Neoadjuvant systemic therapy for pleural mesothelioma patients: a systematic review

Introduction

Pleural mesothelioma is a rare type of cancer that originates from the pleura, the tissue that covers the lungs and the interior wall of the chest cavity (1). This tumor is associated with a poor prognosis (2,3). The role of surgery in managing pleural mesothelioma remains a subject of debate (4,5). The European Society for Medical Oncology (ESMO) guideline [2022] suggests that macroscopic complete resection, involving the removal of all visible and palpable tumor within the hemithorax, may be an option for selected patients treated in experienced centers as part of a multimodality approach (6). The recently published American Society of Clinical Oncology (ASCO) guideline [2025] states that surgical cytoreduction can be offered to highly selected patients with favorable prognostic characteristics, such as those with clinically early-stage (T1–3N0) epithelioid tumors (7). The definition of resectable disease remains a matter of ongoing discussion. While it is generally accepted that patients with metastatic disease are not resectable, the criteria for resectability are inconsistent across different centers and studies (6). There are different types of surgery, including extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) (4). A meta-analysis comparing survival outcomes between P/D and EPP in patients with pleural mesothelioma found a significantly higher proportion of short-term deaths in the EPP group compared to the P/D group (meta-estimate for mortality: 4.5% vs. 1.7%; P<0.05) (8). In addition to the definition of resectable disease the timing of surgery within a multimodality regimen is still controversial. The European Organisation for Research and Treatment of Cancer (EORTC)-1205-LCG trial investigated the optimal sequencing of systemic therapy and surgery, comparing pre- and postoperative chemotherapy (9). The study found no significant difference in the success rate at 20 weeks between the adjuvant and neoadjuvant chemotherapy regimen. Neoadjuvant therapy aims to reduce the size of the malignancy and to provide early treatment of micrometastatic disease (9). Recently, several clinical trials have investigated the efficacy of neoadjuvant treatment in melanoma and non-small cell lung cancer (10,11). Given the increasing number of studies supporting favorable outcomes of neoadjuvant therapy in various tumor types, we aim to systematically review prospective trials evaluating neoadjuvant treatment in pleural mesothelioma to determine its potential benefits in pleural mesothelioma patients. We present this article in accordance with the PRISMA reporting checklist (12) (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-719/rc).

Methods

Data sources and searches

MEDLINE and Embase databases were searched from inception to July 01, 2024 with no language restriction for phase II or III single-arm and randomized controlled trials. Abstracts, conference posters and gray literature were excluded. The screening of eligible publications was carried out independently by two reviewers (I.S. and J.R.). First, the titles and abstracts of all citations were reviewed. After removal of duplicates, the full text of potentially relevant articles was reviewed. Prospective trials were included if they concerned adult patients (aged ≥18 years) with histology-proven pleural mesothelioma treated with neoadjuvant systemic therapy followed by surgery. We also included trials with radiotherapy if radiotherapy was part of the neoadjuvant treatment. Discrepancies were resolved by consensus. The complete search strategy can be found in Appendix 1.

Data extraction

Extracted data included baseline characteristics [disease stage, sample size, World Health Organization (WHO) performance status, sex, histology, age], type of neoadjuvant treatment, number of cycles, response rate of neoadjuvant treatment, type of surgery, application of radiotherapy, survival, peri- and postoperative mortality, resectability, and adverse events. For randomized controlled trials, the hazard ratios for overall survival and their 95% confidence intervals (CIs) were recorded.

Data synthesis and analysis

Data were summarized using descriptive statistics, with median and interquartile range (IQR) for continuous variables and frequencies and percentages for dichotomous variables when individual patient data was available. Pooled estimates were calculated using a fixed-effect model to account for variability between studies. Standard errors were derived from the CIs provided in the studies. Statistical analyses included the calculation of pooled effect sizes with corresponding 95% CIs. A P value <0.05 was considered statistically significant for heterogeneity. All statistical analyses were conducted in RStudio version 4.2.1 and the significance level was set at P<0.05.

Results

A total of 202 papers were initially retrieved through database searching. After the removal of 68 duplicate records, 134 papers remained. Through title and abstract screening, we identified 87 records. An additional 71 papers were excluded after full-text screening because these were reviews, retrospective cohorts, or case reports. Ultimately, 16 publications met the inclusion criteria. These included 12 non-randomized prospective phase II trials, 2 randomized phase II trials, and 2 randomized phase III trials, see Figure 1. The studies collectively included 1,184 patients, of whom 861 (72.7%) were male, with a median age range of 57 to 69 years.

Figure 1 Flowchart of identification of studies.

All trials permitted the inclusion of patients with N1 disease, while 13 trials also included patients with N2 disease (13-25). The studies included between 19 and 335 patients. With regard to histology, 907 patients had an epithelioid subtype, 215 had a non-epithelioid subtype, and histology was unknown for 62 patients. There were seven single-center and nine multicenter studies, conducted in Switzerland, United States of America (USA), Italy, Switzerland, Belgium, the Netherlands, Egypt, United Kingdom (UK), Germany and Japan. See Table 1 for the baseline characteristics.

