Perspectives on the Treatment of Malignant Pleural Mesothelioma

A subsequent study of the

Asbestos exposure is the most common cause of malignant mesothelioma.Arguably the most notable case series that supports this relationship was reported in the 1960s, in what was then the north west of Cape Province in South Africa, where 33 cases were examined, all involving exposure to clinically significant levels of asbestos. 5Asbestos is an excellent insulating material that is strong, cheap, fire-resistant, and durable.][8] Mesothelioma has a latency period of 20 to 50 years. 9Despite the identification of asbestos as an indisputable precipitant of mesothelioma, the precise pathogenetic mechanisms behind the development of the disease remain unclear.Contributing factors such as the persistence of mineral fibers (particularly asbestos) and chronic inflammation, supported by mouse models, have been extensively reviewed elsewhere. 10,11Analysis of the mutational signature of malignant pleural mesothelioma, an emerging research tool for detecting genomic footprints of damage, reveals mutational changes induced by reactive oxygen species.Asbestos-specific signatures have not yet been identified. 12,13n more than 10% of patients with malignant mesothelioma, germline variants have been reported. 14Mutations in the gene encoding BRCA1-associated protein 1 (BAP1) have been shown to accelerate asbestos-induced mesothelioma in mice 15 and are associated with a syndrome consisting of familial cancers in humans, including malignant mesothelioma and uveal melanoma. 16Other deleterious germline variants in DNA repair genes, such as PALB2 and BRCA1/2, also accelerate the development of asbestosinduced mesothelioma in preclinical models and humans. 17The maps are based on data from the U.S. Geological Survey.In 2017, the countries with the most mined asbestos (measured in metric tons) were Russia, Kazakhstan, Brazil, and China (Panel A), and the countries with the greatest use of asbestos (measured in metric tons) were India, China, Russia, Indonesia, and Uzbekistan (Panel B).Three distinct histologic subtypes of pleural mesothelioma phenotypes have traditionally been recognized: epithelioid mesothelioma (accounting for 50 to 60% of cases), which is associated with the most favorable prognosis; sarcomatoid mesothelioma (10% of cases), which is highly invasive and drug-resistant; and biphasic mesothelioma (30 to 40% of cases), which is a mosaic of the other two subtypes.Recent insights reveal an epithelioid-sarcomatoid continuum rather than discrete subclasses, which correlates strongly with molecular markers of epithelial mesenchymal transition. 18The interpatient heterogeneity of the disease has almost certainly hindered clinical trial design and results.The classic histologic subgrouping has also been challenged by the use of deep learning.Examination of both tumor heterogeneity and surrounding tumor stroma has revealed prognostic histopathological features such as inflammation, cellular diversity, and vacuolization within the stroma. 19omprehensive genomic and transcriptomic sequencing of mesothelioma has revealed extensive genomic heterogeneity among patients, which probably underpins the failure of onesize-fits-all approaches to therapy.The mutational landscape of mesothelioma is dominated by the inactivation of tumor suppressor genes, which include BAP1, CDKN2A, NF2, and SETD2. 20,21he protracted interval between initial exposure and diagnosis suggests that mesothelioma, like breast cancer and cervical cancer, has a premalignant state.Indeed, loss of function of BAP1 has been shown to be associated with a carcinoma in situ-like phenotype in the pleura and peritoneum, a potentially important finding for our understanding of the pathogenesis of mesothelioma, which is likely to influence future work exploring preventive therapeutic interventions. 22

Clinic a l Pr esentation
Most patients with malignant pleural mesothelioma present late in the course of the disease, as a result of asymptomatic early development, a sequela of the indolent biologic features of the disorder.The most common presenting symp-toms at diagnosis include breathlessness caused by a pleural effusion or tumor encasement of the lung and the more sinister chest pain due to direct invasion into the chest wall or mediastinum.Fatigue, anorexia, weight loss, sweats, and malaise may also be present and become more frequent as the disease progresses. 23

