Influence of the Combined Use of Pazopanib and Gastric Acid Suppressants on Patients With Sarcoma

Influence of the Combined Use of Pazopanib and Gastric Acid Suppressants on Patients With Sarcoma | 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 Influence of the Combined Use of Pazopanib and Gastric Acid Suppressants on Patients With Sarcoma Tatsuya Isezaki, Hitomi Yuyama, Osamu Yasumuro, Yasutomo Miyaji, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6368835/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Aug, 2025 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted You are reading this latest preprint version Abstract Background: This study evaluated the impact of the combined use of pazopanib hydrochloride (PAZ) and gastric acid suppressants (AS) on the progression-free survival and safety of Japanese patients with sarcoma. Methods: A retrospective study of 99 patients with sarcoma who received PAZ treatment between 2012 and 2020 was conducted. Results: Of these patients, 77 received PAZ and AS (AS combination group) and 22 received PAZ only (non-AS group). The median progression-free survival of the AS group was 116 days, and that of the non-AS group was 403 days (no significant difference; P = 0.361). A confounding factor analysis suggested that sex might influence outcomes; however, AS use alone did not result in a significant difference in outcomes. Adverse effects were observed in 84% of the AS group and 68% of the non-AS group. Conclusions: Co-administration of PAZ and AS did not affect the prognosis or safety of patients. histamine H2 receptor antagonist pazopanib proton pump inhibitor sarcoma Figures Figure 1 Background Malignant soft tissue tumors originate from or differentiate into soft tissues ( 1 ). According to the Surveillance, Epidemiology, and End Results (SEER) database, the incidence rate of malignant soft tissue tumors is 3.4 per 100,000 individuals, thus accounting for less than 1% of all tumors ( 2 ). Treatment for malignant soft tissue tumors includes surgery, chemotherapy, and radiotherapy. Traditionally, chemotherapy for sarcoma has comprised doxorubicin hydrochloride, and ifosfamide. However, in 2012, pazopanib hydrochloride (PAZ), a multi-kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs), such as VEGFR-1, VEGFR-2, and VEGFR-3, platelet-derived growth factor receptors (PDGFRs), such as PDGFR-α and PDGFR-β, and stem cell factor receptor (c-Kit), was approved for the treatment of malignant soft tissue tumors. The combination of PAZ and proton pump inhibitors (PPIs) can reduce the area under the plasma concentration–time curve and maximum plasma concentration ( 3 ). The drug interaction section of the PAZ prescription information indicates that the co-administration of PPIs should be avoided when possible. However, patients who use PAZ treatment may experience gastrointestinal symptoms such as epigastric pain and nausea, leading to treatment discontinuation. In such cases, PPIs or histamine H2 receptor antagonists may be initiated because of their clinical benefits. Additionally, gastric acid suppressants (AS) may be prescribed to prevent gastrointestinal bleeding in patients with a history of ischemic stroke or heart disease who require antiplatelet or anticoagulant therapies. Several studies have examined PAZ and AS combination treatment. A retrospective study of patients with metastatic renal cell carcinoma reported that AS co-administration with PAZ had no significant impact on clinical outcomes ( 4 ). However, a study of patients with malignant soft tissue tumors suggested a potential association between AS use and shortened progression-free survival (PFS) and overall survival ( 5 ). In Japan, a post-marketing survey of PAZ for patients with metastatic soft tissue tumors ( 6 ) reported PFS and overall survival data, including adverse events, but did not specifically analyze AS co-administration with PAZ. Because of the lack of prior research of the efficacy and safety of PAZ and AS co-administration for Japanese patients, this study aimed to clarify the effects of AS on PFS, treatment efficacy, and incidence of gastrointestinal adverse events of patients with sarcoma. Methods This retrospective analysis was conducted using the electronic medical record system of our institution. Patients diagnosed with sarcoma who initiated PAZ treatment at our hospital between November 1, 2012 and January 31, 2020, were included in this study. Patient background factors such as height, weight, age, sex, body mass index, diagnosis, disease stage, recurrence status, treatment history, concomitant use of PPIs or histamine H2 receptor antagonists, presence of gastrointestinal disorders, Eastern Cooperative Oncology Group performance status, and histological classification were collected from the electronic medical records. The primary endpoint was PFS of patients whose treatment comprised PAZ and AS (AS combination group) and that of patients whose treatment comprised PAZ alone (non-AS group). The secondary endpoint was treatment safety, which was evaluated by assessing adverse drug reactions (ADRs) related to PAZ. Among the recorded ADRs, those classified as “serious adverse reactions” according to the PAZ package insert, gastrointestinal toxicities, and characteristic ADRs of PAZ were analyzed. