NCCN Continuing Education
Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals whomanage patientswith cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by theAccreditationCouncil for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-24-004-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until March 10, 2025. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/94831; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: March 10, 2024; Expiration date: March 10, 2025
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Mesothelioma: Pleural
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Mesothelioma: Pleural
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Kristina Gregory, RN, MSN, OCN, Senior Vice President, Clinical Information Programs, NCCN
Lisa Hang, PhD, Oncology Scientist/Senior Medical Writer, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
James Stevenson, MD, Panel Member, has disclosed receiving grant/research support from Alpha Oncology, Amgen Inc., Black Diamond Therapeutics, and Merck & Co., Inc.; and serving as a scientific advisor for Arcus Biosciences.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Bristol Myers Squibb; Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Seagen. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc., Rahway, NJ, USA.
Overview
Mesothelioma is a rare cancer originating from mesothelial surfaces of the pleura (and other sites) that is estimated to occur in approximately 3,500 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 (∼85%). Mesothelioma can also occur in the lining of other sites, such as the peritoneum (∼15%), pericardium, and tunica vaginalis testis.6–9 PM is difficult to treat, because most patients have advanced disease at presentation. Median overall survival (OS) is approximately 1 year after diagnosis of PM, and 5-year OS is approximately 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
The 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. The NCCN Guidelines for Mesothelioma: Pleural are updated annually.
These NCCN Guidelines Insights summarize recent changes to the guidelines, including revisions based on new WHO terminology for mesotheliomas and updated systemic therapy recommendations.
Pathology
The NCCN Guidelines include an extensive section on pathologic evaluation of tumor tissue for diagnosing PM. The goals of assessment are to confirm the pathologic diagnosis of PM and to determine the histology. The histologic subtypes of mesothelioma include epithelioid (most common), sarcomatoid, and biphasic (mixed), which includes both epithelioid and sarcomatoid.4,18–20 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. See “Principles of Pathologic Review” for comprehensive guidance on pathologic evaluation in the full guidelines on NCCN.org (PM-A).
In 2021, the WHO introduced several changes for mesothelioma and mesothelial tumors, including new terminology: (1) diffuse pleural mesothelioma; (2) localized pleural mesothelioma; and (3) well-differentiated papillary mesothelial tumor (WDPMT).18 Mesothelioma in situ was also added as a new entity. The term malignant is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.18 The panel agreed to update the guidelines to align with the updated WHO terminology (Figure 1).
Principles of pathologic review. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Mesothelioma: Pleural, Version 1.2024 [PM-A 1 of 8].
Citation: Journal of the National Comprehensive Cancer Network 22, 2; 10.6004/jnccn.2024.0014
Systemic Therapy
Medically Operable Pleural Mesothelioma
Chemotherapy is recommended by the NCCN panel as a component of multimodality treatment for patients with medically operable PM (see “Principles of Systemic Therapy” in the full guidelines on NCCN.org [PM-B]). Trimodality therapy—using chemotherapy, surgery, and hemithoracic radiation therapy (RT)—has been studied in patients with medically operable PM.21–28 Median survival of up to 20 to 29 months has been reported for patients who complete trimodality therapy.24,27 Nodal status and response to chemotherapy can affect survival.27,29 In patients who do not receive induction chemotherapy before extrapleural pneumonectomy, postoperative sequential chemotherapy with hemithoracic RT is recommended. Alternatively, if the patient undergoes pleurectomy/decortication, hemithoracic pleural intensity-modulated radiation therapy (IMRT) may be considered at centers that have expertise with this therapy. Intraoperative adjuvant therapies—such as hyperthermic pleural lavage, photodynamic therapy, or heated chemotherapy—have also been studied; however, they are of unclear benefit.30–38
The NCCN panel recommends preoperative (induction) chemotherapy with pemetrexed plus cisplatin (or carboplatin) for patients eligible for surgical exploration (Figure 2). Postoperative chemotherapy with pemetrexed plus cisplatin (or carboplatin) is recommended if patients have not received induction chemotherapy. Please refer to the full guidelines on NCCN.org for additional guidance on surgical options and RT.