Di agnosis
Contrast-enhanced computed tomography (CT) of the chest and upper abdomen is recommended as the initial method of investigation. 24Other imaging techniques can be used to support the CT findings.Positron-emission tomography (PET) with CT has been shown to add diagnostic value when the CT results are uncertain regarding a malignant process, although PET-CT findings should be interpreted with caution, since areas of high metabolic activity may represent infection or inflammation. 25Magnetic resonance imaging can provide greater soft-tissue definition, offering more detailed information on isolated foci of disease, chest-wall invasion, or infiltration into surrounding structures. 26When the diagnosis remains uncertain, the more invasive techniques of mediastinoscopy, laparoscopy, endobronchial ultrasonography, and endoscopic ultrasonography are occasionally used if a positive result would influence management. 27Several studies of serum-based and pleural fluid-based biomarkers, such as soluble mesothelin-related peptide and osteopontin, offer little evidence for their use in diagnosing malignant pleural mesothelioma or monitoring treatment effects. 24iagnostic imaging guides histopathological confirmation of malignant pleural mesothelioma.Pleural biopsy is often the preferred diagnostic method; however, examination of pleural fluid is also an acceptable diagnostic method for epithelioid pleural mesothelioma.Diagnostic sensitivity varies widely, and higher rates of successful diagnoses are found in centers specializing in cytologic assessment of pleural effusion. 28,29ncillary studies are key in supporting a histopathological diagnosis of malignant pleural mesothelioma.Immunohistochemical panels for biopsy specimens or cytologically derived cell blocks usually include at least two mesothelial markers (e.g., calretinin, cytokeratin 5/6, Wilms' tumor 1 antigen, or D2-40), which should be positive, and two adenocarcinoma markers (e.g., thyroid transcription factor 1, carcinoembryonic antigen, or Ber-EP4), which should be negative.However, the sensitivity and specificity of these markers for the sarcomatoid subtype are poor.The absence of nuclear expression of BAP1 has emerged as an important diagnostic tool.Nuclear expression has been shown to be lost in up to 60% of cases, most often in the epithelioid subtype. 30In addition to BAP1, p16INK4A and methylthioadenosine phosphorylase, which are frequently deleted on chromosome 9p21.3,have been shown to be helpful as markers of a malignant process 24,31,32 (Fig. 2).

S taging
Patients usually present with localized pleural disease on radiologic assessment.However, post-mortem studies often show widespread, unsuspected dissemination.These findings suggest that metastases may be missed at the initial presentation, potentially leading to understaging. 33everal iterations of staging systems for malignant pleural mesothelioma have been proposed; the most recent is the eighth edition of the International Association for the Study of Lung Cancer tumor-node-metastasis (TNM) grading system. 34Its role in quantifying disease by measuring pleural infiltration, lymph-node involvement, and distant metastatic sites allows for identification of patients who would be candidates for participation in clinical trials of surgery and radiotherapy.Patients known to have advanced disease often proceed to conventional systemic treatment or clinical trial enrollment.The recognized discrepancy between radiologic and postmortem findings complicates The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY COLLEGE LONDON on October 5, 2021.For personal use only.No other uses without permission.
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the development of predictive prognostic tools. 33,35urthermore, other key prognostic variables, such as histologic subtype, are not considered in TNM staging, making prognosis difficult to establish with the use of this approach alone.
Cur r ent Tr e atment L a ndsc a pe Treatment of malignant pleural mesothelioma is guided by staging, histologic subtype, and the patient's functional status.Patients with inoperable disease are assessed for the use of systemic treatment or active symptom control.The latter approach, which focuses on symptom management, is a fundamental aspect of patient care.However, delivering it early rather than when required was not shown to improve quality-oflife measures in the United Kingdom-based RESPECT-Meso randomized trial. 36

