（2026.V1）NCCN临床实践指南：间皮瘤：胸膜

指南综合与多学科· 未分类与其他 · 2026

NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

NCCN Guidelines Index Table of Contents Discussion

*Gregory J. Riely, MD, PhD+ Chair p 1 Memorial Sloan Kettering Cancer Center

*Douglas E. Wood, MD/Vice Chair 1 Fred Hutchinson Cancer Center

*James Stevenson, MD/Lead t Case Comprehensive Cancer Center/University Hospitals Seldman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Dara L. Aisner, MD, PhD≠University of Colorado Cancer Center

Andrea L.Axtell, MD, MPH 1 University of Wisconsin Carbone Center

Jessica R. Bauman, MD $\ddagger$ Fox Chase Cancer Center

Ankit Bharat, MD T 三Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Joe Y. Chang, MD, PhD§The University of Texas MD Anderson Cancer Center

Aakash Desai, MD, MPH $#$O'Neal Comprehensive Cancer Center at UAB

Thomas J. Dilling, MD, MS§Moffitt Cancer Center

Jonathan Dowell, MD+UT Southwestern Simmons Comprehensive Cancer Center

Gregory A. Durm, MD, MS $\dagger$ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Scott Gettinger, MD t P Yale Cancer Center/Smilow Cancer Hospital

Travis E. Grotz, MD 1 Mayo Clinic Comprehensive Cancer Center

Matthew A.Gubens,MD,MS+UCSF Helen Diller Family

Aditya Juloori, MD § The UChicago Medicine Comprehensive Cancer Center

Rudy P. Lackner, MD 1 Fred& Pamela Buffett \& Camela Buffett Cancer Center

Michael Lanuti, MD 11

Benjamin Levy, MD $+$ Johns Hopkins Kimmel Cancer Center

Jules Lin, MD $\eta$ University of Michigan Rogel Cancer Center

Billy W. Loo, Jr, MD, PhD S!Stanford Cancer Institute

Christine M. Lovly, MD, PhD Vanderbilt-Ingram Cancer Center

Fabrian Maldondo, MD E Vanderbilt-Blninger Cancer Center

Daniel Morgenszern, MD $\Phi$ Tsemanian Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Trey C. Mullikin, MD §Duke Cancer Institute

Thomas Ng, MD 9 The University of Tennessee Health Science Center

Dawn Owen, MD, PhD §Mayo Clinic Comprehensive Cancer Center

Dwight H.O. Owen, MD, MSc t

The Ohio State University Comprehensive Cancer Center- James Cancer Hospital and Solove Research Institute

Tejas Patil, MD $\dagger$ University of Colorado Cancer Center

Patricio M. Polanco, MD T UT Southwestern Simmons Comprehensive Cancer Center

Jonathan Riess, MD, MS $+$UC Davis Comprehensive Cancer Center

Ana Lucia Ruano Mendez≠Huntsman Cancer Institute at the University of Utah

Theresa A. Shapiro, MD, PhD ¥ p Johns Hopkins Kimmel Cancer Center

Aditi P. Singh, MD t Abramson Cancer Center at the University of Pennsylvania

Alda Tam, MD φ

The University of Texas MD Anderson Cancer Center

Tawee Tanvetyanon, MD, MPH+

Moffitt Cancer Center

Jane Yanagawa, MD $T_{1}$ UCLA Jonsson Comprehensive Cancer Center

Edwin Yau, MD, PhD

Roswell Park Comprehensive Cancer Center

NCCN Kristina Gregory, RN, MSN Lisa Hang, PhD

Diagnostic/Interventional radiology # Hematology/Hematology oncology # Internal medicine # Medical oncology # Surgery/Surgical oncology # Pathology # Discussion Section Writing ¥ Patient advocacy # Committee

NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

Version 1.2026, 09/19/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

Find an NCCN Member Institution:

https://www.nccn.org/home/memberinstitutions.

NCCN Categories of Evidence and

Consensus: All recommendations are category 2A unless otherwise indicated. See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Mesothelioma: Pleural Panel Members

Summary of the Guidelines Updates

Initial Evaluation (PM-1)

Pretreatment Evaluation (PM-2)

Clinical Stage I and Epithelioid Histology; Non-Surgical Treatment (PM-2)

Clinical Stage II–IV and Epithelioid Histology; Sarcomatoid or Biphasic Histology (any stage),

or Medically Inoperable (any stage); Treatment (PM-2)

Clinical Stage I and Epithelioid Histology; Surgical Evaluation and Treatment (PM-3)

Principles of Pathologic Review (PM-A)

Principles of Supportive Care and Survivorship (PM-B)

Principles of Systemic Therapy (PM-C)

Principles of Radiation Therapy (PM-D)

Principles of Surgery (PM-E)

Staging (ST-1)

Abbreviations (ABBR-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.

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UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for Mesothelioma: Pleural from Version 2.2025 include:PM-1

• Initial Evaluation

Bullet added: Assess for distress

• Footnote b added: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).

PM-B

• Title change: PRINCIPLES OF SUPPORTIVE CARE AND SURVIVORSHIP

• Bullets added for the following NCCN Guidelines

Cancer-Related Fatigue

Management of Immunotherapy-Related Toxicities

Cancer-Associated Venous Thromboembolic Disease

Survivorship

PM-C 1 of 3

• Epithelioid; Biphasic or Sarcomatoid

Subsequent Therapy

◊ Pemetrexed moved from Preferred to Other Recommended

PM-C 2 of 3

• Reference 9 updated.

ST-1 and ST-2

• Table 1: TNM definitions updated as per the 9th edition of the AJCC Cancer Staging System

• Table 2: AJCC Prognostic Groups updated as per the 9th edition of the AJCC Cancer Staging System

NCCN

National Comprehensive Cancer Network

NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

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INITIAL EVALUATION ${}^{a}$

·Chest CT with contrast●Thoracentesis for cytologic assessment●Pleural biopsy[eg, thoracoscopic fusion and/or biopsy[preferred], Abrams needle,mesothelioma team with pretrained www.experience in pleural (minimize number of ports)simuline thickening●Soluble mesothelin-related peptide(SMRP) (optional)recommended .Assess for distress $b$

a There are no data to suggest that screening improves survival.

b Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).Principles of Pathologic Review (PM-A).

Note:All recommendations are category 2A unless otherwise indicated.

National Comprehensive NCCn Guidelines Version 1.2026 CNN Guidelines Index 9NCCn Cancer Mesothelioma: Pleural

![PATHOLOGIC DIAGNOSIS\nPRETREATMENT\nCLINICAL ASSESSMENT\nTREATMENT\nSystemic therapy\nand consider pleural\nProgression\nSystemic therapy\nIMRT${}^{f}$ (preferred)\nSystemic therapy ${}^{i}$\nObservation9\nProgression\nSystemic therapy\no\nProgression\nSurgical evaluation${}^{h}$ \nPM-3\nPleural mesothelioma\nChest/abdomenCT with contrast\nClinical stage I and epithelioid histology\nor\nObservation9\nProgression\nSystemic therapy\nIMRT${}^{f}$ (preferred)\nSystemic therapy\nObservation9\nObservation9\nProgression\nSurgical evaluation${}^{h}$ \nPM-3\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8ab936a401f74921a3bdae505d19dcee_0_2.png) c Principles of Pathologic Review(PM-A).

d Best supportive care is recommended for patients presenting with performance status(PS) 3-4. See Principles of Supportive Care and Survivorship(PM-B).

e Principles of Systemic Therapy(PM-C).

f Pleural intensity-modulated radiation therapy(IMRT) should only be performed in carefully selected patients at centers with experience in this technique. See Principles of Radiation Therapy(PM-D).

9 Observation may be considered for patients who are asymptomatic with minimal burden of disease if systemic therapy is planned at the time of symptomatic or radiographic progression.

h The benefit of surgical resection in pleural mesothelioma is unclear and there is no evidence that patient survival is improved with surgery when combined with systemic therapy versus systemic therapy alone.

i Principles of Supportive Care and Survivorship(PM-B).

Note:All recommendations are category 2A unless otherwise indicated.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figurec21d750fdd064c429fef5c9399a64b51_0_1.png) National Comprehensive Cancer Network®

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TREATMENTi

![PFTs including diffusing capacity of the lung for carbon monoxide (DLCO) FDG-PET/CTj\n systemic optimization\nRedsectable\nPleurectomy/ decortication\nConsider sequential pleural IMRT#\nConsider therapy\nUnresectable\nProgression\nProgression\nSystemic therapy\nsequential pleural IMRT#\nProgression\nSystemic therapy,e\nor\n‘Resectable’\nResectable\n· Systemic therapy^e\n!Principles of Systemic Theraperase's\nUnresectable\nP/Dl\n<Sub Section III\nsequential pleural IMRT#\nSystemic therapy e\nProgression\nSystemic therapy,e\nProgression\nSystemic therapy's\nIntersectable\nProgression\nSystemic therapy e,i\n→\n](2/aj0YEe4oUhYkBdfpda0fYP/figuree23027b657f149ffb5e49d0fef37fd41_0_6.png) e Principles of Systemic Therapy(PM-C).

f Pleural IMRT should only be performed in carefully selected patients at centers with experience in this technique. See Principles of Radiation Therapy(PM-D).

i Principles of Supportive Care and Survivorship(PM-B).

iIf FDG-PET/CT is to be done, recommend obtaining FDG-PET/CT before pleurodesis. Confirm diagnosis of pleural mesothelioma prior to pleurodesis. If pleural mesothelioma is suspected, consider evaluation by a multidisciplinary team with expertise in pleural mesothelioma.

l Principles of Surgery of Surgery(PM-E).

Note:All recommendations are category 2A unless otherwise indicated.

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PM-A 1 OF 8

PRINCIPLES OF PATHOLOGIC REVIEW

References

Pathologic Evaluation

• Mesothelioma originates from the cells in the serosal lining that surrounds the body cavities. Of all mesotheliomas, ~85% arise from the

pleura, ~15% arise from the peritoneum, and the remainder (<1%) originate from the pericardium or the tunica vaginalis.1

• In the United States, diffuse pleural mesothelioma affects ~3,000 patients each year, with an annual incidence of ~1 in 100,000.2,3

• The purpose of the pathologic evaluation of mesothelioma is based on the pathologic assessment of tumor tissue, which can be obtained from core biopsy sampling, pleurectomy, or other more extensive resections such as extrapleural pneumonectomy (EPP). Given its rarity

and overlapping microscopic features with other conditions, the histologic diagnosis of diffuse mesothelioma can be challenging.

• To establish a pathologic diagnosis of mesothelioma, diagnostic tools that are used clinically include histologic assessment,

immunohistochemistry (IHC), cytogenetics, and molecular techniques (eg, targeted next-generation sequencing [NGS], fluorescence in

situ hybridization [FISH], single-nucleotide polymorphism arrays). Despite the multiple diagnostic toolkits, the diagnosis relies primarily on proper histologic assessment and IHC.

• The new edition of the World Health Organization (WHO) Classification of Thoracic Tumors by the International Agency for Research on

Cancer (IARC) introduced the following changes for 2021 from the previous 2015 edition1,4:

New entity: mesothelioma in situ

New terminology: diffuse pleural mesothelioma (instead of diffuse malignant pleural mesothelioma)

New terminology: localized pleural mesothelioma (instead of localized malignant pleural mesothelioma)

New terminology: well-differentiated papillary mesothelial tumor (WDPMT, instead of well-differentiated papillary mesothelioma)

Genetic tumor syndromes involving the thorax: BAP1 tumor predisposition syndrome is a hereditary cancer syndrome caused by

heterozygous germline pathogenic variants in the BAP1 gene.

• The descriptions below refer to diffuse mesothelioma, which will be named mesothelioma for the purpose of simplicity.

Mesothelioma Classification

• Mesothelioma is classified into three histologic types: epithelioid, biphasic (mixed), and sarcomatoid, which have significant prognostic

value.1

• The determination of histologic types is based on the cytologic features of the tumor:

Epithelioid mesothelioma is characterized by epithelioid-to-round cells.

Sarcomatoid mesothelioma is characterized by spindled cells with tapered nuclei.

Biphasic mesothelioma contains both epithelioid and sarcomatoid components in various proportions, with each comprising at least 10%

of the tumor.

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Mesothelioma Classification (continued)

• Within each histologic type, mesothelioma can be divided into several subtypes and patterns based on its cytologic, architectural, and

background stromal features.5

Other rare variants of epithelioid mesothelioma include clear cell, signet ring cell, rhabdoid, deciduoid, and small cell.6-8 Tumor cells are

arranged in diverse architectural patterns that include tubulopapillary, trabecular, solid, acinar, micropapillary, or adenomatoid.

In sarcomatoid mesothelioma, subtypes described include conventional/spindle cell, desmoplastic,9,10 and lymphohistiocytoid.11-13

A subset of sarcomatoid mesothelioma exhibits heterologous differentiation with osteosarcomatous, chondrosarcomatous, and/or

rhabdomyosarcomatous elements.10

The assignment of histologic type can be challenging, given the intertumoral and intratumoral morphologic heterogeneity. Appropriate type

classification of mesothelioma is nonetheless important, given the prognostic significance of different histologic types.

Studies comparing the concordance between histologic type in initial biopsies with subsequent resections have shown that the accuracy

of typing increases with a higher number of biopsies.14 While sarcomatoid histology in biopsies is highly predictive of sarcomatoid

histology in resections, epithelioid histology in biopsies is not entirely specific and is changed to biphasic or sarcomatoid types in

resections in up to 20% of patients.14

Histologic Criteria for Mesothelioma

• In mesothelioma, the goals of histologic assessment are to confirm the pathologic diagnosis and to determine the histologic type, which

allows for prognostication and treatment planning. For the diagnosis of mesothelioma, one needs to establish each of the three conditions

below:

The lesion is diffuse and not solitary. Correlation with clinical and radiologic findings is needed to confirm that the distribution of the tumor

is diffuse rather than solitary. While almost all (>99%) mesotheliomas are diffuse, rare cases of localized pleural mesothelioma have been

described, which are solitary, have a different pathogenesis, and harbor a relatively less aggressive clinical course.15-18

The lesional cells are mesothelial. Given the morphologic overlap between mesothelioma and diverse mimics such as carcinomas, IHC can

be used to confirm the presence of mesothelial differentiation in the tumor cells. Other tools such as cytogenetics and molecular analysis

may also be helpful in some instances (see next page).

The lesional cells are malignant. Histologic assessment is integral to establish that the mesothelial cells are malignant. Morphologic

features that distinguish mesothelioma from reactive conditions include: 1) invasion into adjacent tissue, such as adipose or fibrous

tissue, and skeletal muscle; 2) full-thickness serosal involvement; and 3) formation of expansile nodules (considered as a type of fibrous

tissue invasion). The presence of tissue invasion is considered to be the most reliable criterion in distinguishing mesothelioma from

reactive mesothelial proliferations.19,20 On the other hand, “worrisome” features such as necrosis, cytologic atypia, and mitoses should be

interpreted with caution, since each can be present in reactive pleuritis and do not necessarily indicate malignancy.

• Interpretation can be difficult when there is limited diagnostic tissue, tangential sectioning, artifacts from histologic processing, and/

or entrapment of adjacent structures mimicking invasion.19,21 For a mesothelial proliferation that is suspicious for, but not definitive for

malignancy, one may report the findings as “atypical mesothelial proliferation” and recommend rebiopsy and/or close follow-up.

• In the distinction between mesothelioma and benign, reactive mesothelial proliferations, the role of ancillary studies has been limited until

recently, where BAP1 or MTAP IHC and CDKN2A copy number assessment by FISH may aid in the distinction in some instances (see next

page).22

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References

Immunohistochemistry

Markers to Confirm Mesothelial Differentiation

• IHC is integral to the pathologic diagnosis of mesothelioma in clinical practice.

• Useful IHC markers include: 1) positive markers to confirm mesothelial differentiation, such as WT1, calretinin, and D2-40; and 2) negative

markers to exclude mimics, such as polyclonal carcinoembryonic antigen (CEA), thyroid transcription factor-1 (TTF-1), and claudin-4.23-25

One of the caveats is that no individual IHC marker is entirely sensitive and specific. Therefore, it is recommended that a panel including at least two mesothelial markers (eg, calretinin, WT1, D2-40) and two carcinoma markers (eg, claudin-4, TTF-1, polyclonal CEA) should be used to establish the diagnosis.26

• Broad-spectrum keratins (eg, AE1/AE3, pancytokeratin, MNF116) are not specific and are expressed in both mesothelioma and carcinomas.

• Sarcomatoid mesothelioma often shows focal to absent expression for most mesothelial markers, with the most sensitive marker being

D2-40/podoplanin.27

• Recently, GATA3 has been explored as a potential diagnostic marker for sarcomatoid mesotheliomas since GATA3 is expressed in only ~10% to 20% of sarcomatoid carcinoma28 and strongly expressed in all sarcomatoid/desmoplastic mesotheliomas.29

Markers to Confirm a Mesothelial Malignant Proliferation

• Although the distinction between diffuse or localized mesothelioma and reactive mesothelial proliferations primarily relies on histologic

assessment, this can be challenging in some cases.

• BAP1, MTAP IHC, and CDKN2A (p16) FISH are established markers for diagnosing mesothelioma.22

BAP1 IHC is a specific (though not sensitive) marker to distinguish mesothelioma from reactive mesothelial proliferations.

BAP1 is a tumor suppressor implicated in the pathogenesis of mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal

cell carcinoma.30 Recurrent somatic and/or germline mutations in BAP1 are present in mesothelioma. As a surrogate for BAP1 genomic

status, BAP1 IHC is used as a diagnostic marker for mesothelioma, whereas reactive proliferations have intact BAP1 nuclear staining.

Complete absence of expression or cytoplasmic staining is considered a loss of BAP1 expression. Aberrant BAP1 protein expression,

defined as absence of nuclear BAP1 staining, is present in ~50% to 70% of mesothelioma epithelioid type31-37 but in <20% of sarcomatoid

type.38

MTAP IHC has been used as a diagnostic marker for mesothelioma.39 MTAP is located near CDKN2A on the chromosomal region 9p21.

Loss of cytoplasmic MTAP staining is considered a surrogate for chromosomal 9p loss as determined by concurrent CDKN2A FISH

testing39 and has been reported in ~40% to 60% of mesothelioma but rarely in reactive proliferations.35-37

Although MTAP alone is not sensitive, combined use of BAP1 and MTAP IHC may improve sensitivity and specificity.35-37 Since ~10% to

20% of lung adenocarcinomas have MTAP loss,36 MTAP IHC is not useful for distinction between mesothelioma and lung carcinoma.