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 5.0). The investigated ADRs included epigastric pain, gastric ulcer, duodenal ulcer, gastroesophageal reflux disease, acute gastritis, nausea, vomiting, diarrhea, hepatic failure, increased aspartate aminotransferase level, increased alanine aminotransferase level, increased blood bilirubin level, increased gamma-glutamyl transpeptidase level, hypertension, decreased ejection fraction, prolonged QTc interval, ventricular arrhythmia, myocardial infarction, stroke, transient ischemic attack, thromboembolism, upper gastrointestinal bleeding, lower gastrointestinal bleeding, hematuria, bronchopulmonary hemorrhage, pharyngeal hemorrhage, epistaxis, esophageal perforation, ileal perforation, small intestinal perforation, colonic perforation, esophageal fistula, gastric fistula, duodenal fistula, ileal fistula, colonic fistula, hypothyroidism, hyperthyroidism, nephrotic syndrome, proteinuria, bacteremia, sepsis, pneumonia, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, reversible posterior leukoencephalopathy syndrome, pancreatitis, retinal detachment, palmar-plantar erythrodysesthesia syndrome, and hair color changes. Statistical Analysis Categorical variables were compared using Fisher’s exact test. Continuous variables were analyzed using the Mann-Whitney U test. A survival analysis was conducted using the Kaplan-Meier method, and differences between the AS combination group and non-AS group were assessed using the log-rank test. P < 0.05 was considered statistically significant. To adjust for confounding factors, a Cox proportional hazards regression model was used to analyze variables with potential clinical significance (PAZ and AS combination treatment, performance status, sex, First-line therapy, and recurrence status). Statistical analyses were performed using EZR version 1.61 ( 7 ). Results A total of 99 patients who were prescribed PAZ at our hospital between November 1, 2012 and January 31, 2020, were included in this study. Among them, 77 patients comprised the AS combination group and 22 patients comprised the non-AS group. A comparison of characteristics of patients in the AS combination group and those of patients in the non-AS group revealed a significant difference in height (P < 0.05). However, no significant differences in weight, age, sex, First-line therapy, recurrence status, or treatment history were observed (Table 1). Kaplan-Meier survival curves were created to analyze PFS of patients in the AS combination group and that of patients in the non-AS group (Fig. 1). The median PFS of patients in the AS combination group was 116 days (95% confidence interval [CI], 71–158 days), and that of patients in the non-AS group was 403 days (95% CI, 55 days–not available). The difference between these groups was not significant according to the log-rank test ( P = 0.361). A Cox proportional hazards regression model was used to assess overall survival after adjusting for confounding factors (PAZ and AS combination treatment, performance status, sex, First-line therapy, and recurrence status). Among these factors, sex potentially influenced survival (hazard ratio, 2.20; 95% CI, 1.11–4.35; P = 0.02). Even after adjusting for potential prognostic factors, PAZ and AS combination treatment was not significantly associated with survival (Table 2). During the study period, adverse events were observed in 84% (65/77) of patients in the AS combination group and 68% (15/22) of patients in the non-AS group. Gastrointestinal toxicities, gastric ulcers, duodenal ulcers, esophagitis, and gastritis were not observed in either group. However, epigastric pain occurred in 18.2% (14/77) of patients in the AS combination group and 9.1% (2/22) of patients in the non-AS group. A total of 33 cases of grade ≥ 3 ADRs occurred in patients in the AS combination group. However, only nine cases of grade ≥ 3 ADRs were observed in the non-AS group. Grade 5 ADRs were not observed in either group. Adverse events, such as hepatic failure, QTc interval prolongation, myocardial infarction, ischemic stroke, transient ischemic attack, venous thrombosis, pulmonary embolism, pulmonary hemorrhage, gastrointestinal perforation, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome, retinal detachment, and severe gastrointestinal bleeding, were not observed in either group (Table 3). Discussion This study examined the efficacy and safety of PAZ and AS combination treatment for Japanese patients with sarcoma. PFS (the primary endpoint) was not significantly different between the AS combination group and non-AS group. However, the confounding factor analysis suggested that sex may influence PFS. This study included a higher proportion of men in the AS combination group, thus leading to a potential imbalance in disease classifications (e.g., uterine leiomyosarcoma). Compared to women, men have a higher prevalence of conditions such as gastroesophageal reflux disease, which often necessitates AS treatment ( 8 ). Prior research