Pleural Fluid Management
Patients frequently present with pleural effusions requiring drainage for both symptom relief and diagnostics.Temporary catheterization of the pleural space to draw off fluid is usually accompanied by talc administration.The success rate with this approach is similar to the rates with indwelling catheterization and surgical procedures such as partial pleurectomy and pleurectomy-decortication, although the surgical procedures have higher complication rates and require a longer hospital stay. 37,38

Surgery
Surgical resection for mesothelioma is always incomplete and should be considered palliative (Fig. 3).Median survival after the most radical form of surgery, extrapleural pneumonectomy, is 18 months, with a 5-year survival rate of 14%. 39t remains unclear whether cytoreductive surgery prolongs median survival for patients with malignant pleural mesothelioma.Studies to date have not provided a clear measure of the magnitude of benefit (vs.risk).Geographic inconsistencies in the recommendation of treatment for patients with early-stage disease are well recognized.To measure the efficacy of surgery for mesothelioma, appropriately controlled and wellpowered randomized trials are essential.The only reported data from a randomized trial directly comparing surgery with no surgery are from the United Kingdom-based Mesotheli-oma and Radical Surgery (MARS) feasibility study. 40Patients treated with standard-of-care, platinum-based chemotherapy were randomly assigned, if their cancer had not progressed, to either surgery and radiotherapy or observation alone.Not only was the median overall survival shorter in the surgical group (14.4 months vs. 19.5 months), but morbidity was significantly higher.Although the adjusted hazard ratio for extrapleural pneumonectomy as compared with no extrapleural pneumonectomy was very high (2.75, P = 0.02), it has been argued that this negative study was not sufficiently well powered.The considerable dropout rate from the originally screened 301 patients to 50 patients was problematic.Of the 24 patients randomly assigned to surgery, only 16 (67%) proceeded with surgery and only half of those received postoperative radiotherapy.Furthermore, patients who did not undergo surgery had more favorable biologic disease than those who did undergo surgery, which may have influenced the final outcome. 24,32In response to these findings, MARS2, a randomized phase 3 trial, is assessing whether extended pleurectomy-decortication (a less radical procedure than extrapleural pneumonectomy) (Fig. 3) plus chemotherapy prolongs survival, as compared with chemotherapy alone. 41If the results of this trial are negative, the role of surgery in such patients will be seriously undermined.

Radiotherapy
Randomized, controlled evaluation of radiotherapy has, to date, not shown any improvement in associated survival.Although conducted only as a phase 2 investigation, SAKK 17/04 is probably the most important study to highlight.Patients treated with neoadjuvant chemotherapy and extrapleural pneumonectomy in whom macroscopic clearance of disease was achieved were randomly assigned to either high-dose radiotherapy or surveillance.The trial failed to meet its primary end point of locoregional relapsefree survival; however, this outcome was marred by slow enrollment of patients undergoing extrapleural pneumonectomy and by poor macroscopic clearance, with only a third of the originally recruited patients randomly assigned to either hemithoracic radiotherapy or observation. 42he individual benefit of radiotherapy is challenging to ascertain in a trimodal approach in which both neoadjuvant chemotherapy and radi- The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY COLLEGE LONDON on October 5, 2021.For personal use only.No other uses without permission.
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cal surgery remain under scrutiny.Other approaches, such as intensity-modulated radiotherapy and proton therapy, may reduce off-target damage.
Intensity-modulated radiotherapy is being explored in a phase 3 clinical trial. 43,44adiotherapy used as a prophylactic intervention to prevent chest-wall invasion after the use of diagnostic or therapeutic procedures has been widely abandoned because of negative results from two randomized, open-label phase 3 stud-ies, Prophylactic Irradiation of Tracts (PIT) 45 and Surgical and Large-Bore Procedures in Malignant Pleural Mesothelioma and Radiotherapy trial (SMART).46 Efforts to ascertain the role of radiotherapy in pain control are under way in the randomized SYSTEMS-2 study.47