Among the included studies, 15 trials treated patients with neoadjuvant chemotherapy, while only one trial treated patients with neoadjuvant immunotherapy using durvalumab, either in monotherapy or in combination with tremelimumab, see Table 2. The neoadjuvant treatments consisted of platinum plus gemcitabine (6 trials), platinum plus pemetrexed (12 trials), cisplatin-mitomycin-vinblastine (1 trial), cisplatin-vinorelbine (1 trial), durvalumab monotherapy (1 trial), and durvalumab-tremelimumab (1 trial).

EPP was the surgery of choice in thirteen different studies (n=482; 40.7%), while a (partial) P/D (n=248; 20.9%) was performed in four studies, and extrapleural thoracoplasty (ET) (n=2; 0.2%) in one study, as shown in Table 2. This reflects an evolution in clinical practice rather than just a matter of choice as a meta-analysis assessing survival outcomes in pleural mesothelioma patients comparing P/D and EPP revealed a significantly higher rate of short-term mortality in the EPP group than in the P/D group (meta-estimate for mortality: 4.5% vs. 1.7%; P<0.05) (8).

The 90-day postoperative mortality ranged between 0–13.3%. The pooled estimate for the median overall survival for the intention-to-treat population in the single-arm trials was 17.4 months (95% CI: 15.8–19.0); n=523, see Figure 2. The pooled estimate for the median overall survival for the patients who underwent surgery in the single-arm trials was 21.4 months (95% CI: 19.2–23.7), n=345, see Figure 2. Fourteen trials involved postoperative radiotherapy, see Table 2. The percentage of the intention-to-treat population per study that was ultimately deemed resectable ranged between 42–93%, see Table 2.

Figure 2 Forest plots of survival (A) intention to treat population and (B) surgery population of single arm studies. The overall survival data from Federico et al. (19) is not included in the forest plot because of a missing upper bound of the 95% CI, and Hasegawa et al. (23) only reported the overall survival of the patients who underwent surgery. (A) Forest plots of survival for the intention-to-treat population. (B) Forest plots of survival of the patients who underwent surgery. CI, confidence interval.

Peri- and postoperative grade ≥3 adverse events are summarized for the single-arm studies (see Tables S1,S2). The most common grade ≥3 events in patients treated with neoadjuvant systemic therapy were hematologic adverse events: neutropenia (9.5%), leukopenia (3.8%), and anemia (3.5%). The most common post-surgical grade ≥3 events were arrhythmias (11.1%), pulmonary hemorrhage (4.7%), and pulmonary infection (4.5%).

Randomized controlled trials

Four randomized neoadjuvant trials fulfilled the selection criteria. One phase III trial randomized between treatment with EPP versus no EPP as part of a trimodality regimen and found that the median survival was 14.4 months (range, 5.3–18.7 months) for the EPP group and 19.5 months (range, 13.4 months to not yet reached) for the no EPP group (26). However, the study was powered based on the difference in effectiveness between EPP and natural history data. The second phase III trial randomized patients between chemotherapy plus extended pleurectomy decortication versus chemotherapy alone and found a shorter median survival in the extended pleurectomy decortication and chemotherapy group [19.3 months (IQR, 10.0–33.7 months)] than in the chemotherapy alone group [24.8 months (IQR, 12.6–37.4 months)], P=0.01 (25). In the phase II trial of Lee et al. patients were randomized into three different arm of different neo-adjuvant therapy: one dose of neo-adjuvant durvalumab, one dose of neo-adjuvant durvalumab-tremelimumab and no immunotherapy followed by surgery (24). This is the only study in which patients received immunotherapy as a neo-adjuvant treatment. Raskin et al focused on the sequence of pre- and postoperative chemotherapy and randomized patients in two arms: immediate surgery and deferred surgery (9). No significant preferred sequence for pre- or postoperative chemotherapy was measured.

Interestingly, the only study that used immunotherapy as a neoadjuvant treatment revealed an immunotherapy related toxicity profile in the patient group receiving the neoadjuvant combination immunotherapy (24). Three patients (27.3%) developed grade 3 toxicities, including acneiform rash, hyperglycemia, and drug-induced hepatitis (24). The MARS-2 trial also showed a significantly higher number of serious adverse events in the surgery group compared to the chemotherapy group (incidence rate ratio 3.6, 95% CI: 2.3–5.5, P<0.0001), particularly an increased rate of infections, respiratory and cardiac adverse events and surgery-related adverse events (25). The grade ≥3 adverse events profile of the EORTC 1205 study is consistent with that of other studies that used chemotherapy as a neoadjuvant treatment (9).

Discussion

Our study systematically reviewed prospective neoadjuvant trials for resectable pleural mesothelioma patients and revealed that the pooled median overall survival of the intention-to-treat population in single-arm trials was 17.4 months (95% CI: 15.8–19.0); n=523, with patients undergoing surgery achieving a median overall survival of 21.4 months (95% CI: 19.2–23.7), n=345. The data do not allow a balanced analysis whether neoadjuvant therapy is beneficial, contributing to a better survival, or detrimental, possibly denying patients a surgical procedure from which they might have benefitted or impairing macroscopical complete resection. Our data also shows that the percentage of patients from the intention to treat population who were ultimately deemed operable was highly variable, ranging from 42% to 93%. This wide range highlights how the definition of resectable disease can differ between treating teams. The lack of consensus on the definition of resectability between different studies may explain the heterogeneity of outcomes across various studies.