has indicated that men are more likely than women to require AS treatment ( 9 ), which may explain the sex distribution observed in this study. Even after adjusting for confounding factors, PAZ and AS combination treatment did not significantly affect survival. These findings suggest that PAZ and AS combination treatment does not negatively affect the prognosis of patients with sarcoma. Regarding safety, 84% of patients in the AS combination group and 68% of patients in the non-AS group experienced adverse events. Both groups exhibited gastrointestinal symptoms, such as epigastric pain and nausea, and one case of grade 3 upper gastrointestinal bleeding was observed in the non-AS group. Notably, treatment discontinuation attributable to worsening gastrointestinal symptoms was not observed in the AS combination group. Based on these findings, the use of AS for PAZ-induced gastrointestinal toxicities may help prevent severe adverse events such as gastrointestinal bleeding and reduce treatment discontinuation rates. Furthermore, although previous pharmacokinetic studies have demonstrated that gastric acid suppression reduces the pazopanib plasma concentration, our findings suggest that this reduction might not necessarily result in a clinically significant decrease in PFS among Japanese patients. This discrepancy may be attributable to inter-individual variability in drug metabolism, the compensatory effects of alternative drug absorption pathways, or the fact that the therapeutic window of pazopanib allows for some degree of variability in systemic exposure without significantly affecting efficacy. Another possible explanation is that the effect of AS on pazopanib exposure may be less pronounced in real-world clinical settings than it is in controlled pharmacokinetic studies. In clinical practice, factors such as diet, concomitant medications, and patient adherence can influence drug absorption and metabolism, thereby potentially mitigating the effects of gastric acid suppression. Moreover, some patients may have received counseling regarding optimal administration practices, such as using pazopanib under fasting conditions to maximize absorption, which may have minimized the impact of AS on drug exposure. In terms of safety, the slightly higher incidence of adverse events observed in the AS combination group may reflect underlying gastrointestinal conditions rather than a direct effect of AS on pazopanib toxicity. No significant differences in severe adverse events (grade 4 or grade 5) were detected between groups, thus supporting the notion that PAZ and AS combination treatment does not substantially alter the safety profile of pazopanib. Additionally, the absence of treatment discontinuation attributable to gastrointestinal toxicity in the AS group suggested that AS may help some patients tolerate pazopanib therapy more effectively. Despite these insights, this study had several limitations that should be acknowledged. First, our retrospective study design inherently limited the ability to establish causality between AS use and treatment outcomes. Second, the relatively small sample size, particularly that of the non-AS group, may have limited the statistical power to detect subtle differences in PFS or adverse event rates. Third, although we adjusted for key confounders, such as sex, performance status, sex, First-line therapy, and recurrence status, residual confounding by unmeasured variables was possible. Finally, PAZ treatment adherence and AS treatment adherence were not directly assessed, which could have influenced drug exposure and treatment outcomes. Therefore, further studies are required to validate our findings. Prospective multicenter studies with larger sample sizes should be performed to confirm whether AS use has no meaningful effect on the efficacy of pazopanib for patients with sarcoma. Additionally, pharmacokinetic studies should evaluate pazopanib plasma concentrations in patients using AS under real-world conditions to provide valuable insights regarding the extent to which AS treatment alters drug exposure in clinical practice. Furthermore, therapeutic drug monitoring could play a role in optimizing pazopanib therapy for patients who require gastric acid suppression, thus allowing individualized dose adjustments to maintain therapeutic drug levels. Conclusions In conclusion, our study suggests that AS treatment does not significantly affect the efficacy or safety of PAZ treatment when co-administered to Japanese patients with sarcoma. Although pharmacokinetic data indicated reduced pazopanib exposure with AS use, this does not appear to translate to worse clinical outcomes in real-world settings. These findings support a more flexible approach to the management of patients who require both pazopanib and AS and emphasize the importance of individualized treatment decisions based on clinical needs. Further research including prospective trials and pharmacokinetic analyses are crucial to refining our understanding of interactions between pazopanib and AS and optimizing treatment strategies for patients with sarcoma. Abbreviations ADR adverse drug reaction AS gastric acid