Incidence and Outcomes of Brain Metastasis in Pleural Mesothelioma in the Era of Immunotherapy

Our plain-English summary of Incidence and Outcomes of Brain Metastasis in Pleural Mesothelioma in the Era of Immunotherapy, by M. Stalker, S.L. Walker, E. Lebow, et al (JTO Clinical and Research Reports, 2025).

The study

• Authors: M. Stalker, S.L. Walker, E. Lebow, E.L. Pai, A. Watts, W.T. Hwang, A. Banihashemi, E. Anderson, L. Roshkovan, S.I. Katz, L. Litzky, A.R. Haas, S. Singhal, C.J. Langer, K. Cengel, M.E. Marmarelis
• Journal: JTO Clinical and Research Reports
• Published: 2025;6(5):100823
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Immunotherapy (IO) has reported efficacy in pleural mesothelioma (PM). Brain metastases (BMs) in PM are rare; thus, surveillance brain imaging is not included in the guidelines. We evaluated the incidence of BM by treatment type.

Methods: In this retrospective analysis, patients with PM treated at the University of Pennsylvania between January 1, 2015, and August 31, 2023, were included. Demographic and clinical data were extracted from the medical records. The treatment categories included chemotherapy, single-agent IO, and dual-agent IO. A two-tailed Z score was used to determine a difference in the proportion of BM. Overall survival (OS) was analyzed using the Kaplan-Meier method. Of those with BM, available brain tissue was further analyzed.

Results: In total, 251 patients were included; the median age of the participants was 73 years (range: 35-92 y), 79% were male individuals, 91% were white, and 73% had epithelioid histology. In the study, 102 (40.6%) were treated with chemotherapy, 100 (39.8%) with single-agent IO, and 49 (19.5%) with dual-agent IO. The median OS (mOS) was 21.6 months (95% confidence interval: 17.7-25.5) and did not differ between treatment groups (p = 0.774). A higher proportion of patients treated with IO developed BM than those treated with chemotherapy (6/149 [4%] versus 0/102 [0%]; Z score p = 0.04). The mOS from BM diagnosis was 95 days (range: 16-1025 d). The histomorphology of three patients with available brain tissue were similar to the primary site and reported substantial edema and hemorrhage.

Conclusions: In this retrospective study, clinically significant BM was most prevalent in those exposed to IO and not seen in those receiving chemotherapy despite similar mOS between the groups. Brain imaging should be considered before starting IO in patients with PM.

© 2025 The Authors.

