Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology

Authors:
David S. Ettinger The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Douglas E. Wood Fred Hutchinson Cancer Center

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James Stevenson Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Centerand Cleveland Clinic Taussig Cancer Institute

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Dara L. Aisner University of Colorado Cancer Center

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Wallace Akerley Huntsman Cancer Institute at the University of Utah

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Jessica R. Bauman Fox Chase Cancer Center

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Ankit Bharat Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Debora S. Bruno Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Centerand Cleveland Clinic Taussig Cancer Institute

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

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Lucian R. Chirieac Dana-Farber/Brigham and Women’s Cancer Center

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Malcolm DeCamp University of Wisconsin Carbone Cancer Center

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Thomas J. Dilling Moffitt Cancer Center

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Jonathan Dowell UT Southwestern Simmons Comprehensive Cancer Center

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Gregory A. Durm Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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Scott Gettinger Yale Cancer Center/Smilow Cancer Hospital

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Travis E. Grotz Mayo Clinic Cancer Center

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Matthew A. Gubens UCSF Helen Diller Family Comprehensive Cancer Center

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Aparna Hegde O’Neal Comprehensive Cancer Center at UAB

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Rudy P. Lackner Fred & Pamela Buffett Cancer Center

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Michael Lanuti Mass General Cancer Center

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Jules Lin University of Michigan Rogel Cancer Center

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Billy W. Loo Jr Stanford Cancer Institute

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Christine M. Lovly Vanderbilt-Ingram Cancer Center

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Fabien Maldonado Vanderbilt-Ingram Cancer Center

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Erminia Massarelli City of Hope National Medical Center

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Daniel Morgensztern Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Trey C. Mullikin Duke Cancer Institute

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Thomas Ng The University of Tennessee Health Science Center

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Gregory A. Otterson The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Sandip P. Patel UC San Diego Moores Cancer Center

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Tejas Patil University of Colorado Cancer Center

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Patricio M. Polanco UT Southwestern Simmons Comprehensive Cancer Center

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Gregory J. Riely Memorial Sloan Kettering Cancer Center

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Jonathan Riess UC Davis Comprehensive Cancer Center

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Theresa A. Shapiro The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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

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Alda Tam The University of Texas MD Anderson Cancer Center

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Tawee Tanvetyanon Moffitt Cancer Center

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Jane Yanagawa UCLA Jonsson Comprehensive Cancer Center

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Stephen C. Yang The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Edwin Yau Roswell Park Comprehensive Cancer Center

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Kristina M. Gregory National Comprehensive Cancer Network

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Miranda Hughes National Comprehensive Cancer Network

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Full access

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term “malignant” is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

Overview

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites that is estimated to occur in approximately 3,500 people in the United States every year.15 These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM), which is a less common type (approximately 15%). Most mesothelioma occurs in the pleura (approximately 85%); it can also occur very rarely in other sites, such as the pericardium and tunica vaginalis testis.69 It is estimated that PeM occurs in approximately 300 to 400 people in the United States every year.10 The true incidence may be higher because PeM may not be coded correctly; it may be misdiagnosed as other cancers that typically involve the peritoneum, such as ovarian cancer. The mean age is about 69 years at diagnosis of PeM. One-year overall survival is approximately 46% in patients with PeM, and 5-year overall survival is about 20%; cure is rare.11 Survival is improved for patients who are able to undergo complete cytoreductive surgery (CRS) with intraperitoneal chemotherapy.1216 There are multiple intravenous systemic therapy options for patients who are not candidates for CRS, or those whose disease recurs following CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC).

