Usefulness of protocol-based pharmacotherapy management by pharmacists in cancer patients: a retrospective observational study

Usefulness of protocol-based pharmacotherapy management by pharmacists in cancer patients: a retrospective observational study | 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 Usefulness of protocol-based pharmacotherapy management by pharmacists in cancer patients: a retrospective observational study Satomi Sumikawa, Noriaki Hidaka, Yuya Sakamoto, Noboru Yamashita, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7408890/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Nov, 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: A team-based approach is essential to provide cancer patients with high-quality treatment. To ensure the best possible care while reducing the workload of physicians, Ehime University Hospital has introduced three protocol-based pharmacotherapy management (PBPM) strategies in the field of chemotherapy. First, we introduced PBPM to avoid reactivation of hepatitis B virus (HBV) in patients receiving immunosuppressive therapy or chemotherapy. In this PBPM strategy, pharmacists added laboratory test orders for patients who require regular HBV-DNA quantification (HBV-PBPM). Second, we devised PBPM for measurement of the urine protein/creatinine ratio (UPC) in patients receiving anti-vascular endothelial growth factor therapy. Finally, we introduced PBPM for measurement of serum magnesium in patients receiving anti-epidermal growth factor receptor antibody therapy (Mg-PBPM). In this study, we evaluated the usefulness of these three PBPM strategies in outpatients receiving chemotherapy. Methods : The study included patients treated in the outpatient chemotherapy unit between July 2021 and February 2023. Rates of compliance with laboratory tests in the 6 months before and after introduction of PBPM were compared. Results: Compliance with HBV-DNA quantification improved significantly from 64.0% before PBPM to 85.5% after implementation of PBPM (P=0.001). The median duration of noncompliance was significantly shorter after initiation of PBPM (P=0.003). Compliance with measurement of UPC was already greater than 95% before PBPM and showed no change after implementation (98.7% pre-PBPM vs 98.7% post-PBPM). Compliance with measurement of serum magnesium improved from 95.8% pre-PBPM to 99.2% after starting PBPM, but the improvement was not statistically significant. Conclusions : Introduction of PBPM improves compliance with the laboratory tests required in cancer patients during chemotherapy and enables safer delivery of treatment. PBPM HBV reactivation HBV-DNA anti-vascular endothelial growth factor therapy urine creatinine ratio anti-EGFR antibody serum magnesium Figures Figure 1 Figure 2 BACKGROUND Cancer treatment is becoming increasingly sophisticated and complex, necessitating a team-based approach to ensure that patients receive high-quality treatment. For an effective team-based approach, each healthcare professional must use their expertise, share objectives and information, and divide responsibilities. Collaborative and complementary roles among healthcare providers enable appropriate patient-centered care. In Japan, a 2010 directive from the Ministry of Health, Labour and Welfare recommended pharmacist participation as part of a team-based approach using protocols that were previously agreed upon ( 1 ). These protocols allow pharmacists to make changes to type of medication, dosages, methods of administration, and testing on the basis of shared professional knowledge. Since the introduction of the PBPM Implementation Manual by the Japanese Society of Pharmaceutical Health Care and Sciences in 2016 and practical examples provided by the Japanese Society of Hospital Pharmacists, an increasing number of institutions have initiated protocol-based pharmacotherapy management (PBPM) ( 2 , 3 ). Effective PBPM requires identification of any relevant problems at a facility and collaborative development of solutions by healthcare professionals. Pharmacist-led interventions can increase patient safety, particularly in cases where guidelines and package inserts are not being followed. It has been reported that reactivation of hepatitis B virus (HBV) can be fatal in HBV carriers and in patients with a history of HBV infection who have received immunosuppressive therapy or cancer chemotherapy. Therefore, efforts to prevent reactivation are important in patients who require regular HBV-DNA quantitative testing ( 4 – 6 ). Furthermore, laboratory tests should be performed at each treatment session to determine the feasibility of administering anticancer agents and to detect any adverse effects of these agents at an early stage. In this study, we reviewed the pharmacists’ queries regarding prescriptions received at our outpatient chemotherapy unit over a one-year period and introduced three PBPM strategies that were considered effective. The first PBPM strategy was designed to avoid reactivation of HBV by immunosuppressive therapy or chemotherapy (HBV-PBPM). The aim of the second strategy was to ensure that the urine protein/creatinine ratio (UPC) was measured in patients receiving anti-vascular endothelial growth factor (VEGF) therapy (UPC-PBPM). The third strategy was designed to ensure that serum magnesium was monitored in patients receiving anti-epidermal growth factor receptor (EGFR) antibody therapy (Mg-PBPM). In this study, we evaluated the usefulness of PBPM by investigating rates of compliance with laboratory tests before and after implementation of these strategies. METHODS Development of effective PBPM To identify useful PBPM strategies at our facility, we retrospectively reviewed the pharmacists’ queries regarding prescriptions between April 1, 2021 and March 31, 2022 by searching the electronic medical records and calculating the acceptance rate. The acceptance rate was calculated by dividing the number of queries changed as proposed by the pharmacist by the number of pharmacists’ queries made during the study period. Evaluation of the usefulness of the three PBPM strategies HBV-PBPM Of 1184 patients who received immunosuppressive therapy or chemotherapy in our outpatient chemotherapy unit between July 2021 and July 2022, 280 were HBsAg-positive and/or HBsAg/HBc antibody-positive. Among these 280 patients, those who met any of the following four criteria were excluded: consultation with a hepatologist for HBV reactivation monitoring; receiving cancer chemotherapy prescribed by a hepatologist; nonattendance at the outpatient chemotherapy unit when HBV-DNA monitoring was necessary; and the attending physician did not approve of PBPM by pharmacists. Finally, data for 169 patients were analyzed (Fig. 1 ). In accordance with the Hepatitis B Treatment Guidelines (4th edition) ( 4 ), compliance was evaluated as follows. Patients were assessed as being compliant with rituximab, obinutuzumab, and fludarabine if they underwent monthly testing and as being compliant with immunosuppressive therapy (abatacept, infliximab, and tocilizumab) and other chemotherapy agents if testing was performed every 3 months. Other chemotherapies included single-agent or combination therapies, including immune checkpoint inhibitors (ICIs), cytotoxic agents, and molecular targeted therapies, excluding single-agent hormone therapies. PBPM was introduced in January 2022. The first month after its introduction was designated as a transition (operational awareness) period. The period between July and December 2021 was defined as before the start of PBPM and the period between February and July 2022 as after the start of PBPM. UPC-PBPM Patients who received