Treatment recommendations for stage I–IIIA pleural mesothelioma with epithelioid histology. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Mesothelioma: Pleural, Version 1.2024 [PM-3].
Citation: Journal of the National Comprehensive Cancer Network 22, 2; 10.6004/jnccn.2024.0014
Medically Inoperable Pleural Mesothelioma
First-Line Therapy
CheckMate 743, a phase III randomized trial, assessed first-line therapy with nivolumab plus ipilimumab versus platinum/pemetrexed chemotherapy in 605 patients with unresectable PM.39,40 Many patients had epithelioid histology (75%). Most of the patients were males (77%), and the median age was 69 years.39 Updated results from this trial showed that the median OS was 18.1 months (95% CI, 16.8–21.0) in patients receiving nivolumab plus ipilimumab versus 14.1 months (95% CI, 12.4–16.3) in those receiving chemotherapy (hazard ratio [HR], 0.73; 95% CI, 0.61–0.87).40 The 3-year OS rate was 23.2% (95% CI, 18.4%–28.2%) in the nivolumab plus ipilimumab group versus 15.4% (95% CI, 11.5%–19.9%) in the chemotherapy group.40 The trial was not powered to assess superiority within the subgroups; however, among patients with epithelioid histology, the median OS was 18.2 months (95% CI, 16.9–21.9) in those receiving nivolumab plus ipilimumab versus 16.7 months (95% CI, 14.9–20.3) in those receiving chemotherapy (HR, 0.85; 95% CI, 0.69–1.04).40 Among patients with nonepithelioid histology, the median OS was 18.1 months (95% CI, 12.2–22.8) in those receiving nivolumab plus ipilimumab versus 8.8 months (95% CI, 7.4–10.2) in those receiving chemotherapy (HR, 0.48; 95% CI, 0.34–0.69).40 Grade 3 to 4 treatment-related adverse events (AEs) were similar in both groups: 31% of patients receiving nivolumab plus ipilimumab and 32% of those receiving chemotherapy.40 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.39
A phase III randomized trial assessed cisplatin/pemetrexed versus cisplatin alone in patients with PM who were not candidates for surgery; the combined regimen increased the median survival time by 2.8 months compared with cisplatin alone (12.1 vs 9.3 months, P=.02).41 The pemetrexed/carboplatin regimen was assessed in 3 large phase II studies; the reported median OS ranged from 12.7 to 14 months.42–44 An expanded access trial evaluating cisplatin/pemetrexed or carboplatin/pemetrexed in 1,704 patients with medically inoperable PM demonstrated that the 2 regimens resulted in similar 1-year survival rates.45
A multicenter phase III randomized trial (IFCT-GFPC-0701 MAPS) evaluated the addition of bevacizumab to cisplatin/pemetrexed (with maintenance bevacizumab) versus cisplatin/pemetrexed alone for patients with unresectable PM and performance status (PS) 0–2 who did not have any substantial cardiovascular comorbidity.46 OS was longer in the bevacizumab plus cisplatin/pemetrexed arm by 2.7 months when compared with cisplatin/pemetrexed alone (18.8 vs 16.1 months; HR, 0.77; P=.0167). Grade 3 to 4 AEs were reported in 71% (158/222) of patients receiving the bevacizumab-containing regimen compared with 62% (139/224) of those receiving cisplatin/pemetrexed alone. More grade ≥3 hypertension (23% vs 0%), grade 3 proteinuria (3% vs 0%), and grade 3 to 4 thrombotic events (6% vs 1%) were observed in patients receiving the triplet arm.
A phase II open-label study assessed bevacizumab in combination with carboplatin/pemetrexed as a first-line therapy in 76 patients with unresectable pleural mesothelioma.47 The median OS was 15.3 months. A partial response was observed in 34.2% (26/76) of patients, whereas 57.9% (44/76) had stable disease. Bevacizumab is not recommended for those with uncontrolled hypertension, risk for bleeding or clotting, and substantial cardiovascular morbidity.48
Data from several phase II studies suggest that gemcitabine/cisplatin may also be effective as a first-line treatment option49–51; this regimen may be useful for patients who cannot receive pemetrexed. Other first-line options include pemetrexed or vinorelbine for patients who are not candidates for platinum-based combination therapy.52–54
NCCN Recommendations
The NCCN panel recommends systemic therapy alone for patients with PM and PS 0–2 and are medically inoperable or refuse surgery; have clinical stage IIIB to IV PM, regardless of histology; or have sarcomatoid or biphasic histology, regardless of clinical stage. See Figure 3 for complete treatment recommendations for stage IIIB or IV PM, tumors with sarcomatoid or biphasic histology, or medically inoperable PM.