Tumor-Treating Fields
The noninvasive delivery of alternating electric fields to mesothelioma tumors in combination

Systemic Therapy
Until very recently, clinically meaningful advances in systemic treatment for advanced malignant pleural mesothelioma have been lacking.
In the United States, over half of the patients never receive chemotherapy, largely because of older age, poor performance status, associated coexisting conditions, and ultimately, personal preference. 49The EMPHACIS study defined the first standard-of-care front-line treatment, which received FDA approval in 2004.The study showed a significant increase in median overall survival from 9.3 months with cisplatin alone to 12.1 months with cisplatin combined with pemetrexed. 50Raltitrexed combined with cisplatin was also shown to be superior to cisplatin alone, supporting the use of antifolate treatment for malignant pleural mesothelioma. 51he Mesothelioma Avastin plus Pemetrexed-Cisplatin Study (MAPS) showed that standardof-care chemotherapy combined with bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improved survival (18.8 months, vs. 16.1 months with chemotherapy alone).Despite the small survival advantage, this treatment regimen was never filed for a license.Doubt remains regarding the value of adding bevacizumab to chemotherapy for patients with malignant pleural mesothelioma, especially in view of the increased adverse-event profile associated with combination therapy despite improvements in certain quality-of-life measures such as pain. 52A subsequent study of the multitargeted antiangiogenic kinase inhibitor nintedanib had negative results. 53mmune checkpoint inhibition leading to tumor-suppressive T-cell activation has transformed systemic therapy for multiple solid tumors.Two important studies will imminently alter the way mesothelioma is treated in the future.On the basis of promising activity in pa-tients with relapsed disease, 54 combination immunotherapy with nivolumab and ipilimumab, targeting the immune checkpoints programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4, respectively, has shown superiority as a front-line treatment as compared with standard-of-care chemotherapy (survival, 18.1 months vs. 14.1 months), particularly in patients with nonepithelioid mesothelioma.This prespecified interim analysis led to FDA approval of the combination immunotherapy in 2020, the only systemic treatment for malignant pleural mesothelioma to be approved by the FDA since 2004. 55he adverse-event profile of this regimen in older, more frail patients, as compared with the trial participants, will be observed with interest.Nivolumab alone is also the first drug to be associated with a significant improvement in overall survival among patients with relapsed mesothelioma.The recently reported Checkpoint Blockade for Inhibition of Relapsed Mesothelioma (CONFIRM) study showed a 3-month improvement in overall survival with nivolumab as compared with placebo. 56The benefit was independent of programmed death ligand 1 (PD-L1) expression, a predictive marker of the response to anti-PD-1 therapy in patients with other tumors. 57Survival updates are eagerly awaited, with the hope that a subgroup of patients will have durable responses, as observed in patients with other immunotherapy-sensitive tumors (Table 1).
9][60] Treatment with gemcitabine chemotherapy immediately after front-line chemotherapy (called switch maintenance) offers promise and warrants exploration in a phase 3 study. 61hen durable responses have been observed with front-line chemotherapy, a rechallenge of platinum-pemetrexed can be useful in some patients. 62Vinorelbine, another cytotoxic chemotherapeutic agent, has shown some activity, 63 and the results of a randomized trial should be available in 2021 (ClinicalTrials.govnumber, NCT02139904). 64e Fu t ur e L a ndsc a pe

Combining an immune checkpoint inhibitor with chemotherapy has proved to be synergistic and
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1214
T h e ne w e ngl a nd jou r na l o f m e dicine is now a standard of care for patients with nonsmall-cell lung cancer. 65Accordingly, for patients with mesothelioma, randomized trials targeting either PD-1 or its natural ligand, PD-L1, in combination with chemotherapy have shown potential or are ongoing (NCT02784171). 66On the basis of the results from MAPS 67 and the premise that antiangiogenic agents encourage the differentiation and activity of immune cells, the addition of the PD-L1 inhibitor atezolizumab to pemetrexedcarboplatin and bevacizumab is being evaluated in a randomized phase 3 trial, Bevacizumab and Copyright © 2021 Massachusetts Medical Society.All rights reserved.

