the relative frequency of these symptoms is not consistent in different studies. Other symptoms include weight loss, fevers and sweats^{4 9 10} (Table 3).

Clinical signs

Pleural effusion is often present. Other signs are variable (eg, palpable lymph nodes).¹⁰ Right side predominance of the disease in the order of 1.6:1. This might partially reflect the increased pleural surface area of the right hemithorax.⁴

Usually the first investigation in patients with suspected mesothelioma will be a chest X-ray. The NICE Guideline on Investigation and Referral for Suspected Cancer gives guidance on when a chest X-ray should be offered in suspected MPM (table 4). The CDG noted that smoking and finger clubbing are more appropriate when considering lung cancer, as opposed to mesothelioma.

Evidence statements

Occupational exposure to asbestos is recalled in the majority of patients with MPM. High-risk occupations are ship building and construction/demolition work (including boiler repair, and working as a carpenter or electrician). Level 2-.

Symptoms are not specific to MPM. Common symptoms at presentation include chest pain and breathlessness. Less common symptoms at presentation include weight loss, fatigue, fever and cough. Level 2-.

The most common examination finding at presentation is a pleural effusion (with <1 in 10 presenting with lymphadenopathy or clubbing). Level 2-.

Recommendations

• Do not rule out a diagnosis of MPM on the basis of symptoms and examination findings alone. Grade D.

• Offer an urgent chest X-ray to patients with symptoms and signs as outlined in NICE NG12. Grade D.

• Refer all patients with a chest X-ray suggestive of MPM urgently (via the 2-week wait suspected cancer pathway in England and Wales). Consider referral for further investigation in patients with persistent symptoms and history of asbestos exposure despite normal chest X-ray. Grade D.

• A thorough occupational history should be taken to cover all occupations throughout life. It is important to elicit para exposure by exploring details of relative and/or partner occupations. Grade D.

Evidence statements

The proposed eighth edition of the IASLC TNM staging system predicts survival in surgically and non-surgically treated patients with MPM. Level 3.

Recommendation

• Record staging of MPM according to the version 8 of the IASLC staging proposals. Grade D.

Evidence on diagnostic imaging

The majority of diagnostic evidence evaluates the role of imaging in differentiating benign from malignant pleural disease in general, rather than from MPM specifically. Numerous studies have demonstrated the utility of CT, PET-CT and MRI in the assessment of patients with suspected pleural malignancy.¹³ These studies provide clear guidance on standard morphological characteristics of pleural malignancy using CT and MRI^14–17 and are summarised in table 7 along with reported sensitivities and specificities.^18–22

Pleural malignancy is typically unilateral. Bilateral involvement is rare, accounting for as few as 3% of cases.¹⁵ In 94% of cases of pleural malignancy, there is a pleural effusion on the affected side. However, differentiation between MPM and metastatic pleural malignancy can be challenging. The presence of lung parenchymal involvement or mediastinal or hilar lymph node enlargement may help point towards metastatic pleural disease.²¹ While the presence of pleural plaques is an indicator of prior asbestos exposure, it is not a marker of malignancy per se and effusions can be found in this context as a result of benign asbestos-related pleural effusion.

PET-CT can be used to provide useful functional information additional to morphology. Typically, areas of abnormal malignant pleural thickening have elevated maximal standardised uptake values (SUVmax).^{23 24} Thus, using a SUVmax threshold of >2.0 has been found to accurately differentiate malignant from benign pleural disease with a sensitivity of 88%–100% and specificity of 88%–92%.^25–27 In a meta-analysis of 11 PET-CT studies, this technique had a pooled sensitivity of 95% (95% CI 92% to 97%) and specificity 82% (95% CI 76% to 88%) for differentiation of malignant from benign pleural disease.²⁸ Causes of false negatives include: small volume tumours and those with a low proliferative index, for instance, early stage epithelioid mesothelioma. In addition, false positives may result from inflammatory diseases, tuberculous pleurisy, parapneumonic effusions and prior talc pleurodesis. One study, which included patients with prior talc pleurodesis, reported significantly lower specificity in comparison to other studies (specificity 35.3%), as a result of the high number of false positives in this group.²⁹

Studies using MRI have highlighted its potential in distinguishing benign from malignant pleural disease. Malignant pleural thickening tends to show inhomogenous hyperintensity on proton-density T2-weighted images and enhancement on T1-weighted images following gadolinium injection, in contradistinction to benign disease that is of low signal on both sequences. When these signal characteristics are combined with morphology and a pleural thickening >1 cm, the accuracy of MRI is very high for differentiation of benign from malignant disease with sensitivity of 100% and specificity of 95% in one study (95% confidence intervals not reported).³⁰ More recent studies have highlighted potential utility for diffusion-weighted MR imaging (DWI-MRI) in differentiating pleural malignancy from benign pleural disease, with lower Apparent Diffusion Coefficient (ADC) values being demonstrated in pleural malignancy.^{31 32} Coolen et al also performed DWI-MRI in a study of pleural malignancy and reported that inhomogeneous restriction in diffusion of the thickened pleura differentiates malignant from benign pleural disease with a sensitivity of 92.5% (95% CI 84% to 97%) and specificity of 79% (95% CI 62% to 89%).³³ Gill et al demonstrated that patients with epithelioid MPM have a significantly higher ADC value than those with non-epithelioid MPM and an ADC threshold of 1.1 could differentiate epithelioid MPM from sarcomatoid MPM with a sensitivity of 60% and specificity of 94% (95% CIs not reported).³² These MRI data appear promising but are yet to be validated prospectively and importantly their added value in disease with atypical or equivocal CT signs is unclear.

Evidence on staging

Seventeen^{25 34–49} studies were identified that evaluated the role of various imaging modalities when staging MPM. One systematic review⁵⁰ and one meta-analysis⁵¹ were also identified in the literature. To a degree all imaging modalities are limited in accuracy of staging compared with the gold standard of postoperative histological staging and mediastinoscopic sampling of lymph nodes. However, assessment of limitations is made difficult by the relative infrequency of surgical resection and the use of comparator imaging techniques as the reference point in many of the studies.

Despite the overall benefits of CT scanning when initially assessing patients with suspected mesothelioma, CT performs poorly when compared against other modalities for staging of MPM. CT is particularly poor at assessing T4 stage where assessment of invasion through soft tissue such as diaphragm and chest wall is required. CT also performs poorly at lymph node staging, particularly when detecting involved N2 and N3 nodes. In one study, 37% of the patients were upstaged following a PET scan.³⁵

The role of MRI is limited in staging MPM.^{34 36 37 39 41 42 48} However, MRI does perform better than CT, where tumour-soft tissue delineation is required. For example, MRI has a sensitivity and specificity of 87.5% and 87.5% for stage II disease, and 91% and 100% for stage III disease due to its superiority in detecting invasion into or through chest wall, endothoracic fascia, diaphragmatic muscle and mediastinal fat.³⁶ Table 8 provides a brief summary.

It should also be noted that although Plathow et al³⁶ showed an accuracy of 100% and low interobserver variability when staging patients with MPM with PET-CT, compared with CT and MRI, the results of other smaller studies are mixed.

