Inclusion of anti-vascular therapy as a promising option for later-line treatment of malignant pleural mesothelioma: a retrospective study

Introduction

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy arising from the mesothelial cells lining the pleura, peritoneum, pericardium, and tunica vaginalis. While mesothelioma can develop in any of these sites, the pleural form predominates, accounting for over 80% of all cases (1). According to the 2019 China Cancer Registry Annual Report, 583 new mesothelioma diagnoses were recorded in China in 2016, of which 330 (56.6%) were MPMs. The estimated incidence of MPM in China was approximately 0.86 cases per million population—significantly lower than rates reported in Western countries such as those in Europe and the USA.

Several factors contribute to the risk of developing MPMs, including exposure to asbestos, previous radiation therapies, and genetic factors (2). History of asbestos exposure is considered the most important factor in malignant mesothelioma. However, a study has demonstrated that asbestos has a latency period of 30–40 years or more (3). Also, based on pathological findings, the World Health Organization (WHO) has classified pleural mesothelioma into three main subtypes: epithelioid, biphasic and sarcomatoid (4,5). Despite the uniformly aggressive nature and poor prognosis of MPM, with a median survival ranging from 4 to 12 months and a 5-year survival rate of only 5%, significant prognostic differences exist among histological subtypes. Current evidence indicates that the epithelioid subtype is associated with more favorable outcomes compared to the sarcomatoid and biphasic variants (5-7). Furthermore, patients with epithelioid MPM may represent better candidates for surgical intervention, as this subtype demonstrates improved responsiveness to surgical treatment in select cases (8).

For pleural mesothelioma, surgical resection is always incomplete (1). The current first-line therapeutic standard for MPM consists of platinum-based combination regimens. These include: (I) the dual-agent protocol of pemetrexed plus cisplatin, (II) the triple combination of pemetrexed, cisplatin, and bevacizumab, or (III) immunotherapy-based approaches utilizing nivolumab in combination with ipilimumab (9-13). There is still a lack of evidence that anti-vascular therapy has efficacy in later-line. The purpose of this study is to focus on the efficacy and safety of combining chemotherapy with anti-vascular therapy in the second-line and later-line of MPMs and to provide possible effective treatment recommendations for patients with recurrent pleural mesothelioma after first-line treatment. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-566/rc).

Methods

Study design

This retrospective study enrolled patients diagnosed with clinically advanced (stage III or IV) MPM who were ineligible for surgical resection nor radiotherapy and had completed first-line therapy. Data were collected from six medical institutions: Zhejiang Cancer Hospital (Hangzhou), The Second Affiliated Hospital of Guilin Medical University (Guilin), The First Affiliated Hospital of Xiamen University (Xiamen), Affiliated Hospital of Nanjing University of Chinese Medicine (Nanjing), Zhejiang Provincial People’s Hospital (Hangzhou), and Lishui Municipal Central Hospital (Lishui). The study period extended from May 6, 2006, to June 5, 2023. Sixty of the 85 patients enrolled in the study were treated with carboplatin [area under the curve (AUC) 5] or cisplatin (75 mg/m²) in combination with pemetrexed (500 mg/m²) as first-line therapy. Five patients were treated with pemetrexed alone. Fourteen patients were treated with pemetrexed in combination with carboplatin and bevacizumab, and then with chemotherapy combined with an anti-vascular regimen after immunotherapy resistance. The remaining 6 patients were treated with a dual-immune regimen.

We categorized the patients into a chemotherapy group and a combined anti-vascular therapy group based on second or later-line treatment modalities. Chemotherapy was primarily platinum-based, including pemetrexed (500 mg/m²), d1 and carboplatin (AUC 5) or cisplatin (75 mg/m²), repeated every three weeks. Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) and carboplatin or cisplatin. Gemcitabine (1,000 mg/m²), d1, d8, d15, and cisplatin, repeated every three weeks. Bevacizumab/anlotinib/apatinib are used for anti-vascular therapy. Histological classification was performed according to the WHO criteria. Treatment response was evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Eligible patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–2. Study participants were stratified based on their treatment regimens. The exclusion criteria comprised: (I) history of prior malignancies; and (II) significant hepatic or renal dysfunction [defined as Child-Pugh class B/C or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², respectively]. The study adhered to the principles of the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Zhejiang Cancer Hospital (IRB-2023-1119), and all participating institutions were also informed and agreed with the study. Patients’ informed consent for this retrospective analysis was waived.

