Approach

There is no standard therapy for 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.[63] 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).​[64]

Surgery

Most patients have advanced disease at presentation. Cytoreductive surgery is not recommended in these cases (but practice varies by centre and geography).

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 for the treatment of mesothelioma

Surgery may be suitable in select patients with early-stage disease (e.g., stage TI to 3N0) and an epithelioid histology, but it is unlikely to benefit patients with late-stage disease (e.g., IIIB to IV) and a sarcomatoid histology.[2][47][65][66]

Surgery is by one of two main procedures:[2][47][67][68]

  • Extrapleural pneumonectomy (EPP) removes the parietal and visceral pleura, ipsilateral lung and pericardium, and the hemidiaphragm en bloc.

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

Maximal cytoreduction should only be considered in patients with good preoperative cardiopulmonary function, with no evidence of extrathoracic disease, and who can receive adjuvant or neoadjuvant treatment.[47] Retrospective observational data suggest that outcomes are significantly affected by social determinants of health.[64]

Decisions about suitability for cytoreductive surgery are not based solely on anatomical resectability.[2][47][67]​​ In one phase 3 randomised controlled trial of patients with resectable pleural mesothelioma, a combination of (extended) PD surgery and chemotherapy was associated with worse survival at 2 years (and more serious adverse events) compared with chemotherapy alone.[67]

Limited, low-quality evidence indicates that PD surgery may be associated with reduced short-term mortality (within 30 days) and complications compared with EPP.[69]​ EPP does, however, allow postoperative radiotherapy, which seems to decrease the risk of local recurrence.[47][70][71][72][73]​ Due to the high risk of complications, EPP should only be offered in highly selected patients and in centres of excellence.[47][71]​​​ 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.[47]

Chemotherapy and immunotherapy

Maximal surgical cytoreduction (EPP or lung-sparing [extended] PD) alone is generally insufficient, and patients will also require adjuvant or neoadjuvant chemotherapy.​[2][47]

Chemotherapy is indicated to improve quality of life and survival in all patients, including:​[2][47]

  • those who have undergone maximal surgical cytoreduction (EPP or lung-sparing [extended] PD); cytoreduction alone is generally insufficient, and these patients will require adjuvant or neoadjuvant chemotherapy)

  • those who have unresectable or recurrent mesothelioma (most patients seen in practice).

The preferred approach is chemoimmunotherapy in both epithelioid and non-epitheloid histologies, but pemetrexed plus platinum-based chemotherapy (with or without bevacizumab or pembrolizumab) may be offered as first-line systemic treatment options in patients with epithelioid histology.[47]​ In patients with a non-epithelioid histology who have not received prior systemic therapy, chemotherapy alone is not recommended unless there are contraindications to immunotherapy.[47]

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

Preferred first-line systemic therapies

  • Nivolumab plus ipilimumab (monoclonal antibodies that target programmed death-1 [PD-1] and cytotoxic T-lymphocyte associated antigen-4 [CTLA-4], respectively): a first-line option in patients with newly diagnosed disease.[2][47][74][75]​ For potentially resectable disease, nivolumab plus ipilimumab can be used as neoadjuvant therapy; however, there is insufficient evidence for its use as adjuvant therapy.[2][47][75]​ For unresectable or recurrent mesothelioma, nivolumab plus ipilimumab should be offered first-line.[2][47]​​[74][75]

  • Cisplatin (or carboplatin) plus pemetrexed: often used as adjuvant/neoadjuvant therapy in newly diagnosed patients with resectable disease or as a first-line treatment in patients with unresectable/recurrent disease.[2][47]​ For potentially resectable disease, neoadjuvant cisplatin (or carboplatin) plus pemetrexed facilitates resection and improves survival. Response rates of approximately 30% have been reported for cisplatin-based doublets, with about 75% of patients subsequently undergoing EPP.[58][76][77][78]​ For unresectable or recurrent disease, cisplatin (or carboplatin) plus pemetrexed increases survival and relieves symptoms compared with cisplatin alone.[79]

  • Cisplatin (or carboplatin) plus pemetrexed plus bevacizumab (a monoclonal antibody directed against vascular endothelial growth factor [VEGF]): adding bevacizumab to platinum-based chemotherapy has been shown to improve overall survival compared with chemotherapy alone in one phase 3 open-label randomised trial (performance status >2 excluded).[2][47][80]

  • Cisplatin (or carboplatin) plus pemetrexed plus pembrolizumab (a monoclonal antibody targeting the programmed death receptor-1 [PD-1]): adding pembrolizumab to platinum-based chemotherapy has been shown to improve objective response rate and overall survival compared with chemotherapy alone in phase 3 open-label trials (performance status >1 excluded).​​[2][47][81][82]

Subsequent lines of therapy

There is no standard second-line therapy for malignant pleural mesothelioma.[83][84][85]​ 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][86]

Adverse effects

Be vigilant for new and emerging adverse effects. Immune checkpoint inhibitors are associated with an increased risk of developing myocarditis and autoimmune diabetes (rare).[87][88][89]​ Cisplatin is associated with nephrotoxicity, nausea, and vomiting.[90]​ Carboplatin may be substituted for cisplatin.[2][47][91]

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

Radiotherapy

Maximal surgical cytoreduction (EPP or lung-sparing [extended] PD) alone is generally insufficient, and many patients will also require adjuvant or neoadjuvant radiotherapy (RT).​[2][47]

RT should only be provided in centres with sufficient expertise, with dosing determined by the radiation oncologist.​[2][47]​​​

Neoadjuvant RT may be offered to candidates for non-lung-sparing EPP.[47]​ Adjuvant 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 (including when intervention tracts are histologically positive).[47]

Intensity-modulated radiotherapy (IMRT) techniques reduce the risk of failure after EPP.[58][70][92]​​ Care must be taken to limit the dose to the contralateral lung, given the possibility of lethal pulmonary injury.[93] National Comprehensive Cancer Network (NCCN) guidelines do not recommend hemithoracic pleural IMRT after EPP.[2]

Improved radiation delivery techniques following PD (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.[94][95][96][97]​ Sequential pleural IMRT may be offered after lung-sparing PD.[2]​​[47]​​

Comprehensive RT after PD is generally not recommended due to the risk of radiation pneumonitis.[47][98][99]​​​

It is not clear whether an abbreviated course of RT to decrease malignant seeding after invasive diagnostic procedures is efficacious.[100][101][102]

Prophylactic RT

One systematic review suggests that prophylactic irradiation therapy after video-assisted thoracoscopic surgery (VATS) is not justified.[103]​ One open-label, phase 3, randomised controlled trial 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.[104]

Palliative procedures: unresectable or recurrent disease

Symptomatic relief should be offered to patients as needed. Options include thoracentesis, pleurodesis, palliative RT, and multi-component interventions.

Thoracentesis

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.[105]

Pleurodesis

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.[106]​​ [ Cochrane Clinical Answers logo ] ​​ VATS pleurodesis provides optimal results.[106]​ One randomised study showed that VATS partial pleurectomy was not superior to talc pleurodesis in terms of improving survival or symptom control.[107]

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.[47]

Multi-component interventions

Certain palliative interventions may help to improve symptoms, psychological functioning, and quality of life.[108]​ Examples include nursing programmes, interventions to manage breathlessness, counselling, as well as psychotherapeutic, psychosocial, and educational interventions.[109]​ 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.[110]

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