Comparative Safety Profiling of Sorafenib, Regorafenib, and Lenvatinib in Hepatobiliary-Pancreatic Tumors: Signal Mining and Risk Factor Analysis Using the US FDA Adverse Event Reporting System

Comparative Safety Profiling of Sorafenib, Regorafenib, and Lenvatinib in Hepatobiliary-Pancreatic Tumors: Signal Mining and Risk Factor Analysis Using the US FDA Adverse Event Reporting System | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Safety Profiling of Sorafenib, Regorafenib, and Lenvatinib in Hepatobiliary-Pancreatic Tumors: Signal Mining and Risk Factor Analysis Using the US FDA Adverse Event Reporting System Danping Chen, Yi Tang, Xiudong Yin, Xiaolei Yi, Bin Wang, Fang Zhao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8223458/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Objective: To systematically evaluate the potential adverse event (ADE) risk profiles of sorafenib, regorafenib, and lenvatinib in the treatment of hepatobiliary-pancreatic tumors (HBPT) . Methods: Data from the U.S. FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q4 2024 were extracted. Proportional imbalance analysis (using Reporting Odds Ratio [ROR] and Proportional Reporting Ratio [PRR]) was employed for signal detection, combined with K-means clustering and logistic regression models to analyze risk factors. Results: A total of 10,793 ADE reports were included (sorafenib: 5,195; lenvatinib: 4,878; regorafenib: 720). At the System Organ Class level, the most common ADEs for sorafenib were gastrointestinal disorders (4,088 cases) and skin disorders (2,924 cases). Regorafenib showed tumor progression (316 cases) as its primary signal, while lenvatinib was characterized by metabolism-related abnormalities such as decreased appetite (659 cases). Logistic regression revealed: females had a 2.3-fold higher adjusted risk of alopecia with sorafenib than males (95% CI 1.8–2.9), and for lenvatinib users, every 10 kg increase in body weight elevated the risk of confusion by 18% (OR=1.18, p=0.032). Temporal analysis indicated that 82.6% of ADEs occurred within 30 days of treatment, but sorafenib-related metastatic tumor reports were delayed to a median of 200 days (IQR 150–258). Conclusion: This study is the first to systematically reveal distinct ADE profiles of the three targeted therapies for HBPT. Sorafenib and regorafenib may promote tumor progression through unknown mechanisms, while lenvatinib’s metabolism-related toxicities warrant clinical vigilance. These findings provide evidence-based insights for personalized treatment strategies and early toxicity monitoring. sorafenib regorafenib Lenvatinib hepatobiliary-pancreatic tumors FDA Adverse Event Reporting System Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 1 Introduction Hepatobiliary and pancreatic tumors (HBPT) are common malignant tumors in the digestive system, primarily including hepatocellular carcinoma (HCC), biliary tract cancer (BTC), and pancreatic cancer (PC). These tumors are highly aggressive, prone to early metastasis, and often diagnosed at advanced stages, leading to poor prognosis 1 – 3 .HCC is the most prevalent type of primary liver cancer globally, primarily associated with chronic hepatitis (e.g., hepatitis B or C) and cirrhosis 4 . BTC has a relatively lower incidence but has shown an upward trend in recent years, with complex etiologies potentially linked to biliary tract infections, gallstones, and primary sclerosing cholangitis 5 . PC is often termed the "king of cancers" due to its early symptoms and rapid progression. With a 5-year survival rate of less than 10%, it is one of the solid tumors with the worst prognosis 6 . Treatment strategies for HBPT include surgical resection, liver transplantation, local ablation, chemotherapy, targeted therapy, and immunotherapy 7 . In summary, the highly aggressive nature and late-stage diagnosis of HBPT impose a significant disease burden on patients, underscoring the critical importance of early screening, precise diagnosis, and comprehensive treatment to improve prognosis. In HBPT management, sorafenib, regorafenib, and lenvatinib play pivotal roles. Sorafenib , the first targeted therapy approved for HCC, inhibits multiple tyrosine kinases, extending overall survival and progression-free survival 8 . Regorafenib serves as a second-line treatment for HCC after sorafenib resistance, suppressing various receptor tyrosine kinases and significantly prolonging survival 9 . Lenvatinib , applicable for advanced HCC as first-line therapy and certain thyroid or renal cell cancers, inhibits multiple kinases and exhibits immunomodulatory effects, improving objective response rates and progression-free survival 10 . However, these drugs are associated with adverse effects such as cardiovascular toxicity (hypertension, myocardial ischemia), gastrointestinal reactions (diarrhea, nausea), dermatologic toxicity (rashes), and bleeding risks 11 – 15 . Individual variability in patients leads to differences in the incidence and severity of adverse reactions, necessitating close monitoring during treatment. While these therapies improve prognosis, overlapping mechanisms of action raise concerns about severe adverse events when used in combination. Therefore, in-depth research into the characteristics of these drugs, rational selection of treatment regimens, and effective management of adverse reactions are essential to further enhance therapeutic outcomes and quality of life for HBPT patients. This study aims to conduct a statistical analysis of the adverse events related to the treatment of HBPT (HCC, BTC, and PC) with Sorafenib, Regorafenib, and Lenvatinib based on the FAERS database, and to explore the risk factors for these adverse reactions and provide references for the safe and rational clinical use of Sorafenib, Regorafenib, and Lenvatinib. 2 Materials and methods 2.1 . Data Source and Cleaning Extract all reports from the U.S. FDA Adverse Event Reporting System (FAERS) between Q1 2004 and Q4 2024 where sorafenib, regorafenib, or lenvatinib were listed as the suspected causative agents. Data cleaning steps include: Deduplication : Merge duplicate reports from the same patient (cross-validated using FAERS ID and event occurrence date). Standardization : Convert drug trade names to generic names and encode adverse event terms using MedDRA v26.0 (PT/SOC classifications). Exclusion : Remove reports with >30% missing data in critical fields (age, sex, weight, treatment duration) or those lacking confirmed causality. 2.2. Signal Detection Framework A dual proportional imbalance analysis was applied to detect adverse event (ADE) signals: Reporting Odds Ratio (ROR) : Calculated as ROR=a/cb/d ROR = b / da / c , where a= a = number of target drug-event pairs, b= b = number of other drugs reporting the same event, c= c = number of target drug-other event pairs, and d= d = number of other drug-other event pairs. Proportional Reporting Ratio (PRR) : Calculated as PRR=a/(a+c)b/(b+d) PRR = b /( b + d ) a /( a + c ). Signal Thresholds : Signals were retained if they met all criteria: ROR 95% CI lower limit>1 ROR 95% CIlowerlimit >1, PRR≥2 PRR ≥2, χ2≥4 χ 2≥4, and ≥3≥3 reports for the target event. 2.3. Risk Factor Modeling Cluster Preprocessing: Baseline patient characteristics (age, weight, BMI) were grouped via K-means clustering (optimal cluster number K=3 determined by the elbow method) to identify high-risk subgroups. Regression Analysis: Univariate and multivariate logistic regression models were constructed, incorporating covariates such as sex, baseline liver function (ALT>40 U/L ALT >40 U / L ), and concomitant anti-angiogenic drug use. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. 2.4. Temporal Analysis Non-parametric survival analysis (Kaplan-Meier method) was performed on ADE occurrence time (interval from treatment initiation to event onset). Differences in temporal distributions across drugs/events were assessed using the log-rank test. 3 Results 3.1 Baseline Characteristics of Study Participants To investigate the baseline characteristics of sorafenib-, regorafenib-, and lenvatinib-associated adverse drug events (ADEs) in hepatobiliary-pancreatic tumor (HBPT) treatment, we analyzed FAERS data spanning from the first quarter of 2004 to the fourth quarter of 2024. After excluding non-HBPT-related reports and applying predefined exclusion criteria (e.g., incomplete key variables), a total of 5,195 sorafenib ADE reports, 720 regorafenib ADE reports, and 4,878 lenvatinib ADE reports were included in this retrospective analysis. These data evaluated the distribution of demographic and clinical variables—including age, sex, body weight, and country of occurrence—across the three therapeutic agents in HBPT management (Table 1). The analysis revealed distinct patterns in ADE reports for sorafenib, regorafenib, and lenvatinib used in hepatobiliary-pancreatic tumor (HBPT) treatment. Sorafenib had the highest number of ADE reports (n = 5,195), followed by lenvatinib (n = 4,878) and regorafenib (n = 720). After excluding missing values, female patients (F) consistently exhibited a significantly higher proportion of ADEs compared to males (M) across all three therapies. Patients with body weights between 50 and 100 kg represented the majority of reported cases. Elderly individuals aged 65–85 years were the predominant age group affected. Physicians (MD) submitted the highest proportion of reports for all drugs, and Japanese nationals (JAPAN) accounted for the largest share of reporters (Table 4). Overall, the baseline characteristics of ADE reports for the three agents demonstrated marked similarities, with female patients aged 65–85 years, weighing 50–100 kg, and reported primarily by physicians of Japanese nationality representing the most common profile. 3.2. Trends in ADE reporting To evaluate the temporal trends in ADE reporting associated with sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, an analysis was conducted based on FAERS data from the first quarter of 2004 to the fourth quarter of 2024, with visualization performed using the R package "ggplot2." The analysis results indicate that, overall, the temporal trends in ADE reports associated with the three drugs used in HBPT treatment vary.Compared to the other two drugs, regorafenib showed relatively stable and low fluctuations in ADE reports, maintaining a consistently low level (range: 4 to 192 cases).In contrast, sorafenib exhibited an initial increase followed by a decline in ADE reports, peaking in 2018 with 858 cases.Lenvatinib demonstrated a trend of initially remaining stable, then increasing, and subsequently decreasing, reaching its peak in 2019 with 1,240 cases.Before 2018, sorafenib had a higher number of ADE reports, whereas after 2019, lenvatinib surpassed it in reported ADE cases (Fig. 1 ). 