Distinct Adverse Event Profiles of Eight Chemotherapeutic Agents: A FAERS Database Analysis Focusing on Peripheral Neuropathy

Distinct Adverse Event Profiles of Eight Chemotherapeutic Agents: A FAERS Database Analysis Focusing on Peripheral Neuropathy | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 10 December 2025 V1 Latest version Share on Distinct Adverse Event Profiles of Eight Chemotherapeutic Agents: A FAERS Database Analysis Focusing on Peripheral Neuropathy Authors : Tinghua Feng 0000-0001-5213-843X , Hailiang Zhang , Jinlin Guo 0000-0001-8756-1190 , Menghua Xue , and Liping Liu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176533943.33305815/v1 155 views 136 downloads Contents Abstract 4. Discussion Conclusions Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity of many anticancer agents, impairing patients’ quality of life and treatment continuity. The FDA Adverse Event Reporting System (FAERS) supports post-marketing drug safety surveillance. This study aimed to identify CIPN-related adverse event signals for 8 chemotherapeutics (oxaliplatin, sunitinib, paclitaxel, bortezomib, irinotecan, cytarabine, vincristine, ifosfamide) to inform risk mitigation and CIPN management. Methods: Data spanning from the first quarter of 2004 to the third quarter of 2024 were extracted from the FAERS database and subjected to predefined inclusion and exclusion criteria. Baseline demographic and clinical characteristics were summarized for each drug. We assessed temporal trends in CIPN reporting, estimated time-to-onset of adverse events, and examined associations with age and body weight. Furthermore, putative target genes for each drug were identified and functionally annotated through enrichment analyses. Results: After curation, retained cases were 8,634 (oxaliplatin), 6,732 (sunitinib), 6,575 (paclitaxel), 6,473 (bortezomib), 2,352 (irinotecan), 2,249 (cytarabine), 1,457 (vincristine), 883 (ifosfamide). Paclitaxel showed marked sex disparity (69.8% female vs 21.1% male). Most cases were aged 18–64.9 years (46.5%) and reported from the US. Irinotecan, cytarabine, vincristine, ifosfamide had stable AE counts. Most neurotoxicity occurred 0–30 days post-treatment, with earlier onset in older patients. Enrichment analyses highlighted pathways like p53 signaling. Conclusion: This study delineates distinct and drug-specific adverse event profiles for eight prevalent chemotherapeutic agents. Further prospective investigations are warranted to comprehensively evaluate their safety characteristics and to optimize clinical management strategies for CIPN. Distinct Adverse Event Profiles of Eight Chemotherapeutic Agents: A FAERS Database Analysis Focusing on Peripheral Neuropathy Tinghua Feng 1 , Hailiang Zhang #2 , Jinlin Guo 3 , [1]¿p#1 Menghua Xue 1 ，Liping Liu 4* 1 Department of Ultrasound, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China 2 Oncology Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China 3 Department of Pharmacy, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi Province, People’s Republic of China. 4 * Department of Interventional Ultrasound, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi Province, China. [1]¿p#1 # These authors contributed equally to this work. * Correspondence: Liping Liu, E-mail: [email protected] . Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity of many anticancer agents, impairing patients’ quality of life and treatment continuity. The FDA Adverse Event Reporting System (FAERS) supports post-marketing drug safety surveillance. This study aimed to identify CIPN-related adverse event signals for 8 chemotherapeutics (oxaliplatin, sunitinib, paclitaxel, bortezomib, irinotecan, cytarabine, vincristine, ifosfamide) to inform risk mitigation and CIPN management. Methods: Data spanning from the first quarter of 2004 to the third quarter of 2024 were extracted from the FAERS database and subjected to predefined inclusion and exclusion criteria. Baseline demographic and clinical characteristics were summarized for each drug. We assessed temporal trends in CIPN reporting, estimated time-to-onset of adverse events, and examined associations with age and body weight. Furthermore, putative target genes for each drug were identified and functionally annotated through enrichment analyses. Results: After curation, retained cases were 8,634 (oxaliplatin), 6,732 (sunitinib), 6,575 (paclitaxel), 6,473 (bortezomib), 2,352 (irinotecan), 2,249 (cytarabine), 1,457 (vincristine), 883 (ifosfamide). Paclitaxel showed marked sex disparity (69.8% female vs 21.1% male). Most cases were aged 18–64.9 years (46.5%) and reported from the US. Irinotecan, cytarabine, vincristine, ifosfamide had stable AE counts. Most neurotoxicity occurred 0–30 days post-treatment, with earlier onset in older patients. Enrichment analyses highlighted pathways like p53 signaling. Conclusion: This study delineates distinct and drug-specific adverse event profiles for eight prevalent chemotherapeutic agents. Further prospective investigations are warranted to comprehensively evaluate their safety characteristics and to optimize clinical management strategies for CIPN. Keywords: CIPN, FAERS, Adverse events, Paclitaxel Background Chemotherapy-induced