suppressant PAZ pazopanib hydrochloride PDGFR platelet-derived growth factor receptor PFS progression-free survival PPI proton pump inhibitor VEGFR vascular endothelial growth factor receptor Declarations Ethics approval and consent to participate The study protocol complied with the “Ethical Guidelines for Medical Research Involving Human Subjects” and “Appropriate Handling of Personal Information by Medical and Nursing Care Providers” guidelines and was approved by the Clinical Research Review Committee of Kameda Medical Center (approval number: 19-181-230804). Although this study did not require obtaining direct consent from the patients, we disclosed information about conducting the study and guaranteed an opportunity for refusal. Consent for publication Consent for publication was obtained from the patients. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding No funding was received for this report. Authors’ contributions TI and HY designed the study, acquired the data, and analyzed and interpreted the data. TI wrote the first draft of the manuscript. OY and YM advised the interpretation of the cases and revised the manuscript. RF supervised the writing of the manuscript. All authors read and approved the final manuscript. Acknowledgements We thank the staff of the Department of Pharmacy and the Division of Oncology of Kameda Medical Center for their cooperation. Authors' information (optional) Not applicable. References Japanese Society of Clinical Oncology. New clinical oncology. 6th ed. Tokyo: Nankodo; 2021. p. 523. Cancer S. Statistics. National Cancer Institute. Cancer stat facts: Soft tissue including heart cancer. https://seer.cancer.gov/statfacts/html/soft.html . Accessed 7 Apr 2023. Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC, et al. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol. 2013;71:1635–43. https://doi.org/10.1007/s00280-013-2164-3 . McAlister RK, Aston J, Pollack M, Du L, Koyama T, Chism DD. Effect of concomitant pH-elevating medications with pazopanib on progression-free survival and overall survival in patients with metastatic renal cell carcinoma. Oncologist. 2018;23:686–92. https://doi.org/10.1634/theoncologist.2017-0578 . Mir O, Touati N, Lia M, Litière S, Le Cesne A, Sleijfer S, et al. Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials. Clin Cancer Res. 2019;25:1479–85. https://doi.org/10.1158/1078-0432.CCR-18-2748 . Teshima Y, Nomura S, Fukasawa N. Postmarketing observational study of pazopanib in patients with metastatic soft tissue sarcoma in Japan. Jpn J Clin Oncol. 2021;51:612–21. https://doi.org/10.1093/jjco/hyaa208 . Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8. https://doi.org/10.1038/bmt.2012.244 . Ohara S, Kouzu T, Kawano T, Kusano M. Nationwide epidemiological survey regarding heartburn and reflux esophagitis in Japanese. Nihon Shokakibyo Gakkai Zasshi. 2005;102:1010–24. Sakata Y, Tsuruoka N, Takedomi H, Akutagawa T, Shimoda R, Esaki M, et al. A study on the status of proton pump inhibitor prescriptions using diagnosis procedure combination data in Japan. Digestion. 2020;101:308–15. https://doi.org/10.1159/000498967 . Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table1.xlsx table2.xlsx table3.xlsx Cite Share Download PDF Status: Published Journal Publication published 18 Aug, 2025 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6368835","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":444067327,"identity":"a850bb08-70a1-4cf6-a09c-f7d6c0ad2b99","order_by":0,"name":"Tatsuya 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According to the Surveillance, Epidemiology, and End Results (SEER) database, the incidence rate of malignant soft tissue tumors is 3.4 per 100,000 individuals, thus accounting for less than 1% of all tumors (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Treatment for malignant soft tissue tumors includes surgery, chemotherapy, and radiotherapy.\u003c/p\u003e \u003cp\u003eTraditionally, chemotherapy for sarcoma has comprised doxorubicin hydrochloride, and ifosfamide. However, in 2012, pazopanib hydrochloride (PAZ), a multi-kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs), such as VEGFR-1, VEGFR-2, and VEGFR-3, platelet-derived growth factor receptors (PDGFRs), such as PDGFR-α and PDGFR-β, and stem cell factor receptor (c-Kit), was approved for the treatment of malignant soft tissue tumors.\u003c/p\u003e \u003cp\u003eThe combination of PAZ and proton pump inhibitors (PPIs) can reduce the area under the plasma concentration\u0026ndash;time curve and maximum plasma concentration (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The drug interaction section of the PAZ prescription information indicates that the co-administration of PPIs should be avoided when possible. However, patients who use PAZ treatment may experience gastrointestinal symptoms such as epigastric pain and nausea, leading to treatment discontinuation. In such cases, PPIs or histamine H2 receptor antagonists may be initiated because of their clinical benefits. Additionally, gastric acid suppressants (AS) may be prescribed to prevent gastrointestinal bleeding in patients with a history of ischemic stroke or heart disease who require antiplatelet or anticoagulant therapies.