Abstract Objective: Tumor-targeted drug monotherapy or chemotherapy is becoming increasingly important in cancer treatment, yet the concomitant issue of hematological toxicities is gradually gaining attention. Existing studies lack a comprehensive comparison of the toxicity profiles of different targeted drugs. This study aimed to comprehensively assess the incidence and safety ranking of hematological toxicities associated with tumor-targeted drugs in randomized controlled trials (RCTs) through systematic evaluation and network meta-analysis (NMA). Methods: PubMed, Embase, Cochrane Library, and Web of Science databases were systematically searched for RCTs from inception to March 2025. The primary outcome was anemia, and secondary outcomes were neutropenia, neutrophil count decreased, thrombocytopenia, platelet count decreased, leukopenia, white blood cell (WBC) count decreased, and febrile neutropenia (FN). Two reviewers independently screened studies, extracted data according to pre-specified criteria, and assessed the risk of bias using the Cochrane Collaboration risk of bias tool. Overall incidence, odds ratio (OR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. Funnel plots were used to test the publication bias. Stata 16.0 was used to perform NMA and sensitivity analysis. Results: 27 phase II and III RCTs (n=8985) were included. A total of 136 (1.51% 95% CI 1.26-1.76) treatment-related deaths were documented, of which 2 (1.47% 95% CI 0-3.49) were hematologic toxicities. 1 patient treated with sorafenib plus chemotherapy was reported to have died as a result of pancytopenia and 1 patient treated with chemotherapy (gemcitabine plus cisplatin) died due to anemia. Our study confirmed that chemotherapy with or without a placebo, one targeted drug with chemotherapy was associated with more severe hematologic toxicities compared with the use of one targeted drug, tepotinib plus gefitinib, tivantinib plus erlotinib. In the targeted drug monotherapy category, for the primary outcome, we found that alectinib and gefitinib had a higher risk of all-grade (grade 1-5) and severe-grade (grade 3-5) anemia, respectively. Among secondary outcomes, erlotinib had the highest risk of all and severe grade hematologic toxicities. Chemotherapy has a high level of hematologic toxicities, and our study found that combination chemotherapy with some targeted drugs had a higher risk of hematologic toxicities than chemotherapy alone. Ganitumab plus chemotherapy had the highest risk of grade 1-5 anemia and thrombocytopenia. Afatinib plus chemotherapy had the highest risk of grade 3-5 anemia and thrombocytopenia. Ramucirumab plus chemotherapy had the highest risk of grade 1-5 and 3-5 neutropenia. Veliparib plus chemotherapy had the highest risk of grade 1-5 and 3-5 neutrophil count decreased, and platelet count decreased. Sorafenib plus chemotherapy had the highest risk of grade 1-5 and 3-5 WBC count decreased. Selumetinib plus chemotherapy had the highest risk of grade 1-5 and 3-5 FN. Vandetanib plus chemotherapy had the highest risk of grade 1-5 and 3-5 leukopenia. In terms of subgroup analysis, in non-small cell lung cancer (NSCLC), tepotinib plus gefitinib resulted in the highest safety profile for anemia. Conclusion: Each targeted therapy regimen had a unique safety profile. The same targeted drug ranked differently in terms of risk and probability of hematologic toxicities for grade 1-5 and 3-5. Some targeted drugs with chemotherapy have a higher risk of hematologic toxicities than chemotherapy alone. Early identification and management of hematological toxicities associated with targeted drugs is essential in clinical practice. Systematic Review Registration: PROSPERO CRD420251004854.
Yu et al. (Mon,) studied this question.
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