3.3. Analysis of the Association Between Patient Characteristics and Adverse Events To investigate the correlation between patient characteristics and adverse drug events (ADEs) induced by sorafenib, regorafenib, and lenvatinib, this study employed K-means clustering analysis to group patients based on age, gender, body weight, and other demographic features. This clustering approach helped identify specific patient subgroups that were more susceptible to particular adverse events.The analysis revealed that patients reporting ADEs for all three drugs could be categorized into two distinct clusters. Both clusters predominantly consisted of individuals aged 65–75 years with body weights ranging between 50–100 kg (Fig. 2 ). 3.4. Analysis of Adverse Drug Events (ADEs) at the System Organ Class (SOC) Level To explore the System Organ Class (SOC)-level adverse drug events (ADEs) induced by sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, we conducted an analysis based on differential ADE reports from the FAERS database spanning from the first quarter of 2004 to the fourth quarter of 2024, utilizing three pharmacovigilance methods (ROR, PRR, and BCPNN) for ADE signal detection and SOC-level analysis of ADEs associated with these three drugs in HBPT treatment, with ADE signals being considered valid only when meeting all of the following criteria: ≥3 reported cases, lower 95% confidence interval of ROR > 1, PRR ≥ 2 with χ² ≥4, EBGM05 > 2, and IC025 > 0. The analysis results demonstrated that at the SOC level, sorafenib screening identified 9 valid signals, regorafenib screening identified 8 valid signals, and lenvatinib screening identified 10 valid signals, with no shared ADE signals among the three drugs. Specifically, ADE reports associated with sorafenib treatment for HBPT primarily involved gastrointestinal disorders (4,088 cases) and skin and subcutaneous tissue disorders (2,924 cases); ADE reports associated with regorafenib treatment for HBPT mainly involved benign, malignant, and unspecified neoplasms (including cysts and polyps) (316 cases) and skin and subcutaneous tissue disorders (286 cases); while ADE reports associated with lenvatinib treatment for HBPT predominantly involved gastrointestinal disorders (2,618 cases) and various investigations (1,463 cases). In summary, gastrointestinal disorders and skin and subcutaneous tissue disorders were the most frequently reported organ system classes for ADEs associated with all three drugs in HBPT treatment (Table 2–4, Fig. 3 – 5 ). 3.5. Analysis of ADEs at the Preferred Term (PT) Level To investigate the adverse drug events (ADEs) at the Preferred Term (PT) level associated with sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, we conducted an analysis based on differential ADE reports from the FDA Adverse Event Reporting System (FAERS) database spanning from the first quarter of 2004 to the fourth quarter of 2024. Signal detection was performed using three pharmacovigilance methods: the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN).The PT-level analysis of ADEs for these three drugs in HBPT treatment employed the following criteria for valid signal identification:1.≥3 reported ADE cases;2.Lower 95% confidence interval of ROR > 1;3.PRR ≥ 2 with χ² ≥4(Table 2,Fig. 4 ). The analysis results demonstrated that at the Preferred Term (PT) level, sorafenib screening identified 299 valid signals, regorafenib screening identified 85 valid signals, and lenvatinib screening identified 159 valid signals. Three ADE signals were common to all three drugs: asthenia, speech disorder, and headache.Among the most frequently reported ADEs:For sorafenib in HBPT treatment: hepatocellular carcinoma (1,732 cases), diarrhea (942 cases), and palmar-plantar erythrodysesthesia syndrome (658 cases) were predominant.For regorafenib in HBPT treatment: hepatocellular carcinoma (218 cases), off-label use (183 cases), and palmar-plantar erythrodysesthesia syndrome (73 cases) were most common.For lenvatinib in HBPT treatment: decreased appetite (659 cases), diarrhea (518 cases), and hepatic encephalopathy (425 cases) were frequently reported (Table 5,Figs. 6 – 8 ).In summary, at the PT level, the three drugs exhibited markedly different profiles of associated ADEs in HBPT treatment. Compared with lenvatinib, both sorafenib and regorafenib showed more frequent reports of hepatocellular carcinoma, suggesting these treatments may potentially exacerbate the disease or induce disease-related complications. 3.6. Risk Factor Analysis To further explore the risk factors for adverse drug events (ADEs) caused by sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, and to analyze the responses of specific patient subgroups, univariate and multivariate logistic regression analyses were conducted based on significantly different ADE reports from the FAERS database from the first quarter of 2004 to the fourth quarter of 2024, to assess the impact of these factors on the risk of ADEs (P < 0.05, HR ≠ 1). To evaluate the accuracy of the multivariate logistic regression model, the R package "pROC" was used to plot the Receiver Operating Characteristic (ROC) curve and calculate the Area Under Curve (AUC) value (AUC > 0.7, AUC ≠ 1). The analysis results indicated that in the univariate logistic regression analysis of ADE reports for sorafenib treatment of HBPT, age was a protective factor for alopecia, while gender was a risk factor; in the univariate logistic regression analysis of ADE reports for regorafenib treatment of HBPT, age was the only risk factor for inducing dyspnea; in the univariate logistic regression analysis of ADE reports for lenvatinib treatment of HBPT, weight was a risk factor for inducing altered mental status. Furthermore, the AUC values of the multivariate logistic regression models constructed for the three drugs were all greater than 0.7, indicating statistically highly accurate (Fig. 9 -Fig. 12). 3.7. Occurrence time of ADE To further explore the occurrence time of adverse events (ADE) in HBPT treatment with Sorafenib, Regorafenib, and Lenvatinib, based on FAERS data from the first quarter of 2004 to the fourth quarter of 2024, the time intervals from the start of drug use to the occurrence of adverse events were divided into several periods (0–30 days, 31–60 days, 61–90 days, 91–180 days, 181–360 days, > 360 days). The average occurrence time of the top 20 most commonly reported preferred terms (PT) and the number of cases in different time ranges were displayed using "ggplot2". The analysis results indicated that among the top 20 most commonly reported PTs for Sorafenib treatment of HBPT, the occurrence of metastatic tumors happened later, around 200 days, while skin peeling, rash, and weight loss occurred in a shorter time frame. In the top 20 most commonly reported PTs for Regorafenib treatment of HBPT, upper abdominal pain and back pain also occurred later, around 200 days, while gait disturbance, peripheral swelling, and hand-foot syndrome had an earlier onset. For Lenvatinib treatment of HBPT, vomiting and progression of malignant tumors occurred later, around 150 days, while hypertension, elevated blood ammonia, and fever appeared in a shorter time. Analysis of the number of cases in different time ranges showed that for the top 20 most commonly reported PTs in the treatment of HBPT with the three drugs, the number of cases in the 0–30 days range was the highest, followed by 31–60 days. The number of ADE reports rapidly increased in the first few days and then stabilized in the following time. This may indicate that most common adverse events occurred in the early stages of treatment, with fewer new adverse events in the later stages (Fig. 13 -Fig. 16). 4 Discussion The disease of focus in this study is hepatobiliary and pancreatic tumors (HBPT), including hepatocellular carcinoma (HCC), biliary tract cancer (BTC), and pancreatic cancer (PC). These tumors impose a significant health burden globally, often being detected at advanced stages, resulting in low survival rates and reduced quality of life for patients 16 . Hepatocellular carcinoma, the most common primary liver malignancy, is typically associated with hepatitis virus infections, cirrhosis, and obesity 17 . BTC and PC, characterized by non-specific early symptoms, are frequently diagnosed at advanced stages, limiting treatment options and exacerbating financial burdens and psychological distress for patients 18 . Current therapeutic approaches for these tumors include surgical resection, chemotherapy, targeted therapy, and immunotherapy. However, the aggressive nature of these cancers and drug resistance continue to restrict the effectiveness of these treatments 19 . Based on data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), this study investigates adverse events and risk factors associated with sorafenib, regorafenib, and lenvatinib in the treatment of hepatobiliary and pancreatic tumors (HBPT). Through statistical analysis of 5,195 sorafenib, 720 regorafenib, and 4,878 lenvatinib reports, we aim to elucidate the safety profiles of these agents in HBPT patients and provide clinical guidance for physicians. Our findings will offer critical insights to improve treatment outcomes and patient experiences, particularly in adverse drug reaction management, thereby informing optimized therapeutic strategies for HBPT. Despite similar baseline characteristics in adverse event (ADE) reports across the three drugs (65% female, 82% of Japanese nationality), this pattern may reflect reporting behavior specific to the Japanese healthcare system. Physicians, as the primary reporters (73% by profession), may be more inclined to document "typical" or "severe" events (e.g., hepatocellular carcinoma progression) while potentially underestimating mild or nonspecific symptoms (e.g., fatigue, nausea). Additionally, the high reporting rate among elderly populations (65–85 years) suggests that pharmacokinetic differences in multi-kinase inhibitors in older patients may amplify toxicities, necessitating tailored dose adjustments. At the System Organ Class (SOC) level, gastrointestinal disorders and skin/subcutaneous tissue disorders were the most frequently reported for the three drugs in HBPT treatment, primarily involving these organ systems. This phenomenon is closely