\u003c/p\u003e \u003cp\u003eSeveral studies have examined PAZ and AS combination treatment. A retrospective study of patients with metastatic renal cell carcinoma reported that AS co-administration with PAZ had no significant impact on clinical outcomes (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, a study of patients with malignant soft tissue tumors suggested a potential association between AS use and shortened progression-free survival (PFS) and overall survival (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In Japan, a post-marketing survey of PAZ for patients with metastatic soft tissue tumors (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) reported PFS and overall survival data, including adverse events, but did not specifically analyze AS co-administration with PAZ. Because of the lack of prior research of the efficacy and safety of PAZ and AS co-administration for Japanese patients, this study aimed to clarify the effects of AS on PFS, treatment efficacy, and incidence of gastrointestinal adverse events of patients with sarcoma.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective analysis was conducted using the electronic medical record system of our institution. Patients diagnosed with sarcoma who initiated PAZ treatment at our hospital between November 1, 2012 and January 31, 2020, were included in this study.\u003c/p\u003e \u003cp\u003ePatient background factors such as height, weight, age, sex, body mass index, diagnosis, disease stage, recurrence status, treatment history, concomitant use of PPIs or histamine H2 receptor antagonists, presence of gastrointestinal disorders, Eastern Cooperative Oncology Group performance status, and histological classification were collected from the electronic medical records. The primary endpoint was PFS of patients whose treatment comprised PAZ and AS (AS combination group) and that of patients whose treatment comprised PAZ alone (non-AS group). The secondary endpoint was treatment safety, which was evaluated by assessing adverse drug reactions (ADRs) related to PAZ. Among the recorded ADRs, those classified as \u0026ldquo;serious adverse reactions\u0026rdquo; according to the PAZ package insert, gastrointestinal toxicities, and characteristic ADRs of PAZ were analyzed. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 5.0).\u003c/p\u003e \u003cp\u003eThe investigated ADRs included epigastric pain, gastric ulcer, duodenal ulcer, gastroesophageal reflux disease, acute gastritis, nausea, vomiting, diarrhea, hepatic failure, increased aspartate aminotransferase level, increased alanine aminotransferase level, increased blood bilirubin level, increased gamma-glutamyl transpeptidase level, hypertension, decreased ejection fraction, prolonged QTc interval, ventricular arrhythmia, myocardial infarction, stroke, transient ischemic attack, thromboembolism, upper gastrointestinal bleeding, lower gastrointestinal bleeding, hematuria, bronchopulmonary hemorrhage, pharyngeal hemorrhage, epistaxis, esophageal perforation, ileal perforation, small intestinal perforation, colonic perforation, esophageal fistula, gastric fistula, duodenal fistula, ileal fistula, colonic fistula, hypothyroidism, hyperthyroidism, nephrotic syndrome, proteinuria, bacteremia, sepsis, pneumonia, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, reversible posterior leukoencephalopathy syndrome, pancreatitis, retinal detachment, palmar-plantar erythrodysesthesia syndrome, and hair color changes.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were compared using Fisher\u0026rsquo;s exact test. Continuous variables were analyzed using the Mann-Whitney U test. A survival analysis was conducted using the Kaplan-Meier method, and differences between the AS combination group and non-AS group were assessed using the log-rank test. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eTo adjust for confounding factors, a Cox proportional hazards regression model was used to analyze variables with potential clinical significance (PAZ and AS combination treatment, performance status, sex, First-line therapy, and recurrence status). Statistical analyses were performed using EZR version 1.61 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 99 patients who were prescribed PAZ at our hospital between November 1, 2012 and January 31, 2020, were included in this study. Among them, 77 patients comprised the AS combination group and 22 patients comprised the non-AS group.\u003c/p\u003e \u003cp\u003eA comparison of characteristics of patients in the AS combination group and those of patients in the non-AS group revealed a significant difference in height (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, no significant differences in weight, age, sex, First-line therapy, recurrence status, or treatment history were observed (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eKaplan-Meier survival curves were created to analyze PFS of patients in the AS combination group and that of patients in the non-AS group (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eThe median PFS of patients in the AS combination group was 116 days (95% confidence interval [CI], 71\u0026ndash;158 days), and that of patients in the non-AS group was 403 days (95% CI, 55 days\u0026ndash;not available). The difference between these groups was not significant according to the log-rank test (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.361).