ABSTRACT

Malignant mesotheliomas are rare types of cancers that affect the mesothelial surfaces, usually the pleura and peritoneum. They are associated with asbestos exposure, but due to a latency period of more than 30 years and difficult diagnosis, most cases are not detected until they reach advanced stages. Treatment options for this tumor type are very limited and survival ranges from 12 to 36 months. This review discusses the molecular physiopathology, current diagnosis, and latest therapeutic options for this disease.

Keywords: Pleural Mesothelioma; Treatment; Molecular Alterations.

RESUMO

Mesoteliomas malignos correspondem a um tipo raro de câncer que afeta as superfícies mesoteliais, normalmente a pleura e o peritônio. São associados à exposição ao amianto, porém, devido ao período de latência de mais de 30 anos e seu difícil diagnóstico, a maioria dos casos não é detectada até que estágios avançados sejam alcançados. As opções de tratamento para esse tipo de tumor são bastante limitadas e a taxa de sobrevida varia de 12 a 36 meses. Esta revisão discute a fisiopatologia molecular, o diagnóstico atual e as opções terapêuticas mais recentes para a doença.

Palavras-chave: Mesotelioma pleural; Tratamento; Alterações moleculares.

INTRODUCTION
 
Malignant mesothelioma (MM) is a rare type of cancer associated with occupational or environmental asbestos exposure in 80% of cases.(1) The first case of MM associated with asbestos was reported in the USA, in 1967, due to an epidemic event of MM among miners, which helped to establish the association between asbestos exposure and the disease development. Hitherto rare, MM incidence has been increasing since the second half of the 20th century, a context in which MM has been linked to the indiscriminate use of asbestos over the last century.(2) The true extent of such worldwide MM epidemic is unknown. Currently, the greatest burden of asbestos use concentrates in Brazil, Russia, India, and China.(3)
 
The pleura is the most common site of MM origin (73-85%), followed by the peritoneum (7-18%).(4-6) MM predominantly affects males (male to female ratio 5:1), and the risk increases with age, with a higher prevalence in individuals >65 years of age.(7,8)
 
United Kingdom, Australia and New Zealand have the highest MM incidence rates, while Japan and Central European countries hold the lowest values.(9) It is estimated that between 2005 and 2050, approximately 94,000 cases of MPM and 15,000 cases of malignant peritoneal mesothelioma will have been diagnosed in the USA.(10)
 
Brazil is considered one of the most important producers and exporters of asbestos. MM mortality rate has steadily increased in Brazil, from 0.64 deaths per million population in 1980 to 1.18 deaths per million population in 2002. From 1980 to 2010, a total of 3,718 deaths from mesothelioma were recorded, mostly (2,180) occurring in the southeast of the country. The mortality rate between males and females was balanced, and 80.7% of deaths occurred in people older than 50 years. Nevertheless, a large number of patients remain undiagnosed, resulting in the current low MM incidence in Brazil.(11-13)
 
Germline mutations in cancer predisposition genes are reported in approximately 12% of MPM patients, being more common in younger patients, women, with little or no exposure to asbestos, and those with family history of cancer or individual history of cancer (melanoma, mesothelioma, breast cancer). BAP1 is the most frequently mutated gene in this scenario, accounting for 3-7% of the cases.(14-16)
 
THE ROLE OF ASBESTOS IN MESOTHELIOMA PATHOGENESIS
 
Asbestos is the generic name of six varieties of fibrous minerals found in igneous and metamorphic rocks: Chrysotile (serpentine – white asbestos), Amosite and Actinolite (amphibole – brown asbestos), and Anthophyllite, Crocidolite, and Tremolite (blue asbestos).(14) The association between exposure to amphiboles and malignant pleural mesothelioma (MPM) is well described, and Crocidolite is considered the most oncogenic. It is believed that the thinner and longer (especially those longer than 8.0μm and wider than 0.25μm), the more dangerous the fibers, since they persist longer in the pleura, penetrate into the lungs, causing repeated tissue damage and repair, in addition to local inflammation.(17) Exposure to asbestos and other fibrous minerals can cause asbestosis, lung cancer, benign pleurisy, pleural plaques, and MPM.(18,19) In contrast, asbestos exposure is only very weakly associated with peritoneal malignant mesothelioma (33-50% of patients report previous asbestos exposure) and the timing and duration of exposure do not directly correlate with disease development.(9)
 
Although the association between asbestos exposure and mesothelioma pathogenesis is widely accepted, a common hypothesis has not been reached to explain it. Up to 80% of MPM patients have been previously exposed to asbestos. However, the reason for only a small proportion of asbestos-exposed individuals develop MM (2-10%) remains unknown.(17) (Figure 1).