• Additional IHC markers such as 5-hydroxymethylcytosine (5-hmC), enhancer of zeste homolog 2 (EZH2), cyclin D1, and programmed death ligand 1 (PD-L1), and NF2 by FISH are all potentially useful to distinguish mesothelioma from reactive mesothelial proliferations, but need further study since their utility in clinical practice remains unclear.22

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PRINCIPLES OF PATHOLOGIC REVIEW

References

Immunohistochemistry (continued)

Markers as Potential Prognostic and Predictive Markers

• Recent studies explored IHC targets as potential prognostic and predictive markers.

Patients with pleural mesothelioma, epithelioid type, with loss of BAP1 by IHC and retained p16 expression by IHC have prolonged survival

in both univariate and multivariate analyses.40

Patients with mesothelioma with germline BAP1 mutations have a prolonged survival.41,42

ALK rearrangements by IHC found in rare patients with peritoneal mesothelioma43-46 have shown dramatic response with ALK inhibitor

therapies.47,48

• PD-L1 (CD274), a negative regulator of immune checkpoint, represents a target in immunotherapy, with PD-L1 IHC evaluated as a predictive biomarker in diverse tumor types.49

• The utility of PD-L1 IHC as a predictive marker for immune checkpoint inhibitors and the optimal assessment criteria in mesothelioma remain unclear.

Cytogenetic Features

• Most mesotheliomas are characterized by complex numerical and structural karyotypic alterations.50

• Although no specific chromosomal abnormalities are pathognomonic for mesothelioma, loss of chromosomal region 9p including CDKN2A or 22q including NF2 is noted in a subset of tumors.

Homozygous loss of CDKN2A by FISH testing is present in ~60% of mesotheliomas.51-53

While detection of CDKN2A loss can aid in the distinction of mesothelioma from reactive mesothelial proliferations, CDKN2A loss alone is

not useful in separating mesothelioma from other tumor types, since CDKN2A loss can be found in a substantial fraction of sarcomatoid

mesotheliomas, sarcomatoid carcinomas, and sarcomas.54

Hemizygous loss of NF2 by FISH is present in ~50% of pleural mesotheliomas.55

• A rare subset of pleural mesothelioma harbors a peculiar near-haploid karyotype, with extensive loss of heterozygosity involving nearly all

chromosomes except chromosomes 5 and 7.56

Molecular Features

• Most mesotheliomas are characterized by recurrent mutations in tumor suppressors and epigenetic regulators, including BAP1, NF2, TP53,SETD2, and other genes.56-60 Consistent with its histomorphologic heterogeneity, mesothelioma shows an impressive molecular diversity.

• Alterations are identified in multiple pathways in the regulation of cell cycle, RNA processing, histone regulation, and cell growth.58 BAP1

is one of the most frequently altered genes; mechanisms of BAP1 inactivation include point mutations, copy number loss, inactivating

structural rearrangements, and minute chromosomal deletions.56-58,61-63

• Furthermore, a small subset of pleural mesothelioma harbors unusual genetic alterations: Genomic near-haploidization was described in

rare pleural mesotheliomas that harbor mutations in TP53 and/or SETDB1.56

• Peritoneal mesothelioma has distinct molecular features compared to pleural mesothelioma.64

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References

Molecular Features (continued)

• Oncogenic EWSR1::ATF1 fusion has been described in pleural and peritoneal mesotheliomas in young adults.64,65

ALK rearrangements have been identified in rare patients with peritoneal mesothelioma.43-45,48

• Germline mutations are overall present in 12%–16% of patients with pleural and peritoneal mesotheliomas and primarily involve genes

in the DNA repair and cell cycle regulation, such as BAP1, BRCA2, CDKN2A, TMEM127, VHL, WT1, MRE11A, and MSH6.42,66,67 Germline

mutations appear to be more common in patients who are young, have a family history of mesothelioma, or have a clinical history of other

synchronous malignancies.42,66,68

Differential Diagnosis

• The differential diagnosis of mesothelioma depends on the histologic type (epithelioid, biphasic, or sarcomatoid) under consideration.

Mesothelioma can resemble reactive pleuritis or diverse tumor types, including carcinomas, melanomas, and sarcomas.

• In addition to diffuse mesothelioma, WHO recognizes additional types of mesothelial lesions: 1) localized mesothelioma, 2) WDPMT, and 3)

adenomatoid tumor.1

Localized pleural mesothelioma is microscopically identical to mesothelioma, although it is radiographically and grossly solitary and

circumscribed.15-17 Genetically, localized pleural mesothelioma includes three groups (BAP1-mutant, TRAF7-mutant, and near-haploid),

with similarities but also differences from pleural mesothelioma.18

WDPMT, often an incidental finding in the peritoneum of those assigned female at birth, can occur in the pleura,69 and is genetically

characterized by recurrent mutations in TRAF7 or CDC42.70 Infrequently, WDPMT shows back-to-back papillae with foci of invasion,71

morphologically mimicking mesothelioma. Furthermore, distinction between a mesothelioma with prominent papillary surface projections

and WDPMT can be challenging, particularly in small superficial biopsies.

Adenomatoid tumor primarily affects the genital tracts but rarely can involve the pleura; recurrent mutations in TRAF7 have been described

in adenomatoid tumors of genital type.72

Peritoneal inclusion cyst is a benign, rare tumor that displays multiple mesothelial-lined cysts that may be distinguished from mesothelial

neoplasia. This lesion is almost always located in the peritoneum, although uncommon cases have been described in the pleura. These

cystic proliferations are lined by bland mesothelial cells and lack significant stratification, papillary structures, or atypia.

Mesothelioma in situ is a preinvasive, single-layer surface proliferation of neoplastic mesothelial cells. Since the diagnosis of

mesothelioma in situ cannot be simply made on conventional hematoxylin and eosin (H&E) stains, the diagnosis requires either 1) loss of

BAP1 nuclear expression by IHC; and/or 2) CDKN2A homozygous deletion identified either by FISH or by MTAP IHC (cytoplasmic staining).

Furthermore, no mass lesions should be identified on imaging or thoracoscopy.

National NCCN

National Comprehensive Cancer Network®

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PRINCIPLES OF PATHOLOGIC REVIEW-REFERENCES

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24 Facchetti F, Gentili F, Lonardi S, et al. Claudin-4 in mesothelioma diagnosis.Histopathology 2007;51:261-263.

10 Klebe S, Brownlee NA, Mahar A, et al. Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases. Mod Pathol 2010;23:470-479.

25 Anttila S. Epithelioid lesions of the serosa. Arch Pathol Lab Med 2012;13:241-252.26 Husain AN, Colby TV, Ordonez NG,et al. Guidelines for pathologic diagnosis of malignant mesothelioma 2017 Update of the consensus statement from the

11 Hendersonson DW,Attwood HD,Constance TJ,et al. Lymphohistiocytoid mesothelioma: a rare lymphomatoid variant of predominantly sarcomatoid mesothelioma. Ultrastruct Pathol 1988;12:367-384.

27 Chirieac LR, Pinkus GS, Pinkus JL, et al. The immunohistochemical characterization of sarcomatoid malignant mesothelioma of the pleura. Am J Cancer Res 2011;1:14-24.

12 Yao DX,Shia J,Erlandson RA,et al. Lymphohisticytoid mesothelioma: a clinical,immunohistochemical and ultrastructural study of four cases and literature review.Ultrustructur Pathol 2004;28:213-228.

28 Miettinen M, McCue PA, Sarlomo-Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol 2014;38:13-22.

13 Galateau-Salle F,Attanoos R, Gibbs AR,et al. Lymphohisticytoid variant of malignant mesothelioma of the pleura: a series of 22 cases. Am J Surg Pathol 2007;31:711-716.

29 Berg KB,Churg A.GATA3 immunohistochemistry for distinguishing sarcomatoid and desmoplastic mesothelioma from sarcomatoid carcinoma of the lung. Am J Surg Pathol 2017;41:1221-1225.

14 Chirieac LR, Hung YP, Foo WC, et al. Diagnostic value of biopsy sampling in predicting histology in patients with diffuse malignant pleural mesothelioma. Cancer 2019;125:4164-4171.

30 Carbone M, Yang H, Pass HI, et al. BAP1 and cancer. Nat Rev Cancer 2013;13:153-159.

Continued

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PRINCIPLES OF PATHOLOGIC REVIEW-REFERENCES

31 Sheffield BS, Hwang HC, Lee AF, et al. BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesotheliol proliferations. Am J Surg Pathol 2015;39:977-982.

32 Cigognetti M, Lonardi S, Fisogni S, et al. BAP1(BRCA1-associated protein 1)is a highly specific marker for differentiating mesothelioma from reactive mesotheli 2014 is a highly specific marker for differentiating mesothelioma from reactive mesotheli 2015.28:1043-1057.

33 Andricj I, Jung J, Sheen A, et al. Loss of BAP1 expression is very rare in peritoneal and gynecologic serous adenocarcinomas and can be useful in the differential diagnosis with abdominal mesothelioma. Hum Pathol 2016;51:9-15.

34 Carbone M, Shimizu D, Napolitano A, et al. Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma. Oncotarget 2016;7:59314-59321.

35 Hida T, Hamasaki M, Matsumoto S, et al. Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry, Lung Cancer 2017;104:98-105.

36 Berg KB,Dacic S,Miller C,et al. Utility of methylthioadenosine phosphorylase compared with BAP1 immunohistochemistry, and CDKN2A and NF2 fluorescence in situ hybridization in separating reactive mesotheliolar proliferation from epitheloid malignant mesotheliomas. Arch Pathol Lab Med 2018;142:1549-1553.

37 Kinoshita Y,amasaki M, Yoshimura M, et al. A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleurits. Lung Cancer 2018;125:198-204.

38 Hwang HC,Sheffield BS, Rodriguez S,et al. Utility of BAP1 immunohistochemistry and p16(CDKN2A) FISH in the diagnosis of malignant mesothelioma in effusion cytology specimens.Am J Surg Pathol 2016;40:120-126.

39 Chapel DB, Schulte JJ, Berg K, et al. MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma. Mod Pathol 2020;33:245-254.

40 Chou A,Toon CW,Clarkson A,et al.The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma.Histopathology 2018;72:509-515.

41 Baumann F, Flores E, Napolitano A, et al. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis 2015;36:76-81.

42 Pastorino S, Yoshikawa Y, Pass HI, et al. A subset of mesotheliomas with improved survival occurring in carriers of BAP1 and other germline mutations. J Clin Oncol 2018;36:3485-3494.

43 Hung YP, Dong F, Watkins JC, et al. Identification of ALK rearrangements in malignant peritoneal mesothelioma. JAMA Oncol 2018;4:235-238.

44 Loharamatethoweong K, Puripat N, Aoonjai N,et al.Anaplastic lymphoma kinase(ALK) translocation in paediatric malignant peritoneal mesothelioma: a case report of novel ALK-related tumour spectrum. Histopathology 2016;68:603-607.

45 Mian I, Abdullaev Z, Morrow B, et al. Anaplastic lymphoma gene rearrangement in children and young adults with mesothelioma. J Thorac Oncol 2020;15:457-461.

46 Argani P, Lian DWQ, Agaimy A, et al. Pediatric mesothelioma with ALK fusions:a molecular and pathologic study of 5 cases. Am J Surg Pathol 2021;45:653-661.

47 Ruschoff JH, Gradhand E, Kahraman A, et al. STRN-ALK rearranged malignant peritoneal mesothelioma with dramatic response following certibin treatment.JCO Precision Oncol 2019;3:1-6.

48 Sakata S, Rees H, Parke S, et al. Complete pathological response after certitin for anaplastic lymphoma kinase-rearranged epithelial peritoneal mesothelioma.ANZ J Surg 2021;91:475-476.

49 Postow AA,Callahan MK,Wolchok JD.Immune checkpoint blockade in cancer therapy.J Clin Oncol 2015;33:1974-1982.

50 Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Mesothelioma. Cancer Genet Cytogenet 2001;127:93-110.

51 Illei PB, Rusch VW, Zakowski MF, et al. Homozygous deletion of CDKN2A and codelion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin Cancer Res 2003;9:2108-2113.

52 Dacic S, Kothmaier H, Land S, et al. Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas. Virchows Arch 2008;453:627-635.

53 Chiosea S, Krasinskas A, Cagle PT,et al. Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas. Mod Pathol 2008;21:742-747.

54 Tochigi N, Attanoos R, Chirieac LR, et al. p16 Deletion in sarcomatoid tumors of the lung and pleura. Arch Pathol Lab Med 2013;137:632-636.

55 Kinoshita Y, Hamasaki M, Yoshimura M, et al. Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma. Mod Pathol 2020;33:235-244.

56 Hmeljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov 2018;8:1548-1565.

57 Guo G,Chmielecki J, Goparaju C,et al. Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer Res 2015;75:264-269.

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PRINCIPLES OF PATHOLOGIC REVIEW- REFERENCES

58 Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet 2016;48:407-416.

59 Blum Y, Meiller C, Quetel L, et al. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Nat Commun 2019;10:1333.

60 Quetel L, Meiller C, Assie JB, et al. Genetic alterations of malignant pleural mesothelioma: association to tumor heterogeneity and overall survival. Mol Oncol 2020;14:1207-1223.

61 Bott M, Brevet M, Taylor BS, et al. The nuclear debuiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 2011;43:668-672.

62 Lo lacono M, Monica V, Righi L, et al. Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study.J Thorac Oncol 2015;10:492-499.

63 Yoshikawa Y,Emi M, Hashimoto-Tamaoki T,et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc Natl Acad Sci U S A 2016;113:13432-13437.

64 Offin M, Yang SR, Egger J, et al. Molecular characterization of peritoneal mesotheliomas. J Thorac Oncol 2022;17:455-460.

65 Desmeules P, Joubert P, Zhang L, et al. A subset of malignant malignant young adults are associated with recurrent EWSR1/FUS-ATF1 fusions. Am J Surg Pathol 2017;41:980-988.

66 Panou V,Gadiraju M,Wolin A,et al.Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma. J Clin Oncol 2018;36:2863-2871.

67 Hassan R,Morrow B,Thomas A,et al.Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy. Proc Natl Acad Sci U S A 2019;116:9008-9013.

68 Ohar JA, Cheung M, Talarchek J, et al. Germline BAP1 mutational landscape of asbestos-exposed malignant mesothelioma patients with family history of cancer. Cancer Res 2016;76:206-215.

69 Galateau-Salle F, Vignaud JM, Burke L, et al. Well-differentiated papillary mesothelioma of the pleura: a series of 24 cases. Am J Surg Pathol 2004;28:534-540.

70 Stevers M, Rabban JT, Garg K, et al. Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42. Mod Pathol 2019;32:88-99.

71Churg A,Allen T, Borczuk AC,et al. Well-differentiated papillary mesothelioma with invasive foci.Am J Surg Pathol 2014;38:990-998.

72 Goode B, Joseph NM, Stevers M, et al. Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation. Mod Pathol 2018;31:660-673.

Version 1.2026,09/19/25©2025 National Comprehensive Cancer Network(NCCN),All rights reserved.NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Note: All recommendations are category 2A unless otherwise indicated.

PM-B

a If FDG-PET/CT is to be done, recommend obtaining FDG-PET/CT before pleurodesis. Confirm diagnosis of pleural mesothelioma prior to pleurodesis. If pleural

mesothelioma is suspected, consider evaluation by a multidisciplinary team with expertise in pleural mesothelioma.

1 Abtin F, Quirk MT, Suh RD, et al. Percutaneous cryoablation for the treatment of recurrent malignant pleural mesothelioma: safety, early-term efficacy, and predictors of local recurrence. J Vasc Interv Radiol 2017;28:213-221.

PRINCIPLES OF SUPPORTIVE CARE AND SURVIVORSHIP

• Pleural effusions: Talc pleurodesis or pleural catheter, if required for management of pleural effusion.a Drainage is preferred for candidates with potentially operable disease; drainage or pleurodesis are both options for patients with inoperable disease.

• Radiotherapy and image-guided thermal ablation1 are palliative options for symptomatic pleural disease.

• Pain management: NCCN Guidelines for Adult Cancer Pain

• Nausea/vomiting: NCCN Guidelines for Antiemesis

• Psychosocial distress: NCCN Guidelines for Distress Management

• Fatigue: NCCN Guidelines for Cancer-Related Fatigue

• Immunotherapy-related toxicities: NCCN Guidelines for the Management of Immunotherapy-Related Toxicities

• Venous thromboembolic disease: NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease

• NCCN Guidelines for Palliative Care as indicated

• Smoking cessation counseling and intervention: NCCN Guidelines for Smoking Cessation; NCCN Guidelines for Lung Cancer Screening

• Survivorship: NCCN Guidelines for Survivorship

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|HISTOLOGY|FIRST-LINE THERAPY|PRINCIPLES OF SYSTEMIC THERAPYa,b|SUBSEQUENT THERAPY| |---|---|---|---| ||Preferred|$$\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\left|\le||

a All regimens may also be used for pericardial mesothelioma and tunica vaginalis test mesothelioma.

b Broad molecular tumor profiling is recommended with the goal of identifying rare driver alterations (eg, NTRK or ALK) for which effective drugs may be available or to appropriately counsel patients regarding the availability of clinical trials. ${ }^{25}$

c An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

d Consider rechallenge with pemetrexed-based therapy, if good response to front-line petemetrexed-based treatment. ${ }^{26}$

subcutaneous injection may be substituted for IV nivolumab and hyaluronidase-nvhy has not approved for concurrent use with IV ipilimumab; however, for nivolumab monotherapy, nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.

Note:All recommendations are category 2A unless otherwise indicated.

References on PM-C (2 of 3)

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PRINCIPLES OF SYSTEMIC THERAPY-REFERENCES

1Vogelzang NJ, Rustover MJ, Symanowski J,et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-2644.

2 Castagneto B, Botta M,Aitin I,et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma. Ann Oncol 2008;19:370-373.

3 Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;24:1443-1448.

4Santoro A, O'Brien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonavea patients with malignant pleural mesothelioma.J Thorac Oncol 2008;3:756-763.

5 Ceresoli GL, Zucali PA, Mencoboni M, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer 2013;109:552-558.

6 Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study(MAPS): a randomised, controlled, open-label, Phase 3 trial. Lancet 2016;387:1405-1414.