\u003c/p\u003e \u003cp\u003eA Cox proportional hazards regression model was used to assess overall survival after adjusting for confounding factors (PAZ and AS combination treatment, performance status, sex, First-line therapy, and recurrence status). Among these factors, sex potentially influenced survival (hazard ratio, 2.20; 95% CI, 1.11\u0026ndash;4.35; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). Even after adjusting for potential prognostic factors, PAZ and AS combination treatment was not significantly associated with survival (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eDuring the study period, adverse events were observed in 84% (65/77) of patients in the AS combination group and 68% (15/22) of patients in the non-AS group.\u003c/p\u003e \u003cp\u003eGastrointestinal toxicities, gastric ulcers, duodenal ulcers, esophagitis, and gastritis were not observed in either group. However, epigastric pain occurred in 18.2% (14/77) of patients in the AS combination group and 9.1% (2/22) of patients in the non-AS group.\u003c/p\u003e \u003cp\u003eA total of 33 cases of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 ADRs occurred in patients in the AS combination group. However, only nine cases of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 ADRs were observed in the non-AS group. Grade 5 ADRs were not observed in either group.\u003c/p\u003e \u003cp\u003eAdverse events, such as hepatic failure, QTc interval prolongation, myocardial infarction, ischemic stroke, transient ischemic attack, venous thrombosis, pulmonary embolism, pulmonary hemorrhage, gastrointestinal perforation, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome, retinal detachment, and severe gastrointestinal bleeding, were not observed in either group (Table\u0026nbsp;3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study examined the efficacy and safety of PAZ and AS combination treatment for Japanese patients with sarcoma. PFS (the primary endpoint) was not significantly different between the AS combination group and non-AS group. However, the confounding factor analysis suggested that sex may influence PFS. This study included a higher proportion of men in the AS combination group, thus leading to a potential imbalance in disease classifications (e.g., uterine leiomyosarcoma).\u003c/p\u003e \u003cp\u003eCompared to women, men have a higher prevalence of conditions such as gastroesophageal reflux disease, which often necessitates AS treatment (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Prior research has indicated that men are more likely than women to require AS treatment (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), which may explain the sex distribution observed in this study.\u003c/p\u003e \u003cp\u003eEven after adjusting for confounding factors, PAZ and AS combination treatment did not significantly affect survival. These findings suggest that PAZ and AS combination treatment does not negatively affect the prognosis of patients with sarcoma.\u003c/p\u003e \u003cp\u003eRegarding safety, 84% of patients in the AS combination group and 68% of patients in the non-AS group experienced adverse events. Both groups exhibited gastrointestinal symptoms, such as epigastric pain and nausea, and one case of grade 3 upper gastrointestinal bleeding was observed in the non-AS group. Notably, treatment discontinuation attributable to worsening gastrointestinal symptoms was not observed in the AS combination group.\u003c/p\u003e \u003cp\u003eBased on these findings, the use of AS for PAZ-induced gastrointestinal toxicities may help prevent severe adverse events such as gastrointestinal bleeding and reduce treatment discontinuation rates. Furthermore, although previous pharmacokinetic studies have demonstrated that gastric acid suppression reduces the pazopanib plasma concentration, our findings suggest that this reduction might not necessarily result in a clinically significant decrease in PFS among Japanese patients. This discrepancy may be attributable to inter-individual variability in drug metabolism, the compensatory effects of alternative drug absorption pathways, or the fact that the therapeutic window of pazopanib allows for some degree of variability in systemic exposure without significantly affecting efficacy.\u003c/p\u003e \u003cp\u003eAnother possible explanation is that the effect of AS on pazopanib exposure may be less pronounced in real-world clinical settings than it is in controlled pharmacokinetic studies. In clinical practice, factors such as diet, concomitant medications, and patient adherence can influence drug absorption and metabolism, thereby potentially mitigating the effects of gastric acid suppression. Moreover, some patients may have received counseling regarding optimal administration practices, such as using pazopanib under fasting conditions to maximize absorption, which may have minimized the impact of AS on drug exposure.