 
Mesothelial cells (MC) are highly susceptible to asbestos cytotoxicity, and many pathogenic events may contribute to carcinogenesis during the long latency period between asbestos exposure and tumor development.(20) MC is affected by various cellular changes induced by asbestos, such as DNA damage, cell cycle inhibition, and apoptosis.(21-24) Conversely, MC produces many inflammatory mediators in response to asbestos.(25)
 
The mechanisms through which inflammation affects the development of MM are not fully understood, but growing evidence has supported a link between the local and systemic inflammatory response and patient prognosis.(26) The presence of an intense and sustained systemic inflammatory response characterized by leukocyte migration and cytokine secretion promotes malignant transformation of MC.(27,28) Malignant cells attract myeloid-derived supressor cells (MDSCs), tumor associated macrophages (TAMs), and regulatory lymphocytes (Treg). These cells potentiate tumor development and promote immune escape, extracellular matrix remodeling, and angiogenesis(29,30) (Figure 1).
 
Tumor necrosis factor-alpha (TNFA) and nuclear factor-kB (NF-kB) signaling were also involved in MC response to asbestos. Crocidolite causes the accumulation of macrophages in the pleura and lung, which, in turn, release TNFA. Crocidolite also induces MC to express the TNFA receptor, TNF-R1, as well as to secrete TNFA (thus causing paracrine and autocrine responses).(31) The activation of the NF-kB pathway by TNFA allows MCs bearing asbestos-induced DNA damage to eventually evolve into MM. In fact, by causing the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), whose production is catalyzed by iron, asbestos fibers can induce genotoxicity indirectly, which may lead to a wide spectrum of mutations.(32) Therefore, part of the pathogenetic mechanism of asbestos fibers is thought to be associated with their persistence in the pleura over long periods of time triggering repeated cycles of lesion/repair at the inflammation site.(33-35) Indeed, the presence of inflammatory cells in the tumor is a prognostic factor(26,36-39) (Figure 1).
 
MPM CLINICAL PRESENTATION, DIAGNOSIS, AND CLASSIFICATION
 
The latency period between the first exposure to asbestos and the diagnosis of MM is about 30 years. The unavailability of an effective screening method to detect the disease at an early stage hampers its diagnosis.(40) In turn, the diagnosis is followed by survival ranges between 12 and 30 months for localized disease, and between 8 and 14 months in advanced disease.(41,42) Most newly diagnosed patients have advanced disease, and first-line therapy prolongs survival by an average of about three months.(8,43)
 
The most common clinical manifestation of MPM is progressive dyspnea, usually secondary to pleural effusion formation, associated or not with non-pleuritic chest pain caused by chest wall invasion. Non-productive cough, fever, asthenia, hypoxia, weight loss, or night sweats may also be present. The disease is usually unilateral (95%) and predominantly localized to the right hemithorax (60%). Symptoms usually manifest insidiously and for a long period of time from the initial presentation to diagnosis (3 to 6 months), eventually leading to diagnosis at an advanced stage.(14,43)
 
Diagnosis depends on the integration of clinical presentation, imaging, and pathology. Specifically, pleural effusion appears on physical examination or chest radiography in up to 95% of cases, but its volume decreases with disease progression. The presence of chest pain or a palpable mass suggests invasion of the chest wall and portends surgical inoperability. Thoracic tomography, as well as thoracic magnetic resonance imaging, allows visualization of pleural effusion, the presence of pleural masses, and assessment of the hilar and mediastinal lymph nodes. However, magnetic resonance imaging is a more sensitive method and should be considered in potentially resectable cases.(43) In turn, PET-CT (positron emission tomography-computed tomography) is useful for detecting lymph node involvement, contralateral thoracic involvement, and distant metastases.(14,44) Figure 2 shows representative images of MPM.

 
The 2015 classification of WHO divides MM into epithelioid (60-80%), biphasic (10-15%), and sarcomatoid subtypes (10%), with desmoplastic (2%) features recognized in the sarcomatoid subtype. In some cases, classification can be difficult due to the presence of mixed populations.(45,46)
 
Epithelioid mesotheliomas have architectural, cytologic, and stromal features that allow a variety of differential diagnoses with other neoplasms. In epithelioid mesotheliomas, nuclear atypia and necrosis are independent prognostic factors, allowing the classification of epithelioid mesotheliomas into low and high histologic grades (Figure 3).(47,48)
 