Pragmatically CT (optimised for pleural enhancement) remains the mainstay of imaging for diagnosis and staging of MPM. A number of centres routinely include the abdomen and pelvis in the initial CT scan whereas others perform completion scanning according to the results of other diagnostic tests.

Evidence statements

Overall reported diagnostic accuracy of CT in the detection of pleural malignancy is 68%–97%, with specificity of 78%–89%. Level: 3.

CT and ultrasound features of malignant pleural disease include pleural thickening >1 cm, nodular pleural thickening, mediastinal pleural thickening and interlobar fissural nodularity. Level: 3.

Features favouring MPM over metastatic pleural malignancy are the presence of pleural plaques, involvement of the interlobar fissure and the absence of lung parenchymal involvement. Level: 3.

Overall reported diagnostic accuracy of PET-CT in the detection of pleural malignancy–sensitivity 88%–95%, specificity 35%–100%. Level: 2+.

False positives at PET-CT are common in TB pleuritis, inflammatory disorders of the pleura and previous talc pleurodesis. Level: 3.

Overall reported diagnostic accuracy of MRI in the detection of pleural malignancy–sensitivity 60%–100%, specificity 73%–95%. Level: 2−.

CT has limited accuracy for staging MPM using current staging systems. Level: 3.

MRI is better than CT at detecting invasion through diaphragm and T3 disease (invasion through muscle, bone, mediastinal fat), but has limited sensitivity in nodal staging. Level: 3.

Integrated PET-CT has the highest accuracy for staging MPM. It has better sensitivity across all three criteria T, N and M compared with CT and MRI. Level: 2+.

Recommendations

• Offer CT thorax with contrast (optimised for pleural evaluation) as the initial cross-sectional imaging modality in the evaluation of patients with suspected MPM. Grade D.

• Use of PET-CT for aiding diagnosis of MPM is not recommended in patients who have had prior talc pleurodesis and caution should be employed in populations with a high prevalence of TB. Grade D.

• In patients where differentiating T stage will change management, consider MRI. Grade D.

• In patients where excluding distant metastases will change management, offer PET-CT. Grade D.

Summary of individual immunohistochemistry evidence

A large number of IHC markers have been reviewed and are summarised in table 10, with sensitivity and specificity values where available. It should be noted that the sensitivity and specificity of many of these markers are reduced in sarcomatoid MPM, which frequently does not express any of the typical ‘mesothelial’ markers. In this scenario, expression of keratins may be the only demonstrable feature, which is helpful but non-specific. Additionally, discriminating malignant from benign mesothelial proliferations is not reliable using IHC markers.

Additional techniques

Wu et al⁵⁴ examined p16 FISH to discriminate reactive from malignant mesothelium in 60 patients. Hemizygous or homozygous deletion of p16 was not seen in fibrous pleurisy (FP), but was detected in 66.7% of epithelioid MPM, 87.5% of biphasic MPM and 100% of sarcomatoid cases, highlighting potential utility in the differentiation of MPM from FP. Hida et al⁵⁵ performed BAP1 and p16 FISH in 40 cases of MPM and 20 cases of inflammatory pleuritis. All inflammatory cases and only three mesothelioma cases were negative for both. The presence of BAP1 and or p16 FISH may therefore be helpful in differentiating MPM from benign mesothelial proliferation.

Diagnosis in cytology

This remains a controversial subject. The reliability of an MPM diagnosis on effusion cytology is highly variable (sensitivity ranging from 16% to 73%^{56 57}) and is very much dependent on cytologist experience. Some centres will send clot/cell block sections for the homozygous deletion of the 9p21 band (p16), which can increase diagnostic certainty.

Evidence statements

Glut1 IHC and p16 FISH have potential for discriminating benign from malignant mesothelium. Level 3.

The sensitivity of pleural fluid cytology for the diagnosis of MPM is highly variable and is dependent on the cytologist’s experience. Level 3.

Positive IHC markers for MPM include calretinin, thrombomodulin, CK5/6, CAM5.2, EMA, vimentin, GLUT-1, HBME-1, WT-1, p53. Overall sensitivity is 45%–100%. Level 3.

Negative IHC markers for MPM include Ber-Ep4, MOC-31, CEA, Leu-1, CD15, TTF-1, B72.3. Overall specificity is 53%–100%. Level 3.

A combination of two positive mesothelial markers and two negative adenocarcinoma markers increases diagnostic accuracy. Level 3.

Diagnostic accuracy of IHC markers is reduced in sarcomatoid MPM. Level 3.

Accurate subtyping of IHC markers is reduced in sarcomatoid MPM. Level 3.

Recommendations

• IHC is recommended for the differential diagnosis of MPM in both biopsy and cytology type specimens. Grade D.

• A combination of at least two positive mesothelial (calretinin, cytokeratin 5/6, Wilms tumour 1, D-240) and at least two negative adenocarcinoma immunohistochemical markers (TTF1, CEA, Ber-EP4) should be used in the differential diagnosis of MPM. (Markers listed in likely order of value). Grade D.

• Do not rely on cytology alone to make a diagnosis of MPM unless biopsy is not possible or not required to determine treatment due to patient wishes or poor PS. Grade D.

• Pathologists should report the histological subtype of MPM in all cases. Grade D.

Good practice points

• Biopsies from patients with suspected MPM should be reviewed by a pathologist experienced in the diagnosis of MPM and a second opinion should be sought if there is uncertainty over the diagnosis.

Evidence on diagnostic markers

The most robust body of evidence at present for diagnosis of MPM is for Soluble Mesothelin Related Peptides (SMRP) and Osteopontin, as summarised below:

• A meta-analysis by Cui et al⁵⁸ reviewed 28 publications totalling 7550 patients (1562 MPM and 5988 non-MPM), which confirmed serum SMRP to have an overall sensitivity of 60% and a specificity of 81%, with an area under the curve (AUC) of 0.734.

• The same review also demonstrated that pleural fluid SMRP has an overall sensitivity of 75%, specificity 76% and AUC of 0.809 (total number of patients 1506; 460 MPM and 1046 non-MPM).

• Summary sensitivities and specificities for SMRP and Osteopontin–from two meta-analyses by Hu et al,⁵⁹ reviewing six publications with a total of 906 patients, and Lin et al⁶⁰ reviewing seven publications with a total of 1096 patients (Table 11).

There were a number of studies on Fibulin-3, representing a smaller body of evidence than that above for SMRP and Osteopontin. These are summarised in table 12.

Markers for disease monitoring and assessment of progression

Sixteen^61–76 papers were reviewed in relation to above. Again, SMRP is the most widely studied marker but other biomarkers such as Fibulin-3, Osteopontin, Megakaryocyte potentiating factor (MPF and Hyaluronic acid (HA) were also assessed. Study populations are heterogeneous with regards to their management. Disease progression/stability in these studies has in general been assessed by the use of the modified response evaluation criteria in solid tumours (RECIST).

Overall:

• SMRP shows a positive correlation with tumour bulk.⁶²

• In patients who had EPP, there was a significant drop in SMRP levels (on average 54%). Despite the relationship with tumour bulk, there is no significant correlation with increasing disease stage.

