Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

resectable disease

1st line – surgery

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ACUTE
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resectable disease
1st line – 

surgery

Most patients have advanced disease at presentation, and surgery is not recommended for these patients. However, surgery may be performed to:[2][45][47] obtain diagnostic samples of tumor 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]​ However, surgery is unlikely to be an option for patients with stage IIIB or stage IV disease.[2][64][65]

Surgery alone (extrapleural pneumonectomy [EPP] or pleurectomy decortication) is rarely curative, and the effect on long-term survival remains unclear.[67] Notably, a phase 3 randomized controlled trial has shown that, in patients with resectable pleural mesothelioma, a combination of (extended) pleurectomy decortication surgery and chemotherapy is 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]

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 radiation therapy, which seems to decrease the risk of local recurrence.[67][68][69] However, the risk of developing a complication after EPP is high, even in experienced centers.[68] EPP is most appropriate for patients with epithelioid histology, no lymph node involvement, and sufficient cardiac and pulmonary reserve.

Plus – pre- and/or postoperative chemotherapy

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ACUTE
|
resectable disease
Plus – 

pre- and/or postoperative chemotherapy

Treatment recommended for ALL patients in selected patient group

The choice of therapy usually depends on the type of mesothelioma.[2][47]

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 extrapleural pneumonectomy (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 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 favorable 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 hematologic toxicity associated with pemetrexed.

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

or

carboplatin

-- AND --

pemetrexed

Consider – radiation therapy

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ACUTE
|
resectable disease
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Post-extrapleural pneumonectomy (EPP) radiation therapy (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 tumor.[47]

Intensity-modulated radiation therapy (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 minimizing 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 centers with sufficient expertise.[2]

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

unresectable or recurrent disease

1st line – chemotherapy and/or immunotherapy

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ACUTE
|
unresectable or recurrent disease
1st line – 

chemotherapy and/or immunotherapy

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 hematologic 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 randomized 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 multicenter, randomized, 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]

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]

Primary options

cisplatin

or

carboplatin

-- AND --

pemetrexed

OR

cisplatin

or

carboplatin

-- AND --

pemetrexed

-- AND --

bevacizumab

OR

cisplatin

or

carboplatin

-- AND --

pemetrexed

-- AND --

pembrolizumab

OR

nivolumab

and

ipilimumab

Secondary options

nivolumab

OR

pemetrexed

OR

vinorelbine

OR

gemcitabine

OR

gemcitabine

and

ramucirumab

Consider – radiation therapy

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ACUTE
|
unresectable or recurrent disease
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Radiation therapy 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 radiation therapy to decrease malignant seeding after invasive diagnostic procedures is efficacious is not clear.[96][97][98]

Consider – palliative procedures + supportive care

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ACUTE
|
unresectable or recurrent disease
Consider – 

palliative procedures + supportive care

Treatment recommended for SOME patients in selected patient group

Therapeutic thoracentesis and pleurodesis may provide symptomatic relief.

In addition to aiding diagnosis, thoracentesis can often provide temporary relief for those patients suffering from dyspnea 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 reaccumulation of pleuritic 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 randomized study showed that VATS partial pleurectomy was not superior to talc pleurodesis in terms of improving survival or symptom control.[103]

Certain interventions may help to improve symptoms, psychological functioning, and quality of life.[104] ​Some examples include nursing programs, interventions to manage breathlessness, and counseling, as well as psychotherapeutic, psychosocial, and educational interventions.[104]

Early referral to specialist palliative care (SPC) does not improve health-related quality of life in patients who are cared for in centers with good access to SPC when required.[106]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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