 
In sarcomatoid mesotheliomas, the cells are spindly and distributed in fascicles or in a disorganized architectural arrangement, showing mild to severe cytologic atypia, in addition to the possibily of having heterologous elements. Biphasic mesothelioma must contain at least 10% of epithelioid and sarcomatoid components each, whereas desmoplastic mesothelioma must have at least 50% hyalinized fibrous stroma. Patients with sarcomatoid and biphasic tumors have significantly worse survival than those with epithelioid mesothelioma.(49)
 
Pleural fluid cytology allows MPM diagnosis in up to 1/3 of cases. However, the diagnosis is limited to epithelioid subtype because the sarcomatoid variant does not desquamate into the pleural space. Fine needle aspiration biopsy (FNAB) provides an accuracy of approximately 30%.(50) Unguided pleural biopsy increases the accuracy of FNAB; however, computed tomography-guided pleural biopsy is more sensitive and can establish the diagnosis in ~87% of the cases.(43) The use of video-assisted thoracoscopy/pleuroscopy has an accuracy ≥95% and is the ideal diagnostic method.(51)
 
Histopathological diagnosis of mesothelial lesions imply significant challenges, including differentiation of malignant lesions from benign tumors and reactive mesothelial hyperplasia or reactive fibrous pleurisy. In pleural biopsies, it can be difficult to differentiate between reactive hyperplastic mesothelium and mesothelioma, as both situations involve cytologic atypia, increased cellularity, and mitosis. Infiltration features, vascular pattern, growth pattern, extent of necrosis, and characteristics of the papillae are important criteria that cannot always be evaluated in biopsies. Recently, loss of BAP1 (BRCA1-associated protein-1) expression by IHC, homozygous deletion of CDKN2A (p16) by FISH, and expression of methyl-thio-adenosine phosphorylase (MTAP) by IHC were added as markers to distinguish non-neoplastic from neoplastic cells when mesothelial proliferation is confined to the serosal surface. This may contribute to the differential diagnosis of reactive mesothelial hyperplasia and in situ malignant mesothelioma, as well as reactive mesothelial proliferations (pleurisy) that may extend to the stroma and simulate infiltrative mesothelioma.(52,53) Nuclear expression of the BAP1 protein is preserved in reactive mesothelial cells. In epithelioid mesothelioma, complete loss of expression of BAP1 and deletion of CDKN2A are present in up to 70% of cases.(50)
 
This is complicated because the MPM morphologic patterns can simulate a variety of epithelial and nonepithelial malignancies, including carcinomas, sarcomas, melanomas, lymphomas, among others.(50) Immunohistochemistry (IHC) is crucial to differentiate these entities.(52) However, no single IHC marker is sufficiently sensitive or specific to identify MPM; therefore, the use of panels consisting of at least two carcinoma markers (e.g., pCEA BER -EP4, MOC -31, Claudin 4, HEG1) and two mesothelial markers (i.e., WT1, calretinin, CK5/6, D2-40) is recommended(45,50) (Table 1).

 
Pleural adenomatoid tumor presents as a solitary, noninfiltrative nodule, which may contribute to the differential diagnosis with adenomatoid/microcystic mesothelioma. Somatic mutation of TRAF7 and preservation of BAP1 favor the diagnosis of an adenomatoid tumor.(55)
 
For the diagnosis of metastatic carcinomas, it is recommended to add specific antibodies for primary sites, such as lung adenocarcinomas (TTF-1, napsin A), squamous cell carcinomas (p63, p40), renal cell carcinomas (PAX-8, CAIX), colorectal adenocarcinomas (CDX2), and prostate adenocarcinomas (PSA, NKX.3), in addition to the IHC panel described above. The GATA-3 antibody expressed in breast carcinomas and urothelial carcinomas may also be positive in mesotheliomas. Metastatic melanomas will express S-100, Melan-A, HMB-45, and SOX-10. Epithelioid vascular tumors (hemangioendothelioma and angiosarcoma) express CD34, CD31, and ERG, which are usually absent in mesotheliomas. A solitary pleural tumor may mimic sarcomatoid mesothelioma, nevertheless, they satin for STAT6 and CD34, and bear NAB2-STAT6 gene fusion. In the differential diagnosis of sarcomatoid and biphasic mesothelioma with synovial sarcoma (monophasic and biphasic), molecular testing is recommended to look for SYT-SSX1 or SYT-SSX2 fusions, as both have nuclear labeling for TLE1. It can be challenging to establish a differential IHC diagnosis between sarcomatoid mesothelioma and primary sarcoma of the chest wall or metastases of sarcoma to the pleura, especially when heterologous components are present in the mesothelioma.(50,56) Figure 3 shows representative photomicrographs of MPM.
 
