Efficacy of vitamin B1 in alleviating chemotherapy-induced nausea and vomiting

Efficacy of vitamin B1 in alleviating chemotherapy-induced nausea and vomiting | 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 Efficacy of vitamin B1 in alleviating chemotherapy-induced nausea and vomiting Satoru Matsushima, Hirozumi Sano, Daiki Hori, Masato Yanagi, Daisuke Suzuki, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4250292/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The management of chemotherapy-induced nausea and vomiting (CINV) is of primary concern for both patients with cancer and medical workers. Refractory or breakthrough CINV is especially difficult to deal with and necessitates a different approach. Vitamin B1 deficiency is likely to occur during cancer chemotherapy, with early symptoms of fatigue, anorexia, nausea and vomiting. The efficacy of vitamin B1 for the treatment of delayed or refractory CINV should be confirmed. Methods Serum vitamin B1 level was prospectively measured in patients experiencing persistent nausea and vomiting after chemotherapy. The response to vitamin B1 therapy was evaluated for three consecutive days after vitamin B1 infusion. Moreover, serum level of vitamin B1 at diagnosis of persistent delayed CINV was compared with the level before chemotherapy. Results In total, 408 courses of chemotherapy in 86 patients were analyzed. The median age at hospital admission of the enrolled patients was 10.7 years (0.2–25.2). Among these, 44 (10.8%) episodes of persistent delayed CINV were identified in 26 of the enrolled patients. At day 3, the overall response rate was 79.5%; 21 (47.7%) patients achieved a complete response and 14 (31.8%) patients achieved a partial response. The median vitamin B1 level at diagnosis of CINV was significantly lower than the value before chemotherapy (22.8, range 11.9–49.2 vs. 32.7, range 11.2 − 80.1, respectively, P < 0.001). Conclusion Patients with a malignant disease who experience persistent nausea and vomiting after chemotherapy often exhibit vitamin B1 deficiency. Vitamin B1 infusion may be beneficial for many of these patients. Vitamin B1 deficiency thiamin deficiency chemotherapy-induced nausea and vomiting children adolescents and young adults Figures Figure 1 Figure 2 Introduction Clinical outcomes for malignant tumors in children, and adolescents and young adults (AYAs) have progressed due to the development of treatment strategies and adaptation of medications with new mechanisms of action [ 1 ]. On the other hand, therapy-related complications continue to be an issue. Chemotherapy-induced nausea and vomiting (CINV) is one of the most common adverse effects that affect the quality of life of patients and demand considerable medical resources [ 2 ]. Recently, several antiemetic agents have become available, and several studies focusing on CINV have been conducted [ 3 , 4 ]. However, methods to prevent and manage breakthrough or refractory CINV have not yet been established. Vitamin B1, also known as thiamin, is a water-soluble vitamin that is essential for several physiological functions. One important function is its contribution to cellular energy metabolism as a cofactor in the pentose phosphate pathway, glycolysis and Krebs cycles. Vitamin B1 also helps in the synthesis of nucleic acids, neurotransmitters and myelin, thereby protecting nerve cell functions [ 5 ]. The body can only store a small amount of vitamin B1, and the half-life of thiamin in blood is short. Thus, vitamin B1 deficiency is likely to occur if ongoing dietary intake is disrupted [ 6 ]. The most common organs susceptible to a lack of vitamin B1 are brain tissue and cardiac muscle, which constantly consume a high level of glucose. The symptoms of a lack of glucose in these organs include ataxia, nystagmus, peripheral neuropathy (dry beriberi), tachycardia, edema and heart failure (wet beriberi) [ 7 , 8 ]. The most severe manifestation is Wernicke-Korsakoff syndrome, which is characterized by encephalopathy, seizure and amnesia. Wernicke-Korsakoff syndrome has been reported in several patients who have undergone cancer chemotherapy [ 9 – 11 ]. However, these manifestations could have been caused by other medical conditions. Furthermore, the early symptoms of vitamin B1 deficiency, such as fatigue, anorexia, nausea and vomiting, are not specific presentations in patients with a malignant disease. Consequently, vitamin B1 deficiency is likely to be overlooked, although it occurs more often among hospitalized patients [ 12 – 17 ]. At our institution, serum level of vitamin B1 is evaluated in children and AYAs with a malignant disease who are suffering from delayed recovery from CINV, and thiamin administration is implemented before diagnosis of vitamin B1 deficiency. Some of these patients experience improvement of their symptoms within hours or days of vitamin B1 infusion. However, little attention has been paid to vitamin B1 as a potential treatment option for patients with persistent CINV. Therefore, the present study aimed to verify the efficacy of vitamin B1 for delayed or refractory CINV. Methods Patient Population and Study Design This study prospectively evaluated the serum level of vitamin B1 at diagnosis of persistent delayed CINV as well as the response to vitamin B1 infusion. The patient population of this study was children (< 15 years of age) and AYAs (≥ 15 years of age) with a malignant disease who underwent chemotherapy at the Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, from March 2022 to September 2023. Analyses were conducted based on all data obtained up to October 2023. The conditioning regimens for hematopoietic cell transplantation were not analyzed in this study. The treatment courses for blinatumomab or all-trans retinoic acid monotherapy, and dasatinib plus predonisolone were also excluded from the analysis. Moreover, several patients who received total parenteral nutrition due to continual inadequate oral intake were not included, as the administered formula contains a small amount of vitamin B1. In general, vitamin B1 is administered to patients experiencing nausea and vomiting that persists for more than five days after the end of chemotherapy, which is the period that defines persistent delayed CINV, and when a differential diagnosis other than CINV is not considered [ 18 , 19 ].However, the actual timing of the application of vitamin B1 therapy depends on the clinical situation, and the duration of the therapy can range from three to seven days. The antiemetic agent used in the present study was the parenteral 5-HT3 antagonist ondansetron, which was used on the day of chemotherapy every 12 hours and within 24 hours after chemotherapy. Antihistamines