Similar to pleural mesothelioma, the histologic subtypes of PeM include epithelioid (most common), sarcomatoid, and biphasic (also known as mixed, containing both epithelioid and sarcomatoid components).4,1719 Patients with epithelioid histology have better outcomes than those with either biphasic or sarcomatoid histologies; histology is used to direct treatment.15 Similarities exist between PeM and pleural mesothelioma, but there are unique differences.15 PeM is diagnosed in equal numbers of males and females; pleural mesothelioma is more common in males.11 In addition, PeM may occur in younger patients, whereas pleural mesothelioma typically occurs in older patients. Many patients with PeM have idiopathic disease.20 Pleural mesothelioma is typically caused by asbestos exposure; however, PeM is less frequently associated with asbestos exposure.2124 The incidence of pleural mesothelioma and PeM is decreasing in the United States because asbestos use has decreased since the 1970s.1,5,2528 Although asbestos is no longer mined in the United States, it is still imported.28 Genetic factors play a role in some patients with PeM, with families carrying a germline mutation in the BRCA1-associated protein-1 (BAP1) gene; a few patients have somatic mutations, such as anaplastic lymphoma kinase (ALK) rearrangements or rare fusions.2937

Patients with PeM present with abdominal signs and symptoms, such as ascites, pain, distension, and an abdominal mass.11,38 They often have a high symptom burden compared with patients who have other types of cancer. The diagnosis of PeM may be delayed, because symptoms are nonspecific.11,21,24,38 Thus, many patients with PeM have advanced disease at diagnosis.11 Although PeM can spread extensively in the abdomen, it less commonly metastasizes beyond the abdominal cavity.24

These NCCN Guidelines for Mesothelioma: Peritoneal were first published in 2021 and will be updated at least once every year. For the 2023 update (Version 1), the NCCN panel revised the title of the guideline to “Mesothelioma: Peritoneal” to align with the pleural mesothelioma guidelines; the previous title was “Malignant Peritoneal Mesothelioma.” The term “malignant” is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.39 The pathology section was also updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose; PeM has distinct molecular features when compared with pleural mesothelioma (see “Principles of Pathologic Review” in the algorithm, page 967).40 A new abbreviations list was also added to the guidelines. Additional supplementary material in the NCCN Guidelines for Mesothelioma: Peritoneal includes the “Principles of Pathologic Review” (page 967), “Principles of Surgery” (page 972), “Principles of Systemic Therapy” (page 974), and “Principles of Supportive Care” (page 975). These NCCN Guidelines for Mesothelioma: Peritoneal were developed by panel members who also developed the NCCN Guidelines for Mesothelioma: Pleural and the NCCN Guidelines for Non–Small Cell Lung Cancer (available at NCCN.org).

Guidelines Update Methodology

Complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria

Prior to the update of the NCCN Guidelines for Mesothelioma: Peritoneal, an electronic search of the PubMed database was performed to obtain key literature in PeM published since the previous Guidelines update, using the search term: peritoneal 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 II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. The data from key PubMed articles and articles from additional sources deemed as relevant to these guidelines as discussed by the panel during the guidelines update have been included in this version of the “Discussion” section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; antiracist, anticlassist, antimisogynist, antiageist, antiableist, and anti-fat–biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate nongendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms “men,” “women,” “female,” and “male” when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Diagnosis

Initial Evaluation

Patients with PeM present with abdominal signs and symptoms, such as ascites (77%), pain (69%), distension, and an abdominal mass (30%); they may also present with weight loss, fatigue, anorexia, asthenia, nausea, early satiety, and intestinal obstruction (see the NCCN Guidelines for Adult Cancer Pain, available at NCCN.org).11,21,38 The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare.11,24,38

To diagnose PeM, initial evaluations include CT imaging of the chest/abdomen/pelvis and laparoscopy to obtain a biopsy of the abdominal mass/nodule(s). On CT, diffuse distribution in the abdomen and the absence of lymph nodes or distant metastases suggest PeM; however, there are no specific imaging findings for PeM.24,41,42 Laparoscopy is also performed to assess whether complete CRS is possible.24 Fine-needle aspiration of the nodule/mass is not recommended for diagnosis, because fine-needle aspiration cannot differentiate between the different histologic subtypes of PeM, including epithelioid, sarcomatoid, and biphasic. Using paracentesis fluid (cytology) is also not recommended for diagnosis because invasion cannot be detected using cytology.21,24 Measurement of soluble mesothelin-related peptide and CA-125 levels may be considered, and these levels may correlate with disease status. For patients with suspected PeM, the NCCN Guidelines for Mesothelioma: Peritoneal recommend an initial evaluation including (1) CT with contrast of the chest, abdomen, and pelvis; (2) biopsies of the nodule/mass using a midline laparoscopy; and (3) serum markers.21,42,43