7 Popat S,Felip E,Dafni U,et al.BEAT-meso: A randomized phase III study of bevacizumab(B) and standard chemotherapy(C) with or without atezolizumab(A), as first-line treatment(TX) for advanced pleural mesothelioma(PM)-Results from the ETOP 13-18 trial. J Clin Oncol 2024;42(Suppl):Abstract LBA8002.

8 Chu Q, Perrone F, Greillier L,et al. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy,and France: a phase 3, open-label, randomised controlled trial. Lancet 2023;16;402:2295-2306.

9 Peters S,Scherpereel A,Cornelissen R,et al. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol 2022;33:488-499.

10 Nowak AK, Byrne MJ, Willians R, et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002;87:491-496.

11 Van Haarst JM, Baas J, Manegold CH, et al. Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer 2002;86:342-345.

12 Favaretto AG,Aversa SM, Paccagnella A,et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase ll study. Cancer 2003;97:2791-2797.

13 Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaive and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. J Thorac Oncol 2008;3:764-771.

14 Muers MF, Stephens RJ, Fisher P, et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma(MS01): a multicentre randomly comprised trial. Lancet 2003;371:1685-1694.

15 Scherpereel A, Mazieres J, Greillier L, et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma(IFCT-1501 MAPS2): a multicentre, open-label, randomized, non-comparative, phase 2 trial.Lancet Oncol 2019;20:239-253.

16 Fennell DA, Ewings Osttensmeier C, et al: CONFIRM trial investigators Nivolumab versus placebo in patients with relapsed malignant mesothelioma(CONFIRM); a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 2021;22:1530-1540.

17 Disselhorst MJ, Quispel-Janssen J, Lalezari F, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma(INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med 2019;7:260-270.

PM-C

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF SYSTEMIC THERAPY-REFERENCES

18 Jassem J, Ramlau R, Santoro A, et al. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol 2008;26:1698-1704.

19 Zucal PA,Simonelli M,Michetti G,et al.Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung Cancer 2012;75:360-367.

20 Manegold C, Symanowski J, Gatzemeier U,et al.Second-line(post-study)chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol 2005;16:923-927.

21 van Meerbeeck JP, Baas P, Debruyne C, et al. A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999;85:2577-2582.

22 Pinto C,Zucali PA, Pagano M,et al. Gemcitabine with or without ramucimab as second-line treatment for malignant pleural mesothelioma(RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2021;22:1438-1447.

23 Stebbing P, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorebine in relapsed malignant pleural mesothelioma. Lung Cancer 2009;63:94-97.

24 Zauderer MG, Kass SL, Woo K, et al. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer 2014;84:271-274.

25 Leal JL, Peters G, Szaukommessel M, et al. NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumors and non-small cell lung cancer. Lung Cancer 2020;146:154-159.

26 Bearz A, Talamini R, Rossoni G, et al. Re-challenge with pemetrezed in advanced mesothelioma: a multi-institutional experience. BMC Res Notes 2012;5:482.

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NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

PM-D 1 OF 3 Radiation Techniques (PM-D 2 of 3)

References (PM-D 3 of 3)

PRINCIPLES OF RADIATION THERAPY

General Principles

• Recommendations regarding RT should be made by radiation oncologists with experience in managing pleural mesothelioma.

• The best timing for delivering RT after surgical intervention and/or in conjunction with chemotherapy should be discussed by a

multidisciplinary team including radiation oncologists, surgeons, medical oncologists, diagnostic imaging specialists, and pulmonologists.

• PET scanning for treatment planning can be used as indicated.

• Prophylactic RT is not routinely recommended to prevent instrument-tract recurrence after pleural intervention.1

• RT is an effective palliative treatment for relief of chest pain, bronchial or esophageal obstruction, or other symptomatic sites associated

with mesothelioma.

• A randomized phase III trial in patients with non-metastatic pleural mesothelioma who underwent non-radical lung-sparing surgery found

substantially greater overall survival with sequential pleural intensity-modulated RT (IMRT) compared to palliative RT.2 Sequential pleural

IMRT after P/D in the presence of an intact lung may be considered in centers with experience and expertise in these methods, given the

technical difficulty of this treatment.3-5

• Advanced technologies may be used, such as image-guided RT (IGRT) for treatment involving IMRT/stereotactic radiosurgery (SRS)/

stereotactic body RT (SBRT), and intensity-modulated proton therapy (IMPT).6

Radiation Dose and Volume

• The dose of radiation should be based on the purpose of the treatment. See Recommended Doses for Radiation Therapy (PM-D 2 of 3).

• A dose ≥60 Gy should be delivered to macroscopic residual tumors if the doses to adjacent normal structures are limited to their tolerances.

In addition to covering the surgical bed within the thorax, the volume of postoperative radiation should also include the surgical scars and biopsy tracks in the chest wall.7-9

• Daily doses of 4 Gy appear to be more efficacious than fractions of <4 Gy in providing relief from chest pain associated with

mesothelioma,8,10 although the optimal daily and total dose of RT for palliative purposes remains unclear.

• For patients with residual tumors, some experienced investigators have used brachytherapy or intraoperative external beam RT (EBRT) in

combination with surgery.

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PRINCIPLES OF RADIATION THERAPY

Recommended Doses for Radiation Therapy

|Treatment type|Total dose|Fraction size|Treatment duration| |---|---|---|---| |Palliative|||| |Chest wall pain from recurrent nodules|20-40 Gy or 30 Gy|≥4 Gy 3 Gy|1-2 weeks 2 weeks| |Multiple brain or bone metastases|30 Gy|3 Gy|2 weeks| |Post P/D Higher dose to higher risk areas|45-60 Gy|1.8-2 Gy|5-6 weeks|

Radiation Techniques

●Use of highly conformal radiation technology(IMRT) is the preferred choice based on comprehensive consideration of target coverage and clinically relevant normal tissue tolerance.4,11 Advanced technologies are appropriate when needed to deliver curative RT safely.These technologies include(but are not limited to) 4D-CT and/or PET/CT simulation, IMRT/volumetric modulated arc therapy(VMAT), IGRT, motion management, and proton therapy.

●Special attention should be paid to minimize radiation to the contralateral lung,12 as the risk of fatal pneumonitis with IMRT is excessively high when strict limits are not applied.13 The contralateral uninvolved mean lung dose(MLD) should be kept as low as possible, preferably<8.5 Gy.The low-dose volume should be minimized.14 For postoperative RT for patients who have P/D, other recommended specific lung-preserving techniques are advised. Limit the ipsilateral lung dose to decrease risk of pneumonitis and keep total MLD<21 Gy and V20<40%and contralateral lung V20<7% and MLD<8 Gy.15

●The gross tumor volume(GTV) should include any grossly visible tumor. Surgical clips(indicative of gross residual tumor) should be included for postoperative adjuvant RT.

●The clinical target volume(CTV) for adjuvant RT after P/D should encompass the entire pleural surface(for partial resection cases), surgical clips, and any potential sites with residual disease.

●Extensive elective nodal irradiation (ENI)(entire mediastinum and bilateral supraclavicular nodal regions) is not recommended.

●The planning target volume(PTV) should consider the target motion and daily setup errors. The PTV margin should be based on the individual patient's motion, simulation techniques used(with and without inclusion motion), and reproducibility of each clinic's daily setup.

General Principles and Radiation Dose and Volume(PM-D 1 of 3)

Note: All recommendations are category 2A unless otherwise indicated.

References (PM-D 3 of 3)

PM-D 2 OF 3

National Comprehensive

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PRINCIPLES OF RADIATION THERAPY-REFERENCES

1 Clive AO,Taylor H, Dobson L, et al. Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma(SMART): a multicentre, open-label, phase 3,randomised controlled trial. Lancet Oncol 2016;17:1094-1104.

2 Trovo M, Relevant A, Polesel J, et al. Radical hemithoracic radiotherapy versus palliative radiotherapy in non-metastatic malignant pleural mesothelioma: results from a phase 3 randomized trial. In J Radiat Oncol Biol Phys 2021;109:1368-1376.

3Rimmer A,Zauderer MG,Gomez DR,et al.Phase II study of hemthoracic intensity-modulated pleural radiation therapy(IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma. J Clin Oncol 2016;34:2761-2768.

4 Shaikh F, Zauderer MG, von Reibnitz D, et al. Improved outcomes with modern lung-sparing trimodality therapy in patients with malignant pleural mesothelioma.J Thorac Oncol 2017;12:993-1000.

5Minatel E, Trovo M, Bearz A, et al. Radical radiation therapy after lung-sparing surgery for malignant pleural mesothelioma: survival, pattern of failure, and prognostic factors. Int J Radiat Oncol Biol Phys 2015;93:606-613.

6 Zeng J, Badiyan SN, Garces Yi, et al. Consensus statement on proton therapy in mesothelioma. Pract Radiat Oncol 2021;11:119-133.

7 Boutin C, Rey F, Viallat JR. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest 1995;108:754-758.

8 de Graaf-Strukowska L, van der Zee J, van Putten W, Senan S. Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura-a single-institution experience with 189 patients. Int J Radiol Oncol Biol Phys 1999;43:511-516.

9 de Bree E, van Ruth S, Baas P, et al. Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thyma. Chest 2002;121:480-487.

10 Ball DL, Cruickshank DG. The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 1990;13:4-9.

11 Chance WW,Rice DC,Allen PK,et al. Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. Int J Radiat Oncol Biol Phys 2015;91:149-156.

12 Rice DC, Stevens CW, Correa AM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 2007;84:1685-1692; discussion 1692-1693.

13 Allen AM, Czriminska M, Janne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 2006;65:640-645.

14 Krayenuehl J, Oertel S, Davis JB, Ciernik IF. Combined photon and electron three-dimensional conformal versus intensity-modulated radiotherapy with integrated boost for adjuvant treatment of malignant pleural mesothelioma after pleuropneumonetomy. Int J Radiat Oncol Biol Phys 2007;69:1593-1599.

15 Patel R, Ludmir EB, Miccio JA, et al. Disease-related outcomes and toxicities of intensity modulated radiation therapy after lung-sparing pleurectomy for malignant pleural mesothelioma: a systematic review. Pract Radiat Oncol 2020;10:423-433.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF SURGERY1

●Surgical resection should be performed on carefully evaluated patients by thoracic surgeons with experience in managing pleural mesothelioma.

●Decisions regarding surgical options for treatment are highly enhanced at accurate histology. Pleural biopsy for diagnosis should provide enough tissue for differentiation of epithelioid, sarcomatoid, or mixed histology and clearly exclude metastatic pleural involvement of

●For patients being considered for surgery, a single-port or thorcoscopy on the line of the potential incision is recommended.

●The goal of surgery is complete gross cytreduction of the tumor. The goal of cytoreductive surgery is“macroscopic complete resection”-in other words, removal of AL visible or palpable tumors. In cases where this is not possible, such as in multiple sites of chest wall invasion,surgery should be aborted. If it is possible to remove most of the gross disease to help with postoperative management, with a minimal impact on morbidity, then surgery should be continued.

●The surgical choices are: 1) P/D with mediastinal lymph node sampling, which is defined as complete removal of the pleura and all gross tumor $\pm$ en-bloc resection of pericardium and/or diaphragm with reconstruction; and 2) EPP, which is defined as en-bloc resection of the pleura, lung,

●For early-stage disease (confined to the pleural envelope, no clinical evidence for lymph node involvement) with favorable histology(epithelioid), P/D may be considered but it is unclear whether there is benefit over systemic therapy alone. There is controversy regarding a decision for surgical resection that needs to be weighed, taking into account tumor histology, distribution, the patient's pulmonary reserve, and availability of adjuvant and intraoperative strategies. P/D is the preferred surgical tumor, distribution, the patient's pulmonary reserve, and complete gross cytoreduction. EPP may be selected in certain cases that require careful consideration of the total treatment plan that includes

●If N2 disease is identified, prognosis with surgery (and other therapy) is substantially diminished. Surgical resection should only be considered in the setting of a clinical trial or at a center with expertise in pleural mesothelioma.

●If technically appropriate for even more advanced disease, lung-sparing operations like P/D reduce the risk for perioperative mortality and may be acceptable in terms of achieving complete macroscopic resection. P/D can provide excellent symptomatic control of recurrent pleural effusions.

●Intraoperative adjuvant therapy is still under investigation but may be considered as part of a reasonable multidisciplinary approach to this locally aggressive disease.

●After recovery from surgery, patients should be referred for adjuvant therapy, which may include chemotherapy and RT depending on whether any preoperative therapy was used and on the pathologic analysis of the surgical specimen.

${}^{1}$ Rice D., Rusch V., Pass H., et al. Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: A consensus report of the International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group. J Thorac Oncol 2011;6:1304-1312.

2 Flores RM, Pass HI, Seshan VE, et al. Extrapleal pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620-626.

${}^{3}$ Spaggiari L, Marulli G, Boyolato P, et al. Extrapleural pneumonectomy for malignant mesothelioma: an Italian multicenter retrospective study. Ann Thorac Surg 2014;97:1859-1865.

4 Flores RM,Riedel E,Donington JS,et al.Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based(Surveillance, Epidemiology, and End Results[SEER]) population.J Thorac Oncol 2010;5:1649-1654.

5 Treasure T, Lang-Lazdunski L, Waller D, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery(MARS) randomised feasibility study. Lancet Oncol 2011;12:763-772.

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

NCCN Guidelines Index Table of Contents Discussion

Table 1. Definitions for T, N, M (9th Edition)

Clinical T(cT)

T T Criteria

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor limited to the ipsilateral pleura Psumt≤12 mm and no involvement of the fissure(Fmax±≤5 mm)

T2 Tumor involving each of the ipsilateral pleura with Psumt≤12 mm,and with any of the following:

-involvement of the fissure (Fmax $\sharp $ >5 mm)

- mediastinal fat invasion

- solitary area of chest wall soft tissue invasion

Tumor involving each of the ipsilateral pleura with Psumt>12 mm but≤30 mm, with or without:

- involvement of the fissure(Fmax$\sharp\sharp$ >5 mm)

- mediastinal fat invasion

- solitary area of chest wall soft tissue invasion

T3 Tumor involving the ipsilateral pleura with Psumt>30 mm, with or without:

-involvement of the fissure(Fmax $\sharp $ >5 mm)

- mediastinal fat invasion

- solitary area of chest wall soft tissue invasion

T4 Tumor with invasion of any of the following:

- chest wall bony invasion(rib)

- mediastinal organs(heart, spine, esophagus, trachea, great vessels)

- diffuse chest wall invasion

- direct tumor extension through the diaphragm or pericardium

- direct tumor extension to the contralateral pleura

- presence of malignant pericardial effusion

Pathological T(pT)

T C criteria

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor limited to the ipsilateral pleura with no involvement of the fissure

T2 Tumor involving the ipsilateral pleura with any of the following:

- involvement of the fissure

- ipsilateral lung parenchyma invasion

- diaphragm(non-transmural) invasion

T3 Tumor limited to the ipsilateral pleura(with or without fissure involvement)and with invasion of any of the following:

- mediastinal fat

- surface of the pericardium

- endothoracic fascia

- solitary area of chest wall soft tissue

T4 Tumor with invasion of any of the following:

- chest wall bony invasion(rib)

- mediastinal organs(heart, spine, esophagus, trachea, great vessels)

- diffuse chest wall invasion

- transmural invasion of the diaphragm or pericardium

- direct extension to the contralateral pleura

- presence of malignant pericardial effusion

† Psum = pmax1+pmax2+pmax3(sum of 3 measurements of maximal pleural thickness measured on axial images along the chest wall or mediastinum in each of the three divisions of the chest-- upper, middle, and lower divided by two lines: one at the top of the aortic arch and the second drawn at the top of the left atrium)$\ddot{\text{u}}$ Fmax = maximal thickness of pleural tumor along the fissures measured on the sagittal images

©,2024,American College of Surgeons, All Rights Reserved. Used with permission of the American College of Surgeons, Chicago, Illinois.The original source for this information is the AJCC Cancer Staging System.

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

NCCN Guidelines Index Table of Contents Discussion

Table 1. Definitions for T,N,M

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

NO No tumor involvement of regional lymph node(s)

N1 Tumor involvement of ipsilateral bronchopulmonary,hilar,or mediastinal(including the internal mammary, peridiaphragmatic,pericardial fat pad, or intercostal lymph nodes) regional lymph nodes

N2 Tumor involvement of contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes

M Distant Metastasis

cM0 No distant metastasis

cM1 Distant metastasis

pM1 Microscopic confirmation of distant metastasis

Table 2. AJCC Prognostic Groups(9th Edition)

||T|N|M| |---|---|---|---| |Stage I|T1|NO|MO| |Stage II|T2|NO|MO| ||T1|N1|MO| |Stage IIIA|T2|N1|MO| ||T3|NO-N1|MO| ||T1-T3|N2|MO| |Stage IIIB|T4|Any N|MO| |Stage IV|Any T|Any N|M1|

NCCN Guidelines Index Table of Contents Discussion

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

3D-CRT three-dimensional conformal radiation therapy 4D-CT four-dimensional computed tomography 5-hmC 5-hydroxymethylcytosine CTAC carinoembryonic antigen CTV clinical target volume DLCO diffusing capacity of the lung for carbon monoxide EBRT external beam radiation therapy EBUS/ endocrobinal ultrasound EUS ENI elective nodal irradiation EPP extrapleural pneumonectomy EZH2 enhancer of zeste homolog 2 FDG fluorodeoxyglucose FISH fluorescence in situ hybridization FNA fine-needle aspiration GTV gross tumor volume H&E hematoxylin and eosin IGIR image-guided radiation IHC immunohistochemistry IMPT intensity-modulated proton therapy IMRT intensity-modulated radiation therapy

ABBREVIATIONS MLD

PFT pulmonary function test PS performance status

PTV planning target volume

SBRT stereotactic body radiation therapy

SMRP soluble mesothelin-related peptide

TTF-1 thyroid transcription factor-1

VATS video-assisted thoracic surgery

VMAT volumetric modulated arc therapy

WDPMT well-differentiated papillary mesothelial tumor

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

NCCN Guidelines Index Table of Contents Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is uniform NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

![NCCN\nNCCN\nConcomprehensive\nNCCN\nNetwork®\n](2/aj0YEe4oUhYkBdfpda0fYP/figureb7eef2570ac843d59f56218694b5f33a_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

Discussion

This discussion corresponds to the NCCN Guidelines for Mesothelioma: Pleural. Last updated: October 17, 2022

Overview......MS-2

Literature Search Criteria and Guidelines Update Methodology ... MS-3

Diagnosis $\ldots$ MS-3

Presentation and Evaluation.MS-3

Pathology $\ldots$ MS-3

Management \nDisms-4

Pretreatment Evaluation..MS-5

Staging .MS-5

Surgery.MS-5

Systemic Therapy..MS-7

Medically Operable PM...MS-7

Medically Inoperable PM...MS-8

Subsequent Systemic Therapy.MS-10

Radiation Therapy.MS-11

Summary..3MS-13

References.MS-14

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

Overview

Mesothelioma is a rare cancer originating in mesothelial surfaces of the pleura and other sites that is estimated to occur in approximately 3500 people in the United States every year.1-5 These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) focus on pleural mesothelioma (PM), which is the most common type (approximately 85%).Mesothelioma can also occur in the lining of other sites, such as the peritoneum (approximately 15%), pericardium, and tunica vaginalis testis. ${ }^{[4-9]}$ PM is difficult to treat, because most patients have advanced disease at presentation. Median overall survival is approximately 1 year after diagnosis of PM, and 5-year overall survival is about 10%; cure is rare. ${ }^{2,10-14}$ PM occurs mainly in older males (median age at diagnosis, 72 years) who have been exposed to asbestos, although death occurs decades after exposure (approximately 32 years later [range, 13-70 years) $){ }^{14-17}$

These NCCN Guidelines® for Mesothelioma: Pleural were first published in 2010 and have been subsequently updated every year. The Summary of the Guidelines Updates section in the algorithm briefly describes the new changes for 2022, which are described in greater detail in this revised Discussion text; recent references have been added. For example, a new section on pathology was added for the 2022 update(see Principles of Pathologic Review in the algorithm). Additional supplementary material in the NCCN Guidelines for Mesothelioma: Pleural includes the Principles of Systemic Therapy, Principles of Supportive Care, Principles of Surgery,and Principles of Radiation Therapy. These NCCN Guidelines for Mesothelioma: Pleural were developed and are updated by panel members who also update the NCCN Guidelines for Mesothelioma:Peritoneal and the NCCN Guidelines for Non-Small Cell Lung Cancer.