• Mean and median SMRP levels for those with progressive disease showed a significant difference compared with patients with partial/complete response and stable disease.⁶²

• A falling SMRP level between baseline and two cycles of chemotherapy was associated with a longer ‘time to progression’ of disease. Fibulin-3 failed to show a similar relationship.⁷⁵

• Low Fibulin-3 at diagnosis is associated with a prolonged survival.⁶¹

Outcome prediction

Four studies^{71 72 74 75} assessed the independent predictive value of biomarkers on overall survival in MPM, accounting for the recognised prognostic indicators of histological subtype, age and PS. These demonstrate:

• The modified Glasgow Prognostic Score (mGPS) (serum, C reactive protein (CRP) and albumin level at baseline) and blood neutrophil-to-lymphocyte ratio (NLR) are independent predictors of overall survival (HR 2.6 and 2.0, respectively).⁷¹

• Pleural fluid HA level (<225 mg/L) is independently associated with overall survival (RR 0.63).⁷²

• Resection specimen staining for smoothened SMO transmembrane receptor (HR 1.06) was an independent predictor of overall survival.⁷⁴

A fall in SMRP between baseline and an interval of 6–8 weeks (post two cycles of chemotherapy) is predictive of radiographic stability of disease. A falling SMRP level at completion of chemotherapy is strongly associated with a longer survival.⁷⁵ Baseline SMRP was unable to predict survival. Apart from SMRP in the SWAMP study,⁷⁵ none of the other markers have been prospectively validated.

Biomarkers for screening

Five studies^77–81 explored the potential role of biomarkers in screening for MPM. All five studies looked at SMRP but two studies also looked at Osteopontin, CA-125 and cytokeratin fragment 19.^{58 75} Studies were heterogeneous particularly with regards to the cut-off value of SMRP, duration of follow-up and the patient populations (other cancers/control groups). Despite these differences, SMRP tended to be higher in those with asbestos-related disorders such as asbestosis or diffuse pleural thickening, and in renal impairment. One study found SMRP levels are also elevated in other cancers such as lung, ovarian, pancreatic and endometrial cancer, but the populations of patients with these cancers were small.

Evidence statements

Recommendations

• Do not offer biomarkers in isolation as a diagnostic test in MPM. Grade B.

• Consider biomarker testing in patients with suspicious cytology who are not fit enough for more invasive diagnostic tests. Grade B.

• Do not routinely offer biomarker testing to predict treatment response or survival. Grade B.

• Do not offer biomarker testing to screen for MPM. Grade C.

Research recommendation

Further research is required to identify biomarkers that reliably predict treatment response within clinical practice.

Evidence from very large studies

Three retrospective studies were identified, which included more than 5000 patients from population-level registries.^90–92 These consistently demonstrate that increasing age, male sex, advanced stage and non-epithelioid histology are prognostic of worse overall survival. Although this evidence is of low quality, being retrospective, the size of the datasets studied and the absence of any contradictory evidence increases the confidence in these findings.

Findings from the National Lung Cancer Audit

In 2015, Beckett et al published data from 8740 mesothelioma cases included in the National Lung Cancer Audit.³ This is the largest prospectively collected case series in the literature. It has the advantage of reflecting the characteristics of unselected incident cases. In this respect, it differs from the populations of clinical trial recruits who have been used to derive, for example, the EORTC and CALGB prognostic scores (see below). Poorer PS and non-epithelioid histology were associated with shorter overall survival in this cohort. Survival by sex is not reported.

The EORTC prognostic score

This was derived by Curran et al⁸³ in 1998 based on maximum-likelihood parameter estimates of the prognostic factors retained in a multivariate model derived from a population of 204 patients (89% male) entered into clinical trials of chemotherapy in Europe. All patients were PS 0–2. More detail on the score can be found at appendix 2.

CALGB prognostic groups

Herndon et al studied prognostic factors in a group of 337 patients with MPM not previously treated with chemotherapy who were entered into phase II trials of chemotherapy.⁸⁷ Cox survival and exponential regression trees were used to determine prognostic importance of pretreatment patient characteristics. Terminal nodes were amalgamated to form six distinct prognostic subgroups.

The derived prognostic groups are complex, and continuous variables are dichotomised differently for different subgroups (eg, Hb and WBC). Edwards et al validated the CALGB groups in a retrospective study conducted in a UK population.⁸⁶

Meniawy et al have validated the CALGB prognostic group method in a recent, large study in Western Australia, in a population of patients where 62% received chemotherapy. This is considerably higher than the proportion of patients currently receiving chemotherapy for mesothelioma in the UK and therefore the median survival estimates derived from the validation study are likely to be considerably better than those observed in the UK.

The neutrophil-to-lymphocyte ratio

Five studies have considered the NLR in mesothelioma. The evidence on the prognostic utility of NLR was reviewed by Meniawy et al.⁸⁵ They concluded that the cut-off value chosen for NLR is variable, the independent predictive effect inconsistent and the NLR has not been validated in a prospective study. More information about the studies can be found in appendix 2.

The modified Glasgow prognostic score

The mGPS stratifies patients with cancer according to CRP and serum albumin. This was found to be an independent predictor of overall survival in MPM in one study⁷¹ (HR 2.6, 95% CI 1.6 to 4.2, P<0.001) but has not been the subject of prospective validation.

Prognostic model using decision tree analysis

Brims et al derived a prognostic model using classification and regression tree analysis from an unselected population of 482 patients newly diagnosed with MPM in Western Australia, of whom 274 were collected retrospectively and 208 prospectively.⁸⁹ Unlike the cohorts used to derive the CALGB and EORTC models, which were of participants in chemotherapy trials, this paper included all patients with a confirmed diagnosis of MPM within the inclusion period. The model was validated in a cohort of 177 patients with MPM prospectively collected in Bristol, UK. The validation cohort is likely to be highly representative of typical new patients with MPM presenting in the UK. The model was used to predict death at 18 months. The variable with the greatest influence on survival in the derivation cohort was weight loss, defined as any weight loss considered significant by the medical team. The decision tree for classifying patients into prognostic groups in this study is shown in table 13. The variables having an influence on prognosis within this model are histological subtype, weight loss, PS, Hb and serum albumin. The C-statistic for the derivation cohort was 0.76 and the sensitivity 94.5% (95% CI 91.4% to 96.7%) and the specificity 38.2% (95% CI 30.6% to 46.3%). The positive predictive value for death at 18 months was 76% (95% CI 71.5% to 80.1%). The C-statistic for model performance in the validation cohort was 0.68 (95% CI 0.60 to 0.75).

The model can be found in appendix 2.

The LENT score

Clive and others derived the LENT score, for predicting survival in patients presenting with malignant pleural effusion (MPE).⁸⁸ The LENT score uses pleural fluid LDH (>1500) IU/L, ECOG PS, NLR and tumour type to calculate a prognostic score (see appendix 3 for a full description of the scoring system). Data from three large international cohorts of patients were used to study the effect of the malignant cell type on survival. A more detailed analysis of individual prognostic factors was then undertaken in two prospectively collected UK cohorts of patients presenting with MPE. One cohort was used to derive a prognostic score and the second to validate it. Fourteen predefined variables, recorded at presentation, were studied to ascertain their influence on survival using a multivariable Cox proportional hazard method. A prognostic score was then developed using the results of the international cohort for cell type and the UK cohort multivariable analysis.

