https://dx.doi.org/10.36416/1806-3756/e20210129
“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.
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.
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.”