Approach

There is no standard therapy for malignant pleural mesothelioma. Few prospective studies have been conducted evaluating differing treatment approaches.

Therapy must be individualised based on the stage of disease at presentation, histology, and general health of the patient. Use the UICC TNM staging system for clinical and pathological staging.[45]

Good clinical practice should ensure the avoidance of treatment delays, use of multidisciplinary care that adheres to current guidelines, and the early integration of palliative care teams or consultants.[62] Treatment decisions should be made by consultants with experience in managing pleural mesothelioma; where possible, treat patients with mesothelioma in clinical trials or in consultant centres.[2]

Median survival remains poor (see Prognosis for survival data).​[63]

Surgery

May be performed to:[2][45][47]

  • Obtain diagnostic samples of tumour tissue and to stage the patient

  • Control pleural effusion when chest tube drainage is not successful, and

  • Contribute to multimodal therapy (e.g., macroscopic resection in combination with other modalities in selected patients).

Cytoreductive surgery may be considered in select patients with early stage disease (e.g., clinical stage I with epithelioid histology).[2][64][65]​​ Surgery is unlikely to be an option for patients with stage IIIB or stage IV disease.[2][64][65]

Extra-pleural pneumonectomy (EPP) or pleurectomy decortication alone is rarely curative, and is usually employed in the setting of multimodality therapy involving chemotherapy (and/or immunotherapy) with or without radiation.[2]​ One phase 3 randomised controlled trial found that, in patients with resectable pleural mesothelioma, a combination of (extended) pleurectomy decortication surgery and chemotherapy was associated with worse survival at 2 years (and more serious adverse events) than chemotherapy alone.[66] Retrospective observational data suggest that outcomes are significantly affected by social determinants of health.[63]

Surgical options

EPP removes the parietal and visceral pleura, ipsilateral lung and pericardium, and the hemidiaphragm en bloc. Pleurectomy with decortication is a more limited procedure involving removal of the parietal pleura from the chest wall, mediastinum, pericardium, and diaphragm, as well as removal of the visceral pleura from the ipsilateral lung (decortication). The ipsilateral lung remains intact.

The superiority of EPP over pleurectomy with decortication has not been demonstrated, but EPP does facilitate postoperative radiotherapy, which seems to decrease the risk of local recurrence.[67][68][69][70]​​​ However, the risk of developing a complication after EPP is high, even in experienced centres.[68] EPP is most appropriate for patients with epithelioid histology, no lymph node involvement, and sufficient cardiac and pulmonary reserve. Surgery does not confer a significant survival benefit in sarcomatoid mesothelioma.

Chemotherapy and immunotherapy: resectable disease

The choice of therapy usually depends on the type of mesothelioma.

For potentially resectable mesothelioma, cisplatin- or carboplatin-based induction chemotherapy (pemetrexed plus cisplatin or carboplatin) is usually given preoperatively to facilitate resection and improve survival. Response rates of approximately 30% have been reported for cisplatin-based doublets, with about 75% of patients subsequently undergoing EPP.[57][71][72][73] Adjuvant cisplatin-based chemotherapy is often given in patients who have undergone EPP.

Patients should have a good performance status to be considered eligible for chemotherapy with or without immunotherapy.[2][47]

Cisplatin (or carboplatin) plus pemetrexed

Cisplatin plus pemetrexed is a recommended first-line chemotherapy regimen in appropriately selected patients.[2][47] Cisplatin is, however, associated with nephrotoxicity, nausea, and vomiting.[74]

​Carboplatin may be substituted for cisplatin based on its favourable safety profile and ease of administration.[2][47][75]

Vitamin supplementation, particularly vitamin B12 and folic acid, should be added to reduce the risk of haematologic toxicity associated with pemetrexed.

Chemotherapy and immunotherapy: unresectable or recurrent disease

The choice of therapy usually depends on the type of mesothelioma.

Patients should have a good performance status to be considered eligible for chemotherapy with or without immunotherapy.[2][47]

In patients with unresectable or recurrent mesothelioma, chemotherapy is often given to improve quality of life and survival. The preferred first-line systemic therapies in patients with unresectable malignant disease include chemotherapy with or without targeted therapies, and targeted therapies alone.[2][45]

  • Cisplatin (or carboplatin) plus pemetrexed: increases survival and relieves symptoms in patients with unresectable mesothelioma, when compared with cisplatin alone.[76] Cisplatin is, however, associated with nephrotoxicity, nausea, and vomiting.[74] Carboplatin may be substituted for cisplatin.[2][47]​​[75]​​ Vitamin supplementation, particularly vitamin B12 and folic acid, should be added to reduce the risk of haematological toxicity associated with pemetrexed. 