The only phase III study that has compared neoadjuvant chemotherapy plus extended pleurectomy decortication versus chemotherapy alone found a shorter median overall survival in the extended pleurectomy decortication and chemotherapy group [19.3 months (IQR, 10.0–33.7 months)] compared to the chemotherapy alone group [24.8 months (IQR, 12.6–37.4 months)], but was criticized for its high 90-day mortality and lower median OS compared to other trials (25). This review does not provide new insights into the adverse effects of neoadjuvant chemotherapy treatment studies. The most common grade ≥3 adverse events in patients treated with neoadjuvant chemotherapy were hematologic events. After surgery, the most frequent grade ≥3 events were arrhythmias (11.1%), pulmonary hemorrhage (4.7%), and pulmonary infection (4.5%). However, the only study that treated patients with neoadjuvant immunotherapy showed a different side effect profile, particularly immune therapy-related adverse events, compared to the neoadjuvant chemotherapy studies. Unfortunately, not all trials reported uniformly on adverse events. Patients undergoing surgery who have experienced grade 3 hematologic events due to neoadjuvant chemotherapy may be more susceptible to pulmonary hemorrhage and infection. This raises the hypothesis of whether neoadjuvant treatment with immunotherapy (which has less hematologic toxicity) would be a better neoadjuvant treatment option. No trials in which neoadjuvant chemotherapy and immunotherapy are combined have been published so far, but the first trials are currently recruiting. Another discrepancy in reporting results between the studies is that complete response is defined differently. Most studies define complete response as a macroscopically complete response, and these percentages are very high. However, when looking at the studies that define complete response as pathological/microscopically complete response, the percentage is much lower (see Table 2).

To our knowledge, this is the first systematic review that evaluates neoadjuvant treatment for resectable pleural mesothelioma. Our review highlights the variation in inclusion criteria (N-stage), neoadjuvant therapies, adjuvant treatments, surgical procedures and definition of resectable disease and complete response. By summarizing the results of all prospective trials, we provide a comprehensive overview of treatment regimens, perioperative outcomes and survival. This study has several limitations. First, the inclusion of both single-arm and randomized trials introduces variability in treatment protocols and outcome measures, making direct comparisons challenging. Second, the predominance of single-arm phase II studies among the trials included limits the generalizability of the findings. Furthermore, the heterogeneity in patient selection criteria, particularly concerning the definition of resectability, and adjuvant treatment complicates the ability to draw definitive conclusions. Additionally, the surgical procedure evolved from EPP in earlier trials to extended P/D, reflecting new insights into survival outcomes in pleural mesothelioma patients. Studies comparing P/D and EPP have shown a significantly higher rate of short-term mortality in the EPP group compared to the P/D group (8).

Despite these limitations, the strengths of our study lie in its systematic approach, the exclusive inclusion of prospective trials, and its focus on neoadjuvant therapy. This is an area that remains underexplored in the management of pleural mesothelioma. Additionally, with dual immunotherapy emerging as a new treatment for non-resectable pleural mesothelioma, it highlights that immunotherapy could be an option for neoadjuvant treatment that should be explored further. Our review emphasizes the need for standardized reporting in phase II (neoadjuvant) studies in mesothelioma. There is also a need for more randomized controlled trials to demonstrate the added value of surgery, as the only study comparing neoadjuvant treatment with surgical treatment, the MARS-2 trial, showed significantly worse survival in the surgical group (25). Furthermore, this study highlights the need for standardized criteria for resectability and surgery type within multimodality regimens. We believe that, for a new randomized trial, resectability should be clearly defined. Additionally, since nivolumab/ipilimumab is a new first-line therapy, this treatment should be included as a treatment option, and the trial should stratify for neoadjuvant immunotherapy or chemotherapy. By identifying the variability and gaps in current research, we provide a foundation for future studies aimed at optimizing neoadjuvant strategies and improving survival outcomes for this challenging disease.

Conclusions

In conclusion, our systematic review highlights the limited evidence supporting the role of surgery in neoadjuvant strategies for pleural mesothelioma, as the only study comparing neoadjuvant treatment with surgical treatment is the MARS-2 trial showed significantly worse survival in the surgical group. This emphasizes the need for more randomized controlled trials to clarify its added value. The variability in treatment protocols, inclusion criteria, and surgical approaches underscores the necessity for standardized definitions and methodologies to enable meaningful comparisons and improve treatment outcomes. By addressing these gaps, future research can build upon our findings to optimize multimodality regimens and advance the management of this challenging disease.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-719/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-719/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-719/coif). J.R. declares receiving funding from Daiichi Sankyo, AstraZeneca, Janssen, GSK, MSD, BMS for attending conferences and funding from Roche, Merck, AstraZeneca, Pfizer, BMS for consultancy. J.A.B. declares receiving funding of an investigator-initiated study by Merck. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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