Patients with moderate-risk and high-risk LENT scores had hazard ratios (95% CI) for mortality of 1.49 (1.03–2.15) and 5.97 (3.58–9.97) compared with those with low-risk LENT scores. The relation between LENT score and median survival is shown in table 14.

Symptoms

Chest wall pain and weight loss have been studied as prognostic variables.^{82 85 87} In retrospective case series, chest pain was independently associated with poorer overall survival in all three studies but has not been subjected to prospective validation. The findings with respect to weight loss are inconsistent. Weight loss was independently predictive of survival in two studies^{85 87} but not in the third.⁸²

Evidence statements

Increasing age, male sex, non-epithelioid histology, advanced stage and poorer PS independently predict poorer survival in MPM. Level 2+.

The LENT prognostic score provides an approximate estimate of median survival, at presentation, in patients presenting with a pleural effusion due to MPM. Level 2+.

The EPS and CALGB prognostic groups reliably separate patients into groups with better and worse overall survival but they have been studied only retrospectively, in patients with better PS and treated with chemotherapy in the majority. Level 2+.

Markers of inflammation including WBC, platelet count, CRP, serum albumin, PLR and NLR may predict survival, but further studies are required, particularly prospectively, to validate this. Level 3.

The decision tree model separated unselected UK patients newly diagnosed with MPM into groups with differing median survival using variables that are routinely collected in almost all patients. Level 2+.

Recommendations

• Consider calculating a prognostic score in patients with MPM at diagnosis. Grade D.

• Prognostic scores can provide useful survival information for patients and doctors, but should not be used in treatment decision-making. Grade D.

• When calculating a prognostic score use one of the following:

  1. The EORTC prognostic score;

  2. The CALGB score;

  3. The modified Glasgow Prognostic Score (mGPS);

  4. The LENT score if a pleural effusion is present;

  5. The decision tree analysis.

The decision tree analysis scoring systems is likely to be the most useful in routine clinical practice. Grade D.

Evidence statements

Pleural effusion due to MPM may have a lower pleurodesis success rate than other malignant effusions. Level 2-.

No single fluid control technique (surgical including pleurectomy and VATS, thoracoscopic talc poudrage, talc slurry or IPC) has been shown to be superior in terms of patient symptoms or pleurodesis success in MPM. Level 1-.

VATS-PP has been shown to be more expensive, associated with greater complications and longer hospital stay than talc slurry pleurodesis. Level 1+.

VATS-PP is associated with minor improvement in quality of life versus talc slurry in those patients who survive >6 months. Level 1-.

Indwelling pleural catheters and talc slurry pleurodesis have similar patient-related outcomes in malignant effusion and MPM. Level 1++.

Recommendations

• Offer either talc (via slurry or poudrage) or indwelling pleural catheters for symptomatic pleural effusion in MPM, informed by patient choice. Grade A.

• Talc slurry or thoracoscopic talc poudrage pleurodesis should be offered to patients with MPM in preference to a VATS-PP surgical approach for fluid control in MPM. Grade A.

Evidence review

95 papers were identified and reviewed, of which 12 were considered in detail.^{83 93 103–112} There were two RCTs, four systematic reviews, four prospective observational studies and two retrospective studies.

Pleurectomy

A systematic review has been performed of 34 studies involving 1916 patients who underwent pleurectomy.¹¹⁰ These included 12 studies on extended PD, 8 studies on PD and 14 studies on PP. All the studies were observational with high risk of selection bias. Perioperative mortality ranged from 0% to 11% and perioperative morbidity ranged from 13% to 43%. Median overall survival ranged from 7.1 to 31.7 months and disease-free survival ranged from 6 to 16 months.

The MesoVATS trial randomised 196 patients with suspected or confirmed mesothelioma (of whom 175 had mesothelioma) between talc pleurodesis or VATS-PP.⁹³ The primary outcome was survival at 1 year, which was 52% (95% CI 41 to 62) in the VAT-PP group and 57% (95% 46 to 66) in the talc pleurodesis group (HR 1.04 (95% CI 0.76 to 1.42); P=0·81). Surgical complications were significantly more common after VAT-PP than after talc pleurodesis, occurring in 24 (31%) of 78 patients who completed VAT-PP versus 10 (14%) of 73 patients who completed talc pleurodesis (P=0.019). Median hospital stay was longer at 7 days (IQR 5–11) in patients who received VAT-PP compared with 3 days (2–5) for those who received talc pleurodesis (P<0.0001).

Extended pleurectomy decortication and Extra-pleural pneumonectomy

The Mesothelioma and Radical Surgery (MARS) feasibility study assessed EPP versus no EPP for patients with MPM.¹⁰³ Patients with pathologically confirmed mesothelioma deemed fit enough to undergo trimodal therapy were included. All patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned to EPP followed by postoperative hemithorax irradiation or to no EPP. Of 112 patients registered, 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. EPP was completed satisfactorily in 16 of 24 patients assigned to EPP. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The HR for overall survival between the EPP and no EPP groups was 1.90 (95% CI 0.92 to 3.93; exact P=0.082), and after adjustment for sex, histological subtype, stage and age the HR was 2.75 (95% CI 1.21 to 6.26; P=0·016). Median survival was 14.4 months (5.3–18.7) for the EPP group and 19.5 months (13.4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses.

There has been much discussion around the validity of the MARS trial results. In particular, criticism that the study was not powered to detect a survival advantage attributable to EPP and that the operative mortality was higher than that of other contemporary series. The MARS trial authors have subsequently responded that the EPP mortality in MARS (2 of 19; 10.5%; 95% confidence limits 1.3% to 33.1%) lies within the range reported in a systematic review of 34 studies, including 2320 patients, where 30-day mortality ranged from 0% to 11.8%.¹¹³ Furthermore, the authors note that the median survival of patients in the EPP arm of MARS of 14.4 months from randomisation is in keeping with major series in the literature which report median survival times of 10 to 14 months.

Cao et al¹⁰⁸ performed a systemic review of 34 studies with 2462 patients who underwent EPP for MPM. All the studies were observational and subject to high risk of selection bias. The median overall survival varied from 9.4 to 27.5 months, and 1-year, 2-year and 5-year survival rates ranged from 36% to 83%, 5% to 59% and 0% to 24%, respectively. Overall perioperative mortality rates ranged from 0% to 11.8%, and the perioperative morbidity rates ranged from 22% to 82%. Quality of life assessments from three studies reported improvements in nearly all domains at 3 months postoperatively. Patients who underwent trimodality therapy involving EPP and adjuvant chemoradiotherapy had a median overall survival of 13–23.9 months.