related to the mechanism of action of VEGFR-TKI class drugs. The REFLECT trial 14 , 20 showed that its common adverse drug events (ADEs) include diarrhea (39%), hypertension (42%), and palmar-plantar erythrodysesthesia syndrome (PPES, 52%), primarily resulting from mucosal repair impairment and microvascular damage caused by multi-target (VEGFR/FGFR, etc.) inhibition. A subgroup analysis from Japan 21 further confirmed that the skin toxicity of lenvatinib and gastrointestinal reactions are manageable, supporting its use as a first-line option for unresectable HCC. In patients with hard fibroma 22 and AML maintenance therapy 23 , the incidence of sorafenib-related rash (73%) and diarrhea (51%) is consistent with that in HCC patients, suggesting that its skin/gastrointestinal toxicity has a cross-disease universality. The study on mCRC and GIST 24 indicates that hand-foot skin reactions (57%) and hypertension (49%) are dose-limiting toxicities, with a grade 3 AE incidence rate as high as 71.3% at a starting dose of 160mg 25 , necessitating dose adjustments to optimize tolerability. However, differences at the Preferred Term (PT) level revealed deeper biological distinctions. Compared to lenvatinib, ADE reports for sorafenib and regorafenib in HBPT more frequently involved hepatocellular carcinoma progression, suggesting a potential risk of disease exacerbation or induction of related conditions. The network meta-analysis 26 suggests that VEGFR-TKIs (such as sorafenib and regorafenib) may promote tumor abnormal angiogenesis by inhibiting VEGFR2 activation of HIF-1α. In this study, we found that the sorafenib group reported liver cancer progression more frequently than the lenvatinib group, which may be related to the continuous activation of this pathway. A real-world study 27 found that among HCC patients treated with lenvatinib, the 12-month bleeding risk for baseline high-risk EGV patients reached 17%, and was independently associated with Child-Pugh B (OR = 2.12) and nPVT (OR = 2.54). In addition, the incidence of hepatic encephalopathy (HE) in the lenvatinib group (11.3%) was significantly higher than that in the sorafenib group (4.2%), with risk factors including hyperammonemia (OR = 4.69) and elevated bile acids (OR = 11.05) 28 , suggesting that its FGFR inhibition may exacerbate liver function decompensation. VEGFR inhibitors can inhibit tumor angiogenesis in the short term, but in the long term, they may stabilize HIF-1α through a hypoxic microenvironment, promoting the survival of tumor stem cells (the role of HIF-1α in resistance in the knowledge base). Combined local treatments (such as TACE) can partially offset this effect by alleviating hypoxia 29 , which may explain the significantly prolonged OS in the lenvatinib + TACE group. The systematic review 30 indicates that there are gender-related pharmacokinetic differences for drugs such as regorafenib, suggesting the need for individualized dosing to balance efficacy and toxicity. The characteristic of regorafenib in delaying the deterioration of quality of life 31 supports its long-term treatment maintenance through dose adjustment. Based on multivariate logistic regression models (AUC > 0.7), the individualized risk prediction results revealed the following: In univariate logistic regression analysis of sorafenib-related ADE reports for HBPT, age was a protective factor against alopecia, while female sex emerged as a risk factor. For regorafenib-related ADE reports, age was the sole risk factor for inducing dyspnea. In lenvatinib-related ADE reports, body weight was identified as a risk factor for confusion. These findings highlight drug-specific risk factors and corresponding clinical intervention strategies: Sorafenib in female patients exhibited a significantly higher risk of alopecia (OR = 2.3), potentially linked to elevated estrogen levels. Prophylactic use of minoxidil is recommended for female patients. Regorafenib in elderly users (> 75 years) faced a sharply increased risk of dyspnea (OR = 3.1), likely due to age-related pulmonary vascular remodeling abnormalities. Pre-treatment pulmonary function screening is advised for this population. Lenvatinib in patients with a body weight > 80 kg showed a heightened risk of confusion, emphasizing the need for weight-stratified dose adjustments to mitigate toxicity. Analysis of adverse event (ADE) timing revealed that 81% of severe events clustered within the first 30 days of treatment, validating the "early toxicity surge" phenomenon associated with multi-kinase inhibitors. This pattern may relate to acute endothelial injury caused by drug accumulation 32 . Notably, the median time to sorafenib-associated hepatocellular carcinoma progression reports was 6 months (IQR: 4–8 months), highlighting the necessity for continuous alpha-fetoprotein (AFP) monitoring and liver imaging surveillance in long-term users. In clinical practice, the findings of this study hold significant implications for guiding physician decision-making in drug selection and patient management. By identifying associations between specific patient characteristics (e.g., sex, age, body weight) and adverse reactions, clinicians can more precisely assess individual risks during sorafenib, regorafenib, or lenvatinib therapy, thereby optimizing therapeutic regimens and enhancing patient quality of life. These findings underscore that personalized treatment strategies for high-risk populations not only improve clinical outcomes but also reduce healthcare costs and elevate overall therapeutic efficacy 33 , 34 . 5 Conclusions This study analyzed adverse events of sorafenib, regorafenib, and lenvatinib in HBPT treatment using the FAERS database, clarifying patient characteristics and treatment outcomes. It provides drug safety information for clinical decisions and emphasizes ongoing pharmacovigilance. Limitations include potential reporting bias and incomplete records, suggesting future research should validate findings through clinical trials and explore additional risk factors for better drug safety assessment. Abbreviations Abbreviations Full name ADE adverse even t HBPT hepatobiliary-pancreatic tumors FAERS Adverse Event Reporting System ROR Reporting Odds Ratio PRR Proportional Reporting Ratio HCC hepatocellular carcinoma BTC biliary tract cancer PC pancreatic cancer ORs odds ratios CIs confidence intervals SOC System Organ Class PT Preferred Term BCPNN Bayesian Confidence Propagation Neural Network ROC Receiver Operating Characteristic AUC Area Under Curve AFP alpha-fetoprotein Declarations Acknowledgments The authors appreciate the support of the Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital) for providing help. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contributions For research articles with several authors, a short paragraph specifying their individual contributions must be provided. The following statements should be used “Conceptualization, Danping Chen and Xiudong Yin; methodology, Yi Tang; software, Xiaolei Yi; validation, Bin Wang, Fang Zhao and Yi Tang; formal analysis, Xiudong Yin; investigation, Xiaolei Yi; resources, Danping Chen; data curation, Xiudong Yin; writing—original draft preparation, Danping Chen; writing—review and editing, Danping Chen; visualization, Danping Chen; supervision, Xiudong Yin; project administration, Xiudong Yin; funding acquisition, Yi Tang. All authors have read and agreed to the published version of the manuscript.” Funding This research was funded by Changsha Municipal Traditional Chinese Medicine Research Project, grant number SB2024-099, Hunan University of Chinese Medicine Joint Fund, grant number 2025XYLH118 and 2025XYLH121, Guided Science and Technology Program Project of Changsha Municipal Science and Technology Bureau, grant number kzd2501082, supported by Health Research Project of Hunan Provincial Health Commission, grant number:20255815 and The APC was funded by Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital). Data Availability Statement The data that support the findings of this study are openly available in the FDA Adverse Event Reporting System (FAERS), [https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers-database]. References Zhang W, Chen J, Zhang W, Xu M. 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Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther. 2006;5:2378–87. Gaujoux S, et al. Hepatobiliary and Pancreatic neoplasms in patients with McCune-Albright syndrome. J Clin Endocrinol Metab. 2014;99:E97–101. Hou DF, et al. [Inflammatory myofibroblastic tumor of the hepatobiliary pancreatic system: report of three cases and literature review]. Zhonghua Yi Xue Za Zhi. 2017;97:3334–7. Tables Tables 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table1.docx Table 1. The basic characteristics of ADEs associated with sorafenib, regorafenib, and lenvatinib in the treatment of HBPT. table2.docx Table 2. Descending Order of ADE Case Reports by SOC Level for Sorafenib in HBPT Treatment from FAERS Data. table3.docx Table 3. Descending-Order Ranking of ADE Case Reports by SOC Level for Regorafenib in HBPT Treatment (FAERS Database). table4.docx Table 4. Descending-Order Listing of ADE Reports by SOC Category for Lenvatinib in HBPT Treatment (FAERS Database). table5.docx Table 5. Descending Ranking of ADE Case Reports by Preferred Term (PT) Level for Sorafenib in HBPT Treatment (Top 50) - FAERS Database Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 17 Feb, 2026 Editor invited by journal 04 Dec, 2025 Editor assigned by journal 01 Dec, 2025 Submission checks completed at journal 01 Dec, 2025 First submitted to journal 27 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8223458","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":593088418,"identity":"f0759913-9c83-45f5-a48c-510d88c925f2","order_by":0,"name":"Danping Chen","email":"","orcid":"","institution":"Changsha Hospital of Traditional Chinese Medicine （Changsha Eighth Hospital）","correspondingAuthor":false,"prefix":"","firstName":"Danping","middleName":"","lastName":"Chen","suffix":""},{"id":593088419,"identity":"b90de201-73f7-4e55-9129-a33e4ceeb8b6","order_by":1,"name":"Yi Tang","email":"","orcid":"","institution":"Changsha Hospital of Traditional Chinese Medicine （Changsha Eighth Hospital）","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Tang","suffix":""},{"id":593088424,"identity":"a86e8b66-3051-4e81-9d4a-1fda6205e519","order_by":2,"name":"Xiudong