anti-VEGF agents (bevacizumab, ramucirumab, aflibercept) between February 2022 and February 2023 were evaluated. A total of 1228 doses were analyzed. Compliance was defined as having the UPC ratio measured on the day of treatment. PBPM was introduced in August 2022. The first month after its introduction was designated as a transition (operational awareness) period. The period between February 2022 and July 2022 was designated as the period before introduction of PBPM and the period between September 2022 and February 2023 as the period after introduction of PBPM. Mg-PBPM Patients receiving anti-EGFR antibody therapy (cetuximab, panitumumab) between February 2022 and February 2023 were evaluated. A total of 217 doses were analyzed. Compliance was defined as having serum magnesium measured on the day of treatment. The first month after its introduction was designated as a transition (operational awareness) period. The period between February 2022 and July 2022 was designated as the period before introduction of PBPM and the period between September 2022 and February 2023 as the period after introduction of PBPM. Changes in queries by pharmacists after introduction of PBPM and in the annual number of tests ordered by pharmacists We investigated changes in the types of queries after introduction of the three types of PBPM. We assessed the number of queries and the number of cases accepted regarding laboratory test items for the 2021 fiscal year (FY) before introduction of PBPM, the 2022 FY during the PBPM introduction period, and the 2023 FY after introduction of PBPM. We also investigated the annual changes in the numbers of tests ordered by pharmacists for the three types of PBPM. Statistical analysis Qualitative data were analyzed using Fisher’s exact test and quantitative data using the Mann‒Whitney U test. All statistical analyses were performed utilizing Easy-R (EZR) version 1.61 (2022; Jichi Medical University, Saitama, Japan) ( 7 ). A P-value of < 0.05 was considered statistically significant. RESULTS Development of effective PBPM Between April 2021 and March 2022, 480 queries from pharmacist regarding prescriptions were recorded. The most common errors concerned an order (n = 116, acceptance rate 95%), followed by HBV-related issues (n = 94, acceptance rate 64%) and additional laboratory tests (n = 81, acceptance rate 85%). Before the start of PBPM, there were 480 queries regarding prescriptions in the outpatient chemotherapy unit, with an overall acceptance rate of 76% (Table 1). The prescription queries were HBV-related in 20% of cases. Usefulness of the three PBPM strategies HBV-PBPM The final analysis included 86 patients before PBPM and 83 patients after PBPM. After the start of PBPM, the frequency of laboratory tests ordered by pharmacists increased significantly to 25% (P < 0.001). The median duration of noncompliance was 5 months before PBPM and 4 months after starting PBPM. The range of the noncompliance period was significantly shorter after initiation of PBPM (P = 0.003) (Table 2). HBV-DNA should have been measured at monthly intervals in patients receiving rituximab who were HBs/HBc antibody-positive, but were not measured in three cases during the study period. Two of these patients were from the pre-PBPM period and one was from the post-PBPM period. In the two patients who received rituximab before PBPM, HBV-DNA quantification was performed at 2 and 3 months. One patient received rituximab after initiation of PBPM, and HBV-DNA quantification was performed at 3 months. The rate of compliance with HBV-DNA quantification improved significantly from 64.0–85.5% (P = 0.001) (Table 2). UPC-PBPM There were 634 treatments before PBPM and 594 after initiation of PBPM. Bevacizumab was the most frequently used agent, accounting for approximately 80% of cases. This agent was used most frequently for colorectal cancer, accounting for 27% of cases. The rate of compliance with measurement of UPC remained at 98.7% in both periods; however, the percentage of laboratory tests ordered by pharmacists increased to 1.5% after introduction of PBPM (Table 3). Mg-PBPM There were 95 treatments before PBPM and 122 after the start of PBPM. The proportion of patients receiving panitumumab decreased from 73.3% before PBPM to 48.4% after starting PBPM. The prevalence of colorectal cancer was 82.1% in the pre-PBPM period and 71.3% in the PBPM period. The frequency of serum magnesium levels with a Common Terminology Criteria for Adverse Events grade of ≤ 1 was 95.8% in the pre-PBPM period and 95.1% in the PBPM period. The rate of compliance with serum magnesium measurement increased slightly from 95.8–99.2% after implementation of Mg-PBPM. After implementation of PBPM, 3.3% of laboratory tests were ordered by pharmacists (Table 4). Changes in types of pharmacists’ queries after the start of PBPM There were 480 queries from pharmacists to physicians in the 2021 FY, which decreased to 462 in the 2022 FY. After the start of PBPM, the percentage of queries regarding HBV-related prescriptions decreased markedly from 20–4% (Fig. 2 ). The number of queries regarding measurement of the UPC ratio was high in the 2022 FY and decreased after introduction of UPC-PBPM (Tables 5 and 6). However, it became clear that the number of queries related to ICI therapy has been increasing year by year (Table 5). DISCUSSION In this study, we investigated the number of prescription queries from pharmacists to physicians and their acceptance rates in our outpatient chemotherapy unit and introduced three PBPM strategies that we anticipated would be effective. It was thought that more effective interventions could be made by clarifying the problems at our own facility ( 8 ). Our survey revealed that rates of compliance with HBV-DNA quantification improved significantly after implementation of PBPM. Before the start of PBPM, requests for additional tests were made by telephone, email, or via the medical records, but the compliance rate was low at 64%. The compliance rate increased significantly to 85.5% when the pharmacists started PBPM (P = 0.001). The median duration of noncompliance decreased significantly from 5 months (range 2–8) in the pre-PBPM period to 4 months (range 3–4) in the PBPM period (P = 0.003). The durations of noncompliance before initiation of PBPM were 2 months (n = 1), 3 months (n = 1), 4 months (n = 11), 5 months (n = 11), 6 months (n = 2), 7 months (n = 2), and 8 months (n = 3). After the start of PBPM, there was 1 case of noncompliance for 3 months and 11 cases for 4 months. Previous studies have reported increases in the implementation rate of HBV-DNA monitoring to 66.7% (n = 12) ( 5 ), 81.8% (n = 44) ( 6 ), 93.9% (n = 23) ( 9 ), 98.3% (n = 28) ( 10 ), and 100% (n = 21) ( 11 ) following initiation of PBPM by pharmacists. Our HBV-DNA quantification survey included a larger number of patients than in previous reports, with an adherence rate of 85.5% in 83 patients. Twelve patients not adhere to the protocol because the pharmacist forgot to order the test; however, the nonadherence period was 4 months in all cases, and the test was performed in the month following that in which it was required. We believe that pharmacist-driven PBPM minimizes the risk of HBV reactivation in cancer patients and may contribute to safer implementation of chemotherapy. The American College of Clinical Pharmacy released position statements on collaborative drug therapy management (CDTM) in the United States in 1997 and 2003. Since 2003, CDTM has spread throughout the United States, promoting team-based medical care and reducing the workload of physicians ( 12 ). The CDTM activities implemented include requesting clinical