peripheral neuropathy (CIPN) is a clinically significant adverse effect caused by damage to peripheral nerves resulting in administration of chemotherapeutic agents[1]. This condition manifests through a spectrum of sensory, motor, and autonomic symptoms. Sensory abnormalities—such as numbness, tingling, and spontaneous pain predominantly in the distal extremities—are most frequently reported and may exhibit proximal progression[2]. Motor symptoms, including muscular weakness and gait instability, occur less commonly yet can substantially compromise functional capacity and daily activities[3]. Autonomic manifestations, including orthostatic hypotension and constipation, are relatively uncommon yet impactful[4]. CIPN develops in approximately 30% to 40% of patients receiving neurotoxic chemotherapeutic agents, with considerable interindividual variability in severity[5]. Several risk factors contribute to CIPN development, including drug-specific variables (e.g., single and cumulative dose), patient-related characteristics (e.g., advanced age, comorbidities such as diabetes or obesity, history of smoking or alcohol consumption, and pre-existing neurological conditions), and genetic predispositions[6]. Chemotherapeutic agents commonly associated with CIPN include platinum-based compounds (e.g., oxaliplatin, cisplatin), taxanes (e.g., paclitaxel, docetaxel), epothilones (e.g., ixabepilone), immunomodulatory drugs (e.g., thalidomide), vinca alkaloids (e.g., vincristine, vinorelbine), proteasome inhibitors (e.g., bortezomib), and select tyrosine kinase inhibitors (e.g., sorafenib)[7]. Variations in clinical presentation and severity of CIPN are influenced by the specific drug, treatment protocol, and cumulative exposure. For example, oxaliplatin is frequently associated with acute sensory symptoms[8], whereas paclitaxel tends to induce a more chronic albeit often less severe neurotoxic profile[9]. Given its high prevalence and potential to cause long-term disability, CIPN not only impairs quality of life but may also lead to chemotherapy dose reduction or discontinuation, thereby adversely affecting oncologic outcomes[10]. Consequently, systematic evaluation of neurotoxic signals across diverse drug classes is imperative for enhancing clinical safety and patient care. The FDA Adverse Event Reporting System (FAERS) is one of the world’s largest pharmacovigilance databases globally and an invaluable resource an invaluable resource for post-marketing drug safety monitoring[11]. This publicly accessible database collects spontaneous reports of adverse events from healthcare professionals and consumers, enabling the detection of potential safety signals through disproportionality analysis[12, 13]. Numerous studies using FAERS data have characterized adverse reaction profiles of various anticancer agents and proposed potential risk mitigation strategies. For example, omeprazole has been identified as a potential preventive agent for oxaliplatin-induced CIPN[14], and simvastatin may alleviate neuropathic symptoms through drug repurposing approaches[15]. Combination therapies involving pembrolizumab and paclitaxel is associated with an elevated incidence of immune-related adverse events such as adrenal insufficiency and myocarditis[16]. Furthermore, bortezomib has been associated with cytomegalovirus infection[17], sunitinib with pleural effusion and tumor progression[18], and irinotecan with adverse events demonstrating distinct temporal and geographic patterns[19]. Collectively, these findings demonstrate the utility of FAERS in characterizing drug safety profiles and support its application to delineate CIPN risks associated with oxaliplatin, sunitinib, paclitaxel, bortezomib, irinotecan, cytarabine, vincristine, and ifosfamide. Systematic analysis of such data can facilitate early risk identification, treatment regimen optimization, and inform the development of tailored preventive measures. This study, based on the FAERS database, systematically analyzes the clinical characteristics, dynamic timing of onset, and molecular mechanisms of CIPN (CIPN) associated with eight chemotherapeutic agents: oxaliplatin, sunitinib, paclitaxel, bortezomib, irinotecan, cytarabine, vincristine, and ifosfamide By integrating adverse event signals with functional enrichment analyses of drug targets and pathway mappings, we aim to identify drug-specific and class-effect neurotoxic patterns. The findings from this comprehensive pharmacovigilance investigation are expected to provide actionable insights that may inform risk prediction models, enhance patient management strategies, and ultimately improve therapeutic safety outcomes in oncologic practice. 