Treatment recommendations for stage IIIB or IV pleural mesothelioma, tumors with sarcomatoid or biphasic histology, or medically inoperable pleural mesothelioma. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Mesothelioma: Pleural, Version 1.2024 [PM-2].
Citation: Journal of the National Comprehensive Cancer Network 22, 2; 10.6004/jnccn.2024.0014
Systemic therapy followed by consideration of pleural IMRT is also recommended as an option for stage I–IIIA PM with epithelioid histology deemed unresectable following surgical exploration. For the 2023 update (Version 1), the panel clarified that systemic therapy may be appropriate for select patients with clinical stage I–IIIA PM and epithelioid histology who are not candidates for surgical exploration. Observation can also be considered for patients with PM who are asymptomatic with minimal burden of disease if systemic therapy is planned at the time of symptomatic or radiographic progression. See Figure 2 for complete treatment recommendations for stage I–IIIA PM with epithelioid histology.
Nivolumab plus ipilimumab (category 1) is included as a preferred first-line systemic therapy option for eligible patients with unresectable PM, regardless of histology, based on clinical trial data and the FDA approval.39,40 Testing for PD-L1 is not required for prescribing nivolumab for therapy for patients with PM. Immune-related AEs, such as pneumonitis, may occur with nivolumab plus ipilimumab (see NCCN Guidelines for Management of Immunotherapy-Related Toxicities, available at NCCN.org).55–57
The NCCN panel recommends cisplatin/pemetrexed (category 1) as a first-line therapy option for patients with PM based on clinical trial data and the FDA approval.39,41,46,58–60 The addition of bevacizumab to this regimen (also category 1) is recommended only for unresectable disease. An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
For patients who are not candidates for cisplatin, substitution with carboplatin can be considered. Pemetrexed/carboplatin regimens (with or without bevacizumab) are category 2A options for first-line therapy.
Pemetrexed/platinum regimens (with or without bevacizumab) are included in the guidelines as “Preferred” options for PM with epithelioid histology, and as “Other Recommended” options for PM with biphasic or sarcomatoid histology. The panel recommends the following as regimens that may be “Useful in Certain Circumstances,” regardless of histology: (1) gemcitabine/cisplatin (or carboplatin), (2) pemetrexed, or (3) vinorelbine.
All of the recommended systemic therapy regimens are also appropriate for the treatment of pericardial mesothelioma and tunica vaginalis testis mesothelioma. The panel also recommends broad molecular tumor profiling to identify any rare driver alterations (eg, NTRK or ALK) and appropriate targeted therapy opportunities or to counsel patients about the availability of potential clinical trials. See Figure 4 for a complete list of recommended systemic therapy options for PM.
Principles of systemic therapy. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Mesothelioma: Pleural, Version 1.2024 [PM-B 1 of 2].
Citation: Journal of the National Comprehensive Cancer Network 22, 2; 10.6004/jnccn.2024.0014
Subsequent Therapy
Historically, there have been limited data available to guide second-line and beyond (subsequent) therapy in patients with PM.38,61–64 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.65–70
CONFIRM, a phase III randomized trial, assessed nivolumab (67%) versus placebo (33%) in 332 patients with PM after progression on platinum-based chemotherapy.65 Most patients had PM (95%) and epithelioid histology (88%). Median OS 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; P=.009). Grade 3 or worse AEs were reported in 3% of patients receiving nivolumab (diarrhea and infusion-related reaction, 6/221). Serious AEs were similar between the groups (41% for nivolumab vs 44% for placebo).