laboratory tests, adjusting the strength of medication, and changing the frequency of administration ( 13 ). In Japan, the Japanese Society of Pharmaceutical Health Care and Sciences released a manual introducing PBPM in 2016 ( 3 ) and the Japanese Hospital Pharmacists Association introduced specific practical examples of PBPM in the same year ( 2 ), which led to an increase in the number of facilities actively introducing PBPM. PBPM has been reported to be useful in cancer chemotherapy ( 14 – 16 ), when administering high-risk agents ( 17 – 19 ), in patients with human immunodeficiency virus ( 20 ) in Japan. While the usefulness of PBPM in patients receiving immunosuppressive therapy or injectable anticancer therapy has been reported ( 21 ), the rate of implementation of HBV monitoring in patients receiving oral anticancer agents is reportedly low ( 10 ). Therefore, PBPM should be considered for these patients. While the present study demonstrated the usefulness of PBPM for HBV-DNA monitoring, it could not confirm that PBPM by pharmacists was useful in terms of increasing the rates of compliance with measurement of the UPC ratio during anti-VEGF therapy or the serum magnesium level during anti-EGFR antibody therapy. In Japan, PBPM has been implemented in many facilities for measurement of the UPC ratio and serum magnesium level and has been discussed at academic conferences. However, to the best of our knowledge, there are few published reports on this topic. According to the report by Ito et al., the introduction of PBPM increased the rate of urine testing from 74.7–99.2% ( 22 ). While PBPM is very effective in terms of increasing measurement rates, at our institution, where the pre-PBPM measurement rate was already high, the usefulness of UPC-PBPM and Mg-PBPM was not demonstrated. The reason for this is that in the case of HBV-DNA quantitative testing, which requires measurement every 3 months, after ordering the necessary test items for each treatment, it is necessary to order HBV-DNA quantitative testing at the required time separately. The UPC ratio and serum magnesium level requires measurement at each treatment, and the frequency of forgetting to measure is low because physicians copy the blood draw order from the previous treatment and re-order it. We introduced UPC-PBPM and Mg-PBPM anticipating that they would be useful, but in reality, the number of tests ordered by pharmacists was low. Therefore, we revisited the content of queries regarding test items after introducing UPC-PBPM and Mg-PBPM. Forty-five (38.1%) of the 118 queries concerned items requiring regular testing, including thyroid-stimulating hormone, FT4, FT3, KL-6, and urine tests, in patients receiving ICIs in the 2022 YR. Moreover, the number of queries related to ICIs increased in the following year. Previous research has demonstrated the usefulness of implementing PBPM for testing when ICIs are used ( 14 ), and the findings at our hospital also suggest the need to initiate PBPM in the future. Furthermore, despite the initiation of PBPM, 25 (21.2%) of the 118 queries in the 2022 FY and 13 (7.1%) of the 182 queries in 2023 FY concerned measurement of the UPC ratio or serum magnesium level, suggesting that physicians may not have delegated ordering authority to pharmacists. Physicians at our hospital delegate ordering authority to pharmacists but must operate the electronic medical records system themselves to establish the necessary settings. This process is cumbersome and may hinder the delegation of authority. Furthermore, Alhossan et al. identified a lack of knowledge among other healthcare professionals regarding PBPM ( 23 ). The knowledge that PBPM can positively influence outcomes related to pharmacotherapy should be shared with other healthcare professionals. While the implementation of PBPM by pharmacists has little financial impact on hospitals, it can increase the value of pharmacists and contribute to team-based care ( 24 ). CONCLUSION The introduction of PBPM improves compliance with the laboratory test items necessary during chemotherapy for cancer patients and enables the delivery of safe treatment. Abbreviations ACCP American College of Clinical Pharmacy CDTM collaborative drug therapy management EGFR epidermal growth factor receptor HBV hepatitis B virus ICIs immune checkpoint inhibitors PBPM protocol-based pharmacotherapy management UPC urine protein/creatinine VEGF vascular endothelial growth factor Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (2015) published by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare. The study was approved by the Ethics Committee of Ehime University Hospital (approval number 2506003). Informed consent was obtained via the opt-out route on the hospital’s website. Consent for publication Not applicable. Availability of data and materials All the data generated or analyzed during this study are included in this article. Competing interests All the authors declare that they have no conflicts of interest relevant to this work. Funding Not applicable. Author contributions All the authors contributed to the study conception and design. SS was involved in data collection. SS, NH, YS, NY, SW, and MT were involved in the analysis and interpretation of the data and the drafting of the manuscript. All the authors read and approved the final version of the manuscript. Acknowledgments The authors thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. References Ministry of Health, Labour and Welfare. Promotion of team medical care through collaboration with medical staffs. 2010. Available from: https://www.mhlw.go.jp/topics/2013/02/dl/tp0215-01-09d.pdf. Japanese Society of Hospital Pharmacists. How to facilitate protocol-based pharmacotherapy management (PBPM) and specific practical examples (Ver.1.0). 2016 . Available from: https://www.jshp.or.jp/activity/guideline/20160331-1.pdf. 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Barriers interfering with establishment of Collaborative Drug Therapy Management (CDTM) agreements between clinical pharmacists and physicians. Saudi Pharm J. 2019;27(5):713-6. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6598211/pdf/main.pdf doi: 10.1016/j.jsps.2019.04.006 Thomas J, Bharmal M, Lin SW, Punekar Y. Survey of pharmacist collaborative drug therapy management in hospitals. Am J Health Syst Pharm. 2006;63(24):2489-99. Available from: https://academic.oup.com/ajhp/article-abstract/63/24/2489/5134611?redirectedFrom=fulltext&login=truedoi: 10.2146/ajhp050205 Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx Table3.xlsx Table4.xlsx Table5.xlsx Table6.xlsx Cite Share Download PDF Status: Published Journal Publication published 12 Nov, 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-7408890","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":504940614,"identity":"c6f11c94-96c4-4d74-9fc4-c9bf19649df4","order_by":0,"name":"Satomi Sumikawa","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satomi","middleName":"","lastName":"Sumikawa","suffix":""},{"id":504940619,"identity":"50746352-b9dd-4d5a-8780-e8225541472f","order_by":1,"name":"Noriaki Hidaka","email":"data:image/png;base64,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","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Noriaki","middleName":"","lastName":"Hidaka","suffix":""},{"id":504940621,"identity":"ad028333-cfd2-46a5-8a8c-0925217be950","order_by":2,"name":"Yuya Sakamoto","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuya","middleName":"","lastName":"Sakamoto","suffix":""},{"id":504940622,"identity":"b1204264-df41-4d98-8ce2-7fb4da10116d","order_by":3,"name":"Noboru Yamashita","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Noboru","middleName":"","lastName":"Yamashita","suffix":""},{"id":504940623,"identity":"7255d758-6261-4700-aa24-7a63dffe7944","order_by":4,"name":"Shinichi Watanabe","email":"","orcid":"","institution":"Matsuyama University","correspondingAuthor":false,"prefix":"","firstName":"Shinichi","middleName":"","lastName":"Watanabe","suffix":""},{"id":504940624,"identity":"527cad99-79cb-4f7b-8297-d1f594fc94e1","order_by":5,"name":"Mamoru Tanaka","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mamoru","middleName":"","lastName":"Tanaka","suffix":""}],"badges":[],"createdAt":"2025-08-19 13:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7408890/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7408890/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40780-025-00504-8","type":"published","date":"2025-11-12T15:57:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90307624,"identity":"d628b629-ee7e-4262-97b4-578b81ffd08f","added_by":"auto","created_at":"2025-09-01 09:33:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35442,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSelection of patients for HBV-related PBPM.