2. Methods 2.1 Data acquisition The original data of this study were obtained from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). Reports from the first quarter of 2004 to the third quarter of 2024 (2004 Q1-2024 Q3) since the database was established were selected. For data processing, referring to the recommendations of the U.S. FDA (Food and Drug Administration), the downloaded ASCII data packages were processed through programs and imported into the easyfaers software for data cleaning. In FAERS, adverse events (AEs) were coded using Preferred Terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA) (v 24.0). A specific PT could be assigned to multiple High-Level Terms (HLTs), High-Level Group Terms (HLGTs), and System Organ Classes (SOCs). In addition, all PTs representing symptoms, signs, examinations, or diagnoses were grouped into meaningful categories using Standardized MedDRA Queries (SMQs) to define the medical conditions of interest. In this study, drug toxicity events reported since the establishment of the FAERS database were included, and data exclusion is shown in Figure 1 . Finally, 8634 cases of oxaliplatin, 6732 cases of sunitinib, 6575 cases of paclitaxel, 6473 cases of bortezomib, 2352 cases of irinotecan, 2249 cases of cytarabine, 1457 cases of vincristine, and 883 cases of ifosfamide adverse event patients were recruited. The specific numbers are detailed in Additional file 1 . [1]¿p#1 2.2 Data mining In this study, the disproportionality method was used for ADE signal detection. Its basic principle was to compare the difference between the occurrence frequency of the target drug and target event and the background frequency using a 2×2 contingency table for disproportionality analysis. Among disproportionality methods, the reporting odds ratio (ROR) was the most commonly used method at present, with the calculation formula: ROR = (a/c)/(b/d). The 95% confidence interval (CI) of the ROR value was calculated as e^(lnROR ± 1.96√(1/a + 1/b + 1/c + 1/d)). When a ≥ 3 and the lower limit of the 95% CI of the ROR value was > 1, it indicated that a valid ADE signal was generated. The larger the signal value, the stronger the signal, meaning the stronger the association between the target drug and the ADE. [1]¿p#1 2.3 Identification and enrichment analysis of differential metabolites To characterize the adverse events of adverse events associated with oxaliplatin, sunitinib, paclitaxel, bortezomib, irinotecan, cytarabine, vincristine, and ifosfamide respectively, a baseline table was constructed based on the data of drug toxicity events reported since the establishment of the FAERS database. Continuous variables were presented as mean and standard deviation, while categorical variables were described as counts and percentages. 2.4 Analysis of adverse reaction time To evaluate the cumulative change trend of the onset time of neurotoxic adverse reactions after drug treatment, this study, based on data from the FAERS database from the first quarter of 2004 to the third quarter of 2024 (2004 Q1-2024 Q3), used the ggplot2 package (v 4.8.3)[20] to draw proportion plots. To clarify whether there were significant differences among subgroups such as different genders, age groups, and weight groups, data of 8 chemotherapy regimens extracted from the FAERS database from 2004 to 2024 were stratified by age, gender, and weight. The time to onset of CV events was calculated using the formula: time to onset = event start date - treatment start date. The time to onset was described using the median and interquartile range. 2.5 ADE analysis at the PT level Based on FAERS data from the first quarter of 2004 to the third quarter of 2024 (2004 Q1-2024 Q3), this study used ROR (Reporting Odds Ratio), PRR (Proportional Reporting Ratio), BCPNN (Bayesian Confidence Propagation Neural Network), and MGPS (Multi-item Gamma Poisson Shrinker) to perform adverse event (ADE) signal detection at the Preferred Term (PT) level. The criteria for determining signal detection was as follows: the number of AE reports ≥ 3, the lower limit of the 95% CI of the ROR value > 1, PRR ≥ 2 and χ² ≥ 4; EBGM05 > 1. A signal was considered to meet the criteria if any of the above conditions was positive 2.6 Enrichment analysis and protein-protein interaction (PPI) network Genes related to oxaliplatin, sunitinib, paclitaxel, bortezomib, irinotecan, cytarabine, vincristine, and ifosfamide were retrieved from DGIdb and STITCH. Afterwards, the clusterProfiler package (v 4.8.3) [14] [14] was used to perform Gene Ontology (GO) ( P < 0.05) and KEGG enrichments ( P < 0.05). The top 5 terms for each category and the top 20 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were presented based on the count. Additionally, a PPI network was constructed using the STRING database (confidence score ≥ 0.4) (Genes of each drug target were analyzed separately). The results were visualized using Cytoscape (v 3.10.2)[21]. 2.7 Biostatistical analysis R software (v 4.2.2) was used to perform bioinformatics analysis. 