MOLECULAR PATHWAYS OF MM
 
Genomic alterations
 
Understanding the molecular mechanisms associated with the development of MM (Table 2) began with conventional cytogenetics and comparative genomic hybridization (CGH) analyses, which showed numerical alterations in all chromosomes, indicating that losses were more common than gains.(85,86) These studies have revealed a complex pattern of chromosomal aberrations in MPM and suggest that gene copy number alterations (CNA) are a major mechanism of carcinogenesis in this disease.(87) Multiple sites of chromosomal loss have been observed in 1p, 3p, 4, 6q, 9p, 11q, 13q, 14q, 15q, 17p, 18q, and 22q,(64,65,86,87) suggesting the involvement of tumor suppressor genes in deleted regions. Although less common, chromosomal gains of 5p, 7p, 8q, 12p, 17q, and 18q have also been documented.(88)
 

 
Commonly deleted loci include those containing tumor suppressors CDKN2A (cyclin-dependent kinase inhibitor 2A), located on 9p21.3,(57) NF2 (neurofibromin 2), on 22q12,(59,60) BAP1(BRCA1-associated protein-1), located on 3p21.3,(67,89) and TP53, on 17p13. CDKN2A, encoding p16-INK4 and ARF, is the most frequently inactivated tumor suppressor gene in MM, with an incidence of homozygous deletion of 50%.(57,58,77) Loss of CDKN2A is associated with nonepithelial histology(90) and poorer survival.(64,91,92) NF2 encodes the protein Merlin,(59) a transcriptional co-activator associated with ubiquitin ligase complexes and the Hippo pathway.(93,94)
 
Approximately 20-40% of MM have deletions or mutations in BAP1(67,77,78)(67,77,78) and germline mutations in this gene increase the risk of mesothelioma development.(89) In mouse models, inactivation of only one BAP1 allele increases asbestos tumorigenicity.(89) TP53 mutations are present in approximately 8% of MM. Although this incidence is much lower than in other tumor types,(77) it is important to emphasize that CDKN2A, which encodes ARF and reduces MDM2 expression, is often lost. Therefore, deletion of CDKN2A results in an increase in MDM2 expression, which triggers ubiquitination and degradation of p53.(95,96) Thus, the phenotype of decreased p53 expression due to CDKN2A is similar to that of TP53 mutation. Indeed, animal models heterozygous for TP53 develop MM more rapidly when exposed to asbestos.(97)
 
No oncogene has yet been identified in MM, suggesting that MM is a malignancy resulting from inhibition of tumor suppressors rather than transformation by activation of oncogenes.(98)
 
The advancement of next-generation sequencing allowed several groups to provide a comprehensive analysis of molecular alterations in MM, which not only confirmed the previously found CNA but showed that the same genes also have common point mutations.(69,99,100)
 
Bueno et al.(77) published an analysis of 95 MM that confirmed previous findings of tumor suppressor genes CNAs (e.g., BAP1, NF2, CDKN2B, and TP53). In addition, newly identified mutations were described in genes that include histone modifiers such as SETD2, SETDB1, and SETD5, members of the RNA helicase family DDX3X and DDX51, a target of negative mTOR regulation ULK2, and a calcium channel component RYR2.
 
In another landmark study of 74 MM samples, TCGA reported deletion of CDKN2A and loss of NF2 by deletion or mutation. CDKN2A deletions often encompass MTAP, which encodes methylthioadenosine phosphorylase.(81) Loss of CDKN2A was strongly associated with shorter overall survival and non-epithelioid histology.(64,90-92)
 
Two studies, involving 42 patients(73), and a larger cohort of 266 patients(84) employed targeted sequencing of key mutant MPM genes (including BAP1, NF2, TP53, SETD2, LATS2, and the TERT promoter). A molecular classification into epithelioid and sarcomatoid groups was proposed, with BAP1 alterations found preferentially in the epithelioid group, whereas alterations in TP53 and LATS2 were mostly present among the sarcomatoid subtype.(84)
 
In addition to the highly consistent alterations in tumor suppressor genes, rarer genetic alterations have also been described. For example, activating mutations in the canonical MAPK or PI3K/AKT pathways were reported in two cohorts,(70,101) but were not identified in the TCGA cohort.(81) Recurrent novel amplification of RASSF7 was observed in a series of 121 patients and, together with alterations in other genes from the Hippo pathway (NF2, LATS1, and LATS2), suggests a significant contribution of this pathway to tumorigenic processes.(83)
 
BAP1
 
Although the risk of developing MM is much higher among workers of the asbestos industry,(102) not all exposed workers develop the disease. This prompted to the search for genetic factors that predispose to MM, especially in families with multiple affected individuals,(103) which led to the identification of BAP1 gene role.
 