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore the start of PBPM, there were 134 patients in the target group. After 48 exclusions, data for 86 patients were included in the analysis. After the start of PBPM, there were 146 patients in the target group. After 63 exclusions, data for 83 patients were available for analysis. HBV, hepatitis B virus; PBPM,\u003cstrong\u003e \u003c/strong\u003eprotocol-based pharmacotherapy management\u003c/p\u003e","description":"","filename":"Binder61.png","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/79bc087d002690960f95bcb3.png"},{"id":90307627,"identity":"c1e3fd97-9a53-4968-8924-d9c3fad8dfbb","added_by":"auto","created_at":"2025-09-01 09:33:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":116982,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFrequency and nature of prescription queries in the outpatient chemotherapy unit after the start of PBPM.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe total number of prescription queries and percentages for each type of query in the outpatient chemotherapy unit after the start of PBPM are shown. Hepatitis B virus-related prescription queries decreased from 20% to 4% in the post-PBPM period. PBPM,\u003cstrong\u003e \u003c/strong\u003eprotocol-based pharmacotherapy management\u003c/p\u003e","description":"","filename":"Binder62.png","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/8126ae977ebc88fbe274297f.png"},{"id":96105169,"identity":"e1e7ccdd-5d55-46a4-b422-d0d11f6e9255","added_by":"auto","created_at":"2025-11-17 16:09:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":775663,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/5de0499b-64f3-4818-b963-bebcc163092e.pdf"},{"id":90307626,"identity":"f9c7fcac-4fe6-4335-9ef8-a6f5968293e9","added_by":"auto","created_at":"2025-09-01 09:33:23","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10071,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/a425b65ed2a61e9e271dc44e.xlsx"},{"id":90311337,"identity":"1f4fee8e-c8d2-4683-9006-53daeee84f2e","added_by":"auto","created_at":"2025-09-01 09:49:23","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10878,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/a912dac7a25af6e3b55b0b95.xlsx"},{"id":90307630,"identity":"54bff9cf-9857-4135-82e0-7a584f0e3bd1","added_by":"auto","created_at":"2025-09-01 09:33:23","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":10889,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/03cb998e0cda3c574c1653ba.xlsx"},{"id":90310041,"identity":"49664e72-9af7-4c46-900c-efc71feaa83c","added_by":"auto","created_at":"2025-09-01 09:41:23","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":10734,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/c3312f97ce14c299042675c3.xlsx"},{"id":90310039,"identity":"8cd43764-f63a-474b-92f5-c3ea1b8c4080","added_by":"auto","created_at":"2025-09-01 09:41:23","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":9876,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/1e703d67b12cca37d2492489.xlsx"},{"id":90310042,"identity":"21acc1a0-020a-4910-9879-8fa80301123d","added_by":"auto","created_at":"2025-09-01 09:41:23","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":9686,"visible":true,"origin":"","legend":"","description":"","filename":"Table6.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7408890/v1/6b7977fe3dd0b82e1d69f1f8.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Usefulness of protocol-based pharmacotherapy management by pharmacists in cancer patients: a retrospective observational study","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eCancer treatment is becoming increasingly sophisticated and complex, necessitating a team-based approach to ensure that patients receive high-quality treatment. For an effective team-based approach, each healthcare professional must use their expertise, share objectives and information, and divide responsibilities. Collaborative and complementary roles among healthcare providers enable appropriate patient-centered care. In Japan, a 2010 directive from the Ministry of Health, Labour and Welfare recommended pharmacist participation as part of a team-based approach using protocols that were previously agreed upon (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). These protocols allow pharmacists to make changes to type of medication, dosages, methods of administration, and testing on the basis of shared professional knowledge.\u003c/p\u003e\u003cp\u003eSince the introduction of the PBPM Implementation Manual by the Japanese Society of Pharmaceutical Health Care and Sciences in 2016 and practical examples provided by the Japanese Society of Hospital Pharmacists, an increasing number of institutions have initiated protocol-based pharmacotherapy management (PBPM) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Effective PBPM requires identification of any relevant problems at a facility and collaborative development of solutions by healthcare professionals. Pharmacist-led interventions can increase patient safety, particularly in cases where guidelines and package inserts are not being followed.\u003c/p\u003e\u003cp\u003eIt has been reported that reactivation of hepatitis B virus (HBV) can be fatal in HBV carriers and in patients with a history of HBV infection who have received immunosuppressive therapy or cancer chemotherapy. Therefore, efforts to prevent reactivation are important in patients who require regular HBV-DNA quantitative testing (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Furthermore, laboratory tests should be performed at each treatment session to determine the feasibility of administering anticancer agents and to detect any adverse effects of these agents at an early stage. In this study, we reviewed the pharmacists\u0026rsquo; queries regarding prescriptions received at our outpatient chemotherapy unit over a one-year period and introduced three PBPM strategies that were considered effective. The first PBPM strategy was designed to avoid reactivation of HBV by immunosuppressive therapy or chemotherapy (HBV-PBPM). The aim of the second strategy was to ensure that the urine protein/creatinine ratio (UPC) was measured in patients receiving anti-vascular endothelial growth factor (VEGF) therapy (UPC-PBPM). The third strategy was designed to ensure that serum magnesium was monitored in patients receiving anti-epidermal growth factor receptor (EGFR) antibody therapy (Mg-PBPM). In this study, we evaluated the usefulness of PBPM by investigating rates of compliance with laboratory tests before and after implementation of these strategies.