Pathology

Tissue biopsy of the abdominal mass/nodule(s) with histopathology is essential for an accurate diagnosis of PeM, because symptoms, imaging findings, and serum markers are not specific. Patients may have benign and preinvasive mesothelial tumors such as peritoneal inclusion cyst, well-differentiated papillary mesothelial tumor, or mesothelioma in situ.4446 Peritoneal inclusion cyst is very rare; it was previously termed “benign multicystic PeM,” but this term was revised based on the recent WHO classification.4749 Diffuse PeM is malignant and further divided into specific histologic subtypes, including epithelioid, sarcomatoid, or biphasic histology (epithelioid and sarcomatoid histology, also known as “mixed”).17,50 Unless otherwise indicated, these PeM guidelines refer to diffuse PeM, because most patients have diffuse mesothelioma. Although localized pleural mesothelioma may occur, it is very rare; localized PeM is extremely rare.33,5153 Accurate histology is essential, because the treatment options depend on histology. Patients with an epithelioid subtype have longer median overall survival (39 months) compared with patients who have a biphasic subtype (14 months).15 However, median survival is improved if patients are able to undergo cytoreductive surgery (55 months for epithelial histology vs 13 months for biphasic).54 Distinguishing diffuse PeM from peritoneal inclusion cyst and well-differentiated papillary mesothelial tumor is important because treatment options differ; it is also important to distinguish PeM from metastatic carcinomas such as breast, gastrointestinal, liver, lung, ovarian, pancreatic, and renal cell (see “Principles of Pathologic Review” in the algorithm, page 967).55 The differential diagnosis of PeM includes peritoneal carcinomatosis, serous peritoneal carcinoma, tuberculous peritonitis, and alcoholic cirrhosis.24,56

Detailed information about the pathologic evaluation of PeM is provided in the algorithm (see “Principles of Pathologic Review,” page 967) and summarized in this discussion. Because PeM and pleural mesothelioma are similar, the pathology section also contains content about pleural mesothelioma. The classification for pleural mesothelioma was revised based on new recommendations from the WHO.39,57 The classification for PeM has also been revised to align with the pleural mesothelioma guidelines. The term “malignant” is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.39

Histologic assessment and immunohistochemistry (IHC) are the main tools used in the diagnosis of diffuse PeM; however, cytogenetics and molecular techniques are also used. For a diagnosis of mesothelioma, the lesion needs to be diffuse, mesothelial, and malignant. There is no single IHC marker to diagnose PeM. Different IHC markers need to be used to distinguish PeMs from other carcinomas, such as gynecologic malignancies or renal cell carcinomas. A panel of markers is recommended as follows: (1) two mesothelial markers (ie, positive markers), including calretinin and podoplanin (D2-40); and (2) two carcinoma markers (ie, negative markers) including claudin 4, thyroid transcription factor 1 (TTF-1), polyclonal CEA, and paired box gene 8 (PAX8).17,50,5864 Although PAX8 is a carcinoma marker, sometimes PeMs will stain for PAX8.17,65 Wilms tumor protein 1 (WT-1) is generally positive for PeM; however, it is also positive for papillary serous carcinoma.63 For the 2023 update (Version 1), the NCCN panel deleted WT-1 and added PAX8 for the differential diagnosis of PeM. It is important to note that IHC markers for diagnosing PeM differ slightly from those for diagnosing pleural mesothelioma. For example, TTF-1 and D2-40 are not useful for diagnosing PeM, although they are useful for diagnosing pleural mesothelioma.17