are also occasionally used for symptom amelioration. However, no other 5-HT3 antagonists or neurokinin-1 (NK1) receptor antagonists were adopted in this study. Furthermore, other agents used for treating CINV, such as metoclopramide and olanzapine, as well as other non-pharmacological therapies, were not considered in this study. The thiamin status in the enrolled patients was assessed by measurement of the serum level of vitamin B1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used as the method for serum vitamin B1 analysis. The serum level of vitamin B1 was evaluated in all patients before and one week after chemotherapy implementation. If the chemotherapy regimen consisted of several weeks, vitamin B1 was assessed two weeks after the first measurement. The lowest value after chemotherapy was selected for conducting the analysis. Vitamin B1 status was also evaluated before vitamin B1 infusion in patients with persistent delayed CINV. For the vitamin B1 preparation, a vitamin B complex (Vitamedin®ฎ; Alfresa Pharma Corporation, Osaka, Japan) containing vitamins B1, B6 and B12 was used to treat persistent delayed CINV, with a vitamin B1 content of 107 mg. However, a pure vitamin B1 drug (Alinamin®ฎ; Takeda Pharmaceutical Company, Tokyo, Japan), which contains 100 mg of vitamin B1, was used after January 2022. Vitamin B1 deficiency was defined as a serum level of vitamin B1 30 ng/ml were defined as non-thiamin deficiency. Levels between 24 and 30 ng/ml were regarded as borderline. Definitions of Nausea or Vomiting The symptoms of nausea or vomiting were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ 20 ]. Nausea was evaluated according to the following modified scale: adverse event Grade I, oral intake of less than one-half of the ordinary amount; Grade II, oral intake of less than one-third of the ordinary amount and Grade III, little or no oral intake. Vomiting was evaluated according to the CTCAE criteria as follows: Grade I, 1–2 episodes in 24 hours; Grade II, 3–5 episodes in 24 hours; Grade III, more than 5 episodes in 24 hours, or tube feeding or total parenteral nutrition. The grades of nausea and vomiting were prospectively evaluated using the medical charts of the enrolled patients. The response to vitamin B1 therapy was determined based on improvement in the grade of nausea or vomiting in the following three days. Specifically, a complete response (CR) signified no symptoms of nausea and vomiting; a partial response (PR) meant improvement of any grade of nausea or vomiting; a stable disease (SD) indicated no improvement in symptoms; and a progressive disease (PD) indicated a worsening of symptoms. Using these definitions, the response rates on days 1 through 3 were evaluated. Study Outcomes The primary outcome of this study was the determination of the response rate of vitamin B1 therapy in patients with persistent delayed CINV for three days after starting the infusion, and whether vitamin B1 deficiency existed in those patients. Additionally, the serum level of vitamin B1 before and after chemotherapy was compared in both patients with and without CINV. Furthermore, the vitamin B1 serum level was compared between patients with and without CINV both before and after chemotherapy. The amount of change in the vitamin B1 level was also compared between patients with and without CINV. This analysis was limited to patients with a thiamin level > 29.9 ng/ml so that the vitamin B1 level before chemotherapy would be the same in the two groups. It is likely that patients with higher vitamin B1 levels experienced a greater decrease in the serum level of vitamin B1. The other sub-analyses of this study consisted of a comparison of the levels of vitamin B1 between children and AYAs, between males and females and between patients with hematologic tumors and those with solid tumors. Furthermore, whether the level of vitamin B1 before chemotherapy contributes to the development of persistent delayed CINV was investigated. Statistical Analysis The categorical variables of the baseline characteristics of the chemotherapy courses were compared using Fisher’s exact test. The continuous variable of the serum levels of vitamin B1 in the same subjects was compared before and after chemotherapy using the Wilcoxon signed-rank test. The continuous variable of the serum level of vitamin B1 was compared between the groups with or without CINV using the Mann-Whitney U test. To investigate the association between the level of vitamin B1 before chemotherapy and the incidence of persistent delayed CINV, the optimal cut-off value of the level of vitamin B1 was calculated using the receiver operating characteristic (ROC) curve. The point on the ROC curve with a minimum distance from the left upper corner of the unit square was adopted. The patients were then divided into two groups based on the obtained cut-off value, and the incidence of persistent delayed CINV was compared. A p- value of 0.05 or less was considered statistically significant. All statistical analyses were performed with EZR, a graphical user interface for R (The R Foundation for Statistical Computing) [ 21 ]. Results Patient characteristics In total, 86 patients were included in the study, and 408 chemotherapy episodes were analyzed. The median age of the enrolled patients was 10.7 years (range, 0.2–25.2 years), and most had hematologic malignant disease. The patients’ characteristics are detailed in Table 1. Among all the enrolled patients, the median level of vitamin B1 before chemotherapy was 38.5 ng/ml, and the median of the lowest value after chemotherapy was 29.0 ng/ml. Response to vitamin B1 infusion Forty-four (10.8%) episodes of persistent delayed CINV were diagnosed in 26 of the enrolled patients. The median time of the diagnosis after chemotherapy was five days. Vitamedin was administered in 29 (66.0%) episodes, and Alinamin was used in the other 15 (34.0%) episodes. At day 1, the overall response rate (ORR) was 68.2%; 9 (20.5%) patients achieved CR and 21 (47.7%) patients achieved PR. The ORR at day 2 was 81.8%; 11 (25.0%) patients achieved CR and 25 (56.8%) patients achieved PR. At day 3, the ORR was 79.5%; 21 (47.7%) patients achieved CR and 14 (31.8%) patients achieved PR. Additionally, six (13.6%) patients experienced improvement in their symptoms within several hours. Furthermore, the response rate for Alinamin was the same as that for Vitamedin (Table 2). Investigation of vitamin B1 deficiency The median vitamin B1 level at diagnosis of CINV was significantly lower than the value before chemotherapy (22.8 ng/ml, range 11.9–49.2 vs. 32.7 ng/ml, range 11.2 − 80.1, respectively, P < 0.001) (Fig. 1 ). Moreover, the median vitamin B1 level after chemotherapy