Targeting immune checkpoints with immunomodulatory monoclonal antibodies has been shown to be effective in pretreated patients with a variety of solid tumors. A recent Phase II study evaluated the CTLA-4 monoclonal antibody tremelimumab (AstraZeneca) in 29 chemotherapy-resistant malignant mesothelioma patients (28 patients with MPM). The median overall survival was 11.3 months, and 52% of patients had disease control at a median follow-up of 23.1 months.53 Tremelimumab has recently been granted orphan drug approval by the FDA; however, AstraZeneca reported a follow-up phase IIb trial of tremelimumab monotherapy versus placebo as second or third line treatment for mesothelioma (both pleural and peritoneal) and tremilimumab did not improve overall survival in this setting. There is now interest in investigating tremelimumab in combination with additional immunotherapy in this setting. In addition, monoclonal antibodies directed against PD-L1 or PD1 are also currently being investigated in Phase I/II trials in MPM. Prior preclinical series demonstrated that PD1 and PD-L1 are expressed in a significant percentage of MPM and that expression may identify patients with a worse prognosis.54,55 Alley et al recently reported early promising results from their Phase I/II trial of pembrolizumab, a monoclonal antibody against PD1, in pretreated patients with MPM. In the 25 patients with PD1 expressing tumors, there was a 28% overall response rate (7 patients) and a 6 month progression free survival rate of 49.4% at a median follow-up of 8.6 months.56
RT is used as a part of a multimodality approach with the appropriate timing determined by a multidisciplinary team (described in the “Multimodality therapy” section). RT alone is typically not performed as MPM is not sensitive to RT. Radiation can be used to palliate chest wall pain as well as subcutaneous extensions from mesothelioma. Currently, there is no evidence to support routine use of prophylactic radiation, which is at times given to prevent seeding of surgical incisions and port sites.57
Surgical treatment is occasionally performed in carefully selected patients with the intent to resect all visible tumor resulting in macroscopic complete resection, eliminate pleural effusion, improve local symptoms, and to increase the efficacy of adjuvant therapy.58
With regard to palliation of pleural effusion in MPM, Rintoul et al59 performed a Phase III trial of video-assisted throacoscopic partial pleurectomy (VAT-PP) versus talc pleurodesis in 196 MPM patients with a pleural effusion (the MesoVATS trial). The primary end point was overall survival at 12 months, which was 52% in the VAT-PP group and 57% in the talc pleurodesis group (P=0.81). Surgical complications (31% versus 14%) and length of hospital stay (7 versus 3 days) were significantly greater in the VAT-PP patients, whereas the rate of complete resolution of the effusion at 12 months and the quality of life measures were similar in both treatment arms.
Additional surgical approaches for MPM include either pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP). P/D is a complete visceral and parietal pleurectomy with the intent of extirpation of all gross disease. Removal of the ipsilateral diaphragm and/or pericardium may be required if those areas are involved. EPP is an en bloc resection of the lung, visceral and parietal pleura, diaphragm, and adjacent pericardium. The true value of these procedures in mesothelioma is debated extensively in the literature for the following reasons. There have been no definitive comparisons of EPP and P/D or comparisons of these procedures against nonsurgical treatment of mesothelioma. In addition, as will be detailed in the following paragraph, both procedures have significant associated morbidity and mortality. Lastly, neither EPP nor P/D results in a complete R0 resection (ie, a curative intent resection with no remaining macro- or microscopic tumor). They are, therefore, not curative as a single modality of treatment.
A recent systematic literature review of EPP in MPM identified 34 relevant studies from 26 institutions that included over 3,700 patients.60 The reported median overall survivals from these series ranged from 9.4 to 27.5 months, and the 5-year survival rates were from 0% to 24%. If the middle two quartiles were analyzed alone to exclude the outliers, the median survivals were 12–20 months, and 5-year survival rates were 10%–19%. Perioperative mortality rates ranged from 0% to 11.8% with major morbidity seen in 12.5%–48% of patients. The most common complications were atrial arrhythmias, respiratory infections, respiratory failure, pulmonary embolus, and myocardial infarction.
A separate review of 17 articles from 13 centers sought to identify prognostic factors and patient selection criteria for EPP.61 The two factors that consistently predicted for poor outcome with EPP were non-epithelioid histology and N2 nodal involvement. The reviewers concluded that patients in either of these categories should not be considered candidates for EPP.