3. Results 3.1 Results of baseline characteristics Among the 8,634 reports associated with oxaliplatin, the sex distribution was relatively balanced, with males accounting for 47.3% and females 43.0% of cases. The majority of patients (32.6%) fell within the 50–100 kg weight range, and 43.6% were aged between 18 and 64.9 years. Healthcare professionals submitted the largest proportion of reports (32.6%). Geographically, Italy contributed the highest number of reports (15.0%), followed by the United States (13.2%) and France (12.4%) ( Table 1 ). For paclitaxel-associated adverse events (n=6,575), a substantial sex-based disparity was observed, with females comprising 69.8% of reports compared to 21.1% for males. The majority of patients (46.5%) were aged 18–64.9 years, and the United States was the most common reporting country (24.4%) ( Table 2 ). Other agents—sunitinib (59.2% male), bortezomib (43.2% male), irinotecan (44.3% male), cytarabine (45.3% male), and vincristine (50.2% male)—exhibited a male predominance. In contrast, ifosfamide reports showed a higher proportion of females (45.3%). Healthcare providers were the primary reporters for all drugs except ifosfamide, for which occupational therapists (OT) submitted the majority of reports (37.1%) ( Additional files 2-7 ). Temporal analysis revealed an initial decline followed by a gradual increase in reporting frequency for oxaliplatin, paclitaxel, and bortezomib from 2004 to 2024. Sunitinib-associated reports increased from 2006 to 2015, after which they declined. Reporting rates for irinotecan, cytarabine, vincristine, and ifosfamide remained largely stable, with only minor fluctuations noted ( Figure 2 ). [1]¿p#1 3.2 0-30 days: a high-incidence period for adverse reactions The time of onset of neurotoxic adverse reactions after treatment with the 8 drugs The majority of neurotoxic events occurred within the first 30 days following treatment initiation, accounting for approximately 60% of reports across all eight drugs ( Figure 3a–h ). Older age and higher body weight were associated with shorter time-to-onset ( Additional file 8a-b ). [1]¿p#1 3.3 Results of ADE analysis at the PT level All eight drugs generated statistically significant signals across all four disproportionality metrics employed ( Table 3 ). 3.4 Multiple signaling pathways of drug-related targets Enrichment analyses identified target genes for each drug were significantly involved in multiple GO and KEGG pathways. Specifically, oxaliplatin targets were enriched in 1625 GO terms and 105 KEGG pathways; sunitinib in 1455 GO and 50 KEGG; paclitaxel in 1344 GO and 145 KEGG; bortezomib in 575 GO and 95 KEGG; irinotecan in 1116 GO and 132 KEGG; cytarabine in 1080 GO and 75 KEGG; vincristine in 1224 GO and 79 KEGG; and ifosfamide in 487 GO and 31 KEGG pathways ( Figure 4a-h; Additional files 9-16 ). Key pathways identified included those regulating apoptosis, p53 signaling, kinase activity, cell cycle progression, and drug metabolism. PPI network analysis demonstrated extensive and biologically plausible interactions among the identified drug targets ( Additional file 17 ). 4. Discussion CIPN is a dose-limiting toxicity associated with several commonly used chemotherapeutic agents, substantially compromising patients’ quality of life and often impeding treatment continuity[3, 6]. This study focuses on eight medicinal compounds strongly linked to CIPN: oxaliplatin, sunitinib, paclitaxel, bortezomib, irinotecan, cytarabine, vincristine, and ifosfamide. These agents represent major contributors to neurotoxic manifestations in clinical oncology[22]. Although these agents are pharmacologically diverse, their shared propensity to induce neurotoxicity underscores the considerable prevalence and clinical relevance of CIPN in contemporary cancer therapy[10]. This study conducted a comprehensive multidimensional analysis based on the FAERS database. Baseline characterization elucidated disparities in adverse drug reactions across different age and gender groups, while temporal analysis delineated evolving reporting trends. The results demonstrated that adverse events for the eight investigated drugs predominantly occurred within 0–30 days after drug initiation. Moreover, an increase in adverse event reports was associated with advanced age and higher body weight. Furthermore, the study identified and functionally characterized signaling pathways associated with drug-related targets, providing mechanistic insights into neurotoxic outcomes. The findings yield novel evidence to support the identification of high-risk populations and elucidate underlying toxicity mechanisms, thereby informing clinical practice. Analysis of baseline characteristics revealed that adverse event reports exhibited a sex-specific pattern for most of the studied agents. With the exception of paclitaxel and ifosfamide, a higher proportion of reports were associated with male patients for the remaining six drugs, indicating that sex may influence drug safety profiles in a compound-specific manner. Notably, paclitaxel-associated adverse events were predominantly reported in females, accounting for 69.8% of cases, which strongly implies a sex-dependent mechanism underlying its neurotoxicity. Previous investigations suggest that paclitaxel is primarily metabolized by cytochrome P450 enzymes, particularly CYP2C8 and CYP3A4, whose enzymatic activity may be influenced by estrogen levels. This physiological difference could result in reduced clearance and elevated plasma concentrations of paclitaxel in female patients, thereby predisposing them to an increased risk of adverse effects[23]. Additionally, documented differences in pain perception and reporting tendencies between sexes may further contribute to this disparity[24]. Conversely, the higher reporting rates observed among males for other chemotherapeutic agents may be attributable to the increased incidence of certain malignancies—such as colorectal and hepatic