was significantly lower in patients with persistent delayed CINV than in those without persistent delayed CINV (22.5 ng/ml, range 10.7 − 49.2 vs. 30.0 ng/ml, range 12.3 − 95.1, respectively, P < 0.001) (Fig. 2 ). In addition, the median thiamin level at diagnosis of CINV fulfilled the definition of vitamin B1 deficiency. Among the patients who were administered vitamin B1 therapy, 24 (54.5%) had vitamin B1 deficiency, 13 (29.6%) were borderline and 7 (15.9%) had no vitamin B1 deficiency (Table 3). A comparison of background information for patients with and without persistent delayed CINV is available in Table 4. Complementary analysis: comparison of serum vitamin B1 level The median vitamin Bl level before chemotherapy in patients with persistent delayed CINV was also significantly lower than in those without persistent delayed CINV (32.7 ng/ml, range 11.2 − 80.1 vs. 38.7 ng/ml, range 17.4 − 94.8, respectively, P = 0.018) (Figure S1 ). Furthermore, the patients without refractory CINV also experienced a decrease in their levels of vitamin B1 after chemotherapy (30.0 ng/ml, range 12.3–95.1 vs. 38.7 ng/ml, range 17.4 − 94.8, respectively, P < 0.001). However, the median vitamin B1 levels were above the upper limit for thiamin deficiency. For the level of decrease in the serum level of vitamin B1 before and after chemotherapy, it was significantly greater in the patients with persistent delayed CINV than in those without persistent delayed CINV (-14.7, range − 63.0–6.3, vs. -9.3, range − 67.2 − 37.8, respectively, P = 0.005). The median vitamin B1 level before chemotherapy was the same between the groups (39.2 ng/ml, range 30.2–80.1 vs. 41.2 ng/ml, range 30.0 − 94.8, respectively, P = 0.634). These results are shown in Table S1 . The results of the sub-group analyses are shown in Table S2 . The level of vitamin B1 both before and after chemotherapy was significantly lower in female patients than in male patients. Furthermore, the patients whose vitamin B1 levels before chemotherapy were below 31.8 ng/ml, which was the optimal cut-off value generated in this study (AUC, 0.609, 95% CI, 0.508-0.711), more often developed persistent delayed CINV (20.0% vs. 7.6%, P < 0.001) (Table S3 ). Discussion The present study prospectively investigated the efficacy of vitamin B1 in the treatment of persistent delayed CINV. Ten percent of the enrolled patients were diagnosed with persistent delayed CINV; of these, about 80% experienced relief of their symptoms, and 48% were completely free from nausea and vomiting within three days. Several patients even recovered from their symptoms within several hours. The present results suggest that patients with persistent delayed CINV are considerably more likely to have vitamin B1 deficiency. In fact, more than 80% of the patients in the present study had an insufficient level of vitamin B1. In contrast, patients without persistent delayed CINV were less likely to have an insufficient level of vitamin B1 (43%). As there is no established value as an indicator of actual vitamin B1 deficiency, the definition of vitamin B1 deficiency used in the present study was derived from a 95% confidential interval of the nonparametric test in healthy adults. According to a previous study, Wernicke-Korsakoff syndrome is sometimes seen in patients with a vitamin B1 level of more than 24 ng/ml [ 22 ]. Based on these considerations, the range of vitamin B1 deficiency and the borderline we used seem reasonable. The present study also showed that vitamin B1 significantly decreased after the course of chemotherapy in both patients with and without persistent delayed CINV. However, the level of vitamin B1 after chemotherapy decreased more in patients with persistent delayed CINV than in those without persistent delayed CINV, and the amount of the decrease was greater in those with persistent delayed CINV. The results of the present study show a substantial vitamin B1 shortage in patients with persistent delayed CINV following chemotherapy. This would explain why a considerable number of patients suffering from persistent delayed CINV could benefit from vitamin B1 therapy. Chemotherapy-related delayed or breakthrough nausea and vomiting are difficult to manage, especially in children. Moreover, there is little evidence to support the use of additional anti-emetic agents for children with delayed or breakthrough CINV. Drug options include aprepitant, palonosetron, olanzapine and metoclopramide, but the use of these medications is of concern due to potential interactions with chemotherapy agents and possible side effects. Thus, a careful risk-versus-benefit assessment is required when considering these medications. Consequently, other pharmacological or non-pharmacological methods to treat delayed or refractory CINV are needed [ 18 , 23 , 24 ]. Vitamin B1 therapy is a cost-effective and harmless method for treating delayed and refractory CINV and can be safely used in pediatric patients. Therefore, in view of the present results, vitamin B1 infusion can be considered effective for both preventing and treating this condition. However, few studies have explored the possibility of using vitamin B1 for the treatment of delayed CINV or investigated the incidence of vitamin B1 deficiency among pediatric patients undergoing chemotherapy for a malignant disease. Furthermore, there is no information about vitamin B1 in the National Comprehensive Cancer Network (NCCN) guidelines for CINV. Thus, our study would add new insight into the management of delayed or refractory CINV. In the present study, vitamin B1 was administered to patients whose CINV continued for more than five days after chemotherapy. Delayed CINV is generally defined as lasting five days, and it is known that delayed CINV is mediated by substance P and the NK1 receptor [ 25 , 26 ]. However, the mechanisms underlying CINV that persists for more than five days have yet to be elucidated. The evaluation of other etiologies of persistent CINV, including electrolyte abnormalities, diseases related to the brain or gastrointestinal tract and other comorbidities should be considered. Vitamin B1 deficiency is one explanation for persistent nausea and vomiting after chemotherapy. According to several studies, vitamin B1 deficiency results in an imbalance of neurotransmitters and an increase of oxidative and inflammatory stress to nerve cells [ 27 – 29 ]. These conditions could affect the prolongation of CINV symptoms. Nutritional counseling for patients with breast cancer has been found to help alleviate nausea and vomiting. In a previous study, the recommended carbohydrate consists mainly of whole grains, which are rich in vitamin B1 [ 30 ]. The results of the present study are consistent