Treatment of Malignant Pleur al Mesothelioma
Atezolizumab in Malignant Pleural Mesothelioma (BEAT-meso; NCT03762018).Delivery of adenovirus-mediated interferon alfa-2b is currently being evaluated in the phase 3 INFINITE study, on the basis of encouraging phase 2 data showing a disease control rate of 88%. 68Previously treated patients are randomly assigned to receive either intrapleural adenovirus treatment followed by treatment with celecoxib and then gemcitabine or celecoxib and gemcitabine alone, until disease progression or termination of treatment because of toxic effects (NCT03710876).Studies such as these rely on the presence of accumulated pleural fluid to allow for placement of an indwelling pleural catheter, meaning that if the treatment is successful, not all patients are likely to benefit.Local treatment to the pleura has long been a goal for clinicians because of concerns regarding tumor penetration with the use of intravenous treatment.

Cellular Therapy
Manipulating the immune system not only offers the opportunity for longer-term disease control than with chemotherapy but also is associated with fewer toxic effects.Innovative ways of modifying the behavior of the immune system have been explored.Genetically engineered T cells called chimeric antigen receptor T (CAR-T) cells have been designed to target mesothelin, an antigen predominantly but not exclusively seen on mesothelioma cells.A phase 1 clinical trial exploring intrapleural delivery of these CAR-T cells, combined with an immune checkpoint inhibitor, in 19 patients with pleural mesothelioma showed a disease control rate of almost 60%, an exciting finding in such an early-phase study. 69

Molecularly Stratified Therapy
Currently, no predictive biomarkers are in routine use for identifying patients who are likely to benefit from treatment for mesothelioma.However, a greater understanding of the biology of malignant mesothelioma has revealed molecular targets, opening up the possibility of an individualized approach (Fig. 4).
Epigenetic silencing of the enzyme argininosuccinate synthetase 1 (ASS1) represents the first target to undergo molecularly stratified phase 3 evaluation in patients with mesothelioma.Loss of ASS1 leads to a reliance on exogenous arginine for viability 70 and exposes a thera-peutically exploitable vulnerability with the use of arginine deprivation.Treatment with pegylated arginine deiminase (ADI-PEG 20), which leads to a decrease in arginine, has shown efficacy in a randomized phase 2 trial 71 and can be safely combined with chemotherapy. 72Since ASS1 loss is most common in patients with nonepithelioid mesothelioma, a placebo-controlled phase 3 trial evaluating standard chemotherapy with or without ADI-PEG 20 in this subgroup of patients is ongoing (NCT02709512).
Tumor-suppressor gene losses, which predominate in mesothelioma, may confer sensitivity to new small molecules, providing an opportunity for drug development.BAP1 inactivation leads to up-regulation of the oncogenic polycomb repressive complex 2. One of its subunits, enhancer of zeste homolog 2 (EZH2), has been shown to lead to cancer progression. 73A phase 2 multicenter clinical trial of the EZH2 inhibitor tazemetostat in BAP1-inactivated malignant mesothelioma met its primary end point of disease control at 12 weeks (51% of patients). 74aster protocols (trials designed to assess multiple hypotheses) provide a platform that directly addresses interpatient heterogeneity through individualized therapy.Molecular stratification of mesothelioma as a basis for individualizing therapy is now possible.The Mesothelioma Stratified Therapy (MiST) trial is the first rolling, multigroup, phase 2 umbrella study that has been designed to rapidly evaluate new treatments coupled to "multi-omic" interrogation and to identify predictive biomarkers of an exceptional response. 75In one MiST group (patients with BAP1/BRCA1-deficient mesothelioma who received rucaparib), the disease control rate was 58% at 12 weeks and 23% at 24 weeks. 76The MiST protocol is hypothesis-generating, with the aim of accelerating and guiding future stratified, randomized trials.