BAP1 is an enzyme of the c-terminal hydrolase family with pleiotropic activities found in DNA repair complexes associated with BRCA1 and functions as a de-ubiquitinase.(104-106) Expression of BAP1 is associated with reduced tumor growth in several experimental models and interacts with cell cycle regulatory proteins.(107) In addition, BAP1 forms several nuclear complexes that can regulate gene transcription. Therefore, BAP1 is expected to affect a variety of cellular functions, such as chromatin remodeling, cell cycle progression, cell differentiation, and DNA repair. The BAP1 protein is also known to play an important role as an apoptosis inhibitor caused by metabolic stress.(108)
 
Deletions or mutations in BAP1 have been described in approximately 60% of MM,(67,68,70,71,77,78,81) with nearly 85% of peritoneal tumors having BAP1 alterations, comparing with only 20-30% of pleural tumors.(109) BAP1 is also consistently inactivated in clear cell renal carcinomas, uveal melanomas, and cholangiocarcinomas.(110) Most mutations in BAP1 are frameshift or missense, resulting in loss of protein expression.(67,77,78) Accordingly, loss of BAP1 protein expression can be identified by immunostaining of tumor tissue, which is observed in approximately 60% of the cases.(71) Loss of protein expression is observed in approximately 60% of the cases.(111) Despite its high prevalence, loss of BAP1 expression has not been shown to affect overall survival,(71) but has been indicated to affect response to chemotherapy.(107)
 
Point mutations are also present in BAP1 and can lead to amino acid substitution, whose effect on protein activity is not always obvious. For example, mutations I47F, F81V, A95D, and G178V lead to loss of protein stability and amyloid aggregation.(112) On the other hand, mutations such as A95D, Y724X, and 10 F679LfsX37 lead to a change in subcellular location from nuclear to cytoplasmic.(113)
 
Germline mutations in BAP1 are associated with a highly penetrant syndrome of MM. The so-called BAP1 tumor predisposition syndrome (BAP1-TPDS) was identified by three independent research groups investigating MM, cutaneous melanoma, and uveal melanoma. Later, other tumor types such as cholangiocarcinoma, clear cell renal carcinoma, basal cell carcinoma, lung cancer, breast/ovarian carcinoma, meningioma, neuroendocrine tumors, and some types of sarcomas were added to the syndrome spectrum.(89,114) However, the molecular mechanisms involved in these specific tumor types and in disease progression are not understood. Like other tumor suppressor genes, germline mutations in BAP1 are inherited in an autosomal dominant manner. Although penetrance is incomplete and tumor may vary in different members of the same family, more than 80% of gene carriers are affected by at least one type of cancer.(115)
 
MPM is the second most common tumor identified in BAP1-TPDS, comprising 22% of tumors. Comparing with sporadic MPM, the median age of onset in germline-associated MPM is significantly earlier (74 and 46 years, respectively),(111) and survival rates are 7-fold longer.(116)
 
Despite the high relevance of germline mutations in BAP1 in higher risk of developing hereditary MM and other tumors of the syndrome, a significant proportion of families with multiple mesothelioma cases do not have mutations in this gene, suggesting that other genes may predispose to these tumors.(117,118) Along this line, a recent study examined 94 hereditary cancer predisposition genes in 93 mesothelioma patients and detected likely pathogenic mutations in 10% of the cases, with an enrichment of mutations in genes of the homologous recombination DNA repair pathway. Interestingly, patients with mutations in these genes reported exposure to asbestos less frequently.(118)
 
Gene expression profile
 
Genetic alterations leading to phenotypic disorders produce altered gene expression profiles, knowledge of which may improve our understanding of relevant molecular pathways. Early studies using gene expression profiling in MM suggested the existence of two relevant molecular subtypes associated with histological classification: epithelioid and sarcomatoid.(119-121) Interestingly, genes associated with epithelioid-mesenchymal transition (EMT) were enriched in the sarcomatoid group, indicating a more mesenchymal phenotype.(121) Further work suggested that 4 subtypes can be distinguished and are associated with the spectrum from epithelioid to sarcomatoid histology, confirming the differential expression of EMT genes.(77,81) This was corroborated through data reanalysis, which showed that the molecular groups represent a continuum or histo-molecular gradient in which tumors can be dissected into a combination of epithelioid-like (E-score) and sarcomatoid-like (S-score) signatures, whose proportions are associated with prognosis.(122)
 