with this recommendation. Similarly, the sub-analysis in the present study revealed that the level of vitamin B1 decreased more in female patients than in male patients. Moreover, several studies have reported that female patients develop CINV more often than males [ 31 – 33 ]. Thus, a lack of vitamin B1 could underlie these findings. Consequently, dietary interventions that provide sufficient vitamin B1 as well as a vitamin B1 supplement for patients with cancer, especially female patients, are considered important to prevent nausea and vomiting during cancer chemotherapy. The results of this study should be considered in light of some limitations. First, this study was limited by the chemotherapy cycle-based analysis. The analyzed courses were derived from the same patients, and the enrolled patients typically underwent four or five chemotherapy courses. This could have affected the results of the present analyses. Additionally, although there are several methods for evaluating vitamin B1 deficiency, the present study only assessed serum levels of vitamin B1. Other methods, such as evaluating erythrocyte transketolase activity and thiamin pyrophosphate, might be superior to the serum level of vitamin B1 for detecting thiamin deficiency. [ 6 ] However, as these tests are not readily available and are difficult to implement, serum vitamin B1 is considered suitable for clinical settings. Finally, a complex vitamin formulation was used for the majority of patients in the present study. Several reports have shown the efficacy of vitamin B6 for nausea and vomiting in pregnant women [ 34 ]. A previous study has also shown that acupuncture combined with vitamin B6 therapy can reduce the incidence of CINV [ 35 ]. However, the pure vitamin B1 medication used in this study demonstrated the same response rate as the complex vitamin infusion. In conclusion, patients with malignant diseases who experience persistent nausea and vomiting after chemotherapy often have vitamin B1 deficiency, and vitamin B1 therapy may be beneficial for many of these patients. Declarations Author contributions Ryoji Kobayashi : Conceptualization and study design, writing-review and editing. Satoru Matsushima : Date collection, study design, manuscript writing. Hirozumi Sano : Analyzed and clinical data collection, supervision. Masato Yanagi : Analyzed and clinical data collection. Daiki Hori : Analyzed and clinical data collection. Daisuke Suzuki : Analyzed and clinical data collection. Date availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Consent to Participate Written informed consent was obtained from all individual participants included in this study. Ethical approval This study was approved by the Institutional Review Board (IRB) of Sapporo Hokuyu Hospital and was performed in line with the principles of the Declaration of Helsinki. Competing statement The authors declare no competing interests. Conflict of interest statement The authors have no conflicts of interest to declare. Acknowledgment The authors did not receive support from any organization for the submitted work. No funding was received for conducting this study. References Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020;105(11):2524–2539. doi: 10.3324/haematol.2020.247031 . PMID: 33054110 Burke TA, Wisniewski T, Ernst FR. 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Cancer Sci. 2013;104(6):711–717. doi: 10.1111/cas.12146 . McParlin C, O'Donnell A, Robson SC, Beyer F, Moloney E, Bryant A, Bradley J, Muirhead CR, Nelson-Piercy C, Newbury-Birch D, Norman J, Shaw C, Simpson E, Swallow B, Yates L, Vale L. Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review. JAMA. 2016;316(13):1392–1401. doi: 10.1001/jama.2016.14337 . You Q, Yu H, Wu D, Zhang Y, Zheng J, Peng C. Vitamin B6 points PC6 injection during acupuncture can relieve nausea and vomiting in patients with ovarian cancer. Int J Gynecol Cancer. 2009;19(4):567–71. doi: 10.1111/IGC.0b013e31819d8b48 . Tables Table 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Table4.docx FigS1.pptx TableS1.docx TableS2.docx TableS3.docx Figurelegends.docx Cite Share Download PDF Status: Posted 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-4250292","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":292443655,"identity":"1f27d472-8f5a-4ed1-abc3-0f09dc813406","order_by":0,"name":"Satoru 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ryoji","middleName":"","lastName":"Kobayashi","suffix":""}],"badges":[],"createdAt":"2024-04-11 05:14:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4250292/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4250292/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55325928,"identity":"e29995a1-6317-41ac-a6a9-049af9d87cd6","added_by":"auto","created_at":"2024-04-25 17:05:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":48188,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of serum level of vitamin B1 before and after chemotherapy in patients with persistent delayed CINV\u003c/p\u003e","description":"","filename":"Fig16.png","url":"https://assets-eu.researchsquare.com/files/rs-4250292/v1/ae4278318ec002bb6bdbcede.png"},{"id":55325399,"identity":"8609c143-a2b0-4e1c-9c91-4869c7697e59","added_by":"auto","created_at":"2024-04-25 16:57:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":22857,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of serum level of vitamin B1 after chemotherapy between patients with\u003c/p\u003e\n\u003cp\u003eand without persistent delayed CINV\u003c/p\u003e","description":"","filename":"Fig24.png","url":"https://assets-eu.researchsquare.com/files/rs-4250292/v1/e8fbfe860c5a215de91022ef.png"},{"id":61109213,"identity":"446d86b2-6550-42e3-bc28-ee25b3ed57d1","added_by":"auto","created_at":"2024-07-25 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17:05:34","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":23134,"visible":true,"origin":"","legend":"","description":"","filename":"TableS3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4250292/v1/00380dae8b09d684f7de1bd1.docx"},{"id":55325404,"identity":"8e509afc-68f0-498e-8e8b-ff94bc489233","added_by":"auto","created_at":"2024-04-25 16:57:34","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":13828,"visible":true,"origin":"","legend":"","description":"","filename":"Figurelegends.docx","url":"https://assets-eu.researchsquare.com/files/rs-4250292/v1/1bc55f7c74f6270abc8e1856.