Two meta-analyses have been performed comparing outcomes following either PD or EPP. All the studies included in the analyses were observational with high risk of selection bias. The meta-analysis by Taioli et al¹¹⁴ included 1512 patients treated with PD and 1391 treated with EPP. There was a significantly higher proportion of short-term deaths in the EPP group versus the PD group (per cent mortality meta-estimate; 4.5% vs 1.7%; P<0.05). There was no statistically significant difference in 2-year mortality between the two groups, but there was significant heterogeneity. The meta-analysis by Cao et al (2014)¹¹¹ included 632 patients who underwent EPP and 513 patients who underwent EPD.¹¹¹ All-cause perioperative mortality was found to be significantly lower after EPD compared with EPP (2.9% vs 6.8%; RR 0.53; 95% CI 0.31 to 0.91; P=0.02; I²=0%). Perioperative morbidity was also found to be significantly lower after EPD compared with EPP (27.9% vs 62.0%; RR 0.44; 95% CI 0.30 to 0.63; P<0.0001; I²=44%). There were insufficient data for this meta-analysis to compare the overall survival outcomes between the two treatment arms.

The effects of PD on lung function and quality of life have been assessed in a number of small cohort studies. None of these studies compared changes in outcomes with patients who were not selected to undergo surgery and so the results must be interpreted with caution. Mollberg et al found that quality of life scores did not deteriorate in 28 patients with good PS (0–1) who underwent PD.¹⁰⁴ Bölükbas et al found that the mean FVC improved from 55% of predicted to 69% of predicted (P<0.01) in 16 patients who underwent radical pleurectomy.¹⁰⁵ Ploenes et al retrospectively reviewed the outcomes of 25 patients who underwent EPP and 23 who had PD.¹⁰⁷ Pulmonary function was not significantly reduced in the PD group postoperatively. In the EPP group, the median vital capacity fell from 78% of predicted to 48% predicted (P<0.001). Burkholder et al assessed quality of life in 36 patients undergoing PD.¹⁰⁶ Global quality of life scores were unchanged in the 17 patients with PS of 0 and improved in the 19 patients with PS of 1 or 2.

A feasibility multicentre randomised trial comparing EPD to no surgery (MARS-2 trial) is currently recruiting in the UK.¹¹² Results from this surgical trial are awaited with interest.

Evidence statements

VAT-PP has no effect on overall survival and results in increased complications and longer hospital stay than talc pleurodesis. Level 1+.

EPP does not improve survival when added to treatment with chemoradiotherapy. Level 1+.

EPD may result in lower perioperative mortality than EPP. Level 1-.

Quality of life and lung function may not deteriorate in patients selected to undergo pleurectomy decortication. Level 2-.

Recommendations

• Do not offer VATS-PP over talc pleurodesis in MPM. Grade A.

• Do not offer EPP in MPM. Grade B.

• Do not offer EPD outside of a clinical trial. Grade D.

Evidence

The literature search revealed a large volume of evidence assessing the role of systemic treatment. Over two hundred articles were obtained from a search. Of these, 69 were not relevant to the question. Papers were excluded if they involved trimodality therapy or radiotherapy as major features in the trial design. This included papers looking at the role of neoadjuvant or adjuvant chemotherapy in the setting of surgery. Papers were excluded if they involved intrapleural chemotherapy and photodynamic therapy during as part of surgical therapy.

Evidence on first-line systemic therapy

Almost all the first-line studies identified were non-randomised phase II trials. Four large phase III randomised trials comparing novel systemic therapy to 'standard' therapy were identified. Two of the large randomised trials used a control arm of single-agent cisplatin and one used a control arm of active symptom control (ASC). Table 15 summarises phase III trial data.

The first large randomised trial (known as EMPHASIS) to be published in patients with MPM compared 3 weekly intravenous chemotherapy with the antifolate drug pemetrexed at a dose of 500 mg/m² and cisplatin at a dose of 75 mg/m² with a control arm of cisplatin at a dose of 75 mg/m².¹¹⁵ The primary outcome was survival. Secondary outcomes were time to progressive disease, time to treatment failure, tumour response rate and duration of response. 226 patients were randomised to pemetrexed/cisplatin, and 222 to cisplatin alone. The median survival time for pemetrexed/cisplatin-treated patients was longer than for patients receiving cisplatin alone: 12.1 vs 9.3 months, representing a statistically significant difference (P=0.020). The median time to progressive disease was significantly longer for patients who received pemetrexed and cisplatin as compared with patients who received cisplatin alone (5.7 vs 3.9 months; P=0.001). The median time to treatment failure was also significantly longer in the pemetrexed/cisplatin arm than in the control arm. The response rates were 41% for pemetrexed/cisplatin patients vs 17% in the control group.

While this trial was recruiting, the investigators became aware of excessive bone marrow toxicity likely due to folate depletion probably caused by pemetrexed. They decided to give all patients, both in the trial arm and the control arm, vitamin B12 (by intramuscular injection) and folic acid (by tablet) supplementation. Bone marrow toxicity was reduced and vitamin supplementation is now standard for all patients treated with pemetrexed. The incidence of nausea, vomiting, fatigue, diarrhoea, dehydration and stomatitis were significantly higher in the pemetrexed/cisplatin arm.

In 2005, a broadly similar RCT was published by the European Organisation for the Research and Treatment of Cancer (EORTC).¹¹⁶ The experimental arm was the antifolate drug raltitrexed combined with cisplatin (arm B), with a control group of single-agent cisplatin (arm A). Raltitrexed is comparable to pemetrexed in that its main mechanism of action is by inhibiting thymidylate synthase, thereby preventing the formation of precursor pyrimidine nucleotides. End points were overall survival, response rates and quality of life. Patients had to have good PS (WHO 0–2) and adequate haematological, renal and hepatic function. Two hundred and fifty patients were randomised: 80% were male and the median age was 58 years. The main grade 3 or 4 toxicities observed were neutropaenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, the response rate was 13.6% (arm A) vs 23.6% (arm B; P=0.056). Median overall and 1-year survival in arms A and B were 8.8 (95% CI 7.8 to 10.8) vs 11.4 months (95% CI 10.1 to 15), respectively, and 40% vs 46%, respectively (P=0.048).

A large cooperative group based in the UK led by Muers et al organised a large three-arm randomised clinical trial known as MS01.¹¹⁷ Patients were randomised into three groups. Group 1: ASC. The essential elements of ASC were defined as regular follow-up in a specialist clinic; structured physical, psychological and social assessments at every clinic visit; rapid involvement of additional specialists and parallel nursing support. Patients could receive, as required, steroids, analgesic drugs, appetite stimulants, bronchodilators or palliative radiotherapy. Group 2: ASC plus mitomycin, cisplatin and vinblastine chemotherapy (MVP), or group 3: ASC plus vinorelbine chemotherapy. A total of 840 patients (280 in each group) were needed to detect an improvement of 3 months survival; however, due to slow accrual the trial design changed to a two-group comparison by combining the two chemotherapy groups. The two-group design needed a total of 420 patients (140 ASC, 280 ASC plus chemotherapy) to reliably detect an improvement from 9 months median survival with ASC alone to 12 months with ASC plus chemotherapy. Four hundred and nine patients with malignant pleural mesothelioma, from 76 centres in the UK and 2 in Australia, were randomly assigned to ASC alone (n=136); to ASC plus MVP (four cycles of mitomycin 6 mg/m², vinblastine 6 mg/m² and cisplatin 50 mg/m² every 3 weeks (n=137)) or to ASC plus vinorelbine (one injection of vinorelbine 30 mg/m² every week for 12 weeks (n=136)). The results showed that, compared with ASC alone, there was no significant survival benefit for ASC plus chemotherapy (HR 0.89, 95% CI 0.72 to 1.10; P=0.29). Median survival was 7.6 months in the ASC-alone group and 8.5 months in the ASC plus chemotherapy group. There were no between-group differences in four predefined quality of life subscales (physical functioning, pain, dyspnoea and global health status) at any of the assessments in the first 6 months. The trial attracted some criticism for the decision to combine the two different chemotherapy arms, thus reducing the power to detect a significant difference for the separate regimens.¹¹⁸