BAP1 IHC loss is a molecular marker that is useful for diagnosing mesothelioma, especially mesothelioma in situ, which is difficult to diagnose.11,6671 BAP1 is a tumor suppressor gene involved in mesothelioma and other carcinomas. Recurrent somatic and/or germline mutations in BAP1 occur in mesothelioma.11,71 Aberrant BAP1 protein expression, which is defined as absence of nuclear BAP1 IHC staining, occurs in about 50% to 70% of patients with epithelioid mesothelioma but in fewer than 20% of those with sarcomatoid mesothelioma.72 BAP1 IHC is useful for distinguishing mesotheliomas from benign mesothelial tumors. For the 2023 update (Version 1), the panel clarified that complete absence of expression or cytoplasmic staining is considered a loss of BAP1 expression. Methylthioadenosine phosphorylase IHC is another molecular marker that is useful for diagnosing pleural mesotheliomas. Cytoplasmic loss of methylthioadenosine phosphorylase IHC is used to quickly assess the presence of cyclin-dependent kinase inhibitor 2A deletions, which can be measured by fluorescence in situ hybridization. However, fewer patients with PeMs have these deletions (8%–35%) compared with patients with pleural mesotheliomas (60%–74%).40,66,67,73

Management

The NCCN Guidelines for Mesothelioma: Peritoneal recommend that patients with PeM should have their treatment managed by a multidisciplinary team with experience in PeM.12,21 Treatment options for patients with diffuse PeM include surgery and/or systemic therapy.21,74 Select patients with medically operable diffuse PeM and good performance status (PS) are candidates for multimodality therapy, including those with epithelioid histology and unicavitary disease. Systemic therapy is recommended for patients with diffuse PeM who are not eligible for or refuse surgery. Best supportive care is recommended for patients with a PS of 3–4 (see “Principles of Supportive Care” in the algorithm, page 975). Radiation therapy is not recommended as a primary therapy for PeM but can be used selectively for palliation. Treatment options for patients with peritoneal inclusion cyst or well-differentiated papillary mesothelial tumor include (1) observation with imaging surveillance for those with asymptomatic and noninvasive disease; or (2) CRS with or without HIPEC for those who have symptomatic, recurrent, or microinvasive disease.

No phase III randomized trials to determine the best treatment for patients with PeM exist because it is so rare, although there are a few clinical trials.13,14,7577 Because PeM and pleural mesothelioma are similar, systemic therapy recommendations for PeM are based on extrapolating data from clinical trials in pleural mesothelioma; recommendations are also based on clinical trials in PeM, and on the expertise of the panel members (see “Surgery and Intraperitoneal Chemotherapy,” next section, and “Systemic Therapy,” page 969).21

Surgery and Intraperitoneal Chemotherapy

Data show good outcomes for eligible patients with PeM who have CRS and intraperitoneal chemotherapy (see “Clinical Trials,” page 968).13,14,59,7577 Therefore, a multidisciplinary evaluation is recommended to assess whether patients are eligible for surgery. During laparoscopic biopsy, a surgical evaluation is done to assess whether patients are candidates for surgery. After a diagnosis of diffuse PeM, PET/CT is done to determine whether patients have unicavitary or bicavitary disease. Surgery is typically contraindicated in patients with bicavitary disease and those with biphasic or sarcomatoid histology; however, surgery may be considered in select patients with bicavitary disease or low-volume biphasic disease (see “Principles of Surgery” in the algorithm, page 972).78 It is essential that patients receive a careful assessment before surgery is performed. Complete cytoreduction is recommended for eligible patients with epithelioid histology and unicavitary PeM who are medically operable.21,74,76,79

The surgical goal for PeM is CRS to achieve macroscopic complete resection by removing all visible or palpable tumors, which frequently involves a total parietal peritonectomy (see “Principles of Surgery” in the algorithm, page 972). If macroscopic complete resection or near complete cytoreduction is not possible, then surgery should be aborted. Palliative surgery and/or HIPEC can be considered but only if there will be minimal morbidity. There is no accepted staging system for PeM. The peritoneal cancer index scoring system is used to indicate the severity of the symptom burden (see “Principles of Surgery,” page 972).74 A completeness of cytoreduction score of zero (CC-0) indicates no residual disease (see “Principles of Surgery,” page 972).80 A novel staging system based on the peritoneal carcinomatosis index is available.81

Clinical Trials

A multi-institutional study assessed CRS and HIPEC in 401 patients with PeM; 46% had complete or near complete cytoreduction and 92% received HIPEC.76 The median overall survival was 53 months (1–235 months); 3-year and 5-year survival rates were 60% and 47%, respectively. Grade 3–4 complications occurred in 127 patients (31%); 9 patients died perioperatively. A meta-analysis assessed CRS and intraperitoneal chemotherapy in 1,047 patients with PeM.16 Complete cytoreduction was done in 67% of patients (46%–93%). Survival estimates were 84% at 1 year, 59% at 3 years, and 42% at 5 years.