Asbestos use has decreased since the 1970s; however, the United States still has more reported cases and deaths from PM than anywhere else in

<EndOfPara>the world because of the long latency period before the disease occurs.1,18-21 The mortality burden from asbestos-related diseases in the United States did not change from 1999 to 2015.10,22,23 Although asbestos is no longer mined in the United States, it is still imported.21 The incidence of PM is increasing in other countries such as Russia, Western Europe,China, and India.30,20,24-29 Mortality rates from PM are highest in the United Kingdom, Netherlands, and Australia; mortality rates are increasing in Poland, Spain, China, Japan, Argentina, Republic of Korea, and Brazil.12,24,25,30 Russia, China, Brazil, and Canada are the top producers of asbestos.31

Although most mesothelioma is linked to asbestos exposure, reports suggest that ionizing radiation may also cause mesothelioma, such as in patients previously treated with mantle radiation for Hodgkin lymphoma.32-42 Two meta-analyses suggest that non-occupational exposure to asbestos is a risk factor for PM.43,44 Data also suggest that erionite(a mineral that may be found in gravel roads) is associated with mesothelioma.45-48 Genetic factors may also play a role in PM, with rare families carrying a germline mutation in the BRCA1-associated protein-1(BAP1) gene.45,49-58 Patients with germline BAP1 mutations have prolonged survival.53,56 BAP1 is one of the most frequently altered genes in patients with mesotheliomas; however, other genes may also be altered such as NF2, TP53, and SETD2(see Principles of Pathologic Review in the algorithm).59-63 Smoking is not a risk factor for mesothelioma.64 However, patients who smoke and have been exposed to asbestos are at increased risk for lung cancer.65 Patients who smoke should be encouraged to quit because smoking impedes treatment(eg, delays wound healing after surgery)(see the NCCN Guidelines for Smoking Cessation, available at www.NCCN.org).66 Some patients who have been exposed to asbestos only have benign pleural disease, although they may have significant chest pain.67,68 Although screening for mesothelioma has been studied in patients at high risk(ie, those with asbestos exposure),

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

these NCCN Guidelines do not recommend screening for PM because it has not been shown to decrease mortality (see Initial Evaluation in the algorithm).31,65,69-75 Note that data and guidelines about screening for lung cancer with low-dose CT do not apply to PM; there are no data to suggest that screening with low-dose CT improves survival for patients with PM.31,65,76-79

Literature Search Criteria and Guidelines Update Methodology

An electronic search of the PubMed database was performed to obtain key literature on mesothelioma using the following search term: malignant pleural mesothelioma. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase 2; Clinical Trial, Phase 3; Clinical Trial, Phase 4; Guideline; Meta-Analysis; Randomized Controlled Trial; Systematic Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional sources deemed as relevant to these Guidelines and discussed by the panel have been included in this version of the Discussion section (eg,e-publications ahead of print, meeting abstracts). If high-level evidence is lacking, then recommendations are based on the panel's review of lower-level evidence and expert opinion. The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Diagnosis

Presentation and Evaluation

Patients with suspected PM often have dyspnea and chest pain; they may also have pleural effusion, fatigue, insomnia, cough, chest wall mass, loss of appetite, and weight loss(see the NCCN Guidelines for Adult Cancer

Pain, available at www.NCCN.org).30,80,81 Patients with PM often have a high symptom burden when compared with patients who have other types of cancer (see Principles of Supportive Care in the algorithm). Symptoms such as chest pain and/or dyspnea are associated with local disease.Patients often present without distant metastases; CNS metastases are uncommon.69

In patients with recurrent pleural effusion and/or pleural thickening, the recommended initial evaluation for suspected PM includes: 1) CT with contrast of the chest; 2) pleural biopsy(eg, thoracoscopic biopsy[preferred]); and 3) thoracentesis for cytologic assessment of the effusion(see Initial Evaluation in the algorithm).30,31,69,82-87 However, cytologic samples are often negative even when patients have PM.88,89 Fine-needle aspiration(FNA) is not recommended for diagnosis, although endobronchial ultrasound(EBUS)/endoscopic ultrasound(EUS) RNA may be used to assess mediastinal lymph nodes.30

Talc pleurodesis or pleural catheter may be needed for management of pleural effusion(see Principles of Supportive Care in the algorithm). 69,90-99 Drainage is preferred for patients with potentially operable disease,whereas either drainage or pleurodesis are options for patients who are medically inoperable. ${ }^{90}$ Soluble mesothelin-related peptide (SMRP) levels may also be assessed, and these levels may correlate with disease status; ${ }^{100-103}$ osteopontin does not appear to be as useful for diagnosis. ${ }^{69,104-108}$ Other potential diagnostic biomarkers are being assessed.70-72,109-113

Pathology

The NCCN Guidelines include an extensive section on pathologic evaluation of tumor tissue to diagnose PM(see Principles of Pathologic Review in the algorithm). The goals of assessment are to confirm the pathologic diagnosis of PM and to determine the histology. The histologic

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

subtypes of mesothelioma include epithelioid (most common),sarcomatoid, and biphasic (mixed), which includes epithelioid and sarcomatoid.4,63,114,115 Patients with epithelioid histology have better outcomes than those with either mixed or sarcomatoid histologies. It is essential to determine the histology, which is used to direct treatment. The WHO introduced several changes in 2021 for mesothelioma including new terminology: 1) diffuse pleural mesothelioma; 2) localized pleural mesothelioma; and 3) well-differentiated papillary mesothelioma (see Principles of Pathologic Review in the algorithm).63

It can be difficult to distinguish malignant from benign pleural disease(such as reactive pleuritis) and also to distinguish PM from other malignancies such as metastatic adenocarcinoma, melanoma, sarcoma,or other metastases to the pleura. 26,116-123 Almost all PMs are diffuse(>99%); however, rare cases of localized pleural mesothelioma have been diagnosed, which are less aggressive.124-128 It is also difficult to distinguish localized PM from diffuse PM.124 On CT, thymoma metastatic to the pleura can mimic PM; however, pleural effusion does not typically occur with thymoma. Cytologic samples of pleural fluid are often negative or inconclusive, but diagnosis can sometimes be made using cytology. 69,88,89,129,130 Immunohistochemical markers are used to diagnose PM, including markers specific for PM(eg, WT1, calretinin, D2-40) and markers that typically are positive in carcinoma and negative in mesothelioma(eg, thyroid transcription factor 1[TTF-1], polyclonal carcinoembryonic antigen[CEA], claudin-4)(see Principles of Pathologic Review in the algorithm and Protocol for the Examination of Specimens From Patients With Malignant Pleural Mesothelioma from the College of American Pathologists[CAP]). 69,88,117,120,122,131,132 A panel of two positive mesothelial markers and two negative markers is recommended for diagnosis of PM.117 The presence or absence of BAP1 nuclear expression assessed by immunohistochemistry can be used in the differential diagnosis of mesothelioma. 133-135

Rare driver mutations have been identified in patients with PM, such as EWSR1-ATF1 fusions, TP53, NF2, SETDB1, or SETD2.59-62,136,137 A recent analysis in 229 patients with PM identified seven somatic driver mutations including BAP1, NF2, TP53, SETD2, LATS2, DDX3X, and SETDB1;targeted agents are being assessed.136,138-141 NTRK and ALK fusions have been identified in patients with PM, although at very low frequencies(0.6%).138,142,143 Targeted agents are available for NTRK and ALK fusions(see the NCCN Guidelines for Non-Small Cell Lung Cancer, available at www.NCCN.org). Patients with PM have low tumor mutational burden.60.61 For the 2022 update, the NCCN Panel now recommends broad molecular profiling for patients with PM to identify rare driver alterations(eg, ALK or NTRK fusions) for which effective drugs may be available or to counsel patients about clinical trials. 60,138

Management

The NCCN Guidelines recommend that patients with PM be managed by a multidisciplinary team with experience in PM. A general overview of management is provided here; specific details are provided in the following sections(see Surgery, Systemic Therapy, and Radiation Therapy in this Discussion). Treatment options for patients with PM include surgery,radiation therapy(RT), and/or systemic therapy.4 Most patients have advanced disease at presentation, and surgery is not recommended for these patients. Trimodality therapy-using chemotherapy, surgery, and hemithoracic RT-has been assessed in patients with medically operable PM.144-151 Median survival of up to 20 to 29 months has been reported for patients who complete trimodality therapy.147,150 Nodal status and response to systemic therapy can affect survival.150,152 Appropriate patients should be evaluated by radiation oncologists, surgeons, medical oncologists, diagnostic imaging specialists, and pulmonologists to assess if they are candidates for multimodality treatment. Select patients with medically operable disease are candidates for multimodality therapy,including those with clinical stages I to IIIA PM and epithelioid histology

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

and good performance status(PS).148-154 Surgical resection is recommended for certain patients with clinical stage I to IIIA PM who are medically operable and can tolerate the surgery. Patients who are candidates for surgery may have preoperative or postoperative chemotherapy followed by postoperative RT. Systemic therapy alone is recommended for patients with PS 0 to 2 and medically inoperable PM(see Systemic Therapy in this Discussion and Treatment in the algorithm).155,156 Definitive RT alone is not recommended in any setting for patients with PM.

Observation for progression may be considered for patients with PS 0 to 2 who are not eligible for surgery and are asymptomatic with minimal burden of disease if systemic therapy is planned when progression occurs (either radiologic or symptomatic progression). Best supportive care is recommended for patients with PS 3 to 4 (see Chemotherapy in this Discussion and Principles of Systemic Therapy and Principles of Supportive Care in the algorithm). Pleural effusion can be managed using thoracoscopic tal pleurodesis or placement of a drainage catheter.69,90-95,99,157-159 Therapeutic/palliative thoracentesis can also be used to remove pleural fluid and thus decrease dyspnea either before treatment or for patients who are not candidates for more aggressive treatment.30

Pretreatment Evaluation

For patients diagnosed with PM, pretreatment evaluation, using chest and abdominal CT with contrast, is recommended to stage patients and to assess whether patients are candidates for surgery. 83,84,160 For patients with a clinical diagnosis of stages I to IIIA PM with epithelioid histology who are being considered for surgery, additional testing may be done to rule out metastatic disease, including 1) FDG PET/CT; 2) mediastinoscopy or EBUS/EUS FNA of the mediastinal lymph nodes;161,162 3) optional chest MRI with contrast to evaluate possible chest wall, spinal, diaphragmatic, or

vascular involvement; and 4) video-assisted thoracoscopic surgery(VATS)or laparoscopy can be considered if contralateral or peritoneal disease is suspected to rule out transdiaphragmatic extension (eg, extension to the peritoneum is indicative of stage IV [unresectable] disease).163 PET/CT scans should be obtained before pleurodises if practical, because talc produces pleural inflammation, which can affect the fluorodeoxyglucose(FDG) avidity(ie,false-positive result).164-166 Patients with clinical stage I to IIIA epithelioid PM are evaluated to assess whether they can tolerate surgery using 1) pulmonary function tests (PFTs), including diffusing capacity for carbon dioxide (DLCO); 2) perfusion scanning (if forced expiratory volume in 1 second [FEV1] <80%); and 3) cardiac stress tests(see Surgical Evaluation in the algorithm).

Staging

Patients who are not candidates for surgery only have clinical staging. It is difficult to clinically stage patients using CT, MRI, or PET/CT; therefore,patients who have surgery may be upstaged. Understaging is common with PET/CT.166,167 However,PET/CT is useful for determining whether metastatic disease is present.167,168 Surgical staging is performed using the International Mesothelioma Interest Group(IMG) TNM staging system(see Staging in the algorithm), which was approved by the AJCC.169-172

Surgery

Surgery is recommended as a component of combined modality therapy for certain patients with stage I to IIIA PM who are medically operable. ${}^{173}$ The NCCN Panel recommends surgery for certain patients with clinical stage I to IIIA PM and epithelioid histology. ${}^{174}$ Surgery may be considered for certain patients with early-stage PM who have biphasic histology. ${}^{147,175}$ However, surgery is generally not an option for those with stage IIIB or IV PM regardless of histology. It is essential that patients receive a careful assessment before surgery is performed.

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

Surgical correction for patients with PM can include either 1)pleurectomy/decortication(P/D; also known as total pleuretnacy,lung-sparing surgery), which is complete removal of the involved pleura and all gross tumor with or without en-bloc resection of the pericardium and/or diaphragm; or 2) extrapleural pneumonectomy(EPP), which is en-bloc resection of the involved pleura, lung, ipsilateral diaphragm, and often the pericardium(see Principles of Surgery in the algorithm).176 Extended P/D refers to the resection of the diaphragm and pericardium in addition to total pleurectomy.176 Mediastinal nodal dissection is recommended in patients having either P/D or EPP; at least 3 nodal stations should be obtained(see the NCCN Guidelines for Non-Small Cell Lung Cancer, available at www.NCCN.org).The surgical goal for PM is cytoreductive surgery to achieve macroscopic complete resection by removing all visible or palpable tumors. 177,178 If macroscopic complete resection is not possible-such as patients with multiple sites of chest wall invasion-then surgery should be aborted. However, surgery should be continued-if most of the gross disease can be removed-to help with postoperative management and if there will be a minimal impact on morbidity.

The choice of surgery for PM is controversial, because data from randomized controlled trials are not available. 4,30,69,173,179-187 Neither EPP nor P/D will yield an R0 resection. 4,188,189 EPP would often be required to remove all gross tumor in patients with stages II to IIIA PM.81 However,EPP is associated with higher morbidity and mortality.183,190 P/D(ie,lung-preserving surgery) is safer than EPP.190-197 A retrospective analysis(n= 663) suggested that survival was greater after P/D than after EPP, but this analysis may have been confounded by patient selection.4,195 Another retrospective analysis compared EPP(n= 187) versus P/D(n= 95) in patients with PM.198 Median overall survival was 15 months for patients receiving EPP versus 22 months for P/D(P=.276). Perioperative mortality was 11% for those receiving EPP versus 0% for P/D(P=.031).

A large meta-analysis (n=2903) suggests that 30-day mortality is improved with P/D versus EPP; 2-year mortality was similar between the arms.15,183 Another meta-analysis (n=500) suggests that P/D is associated with decreased 30-day mortality and complications (especially supraventricular arrhythmia) when compared with EPP.180 Lung-sparing options, such as P/D, reduce the risk for perioperative mortality when compared with EPP and yield either equal or better long-term survival than non-surgical therapy in patients with more advanced disease.188,199

A feasibility trial (Mesothelioma and Radical Surgery [MARS]) assessed whether patients treated with induction chemotherapy would accept randomization to EPP or no surgery; 112 patients were enrolled in the trial,and 50 patients were randomized. ${ }^{200}$ The authors concluded that due to the observed high rate of surgical mortality, EPP was not beneficial when compared with chemotherapy treatment alone. However, these results were controversial because survival was not the primary outcome of the study, the sample size was small, and the surgical mortality was higher than expected. ${ }^{201}$ An Australian retrospective study (540 patients) reported that several factors yielded increased survival for select patients, including EPP, surgeon experience, and treatment with pemetrezed. ${ }^{202}$

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

symptom control(eg, patients with entrapped lung syndrome, recurrent pleural effusions).31 The NCCN Panel does not generally recommend surgery for patients with stage IIIB to IV PM regardless of histology;systemic therapy is recommended for these patients who have PS 0 to 2(see Systemic Therapy in this Discussion and Treatment in the algorithm).Prognosis with surgery(and other therapy) is substantially diminished in patients with N2 disease. Surgical resection should only be considered for patients with N2 disease at a center of expertise in PM or in a clinical trial.