\u003c/p\u003e \u003cp\u003eIn terms of safety, the slightly higher incidence of adverse events observed in the AS combination group may reflect underlying gastrointestinal conditions rather than a direct effect of AS on pazopanib toxicity. No significant differences in severe adverse events (grade 4 or grade 5) were detected between groups, thus supporting the notion that PAZ and AS combination treatment does not substantially alter the safety profile of pazopanib. Additionally, the absence of treatment discontinuation attributable to gastrointestinal toxicity in the AS group suggested that AS may help some patients tolerate pazopanib therapy more effectively.\u003c/p\u003e \u003cp\u003eDespite these insights, this study had several limitations that should be acknowledged. First, our retrospective study design inherently limited the ability to establish causality between AS use and treatment outcomes. Second, the relatively small sample size, particularly that of the non-AS group, may have limited the statistical power to detect subtle differences in PFS or adverse event rates. Third, although we adjusted for key confounders, such as sex, performance status, sex, First-line therapy, and recurrence status, residual confounding by unmeasured variables was possible. Finally, PAZ treatment adherence and AS treatment adherence were not directly assessed, which could have influenced drug exposure and treatment outcomes.\u003c/p\u003e \u003cp\u003eTherefore, further studies are required to validate our findings. Prospective multicenter studies with larger sample sizes should be performed to confirm whether AS use has no meaningful effect on the efficacy of pazopanib for patients with sarcoma. Additionally, pharmacokinetic studies should evaluate pazopanib plasma concentrations in patients using AS under real-world conditions to provide valuable insights regarding the extent to which AS treatment alters drug exposure in clinical practice. Furthermore, therapeutic drug monitoring could play a role in optimizing pazopanib therapy for patients who require gastric acid suppression, thus allowing individualized dose adjustments to maintain therapeutic drug levels.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our study suggests that AS treatment does not significantly affect the efficacy or safety of PAZ treatment when co-administered to Japanese patients with sarcoma. Although pharmacokinetic data indicated reduced pazopanib exposure with AS use, this does not appear to translate to worse clinical outcomes in real-world settings. These findings support a more flexible approach to the management of patients who require both pazopanib and AS and emphasize the importance of individualized treatment decisions based on clinical needs. Further research including prospective trials and pharmacokinetic analyses are crucial to refining our understanding of interactions between pazopanib and AS and optimizing treatment strategies for patients with sarcoma.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eADR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadverse drug reaction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egastric acid suppressant\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePAZ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epazopanib hydrochloride\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePDGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eplatelet-derived growth factor receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eproton pump inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVEGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evascular endothelial growth factor receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol complied with the “Ethical Guidelines for Medical Research Involving Human Subjects” and “Appropriate Handling of Personal Information by Medical and Nursing Care Providers” guidelines and was approved by the Clinical Research Review Committee of Kameda Medical Center (approval number: 19-181-230804). Although this study did not require obtaining direct consent from the patients, we disclosed information about conducting the study and guaranteed an opportunity for refusal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication was obtained from the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTI and HY designed the study, acquired the data, and analyzed and interpreted the data. TI wrote the first draft of the manuscript. OY and YM advised the interpretation of the cases and revised the manuscript. RF supervised the writing of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the staff of the Department of Pharmacy and the Division of Oncology of Kameda Medical Center for their cooperation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' information (optional)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJapanese Society of Clinical Oncology. New clinical oncology. 6th ed. Tokyo: Nankodo; 2021. p. 523.