Efficacy and safety profile of combining antiangiogenic agents with chemotherapy in patients with advanced malignant pleural mesothelioma: A systematic review and meta-analysis of randomized controlled trials

Our plain-English summary of Efficacy and safety profile of combining antiangiogenic agents with chemotherapy in patients with advanced malignant pleural mesothelioma: A systematic review and meta-analysis of randomized controlled trials, by W. Tian, Q. Guo, D. Fu, et al (PloS One, 2023).

The study

• Authors: W. Tian, Q. Guo, D. Fu, X. Ma, R. Wang
• Journal: PloS One
• Published: 2023;18(12):e0295745
• Type of article: Meta-analysis, Systematic review
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: Several prospective trials had been reported on chemotherapy with or without antiangiogenic agents in patients with advanced malignant pleural mesothelioma (MPM), with diverse results. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of the combination regimen.

Methods: We systematically identified trials in several databases, including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts. All the randomized controlled trials (RCTs) about chemotherapy combined with antiangiogenic agents in advanced MPM were identified. Overall survival (OS) was the primary outcome, while progression-free survival (PFS), overall response rate (ORR) and serious toxicities were the secondary outcomes. Review Manager 5.3 was used to perform the statistical analyses. Stata 12.0 was used to assess the publication bias of egger's test.

Results: 5 randomized controlled trials containing 1250 patients were finally included in this analysis. Statistical analyses showed that the addition of antiangiogenic agents to chemotherapy could prolong OS [HR 0.79 (0.71-0.89), p<0.0001] and PFS [HR 0.75 (0.68-0.84), p<0.00001] in advanced MPM, especially in the epithelioid subgroup, with a tolerable toxicity profile. No significant difference was found in the analysis of ORR [HR 1.13 (0.95-1.35), p = 0.18]. Heterogeneity was found in the analyses of PFS and ORR, which might be caused by the limitation in uniform evaluation of tumor response.

Conclusions: The combination of antiangiogenic agents with chemotherapy showed superior over chemotherapy alone in patients with advanced MPM. More prospective trials should be warranted to identify patients who would most likely benefit from the combination regimen.

Copyright: © 2023 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

In plain English

This article was a systematic review and meta-analysis: the authors pooled results from earlier randomized controlled trials rather than treating patients themselves. They searched medical databases up to June 2023 and included 5 trials with 1250 patients with advanced malignant pleural mesothelioma. The trials compared chemotherapy alone with chemotherapy plus a drug that blocks blood-vessel growth (bevacizumab, nintedanib, cediranib or ramucirumab). The article is about treatment and does not discuss asbestos exposure. In the pooled trials, the combination was associated with longer overall survival (hazard ratio 0.79, 95% CI 0.71–0.89) and longer time until disease progression or death (hazard ratio 0.75, 0.68–0.84). In the epithelioid tissue subtype the survival hazard ratio was 0.84 (0.72–0.97). The authors reported no clear advantage in the non-epithelioid subgroup. Tumor response rates did not differ significantly between the two groups. Severe high blood pressure, neutropenia and diarrhea were more frequent with the combination, and severe anemia was less frequent. The authors concluded that the combination showed an advantage over chemotherapy alone. They noted limitations, including the small number of trials and inconsistent ways of measuring tumors.

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: Systematic review and meta-analysis of randomized controlled trials (phase II and phase III)
• Who was studied: 5 randomized controlled trials with 1250 adult patients with locally advanced or metastatic malignant pleural mesothelioma. The trials were found by a database search up to June 2023. Four trials were first-line treatment and one was second-line.
• Exposure: This is a treatment study; asbestos exposure is not addressed. The intervention was an antiangiogenic drug added to chemotherapy, compared with chemotherapy alone. The drugs were bevacizumab (1 trial), nintedanib (2 trials) and cediranib (1 trial), each added to pemetrexed plus cisplatin as first-line treatment, and ramucirumab (1 trial) added to gemcitabine as second-line treatment.
• Main results:
  • Overall survival, all 5 trials: the combination was associated with longer overall survival than chemotherapy alone, HR 0.79 (0.71–0.89), p less than 0.0001. Heterogeneity between trials was not significant (I2 = 31%).
  • Epithelioid subgroup: the combination was associated with longer survival, HR 0.84 (0.72–0.97), p = 0.02.
  • Non-epithelioid subgroup (4 trials): the authors reported no survival advantage, HR 0.73 (0.53–1.00), p = 0.05, with significant heterogeneity. Using a random-effect model, the HR was 0.78 (0.43–1.40), p = 0.40.
  • First-line trials only (4 trials): overall survival HR 0.85 (0.74–0.99), p = 0.04.
  • Progression-free survival (time from randomization to disease progression or death), all 5 trials: HR 0.75 (0.68–0.84), p less than 0.00001, with significant heterogeneity (I2 = 66%). Using a random-effect model, the HR was 0.75 (0.62–0.91), p = 0.003.
  • Overall response rate (4 trials): no significant difference between the two arms, reported as HR 1.13 (0.95–1.35), p = 0.18.
  • Grade 3 or higher toxicities were more frequent with the combination: hypertension RR 28.11 (8.07–97.89), neutropenia RR 1.20 (1.02–1.41), and diarrhea RR 2.50 (1.22–5.15).
  • Grade 3 or higher anemia was less frequent with the combination, RR 0.51 (0.35–0.73), p = 0.0003. Bleeding events occurred in only 3 patients receiving the combination, in 2 trials.
• The authors' conclusion: The authors concluded that adding antiangiogenic agents to chemotherapy improved overall and progression-free survival in advanced malignant pleural mesothelioma, with a tolerable toxicity profile. They called for more prospective trials to identify the patients most likely to benefit, and for studies of biomarkers.
• Limitations the authors state:
  • Only a small number of studies were included, which limited the power of the analysis.
  • Phase II and phase III trials were combined, and only two trials used overall survival as their primary endpoint.
  • Follow-up differed between trials, so the data were not equally mature.
  • Methods of measuring tumor response were not uniform across trials. This may have affected the progression-free survival and response rate results.
  • Subgroups by age and general condition could not be analyzed because the trials used different cut-off points.
  • None of the trials reported how many patients received oxygen therapy, which could affect outcomes.
  • The trials did not report how many patients underwent pleural biopsy or thoracoscopic surgery (often with pleurodesis), which could affect prognosis.
  • Two trials excluded patients with significant cardiovascular comorbidity, possibly producing a study population with a more favorable prognosis.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Systematic Review, Meta-Analysis, Overall Survival, Progression-Free Survival, Epithelioid.

Related studies

• Exploring efficacy and safety of oral Pirfenidone for progressive, non-IPF lung fibrosis (RELIEF) - a randomized, double-blind, placebo-controlled, parallel group, multi-center, phase II trial — J. Behr, P. Neuser, et al. (2017)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors — R. Bahleda, M.C. Le Deley, et al. (2018)
• Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis — A. Zafar, A.A. Rashid, et al. (2024)
• Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials — N. Druesne-Pecollo, P. Latino-Martel, et al. (2010)
• A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma — A.K. Nowak, C. Brown, et al. (2013)

Browse more research in PloS One, or return to medical research.