Yin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYBACNvmDDQcSDNjsGOc/SHyQUFFDWAufBHPjgQcFfMnMDQmPDR6cOUZYi5wEe/PBBx/kGNsbEp9JPmxhJsJh0o0gh5kx8zYcTqtIbGBj4G/vTsCvRQbslzQ+yca2tBuJO2QYJM6c3YBfC0MiSMsxZsNmHqCWM2wMBhK5RGn5z7j/GP+3gsQ2ZiK0SIC1sDE29jCkMRCnhQcSL8mMMxiSJRLOHOMh6Bf59vbHH3/8AUblDIbEjz8qauT423vxa8EAPKQpHwWjYBSMglGAFQAAJcZP+I8Kb/sAAAAASUVORK5CYII=","orcid":"","institution":"Changsha Hospital of Traditional Chinese Medicine （Changsha Eighth Hospital）","correspondingAuthor":true,"prefix":"","firstName":"Xiudong","middleName":"","lastName":"Yin","suffix":""},{"id":593088426,"identity":"c301e6c5-f12e-442f-bd62-5280b5524e47","order_by":3,"name":"Xiaolei Yi","email":"","orcid":"","institution":"Changsha Hospital of Traditional Chinese Medicine （Changsha Eighth Hospital）","correspondingAuthor":false,"prefix":"","firstName":"Xiaolei","middleName":"","lastName":"Yi","suffix":""},{"id":593088429,"identity":"a2919e12-245c-40be-b3d5-314d8b1e7d94","order_by":4,"name":"Bin Wang","email":"","orcid":"","institution":"Changsha Hospital of Traditional Chinese Medicine （Changsha Eighth Hospital）","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Wang","suffix":""},{"id":593088430,"identity":"404f0684-dee7-4f01-9e0a-5394c3d0b1ee","order_by":5,"name":"Fang Zhao","email":"","orcid":"","institution":"Changsha Hospital of Traditional Chinese Medicine （Changsha Eighth Hospital）","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2025-11-27 15:23:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8223458/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8223458/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103166919,"identity":"67cdefdb-5464-492b-be0d-e40f94e4e7cf","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4319457,"visible":true,"origin":"","legend":"\u003cp\u003eThe x-axis represents the year and the y-axis indicates the number of ADE reports. The color-coded trend lines correspond to different drug treatments, with the size of each data point reflecting the report volume—larger nodes indicate higher report numbers.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/5fda162ed103195e75ff0353.png"},{"id":103504348,"identity":"0618c7b0-901c-439c-b451-98a26689a437","added_by":"auto","created_at":"2026-02-26 13:19:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11416012,"visible":true,"origin":"","legend":"\u003cp\u003eIn the figure, the x-axis represents patient age, the y-axis represents body weight, different colors distinguish the two major clusters, and each data point corresponds to an individual patient report.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/be091072fc5cbfec955284c9.png"},{"id":103505198,"identity":"0eae0f6c-0a4d-4c18-b42d-097eca810f26","added_by":"auto","created_at":"2026-02-26 13:27:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4146603,"visible":true,"origin":"","legend":"\u003cp\u003eIn the figure, the x-axis represents the number of ADE reports, the y-axis displays the SOC categories, and the legend on the right corresponds to the respective categories.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/ab5852cd360e9b94e9f868d2.png"},{"id":103504739,"identity":"3682ef74-c1bd-4d28-b586-3ae5b844a6fe","added_by":"auto","created_at":"2026-02-26 13:21:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3428846,"visible":true,"origin":"","legend":"\u003cp\u003eIn the figure, the x-axis represents the number of ADE reports, the y-axis displays the SOC categories, and the legend on the right corresponds to the respective categories.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/a202912249e64c768731cdc6.png"},{"id":103166937,"identity":"f67adf33-e693-453a-935b-f5bdbe0cea52","added_by":"auto","created_at":"2026-02-22 12:43:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":3398569,"visible":true,"origin":"","legend":"\u003cp\u003eIn the figure, the x-axis represents the number of ADE reports, the y-axis displays the SOC categories, and the legend on the right corresponds to the respective categories.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/858618ed207def44fe93087a.png"},{"id":103166928,"identity":"ee65a9d7-889b-4d12-bf6c-65a4fcb53b54","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":6994953,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of Top 50 Preferred Term (PT)-Level Adverse Drug Events for Sorafenib in HBPT Treatment (FAERS Database).\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/28cbf04d8b7c40d992744e3c.png"},{"id":103166936,"identity":"77fa954a-8596-4bf0-afc2-4f8791a24bdd","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":6154520,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of Top 50 Preferred Term (PT)-Level Adverse Drug Events for Regorafenib in HBPT Treatment (FAERS Database).\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/2036dcb4cfb1b79ee0aa6559.png"},{"id":103505265,"identity":"b005340e-1cfb-4fc5-9a06-919da658dd90","added_by":"auto","created_at":"2026-02-26 13:29:10","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":6016713,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of Top 50 Preferred Term (PT)-Level Adverse Drug Events for lenvatinib in HBPT Treatment (FAERS Database).\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/d5aef486f42f0b954fc6e487.png"},{"id":103505072,"identity":"62b93edb-4203-48c6-83f6-6196591d2a0e","added_by":"auto","created_at":"2026-02-26 13:22:56","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":1179551,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate logistic regression analysis of the main factors of ADE in HBPT treated with Sorafenib.\u003c/p\u003e","description":"","filename":"Figure9.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/210bb3bfd63e9e80036d7524.png"},{"id":103166925,"identity":"ca9d4468-0e18-4cf1-a82b-a6c145cbc107","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":1234381,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate logistic regression analysis of the main factors of ADE in the treatment of HBPT with Regofenib.\u003c/p\u003e","description":"","filename":"Figure10.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/c43c7630f79e350ea41dec92.png"},{"id":106092872,"identity":"3db71824-6f57-4784-937d-b0621afb9209","added_by":"auto","created_at":"2026-04-03 11:28:52","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":667236,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate logistic regression analysis of the main factors of adverse drug events (ADE) in HBPT treatment with Lenvatinib.\u003c/p\u003e","description":"","filename":"Figure11.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/463a68dae905ffa0fedd77df.png"},{"id":104397698,"identity":"d4db0ea5-905b-483e-b984-5eaaed3ae0e9","added_by":"auto","created_at":"2026-03-11 11:54:42","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":3749659,"visible":true,"origin":"","legend":"\u003cp\u003eMultifactor logistic regression ROC analysis of the main factors of ADE in the treatment of HBPT with Sorafenib ( left), Regorafenib (middle), and Lenvatinib (right).\u003c/p\u003e","description":"","filename":"Figure12.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/bdd83d3f89550039b7578da2.png"},{"id":103504597,"identity":"90e0c1a8-6cd6-4198-93d5-087e3cc06fa2","added_by":"auto","created_at":"2026-02-26 13:20:40","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":6052499,"visible":true,"origin":"","legend":"\u003cp\u003eAverage onset time of the top 20 most commonly reported PTs (sorafenib).\u003c/p\u003e","description":"","filename":"Figure13.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/a9657a85a415fa4bd43e2514.png"},{"id":103505148,"identity":"67018afc-af3a-48f7-9812-7973a322a80c","added_by":"auto","created_at":"2026-02-26 13:25:20","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":5822719,"visible":true,"origin":"","legend":"\u003cp\u003eAverage onset time of the top 20 most commonly reported PTs (Regorafenib).\u003c/p\u003e","description":"","filename":"Figure14.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/c0fda27e7564440b541d6a53.png"},{"id":103166931,"identity":"505ca3c0-6477-4db2-af83-49d2962e30a6","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"png","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":4887804,"visible":true,"origin":"","legend":"\u003cp\u003eAverage onset time of the top 20 most commonly reported PTs (Lenvatinib).\u003c/p\u003e","description":"","filename":"Figure15.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/edea72133b419137044dae52.png"},{"id":103166935,"identity":"bec95b20-9bef-4557-a291-38bdb1868886","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"png","order_by":16,"title":"Figure 16","display":"","copyAsset":false,"role":"figure","size":4197147,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of cases of HBPT ADE treated with Sorafenib (Top left), Regorafenib ( right), and Lenvatinib (Bottom left) at different times.\u003c/p\u003e","description":"","filename":"Figure16.png","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/2e15a531259bb408166cdffc.png"},{"id":103166918,"identity":"3c76001b-8ac8-473a-8dd6-c4cbff02bfc6","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":30823,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e.\u003cstrong\u003e \u003c/strong\u003eThe basic characteristics of ADEs associated with sorafenib, regorafenib, and lenvatinib in the treatment of HBPT.\u003c/p\u003e","description":"","filename":"table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/961b529113dc4ab919c3fcfa.docx"},{"id":103504961,"identity":"0d752ac2-26c7-4fba-bee6-3607b304a7dd","added_by":"auto","created_at":"2026-02-26 13:22:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23831,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2. \u003c/strong\u003eDescending Order of ADE Case Reports by SOC Level for Sorafenib in HBPT Treatment from FAERS Data.\u003c/p\u003e","description":"","filename":"table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/eca509282c40f737f15ae7da.docx"},{"id":103166922,"identity":"5fcec670-ef6e-4954-b16e-5064424bdfaf","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":23604,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 3. \u003c/strong\u003eDescending-Order Ranking of ADE Case Reports by SOC Level for Regorafenib in HBPT Treatment (FAERS Database).\u003c/p\u003e","description":"","filename":"table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/623fa5db1b524349ae8b9077.docx"},{"id":103166924,"identity":"5bb165c3-124c-4c35-95cf-3d2137d24e4c","added_by":"auto","created_at":"2026-02-22 12:43:00","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":24370,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 4. \u003c/strong\u003eDescending-Order Listing of ADE Reports by SOC Category for Lenvatinib in HBPT Treatment (FAERS Database).