Systemic Therapy

Chemotherapy is recommended as part of a multimodality regimen for patients with medically operable PM(see Treatment and Principles of Systemic Therapy in the algorithm). Patients with medically operable stage I to IIIA PM can receive chemotherapy either before or after surgery.Systemic therapy alone is recommended for patients with 1) stage IIIB or IV PM(PS 0-2) regardless of histology; 2) those with sarcomatoid or biphasic histology,regardless of clinical stage; or 3) medically inoperable stages I to IV PM, or those who refuse surgery.184,205-207 All of the regimens recommended for PM can also be used for peritoneal mesothelioma,pericardial mesothelioma, and tunica vaginalis testis mesothelioma.7.208-210

Medically Operable PM

Trimodality therapy-using chemotherapy, surgery, and hemithoracic RT-has been studied in patients with medically operable PM. ${}^{144-151}$

Median survival of up to 20 to 29 months has been reported for patients who complete trimodality therapy.147,150 Nodal status and response to chemotherapy can affect survival.${}^{150,152}$ In patients who do not receive induction chemotherapy before EPP, postoperative sequential chemotherapy with hemithoracic RT is recommended; hemithoracic pleural IMRT may be considered at centers that have expertise with this therapy for patients who have had P/D. Intraoperative adjuvant therapies-such as hyperthermic pleural lavage, photodynamic therapy, or

heated chemotherapy-have also been studied, however, they are of unclear benefit.211-220

A phase 2 trial assessed trimodality therapy in 77 eligible patients with resectable PM. ${ }^{150}$ Patients received preoperative chemotherapy with cisplatin/pemetrexed followed by EPP in 54 patients and then hemithoracic RT. In the overall population, median survival was 16.8 months (95% CI, 13.6-23.2). For patients who completed all of the trimodality therapy, median overall survival was 29.1 months with a 2-year survival of 61.2%.

Another phase 2 trial assessed trimodality therapy in eligible patients with resectable PM.147 Patients received preoperative chemotherapy with cisplatin/pemetrexed, carboplatin/pemetrexed, or cisplatin/gemcitabine followed by EPP and intensity-modulated RT(IMRT) in 62 patients.The median overall survival was 20.4 months. The 1-year overall survival rate was 63%; the 2-year overall survival rate was 42%. Patients with biphasic histology had a worse outcome compared with those who had epithelioid histology.

A phase 2 trial assessed trimodality therapy in 61 eligible patients with resectable PM.151 Patients received neoadjuvant therapy with cisplatin/gemcitabine; 45 patients had EPP and 36 patients had postoperative RT. In the overall population, median survival was 19.8 months(95% CI, 14.6-24.5). For patients who EPP, median overall survival was 23 months(95% CI, 16.6-32.9).

A retrospective analysis assessed EPP versus P/D in 663 patients with resectable PM who received trimodality therapy. ${}^{195}$ Patients ( ${}^{28\%}$)received chemotherapy; 14% of patients received chemotherapy and RT.Approximately 60% of patients received EPP. At 5 years, overall survival was 12%. The analysis suggested that survival was greater after P/D than

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after EPP, but this analysis may have been confounded by patient selection.

The NCCN Panel recommends preoperative(induction) chemotherapy with pemetrexed plus(cisplatin or carboplatin) for eligible patients with resectable PM based on clinical trial results.147,150,151 The panel also recommends postoperative chemotherapy if patients have not received induction chemotherapy.

Medically Inoperable PM

First-Line Therapy

Human immune checkpoint inhibitor antibodies, such as nivolumab,inhibit the programmed death-1(PD-1) receptor, which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T cells.221 Ipilimumab is a monoclonal antibody that inhibits cytotoxic T-lymphocyte-associated protein 4(CTLA-4), which is another immune checkpoint; inhibition of CTLA-4 improves T-cell activity, thus increasing the anti-tumor immune response. CheckMate 743, a phase 3 randomized trial, assessed first-line therapy with nivolumab plus ipilimumab versus platinum/pemetrexed chemotherapy in 605 patients with unresectable PM.222 Many patients had epithelid histology(75%). Most of the patients were males(77%), and the median age was 69 years. The median overall survival in the entire population was 18.1 months(95% CI, 16.8-21.4) in patients receiving nivolumab plus ipilimumab versus 14.1 months(95% CI,12.4-16.2) in those receiving chemotherapy(HR,0.74;96.6% CI,0.60-0.91). The 2-year overall survival rate was 41%(95% CI, 35.1%-46.5%) in the nivolumab plus ipilimumab group versus 27%(95% CI, 21.9%-32.4%)in the chemotherapy group in the entire population. Although the trial was not powered to assess superiority within the subgroups, the data are interesting. In patients with epithelioid histology, the median overall survival was 18.7 months(95% CI, 16.9-22.0) in patients receiving nivolumab plus ipilimumab versus 16.5 months(95% CI, 14.9-20.5) in

those receiving chemotherapy(HR,0.86;95% CI,0.69-1.08).In patients with nonepithelioid histology, the median overall survival was 18.1 months(95% CI, 12.2-22.8) in patients receiving nivolumab plus ipilimumab versus 8.8 months(95% CI, 7.4-10.2) in those receiving chemotherapy(HR,0.46;95% CI,0.31-0.68). Grade 3 to 4 treatment-related adverse events were similar in both groups:30%(91/300) of patients receiving nivolumab plus ipilimumab and 32%(91/284) of those receiving chemotherapy. Three treatment-related deaths(1%) occurred in the nivolumab plus ipilimumab group, which were due to pneumonitis,encephalitis, and heart failure; one death(<1%) occurred in the chemotherapy group, which was due to myelosuppression.

The NCCN Panel recommends(category 1) nivolumab plus ipilimumab for eligible patients with unresectable PM based on clinical trial data and the FDA approval(see Principles of Systemic Therapy in the algorithm).222 Testing for PD-L1 is not required for prescribing nivolumab for therapy for patients with PM. Immune-related adverse events, such as pneumonitis, may occur with nivolumab plus ipilimumab(see the NCCN Guidelines for Management of Immunotherapy-Related Toxicities,available at www.NCCN.org).223-225 Intravenous high-dose corticosteroids should be administered based on the severity of the reaction for patients with immune-mediated adverse events. Nivolumab plus ipilimumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated(see prescribing information). Ipilimumab can also cause immune-mediated adverse events such as hepatitis and endocrinopathies.

A phase 3 randomized trial assessed cisplatin/pemetrexed versus cisplatin alone in patients with PM who were not candidates for surgery; the combined regimen increased survival by 2.8 months when compared with cisplatin alone(12.1 vs. 9.3 months, P=.02). ${}^{226}$ The

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pemetreated/carboplatin regimen was assessed in three large phase 2 studies (median survival = 12.7，14， and 14 months, respectively).227-229 A comparison of 1704 patients with medically inoperable PM treated with cisplatin/pemetrexed or carboplatin/pemetrexed as part of an expanded access trial found that outcomes with the regimens were similar.230 The NCCN Panel recommends cisplatin/pemetrexed (category 1) for patients with PM based on clinical trial data and the FDA approval.222,226,231-234 The panel also recommends pemetrexed/carboplatin (category 2A) based on clinical trial data.222,227-229 Carboplatin regimens are recommended for patients who are not eligible for cisplatin.230

A multicenter phase 3 randomized trial(IFCT-GFPC-0701 MAPS)compared adding bevacizumab to cisplatin/pemetrexed with (with maintenance bevacizumab) versus cisplatin/pemetrexed alone for patients with unresectable PM and PS 0 to 2 who did not have bleeding or thrombosis. ${ }^{234}$ Overall survival was increased in the bevacizumab plus chemotherapy arm by 2.7 months when compared with chemotherapy alone (18.8 vs. 16.1 months; HR, 0.77; P=.0167). Grade 3 to 4 adverse events were reported in 71% (158/222) of patients receiving the bevacizumab regimen when compared with 62% (139/224) of those receiving cisplatin/pemetrexed alone. More grade 3 or higher hypertension (23% vs. 0%), grade 3 proteinuria (3.1% vs. 0%), and grade 3 to 4 thrombotic events (6% vs. 1%) were observed in patients receiving the triplet arm. The NCCN Panel recommends (category 1) bevacizumab,cisplatin, and pemetrexed followed by maintenance bevacizumab for bevacizumab-eligible patients with unresectable PM regardless of histology based on this trial (see Principles of Systemic Therapy in the algorithm).${}^{234}$ Contraindications to bevacizumab include uncontrolled hypertension, risk for bleeding or clotting, and substantial cardiovascular morbidity. ${}^{69}$ An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

A phase 2 trial assessed adding bevacizumab to carboplatin/pemetrexed with or without maintenance bevacizumab as first-line therapy for patients with unresectable PM.235 Overall survival was 15.3 months; 34%(26/76) of patients had a partial response and 58%(44/76) had stable disease.Bowel perforation occurred in 4% of patients, and grade 3 to 4 fatigue occurred in 8%; there were 3 toxic deaths. Maintenance bevacizumab(maximum,1 year) was administered to patients without progression and/or severe toxicities. The NCCN Panel recommends(category 2A)adding bevacizumab to carboplatin/pemetrexed with or without maintenance bevacizumab as a first-line therapy option for patients with unresectable PM based on this trial.235 Gemcitabine/cisplatin was assessed in phase 2 studies(median survival, 9.6-14.1 months).236-238 Gemcitabine/cisplatin may be useful for patients who cannot take pemetrexed. The NCCN Panel recommends gemcitabine/cisplatin for eligible patients with unresectable PM based on clinical trial data. 236-238 Other first-line options recommended by NCCN include pemetrexed or vinorelbine for patients who are not candidates for platinum-based combination therapy.239-241

The NCCN Panel recommends systemic therapy alone for patients with PM and PS 0 to 2, including 1) those who are medically inoperable or refuse surgery; 2) those with clinical stage IIIB to IV PM, regardless of histology; or 3) those with sarcomatoid or biphasic histology, regardless of clinical stage. The NCCN Panel has preference stratified the systemic therapy regimens and voted that the following regimens are preferred first-line therapy options for certain patients with unresectable PM: 1)pemetrexed plus(cisplatin or carboplatin) with or without bevacizumab; or 2) nivolumab plus ipilimumab.222,226,228-230 For the 2022 update(Version 1),the panel decided that the pemetrexed/platinum with or without bevacizumab regimens were preferred options.222,226-234 The panel voted that nivolumab plus ipilimumab is a preferred option for patients with biphasic or sarcomatoid histology and is also an option for patients with

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epithelioid histology. The panel voted that the following regimens are useful in certain circumstances: 1) gemcitabine/cisplatin; 2) pemetrexed;or 3) vinorelbine.237,238,240,241

Subsequent Systemic Therapy

Limited data are available to guide second-line and beyond (subsequent)chemotherapy in patients with PM.220,242-245 Data suggest that nivolumab with (or without) ipilimumab may be useful as subsequent systemic therapy for patients with PM who have not received prior immunotherapy.24-2657 Response rates have been low with subsequent chemotherapy(7%-20%), although they are slightly higher with the new immunotherapy regimens.24-249,258,259

Trial Data

CONFIRM, a phase 3 randomized trial, assessed nivolumab(67%) versus placebo(33%) in 332 patients with PM who had progressed after platinum-based chemotherapy.246 Most patients had pleural mesothelioma(95%) and epithelioid histology(88%). Many patients had received third-line therapy (56%). Median overall survival was 10.2 months (95%CI, 8.5-12.1) in patients receiving nivolumab versus 6.9 months (95% CI,5.0-8.0) in those receiving placebo(HR, 0.69; 95% CI, 0.52-0.91). Grade 3 or worse adverse events were reported in 3% of patients receiving nivolumab(diarrhea and infusion-related reaction, 6/221). Serious adverse events were similar between the groups(41% for nivolumab vs. 44% for placebo).

A phase 2 randomized trial(IFCT-1501 MAPS2; n= 125) assessed nivolumab with(or without) ipilimumab as subsequent therapy for patients with PM.247,252,253 Updated results from this trial indicate that median overall survival was 15.9 months (95% CI, 10.7-not reached) in the nivolumab/ipilimumab arm and 11.9 months (95% CI, 6.7-17.7) with nivolumab alone.247,253 The 12-month overall survival rates were 58% with the nivolumab/ipilimumab arm and 49% with nivolumab alone. The overall

response rate was 28%(95% CI, 16%-40%) with nivolumab/ipiliumab versus 19%(95% CI, 8%-29%) with nivolumab alone. The disease control rate at 12 weeks was 52%(32/62) for nivolumab/ipiliumab versus 40%(25/63) for nivolumab alone.247 Positive PD-L1 levels were associated with overall response rate, especially high PD-L1 levels of 25% or more.However, only a few patients had very high PD-L1 expression levels of 50% or more. There were more grade 3 to 4 adverse events in the nivolumab/ipiliumab arm when compared with the nivolumab alone arm(26% vs. 14%) based on updated data; 3 treatment-related deaths were reported in the nivolumab/ipiliumab arm(one each: metabolic encephalopathy, fulminant hepatitis, and acute renal failure).247 A phase 2 Dutch trial (INITIATE) assessed nivolumab/ipiliumab as subsequent therapy in patients with PM.248 Results showed a disease control rate of 68% at 12 weeks (23/34; 95% CI, 50%-83%); 29% (10/34) had a partial response and 38% (13/34) of patients had stable disease.248 Grade 3 treatment-related adverse events were reported in 34% (12/35) of patients; 94% (33/34) of patients had treatment-related adverse events.

PROMISE-meso, a multicenter phase 3 randomized trial, assessed subsequent therapy with pembrolizumab versus either gemcitabine or vinorebine in 144 patients with relapsed PM after progression on platinum-based chemotherapy.260 There was no difference in overall survival between the groups(HR,1.12;95% CI,0.74-1.69;P=.59).

A phase 3 randomized trial assessed subsequent therapy with pemetrexed plus best supportive care versus best supportive care alone in 243 patients with PM who had progressed on systemic therapy.261 Median overall survival was not statistically significant between the arms(8.4 months for pemetrexed vs. 9.7 months for supportive care only; P=.74)probably because patients could cross over to pemetrexed. Data suggest that rechallenging with pemetrexed-based regimens is effective if patients had a good response to first-line pemetrexed.242,259 A retrospective

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multicenter survey reported that rechallenging with a pemetrezed/platinum regimen reduced the risk of death when compared with challenging with pemetrezed alone(HR,0.11;P<.001).259

NCCN Recommendations

Based on these trials, the NCCN Panel recommends the following subsequent therapy options for patients with PM if not administered first line:1) pemetrexed(category 1); or 2)novolumab with(or without)ipilimumab(category 2A).69,250-253,261 The panel decided that if immunotherapy was administered as first-line treatment, then combination pemetrexed/platinum regimens are subsequent therapy options(eg,pemetrexed plus either cisplatin or carboplatin). The NCCN Panel also recommends other subsequent chemotherapy options based on clinical trial data, including 1) rechallenging with pemetrexed-based regimens if patients had a good sustained response to first-line therapy; 2)vinorelbine; or 3) gemcitabine.240,242,259-266 For the 2022 update(Version 1),the NCCN Panel deleted pembrolizumab as a subsequent therapy option for patient with relapsed PM based on updated clinical trial data.260 As previously mentioned, immune-related adverse events, such as pneumonitis, may occur with nivolumab with(or without) ipilimumab(see the NCCN Guidelines for Management of Immunotherapy-Related Toxicities, available at www.NCCN.org).223-225

The NCCN Panel has preference stratified the systemic therapy regimens and voted that the following regimens are preferred subsequent therapy options for certain patients with PM who have progressed on systemic therapy, including 1) pemetrezed if not given first line(category 1); 2)rechallenging with pemetrezed-based regimens if good response with first-line therapy; or 3) nivolumab with(or without) ipilimumab. ${}^{69,250-253,259,261}$ The panel voted that the following regimens are other recommended options: 1) vinorelbine; or 2) gemcitabine. ${}^{260}$

Radiation Therapy

It is very challenging to accurately and safely deliver RT to the entire pleural surface without damaging radiosensitive sites, such as the lung and heart, especially when the lungs are intact. ${}^{267}$ The Principles of Radiation Therapy for PM are described in the algorithm and are summarized in this Discussion. The NCCN Guidelines for Non-Small Cell Lung Cancer are also a useful resource (see Principles of Radiation Therapy). In patients with PM, RT can be used as part of a multimodality regimen; however, RT alone is not recommended for treatment. RT can also be used as palliative therapy for relief of chest pain, bronchial or esophageal obstruction, or other symptomatic sites associated with PM,such as metastases in bone or in the brain (see the algorithm and NCCN Guidelines for Central Nervous System Cancers, available at www.NCCN.org).30,155,268 The dose of radiation should be based on the purpose of treatment.269 The most appropriate timing of delivering RT (ie,after surgical intervention, with [or without] chemotherapy) should be discussed with a multidisciplinary team. After EPP, adjuvant hemithoracic RT may reduce the local recurrence rate.270-273 Patients are candidates for RT if they have good PS, pulmonary function, and kidney function (see Principles of Radiation Therapy in the algorithm). In patients with limited or no resection of disease (ie, in the setting of an intact lung), high-dose conventional RT to the entire hemithorax has not been shown to improve survival and is associated with significant toxicity. 155,274

A phase 3 randomized trial assessed postoperative radical hemithoracic IMRT versus palliative RT given after lung-sparing surgery and chemotherapy in 108 patients with PM.275 The 2-year overall survival rate was 58% in the IMRT arm versus 28% in the palliative RT arm(HR, 0.54;95% CI, 0.31-0.95; P=.031). In the IMRT arm, 11 patients had grade 3 or greater acute toxicity; 17 patients had grade 3 to 4 late toxicity. One patient died. A phase 2 trial(IMPRINT)(n= 27) evaluated the safety of hemithoracic IMRT in patients with PM, given after induction

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chemotherapy and surgery.276 Radiation pneumonitis, which was reversible with corticosteroids, was reported in 30%(95% CI, 14%-50%)of patients(grade 2 in 6 patients, grade 3 in 2 patients). Most patients had stage III or IV PM; most evaluable patients had a partial P/D. In patients with resectable tumors, 2-year overall survival was 59%. Mediastinal nodal failure occurred in 22%(6/27) of patients; distant progression occurred in 48%(13/27) of patients. Another trial assessed postoperative hemithoracic IMRT given after lung-sparing surgery and cisplatin/pemetrexed in 69 patients with PM.277 Patients received either extended P/D(35) or partial pleurectomy(34); the 2-year overall survival was 65% and 64%,respectively. Grade 2 to 3 pneumonitis occurred in 20% of patients; one patient died from pneumonitis. Based on these trials, the NCCN Panel recommends that hemithoracic pleural IMRT can be considered following induction chemotherapy and P/D in certain patients with PM if done in centers with expertise in this technique.275-277