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of vitamin B1 in alleviating chemotherapy-induced nausea and vomiting","fulltext":[{"header":"Introduction","content":"\u003cp\u003eClinical outcomes for malignant tumors in children, and adolescents and young adults (AYAs) have progressed due to the development of treatment strategies and adaptation of medications with new mechanisms of action [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. On the other hand, therapy-related complications continue to be an issue. Chemotherapy-induced nausea and vomiting (CINV) is one of the most common adverse effects that affect the quality of life of patients and demand considerable medical resources [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Recently, several antiemetic agents have become available, and several studies focusing on CINV have been conducted [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, methods to prevent and manage breakthrough or refractory CINV have not yet been established.\u003c/p\u003e \u003cp\u003eVitamin B1, also known as thiamin, is a water-soluble vitamin that is essential for several physiological functions. One important function is its contribution to cellular energy metabolism as a cofactor in the pentose phosphate pathway, glycolysis and Krebs cycles. Vitamin B1 also helps in the synthesis of nucleic acids, neurotransmitters and myelin, thereby protecting nerve cell functions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The body can only store a small amount of vitamin B1, and the half-life of thiamin in blood is short. Thus, vitamin B1 deficiency is likely to occur if ongoing dietary intake is disrupted [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The most common organs susceptible to a lack of vitamin B1 are brain tissue and cardiac muscle, which constantly consume a high level of glucose. The symptoms of a lack of glucose in these organs include ataxia, nystagmus, peripheral neuropathy (dry beriberi), tachycardia, edema and heart failure (wet beriberi) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The most severe manifestation is Wernicke-Korsakoff syndrome, which is characterized by encephalopathy, seizure and amnesia. Wernicke-Korsakoff syndrome has been reported in several patients who have undergone cancer chemotherapy [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, these manifestations could have been caused by other medical conditions. Furthermore, the early symptoms of vitamin B1 deficiency, such as fatigue, anorexia, nausea and vomiting, are not specific presentations in patients with a malignant disease. Consequently, vitamin B1 deficiency is likely to be overlooked, although it occurs more often among hospitalized patients [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt our institution, serum level of vitamin B1 is evaluated in children and AYAs with a malignant disease who are suffering from delayed recovery from CINV, and thiamin administration is implemented before diagnosis of vitamin B1 deficiency. Some of these patients experience improvement of their symptoms within hours or days of vitamin B1 infusion. However, little attention has been paid to vitamin B1 as a potential treatment option for patients with persistent CINV. Therefore, the present study aimed to verify the efficacy of vitamin B1 for delayed or refractory CINV.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Population and Study Design\u003c/h2\u003e \u003cp\u003eThis study prospectively evaluated the serum level of vitamin B1 at diagnosis of persistent delayed CINV as well as the response to vitamin B1 infusion. The patient population of this study was children (\u0026lt;\u0026thinsp;15 years of age) and AYAs (\u0026ge;\u0026thinsp;15 years of age) with a malignant disease who underwent chemotherapy at the Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, from March 2022 to September 2023. Analyses were conducted based on all data obtained up to October 2023. The conditioning regimens for hematopoietic cell transplantation were not analyzed in this study. The treatment courses for blinatumomab or all-trans retinoic acid monotherapy, and dasatinib plus predonisolone were also excluded from the analysis. Moreover, several patients who received total parenteral nutrition due to continual inadequate oral intake were not included, as the administered formula contains a small amount of vitamin B1.\u003c/p\u003e \u003cp\u003eIn general, vitamin B1 is administered to patients experiencing nausea and vomiting that persists for more than five days after the end of chemotherapy, which is the period that defines persistent delayed CINV, and when a differential diagnosis other than CINV is not considered [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].However, the actual timing of the application of vitamin B1 therapy depends on the clinical situation, and the duration of the therapy can range from three to seven days.\u003c/p\u003e \u003cp\u003eThe antiemetic agent used in the present study was the parenteral 5-HT3 antagonist ondansetron, which was used on the day of chemotherapy every 12 hours and within 24 hours after chemotherapy. Antihistamines are also occasionally used for symptom amelioration. However, no other 5-HT3 antagonists or neurokinin-1 (NK1) receptor antagonists were adopted in this study. Furthermore, other agents used for treating CINV, such as metoclopramide and olanzapine, as well as other non-pharmacological therapies, were not considered in this study.\u003c/p\u003e \u003cp\u003eThe thiamin status in the enrolled patients was assessed by measurement of the serum level of vitamin B1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used as the method for serum vitamin B1 analysis. The serum level of vitamin B1 was evaluated in all patients before and one week after chemotherapy implementation. If the chemotherapy regimen consisted of several weeks, vitamin B1 was assessed two weeks after the first measurement. The lowest value after chemotherapy was selected for conducting the analysis. Vitamin B1 status was also evaluated before vitamin B1 infusion in patients with persistent delayed CINV. For the vitamin B1 preparation, a vitamin B complex (Vitamedin\u0026reg;ฎ; Alfresa Pharma Corporation, Osaka, Japan) containing vitamins B1, B6 and B12 was used to treat persistent delayed CINV, with a vitamin B1 content of 107 mg. However, a pure vitamin B1 drug (Alinamin\u0026reg;ฎ; Takeda Pharmaceutical Company, Tokyo, Japan), which contains 100 mg of vitamin B1, was used after January 2022. Vitamin B1 deficiency was defined as a serum level of vitamin B1\u0026thinsp;\u0026lt;\u0026thinsp;24 ng/ml, according to the reference range of the clinical laboratory testing company that examined the samples from the enrolled patients. Vitamin B1 levels\u0026thinsp;\u0026gt;\u0026thinsp;30 ng/ml were defined as non-thiamin deficiency. Levels between 24 and 30 ng/ml were regarded as borderline.