{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:11:48Z","timestamp":1790730708878,"version":"4.1.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tyrosine kinase inhibitors (TKIs) administered as monotherapy have demonstrated limited clinical efficacy in glioblastoma (GBM). This study synthesized evidence from existing randomized controlled trials (RCTs) to evaluate the efficacy and safety of combination treatments incorporating TKIs for GBM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a systematic literature search in PubMed, the Cochrane Library, Web of Science, and Embase to identify RCTs published up to January 10, 2026. The efficacy of treatments was evaluated by progression-free survival (PFS), overall survival (OS), objective response rate (ORR), stable disease (SD), and progressive disease (PD), while safety was assessed by the incidence of adverse events (AEs). Survival outcomes were pooled as hazard ratios (HRs) and dichotomous outcomes as risk ratios (RRs), each reported with 95% confidence intervals (CIs). Heterogeneity across studies was assessed using the Cochrane Q test, I\u00b2 statistic, and 95% prediction intervals (PIs). Trial sequential analysis was incorporated into the meta-analysis to control the likelihood of false-positive and false-negative conclusions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This analysis included 10 RCTs encompassing 1,435 GBM. The overall analysis revealed that combination therapies incorporating TKIs significantly improved PFS (HR [95% CI] = 0.834 [0.697-0.998], 95% PI: 0.506-1.376) and ORR (RR [95% CI] = 1.664 [1.083-2.558], 95% PI: 0.917-2.868) compared with TKI-free control regimens. However, no significant benefits were observed for OS, SD, or PD. Further subgroup analyses stratified by combination regimens (TKIs plus standard chemoradiotherapy or TKIs plus non-standard therapies) and by GBM status (newly diagnosed or recurrent GBM) did not identify any statistically significant efficacy differences (all\n                      <jats:italic>p<\/jats:italic>\n                      &amp;gt; 0.05). Safety analyses indicated that although TKI-containing combination therapies did not increase the overall risk of grade \u2265 3 AEs (RR [95% CI] = 1.177 [0.998-1.388], 95% PI: 0.758-1.826), they were associated with higher incidences of grade \u2265 3 neutropenia, fatigue, and diarrhea, while being associated with a reduced risk of decreased lymphocyte count (all\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study suggests that combination regimens incorporating TKIs may have only modest therapeutic activity for GBM, showing signals of improved PFS and ORR but no OS benefit in the current evidence base. Clinicians should remain vigilant for AEs associated with these combination regimens, ensure close monitoring, and promptly implement appropriate measures to manage and mitigate toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>\n                      , identifier CRD420261293988.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1796708","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T04:13:27Z","timestamp":1776658407000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy and safety of tyrosine kinase inhibitor combination therapy for glioblastoma: a meta-analysis with trial sequential analysis of randomized controlled trials"],"prefix":"10.3389","volume":"16","author":[{"given":"Pan","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University","place":["Chengdu, China"]},{"name":"Department of Neurosurgery, The First People\u2019s Hospital of Longquanyi District","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Physical Examination, The First People\u2019s Hospital of Longquanyi District","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First People\u2019s Hospital of Longquanyi District","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuekang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"v1","DOI":"10.1093\/neuonc\/noac202","article-title":"CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019","volume":"24","author":"Ostrom","year":"2022","journal-title":"Neuro Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.280319","article-title":"Glioblastoma and other Malignant gliomas: a clinical 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