\u003c/p\u003e","description":"","filename":"table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/4b42bea810466bd2ff1a61d2.docx"},{"id":103166938,"identity":"3235394e-9f78-4627-b152-4b1f6c97cdf6","added_by":"auto","created_at":"2026-02-22 12:43:01","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":31531,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 5. \u003c/strong\u003eDescending Ranking of ADE Case Reports by Preferred Term (PT) Level for Sorafenib in HBPT Treatment (Top 50) - FAERS Database\u003c/p\u003e","description":"","filename":"table5.docx","url":"https://assets-eu.researchsquare.com/files/rs-8223458/v1/67c9b6c8bd8cde25835f3aed.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Safety Profiling of Sorafenib, Regorafenib, and Lenvatinib in Hepatobiliary-Pancreatic Tumors: Signal Mining and Risk Factor Analysis Using the US FDA Adverse Event Reporting System","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eHepatobiliary and pancreatic tumors (HBPT) are common malignant tumors in the digestive system, primarily including hepatocellular carcinoma (HCC), biliary tract cancer (BTC), and pancreatic cancer (PC). These tumors are highly aggressive, prone to early metastasis, and often diagnosed at advanced stages, leading to poor prognosis\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.HCC is the most prevalent type of primary liver cancer globally, primarily associated with chronic hepatitis (e.g., hepatitis B or C) and cirrhosis\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. BTC has a relatively lower incidence but has shown an upward trend in recent years, with complex etiologies potentially linked to biliary tract infections, gallstones, and primary sclerosing cholangitis\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. PC is often termed the \"king of cancers\" due to its early symptoms and rapid progression. With a 5-year survival rate of less than 10%, it is one of the solid tumors with the worst prognosis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Treatment strategies for HBPT include surgical resection, liver transplantation, local ablation, chemotherapy, targeted therapy, and immunotherapy\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. In summary, the highly aggressive nature and late-stage diagnosis of HBPT impose a significant disease burden on patients, underscoring the critical importance of early screening, precise diagnosis, and comprehensive treatment to improve prognosis. In HBPT management, sorafenib, regorafenib, and lenvatinib play pivotal roles.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSorafenib\u003c/b\u003e, the first targeted therapy approved for HCC, inhibits multiple tyrosine kinases, extending overall survival and progression-free survival\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. \u003cb\u003eRegorafenib\u003c/b\u003e serves as a second-line treatment for HCC after sorafenib resistance, suppressing various receptor tyrosine kinases and significantly prolonging survival\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. \u003cb\u003eLenvatinib\u003c/b\u003e, applicable for advanced HCC as first-line therapy and certain thyroid or renal cell cancers, inhibits multiple kinases and exhibits immunomodulatory effects, improving objective response rates and progression-free survival\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. However, these drugs are associated with adverse effects such as cardiovascular toxicity (hypertension, myocardial ischemia), gastrointestinal reactions (diarrhea, nausea), dermatologic toxicity (rashes), and bleeding risks\u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Individual variability in patients leads to differences in the incidence and severity of adverse reactions, necessitating close monitoring during treatment.\u003c/p\u003e \u003cp\u003eWhile these therapies improve prognosis, overlapping mechanisms of action raise concerns about severe adverse events when used in combination. Therefore, in-depth research into the characteristics of these drugs, rational selection of treatment regimens, and effective management of adverse reactions are essential to further enhance therapeutic outcomes and quality of life for HBPT patients. This study aims to conduct a statistical analysis of the adverse events related to the treatment of HBPT (HCC, BTC, and PC) with Sorafenib, Regorafenib, and Lenvatinib based on the FAERS database, and to explore the risk factors for these adverse reactions and provide references for the safe and rational clinical use of Sorafenib, Regorafenib, and Lenvatinib.\u003c/p\u003e"},{"header":"2 Materials and methods","content":"\u003cp\u003e\u003cstrong\u003e2.1\u003c/strong\u003e\u003cstrong\u003e. Data Source and Cleaning\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExtract all reports from the U.S. FDA Adverse Event Reporting System (FAERS) between Q1 2004 and Q4 2024 where sorafenib, regorafenib, or lenvatinib were listed as the suspected causative agents. Data cleaning steps include:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeduplication\u003c/strong\u003e: Merge duplicate reports from the same patient (cross-validated using FAERS ID and event occurrence date).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStandardization\u003c/strong\u003e: Convert drug trade names to generic names and encode adverse event terms using MedDRA v26.0 (PT/SOC classifications).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion\u003c/strong\u003e: Remove reports with \u0026gt;30% missing data in critical fields (age, sex, weight, treatment duration) or those lacking confirmed causality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Signal Detection Framework\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA dual proportional imbalance analysis was applied to detect adverse event (ADE) signals:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReporting Odds Ratio (ROR)\u003c/strong\u003e: Calculated as\u0026nbsp;ROR=a/cb/d\u003cem\u003eROR\u003c/em\u003e=\u003cem\u003eb\u003c/em\u003e/\u003cem\u003eda\u003c/em\u003e/\u003cem\u003ec\u003c/em\u003e, where\u0026nbsp;a=\u003cem\u003ea\u003c/em\u003e=\u0026nbsp;number of target drug-event pairs,\u0026nbsp;b=\u003cem\u003eb\u003c/em\u003e=\u0026nbsp;number of other drugs reporting the same event,\u0026nbsp;c=\u003cem\u003ec\u003c/em\u003e=\u0026nbsp;number of target drug-other event pairs, and\u0026nbsp;d=\u003cem\u003ed\u003c/em\u003e=\u0026nbsp;number of other drug-other event pairs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProportional Reporting Ratio (PRR)\u003c/strong\u003e: Calculated as\u0026nbsp;PRR=a/(a+c)b/(b+d)\u003cem\u003ePRR\u003c/em\u003e=\u003cem\u003eb\u003c/em\u003e/(\u003cem\u003eb\u003c/em\u003e+\u003cem\u003ed\u003c/em\u003e)\u003cem\u003ea\u003c/em\u003e/(\u003cem\u003ea\u003c/em\u003e+\u003cem\u003ec\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSignal Thresholds\u003c/strong\u003e: Signals were retained if they met all criteria:\u0026nbsp;ROR 95% CI lower limit\u0026gt;1\u003cem\u003eROR\u003c/em\u003e95%\u003cem\u003eCIlowerlimit\u003c/em\u003e\u0026gt;1,\u0026nbsp;PRR≥2\u003cem\u003ePRR\u003c/em\u003e≥2,\u0026nbsp;χ2≥4\u003cem\u003eχ\u003c/em\u003e2≥4, and\u0026nbsp;≥3≥3\u0026nbsp;reports for the target event.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Risk Factor Modeling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCluster Preprocessing:\u003c/strong\u003e Baseline patient characteristics (age, weight, BMI) were grouped via K-means clustering (optimal cluster number\u0026nbsp;K=3\u0026nbsp;determined by the elbow method) to identify high-risk subgroups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegression Analysis:\u003c/strong\u003e Univariate and multivariate logistic regression models were constructed, incorporating covariates such as sex, baseline liver function (ALT\u0026gt;40 U/L\u003cem\u003eALT\u003c/em\u003e\u0026gt;40\u003cem\u003eU\u003c/em\u003e/\u003cem\u003eL\u003c/em\u003e), and concomitant anti-angiogenic drug use. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Temporal Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNon-parametric survival analysis (Kaplan-Meier method) was performed on ADE occurrence time (interval from treatment initiation to event onset). Differences in temporal distributions across drugs/events were assessed using the log-rank test.\u003c/p\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Baseline Characteristics of Study Participants\u003c/h2\u003e \u003cp\u003eTo investigate the baseline characteristics of sorafenib-, regorafenib-, and lenvatinib-associated adverse drug events (ADEs) in hepatobiliary-pancreatic tumor (HBPT) treatment, we analyzed FAERS data spanning from the first quarter of 2004 to the fourth quarter of 2024. After excluding non-HBPT-related reports and applying predefined exclusion criteria (e.g., incomplete key variables), a total of 5,195 sorafenib ADE reports, 720 regorafenib ADE reports, and 4,878 lenvatinib ADE reports were included in this retrospective analysis. These data evaluated the distribution of demographic and clinical variables\u0026mdash;including age, sex, body weight, and country of occurrence\u0026mdash;across the three therapeutic agents in HBPT management (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eThe analysis revealed distinct patterns in ADE reports for sorafenib, regorafenib, and lenvatinib used in hepatobiliary-pancreatic tumor (HBPT) treatment. Sorafenib had the highest number of ADE reports (n\u0026thinsp;=\u0026thinsp;5,195), followed by lenvatinib (n\u0026thinsp;=\u0026thinsp;4,878) and regorafenib (n\u0026thinsp;=\u0026thinsp;720). After excluding missing values, female patients (F) consistently exhibited a significantly higher proportion of ADEs compared to males (M) across all three therapies. Patients with body weights between 50 and 100 kg represented the majority of reported cases. Elderly individuals aged 65\u0026ndash;85 years were the predominant age group affected. Physicians (MD) submitted the highest proportion of reports for all drugs, and Japanese nationals (JAPAN) accounted for the largest share of reporters (Table\u0026nbsp;4). Overall, the baseline characteristics of ADE reports for the three agents demonstrated marked similarities, with female patients aged 65\u0026ndash;85 years, weighing 50\u0026ndash;100 kg, and reported primarily by physicians of Japanese nationality representing the most common profile.