Conclusions
Progress in improving survival for patients with mesothelioma has been slow.This can be partly explained by a lack of randomized trials, particularly for surgical treatment.Extensive interpatient heterogeneity represents another major barrier, warranting stratified therapy.To accelerate advances in the field, we must embrace rational, well-controlled investigations, as well  Copyright © 2021 Massachusetts Medical Society.All rights reserved.

Figure 1 .
Figure 1.Global Asbestos Mining and Use of Asbestos.

A
Countries with the Most Mined Asbestos in 2017 (estimated metric tons) B Countries with the Greatest Use of Asbestos in 2017 (estimated metric tons) The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY COLLEGE LONDON on October 5, 2021.For personal use only.No other uses without permission.Copyright © 2021 Massachusetts Medical Society.All rights reserved.n engl j med 385;13 nejm.orgSeptember 23, 2021 1209 Treatment of Malignant Pleur al Mesothelioma His t opathol ogic a l a nd Molecul a r He terogeneit y

Figure 2 .
Figure 2. Histopathological Features, Anatomical Distribution, and Radiologic Detection of Malignant Mesothelioma.Panel A shows sheets of epithelioid tumor cells with focal necrosis in lung tissue (hematoxylin and eosin).Panel B shows loss of BAP1 nuclear staining in tumor cells, with BAP1 staining retained in alveolar and inflammatory cells (pink).Panel C shows calretinin (tumor cells with both cytoplasmic and nuclear staining [brown]).Panel D shows some sites of extrapleural dissemination of disease from malignant pleural mesothelioma on the basis of postmortem studies. 33Nodes represent those in hilar, mediastinal, and abdominal locations, and the heart represents pericardium and myocardium.Other sites of extrapleural disease, such as the kidney (9%) and adrenal glands (10%), are not shown.Panel E shows pleural mesothelioma detected on a chest radiograph, and Panel F shows detection on positron-emission tomography-CT.

Figure 3 .
Figure 3. Surgical Approaches to the Treatment of Malignant Pleural Mesothelioma.Partial pleurectomy entails partial removal of malignant pleural mesothelioma and effusion management.With pleurectomy-decortication, the affected pleura is removed, as is any visible tumor.Extended pleurectomy-decortication consists of pleurectomy-decortication plus removal of the pericardium and hemidiaphragm.Extrapleural pneumonectomy entails removal of the lung, pleura, pericardium, and hemidiaphragm, with the goal of macroscopic clearance of disease.

The
New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY COLLEGE LONDON on October 5, 2021.For personal use only.No other uses without permission.Copyright © 2021 Massachusetts Medical Society.All rights reserved.as individualized approaches.Master protocols could accelerate the discovery of new, effective treatments.Continued increases in the incidence of malignant pleural mesothelioma in developing countries warrant ongoing scientific and clinical pursuit of new, effective, and affordable treatments.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Figure 4 .
Figure 4. Future Therapeutic Approaches to Malignant Pleural Mesothelioma.Future treatment decisions may be based on morphologic differences, the immune microenvironment of the tumor, and the genomic or epigenomic landscape that promotes a biomarker-based strategy.
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Table 1 . Notable Phase 3 Clinical Trials of Immunotherapeutic Approaches to Malignant Pleural Mesothelioma (MPM).
CheckMate 743 is the Study of Nivolumab Combined with Ipilimumab versus Pemetrexed and Cisplatin or Carboplatin as First Line Therapy in Unresectable Pleural Mesothelioma Patients, and INFINITE is Efficacy and Safety of rAd-IFN Administered with Celecoxib and Gemcitabine in Patients with Malignant Pleural Mesothelioma.The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY COLLEGE LONDON on October 5, 2021.For personal use only.No other uses without permission.