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions of Nausea or Vomiting\u003c/h2\u003e \u003cp\u003eThe symptoms of nausea or vomiting were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Nausea was evaluated according to the following modified scale: adverse event Grade I, oral intake of less than one-half of the ordinary amount; Grade II, oral intake of less than one-third of the ordinary amount and Grade III, little or no oral intake. Vomiting was evaluated according to the CTCAE criteria as follows: Grade I, 1\u0026ndash;2 episodes in 24 hours; Grade II, 3\u0026ndash;5 episodes in 24 hours; Grade III, more than 5 episodes in 24 hours, or tube feeding or total parenteral nutrition. The grades of nausea and vomiting were prospectively evaluated using the medical charts of the enrolled patients.\u003c/p\u003e \u003cp\u003eThe response to vitamin B1 therapy was determined based on improvement in the grade of nausea or vomiting in the following three days. Specifically, a complete response (CR) signified no symptoms of nausea and vomiting; a partial response (PR) meant improvement of any grade of nausea or vomiting; a stable disease (SD) indicated no improvement in symptoms; and a progressive disease (PD) indicated a worsening of symptoms. Using these definitions, the response rates on days 1 through 3 were evaluated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy Outcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome of this study was the determination of the response rate of vitamin B1 therapy in patients with persistent delayed CINV for three days after starting the infusion, and whether vitamin B1 deficiency existed in those patients. Additionally, the serum level of vitamin B1 before and after chemotherapy was compared in both patients with and without CINV. Furthermore, the vitamin B1 serum level was compared between patients with and without CINV both before and after chemotherapy. The amount of change in the vitamin B1 level was also compared between patients with and without CINV. This analysis was limited to patients with a thiamin level\u0026thinsp;\u0026gt;\u0026thinsp;29.9 ng/ml so that the vitamin B1 level before chemotherapy would be the same in the two groups. It is likely that patients with higher vitamin B1 levels experienced a greater decrease in the serum level of vitamin B1. The other sub-analyses of this study consisted of a comparison of the levels of vitamin B1 between children and AYAs, between males and females and between patients with hematologic tumors and those with solid tumors. Furthermore, whether the level of vitamin B1 before chemotherapy contributes to the development of persistent delayed CINV was investigated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe categorical variables of the baseline characteristics of the chemotherapy courses were compared using Fisher\u0026rsquo;s exact test. The continuous variable of the serum levels of vitamin B1 in the same subjects was compared before and after chemotherapy using the Wilcoxon signed-rank test. The continuous variable of the serum level of vitamin B1 was compared between the groups with or without CINV using the Mann-Whitney U test. To investigate the association between the level of vitamin B1 before chemotherapy and the incidence of persistent delayed CINV, the optimal cut-off value of the level of vitamin B1 was calculated using the receiver operating characteristic (ROC) curve. The point on the ROC curve with a minimum distance from the left upper corner of the unit square was adopted. The patients were then divided into two groups based on the obtained cut-off value, and the incidence of persistent delayed CINV was compared. A \u003cem\u003ep-\u003c/em\u003evalue of 0.05 or less was considered statistically significant. All statistical analyses were performed with EZR, a graphical user interface for R (The R Foundation for Statistical Computing) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eIn total, 86 patients were included in the study, and 408 chemotherapy episodes were analyzed. The median age of the enrolled patients was 10.7 years (range, 0.2\u0026ndash;25.2 years), and most had hematologic malignant disease. The patients\u0026rsquo; characteristics are detailed in Table\u0026nbsp;1. Among all the enrolled patients, the median level of vitamin B1 before chemotherapy was 38.5 ng/ml, and the median of the lowest value after chemotherapy was 29.0 ng/ml.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eResponse to vitamin B1 infusion\u003c/h2\u003e \u003cp\u003eForty-four (10.8%) episodes of persistent delayed CINV were diagnosed in 26 of the enrolled patients. The median time of the diagnosis after chemotherapy was five days. Vitamedin was administered in 29 (66.0%) episodes, and Alinamin was used in the other 15 (34.0%) episodes.\u003c/p\u003e \u003cp\u003eAt day 1, the overall response rate (ORR) was 68.2%; 9 (20.5%) patients achieved CR and 21 (47.7%) patients achieved PR. The ORR at day 2 was 81.8%; 11 (25.0%) patients achieved CR and 25 (56.8%) patients achieved PR. At day 3, the ORR was 79.5%; 21 (47.7%) patients achieved CR and 14 (31.8%) patients achieved PR. Additionally, six (13.6%) patients experienced improvement in their symptoms within several hours. Furthermore, the response rate for Alinamin was the same as that for Vitamedin (Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eInvestigation of vitamin B1 deficiency\u003c/h2\u003e \u003cp\u003eThe median vitamin B1 level at diagnosis of CINV was significantly lower than the value before chemotherapy (22.8 ng/ml, range 11.9\u0026ndash;49.2 vs. 32.7 ng/ml, range 11.2\u0026thinsp;\u0026minus;\u0026thinsp;80.1, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Moreover, the median vitamin B1 level after chemotherapy was significantly lower in patients with persistent delayed CINV than in those without persistent delayed CINV (22.5 ng/ml, range 10.7\u0026thinsp;\u0026minus;\u0026thinsp;49.2 vs. 30.0 ng/ml, range 12.3\u0026thinsp;\u0026minus;\u0026thinsp;95.1, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition, the median thiamin level at diagnosis of CINV fulfilled the definition of vitamin B1 deficiency. Among the patients who were administered vitamin B1 therapy, 24 (54.5%) had vitamin B1 deficiency, 13 (29.6%) were borderline and 7 (15.9%) had no vitamin B1 deficiency (Table\u0026nbsp;3). A comparison of background information for patients with and without persistent delayed CINV is available in Table\u0026nbsp;4.