In a single-institution study, 108 patients with PeM had CRS and HIPEC with cisplatin and either doxorubicin or mitomycin-C.77 The median overall survival was 63.2 months (95% CI, 29.6–96.7). Nineteen patients survived more than 7 years and appeared to be cured. Major morbidity was 38.9%; 2 patients died perioperatively. In another single-institution study, 84 patients with PeM had CRS and HIPEC with cisplatin plus doxorubicin; 66 patients had complete or near complete cytoreduction.14 Almost all patients had epithelioid histology (97.6%). The median overall survival was 38.4 months (95% CI, 23.6–54.3); 5-year survival was 42%. Grade 3–4 complications occurred in 22 patients (26.2%); acute kidney injury occurred in 30 patients (35.7%). Three patients died perioperatively.

A retrospective study (Peritoneal Surface Oncology Group International) assessed CRS and HIPEC in 34 patients with PeM and biphasic histology; 5-year survival was 50.2% (median, 6.8 years) for those who had a complete resection (CC-0).78 Five-year survival was 41.6% (median, 2.8 years) for those who had incomplete CC-1 resections. Median survival was only 4.3 months in those who had incomplete CC-2 resections.

NCCN Recommendations

The NCCN panel recommends CRS and HIPEC for eligible patients with PeM based on trials for PeM and pleural mesothelioma (see “Principles of Surgery” and “Principles of Systemic Therapy” in the algorithm, pages 972 and 974, respectively).21,74 Appropriate patients should be evaluated by surgeons, medical oncologists, and diagnostic imaging specialists to assess if they are candidates for multimodality treatment.

Complete cytoreduction and HIPEC are recommended for patients with unicavitary PeM and epithelioid histology who are medically operable if a complete cytoreduction is achievable. Perioperative systemic therapy should be considered if patients have high-risk features (such as Ki-67 >9%, nodal metastases, high tumor burden [peritoneal cancer index >17]), CC >1, biphasic disease, or bicavitary disease). Although measuring the Ki-67 index is not routinely recommended at diagnosis, it may be useful for helping to define high-risk features. After perioperative therapy, patients may be eligible for CRS and HIPEC. Systemic therapy alone is recommended for patients with PS of 0–2 who are medically inoperable or refuse surgery (see “Systemic Therapy,” next section).

The NCCN panel has preference stratified the intraperitoneal chemotherapy regimens and voted that the following regimens are preferred: (1) cisplatin plus doxorubicin; (2) cisplatin; (3) carboplatin; or (4) cisplatin plus mitomycin (see “Principles of Surgery” in the algorithm, page 972).74,77,8284 The panel has voted that monotherapy mitomycin regimens are useful in certain circumstances.74

Systemic Therapy

Only a few systemic therapy clinical trials have been performed for patients with PeM who are not eligible for surgery.7,8589 Therefore, recommended systemic therapy regimens for PeM are mainly based on clinical trials done in patients with pleural mesothelioma; the NCCN panel has decided that these regimens are equally efficacious for both disease sites (see “Principles of Systemic Therapy,” page 974).21,74,85,89 Details about the systemic therapy clinical trials for pleural mesothelioma are described in the NCCN Guidelines for Mesothelioma: Pleural (available at NCCN.org). For the 2023 update (Version 1), the NCCN panel reorganized the systemic therapy recommendations based on histology and line of therapy. All of the regimens recommended for PeM and pleural mesothelioma may also be used for eligible patients with pericardial mesothelioma and tunica vaginalis testis mesothelioma, which are extremely rare cancers.90,91