cancers[25, 26]—in men, leading to greater utilization of these therapeutics. Moreover, male patients generally exhibit greater body weight and body surface area, often resulting in the administration of higher absolute chemotherapeutic doses[27]. This dosing approach may contribute to an elevated risk of cumulative toxicity. Historically, sex-based disparities in adverse drug reactions have been ascribed to variations in pharmacokinetics[28], hormonal milieu[29], or immune response[30]. However, our findings suggest that such differences cannot be solely explained by biological factors. Instead, they likely arise from a complex interplay of biological characteristics, clinical prescribing patterns, and sociocultural influences. Analysis of age distribution revealed that the majority of adverse events associated with most drugs occurred in individuals aged 18–64.9 years, which aligns with this demographic constituting the primary population undergoing oncological treatment. This pattern may also reflect more frequent documentation and reporting of adverse events due to either higher treatment intensity or longer survival periods [16][16] . In contrast, sorafenib exhibited the highest proportion of adverse event reports among patients older than 65 years, likely attributable to its primary use in treating hepatocellular carcinoma and renal cell carcinoma, both of which exhibit higher incidence in older adults[31]. Advanced age is often associated with multiple comorbidities, impaired hepatic and renal function, and polypharmacy[32], all of which may exacerbate safety risks associated with specific therapeutic agents. Occupational distribution analysis revealed that physicians the predominant reporting group, underscoring the continued reliance on professional medical judgment for the identification and reporting of adverse events. A notably higher proportion of ifosfamide-related reports were submitted by occupational therapists, which may indicate unique documentation pathways in rehabilitative support or long-term follow-up care for patients treated with this agent—a phenomenon warranting further investigation. Geographically, Italy, the United States, and France were overrepresented in adverse event reports across multiple drugs, likely reflecting their well-established pharmacovigilance systems, heightened patient awareness of rights, and extensive participation in international multicenter clinical trials[33]. Analysis of adverse event reporting trends for eight drugs between 2004 and 2024 reveals that temporal variations reflect not only the safety profiles of the agents, but also the evolving dynamics of clinical practice, medical knowledge, and regulatory frameworks[34]. Oxaliplatin, paclitaxel, and bortezomib exhibited a biphasic pattern of initial decline followed by an increase in reporting frequency. This trend may be attributed to initial underreporting following the introduction of generic versions, followed by expanded use in new indications and combination therapies. Additionally, growing emphasis on long-term quality of life—particularly neurotoxicity—and enhanced clinical monitoring have likely contributed to the recent rebound in reporting. Sunitinib demonstrated a gradual increase in reports following its market approval in 2006[35], with a decline observed after 2015—this decline coincided with accumulated clinical experience, optimized risk management strategies, and the availability of alternative therapies. In contrast, irinotecan, cytarabine, vincristine, and ifosfamide maintained relatively stable reporting rates over time, suggesting mature and well-established safety profiles and consistent clinical application patterns. Collectively, these trends underscore that fluctuations in adverse event reporting are influenced by a combination of prescribing behaviors, evolving clinical awareness, and surveillance mechanisms—rather than solely reflecting changes in the intrinsic safety of the drugs. Analysis of the timing of adverse events confirmed a pronounced temporal clustering of CIPN, with the vast majority of cases occurring within 0–30 days after treatment initiation. Furthermore, the analysis revealed significant associations between adverse event development and both age and body weight. The cumulative incidence of adverse events was found to increase over time, with older patients experiencing more rapid onset. This pattern may be attributed to age-related decline in physiological function[36], reduced drug clearance[37], and higher burden of comorbidities[38]. Similarly, the time-dependent increase in risk observed across different body weight groups strongly suggests that administered dosage serves as a critical driver of neurotoxicity. Patients with higher body weight typically receive greater absolute doses of chemotherapeutic agents[39, 40], leading to earlier attainment of toxicity thresholds. Therefore, we recommend implementing enhanced monitoring strategies for elderly and high-body-weight patients, including intensified assessment and patient education during the initial treatment phase to facilitate early detection and intervention for CIPN[41]. Future studies should employ prospective designs to investigate underlying mechanisms