It has been controversial whether immediate(prophylactic) RT is useful for preventing instrument-tract recurrence and pleural intervention. 278-283 An older French trial reported that prophylactic RT was useful for preventing recurrence, but 2 other trials did not find any benefit. 278,282,283 A phase 3 randomized trial(SMART trial) compared prophylactic radiotherapy with deferred radiotherapy to assess the rate of recurrences in patients who had had procedures for PM.284 Patients in the deferred RT arm did not receive RT until procedure-tract metastases were evident. Data showed no difference in procedure-tract recurrence in the prophylactic RT arm(9%[9/102]) versus the deferred RT arm(16%[16/101])(odds ratio[OR], 0.51;95% CI,0.19-1.32). In addition, prophylactic RT did not improve the quality of life, decrease chest pain, or decrease the need for analgesic drugs. However, if patients did not receive chemotherapy, prophylactic RT did decrease the risk for procedure-tract metastases(OR, 0.16; 95% CI,0.02-0.93; P=.021). The NCCN Panel does not routinely recommend prophylactic RT to prevent instrument-tract recurrence after pleural

intervention based on the SMART trial(see Principles of Radiation Therapy in the algorithm).148,189,273,274,284-287 Several prophylactic RT dose regimens are cited in the literature.278,282-284

CT simulation-guided planning using either IMRT or conventional photon/electron RT is acceptable.147,270,272,288 For treatment planning, PET scans can be used as indicated. The clinical target volumes should be reviewed with the thoracic surgeon to ensure coverage of all the volumes at risk. The total doses of radiation are described in the algorithm(see Principles of Radiation Therapy). The postoperative RT doses after EPP are 45 to 60 Gy in 1.8 to 2 Gy, with a higher dose to higher risk areas. A dose of 60 Gy or more is recommended for macroscopic residual tumors,if the doses to normal adjacent structures are limited to their tolerances(see the NCCN Guidelines for Non-Small Cell Lung Cancer, available at www.NCCN.org).154 The volume of postoperative radiation should cover the surgical bed within the thorax.148,189,273,274,286,287 The optimal dose of RT for palliative purposes remains unclear.269,289 For patients with chest pain from PM, total doses of 20 to 40 Gy appear to be effective in providing relief from pain.30,278,279

Hemithoracic pleural IMRT allows for a more conformal high-dose RT and improved coverage to the hemithorax at risk.154,155,270,271,275,276,290-293 Advanced technologies, such as image-guided RT(IGRT), may be used for treatments involving IMRT or helical tomotherapy(HT), stereotactic radiosurgery (SRS), or stereotactic body radiation therapy (SBRT).267,294 Intensity-modulated proton therapy(IMPT) may also be used.295 RT to the contralateral uninvolved lung should be minimized,155,271,296 because fatal pneumonitis may occur with IMRT if strict limits are not applied.297-299 The contralateral uninvolved mean lung dose should be kept as low as possible, preferably less than 8.5 Gy.300 The volume of contralateral lung receiving low-dose RT(eg, 5 Gy) should be minimized.301,302 Hemithoracic IMRT immediately followed by EPP was assessed in 25 patients with

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stage III or IV PM on final pathologic review; for patients with epithelial subtypes of PM,3-year survival reached 84%.292 However,13 patients had grade 3+ surgical complications and one patient died from treatment.The NCCN Panel does not recommend hemithoracic pleural IMRT after EPP.

Summary

These NCCN Guidelines focus on PM, which is the most common type of mesothelioma(approximately 85%). Mesothelioma can also occur in the lining of other sites, such as the peritoneum(approximately 15%),pericardium, and tunica vaginalis testis.6-9 The Summary of the Guidelines Updates section in the algorithm briefly describes the new changes for 2022. This Discussion text for PM describes the recommendations in the algorithm in greater detail, for example, by including the clinical trial data and other references that support the NCCN Panel's recommendations in the algorithm. The Version 2 update reflects the addition of the updated Discussion. The NCCN Pleural Mesothelioma Panel has also developed a guideline for peritoneal mesothelioma(see the NCCN Guidelines for Mesothelioma: Peritoneal, available at www.NCCN.org).

For the 2022 update (Version 1), the NCCN Pleural Mesothelioma Panel decided that the pemetrexed/platinum with or without bevacizumab regimens were preferred first-line therapy options.222,226-234 The NCCN Panel deleted pembrolizumab as a subsequent therapy option for patients with relapsed PM based on updated clinical trial data.260 The panel also clarified that if immunotherapy is administered as first-line therapy then pemetrexed combination regimens are options for subsequent therapy(eg, pemetrexed plus either cisplatin or carboplatin). The panel added a new section on pathology for the 2022 update(see Principles of Pathologic Review in the algorithm).

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References

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2. Special Section - Rare Cancers in Adults. American Cancer Society.Cancer Facts& Figures 2017. Available at:https://tinyurl.com/yb4joe3c.

3.Price B, Ware A. Time trend of mesothelioma incidence in the United States and projection of future cases: an update based on SEER data for 1973 through 2005. Crit Rev Toxicol 2009;39:576-588. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19650718.

4. Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant pleural mesothelioma. J Clin Oncol 2009;27:2081-2090. Available at:http://www.ncbi.nlm.nih.gov/pubmed/19255316.

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6. Grogg J, Fronzaroli JN, Oliveira P, et al. Clinicopathological characteristics and outcomes in men with mesothelioma of the tunica vaginalis testis: analysis of published case-series data. J Cancer Res Clin Oncol 2021;147:2671-2679. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33559739.

7. Carteni G, Manegold C, Garcia GM, et al. Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer 2009;64:211-218. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19042053.

8. Mirarabshahii P, Pillai K, Chua TC, et al. Diffuse malignant peritoneal mesothelioma--an update on treatment. Cancer Treat Rev

2012;38:605-612. Available at:

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9. Chekol SS, Sun CC. Malignant mesothelioma of the tunica vaginalis testis: diagnostic studies and differential diagnosis. Arch Pathol Lab Med 2012;136:113-117. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22208496.

10.Mazurek JM,Syamlal G,Wood JM,et al.Malignant Mesothelioma Mortality- United States, 1999-2015. MMWR Morb Mortal Wkly Rep 2017;66:214-218. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28253224.

11.Meyerhoff RR, Yang CF, Speicher PJ, et al. Impact of mesothelioma histologic subtype on outcomes in the Surveillance, Epidemiology, and End Results database. J Surg Res 2015;196:23-32. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25791825.

12. Musk AW,Olsen Al,Fonso H,et al.Predicting survival in malignant mesothelioma. Eur Respir J 2011;38:1420-1424. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21737558.

13. Linton A,Pavlakis N,O'Connell R,et al.Factors associated with survival in a large series of patients with malignant pleural mesothelioma in New South Wales. Br J Cancer 2014;111:1860-1869. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25188323.

14. Mazurek JM, Blackley DJ, Weissman DN. Malignant Mesothelioma Mortality in Women- United States, 1999-2020. MMWR Morb Mortal Wkly Rep 2022;71:645-649. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35552365.

15. Taioli E, Wolf AS, Camacho-Rivera M, et al. Determinants of Survival in Malignant Pleural Mesothelioma: A Surveillance, Epidemiology, and End Results(SEER) Study of 14,228 Patients. PLoS One 2015;10:e0145039. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26660351.

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16. Lanpear BP, Buncher CR. Latent period for malignant mesothelioma of occupational origin.J Occup Med 1992;34:718-721. Available at:https://www.ncbi.nlm.nih.gov/pubmed/1494965.

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18.Alpert N, van Gerwen M, Taioli E. Epidemiology of mesothelioma in the 21(st) century in Europe and the United States, 40 years after restricted/banned asbestos use. Transl Lung Cancer Res 2020;9:S28-S38. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32206568.

19. Delgermaa V, Takahashi K, Park EK, et al. Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ 2011;89:716-724, 724A-724C. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22084509.

20. ParkEK,Takahashi K,Hoshuyama T,et al.Global magnitude of reported and unreported mesothelioma. Environ Health Perspect 2011;119:514-518. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21463977.

21. Centers for Disease C, Prevention. Malignant mesothelioma mortality--United States, 1999-2005. MMW Morb Mortal Wkly Rep 2009;58:393-396. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19390506.

22. Keshava HB, Tang A, Siddiqui HU, et al. Largely unchanged annual incidence and overall survival of pleural mesothelioma in the USA. World J Surg 2019;43:3239-3247. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31428834.

23. Bang KM, Mazurek JM, Wood JM, Hendricks SA. Diseases attributable to asbestos exposure: years of potential life lost, United States, 1999-2010. Am J Ind Med 2014;57:38-48. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24108494.

24. Abdel-Rahman O. Global trends in mortality from malignant mesothelioma: Analysis of WHO mortality database(1994-2013). Clin Respir J 2018;12:2090-2100. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29424961.

25. Nishikawa K, Takahashi K, Karjalainen A, et al. Recent mortality from pleural mesothelioma, historical patterns of asbestos use, and adoption of bans: a global assessment. Environ Health Perspect 2008;116:1675-1680.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19079719.

26. Larson T, Melnikova N, Davis SI, Jamison P. Incidence and descriptive epidemiology of mesothelioma in the United States, 1999-2002. Int J Occup Environ Health 2007;13:398-403. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18085053.

27.Price B, Ware A. Mesothelioma trends in the United States: an update based on Surveillance, Epidemiology, and End Results Program data for 1973 through 2003. Am J Epidemiol 2004;159:107-112. Available at:https://www.ncbi.nlm.nih.gov/pubmed/14718210.

28.Peto J, Decarli A, La Vecchia C, et al. The European mesothelioma epidemic. Br J Cancer 1999;79:666-672. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10027347.

29. Leigh J, Davidson P, Hendrie L, Berry D, Malignant mesothelioma in Australia, 1945-2000. Am J Ind Med 2002;41:188-201. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11920963.

30. van Zandwijk N, Clarke C, Henderson D, et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. J Thorac Dis 2013;5:E254-307. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24416529.

31. Scherpereel A, Astoul P, Baas P, et al. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J 2010;35:479-495. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19717482.

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NCCN Guidelines Version 1.2026 Mesothelioma: Pleural

32. Chang ET, Lau Gev, Moratse F, Tseta MJ. Therapeutic radiation for lymphoma and risk of second primary malignant mesothelioma. Cancer Causes Control 2017;28:971-979. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28755241.

33. Li X, Brownlee NA, Sporn TA, et al. Malignant(Diffuse) Mesothelioma in Patients With Hematologic Malignancies: A Clinicopathologic Study of 45 Cases.Arch Pathol Lab Med 2015;139:1129-1136. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25844559.

34.Goodman JE, Nascarella MA, Valberg PA. Ionizing radiation: a risk factor for mesothelioma. Cancer Causes Control 2009;20:1237-1254.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19444627.

35. Chirieac LR, Barletta JA, Yeap BY, et al. Clinicopathologic characteristics of malignant mesotheliomas arising in patients with a history of radiation for Hodgkin and non-Hodgkin lymphoma. J Clin Oncol 2013;31:4544-4549. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24248693.

36. Hodgson DC, Gilbert ES, Dores GM, et al. Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma. J Clin Oncol 2007;25:1489-1497. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17372278.

37. Deutsch M, Land SR, Begovic M, et al. An association between postoperative radiotherapy for primary breast cancer in 11 National Surgical Adjuvant Breast and Bowel Project(NSABP) studies and the subsequent appearance of pleural mesothelioma. Am J Clin Oncol 2007;30:294-296. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17551308.

38.Travis LB,Fossa SD,Schonfeld SJ,et al.Second cancers among 40,576 testicular cancer patients: focus on long-term survivors.J Natl Cancer Inst 2005;97:1354-1365. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16174857.

39.Teta MJ, Lau E, Sceurman BK, Wagner ME. Therapeutic radiation for lymphoma: risk of malignant mesothelioma. Cancer 2007;109:1432-1438.Available at:https://www.ncbi.nlm.nih.gov/pubmed/17315168.

40.De Bruin ML,Burgers JA, Baas P, et al. Malignant mesothelioma after radiation treatment for Hodgkin lymphoma. Blood 2009;113:3679-3681.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19234144.

41.Cavazza A,Travis LB,Travis WD,et al.Post-irradiation malignant mesothelioma.Cancer 1996;77:1379-1385.Available at:https://www.ncbi.nlm.nih.gov/pubmed/8608519.

42. Witherby SM, Butnor KJ, Grunberg SM. Malignant mesothelioma following thoracic radiotherapy for lung cancer. Lung Cancer 2007;57:410-413. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17475364.

43. Xu R, Barg FK, Emmett EA, et al. Association between mesothelioma and non-occupational asbestos exposure: systematic review and meta-analysis. Environ Health 2018;17:90. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30567579.

44.Marshi GM,Riordan AS,Keeton KA,Benson SM. Non-occupational exposure to asbestos and risk of pleural mesothelioma: review and meta-analysis. Occup Environ Med 2017;74:838-846. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28935666.

45.Carbone M, Kanodia S, Chao A, et al. Consensus Report of the 2015 Weinman International Conference on Mesothelioma. J Thorac Oncol 2016;11:1246-1262. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27453164.

46. Baumann F, Buck BJ, Metcalf RV, et al. The Presence of Asbestos in the Natural Environment is Likely Related to Mesothelioma in Young Individuals and Women from Southern Nevada. J Thorac Oncol 2015;10:731-737. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25668121.

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47. Van Gosen BS, Blitz TA, Plumlee GS, et al. Geologic occurrences of erionite in the United States: an emerging national public health concern for respiratory disease. Environ Geochem Health 2013;35:419-430.Available at:https://www.ncbi.nlm.nih.gov/pubmed/23315055.

48. Carbone M,Baris YI,Bertino P,et al.Orinite exposure in North Dakota and Turkish villages with mesothelioma. Proc Natl Acad Sci U S A 2011;108:13618-13623. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21788493.

49. Carbone M, Pass HI, Ak G, et al. Medical and surgical care of patients with mesothelioma and their relatives carrying germline BAP1 mutations.J Thorac Oncol 2022;17:873-889. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35462085.

50. Schulco M, La Vecchia M, Aspesi A, et al. Diagnostics of BAP1-tumor predisposition syndrome by a multitesting approach: A ten-year-long experience. Diagnostics(Basel) 2022;12. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35885614.

51. Pilarski R, Carlo MI, Cebulla, Abdel-Rahman M. BAP1 tumor predisposition syndrome. 2016 Oct 13[updated 2022 Mar 24]. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews((R)). Seattle(WA): University of Washington, Seattle

52. Walpole S, Pritchard AL, Cebulla CM, et al. Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. J Natl Cancer Inst 2018;110:1328-1341. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30517737.

53. Pastorino S, Yoshikawa Y, Pass HI, et al. A subset of mesotheliomas with improved survival occurring in carriers of BAP1 and other germline mutations. J Clin Oncol 2018:JCO2018790352. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30376426.

54. Betti M, Casalone E, Ferrante A, Del et al. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett 2017;405:38-45. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28687356.

55. Ohar JA, Cheung M, Talarchek J, et al. Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer. Cancer Res 2016;76:206-215. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26719535.

56.Baumann F,Flores E,Napolitano A,et al.Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival.Carcinogenesis 2015;36:76-81.Available at:https://www.ncbi.nlm.nih.gov/pubmed/25380601.

57.Carbone M, Ferris LK, Baumann F, et al. BAP1 cancer syndrome:malmant mesothelioma, uveal and cutaneous melanoma, and MBAITs.J Transl Med 2012;10:179. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22935333.

58.Testa JR,Cheung M,Pei J,et al.Germine BAP1 mutations predispose to malignant mesothelioma. Nat Genet 2011;43:1022-1025.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21874000.

59. Quetel L, Meiller C, Assie JB, et al. Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival. Mol Oncol 2020;14:1207-1223. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32083805.

60.Hmeljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov 2018;8:1548-1565.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30322867.

61. Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations,gene fusions and splicing alterations. Nat Genet 2016;48:407-416.Available at: https://www.ncbi.nlm.nih.gov/pubmed/26928227.

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62. Guo G, Chmielecki J, Goparaju 0, Cetar al. Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer Res 2015;75:264-269. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25488749.

63. Sauter JL, Dacic S, Galateau-Salle F, et al. The 2021 WHO classification of tumors of the pleura: Advances since the 2015 classification. J Thorac Oncol 2022;17:608-622. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35026477.

64. Mossman BT, Lippmann M, Hesterberg TW,et al. Pulmonary endpoints(lung carcinomas and asbestos) following inhalation exposure to asbestos. J Toxicol Environ Health B Crit Rev 2011;14:76-121.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21534086.

65.Kato K, Gemba K, Ashizawa K, et al. Low-dose chest computed tomography screening of subjects exposed to asbestos. Eur J Radiol 2018;101:124-128. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29571785.

66. Sorensen LT. Wound healing and infection in surgery: the pathophysiological impact of smoking, smoking cessation, and nicotine replacement therapy: a systematic review, Ann Surg 2012;255:1069-1079.Available at:https://www.ncbi.nlm.nih.gov/pubmed/22566015.

67.Allen RK,Cramond T,Lennon D, Waterhouse M. A retrospective study of chest pain in benign asbestos pleural disease. Pain Med 2011;12:1303-1308. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21834915.

68. Ameille J, Brochard P, Letourneux M, et al. Asbestos-related cancer risk in patients with asbestos or pleural plaques. Rev Mal Respir 2011;28:e11-17. Available at:

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69. Kindler HL, Ismaila N, Armato SG, 3rd, et al. Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1343-1373. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29346042.

70.Felten MK,Khatab K, Knoll L,et al. Changes of mesothelin and osteopontin levels over time in formerly asbestos-exposed power industry workers.Int Arch Occup Environ Health 2014;87:195-204. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23423281.

71.Casjens S, Weber DG, Johnen G,et al. Assessment of potential predictors of calretinin and mesothelin to improve the diagnostic performance to detect malignant mesothelioma: results from a population-based cohort study. BMJ Open 2017;7:e017104. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29025836.

72.Johnen G,Gawrych K,Raiko I,et al.Calretinin as a blood-based biomarker for mesothelioma. BMC Cancer 2017;17:386. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28558669.

73. van Meerbee JP, Hillerd Gal. Screening for mesothelioma: more harm than good? Am J Respir Crit Care Med 2008;178:781-782. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18832552.

74. Roberts HC, Patsios DA, Paul NS, et al. Screening for malignant pleural mesothelioma and lung cancer in individuals with a history of asbestos exposure. J Thorac Oncol 2009;4:620-628. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19357540.

75. Pass HI, Carbone M. Current status of screening for malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg 2009;21:97-104. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19822280.

76. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med 2020;382:503-513. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31995683.

77. National Lung Screening Trial Research T. Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial.J Thorac Oncol 2019;14:1732-1742. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31260833.