A more recent trial reported by Zalcman et al presented data on the addition of bevacizumab to pemetrexed and cisplatin chemotherapy for patients with newly diagnosed MPM.¹¹⁹ The trial, called MAPS (Mesothelioma Avastin Cisplatin Pemetrexed Study) was a randomised, controlled, open-label, phase III trial. Patients aged 18–75 years with unresectable MPM who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0–2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT and a life expectancy of >12 weeks from 73 hospitals in France. Patients were stratified by histology (epithelioid vs sarcomatoid or mixed histology subtypes), PS score (0–1 vs 2), study centre or smoking status (never smokers vs smokers)) to receive intravenously 500 mg/m² pemetrexed plus 75 mg/m² cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21-day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to-treat population. 448 patients were randomised to treatment (223 to PCB and 225 to PC). Overall survival was significantly longer with PCB (median 18.8 months (95% CI 15.9 to 22.6)) than with PC (16.1 months (95% CI 14.0 to 17.9); HR 0.77 (95% CI 0.62 to 0.95); P=0.0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3–4 adverse events. More grade 3 events, higher rates of hypertension and more thrombotic events were noted with PCB compared with PC. Bevacizumab treatment is not currently licensed for use in the UK and is not available in the NHS.

An International Expanded Access Programme (EAP) led by Santoro followed more than 3000 patients with mesothelioma treated with single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin.¹²⁰ Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m² in combination with either cisplatin 75 mg/m² or carboplatin AUC 5, once every 21 days with standard premedication. A total of 1704 chemonaïve patients received pemetrexed plus cisplatin (n=843) or pemetrexed plus carboplatin (n=861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumour response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% vs 64.0%) and median time to progressive disease (7 vs 6.9 months). Based on these data, pemetrexed plus carboplatin is generally considered an acceptable alternative two-drug first-line option, especially for patients deemed unfit for cisplatin, although the data on which this practice is based are not from an RCT.

Second-line systemic treatments in MPM

Buikhuisen et al undertook a systematic review of 10 studies reporting on 1251 patients treated with second-line chemotherapy in MPM.¹²¹ The majority of studies were phase II with only two phase III randomised trials. The authors concluded that only a limited number of randomised studies with combination therapy had been conducted. The authors suggested the following as second-line treatment options for patients with MPM: ‘single agent vinorelbine or pemetrexed are acceptable second-line agents for patients relapsing after a first-line platinum combination regardless of whether or not pemetrexed was used in the first-line setting’. They also stated that the ‘low reported activity of the drugs in second line warrants referral of fit patients to participate in clinical trials’.

Jassem et al compared the efficacy and safety of pemetrexed and best supportive care in patients with MPM after first-line chemotherapy (excluding pemetrexed).¹²² Of the 243 patients included, 18.7% of the 143 patients receiving pemetrexed showed a partial response but the median overall survival was not significantly different between the two groups.

The VANTAGE-014 study compared vorinostat, an oral histone deacetylase inhibitor, with placebo in 661 patients with MPM who had previously received one or two systemic regimens.¹²³ Median overall survival for vorinostat was 30.7 weeks (95% CI 26.7 to 36.1) vs 27.1 weeks (95% CI 23.1 to 31.9) for placebo (HR 0.98, 95% CI 0.83 to 1.17, P=0.86).

Anti-PD1 immune checkpoint therapy has potential for the treatment of mesothelioma. Approximately 40% of tumours express PDL1, which is associated with non-epithelioid histology and worse outcome for high expressing tumours.¹²⁴ Keynote 28 is the first phase Ib trial to report on the activity of pembrolizumab in patients with pleural mesothelioma and enrolled 25 patients harbouring PDL1-positive tumours.¹²⁵ This study showed a 20% response rate with durability lasting on average 12 months. Stable disease was 52% giving a disease control rate of 72%. Median overall survival was 18 months. In summary, emerging data suggest anti-PD1 or PDL1 immunotherapy, exhibits efficacy in mesothelioma; however, randomised trials will be needed to confirm the incremental benefit and value. In this regard, the CRUK CONFIRM phase III trial is currently randomising patients 2:1 to nivolumab versus placebo (NCT03063450).

Evidence statements

For patients with MPM with good PS, first-line chemotherapy with cisplatin and pemetrexed leads to longer survival than cisplatin alone. Evidence level 1 + +.

For patients with MPM with good PS, first-line therapy with cisplatin and pemetrexed and bevacizumab leads to longer survival than cisplatin and pemetrexed alone. Evidence level 1 + +.

For patients with MPM with good PS, first-line chemotherapy with cisplatin and raltitrexed leads to longer survival than cisplatin alone. Evidence level 1 + +.

The combination of mitomycin, cisplatin and vinblastine or single agent vinorelbine did not demonstrate survival benefit over active symptom control. Evidence level 1 +.

Carboplatin in combination with pemetrexed is a safe and effective alternative to cisplatin in combination with pemetrexed. Evidence level 3.

Second-line pemetrexed does not improve survival in patients previously treated with first-line chemotherapy regimens that did not include pemetrexed. Evidence level 1+.

Second-line vorinostat does not improve survival in patients previously treated with one or two cycles of chemotherapy. Evidence level 1+.

Recommendations

• Offer patients with MPM with good PS (WHO 0–1) first-line therapy with cisplatin and pemetrexed. Where licensed (not presently in the UK), bevacizumab should be added to this regime. Raltitrexed is an alternative to permetrexed. Grade A.

• Do not offer pemetrexed or vorinostat as second-line treatment for patients with MPM. Grade A.

Good practice points

• Where cisplatin is contraindicated, or has adverse risk, offer carboplatin in combination with pemetrexed.

• First-line clinical trials are an appropriate option for patients with good PS and are recommended above any other option for second-line treatment, provided the patient is of adequate PS.

Prophylactic radiotherapy to procedure tracts

Subcutaneous tumour nodules, seeded up the tract of previous needle or tube insertions, surgical or other invasive procedures, are sometimes observed in patients with MPM. Prophylactic radiotherapy to these sites may have a role in preventing the development of tumour tract nodules.