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eDevelopment of effective PBPM\u003c/h2\u003e\u003cp\u003eTo identify useful PBPM strategies at our facility, we retrospectively reviewed the pharmacists\u0026rsquo; queries regarding prescriptions between April 1, 2021 and March 31, 2022 by searching the electronic medical records and calculating the acceptance rate. The acceptance rate was calculated by dividing the number of queries changed as proposed by the pharmacist by the number of pharmacists\u0026rsquo; queries made during the study period.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEvaluation of the usefulness of the three PBPM strategies\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eHBV-PBPM\u003c/h2\u003e\u003cp\u003eOf 1184 patients who received immunosuppressive therapy or chemotherapy in our outpatient chemotherapy unit between July 2021 and July 2022, 280 were HBsAg-positive and/or HBsAg/HBc antibody-positive. Among these 280 patients, those who met any of the following four criteria were excluded: consultation with a hepatologist for HBV reactivation monitoring; receiving cancer chemotherapy prescribed by a hepatologist; nonattendance at the outpatient chemotherapy unit when HBV-DNA monitoring was necessary; and the attending physician did not approve of PBPM by pharmacists. Finally, data for 169 patients were analyzed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In accordance with the Hepatitis B Treatment Guidelines (4th edition) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), compliance was evaluated as follows. Patients were assessed as being compliant with rituximab, obinutuzumab, and fludarabine if they underwent monthly testing and as being compliant with immunosuppressive therapy (abatacept, infliximab, and tocilizumab) and other chemotherapy agents if testing was performed every 3 months. Other chemotherapies included single-agent or combination therapies, including immune checkpoint inhibitors (ICIs), cytotoxic agents, and molecular targeted therapies, excluding single-agent hormone therapies. PBPM was introduced in January 2022. The first month after its introduction was designated as a transition (operational awareness) period. The period between July and December 2021 was defined as before the start of PBPM and the period between February and July 2022 as after the start of PBPM.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eUPC-PBPM\u003c/h3\u003e\n\u003cp\u003ePatients who received anti-VEGF agents (bevacizumab, ramucirumab, aflibercept) between February 2022 and February 2023 were evaluated. A total of 1228 doses were analyzed. Compliance was defined as having the UPC ratio measured on the day of treatment. PBPM was introduced in August 2022. The first month after its introduction was designated as a transition (operational awareness) period. The period between February 2022 and July 2022 was designated as the period before introduction of PBPM and the period between September 2022 and February 2023 as the period after introduction of PBPM.\u003c/p\u003e\u003cp\u003eMg-PBPM\u003c/p\u003e\u003cp\u003ePatients receiving anti-EGFR antibody therapy (cetuximab, panitumumab) between February 2022 and February 2023 were evaluated. A total of 217 doses were analyzed. Compliance was defined as having serum magnesium measured on the day of treatment. The first month after its introduction was designated as a transition (operational awareness) period. The period between February 2022 and July 2022 was designated as the period before introduction of PBPM and the period between September 2022 and February 2023 as the period after introduction of PBPM.\u003c/p\u003e\u003cp\u003e\u003cb\u003eChanges in queries by pharmacists after introduction of PBPM and in the annual number of tests ordered by pharmacists\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe investigated changes in the types of queries after introduction of the three types of PBPM. We assessed the number of queries and the number of cases accepted regarding laboratory test items for the 2021 fiscal year (FY) before introduction of PBPM, the 2022 FY during the PBPM introduction period, and the 2023 FY after introduction of PBPM. We also investigated the annual changes in the numbers of tests ordered by pharmacists for the three types of PBPM.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eQualitative data were analyzed using Fisher\u0026rsquo;s exact test and quantitative data using the Mann‒Whitney \u003cem\u003eU\u003c/em\u003e test. All statistical analyses were performed utilizing Easy-R (EZR) version 1.61 (2022; Jichi Medical University, Saitama, Japan) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). A P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eDevelopment of effective PBPM\u003c/h2\u003e\u003cp\u003eBetween April 2021 and March 2022, 480 queries from pharmacist regarding prescriptions were recorded. The most common errors concerned an order (n\u0026thinsp;=\u0026thinsp;116, acceptance rate 95%), followed by HBV-related issues (n\u0026thinsp;=\u0026thinsp;94, acceptance rate 64%) and additional laboratory tests (n\u0026thinsp;=\u0026thinsp;81, acceptance rate 85%). Before the start of PBPM, there were 480 queries regarding prescriptions in the outpatient chemotherapy unit, with an overall acceptance rate of 76% (Table\u0026nbsp;1). The prescription queries were HBV-related in 20% of cases.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eUsefulness of the three PBPM strategies\u003c/h3\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eHBV-PBPM\u003c/h2\u003e\u003cp\u003eThe final analysis included 86 patients before PBPM and 83 patients after PBPM. After the start of PBPM, the frequency of laboratory tests ordered by pharmacists increased significantly to 25% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median duration of noncompliance was 5 months before PBPM and 4 months after starting PBPM. The range of the noncompliance period was significantly shorter after initiation of PBPM (P\u0026thinsp;=\u0026thinsp;0.003) (Table\u0026nbsp;2). HBV-DNA should have been measured at monthly intervals in patients receiving rituximab who were HBs/HBc antibody-positive, but were not measured in three cases during the study period. Two of these patients were from the pre-PBPM period and one was from the post-PBPM period. In the two patients who received rituximab before PBPM, HBV-DNA quantification was performed at 2 and 3 months. One patient received rituximab after initiation of PBPM, and HBV-DNA quantification was performed at 3 months. The rate of compliance with HBV-DNA quantification improved significantly from 64.0\u0026ndash;85.5% (P\u0026thinsp;=\u0026thinsp;0.001) (Table\u0026nbsp;2).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eUPC-PBPM\u003c/h2\u003e\u003cp\u003eThere were 634 treatments before PBPM and 594 after initiation of PBPM. Bevacizumab was the most frequently used agent, accounting for approximately 80% of cases. This agent was used most frequently for colorectal cancer, accounting for 27% of cases. The rate of compliance with measurement of UPC remained at 98.7% in both periods; however, the percentage of laboratory tests ordered by pharmacists increased to 1.5% after introduction of PBPM (Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eMg-PBPM\u003c/p\u003e\u003cp\u003eThere were 95 treatments before PBPM and 122 after the start of PBPM. The proportion of patients receiving panitumumab decreased from 73.3% before PBPM to 48.4% after starting PBPM. The prevalence of colorectal cancer was 82.1% in the pre-PBPM period and 71.3% in the PBPM period. The frequency of serum magnesium levels with a Common Terminology Criteria for Adverse Events grade of \u0026le;\u0026thinsp;1 was 95.8% in the pre-PBPM period and 95.1% in the PBPM period. The rate of compliance with serum magnesium measurement increased slightly from 95.8\u0026ndash;99.2% after implementation of Mg-PBPM. After implementation of PBPM, 3.3% of laboratory tests were ordered by pharmacists (Table\u0026nbsp;4).