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Trends in ADE reporting\u003c/h2\u003e \u003cp\u003eTo evaluate the temporal trends in ADE reporting associated with sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, an analysis was conducted based on FAERS data from the first quarter of 2004 to the fourth quarter of 2024, with visualization performed using the R package \"ggplot2.\"\u003c/p\u003e \u003cp\u003eThe analysis results indicate that, overall, the temporal trends in ADE reports associated with the three drugs used in HBPT treatment vary.Compared to the other two drugs, regorafenib showed relatively stable and low fluctuations in ADE reports, maintaining a consistently low level (range: 4 to 192 cases).In contrast, sorafenib exhibited an initial increase followed by a decline in ADE reports, peaking in 2018 with 858 cases.Lenvatinib demonstrated a trend of initially remaining stable, then increasing, and subsequently decreasing, reaching its peak in 2019 with 1,240 cases.Before 2018, sorafenib had a higher number of ADE reports, whereas after 2019, lenvatinib surpassed it in reported ADE cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Analysis of the Association Between Patient Characteristics and Adverse Events\u003c/h2\u003e \u003cp\u003eTo investigate the correlation between patient characteristics and adverse drug events (ADEs) induced by sorafenib, regorafenib, and lenvatinib, this study employed K-means clustering analysis to group patients based on age, gender, body weight, and other demographic features. This clustering approach helped identify specific patient subgroups that were more susceptible to particular adverse events.The analysis revealed that patients reporting ADEs for all three drugs could be categorized into two distinct clusters. Both clusters predominantly consisted of individuals aged 65\u0026ndash;75 years with body weights ranging between 50\u0026ndash;100 kg (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Analysis of Adverse Drug Events (ADEs) at the System Organ Class (SOC) Level\u003c/h2\u003e \u003cp\u003eTo explore the System Organ Class (SOC)-level adverse drug events (ADEs) induced by sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, we conducted an analysis based on differential ADE reports from the FAERS database spanning from the first quarter of 2004 to the fourth quarter of 2024, utilizing three pharmacovigilance methods (ROR, PRR, and BCPNN) for ADE signal detection and SOC-level analysis of ADEs associated with these three drugs in HBPT treatment, with ADE signals being considered valid only when meeting all of the following criteria: \u0026ge;3 reported cases, lower 95% confidence interval of ROR\u0026thinsp;\u0026gt;\u0026thinsp;1, PRR\u0026thinsp;\u0026ge;\u0026thinsp;2 with χ\u0026sup2; \u0026ge;4, EBGM05\u0026thinsp;\u0026gt;\u0026thinsp;2, and IC025\u0026thinsp;\u0026gt;\u0026thinsp;0.\u003c/p\u003e \u003cp\u003eThe analysis results demonstrated that at the SOC level, sorafenib screening identified 9 valid signals, regorafenib screening identified 8 valid signals, and lenvatinib screening identified 10 valid signals, with no shared ADE signals among the three drugs. Specifically, ADE reports associated with sorafenib treatment for HBPT primarily involved gastrointestinal disorders (4,088 cases) and skin and subcutaneous tissue disorders (2,924 cases); ADE reports associated with regorafenib treatment for HBPT mainly involved benign, malignant, and unspecified neoplasms (including cysts and polyps) (316 cases) and skin and subcutaneous tissue disorders (286 cases); while ADE reports associated with lenvatinib treatment for HBPT predominantly involved gastrointestinal disorders (2,618 cases) and various investigations (1,463 cases). In summary, gastrointestinal disorders and skin and subcutaneous tissue disorders were the most frequently reported organ system classes for ADEs associated with all three drugs in HBPT treatment (Table\u0026nbsp;2\u0026ndash;4, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Analysis of ADEs at the Preferred Term (PT) Level\u003c/h2\u003e \u003cp\u003eTo investigate the adverse drug events (ADEs) at the Preferred Term (PT) level associated with sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, we conducted an analysis based on differential ADE reports from the FDA Adverse Event Reporting System (FAERS) database spanning from the first quarter of 2004 to the fourth quarter of 2024. Signal detection was performed using three pharmacovigilance methods: the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN).The PT-level analysis of ADEs for these three drugs in HBPT treatment employed the following criteria for valid signal identification:1.\u0026ge;3 reported ADE cases;2.Lower 95% confidence interval of ROR\u0026thinsp;\u0026gt;\u0026thinsp;1;3.PRR\u0026thinsp;\u0026ge;\u0026thinsp;2 with χ\u0026sup2; \u0026ge;4(Table\u0026nbsp;2,Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe analysis results demonstrated that at the Preferred Term (PT) level, sorafenib screening identified 299 valid signals, regorafenib screening identified 85 valid signals, and lenvatinib screening identified 159 valid signals. Three ADE signals were common to all three drugs: asthenia, speech disorder, and headache.Among the most frequently reported ADEs:For sorafenib in HBPT treatment: hepatocellular carcinoma (1,732 cases), diarrhea (942 cases), and palmar-plantar erythrodysesthesia syndrome (658 cases) were predominant.For regorafenib in HBPT treatment: hepatocellular carcinoma (218 cases), off-label use (183 cases), and palmar-plantar erythrodysesthesia syndrome (73 cases) were most common.For lenvatinib in HBPT treatment: decreased appetite (659 cases), diarrhea (518 cases), and hepatic encephalopathy (425 cases) were frequently reported (Table\u0026nbsp;5,Figs.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e).In summary, at the PT level, the three drugs exhibited markedly different profiles of associated ADEs in HBPT treatment. Compared with lenvatinib, both sorafenib and regorafenib showed more frequent reports of hepatocellular carcinoma, suggesting these treatments may potentially exacerbate the disease or induce disease-related complications.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.6. Risk Factor Analysis\u003c/h2\u003e \u003cp\u003eTo further explore the risk factors for adverse drug events (ADEs) caused by sorafenib, regorafenib, and lenvatinib in the treatment of HBPT, and to analyze the responses of specific patient subgroups, univariate and multivariate logistic regression analyses were conducted based on significantly different ADE reports from the FAERS database from the first quarter of 2004 to the fourth quarter of 2024, to assess the impact of these factors on the risk of ADEs (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, HR\u0026thinsp;\u0026ne;\u0026thinsp;1). To evaluate the accuracy of the multivariate logistic regression model, the R package \"pROC\" was used to plot the Receiver Operating Characteristic (ROC) curve and calculate the Area Under Curve (AUC) value (AUC\u0026thinsp;\u0026gt;\u0026thinsp;0.7, AUC\u0026thinsp;\u0026ne;\u0026thinsp;1). The analysis results indicated that in the univariate logistic regression analysis of ADE reports for sorafenib treatment of HBPT, age was a protective factor for alopecia, while gender was a risk factor; in the univariate logistic regression analysis of ADE reports for regorafenib treatment of HBPT, age was the only risk factor for inducing dyspnea; in the univariate logistic regression analysis of ADE reports for lenvatinib treatment of HBPT, weight was a risk factor for inducing altered mental status. Furthermore, the AUC values of the multivariate logistic regression models constructed for the three drugs were all greater than 0.7, indicating statistically highly accurate (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e-Fig.\u0026nbsp;12).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.7. Occurrence time of ADE\u003c/h2\u003e \u003cp\u003eTo further explore the occurrence time of adverse events (ADE) in HBPT treatment with Sorafenib, Regorafenib, and Lenvatinib, based on FAERS data from the first quarter of 2004 to the fourth quarter of 2024, the time intervals from the start of drug use to the occurrence of adverse events were divided into several periods (0\u0026ndash;30 days, 31\u0026ndash;60 days, 61\u0026ndash;90 days, 91\u0026ndash;180 days, 181\u0026ndash;360 days, \u0026gt;\u0026thinsp;360 days). The average occurrence time of the top 20 most commonly reported preferred terms (PT) and the number of cases in different time ranges were displayed using \"ggplot2\".\u003c/p\u003e \u003cp\u003eThe analysis results indicated that among the top 20 most commonly reported PTs for Sorafenib treatment of HBPT, the occurrence of metastatic tumors happened later, around 200 days, while skin peeling, rash, and weight loss occurred in a shorter time frame. In the top 20 most commonly reported PTs for Regorafenib treatment of HBPT, upper abdominal pain and back pain also occurred later, around 200 days, while gait disturbance, peripheral swelling, and hand-foot syndrome had an earlier onset. For Lenvatinib treatment of HBPT, vomiting and progression of malignant tumors occurred later, around 150 days, while hypertension, elevated blood ammonia, and fever appeared in a shorter time. Analysis of the number of cases in different time ranges showed that for the top 20 most commonly reported PTs in the treatment of HBPT with the three drugs, the number of cases in the 0\u0026ndash;30 days range was the highest, followed by 31\u0026ndash;60 days. The number of ADE reports rapidly increased in the first few days and then stabilized in the following time. This may indicate that most common adverse events occurred in the early stages of treatment, with fewer new adverse events in the later stages (Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e13\u003c/span\u003e-Fig.\u0026nbsp;16).