Evidence review

Four RCTs comparing prophylactic radiotherapy to procedure tracts to no radiotherapy, and a systematic review (written before the 2016 RCT was published) are evaluated.^126–130 The study by Boutin et al was conducted in the era before chemotherapy was routinely offered to patients with MPM fit enough to receive it.¹²⁶ All patients had both an Abrams biopsy and a thoracoscopy before randomisation. The incidence of metastatic nodules in the control group was high (40%) and has not been replicated in any other observational studies. The studies by Bydder et al and O’Rourke et al excluded patients who had received prior chemotherapy.^{127 128} Information regarding subsequent chemotherapy treatment was not available. The incidence of chest wall nodules in the control groups were lower and the differences in the incidence of nodules between treatment groups not significantly different. It has been questioned whether these studies were adequately powered.¹³⁰

The SMART trial was a randomised, multicentre, phase III trial evaluating whether prophylactic radiotherapy reduces the incidence of procedure tract metastases after surgical and large bore pleural procedures.¹²⁹ Eligible patients were recruited from 22 UK hospitals and randomised (1:1) to immediate radiotherapy (21 Gy in three fractions over three working days), or deferred radiotherapy (same dose given if a procedure tract metastasis (PTM) developed). Two hundred three patients were randomised (102 to immediate radiotherapy, 101 to deferred radiotherapy). No statistically significant difference was identified in the PTM rates of the immediate and deferred radiotherapy groups (9/102 (8.8%) vs 16/101 (15.8%), respectively; OR 0.51, 95% CI 0.19 to 1.32; P=0.14). There was no difference identified in quality of life, chest pain, analgesia requirements or survival of the two groups.

A Phase III Randomised Trial of Prophylactic Irradiation of Tracts in Patients with Malignant Pleural Mesothelioma Following Invasive Chest Wall Intervention (the PIT trial) was due to complete recruitment in June 2016 and results are expected in 2017.¹³¹ Table 16 provides a summary of trials comparing prophylactic and procedure tracts with no radiotherapy.

Evidence statements

Three out of four RCTs did not show a reduction in procedure tract metastases with prophylactic radiotherapy to chest wall procedure tracts. Level 1+.

Prophylactic radiotherapy to chest wall procedure tract has not been shown to improve quality of life, chest pain, analgesia requirements or survival. Level 1+.

Recommendation

• Do not offer prophylactic radiotherapy to chest wall procedure tracts routinely. Grade A.

Radiotherapy as part of multimodality treatment

The role of radiotherapy as part of the multimodality treatment of MPM is controversial. Radiotherapy can be delivered either as the sole local treatment modality after chemotherapy or as an adjuvant/neoadjuvant treatment in the context of a surgical approach. However, as MPM typically involves large areas of the pleura, the delivery of radical doses of radiotherapy are limited by the surrounding organs at risk such as normal lung, liver, heart and spinal cord.

A number of important remarks should be made with regards to the interpretation of the available literature. First, the majority of studies identified evaluated multimodality treatment and very few investigated specifically the role of preoperative/postoperative radiotherapy or radiotherapy alone. Second, the majority of the studies identified evaluated RT in the context of EPP, which is now very rarely performed in the UK. Lastly, none of the studies reviewed included surgical or radiotherapy quality assurance. Specifically, the majority of the studies reviewed had no built-in radiation dose constraints for organs at risk.

Evidence review

Twenty-one studies were identified which included radiotherapy as part of the multimodality treatment.^{103 132–151} One evaluated preoperative radiotherapy (in the context of EPP),¹³² 2 hemithoracic radiotherapy alone^{133 134} and 17 postoperative radiotherapy (4 in the context of pleurectomy decortication and 13 in the context of EPP).

Four studies were retrospective cohort series and 16 were prospective studies, of which only 4 are multicentre and 2 are RCTs.

Studies evaluating postoperative radiotherapy either after EPP or PD have shown that radiotherapy in the context of multimodality treatment is feasible, but some severe toxicities, particularly pneumonitis have been reported.^{103 135–150} The rate of grade 5 radiation pneumonitis ranges from 0% to 46% in the studies that have reported radiotherapy-related toxicity and a lung dose-volume effect was identified in patients who developed grade 3+ radiation pneumonitis.^{135 140 142–144}

Only one RCT specifically evaluated the role of postoperative radiotherapy and showed no benefit for this treatment.¹⁵⁰ The Swiss Group for Clinical Cancer Research (SAKK) trial is a two-part multicentre randomised phase II study, analysed on intention to treat. It included patients with pathologically confirmed MPM, resectable TNM stages T1–3 N0–2, M0, WHO PS 0–1 and age <70 years. In part 1 of the study, patients were given three cycles of neoadjuvant chemotherapy followed by EPP; the primary end point was complete macroscopic resection (R0–1). In part 2, patients with complete macroscopic resection were randomly assigned to receive adjuvant radiotherapy or not (three-dimensional conformal radiotherapy or intensity-modulated radiotherapy was permitted with dose ranging from 55.9 to 57.6 Gy, using a boost technique). The primary end point was locoregional relapse-free survival. One hundred fifty-one patients were evaluable after neoadjuvant chemotherapy, of whom 75% had EPP and 64% complete macroscopic resection. Fifty-four patients were enrolled in part 2. Median locoregional relapse-free survival from surgery was 7.6 months (95% CI 4.5 to 10.7) in the no radiotherapy group and 9.4 months (95% CI 6.5 to 11.9) in the radiotherapy group. Median overall survival calculated from registration for patients in part 2 was 20.8 months (95% CI 14.4 to 27.8) in the no radiotherapy group and 19.3 months (95% CI 11.5 to 21.8) in the radiotherapy group. One patient died of grade 5 radiation pneumonitis. However, it should be noted the trial was terminated earlier than planned due to slow accrual (at 73% of the accrual).

Evidence statements

Postoperative radiotherapy after chemotherapy and EPP has not been shown to improve survival. Level 1+.

Postoperative radiotherapy after chemotherapy and pleurectomy decortication has not been shown to improve survival. Level 2-.

Preoperative radiotherapy has not been shown to improve survival. Level 2-.

Radical radiotherapy used in isolation has not been shown to improve survival. Level 2-.

Recommendation

• Do not offer preoperative or postoperative radiotherapy in MPM. Grade A.

Radiotherapy for symptom palliation

Symptoms in MPM include pain, breathlessness and cough. Palliative radiotherapy has been used in an attempt to control these symptoms, as well as for other indications.

Evidence review

There are six studies, of which two explore whole hemithorax irradiation^{133 152} and four of localised treatment to areas of disease and/or symptoms.^153–156 There are two systematic reviews addressing the role of radiotherapy for symptom palliation.^{157 158}

Of the hemithorax studies, a retrospective case series described no change in chest pain or PS in 47 patients treated with 40 Gy in 20 fractions.¹³³ The other was a prospective phase II study without controls, including 19 patients treated with 30 Gy in 10 fractions.¹⁵² It reported an improvement in pain control in 68% at 1 month, but this was not maintained (1). Toxicity was not reported in this study.

The localised treatment studies showed variable response rates (in terms of pain improvement). The dose and duration of response were also variable in these uncontrolled reports. The results are summarised in table 17.