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eChanges in types of pharmacists\u0026rsquo; queries after the start of PBPM\u003c/h2\u003e\u003cp\u003eThere were 480 queries from pharmacists to physicians in the 2021 FY, which decreased to 462 in the 2022 FY. After the start of PBPM, the percentage of queries regarding HBV-related prescriptions decreased markedly from 20\u0026ndash;4% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe number of queries regarding measurement of the UPC ratio was high in the 2022 FY and decreased after introduction of UPC-PBPM (Tables\u0026nbsp;5 and 6). However, it became clear that the number of queries related to ICI therapy has been increasing year by year (Table\u0026nbsp;5).\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we investigated the number of prescription queries from pharmacists to physicians and their acceptance rates in our outpatient chemotherapy unit and introduced three PBPM strategies that we anticipated would be effective. It was thought that more effective interventions could be made by clarifying the problems at our own facility (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Our survey revealed that rates of compliance with HBV-DNA quantification improved significantly after implementation of PBPM. Before the start of PBPM, requests for additional tests were made by telephone, email, or via the medical records, but the compliance rate was low at 64%. The compliance rate increased significantly to 85.5% when the pharmacists started PBPM (P\u0026thinsp;=\u0026thinsp;0.001). The median duration of noncompliance decreased significantly from 5 months (range 2\u0026ndash;8) in the pre-PBPM period to 4 months (range 3\u0026ndash;4) in the PBPM period (P\u0026thinsp;=\u0026thinsp;0.003). The durations of noncompliance before initiation of PBPM were 2 months (n\u0026thinsp;=\u0026thinsp;1), 3 months (n\u0026thinsp;=\u0026thinsp;1), 4 months (n\u0026thinsp;=\u0026thinsp;11), 5 months (n\u0026thinsp;=\u0026thinsp;11), 6 months (n\u0026thinsp;=\u0026thinsp;2), 7 months (n\u0026thinsp;=\u0026thinsp;2), and 8 months (n\u0026thinsp;=\u0026thinsp;3). After the start of PBPM, there was 1 case of noncompliance for 3 months and 11 cases for 4 months. Previous studies have reported increases in the implementation rate of HBV-DNA monitoring to 66.7% (n\u0026thinsp;=\u0026thinsp;12) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), 81.8% (n\u0026thinsp;=\u0026thinsp;44) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), 93.9% (n\u0026thinsp;=\u0026thinsp;23) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), 98.3% (n\u0026thinsp;=\u0026thinsp;28) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and 100% (n\u0026thinsp;=\u0026thinsp;21) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) following initiation of PBPM by pharmacists. Our HBV-DNA quantification survey included a larger number of patients than in previous reports, with an adherence rate of 85.5% in 83 patients. Twelve patients not adhere to the protocol because the pharmacist forgot to order the test; however, the nonadherence period was 4 months in all cases, and the test was performed in the month following that in which it was required. We believe that pharmacist-driven PBPM minimizes the risk of HBV reactivation in cancer patients and may contribute to safer implementation of chemotherapy.\u003c/p\u003e\u003cp\u003eThe American College of Clinical Pharmacy released position statements on collaborative drug therapy management (CDTM) in the United States in 1997 and 2003. Since 2003, CDTM has spread throughout the United States, promoting team-based medical care and reducing the workload of physicians (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The CDTM activities implemented include requesting clinical laboratory tests, adjusting the strength of medication, and changing the frequency of administration (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In Japan, the Japanese Society of Pharmaceutical Health Care and Sciences released a manual introducing PBPM in 2016 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) and the Japanese Hospital Pharmacists Association introduced specific practical examples of PBPM in the same year (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), which led to an increase in the number of facilities actively introducing PBPM. PBPM has been reported to be useful in cancer chemotherapy (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), when administering high-risk agents (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), in patients with human immunodeficiency virus (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) in Japan. While the usefulness of PBPM in patients receiving immunosuppressive therapy or injectable anticancer therapy has been reported (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), the rate of implementation of HBV monitoring in patients receiving oral anticancer agents is reportedly low (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Therefore, PBPM should be considered for these patients. While the present study demonstrated the usefulness of PBPM for HBV-DNA monitoring, it could not confirm that PBPM by pharmacists was useful in terms of increasing the rates of compliance with measurement of the UPC ratio during anti-VEGF therapy or the serum magnesium level during anti-EGFR antibody therapy. In Japan, PBPM has been implemented in many facilities for measurement of the UPC ratio and serum magnesium level and has been discussed at academic conferences. However, to the best of our knowledge, there are few published reports on this topic. According to the report by Ito et al., the introduction of PBPM increased the rate of urine testing from 74.7\u0026ndash;99.2% (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). While PBPM is very effective in terms of increasing measurement rates, at our institution, where the pre-PBPM measurement rate was already high, the usefulness of UPC-PBPM and Mg-PBPM was not demonstrated. The reason for this is that in the case of HBV-DNA quantitative testing, which requires measurement every 3 months, after ordering the necessary test items for each treatment, it is necessary to order HBV-DNA quantitative testing at the required time separately. The UPC ratio and serum magnesium level requires measurement at each treatment, and the frequency of forgetting to measure is low because physicians copy the blood draw order from the previous treatment and re-order it. We introduced UPC-PBPM and Mg-PBPM anticipating that they would be useful, but in reality, the number of tests ordered by pharmacists was low. Therefore, we revisited the content of queries regarding test items after introducing UPC-PBPM and Mg-PBPM. Forty-five (38.1%) of the 118 queries concerned items requiring regular testing, including thyroid-stimulating hormone, FT4, FT3, KL-6, and urine tests, in patients receiving ICIs in the 2022 YR. Moreover, the number of queries related to ICIs increased in the following year. Previous research has demonstrated the usefulness of implementing PBPM for testing when ICIs are used (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), and the findings at our hospital also