Clinical Trials

The International Expanded Access Program assessed pemetrexed regimens in patients with mesothelioma who were not eligible for surgery.9294 A subset of 98 patients with PeM received pemetrexed regimens.86 Median survival was not reached for patients receiving first-line therapy with either pemetrexed alone or pemetrexed plus cisplatin; response rate was 25%. Median survival was 13.1 months for patients with PeM receiving second-line therapy with either pemetrexed alone or pemetrexed plus cisplatin; response rates were 23.3%. Updated results from the Expanded Access Program were published for 109 patients with PeM receiving pemetrexed regimens who were not eligible for surgery.7 Patients received pemetrexed, pemetrexed plus cisplatin, or pemetrexed plus carboplatin as either first-line or second-line therapy. For pemetrexed plus cisplatin, 1-year survival was 57.4% (95% CI, 10.3%–100%). For patients receiving pemetrexed alone, median survival was 10.3 months; 1-year survival was 41.5% (95% CI, 4.6%–78.4%). Survival rates are not available for pemetrexed plus carboplatin. The most frequent grade 3–4 adverse event was neutropenia (34.6%).

Several small studies done in Japan assessed pemetrexed regimens in patients with PeM. One study assessed first-line therapy with pemetrexed plus cisplatin in 24 patients with PeM.95 There were 2 complete responses and 9 partial responses. Median overall survival was 15.8 months. Another study assessed first-line therapy with pemetrexed plus cisplatin in 29 patients with PeM.89 Median overall survival was 15.4 months (95% CI, 9.5–21.2). Grade 3–4 adverse events included leukopenia (21%), neutropenia (17%), anemia (14%), and thrombocytopenia (3%). Updated results were reported from this group in 54 patients with PeM who received first-line therapy with pemetrexed plus platinum.87 Median overall survival was 16.6 months. This study also assessed second-line therapy in 26 patients with PeM.87 Patients received gemcitabine (12), taxane (6), nivolumab (3), and other agents (5). Median overall survival was 16.9 months. Several small studies have reported that PeM responds to first-line therapy with gemcitabine plus cisplatin.9698 Data also show that first-line therapy with gemcitabine plus pemetrexed is effective, although this regimen is toxic (grade 3–4 neutropenia, 60%).99

A phase II trial assessed atezolizumab plus bevacizumab as subsequent therapy for 20 patients with advanced and unresectable PeM who had progression on or were intolerant to pemetrexed plus platinum chemotherapy.85 Many patients were women (60%) and did not have previous exposure to asbestos (75%). The median age was 63 years. Most patients had epithelioid histology (90%); 10% had biphasic histology. One patient had previously received bevacizumab. The response rate was 40% (8/20; 95% CI, 19%–64%). Overall survival at 1 year was 85% (95% CI, 60%–95%). Grade 3 treatment-emergent adverse events occurred in 50% of patients (10/20), including hypertension (40%) and anemia (10%). Grade 3 immune-related adverse events—pancreatitis and thrombocytopenia—occurred in 2 patients (10%), which required stopping treatment.

A cohort study assessed subsequent therapy with immune checkpoint inhibitors (ICIs) in 29 patients with PeM.100 Most patients had received one line of therapy (83%, 24/29). Many patients received subsequent therapy with nivolumab plus ipilimumab (69%, 20/29); some patients received single-agent ICIs (31%, 9/29), including nivolumab (n=4), pembrolizumab (n=3), or atezolizumab (n=2). The overall response rate was 19% (5/26; 95% CI, 6.6%–39%). Patients responded to ICIs regardless of whether they had responded to previous platinum-based chemotherapy. The median duration of overall survival was 19 months (95% CI, 7.4–43). The 1-year overall survival rate was 68% (95% CI, 45%–83%). Five patients (17%) had moderate or severe side effects, including edema and increased creatinine levels.

CONFIRM, a phase III randomized trial, assessed nivolumab (67%) versus placebo (33%) in 332 patients with pleural mesothelioma who had progressed after platinum-based chemotherapy.88 Most patients had pleural mesothelioma (95%) and epithelioid histology (88%); a few patients had PeM (n=16). 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 (hazard ratio, 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).