A randomised phase II study opened to recruitment in the UK in August 2016 aiming to establish optimal dose/fractionation for symptom control in MPM (SYSTEMS2 SRCTN12698107).

Evidence statements

Hemithorax radiotherapy has not been shown to have a consistent impact on chest pain or PS in MPM. Level 3.

Localised radiotherapy can improve pain control in MPM, although the effect is variable and is short lived. Level 3.

Radiation dose fractionation utilised in studies of localised radiotherapy for pain control in MPM are variable. The optimal dose is not known. Level 3.

Recommendations

• Do not offer hemithorax radiotherapy for MPM. Grade D.

• Consider palliative radiotherapy for localised pain in MPM where the pain distribution matches areas of underlying disease. Grade D.

Research recommendation

Further prospective randomised clinical trials are required to determine the role of radiotherapy for symptom control in MPM and the optimal dose fractionation.

Evidence statement

There are no studies of symptom control that specifically relate to MPM.

Good practice point

• Symptoms in MPM should be managed as per current guidelines for cancer in general (table 18) and early involvement of palliative care specialists is recommended.

Care in multidisciplinary teams

Multidisciplinary team (MDT) meetings are an established feature in cancer services. Widespread adoption and development, despite very little supporting evidence, has been seen across all tumour types over the last two decades. There is a suggestion that MDT working improves recruitment to clinical trials¹⁶⁰ and that patients find MDT working reassuring and improves their experience of care.^{161 162}

To support the development of MDTs, the National Cancer Action Team published Guidelines on Characteristics of an Effective MDT (NCAT 2010), although given the mesothelioma incidence the option of virtual MDT working should be considered.¹⁶³ NHS England has outlined their commissioning expectations for mesothelioma and recommended the establishment of specialist mesothelioma MDTs which should manage a minimum of 25 patients per year (NHS England 2013).

Bibby et al¹⁶⁴ recently published a retrospective evaluation of their specialist regional mesothelioma MDT based on the south-west of England.¹⁶⁴ Of the 210 cases that were reviewed by the specialist MDT, 10% had their diagnoses overturned and 20% were enrolled into a clinical trial.

Evidence statement

Specialist MPM multidisciplinary meetings may improve diagnostic accuracy and recruitment to clinical trials. Evidence Level 3.

Recommendation

• Consider referring MPM cases to a regional mesothelioma MDT. Grade D.

Good practice points

• All mesothelioma cases should be discussed in a timely fashion by a MDT that reviews a sufficient number of cases to maintain expertise and competence in the diagnosis and treatment of MPM.

• The MDT membership should fulfil the requirements set by national cancer peer review (to include a named clinical nurse specialist for MPM).

• The MDT should maintain an up-to-date portfolio of mesothelioma trials and offer recruitment to all eligible patients.

Information needs of patients

Patients undergoing investigation and treatment for mesothelioma may have unmet psychosocial and information needs. A clear understanding is essential for patients and their carers to make informed choices about the options for management. They may need professional support when interpreting information. The NICE guideline on the management of lung cancer (CG121) made detailed recommendations on the information and support needs of patients, some of which will be applicable to MPM.¹⁶⁵ The National Lung Cancer Forum for Nurses has emphasised the key role of the lung clinical nurse specialist in providing information and support to patients and has produced specific guidance for managing patients with mesothelioma https://www.nlcfn.org.uk/. There are 14 mesothelioma-specific clinical nurse specialists in the UK.

Evidence review

The search revealed 13 abstracts potentially relevant to this question. Eight studies were of sufficient quality and relevance to be included in the review, of which 4 included fewer than 30 patients; therefore, the volume of evidence is limited. The studies can be grouped in those assessing emotional support, compensation and intervention.

Compensation

Chamming’s et al¹⁷¹ performed a linked database study in 2407 patients in France and determined that 30% of patients with MPM did not claim occupational disease compensation.¹⁷¹ Claims were lower in older patients, women and white collar workers. A similar study by Cree et al¹⁷² of 568 patients with MPM in Canada demonstrated that only 42% filed a claim.¹⁷² A retrospective case note review¹⁷³ performed in North America identified 16 patients with mesothelioma treated at three Department of Veteran Affairs hospitals of whom only one had documented advice on compensation.¹⁷³

Every serious illness creates extra costs for patients and their families and mesothelioma is no exception. Mesothelioma is usually caused by exposure to asbestos. The industrial nature of mesothelioma means patients often have complex benefit and compensation claims.

There are two main ways to get additional financial support when someone is diagnosed with mesothelioma in the UK:

1. State benefits;

2. Pursuing a civil compensation claim.

For all civil claims, there is a 3-year time limit from the first date the patient became aware that there is evidence of a compensable asbestos-related disease.

Evidence statement

Patients with MPM and their relatives have reduced quality of life compared with healthy controls. Level 2+.

A diagnosis of MPM causes high levels of psychosocial distress. Level qualitative.

Documentation of compensation advice and subsequent claims are variable. Level 3.

Recommendations

• Offer accurate and understandable information to patients and carers about compensation for MPM. Grade D.

• Offer patients with MPM and their carers the opportunity to discuss concerns regarding their disease. Grade D.

Follow-up strategies

The literature search did not reveal any evidence pertaining to who and how patients with MPM should be followed up. The search identified 12 papers that were thought to be relevant to the imaging component of this question. Following review of the 12 abstracts, 9 papers^174–182 were fully critiqued to answer the question regarding the best form of imaging when following up patients with MPM.

None of the papers reviewed was from the UK, but a large number were from within the European region. The rest from Australia, the USA and Turkey. Given the patient populations are generally similar, this evidence is broadly applicable to the UK population. Most of the studies are from the prepemetrexed cisplatin chemotherapy era but for the purpose of answering the specific question here about follow-up, the results are generally acceptable.

The papers reviewed were consistent in their findings that a bidimensional method of assessing tumour volume is inadequate in MPM.¹⁸² A number of the studies compared Response Evaluation Criteria In Solid Tumors (RECIST) with mRECIST CT criteria. Modified RECIST, despite having its limitations, remains the best method of assessing tumour response when followed up over a period of time.^{174 183}

One study demonstrated using mRECIST criteria in MRI can be better at soft tissue/tumour delineation and pleural effusion identification, when compared with mRECIST criteria in CT.¹⁸⁴

Three studies explored the role of volumetric assessment (using Cavalieri principle) of the tumour on CT.^{146 177 178} No significant intraclass or interobserver variability noted, but this method is a time consuming and onerous way of measuring tumour in MPM therefore limiting its clinical utility.

Evidence statements

CT scanning using modified response evaluation criteria in solid tumours (RECIST) for interpretation gives the best assessment of tumour response to chemotherapy. Level 3.

Recommendation

• In patients with MPM where accurate determination of radiological progression is required, consider CT with mRECIST measurement. Grade D.

Good practice point

• A personalised care approach should be considered for each patient.

Patients should be offered 3–4 monthly follow-up appointments with an oncologist, respiratory physician or specialist nurse according to their current treatment plan. If patients wish to be seen less frequently, offer regular telephone follow-up with specialist nurse with an option to attend clinic in the event of clinical deterioration.