suggest the need to initiate PBPM in the future. Furthermore, despite the initiation of PBPM, 25 (21.2%) of the 118 queries in the 2022 FY and 13 (7.1%) of the 182 queries in 2023 FY concerned measurement of the UPC ratio or serum magnesium level, suggesting that physicians may not have delegated ordering authority to pharmacists. Physicians at our hospital delegate ordering authority to pharmacists but must operate the electronic medical records system themselves to establish the necessary settings. This process is cumbersome and may hinder the delegation of authority. Furthermore, Alhossan et al. identified a lack of knowledge among other healthcare professionals regarding PBPM (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The knowledge that PBPM can positively influence outcomes related to pharmacotherapy should be shared with other healthcare professionals. While the implementation of PBPM by pharmacists has little financial impact on hospitals, it can increase the value of pharmacists and contribute to team-based care (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe introduction of PBPM improves compliance with the laboratory test items necessary during chemotherapy for cancer patients and enables the delivery of safe treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eACCP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmerican College of Clinical Pharmacy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCDTM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecollaborative drug therapy management\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEGFR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eepidermal growth factor receptor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHBV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehepatitis B virus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICIs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eimmune checkpoint inhibitors\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePBPM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprotocol-based pharmacotherapy management\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUPC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eurine protein/creatinine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eVEGF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003evascular endothelial growth factor\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\u003eThis study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (2015) published by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare. The study was approved by the Ethics Committee of Ehime University Hospital (approval number 2506003). Informed consent was obtained via the opt-out route on the hospital’s website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the data generated or analyzed during this study are included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declare that they have no conflicts of interest relevant to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors contributed to the study conception and design. SS was involved in data collection. SS, NH, YS, NY, SW, and MT were involved in the analysis and interpretation of the data and the drafting of the manuscript. All the authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMinistry of Health, Labour and Welfare. Promotion of team medical care through collaboration with medical staffs. 2010. Available from: https://www.mhlw.go.jp/topics/2013/02/dl/tp0215-01-09d.pdf.\u003c/li\u003e\n \u003cli\u003eJapanese Society of Hospital Pharmacists. How to facilitate protocol-based pharmacotherapy management (PBPM) and specific practical examples (Ver.1.0). 2016 . Available from: https://www.jshp.or.jp/activity/guideline/20160331-1.pdf.\u003c/li\u003e\n \u003cli\u003eJapanese Society of Pharmaceutical Health Care and Sciences. Protocol-Based Pharmacotherapy Management (PBPM) Implementation Manual. 2016 . Available from: https://www.jsphcs.jp/wp-content/uploads/2024/10/20160613-1.pdf.\u003c/li\u003e\n \u003cli\u003eThe Japan Society of Hepatology. Hepatitis B Treatment Guidelines. 2022. Available from: https://www.jsh.or.jp/lib/files/medical/guidelines/jsh_guidlines/B_v4.pdf.\u003c/li\u003e\n \u003cli\u003eAkira T, Ryoo T, Yasuhiro S, Seiichi M, Yuji W, Tomoyuki O, et al. Evaluation of the implementation of HBV-related marker testing during cancer chemotherapy and the effectiveness of medical safety measures. Journal of Japanese Society of Pharmaceutical Oncology. 2017(6):16-23. Available from: https://jaspo-oncology.org/file/224#page=18\u003c/li\u003e\n \u003cli\u003eChieko S, Masaaki I, Takao O, Naoyuki U. Construction of Protocol-Based Pharmacotherapy Management (PBPM) Using an Electronic Medical Record Interlocking Support System to Prevent Hepatitis B Virus Reactivation Induced by Cancer Chemotherapy. Jpn. J. Pharm. Health Care Sci. 2022;48(1):9-19. Available from: https://www.jstage.jst.go.jp/article/jjphcs/48/1/48_9/_pdf/-char/ja doi : 10.5649/jjphcs.48.9\u003c/li\u003e\n \u003cli\u003eKanda Y. Investigation of the freely available easy-to-use software \u0026apos;EZR\u0026apos; for medical statistics. Bone Marrow Transplant. 2013;48(3):452-8. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3590441/ doi: 10.1038/bmt.2012.244\u003c/li\u003e\n \u003cli\u003eSato M, Fujita S, Kimura M, Takeuchi K, Hamahata Y, Matsuda Y. Designing Effective Protocol-Based Pharmacotherapy Management: Assessment of the Development Processes and Outcomes in Inflammatory Bowel Disease Care Prescription Management. Pharmacy (Basel). 2025;13(1). Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11860031/pdf/pharmacy-13-00017.pdf doi: 10.3390/pharmacy13010017\u003c/li\u003e\n \u003cli\u003eDaisuke M, Hiroki T, Kensaku Y, Toru M, Daiki Y, Yukiko A, et al. Pharmacist Orderings for Blood and Urine Tests Related to Pharmaceuticals -Practice of Protocol-Based Pharmacotherapy Management (PBPM)-. Jpn. J. Pharm. Health Care Sci. 2021;47(7):345-57. Available from: https://www.jstage.jst.go.jp/article/jjphcs/47/7/47_345/_pdf/-char/ja doi: 10.5649/jjphcs.47.345\u003c/li\u003e\n \u003cli\u003eKeiko F, Hideki K, Akane N, Masahiro O, Yukiomi Eguchi, et al. [The Department of Pharmacy at Fukuoka University Hospital\u0026apos;s Role in Preventing Hepatitis B Virus Reactivation in Patients Taking Oral Anticancer Drugs]. Gan To Kagaku Ryoho. 2023;50(8):885-9. Available from: https://mol.medicalonline.jp/library/journal/download?GoodsID=ab8gtkrc/2023/005008/011\u0026amp;name=0885-0889j\u0026amp;UserID=133.71.173.33\u0026amp;base=jamas_pdf\u003c/li\u003e\n \u003cli\u003eHiroyuki W, Ikuko H, Yuka N, Noriyuki H, Tatsuichi A, Takashi Y. Evaluation of effectiveness and implementation of protocol-based pharmacotherapy management for prevention of hepatitis B virus reactivation induced cancer chemotherapy. Journal of Japanese Society of Pharmaceutical. Oncology. 2016;5:13-18. Available from: https://jaspo-oncology.org/file/225#page=15\u003c/li\u003e\n \u003cli\u003eMcBane SE, Dopp AL, Abe A, Benavides S, Chester EA, Dixon DL, et al. Collaborative drug therapy management and comprehensive medication management-2015. Pharmacotherapy. 2015;35(4):e39-50. Available from: https://accpjournals.onlinelibrary.wiley.com/ doi/10.1002/phar.1563doi: 10.1002/phar.1563\u003c/li\u003e\n \u003cli\u003eMishra P, Thomas J. Survey of collaborative drug therapy management in U.S. hospitals. Am J Health Syst Pharm. 2017;74(21):1791-905. Available from: https://academic.oup.com/ajhp/article-abstract/74/21/1791/5102691?redirectedFrom=fulltext#google_vignettedoi: 10.2146/ajhp151058\u003c/li\u003e\n \u003cli\u003eIkesue H, Kusuda K, Satsuma Y, Nishiwaki F, Miura R, Masuda Y, et al. Evaluation of the usefulness of protocol-based pharmacist-facilitated laboratory monitoring to ensure the safety of immune checkpoint inhibitors in patients with lung cancer. J Clin Pharm Ther. 2020;45(6):1288-94. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7687122/pdf/JCPT-45-1288.pdf doi: 10.1111/jcpt.13207\u003c/li\u003e\n \u003cli\u003eNakamura N, Shiraiwa H, Haruna Y, Ichijima T, Takeda T, Hasegawa K, et al. Effectiveness of protocol-based pharmacotherapy management collaboration between hospital and community pharmacists to address capecitabine-related hand-foot syndrome in cancer patients: a retrospective study. J Pharm Health Care Sci. 2021;7(1):8. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7919314/pdf/40780_2021_Article_191.pdf doi: 10.1186/s40780-021-00191-1 doi: 10.1186/s40780-021-00191-1\u003c/li\u003e\n \u003cli\u003eYanagawa T, Kataoka K, Yamashita N, Yanai M, Tanaka K, Bando J, et al. [Effects of Introducing PBPM for Outpatient Cancer Drug Therapy and Its Impact on Physician Workload]. Gan To Kagaku Ryoho. 2024;51(7):747-51. Available from: https://www.pieronline.jp/content/article/0385-0684/51070/747\u003c/li\u003e\n \u003cli\u003eAsai Y, Nakano Y, Yanagawa T, Takahashi M, Iwamoto T. Impact of a Collaborative Pharmacist-Cardiovascular Surgeon Protocol for High Risk of Postoperative Delirium on Benzodiazepine Prescription Trends in Hospitalized Patients. Biol Pharm Bull. 2025;48(2):177-83. Available from: https://www.jstage.jst.go.jp/article/bpb/48/2/48_b24-00708/_pdf/-char/en doi: 10.1248/bpb.b24-00708\u003c/li\u003e\n \u003cli\u003eAsai Y, Yanagawa T, Takahashi M. Effect of pharmacist-led intervention protocol on preventing postoperative delirium after elective cardiovascular surgery. PLoS One. 2023;18(10):e0292786. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10569577/pdf/pone.0292786.pdf doi: 10.1371/journal.pone.0292786\u003c/li\u003e\n \u003cli\u003eKatada Y, Nakagawa S, Minakata K, Odaka M, Taue H, Sato Y, et al. Efficacy of protocol-based pharmacotherapy management on anticoagulation with warfarin for patients with cardiovascular surgery. J Clin Pharm Ther. 2017;42(5):591-7. Available from: https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcpt.12560 doi: 10.1111/jcpt.12560\u003c/li\u003e\n \u003cli\u003eUrano K, Ishibashi M, Matsumoto T, Ohishi K, Muraki Y, Iwamoto T, et al. Impact of physician-pharmacist collaborative protocol-based pharmacotherapy management for HIV outpatients: a retrospective cohort study. J Pharm Health Care Sci. 2020;6:9. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7193403/pdf/40780_2020_Article_165.pdf doi: 10.1186/s40780-020-00165-9\u003c/li\u003e\n \u003cli\u003eKomuro M, Toda Y, Ishikawa S, Hyakutake H, Watanabe T, Shimanuki Y, et al. [Operational Construction and Effectiveness Verification of an HBV Reactivation Management Protocol for Cancer Chemotherapy Patients Based on Medical Information System Safety Management]. Gan To Kagaku Ryoho. 2025;52(6):457-61. Available from: https://www.pieronline.jp/content/article/0385-0684/52060/457\u003c/li\u003e\n \u003cli\u003eMinori I, Yasuhiko S, Keiji S, Shinichi K, Kouichi H. Approach for Appropriate Use of Urinary Protein Related Anti-VEGF Antibody by Introducing the PBPM. J. Jpn. Soc. Hosp. Pharm. 2017;53(6):703-7. Available from: https://mol.medicalonline.jp/library/journal/download?GoodsID=dg4hppha/2017/005306/008\u0026amp;name=0703-0707j\u0026amp;UserID=133.71.173.33\u0026amp;base=jamas_pdf\u003c/li\u003e\n \u003cli\u003eAlhossan A, Alazba A. Barriers interfering with establishment of Collaborative Drug Therapy Management (CDTM) agreements between clinical pharmacists and physicians. Saudi Pharm J. 2019;27(5):713-6. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6598211/pdf/main.pdf doi: 10.1016/j.jsps.2019.04.006\u003c/li\u003e\n \u003cli\u003eThomas J, Bharmal M, Lin SW, Punekar Y. Survey of pharmacist collaborative drug therapy management in hospitals. Am J Health Syst Pharm. 2006;63(24):2489-99. Available from: https://academic.oup.com/ajhp/article-abstract/63/24/2489/5134611?redirectedFrom=fulltext\u0026amp;login=truedoi: 10.2146/ajhp050205\u003c/li\u003e\n\u003c/ol\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":"PBPM, HBV reactivation, HBV-DNA, anti-vascular endothelial growth factor therapy, urine creatinine ratio, anti-EGFR antibody, serum magnesium","lastPublishedDoi":"10.21203/rs.3.rs-7408890/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7408890/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eA team-based approach is essential to provide cancer patients with high-quality treatment. To ensure the best possible care while reducing the workload of physicians, Ehime University Hospital has introduced three protocol-based pharmacotherapy management (PBPM) strategies in the field of chemotherapy. First, we introduced PBPM to avoid reactivation of hepatitis B virus (HBV) in patients receiving immunosuppressive therapy or chemotherapy. In this PBPM strategy, pharmacists added laboratory test orders for patients who require regular HBV-DNA quantification (HBV-PBPM). Second, we devised PBPM for measurement of the urine protein/creatinine ratio (UPC) in patients receiving anti-vascular endothelial growth factor therapy. Finally, we introduced PBPM for measurement of serum magnesium in patients receiving anti-epidermal growth factor receptor antibody therapy (Mg-PBPM). In this study, we evaluated the usefulness of these three PBPM strategies in outpatients receiving chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The study included patients treated in the outpatient chemotherapy unit between July 2021 and February 2023. Rates of compliance with laboratory tests in the 6 months before and after introduction of PBPM were compared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Compliance with HBV-DNA quantification improved significantly from 64.0% before PBPM to 85.5% after implementation of PBPM (P=0.001). The median duration of noncompliance was significantly shorter after initiation of PBPM (P=0.003). Compliance with measurement of UPC was already greater than 95% before PBPM and showed no change after implementation (98.7% pre-PBPM vs 98.7% post-PBPM). Compliance with measurement of serum magnesium improved from 95.8% pre-PBPM to 99.2% after starting PBPM, but the improvement was not statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Introduction of PBPM improves compliance with the laboratory tests required in cancer patients during chemotherapy and enables safer delivery of treatment.\u003c/p\u003e","manuscriptTitle":"Usefulness of protocol-based pharmacotherapy management by pharmacists in cancer patients: a retrospective observational study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 09:33:18","doi":"10.21203/rs.3.rs-7408890/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":"5df72e8c-0335-49da-bf02-0e1b0b395936","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T16:03:59+00:00","versionOfRecord":{"articleIdentity":"rs-7408890","link":"https://doi.org/10.1186/s40780-025-00504-8","journal":{"identity":"journal-of-pharmaceutical-health-care-and-sciences","isVorOnly":false,"title":"Journal of Pharmaceutical Health Care and Sciences"},"publishedOn":"2025-11-12 15:57:26","publishedOnDateReadable":"November 12th, 2025"},"versionCreatedAt":"2025-09-01 09:33:18","video":"","vorDoi":"10.1186/s40780-025-00504-8","vorDoiUrl":"https://doi.org/10.1186/s40780-025-00504-8","workflowStages":[]},"version":"v1","identity":"rs-7408890","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7408890","identity":"rs-7408890","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}