Treatment responses and toxicity

Patient clinical data were extracted from electronic medical records following a standardized protocol. All therapeutic interventions complied with the National Comprehensive Cancer Network (NCCN) evidence-based dosing and administration protocols. Two independent oncologists assessed tumor response according to the mRECIST v1.1, utilizing chest computed tomography (CT) and/or brain magnetic resonance imaging (MRI) scans at bi-cycle intervals or upon early detection of progression-related symptoms. The objective response rate (ORR) was calculated as the percentage of patients exhibiting complete response (CR) or partial response (PR), while the disease control rate (DCR) included patients demonstrating CR, PR, or stable disease (SD). Overall survival (OS) was determined from the initiation of antiangiogenic therapy until death or final follow-up. Progression-free survival (PFS) was defined as the duration from treatment commencement to radiologically confirmed disease progression, mortality, or last evaluation for non-progressing cases.

Assessment of adverse events

Treatment-emergent toxicities were assessed and classified based on the severity grading system outlined in CTCAE v5.0 (Common Terminology Criteria for Adverse Events, version 5.0). Two independent physicians assessed each event and assigned severity grades ranging from 1 (mild) to 5 (death). To ensure consistency in grading, any discrepancies between assessors were resolved through:

• Comprehensive review of medical records.
• Additional diagnostic tests when indicated.
• Consensus discussion with a third senior oncologist when necessary.

Statistical analysis

All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 9.2.0 (GraphPad Software, San Diego, CA, USA). Categorical variables were compared using either Pearson’s Chi-squared test or Fisher’s exact test, as appropriate for the sample size distribution. Time-to-event outcomes, including PFS and OS, were analyzed using Kaplan-Meier methodology with log-rank tests for between-group comparisons. For multivariate assessment of prognostic factors, we performed Cox proportional hazards regression analysis. All reported P values were two-tailed, with statistical significance defined a priori as P<0.05. Hazard ratios with corresponding 95% confidence intervals were calculated for all Cox model analyses.

Results

Patient characteristics

This multicenter study analyzed patients receiving second-line or subsequent systemic therapy between May 2006 and June 2023. As detailed in Table 1, the cohort (n=85) had a median age of 53 years (range: 13–78) with near-equal gender distribution (47.1% male, 52.9% female). Most cases presented with advanced disease (stage IV: 78.8%), with epithelioid histology predominating (63.5%). Metastatic spread beyond the thorax was observed in 55.3% of cases. PS assessment revealed 89.4% of patients maintained good functional capacity (ECOG PS 0–1), while 10.6% were PS 2. Relevant medical history included smoking (45.9%), prior surgical intervention (40.0%), and radiotherapy exposure (21.2%).

The study population comprised two treatment groups: 34 patients receiving chemotherapy alone and 51 patients treated with combination chemotherapy plus antiangiogenic agents (bevacizumab, apatinib, or anlotinib). As detailed in Table 2, demographic analysis revealed the chemotherapy-only group had a median age of 49 years (range: 40–64 years), compared to 53 years (range: 13–78 years) in the combination therapy group. There are 21 males (61.8%) in group chemotherapy. And the majority of group containing anti-vascular therapy are male (52.9%, 27/51) and 54.9% (28/51) are smokers. Three of the patients chemotherapy had ECOG PS of 2, with the remaining patients having 0 to 1. As for group combining chemotherapy with anti-vascular therapy, six patients (11.8%) had ECOG PS of 2, with the remaining being 0 to 1 (88.2%). Extrathoracic metastases were observed in 17 patients (50.0%) in group chemotherapy and 30 patients (58.8%) in another group. Eighteen (18/34, 52.9%) had undergone early surgical resection and 6 (6/34, 17.6%) had undergone previous radiotherapy in group chemotherapy, while there is 16 (16/51, 31.4%) had undergone early surgical resection and 12 (12/51, 23.5%) had undergone previous radiotherapy in another.