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78. Baas P, Fennell D, Kerr KM, et al. Malignant pleural mesothelioma:ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol 2015;26 Suppl 5:v31-39. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26223247.

79. National Lung Screening Trial Research T, Aberle DR, Adams AM,et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21714641.

80.Dyer DS,Mohammed TL, Kirsch J, et al. ACR appropriateness Criteria(R) chronic dyspnea: suspected pulmonary origin. J Thorac Imaging 2013;28:W64-66. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23846109.

81.Gadgeel S, Pass H. Malignant mesothelioma. Commun Oncol 2006;3:215-224. Available at:

82. Rossi G, Davoli F, Poletti V, et al. When the diagnosis of mesothelioma challenges textbooks and guidelines. J Clin Med 2021;10.Available at:https://www.ncbi.nlm.nih.gov/pubmed/34070888.

83. Expert Panel on Thoracic I, Bacchus L, Shah RD, et al. ACR Appropriateness Criteria Review ACR Appropriateness Criteria(R)Occupational Lung Diseases. J Thorac Imaging 2016;31:W1-3. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26656194.

84. Armato SG, 3rd, Coolen J, Nowak AK, et al. Imaging in pleural mesothelioma: A review of the 12th International Conference of the International Mesothelioma Interest Group. Lung Cancer 2015;90:148-154. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26298162.

85. Armato SG, 3rd, Labby ZE, Coolen J, et al. Imaging in pleural mesothelioma: a review of the 11th International Conference of the International Mesothelioma Interest Group. Lung Cancer 2013;82:190-196. Available at:

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86.Kao SC,Yan TD,Lee K,et al.Accuracy of diagnostic biopsy for the histological subtype of malignant pleural mesothelioma. J Thorac Oncol 2011;6:602-605. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21266919.

87.Greillier L, Cavailles A, Fraticelli A, et al. Accuracy of pleural biopsy using thoracoscopy for the diagnosis of histologic subtype in patients with malignant pleural mesothelioma. Cancer 2007;110:2248-2252. Available at:https://www.ncbi.nlm.nih.gov/pubmed/217886249.

88.Henderson DW, Reid G, Kao SC, et al. Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis,biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelioma hyperplasia, and biomarkers. J Clin Pathol 2013;66:847-853. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23814259.

89. Paintal A, Raparia K, Zakowski MF, Nayar R. The diagnosis of malignant mesothelioma in effusion cytology: a reappraisal and results of a multi-institution survey. Cancer Cytopathol 2013;121:703-707. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24039177.

90. Feller-Kopman DJ, Redy CB, DeCamp MM, et al. Management of Malignant Pleural Effusions. An Official ATS/STS/STR Clinical Practice Guideline. Am J Respir Crit Care Med 2018;198:839-849. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30272503.

91.Thomas R,Fysh ETH,Smith NA,et al.Effect of an Indwelling Pleural Catheter vs Talc Pleurodesis on Hospitalization Days in Patients With Malignant Pleural Effusion: The AMPLE Randomized Clinical Trial. JAMA 2017;318:1903-1912. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29164255.

92. Bhatnagar R, Keenan EK, Morley AJ, et al. Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion. N Engl J Med 2018;378:1313-1322. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29617585.

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93. Feller-Kopman D, Light R. Pleural Disease. N Engl J Med 2018;378:1754. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/2971914.

94. Boshuizen RC,Vd Noort V,Burgers JA,et al.A randomized controlled trial comparing indwelling pleural catheters with talc pleurodesis

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95. Hunt BM, Farivar AS, Vallieres E, et al. Thoracoscopic talc versus tunneled pleural catheters for palliation of malignant pleural effusions. Ann Thorac Surg 2012;94:1053-1057; discussion 1057-1059. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22513274.

96. Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest 2006;129:362-368. Available at:

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97. Schneider T, Reimer P, Storz K, et al. Recurrent pleural effusion: who benefits from a tunneled pleural catheter? Thorac Cardiovasc Surg 2009;57:42-46. Available at:

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98.Zahid I, Routledge T, Bille A, Scarci M. What is the best treatment for malignant pleural effusions? Interact Cardiovasc Thorac Surg 2011;12:818-823. Available at:

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99.Arapis K,Caliandro R,Stern JB,et al.Thoracoscopic palliative treatment of malignant pleural effusions: results in 273 patients. Surg Endosc 2006;20:919-923.Available at:https://www.ncbi.nlm.nih.gov/pubmed/16738983.

https://www.ncbi.nlm.nih.gov/pubmed/16738983.

100. Hollevoet K, Reitsma JB, Creaney J, et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. J Clin Oncol 2012;30:1541-1549. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22412141.

101. Schneider J, Hoffmann H, Dienemann H, et al. Diagnostic and prognostic value of soluble mesothelin-related proteins in patients with malignant pleural mesothelioma in comparison with benign asbestos and lung cancer. J Thorac Oncol 2008;3:1317-1324. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18978568.

102. Luo L, Shi HZ, Liang QL, et al. Diagnostic value of soluble mesothelin-related peptides for malignant mesothelioma: a meta-analysis.Respir Med 2010;104:149-156. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19945835.

103. Hollevoet K, Nackaerts K, Thimont J, et al. Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor in mesothelioma. Am J Respir Crit Care Med 2010;181:620-625. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20075387.

104. Wheatley-Price P, Yang B, Patsios D, et al. Soluble mesothelin-related Peptide and osteopontin as markers of response in malignant mesothelioma. J Clin Oncol 2010;28:3316-3322. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20498407.

105. Creaney J, Yeoman D, Demelker Y, et al. Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma. J Thorac Oncol 2008;3:851-857, Available at:https://www.ncbi.nlm.nih.gov/pubmed/18670302.

106. Grigoriu BD, Scherpereel A, Devos P, et al. Utility of osteopontin and serum mesothelin in malignant pleural mesothelioma diagnosis and prognosis assessment. Clin Cancer Res 2007;13:2928-2935. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17504993.

107.Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 2005;353:1564-1573. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16221779.

108. Cristaudo A, Foddis R, Vivaldi A, et al. Clinical significance of serum mesothelin in patients with mesothelioma and lung cancer. Clin Cancer

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Res 2007;13:5076-5081. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17785560.

109. Panou V, Vyberg M, Weinreich UM, et al. The established and future biomarkers of malignant pleural mesothelioma. Cancer Treat Rev 2015;41:486-495. Available at:

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110. Creaney J, Dick IM, Robinson BW. Comparison of mesotheliin and fibulin-3 in pleural fluid and serum as markers in malignant mesothelioma.Curr Opin Pulm Med 2015;21:352-356. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26016578.

111.Ostroff RM,Mehan MR,Stewart A,et al.Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool. PLoS One 2012;7:e46091. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23056237.

112. Pass HI, Levin SM, Harbut MR, et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med 2012;367:1417-1427. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23050525.

113. Brims FJ, Lee YC, Creaney J. The continual search for ideal biomarkers for mesothelioma: the hurdles. J Thorac Dis 2013;5:364-366.Available at: https://www.ncbi.nlm.nih.gov/pubmed/23825777.

114. Galateau-Salle F,Churg A,Roggli V,et al.The 2015 World Health Organization Classification of Tumors of the Pleura: Advances since the 2004 Classification.J Thorac Oncol 2016;11:142-154. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26811225.

115. Henderson DW, Reid G, Kao SC, et al. Challenges and controversies in the diagnosis of malignant mesothelioma: Part 2. Malignant mesothelioma subtypes, pleural synovial sarcoma, molecular and prognostic aspects of mesothelioma, BAP1, aquaporin-1 and microRNA. J Clin Pathol 2013;66:854-861. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23833051.

116. Chung A, Attanoos R, Borczuk AC, et al. Dataset for Reporting of Malignant Mesothelioma of the Pleura or Peritoneum: Recommendations From the International Collaboration on Cancer Reporting(ICCR). Arch Pathol Lab Med 2016;140:1104-1110. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2703177.

117. Husain AN, Colby TV, Ordonez NG, et al. Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 2018;142:89-108. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28686500.

118. Marchevsky AM, LeStang N, Hiroshima K, et al. The differential diagnosis between pleural sarcomatoid mesothelioma and spindle cell/pleomorphic(sarcomatoid) carcinomas of the lung: evidence-based guidelines from the International Mesothelioma Panel and the MESOPATH National Reference Center. Hum Pathol 2017;67:160-168.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28782639.

119. Arif Q, Husain AN. Malignant Mesothelioma Diagnosis. Arch Pathol Lab Med 2015;139:978-980. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26230591.

120. Husain AN, Colby T, Ordonez N, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 2013;137:647-667. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22929121.

121.Chirieac LR, Pinkus GS, Pinkus JL, et al. The immunohistochemical characterization of sarcomatoid malignant mesothelioma of the pleura. Am J Cancer Res 2011;1:14-24. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21969119.

122. Husain AN, Colby TV, Ordonez NG, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 2009;133:1317-1331. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19653732.

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123. Ordonez NG. What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol 2007;38:1-16. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17056092.

124. Marchovsky AM, Khoor A, Walts AE, et al. Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel. Mod Pathol 2020;33:281-296. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31485011.

125. Hung YP, Dong F, Torre M, et al. Molecular characterization of diffuse malignant peritoneal mesothelioma. Mod Pathol 2020;33:2269-2279. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32504035.

126. Hung YP, Dong F, Dubuc AM, et al. Molecular characterization of localized pleural mesothelioma. Mod Pathol 2020;33:271-280. Available at:at:https://www.ncbi.nlm.nih.gov/pubmed/31371807.

127.Allen TC,Cagle PT,Churg AM,et al. Localized malignant mesothelioma. Am J Surg Pathol 2005;29:866-873. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15958850.

128.Okike N,Bernatz PE, Woolner LB. Localized mesothelioma of the pleura: benign and malignant variants. J Thorac Cardiovasc Surg 1978;75:363-372. Available at:

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129.Hjerpe A, Ascoli V, Bedrossian CW,et al. Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma. Complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology. Acta Cytol 2015;59:2-16. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25824655.

130. Ray M, Kindler HL. Malignent pleural mesothelioma: an update on biomarkers and treatment. Chest 2009;136:888-896. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19736192.

131. Chapel DB,Churg A,Santoni-Rugiu E,et al. Molecular pathways and diagnosis in malignant mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group. Lung Cancer 2019;127:69-75.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30642555.

132. Schneider F, Roden AC, Dacic S, Baker TP. Protocol for the examination of specimens from patients with malignant pleural mesothelioma. Version 4.1.0.0. Based on AJCC/UICC TNM, 8th edition.Protocol web posting date: June 2021: Collage of American Pathologists;2022. Available at:https://documents.cap.org/protocols/PleuraPericard 4.1.0.0.REL CAPC.pdf.

133. De Rienzo A, Chirieac LR, Hung YP, et al. Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma. J Pathol 2021;253:68-79.Available at:https://www.ncbi.nlm.nih.gov/pubmed/32944962.

134.Righi L, Duregon E, Vatrano S, et al. BRCA1-associated protein 1(BAP1) immunohistochemical expression as a diagnostic tool in malignant pleural mesothelioma classification: a large retrospective study. J Thorac Oncol 2016;11:2006-2017. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27422796.

135. Wang LM, Shi ZW, Wang JL, et al. Diagnostic accuracy of BRCA1-associated protein 1 in malignant mesothelioma: a meta-analysis.Oncotarget 2017;8:68863-68872.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28978163.

136. Creaney J, Patch AM, Addala V, et al. Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma. Genome Med 2022;14:58. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35637530.

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137. Desmeules P, Joubert P, Zhang L, et al. A subset of malignant mesotheliomas in young adults are associated with recurrent EWSR1/FUS-ATF1 fusions. Am J Surg Pathol 2017;41:980-988. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28505004.

138.Leal JL,Peters G,Szaumkessel M,et al.NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer. Lung Cancer 2020;146:154-159. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32540558.

139. Ghafoor A, Mian I, Wagner C, et al. Phase 2 study of olaparib in malignant mesothelioma and correlation of efficacy with germline or somatic mutations in BAP1 gene. JTO Clin Res Rep 2021;2:100231.Available at:https://www.ncbi.nlm.nih.gov/pubmed/34661178.

140. Fennell DA, King A, Mohammed S, et al. Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label,cingle-arm, phase 2a clinical trial. Lancet Respir Med 2021;9:593-600.Available at: https://www.ncbi.nlm.nih.gov/pubmed/33515503.

141. Fennell DA, King A, Mohammed S, et al. Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label,phase 2 trial. Lancet Oncol 2022;23:374-381. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35157829.

142. Cordier F,Van der Meulen J, van Roy N,et al.Malignant pleural mesothelioma with an EML4-ALK fusion: Expect the unexpected! Pathol Res Pract 2022;231:153772. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35074700.

143. Bronte G, Delmonte A, Burgio MA, et al. Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement. Lung Cancer 2020;142:47-50.Available at:https://www.ncbi.nlm.nih.gov/pubmed/32088605.

144. Kapeles M, Gensheimer MF, Mart DA, et al. Trimodality Treatment of Malignant Pleural Mesothelioma: An Institutional Review. Am J Clin Oncol

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145. Nelson DB, Rice DC, Niu J, et al. Long-Term Survival Outcomes of Cancer-Directed Surgery for Malignant Pleural Mesothelioma: Propensity Score Matching Analysis. J Clin Oncol 2017;35:3354-3362. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28817374.

146. Vogl SE. Guarantee-Time Bias and Benefits of Surgery for Pleural Mesothelioma. J Clin Oncol 2018;36:624-625. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29303626.

147.Thieke C,Nicolay NH, Sterzing F, et al. Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy,extrapleural pneumonectomy and intensity-modulated radiotherapy.Radiat Oncol 2015;10:267. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26715491.

148. Bolukbas S, Manegold C, Eberlein M, et al. Survival after trimodality therapy for malignant pleural mesothelioma: Radical Pleurectomy,chemotherapy with Cisplatin/Pemetrexed and radiotherapy. Lung Cancer 2011;71:75-81. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19765853.

149.de Perrot M.Feld R.Cho BC,et al.Trimodyal therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27:1413-1418. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19224855.

150.Krug LM, Pass HI, Rusch VW, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27:3007-3013. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19364962.

151. Weder W, Stahel RA, Bernhard J, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in

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malignant pleural mesothelioma. Ann Oncol 2007;18:1196-1202. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17429100.

152. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins,extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients.J Thorac Cardiovasc Surg 1999;117:54-63; discussion 63-55. Available at:https://www.ncbi.nlm.nih.gov/pubmed/9869758.

153.Frick AE, Nackaerts K, Moons J,et al. Combined modality treatment for malignant pleural mesothelioma: a single-centre long-term survival analysis using extrapleural pneumonectomy. Eur J Cardiothorac Surg 2019;55:934-941.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30535191.

154. Shaikh F, Zauderer MG, von Reibnitz D, et al. Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma.J Thorac Oncol 2017;12:993-1000. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28341225.

155. Baldini EH. Radiation therapy options for malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg 2009;21:159-163.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19822288.

156. Baldini EH. External beam radiation therapy for the treatment of pleural mesothelioma. Thorac Surg Clin 2004;14:543-548. Available at:https://www.ncbi.nlm.nih.gov/pubmed/1559061.

157. Aelony Y, Yao JF. Prolonged survival after talc poudrage for malignant pleural mesothelioma: case series. Respirology 2005;10:649-655. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16268920.

158. Schulze M, Boehle AS, Kurdow R, et al. Effective treatment of malignant pleural effusion by minimal invasive thoracic surgery:thoracoscopic talc pleurodesis and pleuroperitoneal shunts in 101 patients. Ann Thorac Surg 2001;71:1809-1812. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11426752.

159. Petrou M, Kaplan D, Goldstraw P. Management of recurrent malignant pleuroperitoneal shunting. The complementary role tal pleuroperitoneal shunting. Cancer 1995;75:801-805. Available at:https://www.ncbi.nlm.nih.gov/pubmed/7530167.

160.De Paoli L, Quaia E, Poillucci G, et al. Imaging characteristics of pleural tumours. Insights Imaging 2015;6:729-740. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26475741.

161. Rice DC, Steliga MA, Stewart J, et al. Endoscopic ultrasound-guided fine needle aspiration for staging of malignant pleural mesothelioma. Ann Thorac Surg 2009;88:862-868; discussion 868-869. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19699913.

162. Pilling JE, Stewart JD. Martin-Ucar AE, et al. The case for routine cervical mediastinoscopy prior to radical surgery for malignant pleural mesothelioma. Eur J Cardiothorac Surg 2004;25:497-501. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15037261.

163. Grossebner MW, Arifi AA, Goddard M, Ritchie AJ. Mesothelioma--VATS biopsy and lung mobilization improves diagnosis and palliation. Eur J Cardiothorac Surg 1999;16:619-623. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19647830.

164.Ammadzadehfar H, Palmedo H, Strunk H,et al. False positive 18F-FDG-PET/CT in a patient after talc pleurodesis. Lung Cancer 2007;58:418-421. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17624474.

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165.Nguyen NC, Tran I, Hueser CN, et al. F-18 FDG PET/CT characterization of talc pleurodesis-induced pleural changes over time: a retrospective study. Clin Nucl Med 2009;34:886-890. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20139823.

166. Pilling J, Dartnell JA, Lang-Lazdunski L. Integrated positron emission tomography-computed tomography does not accurately stage intrathoracic disease of patients undergoing trimodality therapy for malignant pleural mesothelioma. Thorac Cardiovasc Surg 2010;58:215-219. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20514576.

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167. Wilcox BE, Subramaniam RM, Peller PJ, et al. Utility of integrated computed tomography-positron emission tomography for selection of operable malignant pleural mesothelioma. Clin Lung Cancer 2009;10:244-248. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19632941.

168. Flores RM, Akhurst T, Gonen M, et al. Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2003;126:11-16. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12878934

169.Amin MB,Greene FL,Byrd DR.AJCC Cancer Staging Manual,8th edition: Springer International Publishing; 2017:1-1024.

170. Bonomi M, De Filippis C, Lopci E, et al. Clinical staging of malignant pleural mesothelioma: current perspectives of Lung Cancer(Auckl)2017;8:127-139. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28860886.

171. Rusch VW, Giroux D. Do we need a revised staging system for malignant pleural mesothelioma? Analysis of the IASLC database. Ann Cardiothorac Surg 2012;1:438-448. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23977534.