MPM TREATMENT
 
Prognostic factors
 
Established prognostic indicators, such as histologic subtype, age, and sex, can provide some information to predict patient survival, but there are few definitive and specific prognostic indicators routinely used to predict likely outcomes in individual patients. The European Organization for Research and Treatment of Cancer (EORTC) suggests that poor performance status, leukocytosis, sarcomatoid type, and male individuals are associated with poorer prognosis.(123) Meanwhile, the CALGB score includes age of 75 years, non-epithelioid histology, LDH 500UI/L, pleural involvement, platelets 400,000/mm3, chest pain, and poor PS as unfavorable prognostic factors.(124) Other prognostic indices include weight loss, hemoglobin, and serum albumin levels,(125) or WBC.(126)
 
In addition to its involvement in pathogenesis, systemic inflammation is associated with overall survival and response to treatment. Prognostic factors based on inflammatory response, which include the combination of C-reactive protein and albumin, the combination of neutrophil and lymphocyte counts (neutrophil-to-lymphocyte ratio, NLR), and the combination of platelet and lymphocyte counts are associated with survival in patients with various cancers, including MPM, with higher levels predicting poorer survival.(39)
 
Surgery
 
In the setting of resectable disease, treatment of MPM is based on trimodal therapy: surgery, chemotherapy (neoadjuvant or adjuvant), and radiotherapy, especially in patients without lymph node involvement.(127)
 
Generally, prognosis is dismal, as most patients have unresectable disease at diagnosis or are considered inoperable due to age, performance status, or comorbidities. It is important for patients who are candidates for surgery to undergo EBUS (endobronchial ultrasound) or mediastinoscopy, as mediastinal lymph node dissemination is a poor prognostic factor in MPM.(14)
 
For resectable tumors, the three most commonly used surgical procedures in the treatment of mesothelioma are thoracoscopy with pleurodesis, pleurectomy/decortication, and extrapleural pneumonectomy.(43)
 
Pleurectomy/decortication is a surgical procedure aimed at reducing tumor burden. This procedure is performed through open thoracotomy and consists of removing the parietal pleura, including the portion adjacent to the mediastinum, pericardium, and diaphragm (often requiring removing a portion of the diaphragm), and removal of the visceral pleura to decorticate the lung. This treatment provides relief of local symptoms and prevents recurrence of pleural effusion, but usually implies a high rate of locoregional (80% to 90%) or distant recurrence (10% to 36%), in addition to being usually not curative.(43)
 
However, the role of pleurectomy/decortication is debatable. The MesoVATS trial compared talc pleurodesis with video-assisted thoracoscopic partial pleurectomy (VAT -PP). VAT-PP did not result in a better OS (HR =1.04; 95%CI 0.76-1.42; p=0.81) and had a higher rate of surgical complications (31% x 14%, p=0.019); in addition, quality of life at 6 months was better in the VAT -PP group.(128)
 
Extrapleural pneumonectomy (EPP) is considered a more aggressive technique for involving “en bloc” removal of tissue in the hemithorax, including visceral and parietal pleura, affected lung, mediastinal lymph nodes, diaphragm, and pericardium. It is not usually considered in patients with limiting comorbidities, low performance status, mediastinal lymph node involvement, or sarcomatoid histology because of the morbidity and mortality and poorer prognosis among these patients.(129)
 
Pleurodesis is a procedure to remove fluid accumulation in the pleural space. It involves drainage of the fluid through thoracoscopy under general anesthesia or sedation or by inserting a thoracic tube through thoracostomy. After removing the fluid, sclerosing chemicals are introduced into the pleural cavity to prevent the fluid from accumulating again.(130)
 
A comparison between extrapleural pneumonectomy or pleurectomy/decortication in 663 patients revealed significant differences in survival, with a 1.4-fold higher risk of death for extrapleural pneumonectomy (p=0.001), after controlling for disease stage, histology, gender, and multimodality therapy.(131) In another randomized controlled trial, patients receiving platinum-based neoadjuvant chemotherapy were randomized to extrapleural pneumonectomy or not. No survival or quality-of-life differences were observed between the groups.(132)
 
Radiotherapy
 
The main current indications for radiotherapy in MPM are: hemithoracic radiotherapy before or after extrapleural pneumonectomy, hemithoracic radiotherapy after decortication/pleurectomy, and palliative radiotherapy to relieve local symptoms.(133)
 
Radical hemithoracic radiotherapy (RHR) can be performed after extrapleural pneumonectomy to improve local control, although it is associated with in-field failure rates of 15% to 35%.(134) Although the topic is still debated, several treatment guidelines recommend RHR, such as the NCCN (National Comprehensive Cancer Center).
 