A phase II randomized trial (IFCT-1501 MAPS2; n=125) assessed nivolumab with (or without) ipilimumab as subsequent therapy for patients with PM.66,68,69 Updated results from this trial showed that the median OS 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.66,69 The 12-month OS rates were 58% with the nivolumab/ipilimumab arm and 49% with nivolumab alone. The disease control rate at 12 weeks was 52% (32/62) for nivolumab/ipilimumab versus 40% (25/63) for nivolumab alone.66 Positive PD-L1 levels were associated with overall response rate, especially high PD-L1 levels of ≥25%. However, only a few patients had high PD-L1 expression levels of ≥50%. There were more grade 3 to 4 AEs in the nivolumab/ipilimumab arm compared with the nivolumab alone arm (26% vs 14%) based on updated data; 3 treatment-related deaths were reported in the nivolumab/ipilimumab arm (one each: metabolic encephalopathy, fulminant hepatitis, and acute renal failure).66 A phase II single-arm study in the Netherlands (INITIATE) also assessed nivolumab/ipilimumab as subsequent therapy in patients with PM.67 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.67 Grade 3 treatment-related AEs were reported in 34% (12/35) of patients; 94% (33/35) of patients had treatment-related AEs.
The panel has also considered the efficacy of chemotherapy-based regimens after progression on first-line therapy. A phase III randomized trial assessed subsequent therapy with pemetrexed plus best supportive care versus best supportive care alone in 243 patients with PM after progression on chemotherapy (excluding pemetrexed).71 Median OS was not statistically significant between the arms (8.4 months for pemetrexed and supportive care vs 9.7 months for supportive care only; P=.74); however, this result may be explained in part due to the design of the study, because patients could cross over to pemetrexed.
Based on available data, the panel consensus is that rechallenging with pemetrexed-based regimens can be effective if there was a good disease response following first-line pemetrexed.61,72 A retrospective multicenter database study reported that rechallenging with a pemetrexed/platinum regimen reduced the risk of death when compared with rechallenging with pemetrexed alone (HR, 0.11; P<.001).72
PROMISE-meso, a multicenter phase III randomized trial, assessed subsequent therapy with pembrolizumab versus either gemcitabine or vinorelbine in 144 patients with relapsed PM after progression on platinum-based chemotherapy.73 There was no significant difference in OS between the groups (HR, 1.12; 95% CI, 0.74–1.69; P=.59). The panel continues to support the inclusion of single-agent vinorelbine and single-agent gemcitabine, but not pembrolizumab, as subsequent therapy options based on data from this trial and other published studies.73–77
The RAMES phase II randomized trial evaluated gemcitabine with or without ramucirumab as a subsequent therapy in 161 patients with PM after progression on platinum/pemetrexed chemotherapy.78 The median OS was longer in patients who received both gemcitabine and ramucirumab than in those who received gemcitabine and placebo (13.8 vs 7.5 months; HR 0.71; P=.028).
NCCN Recommendations
The NCCN Panel recommends nivolumab (with or without ipilimumab) as a preferred subsequent therapy option, if chemotherapy was administered in the first-line setting, regardless of histology. Rechallenge with pemetrexed-based therapy can also be considered if there was a good response to front-line pemetrexed-based therapy.
If nivolumab/ipilimumab was administered as first-line therapy, the panel recommends the following regimens as preferred subsequent therapy options: (1) pemetrexed (category 1), or (2) cisplatin (or carboplatin) and pemetrexed (with or without bevacizumab). Other recommended options in this setting include: (1) vinorelbine, or (2) gemcitabine (with or without ramucirumab). For the 2022 update (Version 1), the NCCN panel removed pembrolizumab as a subsequent therapy option for patients with relapsed PM based on updated data.73
See Figure 4 for a complete list of recommended systemic therapy options for PM.
Summary
The NCCN Guidelines for Mesothelioma: Pleural have been revised to align with updated WHO classification for mesotheliomas. The NCCN panel has also provided updated recommendations for first-line and subsequent systemic therapy options for the treatment of pleural mesothelioma based on available data. The guidelines will continue to be updated annually based on clinical evidence and panel consensus.
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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
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