172. Edge SB, Byrd DR, Compton CC, al.e.AJCC Cancer Staging Manual, 7th edition. New York: Springer;2010.

173. Kaufman AJ, Flores RM. Surgical treatment of malignant pleural mesothelioma. Curr Treat Options Oncol 2011;12:201-216. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21465419.

174.Kim S, Bull DA, Garland L, et al. Is There a Role for Cancer-Directed Surgery in Early-Stage Sarcomatoid or Biphasic Mesothelioma? Ann Thorac Surg 2019;107:194-201. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30278171.

175. Lococo F, Torricelli F, Lang-Lazdunski L, et al. Survival results in biphasic malignant pleural mesothelioma patients: A multicentric analysis.

J Thorac Cardiovasc Surg 2020;159:1584-1593 e1582. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31590954.

176. Rice D, Rusch V, Pass H, et al. Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group. J Thorac Oncol 2011;6:1304-1312. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21847060.

177. Bolukbas S, Eberlein M, Fisseler-Eckhoff A, Schirren J. Radical pleurectomy and chemoradiation for malignant pleural mesothelioma: the outcome of incomplete resections. Lung Cancer 2013;81:241-246.Available at:https://www.ncbi.nlm.nih.gov/pubmed/23688589.

178. Sugarbaker DJ, Wolf AS, Chirieac LR, et al. Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy. Eur J Cardiothorac Surg 2011;40:298-303. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21310625.

179.Abdel-Rahman O,Elsayed Z,Mohamed H,Eltobgy M. Radical multimodality therapy for malignant pleural mesothelioma. Cochrane Database Syst Rev 2018;1:CD012605. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29309720.

180. van Gerwen M, Wolf A, Liu B, et al. Short-term outcomes of pleurectomy decortication and extrapleural pneumonectomy in mesothelioma.J Surg Oncol 2018;118:1178-1187. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30293239.

181.Taioli E, van Gerwen M, Mihalopoulos M, et al. Review of malignant pleural mesothelioma survival after talc pleurodesis or surgery. J Thorac Dis 2017;9:5423-5433. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29312753.

182. Teh E, Fiorentino F,Tan C, Treasure T. A systematic review of lung-sparing extirpative surgery for pleural mesothelioma. J R Soc Med

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2011;104:69-80. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21282797.

183.Cao C,Tian D,Park J,et al.A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer 2014;83:240-245. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24360321.

184. Bovolato P, Casadio C, Bille A, et al. Does surgery improve survival of patients with malignant pleural mesothelioma?: a multicenter retrospective analysis of 1365 consecutive patients. J Thorac Oncol 2014;9:390-396. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24518090.

185. Kinder HL. Surgery for mesothelioma? The debate continues. Lancet Oncol 2011;12:713-714. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21723780.

186. Rice D. Surgical therapy of mesothelioma. Recent Results Cancer Res 2011;189:97-125. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21479898.

187. Maziak DE, Gagliardi A, Haynes AE, et al. Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary. Lung Cancer 2005;48:157-169. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15829316.

188.Friedberg JS. The state of the art in the technical performance of lung-sparing operations for malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg 2013;25:125-143. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24216529.

189.Hasani A, Alvarez JM, Wyatt JM, et al. Outcome for patients with malignant pleural mesothelioma referred for Trimodality therapy in Western Australia. J Thorac Oncol 2009;4:1010-1016. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19546819.

190.Schipper PH,Nichols FC,Thomse KM,et al.Malignant pleural mesothelioma: surgical management in 285 patients. Ann Thorac Surg

2008;85:257-264; discussion 264. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18154820.

191. Nakas A, von Meyenfeldt E, Lau K, et al. Long-term survival after lung-sparing total pleurocture for locally advanced(International Mesothelioma Interest Group Stage T3-T4) non-sarcomatoid malignant pleural mesothelioma. Eur J Cardiothorac Surg 2012;41:1031-1036.Available at: https://www.ncbi.nlm.nih.gov/pubmed/22219469.

192. Bille A, Belcher E, Raubenheimer H, et al. Induction chemotherapy,extrapleural pneumonectomy, and adjuvant radiotherapy for malignant pleural mesothelioma: experience of Guy's and St Thomas' hospitals. Gen Thorac Cardiovasc Surg 2012;60:289-296. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22453539.

193. Zahid I, Sharif S, Routledge T, Scarci M. Is pleurectomy and decocertion superior to palliative care in the treatment of malignant pleural mesothelioma? Interact Cardiovasc Thorac Surg 2011;12:812-817.Available at: https://www.ncbi.nlm.nih.gov/pubmed/21345818.

194. Shahin Y, Wellham J, Jappie R, et al. How successful is lung-preserving radical surgery in the mesothelioma and radical surgery-trial environment? A case-controlled analysis. Eur J Cardiothorac Surg 2011;39:360-363. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20692844.

195. Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620-626,626 e621-623. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18329481.

196. Sugarbaker DJ, Jaklitsch MT, Bueno R, et al. Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 2004;128:138-146. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15224033.

https://www.ncbi.nlm.nih.gov/pubmed/15224033.

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197. Yan TD, Boyer M, Tin M,et al. Extrapleural pneumonectomy for malignant pleural mesothelioma: outcomes of treatment and prognostic factors.J Thorac Cardiovasc Surg 2009;138:619-624. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19698846.

198.Zhou N,Rice DC, Tsao AS,et al.Extrapleural pneumonectomy versus pleurectomy/decortication for malignant pleural mesothelioma. Ann Thorac Surg 2022;113:200-208. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33971174.

199.Halstead JC, Lim E, Venkateswaran RM, et al. Improved survival with VATS pleurectomy-decortication in advanced malignant mesothelioma.Eur J Surg Oncol 2005;31:314-320. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15780570.

200.Treasure T,Lang-Lazdunski L, Waller D,et al.Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery(MARS) randomised feasibility study. Lancet Oncol 2011;12:763-772. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21723781.

201. Weder W, Stahel RA, Baas P, et al. The MARS feasibility trial:conclusions not supported by data. Lancet Oncol 2011;12:1093-1094,author reply 1094-1095. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22041539.

202. Yan TD,Cao CQ, Boyer M, et al. Improving survival results after surgical management of malignant pleural mesothelioma: an Australian institution experience. Ann Thorac Cardiovasc Surg 2011;17:243-249.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21697784.

203. Flores RM,Riedel E, Donington JS, et al. Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based(Surveillance, Epidemiology,and End Results[SEER]) population. J Thorac Oncol 2010;5:1649-1654.Available at:https://www.ncbi.nlm.nih.gov/pubmed/20871264.

204.Spaggiari L, Marulli G, Bovolato P, et al. Extrapeleural pneumonectomy for malignant mesothelioma: an Italian multicenter retrospective study. Ann Thorac Surg 2014;97:1859-1865. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24726598.

205. Blomberg C, Nilsson J, Holgersson G, et al. Randomized Trials of Systemic Medically-treated Malignant Mesothelioma: A Systematic Review. Anticancer Res 2015;35:2493-2501.Available at:https://www.ncbi.nlm.nih.gov/pubmed/25964522.

206. Kelly RJ, Sharon E, Hassan R. Chemotherapy and targeted therapies for unresectable malignant mesothelioma. Lung Cancer 2011;73:256-263.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21620512.

207.Ellis P, Davies AM, Evans WK, et al. The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline. J Thorac Oncol 2006;1:591-601. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17409924.

208.Kim ST,Park JY,Lee J,et al.The efficacy of the frontline platinum-based combination chemotherapy in malignant peritoneal mesothelioma. Jpn J Clin Oncol 2010;40:1031-1036. Available at:https://ncbi.ncbi.nlm.nih.gov/pubmed/20534685.

209.Recab P.Rosenzweig B,Bazzi WM,et al. Malignant Mesothelioma and the Tunica Vaginalis Testis: Outcomes Following Surgical Management Beyond Radical Orchiatey. Urology 2017;107:166-170. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28416299.

210.Kim JS,Lim SY,Hwang J,et al.A Case Report of Primary Pericardial Malignant Mesothelioma Treated with Pemetrezed and Cisplatin. J Korean Med Sci 2017;32:1879-1884. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28960045.

211.Srinivasan G,Sidhu GS,Williamsonn EA,et al.Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition. Cancer Chemother Pharmacol 2017;80:861-867. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2875616.

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212. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication,hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc Surg 2015;149:558-565; discussion 565-556. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25726878.

213. Lang-Lazdunski L, Bille A, Belcher E, et al.Pleurectomy/decortation, hyperthermic pleural lavage with povidone-idine followed by adjuvant chemotherapy in patients with malignant pleural mesothelioma. J Thorac Oncol 2011;6:1746-1752.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21876457.

214.Friedberg JS, Culligan MJ, Mick R, et al. Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma.Ann Thorac Surg 2012;93:1658-1665; discussion 1665-1657. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22541196.

215.Sugarbaker DJ, Gill RR, Yeap BY, et al. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg 2013;145:955-963. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23434448.

216.Simone CB,2nd, Cengel KA. Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol 2014;41:820-830.Available at:https://www.ncbi.nlm.nih.gov/pubmed/25499640.

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219. de Bree E, van Ruth S, Baas P, et al. Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma. Chest 2002;121:480-487. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11834661.

220.Kotova S, Wong RM, Cameron RB. New and emerging therapeutic options for malignant pleural mesothelioma: review of early clinical trials.Cancer Manag Res 2015;7:51-63. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25670913.

221.Horn L, Spigel DR, Vokes EE, et al. Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced-N-small-Cell Lung Cancer:Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). J Clin Oncol 2017;35:3924-3933.Available at:https://www.ncbi.nlm.nih.gov/pubmed/29023213.

222.Baas P,Scherpereel A, Nowak AK,et al.First-line-nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma(CheckMate 743):a multicentre,randomised,open-label, phase 3 trial. Lancet 2021;397:375-386. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33485464.

223. Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis.JAMA Oncol 2016;2:1607-1616. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27540850.

224. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-Liogramed Death Ligand 1 Therapy.J Clin Oncol 2017;35:709-717. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27646942.

225.Sgambato A,Casaluce F,Sacco PC,et al.Anti PD-1 and PDL-1 Immunotherapy in the Treatment of Advanced Non- Small Cell Lung

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Cancer(NSCLC): A Review on Toxicity Profile and its Management. Curr Drug Saf 2016;11:62-68. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26412670.

226. Vogelzang NJ, Rustover JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-2644.Available at:https://www.ncbi.nlm.nih.gov/pubmed/12860938.

227.Katirtzoglou N,Gkiozos I,Makrilia N,et al.Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study. Clin Lung Cancer 2010;11:30-35.Available at:https://www.ncbi.nlm.nih.gov/pubmed/20085865.

228. Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrezed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;24:1443-1448. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16549838.

229. Castagneto B, Botta M, Aitini E, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma(MPM). Ann Oncol 2008;19:370-373. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18156144.

230. Santoro A, O'Brien ME, Stahel RA, et al. Pemetrezed plus cisplatin or pemetrezed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program.J Thorac Oncol 2008;3:756-763. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18594322.

231. Kondola S, Manners D, Nowak AK. Malignant pleural mesothelioma:an update on diagnosis and treatment options. Ther Adv Respir Dis 2016;10:275-288. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26873306.

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233. Krug LM. An overview of chemotherapy for mesothelioma. Hematol Oncol Clin North Am 2005;19:1117-1136, vii. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16325127.

234. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study(MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 2016;387:1405-1414. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26719230.

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236. Arrieta O, Lopez-Macias D, Mendoza-Garcia VO, et al. A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma.Cancer Chemother Pharmacol 2014;73:975-982. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24687408.

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239. Scagliotti GV, Shin D-M, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 2003;21:1556-1561.Available at:http://www.ncbi.nlm.nih.gov/pubmed/12697881.

240. Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaive and pretreated patients with malignant pleural mesothelioma:

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results of an International Expanded Access Program. J Thorac Oncol 2008;3:764-771. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18594323.

241. Muers MF, Stephens RJ, Fisher P, et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma(MS01): a multicentre randomised trial. Lancet 2008;371:1685-1694. Available at:http://www.ncbi.nlm.nih.gov/pubmed/18486741.

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247. Scherpereel A, Mazieres J, Greillier L, et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma(IFCT-1501 MAPS2): a multicentre, open-label, randomised,non-comparative, phase 2 trial. Lancet Oncol 2019;20:239-253. Available at:https://www.ncbi.nlm.nih.gov/pubmed/3060609.

248. Disselhorst MJ, Quispel-Janssen J, Lalezari F, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma(INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med 2019;7:260-270. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30660511.

249. Metaxas Y, Rivalland G, Mauti LA, et al. Pembrolizumab as Palliative Immunotherapy in Malignant Pleural Mesothelioma. J Thorac Oncol 2018;13:1784-1791. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30142389.

250.Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma(KEYNOTE-028): preliminary results from a non-randomised, open-label,phase 1b trial. Lancet Oncol 2017;18:623-630. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2223868.

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252. Scherpereel A, Mazieres J, Greiller L, et al. Second- or third-line nivolumab(Nivo) versus nivo plus ipilimumab(Ipi) in malignant pleural LBA8507. Available at:http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.18 suppl.LBA8507.

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254. Alley EW,Molife LR,Santoro A,et al. Clinical safety and efficacy of pembrolizumab(MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028[abstract]. Cancer

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Research 2015;75:Abstract CT103. Available at:https://tinyurl.com/y9xqndc4.

255.Alley EW,Schellens JH,Santoro A,et al.Single-agent pembrolizumab for patients with malignant pleural mesothelioma(MPM)[abstract]. World Conference on Lung Cancer. Denver, Colorado: IASCL;2015:Abstract 3011. Available at: https://tinyurl.com/ybrtdp2c.

256. Marcq E, Pauwels P, van Merseebeck JP, Smits EL. Targeting immune checkpoints: New opportunity for mesothelioma treatment?Cancer Treat Rev 2015;41:914-924. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26433514.

257. Calabro L, Morra A, Fonsatti E, et al. Efficacy and safety of an intensified schedule of tremulumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med 2015;3:301-309. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25819643.

258. Buikhuisen WA, Hiddinga Bla, Baas P, van Meerbeeck JP. Second line therapy in malignant pleural mesothelioma: A systematic review. Lung Cancer 2015;89:223-231. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26162564.

259.Zucali PA, Simonelli M, Michetti G, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung Cancer 2012;75:360-367. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21937142.

260. Popat S, Curioni-Fontecedro A, Dafni U, et al. A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma:the European Thoracic Oncology Platform(ETOP 9-15) PROMISE-meso trial. Ann Oncol 2020;31:1734-1745. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32976938.

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263. Janne PA, Wozniak AJ, Belani CP, et al. Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program.J Thorac Oncol 2006;1:506-512. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17409909.

264. van Meerbee JP, Baas P, Debruyne C, et al. A Phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999;85:2577-2582. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10375105.

265.Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009;63:94-97. Available at:

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266. Manegold C, Symanowski J, Gatzemeier U, et al. Second-line(post-study) chemotherapy received by patients treated in the phase III trial of pemetrezed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol 2005;16:923-927. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15824080.

267. Ashton M O,Rourke N, Currie S, et al. The role of radical radiotherapy in the management of malignant pleural mesothelioma: A systematic review. Radiother Oncol 2017;125:1-12. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28859932.

268. Price A. What is the role of radiotherapy in malignant pleural mesothelioma? Oncologist 2011;16:359-365. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21346022.

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269. van Thiel ER, Surmont VF, van Meerbeeck JP. Malignant pleural mesothelioma: when is radiation therapy indicated? Expert Rev Anticancer Ther 2011;11:551-560. Available at:

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270.Gomez DR, Hong DS, Allen PK, et al. Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensity-modulated radiation therapy for malignant pleural mesothelioma.J Thorac Oncol 2013;8:238-245. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23247629.

271. Rice DC, Stevens CW, Correa AM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 2007;84:1685-1692; discussion 1692-1683. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17954086.

272. Yajnik S, Rosenzweig KE, Mychalczak B, et al. Hemthoracic radiation after extrapleural pneumonectomy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2003;56:1319-1326. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12873676.

273. Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122:788-795. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11581615.

274.Gupta V,Mychalczak B, Krug L,et al.Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2005;63:1045-1052. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16054774.

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281. Davies HE, Musk AW, Lee YC. Prophylactic radiotherapy for pleural puncture sites in mesothelioma: the controversy continues. Curr Opin Pulm Med 2008;14:326-330. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18520267.

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283. Bydder S, Phillips M, Joseph DJ,et al. A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma. Br J Cancer 2004;91:9-10. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15199394.

284. Clive AO, Taylor H, Dobson L, et al. Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma(SMART): a multicentre, open-label, phase 3, randomised controlled trial. Lancet Oncol 2016;17:1094-1104. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27345639

285. Stewart SA, Clive AO, Maskell NA, Penz E. Evaluating quality of life and cost implications of prophylactic radiotherapy in mesothelioma: Health economic analysis of the SMART trial. PLoS One 2018;13:e0190257.Available at:https://www.ncbi.nlm.nih.gov/pubmed/29401495.

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287. Baldini EH, Recht A, Strauss GM, et al. Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1997;63:334-338. Available at:https://www.ncbi.nlm.nih.gov/pubmed/9033296.

288.Chance WW, Rice DC, Allen PK, et al. Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. Int J Radiat Oncol Biol Phys 2015;91:149-156. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25442335.

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297.Allen A, Czerminska M, Janne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma.Int J Radiat Oncol Biol Phys 2006;65:640-645. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16751058.

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表 1
HISTOLOGY	FIRST-LINE THERAPY	PRINCIPLES OF SYSTEMIC THERAPYa,b	SUBSEQUENT THERAPY
	Preferred	$$\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\left	\le

表 2
Treatment type	Total dose	Fraction size	Treatment duration
Palliative
Chest wall pain from recurrent nodules	20-40 Gy or 30 Gy	≥4 Gy 3 Gy	1-2 weeks 2 weeks
Multiple brain or bone metastases	30 Gy	3 Gy	2 weeks
Post P/D Higher dose to higher risk areas	45-60 Gy	1.8-2 Gy	5-6 weeks

表 3
	T	N	M
Stage I	T1	NO	MO
Stage II	T2	NO	MO
	T1	N1	MO
Stage IIIA	T2	N1	MO
	T3	NO-N1	MO
	T1-T3	N2	MO
Stage IIIB	T4	Any N	MO
Stage IV	Any T	Any N	M1

表 4
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is uniform NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 5
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

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引用 / 出处

（2026.V1）NCCN临床实践指南：间皮瘤：胸膜. 2026.