The SAKK 17/04 trial,(135) a prospective phase II, investigated the role of adjuvant RHR after platinum-based neoadjuvant chemotherapy followed by extrapleural pneumonectomy. Patients were randomized to radiotherapy vs observation. There was no significant difference between the groups. More recently, a phase III study compared RHR with palliative radiotherapy after non-radical lung sparing surgery and chemotherapy, reaching better OS in the RHR arm (2-year OS 58% x 28%; HR 0.58, 95CI 0.31-0.95, p=0.031), at the cost of higher grade 3/4 toxicity.(136)
 
The rationale for the use of neoadjuvant hemithoracic radiotherapy prior to extrapleural pneumonectomy arose from observing a frequent tumor spread to the contralateral lung and peritoneum, which may be related to surgery. The SMART (Surgery for Mesothelioma After Radiation Therapy) strategy(137) was developed to achieve lower spread rates associated with surgical intervention. The authors observed a median overall survival of 51 months and a median disease-free survival of 47 months for epithelioid pleural mesothelioma, suggesting such strategy to provide some benefit to this population.
 
Following the publication of controversial data from the MARS-1 study, the use of extrapleural pneumectomy has declined in recent years in favor of lung-sparing techniques, such as pleurectomy and lung decortication. The IMPRINT study, a prospective phase II trial, demonstrated the safety of delivering intensity-modulated radiotherapy to the hemithorax concurrently with chemotherapy in patients who had undergone pleurectomy and lung decortication.(138)
 
In the palliative context, radiotherapy can be used to control a range of symptoms for which drug treatment is sometimes inadequate, such as chest pain associated with chest wall invasion, hemoptysis, cough or dyspnea, as well as to prevent spinal cord compression.(139)
 
Systemic treatment
 
Systemic chemotherapy is the treatment of choice in the setting of unresectable disease and for patients with relapsed disease or that do not wish to have surgery(9) (Figure 4). In first-line chemotherapy, regimens containing platinum have higher response rates than platinum-free regimens.(140) Pemetrexed-based regimens have been the first-line systemic chemotherapy option in most institutions, although no consensus has been reached on which agent(s) should be used to supplement pemetrexed.(9) Substituting cisplatin with carboplatin resulted in an ORR of 25-29%, but with better toxicity profile and similar OS.(141)

 
The addition of bevacizumab to cisplatin and pemetrexed in the first-line setting improved OS (18.8 months vs. 16.1 months) and progression-free survival (PFS) (9.2 months vs. 7.3 months) compared with cisplatin and pemetrexed in a recent phase III study (MAPS).(142) However, the use of anti-angiogenic drugs in combination with chemotherapy is not widespread, as other trials testing angiokinase inhibitors, such as cediranib and nintedanib, were negative.(5,143,144) Nevertheless, ramucirumab, an anti-VEGFR-2 antibody, was combined with gemcitabine in a randomized phase II trial (RAMES trial) and compared with gemcitabine as a single agent in second-line MPM not previously treated with antiangiogenic drugs. The combination doubled median OS (7.5 x 13.8 months) and median PFS (3.3 x 6.2 months), although no difference in ORR was observed.(145)
 
The use of immune checkpoint inhibitors (ICI) has revolutionized the treatment of various tumor types in recent years.(26) Immunotherapy is a treatment modality that explores the patient’s immune system to eliminate tumor cells. Examples of immunotherapeutic approaches currently under investigation include inhibitors of T-cell immune checkpoints or agonists of T-cell activation pathways, the use of cytokines such as IL-12 and IL-15, therapeutic vaccines, elimination of immunosuppressive cells, and modulation of other components of the immune response.(146)
 
CTLA4 is a T cell receptor that plays a key role in preventing T cell hyperactivation.(147) CTLA4 signaling decreases T cell activation and the ability of memory T cells to support an immune response.(148) Greater inhibition of tumor growth was observed upon administering anti-CTLA4 monoclonal antibody between cycles of cisplatin in mesothelioma mouse models.(149) Furthermore, CTLA4 blockade alternating with cisplatin treatment inhibited tumor cell proliferation while increasing the number of T lymphocytes infiltrating the tumor. Despite these results, DETERMINE, a multicenter, randomized, placebo-controlled phase IIB trial, failed to show any improvement in OS with the use of tremelimumab (an anti-CTLA4 antibody) in relation to placebo in second- and third-line(150) (Table 3).
 