Somatic ALK rearrangements have been identified in a few young patients with PeM who did not have other genetic alterations.32,37,101103 In 25 young patients (≤40 years of age) with PeM, 2 (8%) had an ALK rearrangement: a 14-year-old female and a 27-year-old male.102 They did not have a history of asbestos exposure or radiation therapy and did not have predisposing germline mutations. The 14-year-old female responded to therapy and survived more than 5 years from the diagnosis of PeM.102 A dramatic response with ceritinib was reported in a 13-year-old girl with PeM who had an ALK rearrangement.104 Other case reports have reported that patients may respond to crizotinib.37,105

NCCN Recommendations

The NCCN panel recommends systemic therapy alone for patients with a PS of 0–2 and diffuse PeM, including those (1) who are medically inoperable, for whom a complete CRS cannot be achieved, or who refuse surgery; (2) with bicavitary disease regardless of histology and stage; (3) with sarcomatoid or biphasic histology regardless of stage; or (4) with recurrence after previous CRS and HIPEC. Surgery may be considered in select patients with bicavitary disease or low-volume biphasic disease (see “Principles of Surgery” in the algorithm, page 972).78 The systemic therapy regimens are also recommended for eligible patients with pleural mesothelioma, pericardial mesothelioma, and tunica vaginalis testis mesothelioma.7,90,92

Although about 50% of patients with PeM have positive PD-L1 expression levels, the NCCN panel does not require PD-L1 testing before using ICIs based on clinical trial data.61,85,88 ICIs are associated with unique immune-mediated adverse events, such as endocrine disorders, that are not seen with traditional cytotoxic chemotherapy. Therefore, healthcare providers should be aware of the spectrum of potential immune-mediated adverse events, know how to manage the adverse events, and educate their patients about possible side effects (see the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities, available at NCCN.org). Atezolizumab, nivolumab, or ipilimumab should be discontinued for patients with severe or life-threatening pneumonitis or myocarditis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated-mediated adverse events when indicated (see prescribing information).

The NCCN panel has preference stratified the first-line systemic therapy regimens for eligible patients with PeM and epithelioid histology who are not eligible for surgery and voted that the following regimens are preferred options: (1) pemetrexed plus cisplatin plus bevacizumab; (2) pemetrexed plus cisplatin; or (3) nivolumab plus ipilimumab.7,86,106,107 Carboplatin is recommended if patients are not candidates for cisplatin, regardless of histology.7,92 The panel voted that the following regimens are useful in certain circumstances for eligible patients with PeM and epithelioid histology: (1) gemcitabine plus cisplatin; (2) pemetrexed; or (3) vinorelbine.86,96,108111

The NCCN panel has preference stratified the first-line systemic therapy regimens for eligible patients with PeM and biphasic or sarcomatoid histology who are not eligible for surgery and voted that nivolumab plus ipilimumab is the preferred option.107 The panel voted that the following are other recommended regimens: (1) pemetrexed plus cisplatin plus bevacizumab; or (2) pemetrexed plus cisplatin.7,86,106 The panel voted that the following regimens are useful in certain circumstances: (1) gemcitabine plus cisplatin; (2) pemetrexed; or (3) vinorelbine.86,96,108111 Carboplatin is recommended if patients are not candidates for cisplatin, regardless of histology.

The NCCN panel has also preference stratified the subsequent (second-line and beyond) systemic therapy regimens for eligible patients with PeM and voted that the following regimens are preferred, regardless of histology, if they were not given first line: (1) pemetrexed plus cisplatin plus bevacizumab; (2) pemetrexed plus cisplatin; (3) pemetrexed; or (4) nivolumab plus ipilimumab.88,112114 However, pemetrexed regimens may be given again as subsequent systemic therapy if a good sustained response was obtained when the initial chemotherapy was interrupted.115,116 The panel decided that the following are other recommended subsequent therapy regimens: (1) atezolizumab plus bevacizumab; (2) vinorelbine; or (3) gemcitabine.85,117120 For the 2023 update (Version 1), the NCCN panel clarified that atezolizumab plus bevacizumab should only be considered as subsequent therapy if patients have not previously been treated with ICIs.