and ultimately develop individualized risk prediction models. At the molecular and mechanistic level, this study revealed that the eight anticancer agents converge on core biological pathways—including cellular stress response, DNA repair and replication, and cell cycle regulation—indicating that their therapeutic efficacy stems from the initiation of broad intracellular cascades rather than isolated actions. This network-level effect underpins their antitumor activity while also frequently contributing to inevitable adverse effects. Furthermore, the extensive protein-protein interactions among distinct drug targets provide a theoretical foundation for exploring combination therapy regimens. Using oxaliplatin as an example, our analytical results align closely with its established mechanism of action. The drug primarily induces DNA damage and apoptosis through activation of the p53 signaling pathway, which constitutes its core antitumor activity[42, 43]. Previous studies have demonstrated that duloxetine alleviates oxaliplatin-induced peripheral neuropathy by inhibiting the p53 signaling pathway[44]. Additionally, significant enrichment was observed in pathways associated with ATPase-coupled transmembrane transporter activity, providing novel insights into the peripheral neuropathy associated with oxaliplatin therapy and suggesting that disruption of ion homeostasis may represent an underlying mechanism for its neurotoxicity[45]. In the analysis of paclitaxel, we not only confirmed paclitaxel’s central role in regulating cell cycle progression but also identified unexpected associations with specific pathways[46]. For instance, enrichment signals were detected in pathways related to epithelial cell migration and gap junction communication, suggesting that paclitaxel may indirectly influence intercellular communication and motility via microtubule stabilization[47], thereby potentially inhibiting tumor metastasis. These findings expand our understanding of paclitaxel’s mechanisms of action and provide new directions for investigating its potential extracellular toxicities. This study systematically analyzed the FAERS database to elucidate the common and distinct features among eight drugs with respect to adverse reaction profiles, temporal dynamics, safety signal magnitudes, and pathway enrichment, thereby offering valuable insights into rational clinical medication Furthermore, analysis of drug-related targets and enriched pathways provides novel perspectives to advance understanding of the molecular mechanisms of CIPN and developing preventive and therapeutic strategies. This study has several limitations. First, as the FAERS is a spontaneous reporting system involving both healthcare professionals and non-medical specialists, potential issues include spelling errors, missing data fields, and inconsistent formatting, in addition to possible selection bias. Second, the database predominantly comprises reports from European and American populations, with underrepresentation of Asian and other ethnic groups, thereby limiting the geographical generalizability of the findings. Third, the lack of detailed demographic and biomarker data impedes in-depth exploration of incidence disparities and their underlying mechanisms. Fourth, the analysis could not account for confounding factors such as treatment regimens, concomitant medications, and pre-existing neuropathies. Finally, the conclusions are derived from signal detection involving only eight drugs; extrapolation of these findings to other populations or agents requires validation through independent studies. Conclusions Through a systematic analysis of adverse event reports from the FDA Adverse Event Reporting System (FAERS) involving eight commonly used chemotherapeutic agents, this study elucidated distinctive patterns in their occurrence, demographic distribution, and temporal dynamics. The results demonstrated marked disparities in sex distribution among chemotherapy-induced peripheral neuropathies—paclitaxel-associated reports were predominantly female, whereas most other agents showed a male predominance. Neurotoxic events were largely concentrated within the initial treatment phase (0–30 days), with older patients exhibiting an earlier onset trend. These findings not only underscore the heterogeneous nature of CIPN, but also suggest that its pathogenesis may involve complex interactions between drug-specific metabolic pathways and individual patient factors. Based on this evidence, we recommend the implementation of individualized neurotoxicity monitoring and risk management strategies in clinical practice, tailored to the specific drug regimen and patient profile. Furthermore, this study provides important direction for future research into the mechanisms of action involving specific signaling pathways. List of Abbreviation Abbreviation Full Name CIPN Chemotherapy-induced peripheral neuropathy FAERS FDA Adverse Event Reporting System FDA Food and Drug Administration PTs Preferred Terms MedDRA Medical Dictionary for Regulatory Activities HLTs High-Level Terms HLGTs High-Level Group Terms SOCs System Organ Classes SMQs Standardized MedDRA Queries ROR Reporting Odds Ratio CI Confidence Interval ADE Adverse Drug