 
PD1 is also an immune checkpoint and has two ligands: PD -L1 and PD -L2. Overexpression of the PD1 receptor plays a key role in T cell exhaustion and is an important factor during the normal immune response in preventing the onset of autoimmunity.(158) PD-L1 is highly expressed in MPM.(159) Positive PD-L1 expression was reported in 40% of 106 mesothelioma specimens, 21% in the epithelioid subtype, 94% in the sarcomatoid subtype, and 57% in the biphasic subtype.(160) Some studies reported worse survival rates in cases of MM with tumor PD-L1 expression,(161,162) whereas others reported no significant difference in survival between cases of MM with and without PD-L1 expression.(163)
 
Several phase II trials investigated the activity of anti-PD1 antibodies as second-line therapy for pleural mesothelioma and reported an ORR of 9.4-29% and a median PFS of 2.6-6.2 months. Recently, however, a phase III trial (PROMISE-meso) randomized 144 patients with advanced MM who had progressed to previous systemic chemotherapy to receive pembrolizumab or chemotherapy (gemcitabine or vinorelbine). There was no significant difference in PFS (primary endpoint) or OS, but response rate was higher among patients treated with pembrolizumab (22% x 6%). No association with PD-L1 expression was observed.(164) In contrast, the CONFIRM trial compared nivolumab with placebo in the same scenario and found improved OS (9.2 vs 6.6 months; HR 0.72; 95%CI 0.55-0.94; p=0.02) and PFS (3.0 vs 1.8 months; HR 0.62; 95%CI 0.49-0.78; p 0.001).(165) This suggests that ICIs are active against MM, although not superior to chemotherapy when used in second or further lines.
 
A French multicenter, randomized, phase II study (MAPS-2) compared nivolumab (anti-PD1) with nivolumab in combination with ipilimumab (anti-CTLA4) in patients who had failed first- or second-line therapy. The 12-week disease control rate was 44% in the nivolumab group and 50% in the combination group. High expression of PD-L1 was associated with a higher response rate.(5) Other phase II studies showed similar results (Table 3).
 
In the wake of these promising results, the CheckMate-743 trial, a randomized phase III trial, compared the combination of ipilimumab and nivolumab (IO+IO) with cisplatin/carboplatin plus pemetrexed as first-line therapy for unresectable MPM. The study showed a longer OS in the group of patients treated with IO+IO (18.1 x 14.1 months; HR 0.74 95%CI 0.6-0.91; p=0.002). OS at 2 years was 41% and 27% for IO+IO and chemotherapy, respectively. Both histologies benefited from treatment with IO+IO, although the relative improvement was greater in patients with non-epithelioid tumors. CheckMate-743 established this combination as the new standard first-line therapy for metastatic or unresectable MPM.
 
There is no consensus regarding second-line systemic therapy for advanced pleural mesothelioma, and commonly used drugs are associated with poor response rates and short median survival.(166) Patients who benefited from previous treatment with pemetrexed-containing regimens or who have not been previously exposed to pemetrexed may be treated with pemetrexed,(167,168) otherwise, patients are treated with gemcitabine, vinorelbine, or doxorubicin.(169) Vinorelbine is the only drug directly compared with best supportive care as second-line therapy in advanced MM in a randomized trial (VIM trial) and was associated with improved PFS (median PFS: 4.2 x 2.8 months; HR 0.59; 95%CI 0.41-0.85; one-sided p=0.0017), but had no impact on OS.(165) Figure 4 summarizes the current management of pleural mesothelioma.
 
More recently, two single-arm phase 2 trials investigated the role of durvalumab in combination with standard platinum- and pemetrexed-based chemotherapy in the first-line treatment of MPM. The first study (PrECOG 0505) showed a median OS of 20.4 months.(170) The OS was 70.4% at 12 months and 44.2% at 24 months. The second study (DREAM) showed a median OS of 18.4 months, a median PFS of 6.7 months, and an ORR of 48%.(171) Given the promising results, a phase III trial will start enrollment soon.
 
There are several ongoing clinical trials investigating new therapies for MPM (Table 4), and the future is likely to bring new hope for these patients.

 
CONCLUSION
 
MPM is largely preventable and global efforts should be made to ban the asbestos industry once and for all. Despite some recent advances, this rare but serious condition still represents an unmet medical need and lacks robust prospective studies to better understand its pathophysiology, as well as randomized trials to define more effective treatments for patients.
 
ACKNOWLEDGMENTS
 
This work was supported by the National Institute of Translational Oncology and Innovation (INCITO-INOTE). CAPES fellowships to CHC and GV are gratefully acknowledged.
 
AUTHOR CONTRIBUTIONS
 
GNMH: final manuscript review and submission, manuscript draft elaboration, literature review, table and graphics construction, conceptualization.
CHC: manuscript draft elaboration, literature review.
CALP: manuscript draft elaboration, literature review, pathological specimens microphotographies.
GV: manuscript draft elaboration, literature review.
JRN: manuscript draft elaboration, literature review.
VCCL: final manuscript review, manuscript draft elaboration, literature review, table and graphics construction, treatment flow chart elaboration, conceptualization, oversight.
 
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