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCancer S. Statistics. National Cancer Institute. Cancer stat facts: Soft tissue including heart cancer. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://seer.cancer.gov/statfacts/html/soft.html\u003c/span\u003e\u003cspan address=\"https://seer.cancer.gov/statfacts/html/soft.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 7 Apr 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC, et al. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol. 2013;71:1635\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00280-013-2164-3\u003c/span\u003e\u003cspan address=\"10.1007/s00280-013-2164-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcAlister RK, Aston J, Pollack M, Du L, Koyama T, Chism DD. Effect of concomitant pH-elevating medications with pazopanib on progression-free survival and overall survival in patients with metastatic renal cell carcinoma. Oncologist. 2018;23:686\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1634/theoncologist.2017-0578\u003c/span\u003e\u003cspan address=\"10.1634/theoncologist.2017-0578\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMir O, Touati N, Lia M, Liti\u0026egrave;re S, Le Cesne A, Sleijfer S, et al. Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials. Clin Cancer Res. 2019;25:1479\u0026ndash;85. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1158/1078-0432.CCR-18-2748\u003c/span\u003e\u003cspan address=\"10.1158/1078-0432.CCR-18-2748\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeshima Y, Nomura S, Fukasawa N. Postmarketing observational study of pazopanib in patients with metastatic soft tissue sarcoma in Japan. Jpn J Clin Oncol. 2021;51:612\u0026ndash;21. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/jjco/hyaa208\u003c/span\u003e\u003cspan address=\"10.1093/jjco/hyaa208\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanda Y. Investigation of the freely available easy-to-use software \u0026lsquo;EZR\u0026rsquo; for medical statistics. Bone Marrow Transpl. 2013;48:452\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/bmt.2012.244\u003c/span\u003e\u003cspan address=\"10.1038/bmt.2012.244\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhara S, Kouzu T, Kawano T, Kusano M. Nationwide epidemiological survey regarding heartburn and reflux esophagitis in Japanese. Nihon Shokakibyo Gakkai Zasshi. 2005;102:1010\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSakata Y, Tsuruoka N, Takedomi H, Akutagawa T, Shimoda R, Esaki M, et al. A study on the status of proton pump inhibitor prescriptions using diagnosis procedure combination data in Japan. Digestion. 2020;101:308\u0026ndash;15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1159/000498967\u003c/span\u003e\u003cspan address=\"10.1159/000498967\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"histamine H2 receptor antagonist, pazopanib, proton pump inhibitor, sarcoma","lastPublishedDoi":"10.21203/rs.3.rs-6368835/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6368835/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThis study evaluated the impact of the combined use of pazopanib hydrochloride (PAZ) and gastric acid suppressants (AS) on the progression-free survival and safety of Japanese patients with sarcoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA retrospective study of 99 patients with sarcoma who received PAZ treatment between 2012 and 2020 was conducted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOf these patients, 77 received PAZ and AS (AS combination group) and 22 received PAZ only (non-AS group). The median progression-free survival of the AS group was 116 days, and that of the non-AS group was 403 days (no significant difference; \u003cem\u003eP\u003c/em\u003e = 0.361). A confounding factor analysis suggested that sex might influence outcomes; however, AS use alone did not result in a significant difference in outcomes. Adverse effects were observed in 84% of the AS group and 68% of the non-AS group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eCo-administration of PAZ and AS did not affect the prognosis or safety of patients.\u003c/p\u003e","manuscriptTitle":"Influence of the Combined Use of Pazopanib and Gastric Acid Suppressants on Patients With Sarcoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 03:03:19","doi":"10.21203/rs.3.rs-6368835/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a76a086-5d5d-4c39-b471-c11d0af5d603","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:38:20+00:00","versionOfRecord":{"articleIdentity":"rs-6368835","link":"https://doi.org/10.1186/s40780-025-00477-8","journal":{"identity":"journal-of-pharmaceutical-health-care-and-sciences","isVorOnly":false,"title":"Journal of Pharmaceutical Health Care and Sciences"},"publishedOn":"2025-08-18 16:29:57","publishedOnDateReadable":"August 18th, 2025"},"versionCreatedAt":"2025-05-07 03:03:19","video":"","vorDoi":"10.1186/s40780-025-00477-8","vorDoiUrl":"https://doi.org/10.1186/s40780-025-00477-8","workflowStages":[]},"version":"v1","identity":"rs-6368835","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6368835","identity":"rs-6368835","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}