Treatment response and survival analysis

The overall cohort demonstrated an ORR of 12.5% and a DCR of 83.3%. Survival analysis revealed median PFS of 3.73 months [95% confidence interval (CI): 3.29–4.18] and OS of 12.40 months (95% CI: 9.72–15.08). Corresponding Kaplan-Meier survival curves for the 85 MPM patients are presented in Figure 1A,1B. Figure 1C shows the significant difference in median PFS between chemotherapy and combining chemotherapy with anti-vascular therapy in second-line and third-line treatment for MPMs (3.00 vs. 4.57 months, P=0.004). Notably, patients in the group combining chemotherapy with anti-vascular therapy exhibited a superior median OS compared to those who underwent chemotherapy (13.00 vs. 10.03 months, P=0.04) (Figure 1D). We further analyzed monoclonal antibodies (bevacizumab) and small molecule tyrosine kinase inhibitors (TKIs) (apatinib, amlotinib). It was found that the monoclonal antibody did not demonstrate superiority in PFS compared to small molecule TKIs (4.80 vs. 3.93 months, P=0.57), but exhibited a statistically significant difference in OS (19.00 vs. 10.00 months, P=0.009). Figure 2 shows the assessment of the efficacy of mesothelioma patients receiving anti-vascular therapy and the time to treatment discontinuation for MPM patients in all. Both univariate and multivariate Cox regression analyses incorporated the following clinically relevant covariates: gender, age (categorized as ≤60 vs. >60 years), smoking history (never/former/current), prior surgical intervention, radiotherapy exposure, ECOG PS (0–1 vs. 2), disease stage (III vs. IV), metastatic status (intra- vs. extra-thoracic), and treatment modality (chemotherapy alone vs. combination therapy). We found that gender as well as treatment mode showed statistical differences in the univariate analysis, with a P value of 0.02 [hazard ratio (HR) =1.685; 95% CI: 1.070–2.653], 0.004 (HR =0.510; 95% CI: 0.321–0.810). However, only the treatment mode demonstrated statistical differences in the multivariate analysis, with a P value of 0.001 (HR =0.425; 95% CI: 0.251–0.720) (Table 3). Multivariate analysis identified treatment modality as an independent prognostic factor significantly associated with PFS in this cohort (Figure 3).

Figure 1 Kaplan-Meier estimates PFS and OS. (A) PFS of the whole cohort of MPM patients in the second and later line therapy (n=85, mPFS =3.73 months); (B) OS of the whole cohort of MPM patients in the second and later line therapy (n=85, mOS =12.40 months); (C) PFS of patients with chemotherapy and chemotherapy with anti-vascular therapy exhibited the difference (3.00 vs. 4.57 months, P=0.004); (D) OS of patients with chemotherapy and chemotherapy with anti-vascular therapy exhibited the difference (10.03 vs. 13.00 months, P=0.04). CI, confidence interval; mOS, median overall survival; mPFS, median progression-free survival; MPM, malignant pleural mesothelioma; OS, overall survival; PFS, progression-free survival.

Figure 2 Anti-vascular therapy in MPM: efficacy and treatment duration. (A) A waterfall plot using the number of patients as the x-axis and the best response as the y-axis, showing the assessment of the efficacy of anti-vascular therapies received by mesothelioma patients; (B) a swimmer plot showing the time to treatment discontinuation for MPM patients in all. MPM, malignant pleural mesothelioma; PD, progression of disease; PR, partial response; SD, stable disease.

Figure 3 Forest plot of potential factors affecting progression-free survival in the second and later line treatment for MPM, using a Cox proportional hazards model. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; MPM, malignant pleural mesothelioma.

Safety and toxicity

In the course of treatment, 63 adverse reactions occurred in 51 MPMs who received anti-vascular therapy, mainly grade 1–2 treatment-related adverse events (TRAEs) (87.3%, 55/63), including diarrhea, hypertension, anemia, lymphocytopenia, leukopenia, neutropenia, thrombocytopenia and albuminuria. The incidence of grades 3–4 TRAEs was 12.7% (8/63), occurring in 6 patients, including hypertension (3.2%, 2/63), anemia (4.8%, 3/63), lymphocytopenia (1.6%, 1/63), neutropenia (3.2%, 2/63). During the study period, we found six of them discontinuation due to the toxicity of the study drugs; fortunately and none of the patients died due to drug toxicity (Table 4).

Discussion

This investigation represents, to the best of our knowledge, the first comprehensive evaluation of antiangiogenic treatment outcomes in advanced-line MPM. Our findings provide novel insights into both the therapeutic potential and safety profile of this treatment approach for refractory MPM cases. Our findings demonstrated that containing anti-vascular therapy shows a promising efficacy in the second-line treatment or further lines, which may provide a possible effective treatment recommendation for patients.