Event PRR Proportional Reporting Ratio BCPNN Bayesian Confidence Propagation Neural Network MGPS Multi-item Gamma Poisson Shrinker EBGM05 Empirical Bayes Geometric Mean 05 PPI Protein-Protein Interaction DGIdb Drug-Gene Interaction Database GO Gene Ontology KEGG Kyoto Encyclopedia of Genes and Genomes OT Occupational Therapists CYP Cytochrome P450 Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets analyzed during the current study are available in the FDA Adverse Event Reporting System (FAERS) database at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Competing interests The authors declare that they have no competing interests. Funding This research was funded by the Natural Science Foundation of Shanxi Province (Grant No.20240302122389 ). Authors’ contributions FT and ZH: Designed the study.FT, ZH and XM: Performed the data analysis.FT and XM: Managed and verified all data.FT and ZH: Drafted the manuscript.GJ and LL: Revised and edited the All authors: Critically reviewed the manuscript, interpreted the results, and read and approved the final version. Acknowledgements We would like to extend our sincere gratitude to all who have supported this research. We are particularly indebted to Mr. Li Haixu for his expert guidance and invaluable advice on statistical data analysis. 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Baseline characteristics of participants treated with oxaliplatin n level Overall 8634 SEX_category (%) Female 3709 (43.0%） Male 4086 (47.3%） Missing 839 ( 9.7%） WT_category (%) 100 kg 161 ( 1.9%） Missing 5402 (62.6%） AGE_category (%) 85 age 18 ( 0.2%） 18~64.9 age 3764 (43.6%） 65~85 age 3194 (37.0%） Missing 1635 (18.9%） OCCP_COD_category (%) CN 428 ( 5.0%） HP 1464 (17.0%） LW 18 ( 0.2%） MD 2818 (32.6%） OT 2318 (26.9%） PH 1339 (15.5%） Missing 248 ( 2.9%） REPORTER_COUNTRY_category (%) Argentina 2 ( 0.0%） Austria 39 ( 0.5%） Australia 61 ( 0.7%） Bosnia and Herzegovina 2 ( 0.0%） Belgium 127 ( 1.5%） Bulgaria 7 ( 0.1%） Brazil 82 ( 0.9%） Canada 351 ( 4.1%） Switzerland 29 ( 0.3%） Chile 7 ( 0.1%） China 245 ( 2.8%） Colombia 1 ( 0.0%） Czech Republic 148 ( 1.7%） Germany 481 ( 5.6%） Denmark 60 ( 0.7%） Algeria 3 ( 0.0%） Estonia 3 ( 0.0%） Egypt 9 ( 0.1%） Spain 282 ( 3.3%） Finland 27 ( 0.3%） France 1074 (12.4%） United Kingdom 653 ( 7.6%） Greece 53 ( 0.6%） Hong Kong 4 ( 0.0%） Croatia 23 ( 0.3%） Hungary 26 ( 0.3%） Indonesia 6 ( 0.1%） Ireland 11 ( 0.1%） Israel 18 ( 0.2%） India 37 ( 0.4%） Iran 9 ( 0.1%） Iraq 1 ( 0.0%） Italy 1297 (15.0%） Japan 784 ( 9.1%） South Korea 38 ( 0.4%） North Korea 2 ( 0.0%） Lebanon 12 ( 0.1%） Lithuania 4 ( 0.0%） Luxembourg 6 ( 0.1%） Latvia 1 ( 0.0%） Morocco 3 ( 0.0%） Malaysia 13 ( 0.2%） Mexico 2 ( 0.0%） Netherlands 418 ( 4.8%） Nigeria 1 ( 0.0%） Norway 24 ( 0.3%） New Zealand 8 ( 0.1%） Oman 2 ( 0.0%） Philippines 1 ( 0.0%） Poland 210 ( 2.4%） Portugal 131 ( 1.5%） Qatar 1 ( 0.0%） Romania 86 ( 1.0%） Serbia 9 ( 0.1%） Russia 15 ( 0.2%） Saudi Arabia 4 ( 0.0%） Sweden 83 ( 1.0%） Singapore 9 ( 0.1%） Slovenia 10 ( 0.1%） Slovakia 15 ( 0.2%） South Africa 8 ( 0.1%） Taiwan 20 ( 0.2%） Thailand 7 ( 0.1%） Tunisia 5 ( 0.1%） Turkey 21 ( 0.2%） Ukraine 1 ( 0.0%） United States 1136 (13.2%） Vietnam 4 ( 0.0%） Missing 362 ( 4.2%） Note: 0.0% indicates a very low proportion, <0.001%. Table 2. Baseline characteristics of participants treated with paclitaxel n level Overall 6575 SEX_category (%) Female 4589 (69.8%) Male 1389 (21.1%) Missing 597 ( 9.1%) WT_category (%) 100 kg 172 ( 2.6%) Missing 3792 (57.7%) AGE_category (%) 85 age 31 ( 0.5%) 18~64.9 age 3057 (46.5%) 65~85 age 2185 (33.2%) Missing 1281 (19.%5) OCCP_COD_category (%) CN 600 ( 9.1%) HP 872 (13.3%) LW 24 ( 0.4%) MD 1983 (30.2%) OT 1794 (27.3%) PH 1005 (15.%3) Missing 291 ( 4.4%) REPORTER_COUNTRY_category (%) Argentina 1 ( 0.0%) Austria 59 ( 0.9%) Australia 63 ( 1.0%) Bosnia and Herzegovina 1 ( 0.0%) Belgium 109 ( 1.7%) Bulgaria 2 ( 0.0%) Brazil 69 ( 1.0%) Canada 304 ( 4.6%) Switzerland 17 ( 0.3%) China 153 ( 2.3%) Chile 6 ( 0.1%) Colombia 13 ( 0.2%) Cyprus 1 ( 0.0%) Czech Republic 85 ( 1.3%) Germany 543 ( 8.3%) Denmark 73 ( 1.1%) Egypt 59 ( 0.9%) Spain 294 ( 4.5%) Finland 27 ( 0.4%) France 583 ( 8.9%) United Kingdom 336 ( 5.1%) Greece 26 ( 0.4%) Croatia 25 ( 0.4%) Hungary 14 ( 0.2%) Ireland 11 ( 0.2%) Israel 7 ( 0.1%) Isle of Man 1 ( 0.0%) India 11 ( 0.2%) Iran 3 ( 0.0%) Italy 753 (11.5%) Japan 413 ( 6.3%) Jamaica 1 ( 0.0%) Kenya 1 ( 0.0%) South Korea 19 ( 0.3%) Lebanon 2 ( 0.0%) Lithuania 7 ( 0.1%) Luxembourg 6 ( 0.1%) Morocco 3 ( 0.0%) Mexico 5 ( 0.1%) Malaysia 24 ( 0.4%) New Caledonia 2 ( 0.0%) Netherlands 160 ( 2.4%) New Zealand 3 ( 0.0%) Norway 9 ( 0.1%) Peru 2 ( 0.0%) Philippines 2 ( 0.0%) Poland 109 ( 1.7%) Portugal 80 ( 1.2%) Romania 18 ( 0.3%) Serbia 8 ( 0.1%) Russia 7 ( 0.1%) Saudi Arabia 2 ( 0.0%) Sweden 41 ( 0.6%) Singapore 6 ( 0.1%) Slovenia 10 ( 0.2%) Slovakia 12 ( 0.2%) South Africa 9 ( 0.1%) Taiwan 14 ( 0.2%) Thailand 6 ( 0.1%) Turkey 24 ( 0.4%) United Arab Emirates 1 ( 0.0%) United States 1602 (24.4%) Missing 362 ( 4.2%） Note: 0.0% indicates a very low proportion, <0.001%. Table 3. Adverse event signal (ADE) analysis based on PT level. [1]¿p#1 DRUG Case number PRR（X 2 ） ROR（95%CI） EBGM（EBGM05） OXALIPLATIN 8634 1.6 ( 2348.72 ) 1.83 ( 1.78 - 1.87 ) 1.6 ( 1.57 ) SUNITINIB 6732 1.07 ( 