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComplementary analysis: comparison of serum vitamin B1 level\u003c/h2\u003e \u003cp\u003eThe median vitamin Bl level before chemotherapy in patients with persistent delayed CINV was also significantly lower than in those without persistent delayed CINV (32.7 ng/ml, range 11.2\u0026thinsp;\u0026minus;\u0026thinsp;80.1 vs. 38.7 ng/ml, range 17.4\u0026thinsp;\u0026minus;\u0026thinsp;94.8, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018) (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Furthermore, the patients without refractory CINV also experienced a decrease in their levels of vitamin B1 after chemotherapy (30.0 ng/ml, range 12.3\u0026ndash;95.1 vs. 38.7 ng/ml, range 17.4\u0026thinsp;\u0026minus;\u0026thinsp;94.8, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, the median vitamin B1 levels were above the upper limit for thiamin deficiency.\u003c/p\u003e \u003cp\u003eFor the level of decrease in the serum level of vitamin B1 before and after chemotherapy, it was significantly greater in the patients with persistent delayed CINV than in those without persistent delayed CINV (-14.7, range \u0026minus;\u0026thinsp;63.0\u0026ndash;6.3, vs. -9.3, range \u0026minus;\u0026thinsp;67.2\u0026thinsp;\u0026minus;\u0026thinsp;37.8, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). The median vitamin B1 level before chemotherapy was the same between the groups (39.2 ng/ml, range 30.2\u0026ndash;80.1 vs. 41.2 ng/ml, range 30.0\u0026thinsp;\u0026minus;\u0026thinsp;94.8, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.634). These results are shown in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe results of the sub-group analyses are shown in Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e. The level of vitamin B1 both before and after chemotherapy was significantly lower in female patients than in male patients. Furthermore, the patients whose vitamin B1 levels before chemotherapy were below 31.8 ng/ml, which was the optimal cut-off value generated in this study (AUC, 0.609, 95% CI, 0.508-0.711), more often developed persistent delayed CINV (20.0% vs. 7.6%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study prospectively investigated the efficacy of vitamin B1 in the treatment of persistent delayed CINV. Ten percent of the enrolled patients were diagnosed with persistent delayed CINV; of these, about 80% experienced relief of their symptoms, and 48% were completely free from nausea and vomiting within three days. Several patients even recovered from their symptoms within several hours. The present results suggest that patients with persistent delayed CINV are considerably more likely to have vitamin B1 deficiency. In fact, more than 80% of the patients in the present study had an insufficient level of vitamin B1. In contrast, patients without persistent delayed CINV were less likely to have an insufficient level of vitamin B1 (43%). As there is no established value as an indicator of actual vitamin B1 deficiency, the definition of vitamin B1 deficiency used in the present study was derived from a 95% confidential interval of the nonparametric test in healthy adults. According to a previous study, Wernicke-Korsakoff syndrome is sometimes seen in patients with a vitamin B1 level of more than 24 ng/ml [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Based on these considerations, the range of vitamin B1 deficiency and the borderline we used seem reasonable.\u003c/p\u003e \u003cp\u003eThe present study also showed that vitamin B1 significantly decreased after the course of chemotherapy in both patients with and without persistent delayed CINV. However, the level of vitamin B1 after chemotherapy decreased more in patients with persistent delayed CINV than in those without persistent delayed CINV, and the amount of the decrease was greater in those with persistent delayed CINV. The results of the present study show a substantial vitamin B1 shortage in patients with persistent delayed CINV following chemotherapy. This would explain why a considerable number of patients suffering from persistent delayed CINV could benefit from vitamin B1 therapy.\u003c/p\u003e \u003cp\u003eChemotherapy-related delayed or breakthrough nausea and vomiting are difficult to manage, especially in children. Moreover, there is little evidence to support the use of additional anti-emetic agents for children with delayed or breakthrough CINV. Drug options include aprepitant, palonosetron, olanzapine and metoclopramide, but the use of these medications is of concern due to potential interactions with chemotherapy agents and possible side effects. Thus, a careful risk-versus-benefit assessment is required when considering these medications. Consequently, other pharmacological or non-pharmacological methods to treat delayed or refractory CINV are needed [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVitamin B1 therapy is a cost-effective and harmless method for treating delayed and refractory CINV and can be safely used in pediatric patients. Therefore, in view of the present results, vitamin B1 infusion can be considered effective for both preventing and treating this condition. However, few studies have explored the possibility of using vitamin B1 for the treatment of delayed CINV or investigated the incidence of vitamin B1 deficiency among pediatric patients undergoing chemotherapy for a malignant disease. Furthermore, there is no information about vitamin B1 in the National Comprehensive Cancer Network (NCCN) guidelines for CINV. Thus, our study would add new insight into the management of delayed or refractory CINV.\u003c/p\u003e \u003cp\u003eIn the present study, vitamin B1 was administered to patients whose CINV continued for more than five days after chemotherapy. Delayed CINV is generally defined as lasting five days, and it is known that delayed CINV is mediated by substance P and the NK1 receptor [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, the mechanisms underlying CINV that persists for more than five days have yet to be elucidated. The evaluation of other etiologies of persistent CINV, including electrolyte abnormalities, diseases related to the brain or gastrointestinal tract and other comorbidities should be considered. Vitamin B1 deficiency is one explanation for persistent nausea and vomiting after chemotherapy. According to several studies, vitamin B1 deficiency results in an imbalance of neurotransmitters and an increase of oxidative and inflammatory stress to nerve cells [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. These conditions could affect the prolongation of CINV symptoms. Nutritional counseling for patients with breast cancer has been found to help alleviate nausea and vomiting. In a previous study, the recommended carbohydrate consists mainly of whole grains, which are rich in vitamin B1 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The results of the present study are consistent with this recommendation. Similarly, the sub-analysis in the present study revealed that the level of vitamin B1 decreased more in female patients than in male patients. Moreover, several studies have reported that female patients develop CINV more often than males [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Thus, a lack of vitamin B1 could underlie these findings. Consequently, dietary interventions that provide sufficient vitamin B1 as well as a vitamin B1 supplement for patients with cancer, especially female patients, are considered important to prevent nausea and vomiting during cancer chemotherapy.