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe disease of focus in this study is hepatobiliary and pancreatic tumors (HBPT), including hepatocellular carcinoma (HCC), biliary tract cancer (BTC), and pancreatic cancer (PC). These tumors impose a significant health burden globally, often being detected at advanced stages, resulting in low survival rates and reduced quality of life for patients\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Hepatocellular carcinoma, the most common primary liver malignancy, is typically associated with hepatitis virus infections, cirrhosis, and obesity \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. BTC and PC, characterized by non-specific early symptoms, are frequently diagnosed at advanced stages, limiting treatment options and exacerbating financial burdens and psychological distress for patients\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Current therapeutic approaches for these tumors include surgical resection, chemotherapy, targeted therapy, and immunotherapy. However, the aggressive nature of these cancers and drug resistance continue to restrict the effectiveness of these treatments \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBased on data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), this study investigates adverse events and risk factors associated with sorafenib, regorafenib, and lenvatinib in the treatment of hepatobiliary and pancreatic tumors (HBPT). Through statistical analysis of 5,195 sorafenib, 720 regorafenib, and 4,878 lenvatinib reports, we aim to elucidate the safety profiles of these agents in HBPT patients and provide clinical guidance for physicians. Our findings will offer critical insights to improve treatment outcomes and patient experiences, particularly in adverse drug reaction management, thereby informing optimized therapeutic strategies for HBPT.\u003c/p\u003e \u003cp\u003eDespite similar baseline characteristics in adverse event (ADE) reports across the three drugs (65% female, 82% of Japanese nationality), this pattern may reflect reporting behavior specific to the Japanese healthcare system. Physicians, as the primary reporters (73% by profession), may be more inclined to document \"typical\" or \"severe\" events (e.g., hepatocellular carcinoma progression) while potentially underestimating mild or nonspecific symptoms (e.g., fatigue, nausea). Additionally, the high reporting rate among elderly populations (65\u0026ndash;85 years) suggests that pharmacokinetic differences in multi-kinase inhibitors in older patients may amplify toxicities, necessitating tailored dose adjustments.\u003c/p\u003e \u003cp\u003eAt the System Organ Class (SOC) level, gastrointestinal disorders and skin/subcutaneous tissue disorders were the most frequently reported for the three drugs in HBPT treatment, primarily involving these organ systems. This phenomenon is closely related to the mechanism of action of VEGFR-TKI class drugs. The REFLECT trial\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e showed that its common adverse drug events (ADEs) include diarrhea (39%), hypertension (42%), and palmar-plantar erythrodysesthesia syndrome (PPES, 52%), primarily resulting from mucosal repair impairment and microvascular damage caused by multi-target (VEGFR/FGFR, etc.) inhibition. A subgroup analysis from Japan\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e further confirmed that the skin toxicity of lenvatinib and gastrointestinal reactions are manageable, supporting its use as a first-line option for unresectable HCC. In patients with hard fibroma\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e and AML maintenance therapy\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, the incidence of sorafenib-related rash (73%) and diarrhea (51%) is consistent with that in HCC patients, suggesting that its skin/gastrointestinal toxicity has a cross-disease universality. The study on mCRC and GIST\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e indicates that hand-foot skin reactions (57%) and hypertension (49%) are dose-limiting toxicities, with a grade 3 AE incidence rate as high as 71.3% at a starting dose of 160mg\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, necessitating dose adjustments to optimize tolerability.\u003c/p\u003e \u003cp\u003eHowever, differences at the Preferred Term (PT) level revealed deeper biological distinctions. Compared to lenvatinib, ADE reports for sorafenib and regorafenib in HBPT more frequently involved hepatocellular carcinoma progression, suggesting a potential risk of disease exacerbation or induction of related conditions. The network meta-analysis\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e suggests that VEGFR-TKIs (such as sorafenib and regorafenib) may promote tumor abnormal angiogenesis by inhibiting VEGFR2 activation of HIF-1α. In this study, we found that the sorafenib group reported liver cancer progression more frequently than the lenvatinib group, which may be related to the continuous activation of this pathway. A real-world study\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e found that among HCC patients treated with lenvatinib, the 12-month bleeding risk for baseline high-risk EGV patients reached 17%, and was independently associated with Child-Pugh B (OR\u0026thinsp;=\u0026thinsp;2.12) and nPVT (OR\u0026thinsp;=\u0026thinsp;2.54). In addition, the incidence of hepatic encephalopathy (HE) in the lenvatinib group (11.3%) was significantly higher than that in the sorafenib group (4.2%), with risk factors including hyperammonemia (OR\u0026thinsp;=\u0026thinsp;4.69) and elevated bile acids (OR\u0026thinsp;=\u0026thinsp;11.05)\u003csup\u003e28\u003c/sup\u003e, suggesting that its FGFR inhibition may exacerbate liver function decompensation.\u003c/p\u003e \u003cp\u003eVEGFR inhibitors can inhibit tumor angiogenesis in the short term, but in the long term, they may stabilize HIF-1α through a hypoxic microenvironment, promoting the survival of tumor stem cells (the role of HIF-1α in resistance in the knowledge base). Combined local treatments (such as TACE) can partially offset this effect by alleviating hypoxia\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, which may explain the significantly prolonged OS in the lenvatinib\u0026thinsp;+\u0026thinsp;TACE group. The systematic review\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e indicates that there are gender-related pharmacokinetic differences for drugs such as regorafenib, suggesting the need for individualized dosing to balance efficacy and toxicity. The characteristic of regorafenib in delaying the deterioration of quality of life\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e supports its long-term treatment maintenance through dose adjustment.\u003c/p\u003e \u003cp\u003eBased on multivariate logistic regression models (AUC\u0026thinsp;\u0026gt;\u0026thinsp;0.7), the individualized risk prediction results revealed the following: In univariate logistic regression analysis of sorafenib-related ADE reports for HBPT, age was a protective factor against alopecia, while female sex emerged as a risk factor. For regorafenib-related ADE reports, age was the sole risk factor for inducing dyspnea. In lenvatinib-related ADE reports, body weight was identified as a risk factor for confusion. These findings highlight drug-specific risk factors and corresponding clinical intervention strategies: Sorafenib in female patients exhibited a significantly higher risk of alopecia (OR\u0026thinsp;=\u0026thinsp;2.3), potentially linked to elevated estrogen levels. Prophylactic use of minoxidil is recommended for female patients. Regorafenib in elderly users (\u0026gt;\u0026thinsp;75 years) faced a sharply increased risk of dyspnea (OR\u0026thinsp;=\u0026thinsp;3.1), likely due to age-related pulmonary vascular remodeling abnormalities. Pre-treatment pulmonary function screening is advised for this population. Lenvatinib in patients with a body weight\u0026thinsp;\u0026gt;\u0026thinsp;80 kg showed a heightened risk of confusion, emphasizing the need for weight-stratified dose adjustments to mitigate toxicity.\u003c/p\u003e \u003cp\u003eAnalysis of adverse event (ADE) timing revealed that 81% of severe events clustered within the first 30 days of treatment, validating the \"early toxicity surge\" phenomenon associated with multi-kinase inhibitors. This pattern may relate to acute endothelial injury caused by drug accumulation\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Notably, the median time to sorafenib-associated hepatocellular carcinoma progression reports was 6 months (IQR: 4\u0026ndash;8 months), highlighting the necessity for continuous alpha-fetoprotein (AFP) monitoring and liver imaging surveillance in long-term users.\u003c/p\u003e \u003cp\u003eIn clinical practice, the findings of this study hold significant implications for guiding physician decision-making in drug selection and patient management. By identifying associations between specific patient characteristics (e.g., sex, age, body weight) and adverse reactions, clinicians can more precisely assess individual risks during sorafenib, regorafenib, or lenvatinib therapy, thereby optimizing therapeutic regimens and enhancing patient quality of life. These findings underscore that personalized treatment strategies for high-risk populations not only improve clinical outcomes but also reduce healthcare costs and elevate overall therapeutic efficacy \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e .\u003c/p\u003e"},{"header":"5 Conclusions","content":"\u003cp\u003eThis study analyzed adverse events of sorafenib, regorafenib, and lenvatinib in HBPT treatment using the FAERS database, clarifying patient characteristics and treatment outcomes. It provides drug safety information for clinical decisions and emphasizes ongoing pharmacovigilance. Limitations include potential reporting bias and incomplete records, suggesting future research should validate findings through clinical trials and explore additional risk factors for better drug safety assessment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"660\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFull name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eADE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;adverse even\u003c/strong\u003e\u003cstrong\u003et\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHBPT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003ch2\u003ehepatobiliary-pancreatic tumors\u003c/h2\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFAERS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse Event Reporting System\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReporting Odds Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProportional Reporting Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;HCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehepatocellular carcinoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;BTC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ebiliary tract cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epancreatic cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eORs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eodds ratios\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003econfidence intervals\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSystem Organ Class\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreferred Term\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCPNN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBayesian Confidence Propagation Neural Network\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReceiver Operating Characteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArea Under Curve\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 381px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ealpha-fetoprotein\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003ch1\u003eAcknowledgments\u003c/h1\u003e\n\u003cp\u003eThe authors appreciate the support of the Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital)\u0026nbsp;for providing help.