39.31 ) 1.09 ( 1.06 - 1.12 ) 1.07 ( 1.05 ) PACLITAXEL 6575 1.08 ( 44.94 ) 1.1 ( 1.07 - 1.13 ) 1.08 ( 1.05 ) BORTEZOMIB 6473 1.18 ( 205.62 ) 1.22 ( 1.19 - 1.25 ) 1.18 ( 1.15 ) IRINOTECAN 2352 1.04 ( 5.22 ) 1.05 ( 1.01 - 1.1 ) 1.04 ( 1.01 ) CYTARABINE 2249 1.11 ( 27.09 ) 1.13 ( 1.08 - 1.18 ) 1.11 ( 1.06 ) VINCRISTINE 1457 1.14 ( 30.14 ) 1.17 ( 1.11 - 1.24 ) 1.14 ( 1.09 ) IFOSFAMIDE 883 1.72 ( 322.15 ) 2.02 ( 1.87 - 2.19 ) 1.72 ( 1.61 ) Note: ROR, Reporting Odds Ratio; PRR, Proportional Reporting Ratio; CI, Confidence Interval; χ 2 , Chi-square; EBGM05, the lower limit of the 95% one-sided confidence interval of EBGM. [1]¿p#1 Figure Legends Figure 1. Data inclusion and exclusion flowchart of the study. Figure 2. Temporal characteristics curve of adverse event reports. The x-axis represents the years, and the y-axis represents the number of reported cases. Different colors represent different drugs, and larger dots indicate a higher number of adverse event reports. Figure 3. Cumulative change trend of the occurrence time of neuropathy adverse events following different drug treatments. (a) oxaliplatin. (b) paclitaxel. (c) sunitinib. (d) ifosfamide. (e) irinotecan. (f) cytarabine. (g) vincristine. (h) bortezomib. The y-axis represents the time of onset, while the left side of the x-axis (red) shows the proportion, and the right side (blue) represents the number of reported cases. Figure 4. GO/KEGG enrichment analysis of target genes corresponding to the eight drugs. (a) oxaliplatin. (b) sunitinib. (c) paclitaxel. (d) bortezomib. (e) irinotecan. (f) cytarabine. (g) vincristine. (h) ifosfamide. In each panel, the upper plot represents the GO enrichment analysis bar chart, where longer bars indicate a higher number of enriched genes. The lower plot shows the KEGG enrichment analysis bubble chart, where larger bubbles represent more enriched genes, and the more orange the bubble, the more significant the enrichment. Additional files Additional file 1. Participant inclusion table for the eight drugs Additional file 2. Baseline characteristics of participants treated with sunitinib Additional file 3. Baseline characteristics of participants treated with bortezomib Additional file 4. Baseline characteristics of participants treated with irinotecan Additional file 5. Baseline characteristics of participants treated with cytarabine Additional file 6. Baseline characteristics of participants treated with vincristine Additional file 7. Baseline characteristics of participants treated with ifosfamide Additional file 8. Cumulative probability of adverse events and time to onset for different drugs in subgroups. (a) Age group. From left to right: bortezomib, cytarabine, ifosfamide, oxaliplatin, paclitaxel. Different colors represent different age groups. (b) Weight group. From left to right: bortezomib, cytarabine, ifosfamide, irinotecan, oxaliplatin, paclitaxel, sunitinib, vincristine. Different colors represent different weight ranges. Additional file 9. GO/KEGG enrichment analysis results of oxaliplatin-related target genes Additional file 10. GO/KEGG enrichment analysis results of sunitinib-related target genes Additional file 11. GO/KEGG enrichment analysis results of paclitaxel-related target genes Additional file 12. GO/KEGG enrichment analysis results of bortezomib-related target genes Additional file 13. GO/KEGG enrichment analysis results of irinotecan-related target genes Additional file 14. GO/KEGG enrichment analysis results of cytarabine-related target genes Additional file 15. GO/KEGG enrichment analysis results of vincristine-related target genes Additional file 16. GO/KEGG enrichment analysis results of ifosfamide-related target genes Additional file 17. PPI network of target genes for different drugs. From left to right: bortezomib, cytarabine, ifosfamide, irinotecan, oxaliplatin, paclitaxel, sunitinib, vincristine. The outer color closer to red indicates a higher degree of the target gene, and the inner color darker indicates a higher score. Supplementary Material File (figure 1.tif) Download 2.90 MB File (figure 2.tif) Download 4.33 MB File (figure 3.tif) Download 1.35 MB File (figure 4.tif) Download 6.13 MB File (tables.xls) Download 39.50 KB Information & Authors Information Version history V1 Version 1 10 December 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Tinghua Feng 0000-0001-5213-843X Shanxi Bethune Hospital View all articles by this author Hailiang Zhang Shanxi Bethune Hospital View all articles by this author Jinlin Guo 0000-0001-8756-1190 Shanxi Provincial People's Hospital View all articles by this author Menghua Xue Shanxi Bethune Hospital View all articles by this author Liping Liu [email protected] First Hospital of Shanxi Medical University View all articles by this author Metrics & Citations Metrics Article Usage 155 views 136 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Tinghua Feng, Hailiang Zhang, Jinlin Guo, et al. Distinct Adverse Event Profiles of Eight Chemotherapeutic Agents: A FAERS Database Analysis Focusing on Peripheral Neuropathy. Authorea . 10 December 2025. DOI: https://doi.org/10.22541/au.176533943.33305815/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. 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