\u003c/p\u003e \u003cp\u003eThe results of this study should be considered in light of some limitations. First, this study was limited by the chemotherapy cycle-based analysis. The analyzed courses were derived from the same patients, and the enrolled patients typically underwent four or five chemotherapy courses. This could have affected the results of the present analyses. Additionally, although there are several methods for evaluating vitamin B1 deficiency, the present study only assessed serum levels of vitamin B1. Other methods, such as evaluating erythrocyte transketolase activity and thiamin pyrophosphate, might be superior to the serum level of vitamin B1 for detecting thiamin deficiency. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] However, as these tests are not readily available and are difficult to implement, serum vitamin B1 is considered suitable for clinical settings. Finally, a complex vitamin formulation was used for the majority of patients in the present study. Several reports have shown the efficacy of vitamin B6 for nausea and vomiting in pregnant women [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. A previous study has also shown that acupuncture combined with vitamin B6 therapy can reduce the incidence of CINV [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, the pure vitamin B1 medication used in this study demonstrated the same response rate as the complex vitamin infusion.\u003c/p\u003e \u003cp\u003eIn conclusion, patients with malignant diseases who experience persistent nausea and vomiting after chemotherapy often have vitamin B1 deficiency, and vitamin B1 therapy may be beneficial for many of these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRyoji Kobayashi\u003c/strong\u003e: Conceptualization and study design, writing-review and editing. \u003cstrong\u003eSatoru Matsushima\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Date collection, study design, manuscript writing. \u003cstrong\u003eHirozumi Sano\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Analyzed and clinical data collection, supervision. \u003cstrong\u003eMasato Yanagi\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Analyzed and clinical data collection.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eDaiki Hori\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Analyzed and clinical data collection. \u003cstrong\u003eDaisuke Suzuki\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Analyzed and clinical data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDate availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from all individual participants included in this study. \u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003eThis study was approved by the Institutional Review Board (IRB) of Sapporo Hokuyu Hospital and was performed in line with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting statement\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted work. 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Int J Gynecol Cancer. 2009;19(4):567\u0026ndash;71. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/IGC.0b013e31819d8b48\u003c/span\u003e\u003cspan address=\"10.1111/IGC.0b013e31819d8b48\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 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":false,"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":"Vitamin B1 deficiency, thiamin deficiency, chemotherapy-induced nausea and vomiting, children, adolescents and young adults","lastPublishedDoi":"10.21203/rs.3.rs-4250292/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4250292/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe management of chemotherapy-induced nausea and vomiting (CINV) is of primary concern for both patients with cancer and medical workers. Refractory or breakthrough CINV is especially difficult to deal with and necessitates a different approach. Vitamin B1 deficiency is likely to occur during cancer chemotherapy, with early symptoms of fatigue, anorexia, nausea and vomiting. The efficacy of vitamin B1 for the treatment of delayed or refractory CINV should be confirmed.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSerum vitamin B1 level was prospectively measured in patients experiencing persistent nausea and vomiting after chemotherapy. The response to vitamin B1 therapy was evaluated for three consecutive days after vitamin B1 infusion. Moreover, serum level of vitamin B1 at diagnosis of persistent delayed CINV was compared with the level before chemotherapy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 408 courses of chemotherapy in 86 patients were analyzed. The median age at hospital admission of the enrolled patients was 10.7 years (0.2\u0026ndash;25.2). Among these, 44 (10.8%) episodes of persistent delayed CINV were identified in 26 of the enrolled patients. At day 3, the overall response rate was 79.5%; 21 (47.7%) patients achieved a complete response and 14 (31.8%) patients achieved a partial response. The median vitamin B1 level at diagnosis of CINV was significantly lower than the value before chemotherapy (22.8, range 11.9\u0026ndash;49.2 vs. 32.7, range 11.2\u0026thinsp;\u0026minus;\u0026thinsp;80.1, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePatients with a malignant disease who experience persistent nausea and vomiting after chemotherapy often exhibit vitamin B1 deficiency. Vitamin B1 infusion may be beneficial for many of these patients.\u003c/p\u003e","manuscriptTitle":"Efficacy of vitamin B1 in alleviating chemotherapy-induced nausea and vomiting","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-25 16:57:29","doi":"10.21203/rs.3.rs-4250292/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":"8f3ef749-3932-473a-a1a3-bff183570b7f","owner":[],"postedDate":"April 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-15T06:07:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-25 16:57:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4250292","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4250292","identity":"rs-4250292","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}