The first-line treatment for MPM typically involves a combination of pemetrexed and cisplatin, or a triple regimen consisting of pemetrexed, cisplatin, and either bevacizumab or the combination of nivolumab with ipilimumab (2,10,11,14). Vogelzang et al. performed a phase III randomized trial and found that combined therapy prolonged median OS by 2.8 months compared to cisplatin monotherapy (12.1 vs. 9.3 months, P=0.02) (9). CheckMate-743 is an open-label, multicenter, randomized phase III trial that evaluates the efficacy of nivolumab with ipilimumab in the treatment of MPM compared to standard chemotherapy. Results showed that this regimen significantly reduced the risk of death and prolonged median survival by 4 months (18.1 vs. 14.1 months, P=0.002).

For patients with MPM progressing after first-line therapy, pemetrexed-based chemotherapy remains a recommended option for those who did not receive pemetrexed in the initial treatment setting (15). In addition, the exploration of second-line and later-line treatment modes for mesothelioma is still lacking. A retrospective study has shown that gemcitabine and vinorelbine have some benefit and can be used when no other options are available (16). Another phase II trial that evaluated vinorelbine in combination with gemcitabine in relapsed patients who had received pemetrexed as first-line therapy showed a median OS of 10.9 months, indicating that vinorelbine in combination with gemcitabine has some antitumor activity in patients who have failed first-line therapy (17).

Since mesothelioma patients have very high levels of vascular endothelial growth factor (VEGF), there is more exploration of anti-vascular therapy, especially bevacizumab, for the treatment of MPM. A multicenter, randomized, open-label phase III clinical trial evaluated the efficacy and safety of pemetrexed-cisplatin-bevacizumab triple therapy versus standard pemetrexed-cisplatin doublet chemotherapy in patients with previously untreated, unresectable MPM. The results confirmed that in first-line treatment, combined bevacizumab increased median PFS by 1.8 months (5.7 vs. 3.9 months, P=0.001) and median survival by 2.7 months compared with chemotherapy alone (18.8 vs. 16.1 months, P=0.02), which established the first-line treatment mode (9). However, the exploration of anti-vascular therapy for MPM in second-line or later-line is still lacking. A randomized phase II trial combining cisplatin and gemcitabine with bevacizumab for chemotherapy-naive patients did not show an overall benefit of the regimen despite promising preclinical data (18).

As an anti-vascular agent, it has been used as a standard later-line treatment in lung cancer, but has only been reported in a small percentage of MPMs (19,20).

Due to the lack of anti-vascular therapy in the later-line of MPMs in the past, we conducted a systematic study on it. We found that compared with chemotherapy, containing anti-vascular therapy has shown a promising efficacy, which prolonged the median PFS by 4 months and median OS by 5 months. We found that in the small-molecule inhibitor of angiogenesis, one patient (7.1%) achieved PR and 10 (71.4%) patients had SD, while in the group of macromolecular monoclonal antibody, the ORR was 21.6% and DCR was 94.7%. Among the 33 patients treated with anti-vascular therapy, the most common treatment-related grade 3–4 adverse events were anemia, hypertension, lymphocytopenia, and neutropenia, with no treatment-related deaths. These results indicate that combining chemotherapy with anti-vascular therapy may be recommended as an effective therapeutic modality in second-line or later-line treatment of patients with MPM.

This study has several limitations, including its retrospective design, which may introduce inherent biases, and the lack of in-depth pathological subgroup analysis. Although our findings suggest a potential alternative treatment for advanced MPM, prospective studies are needed to validate these results.

Conclusions

Our findings demonstrate that anti-vascular therapy exhibits clinically meaningful activity with a manageable safety profile in patients with relapsed MPM. These results suggest a potential therapeutic strategy for advanced-line treatment of this aggressive malignancy.

Acknowledgments

The authors would like to appreciate all patients and their families for their cooperation and participation. Additionally, we are thankful to all research staff and co-investigators involved in this investigation.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-566/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-566/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-566/prf

Funding: This work was supported by Natural Science Foundation of Zhejiang Province (No. Y22H227294), the China Postdoctoral Science Foundation (No. 2022M723207), the Medical Research Foundation of Zhejiang Province (No. 2023KY666), the Chinese Medicine Science Foundation of Zhejiang Province (No. 2024ZL372), the Qiantang Cross-Fund Project (No. 2023-2016) and the Anhui Provincial Health Research Program (No. AHWJ2022b101).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-566/coif). The authors have 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. The study adhered to the principles of the Declaration of Helsinki and its subsequent amendments and approval of the study protocol was obtained from the Ethics Committee of Zhejiang Cancer Hospital (approval No. IRB-2023-1119). All participating institutions were also informed and agreed with the study. Patients’ informed consent for this retrospective analysis was waived.

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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