In plain English

This retrospective cohort study looked at 251 adults with pleural mesothelioma treated within the University of Pennsylvania Health System between January 1, 2015, and August 31, 2023. It asked how often brain metastases (cancer spread to the brain) were diagnosed, by type of treatment. Patients were grouped as chemotherapy without immunotherapy (102), single-agent immunotherapy (100), or dual-agent immunotherapy with ipilimumab and nivolumab (49). Median overall survival was similar across the three groups. Brain metastases were found in 6 of 149 immunotherapy patients (4%) and 0 of 102 chemotherapy patients (p = 0.04). The difference between dual-agent (4 of 49, 8.2%) and single-agent immunotherapy (2 of 100, 2%) was not statistically significant. Only 121 patients (48%) ever had brain imaging. All six patients with brain metastases had symptoms, and median survival after that diagnosis was 95 days. The authors concluded that diagnosed brain metastases were more prevalent after immunotherapy and that more brain surveillance is warranted. They noted that the study was retrospective and that brain imaging was not done routinely, so the true incidence is unknown.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective cohort study using medical records from one health system, with tissue analysis of available brain metastasis samples
• Who was studied: 251 adults with pleural mesothelioma treated within the University of Pennsylvania Health System between January 1, 2015, and August 31, 2023 (data cutoff June 28, 2024). Median age 73, 79% male, 91% white, 73% epithelioid histology. Patients with peritoneal mesothelioma were excluded.
• Exposure: Type of cancer treatment received at any line of therapy: chemotherapy without ever receiving immunotherapy, single-agent immunotherapy (mainly pembrolizumab), or dual-agent immunotherapy (ipilimumab plus nivolumab). The study does not examine asbestos exposure.
• Main results:
  • Of the 251 patients, 102 (40.6%) received chemotherapy, 100 (39.8%) single-agent immunotherapy and 49 (19.5%) dual-agent immunotherapy
  • Median overall survival was 16.4 months for chemotherapy, 24.0 months for single-agent immunotherapy and 20.6 months for dual-agent immunotherapy, with confidence intervals as printed
  • Median overall survival was similar across the three treatment groups (log-rank p = 0.774)
  • Brain metastases developed in 6 of 149 (4%) immunotherapy-treated patients versus 0 of 102 (0%) chemotherapy-treated patients (Z score p = 0.04)
  • Brain metastases occurred in 4 of 49 (8.2%) dual-agent (ipilimumab/nivolumab) patients versus 2 of 100 (2%) single-agent immunotherapy patients. This difference was not statistically significant (p = 0.072).
  • Only 121 of the 251 patients (48%) had brain imaging at any point
  • Among the 121 patients with brain imaging (sensitivity analysis), brain metastases occurred in 4 of 33 (12%) dual-agent immunotherapy patients versus 0 of 42 (0%) chemotherapy patients (p = 0.020)
  • Among patients with brain imaging, 6 of 79 (7%) of any-immunotherapy patients versus 0 of 42 (0%) chemotherapy patients developed brain metastases. The authors described this as a trend toward significance (p = 0.067).
  • All six patients with brain metastases had symptoms that prompted the brain imaging
  • Median survival after brain metastasis diagnosis was 95 days (range 16 to 1025 days) among the six patients
  • Brain tissue from three of the six patients looked similar to the primary tumor (two sarcomatoid, one epithelioid). Macrophages (CD163 positive) were the dominant inflammatory cells.
  • Patients with brain imaging had longer median overall survival than those without: 25.9 months versus 17.7 months (p = 0.01)
• The authors' conclusion: The authors concluded that diagnosed brain metastases were more prevalent in pleural mesothelioma patients who had received immunotherapy, and that patients who develop brain metastases have a poor prognosis. They called for more research on treatment and stated that more brain surveillance is warranted, particularly for those receiving checkpoint blockade.
• Limitations the authors state:
  • The study was retrospective, and pleural mesothelioma is rare
  • This was a real-world cohort, so some data were missing for some patients
  • Brain imaging was not done for everyone because it is not routinely recommended for patients without symptoms
  • The true incidence of brain metastases would require a cohort with routine surveillance brain imaging

Topics

Medical terms in this study, explained in our Lexicon: Metastasis, Pleural Mesothelioma, Immunotherapy, Chemotherapy, Overall Survival, Epithelioid, Histology, confidence interval.

Related studies

• Brain metastasis in malignant pleural mesothelioma — A. Kawai, Y. Nagasaka, et al. (1997)
• Brain metastasis in malignant pleural mesothelioma presenting as intratumoral hemorrhage — T. Ishikawa, H. Wanifuchi, et al. (2010)
• Gamma knife radiosurgery of brain metastasis from malignant pleural mesothelioma--report of three cases with autopsy study in a case — T. Kobayashi, T. Tsugawa, et al. (2014)
• Brain Metastasis of Pleural Mesothelioma after a Subarachnoid Hemorrhage — A. Hirooka, A. Tamiya, et al. (2016)
• A case of brain metastasis with pathological transformation of long-surviving malignant pleural mesothelioma: illustrative case — R. Noda, S. Yanagisawa, et al. (2021)
• Genetic and Immunohistochemical Profiling of Malignant Mesothelioma With Brain Metastasis: A Report of Two Cases — P.M. Harary, Y.S. Hori, et al. (2026)

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