  • Cisplatin (or carboplatin) plus pemetrexed plus bevacizumab: addition of bevacizumab (a monoclonal antibody directed against vascular endothelial growth factor [VEGF]) to cisplatin plus pemetrexed improved overall survival compared with chemotherapy alone in a phase 3 open-label randomised trial.[77] Patients with performance status >2 were excluded from the trial. Carboplatin may be substituted for cisplatin.[2][47][75]​ 

  • Cisplatin (or carboplatin) plus pemetrexed plus pembrolizumab: the addition of pembrolizumab (a monoclonal antibody targeting programmed death receptor-1 [PD-1]) receptor to platinum-based chemotherapy improved objective response rate and overall survival, compared with chemotherapy alone, in phase 3 open-label trials.[78][79] Patients with a performance status >1 were excluded. Carboplatin may be substituted for cisplatin.[2][47][75]​ 

  • Nivolumab plus ipilimumab: nivolumab (a monoclonal antibody targeting PD-1) plus ipilimumab (a monoclonal antibody targeting cytotoxic T-lymphocyte associated antigen-4 [CTLA-4]) significantly extended overall survival compared with standard-of-care chemotherapy (median overall survival 18.1 months vs. 14.1 months) in a multicentre, randomised, open-label, phase 3 trial of patients with unresectable untreated malignant pleural mesothelioma.[80] Two-year overall survival rates were 41% in the nivolumab plus ipilimumab group and 27% in the chemotherapy group.[80] Combination therapy with nivolumab plus ipilimumab is approved in the US and Europe as a first-line treatment option for adults with unresectable malignant pleural mesothelioma.

Be vigilant for new and emerging adverse effects. Combination immune checkpoint inhibitor therapy (e.g., nivolumab plus ipilimumab) may increase the risk of developing myocarditis compared with single therapy.[81][82]​ Immune checkpoint inhibitor-associated autoimmune diabetes, which appears distinct from type 1 diabetes (e.g., lower prevalence of autoantibodies, but earlier presentation and greater risk of diabetic ketoacidosis in those with autoantibodies), is a rare complication.[83]

Subsequent lines of therapy

There is no standard second-line therapy for malignant pleural mesothelioma.[84][85]​​[86] Generally, it is appropriate to treat patients with an alternative first-line regimen if another has failed: for example, trial immune checkpoint inhibitor therapy if first-line chemotherapy has failed (and vice versa).[2]

Nivolumab alone, pemetrexed alone, vinorelbine alone, or gemcitabine with or without ramucirumab may be offered as second-line therapies.[2][47][87]

Radiotherapy

Post-EPP radiotherapy (RT) to the ipsilateral chest cavity and chest wall can be used as adjuvant therapy, or to relieve symptoms arising from local/regional growth of tumour.[47] 

Intensity-modulated radiotherapy (IMRT) techniques may be used to reduce the risk of failure after EPP.[57][67][88]​ Care must be taken to limit the dose to the contralateral lung, given the possibility of lethal pulmonary injury.[89] National Comprehensive Cancer Network (NCCN) guidelines do not recommend hemithoracic pleural IMRT after EPP.[2]

Improved radiation delivery techniques following pleurectomy with decortication (such as IMRT) allow delivery of adequate doses to target structures (while minimising the risk of radiation pneumonitis), and increase overall survival compared with palliative RT.[90][91][92][93] Sequential pleural IMRT after lung-sparing pleurectomy with decortication may be offered in centres with sufficient expertise.[2]​​​

Comprehensive RT after pleurectomy with decortication is generally not recommended due to the risk of radiation pneumonitis.[47][94][95]​​

Palliative RT

​RT can be used to palliate local sites of disease that may be causing distressing symptoms, most commonly pain due to chest wall invasion or shortness of breath due to airway obstruction. Whether an abbreviated course of RT to decrease malignant seeding after invasive diagnostic procedures is efficacious is not clear.[96][97][98]​​

One systematic review suggests that prophylactic irradiation therapy after video-assisted thoracoscopic surgery is not justified.[99] One study of prophylactic RT to prevent procedure-tract metastases after large-bore pleural interventions found no significant difference in the incidence of procedure-tract metastases in the immediate and deferred RT groups.[100]

Palliative procedures: unresectable or recurrent disease

Thoracentesis and pleurodesis may provide symptomatic relief.

In addition to aiding diagnosis, thoracentesis can often provide temporary relief for those patients suffering from dyspnoea as a consequence of a large pleural effusion. In patients with breathlessness, aggressive daily drainage provides no additional benefit over a symptom-driven approach.[101]

Pleurodesis, defined as the artificial obliteration of the pleural space, can be performed to prevent re-accumulation of pleural fluid. Talc pleurodesis seems to be the most effective sclerosant.[102]​​ [ Cochrane Clinical Answers logo ] ​ Video-assisted thoracoscopic surgery (VATS) pleurodesis provides optimal results.[102]​ One randomised study showed that VATS partial pleurectomy was not superior to talc pleurodesis in terms of improving survival or symptom control.[103]

Certain palliative interventions may help to improve symptoms, psychological functioning, and quality of life.[104]​ Examples include nursing programmes, interventions to manage breathlessness, counselling, as well as psychotherapeutic, psychosocial, and educational interventions.[105]​ Early referral to specialist palliative care does not improve health-related quality of life in patients who are cared for in centres with good access when required.[106]

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