\u0026nbsp;\u003c/p\u003e\n\u003ch1\u003eConflict of Interest\u003c/h1\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003ch1\u003eAuthor Contributions\u003c/h1\u003e\n\u003cp\u003eFor research articles with several authors, a short paragraph specifying their individual contributions must be provided. The following statements should be used “Conceptualization, Danping Chen\u0026nbsp;and Xiudong Yin; methodology, Yi Tang; software, Xiaolei Yi; validation, Bin Wang, Fang Zhao and Yi Tang; formal analysis, Xiudong Yin; investigation, Xiaolei Yi; resources, Danping Chen; data curation, Xiudong Yin; writing—original draft preparation, Danping Chen; writing—review and editing, Danping Chen; visualization, Danping Chen; supervision, Xiudong Yin; project administration, Xiudong Yin; funding acquisition, Yi Tang. All authors have read and agreed to the published version of the manuscript.”\u003c/p\u003e\n\u003ch1\u003eFunding\u003c/h1\u003e\n\u003cp\u003eThis research was funded by Changsha Municipal Traditional Chinese Medicine Research Project, grant number SB2024-099, Hunan University of Chinese Medicine Joint Fund, grant number 2025XYLH118 and\u0026nbsp;2025XYLH121, Guided Science and Technology Program Project of Changsha Municipal Science and Technology Bureau, grant number kzd2501082,\u0026nbsp;supported by Health Research Project of Hunan Provincial Health Commission,\u0026nbsp;grant number:20255815 and The APC was funded by Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital).\u003c/p\u003e\n\u003ch1\u003eData Availability Statement\u003c/h1\u003e\n\u003cp\u003eThe data that support the findings of this study are openly available in the FDA Adverse Event Reporting System (FAERS), [https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers-database].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhang W, Chen J, Zhang W, Xu M. Advances in Endoscopic Ultrasound in Pancreatic Cancer Screening, Diagnosis, and Palliative Care. Biomedicines 13(2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu C, Wu H, Mao Y, Chen W, Chen S. Exosomal microRNAs in hepatocellular carcinoma. Cancer Cell Int. 2021;21:254.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu ZI, Lim KH. Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022. Cancers (Basel) 14(2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKazi IA et al. Role of Imaging in Screening for Hepatocellular Carcinoma. Cancers (Basel) 16(2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePascale A, Rosmorduc O, Duclos-Vall\u0026eacute;e JC. New epidemiologic trends in cholangiocarcinoma. Clin Res Hepatol Gastroenterol. 2023;47:102223.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao D, et al. 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Expert Rev Clin Pharmacol. 2021;14:1353\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLlovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi J, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrothey A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKudo M, et al. 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Non-traditional risk factors are important contributors to the racial disparity in diabetes risk: the atherosclerosis risk in communities study. J Gen Intern Med. 2014;29:290\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTawfik KA, Jabeen A. Pharmaceuticals safety practices-a comparative pilot study. Int J Health Sci (Qassim). 2013;7:317\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Salama ZT, Syed YY, Scott LJ, Lenvatinib. A Review in Hepatocellular Carcinoma. Drugs. 2019;79:665\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamashita T, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020;55:113\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGounder MM, et al. Sorafenib for Advanced and Refractory Desmoid Tumors. N Engl J Med. 2018;379:2417\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXuan L, et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020;21:1201\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede la Fouchardi\u0026egrave;re C. Regorafenib in the treatment of metastatic colorectal cancer. Future Oncol. 2018;14:2239\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie G, et al. Meta-Analysis of Regorafenib-Associated Adverse Events and Their Management in Colorectal and Gastrointestinal Stromal Cancers. Adv Ther. 2019;36:1986\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDas A, et al. Bleeding with vascular endothelial growth factor tyrosine kinase inhibitor: A network meta-analysis. Crit Rev Oncol Hematol. 2021;157:103186.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIavarone M, et al. Incidence and Predictors of Esophagogastric Varices Bleeding in Patients with Hepatocellular Carcinoma in Lenvatinib. Liver Cancer. 2024;13:215\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen B, et al. Risk Factors for Hepatic Encephalopathy in Hepatocellular Carcinoma After Sorafenib or Lenvatinib Treatment: A Real-World Study. Drug Des Devel Ther. 2022;16:4429\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng Z, et al. Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH). J Clin Oncol. 2023;41:117\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelahousse J, et al. Sex differences in the pharmacokinetics of anticancer drugs: a systematic review. ESMO Open. 2024;9:104002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHofheinz RD, et al. Effect of Regorafenib in Delaying Definitive Deterioration in Health-Related Quality of Life in Patients with Advanced Cancer of Three Different Tumor Types. Cancer Manag Res. 2021;13:5523\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu C, et al. Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther. 2006;5:2378\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaujoux S, et al. Hepatobiliary and Pancreatic neoplasms in patients with McCune-Albright syndrome. J Clin Endocrinol Metab. 2014;99:E97\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHou DF, et al. [Inflammatory myofibroblastic tumor of the hepatobiliary pancreatic system: report of three cases and literature review]. Zhonghua Yi Xue Za Zhi. 2017;97:3334\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":false,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sorafenib, regorafenib, Lenvatinib, hepatobiliary-pancreatic tumors, FDA Adverse Event Reporting System","lastPublishedDoi":"10.21203/rs.3.rs-8223458/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8223458/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo systematically evaluate the potential adverse event (ADE) risk profiles of sorafenib, regorafenib, and lenvatinib in the treatment of hepatobiliary-pancreatic tumors (HBPT)\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eData from the U.S. FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q4 2024 were extracted. Proportional imbalance analysis (using Reporting Odds Ratio [ROR] and Proportional Reporting Ratio [PRR]) was employed for signal detection, combined with K-means clustering and logistic regression models to analyze risk factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 10,793 ADE reports were included (sorafenib: 5,195; lenvatinib: 4,878; regorafenib: 720). At the System Organ Class level, the most common ADEs for sorafenib were gastrointestinal disorders (4,088 cases) and skin disorders (2,924 cases). Regorafenib showed tumor progression (316 cases) as its primary signal, while lenvatinib was characterized by metabolism-related abnormalities such as decreased appetite (659 cases). Logistic regression revealed: females had a 2.3-fold higher adjusted risk of alopecia with sorafenib than males (95% CI 1.8–2.9), and for lenvatinib users, every 10 kg increase in body weight elevated the risk of confusion by 18% (OR=1.18, p=0.032). Temporal analysis indicated that 82.6% of ADEs occurred within 30 days of treatment, but sorafenib-related metastatic tumor reports were delayed to a median of 200 days (IQR 150–258).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThis study is the first to systematically reveal distinct ADE profiles of the three targeted therapies for HBPT. Sorafenib and regorafenib may promote tumor progression through unknown mechanisms, while lenvatinib’s metabolism-related toxicities warrant clinical vigilance. These findings provide evidence-based insights for personalized treatment strategies and early toxicity monitoring.\u003c/p\u003e","manuscriptTitle":"Comparative Safety Profiling of Sorafenib, Regorafenib, and Lenvatinib in Hepatobiliary-Pancreatic Tumors: Signal Mining and Risk Factor Analysis Using the US FDA Adverse Event Reporting System","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 12:42:55","doi":"10.21203/rs.3.rs-8223458/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-02-17T08:42:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-04T12:34:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-02T04:40:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-02T04:39:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-11-27T15:09:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"38efc333-83de-41e8-8518-214a86a537bc","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-22T12:42:55+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 12:42:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8223458","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8223458","identity":"rs-8223458","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}