Summary

These NCCN Guidelines focus on PeM. This discussion text for PeM 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. For the 2023 update (Version 1), the NCCN panel revised the title of the guideline to “Mesothelioma: Peritoneal” to align with the pleural mesothelioma guidelines; the previous title was “Malignant Peritoneal Mesothelioma.” The term “malignant” is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.39 The classification for pleural mesothelioma was revised based on new recommendations from the WHO.39,57 The classification for PeM has been revised to align with the pleural mesothelioma guidelines. A new abbreviations list was also added to the guidelines.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum (15%), pleura (85%), and other sites. It is estimated to occur in approximately 3,500 people in the United States every year.14 PeM is estimated to occur in approximately 300 to 400 people in the United States every year.10 The mean age is approximately 69 years at diagnosis of PeM. One-year overall survival is approximately 46% in patients with PeM, and 5-year overall survival is approximately 20%; cure is rare.2,11,121124

Patients with PeM present with abdominal signs and symptoms such as pain, distension, ascites, and an abdominal mass.11,38 Patients with PeM often have a high symptom burden compared with patients who have other types of cancer. The diagnosis of PeM may be delayed because symptoms are nonspecific.11,24,38 Thus, many patients have advanced disease at diagnosis.11 Although PeM can spread extensively in the abdomen, it rarely metastasizes beyond the abdominal cavity.24 For the 2023 update (Version 1), the NCCN panel revised the pathology section to include new information about markers used to identify PeM, which is difficult to diagnose and has distinct molecular features when compared with pleural mesothelioma (see “Principles of Pathologic Review,” in the algorithm, page 967).40 There is no single IHC marker to diagnose PeM. Different IHC markers need to be used to distinguish PeMs from other carcinomas, such as gynecologic malignancies or renal cell carcinomas. A panel of markers is recommended as follows: (1) two mesothelial markers (ie, positive markers), including calretinin and podoplanin (D2-40); and (2) two carcinoma markers (ie, negative markers) including claudin 4, TTF-1, polyclonal CEA, and PAX8.17,50,5864 Although PAX8 is a carcinoma marker, sometimes PeM will stain for PAX8.17,65 WT-1 is generally positive for PeM; however, it is also positive for papillary serous carcinoma.63 For the 2023 update (Version 1), the NCCN panel deleted WT-1 and added PAX8 for the differential diagnosis of PeM.

Data show good outcomes for eligible patients with PeM who have CRS and intraperitoneal chemotherapy.13,14,7577 Therefore, a multidisciplinary evaluation is recommended to assess whether patients are eligible for surgery. Multiple intravenous systemic therapy options exist for patients who are not candidates for CRS or whose disease recurs after CRS with or without HIPEC. Recommended systemic therapy regimens for PeM are mainly based on clinical trials with patients with pleural mesothelioma; the NCCN panel has decided that these regimens are equally efficacious for both disease sites.21,74,89 Details about the systemic therapy clinical trials for pleural mesothelioma are described in the discussion for pleural mesothelioma (see the NCCN Guidelines for Mesothelioma: Pleural, available at NCCN.org). For the 2023 update (Version 1), the NCCN panel reorganized the systemic therapy recommendations for PeM based on histology and line of therapy. The NCCN panel also clarified that atezolizumab plus bevacizumab should only be considered as a subsequent therapy option for patients with PeM if they have not previously been treated with ICIs.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus 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 noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (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 complete NCCN Guidelines for Mesothelioma: Peritoneal are not printed in this issue of JNCCN but can be accessed online at NCCN.org.

© 2023, National Comprehensive Cancer Network® (NCCN®). All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Mesothelioma: Peritoneal Panel

At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Mesothelioma: Peritoneal Panel members can be found on page 979. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)

The complete and most recent version of these guidelines is available free of charge at NCCN.org.

Individual Disclosures for the Mesothelioma: Peritoneal Panel
Individual Disclosures for the Mesothelioma: Peritoneal Panel

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