{"paper_id":"1561cdeb-1e51-4175-bac5-8b5d0c276f4c","body_text":"Adjuvant S-1 Plus Metformin after Pancreatic Cancer Resection: A Multicenter Randomized Phase II Trial | 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 Adjuvant S-1 Plus Metformin after Pancreatic Cancer Resection: A Multicenter Randomized Phase II Trial Masayuki Furukawa, Masato Narita, Ichiro Sakamoto, Yutaka Itoh, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9445035/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Six months of adjuvant S-1 is the standard treatment for resected pancreatic cancer in Japan. Metformin has demonstrated potential anticancer effects in preclinical and observational studies. This study aimed to evaluate whether adding metformin to S-1 improves 2-year survival after pancreatic cancer resection. Methods This multicenter, randomized, open-label Phase II trial enrolled patients with histologically confirmed Stage I–II invasive pancreatic ductal carcinoma who underwent curative resection. Patients were randomized to receive S-1 plus metformin (Group A) or S-1 alone (Group B). S-1 was administered for 6 months in both groups, and metformin for 2 years in Group A. The primary endpoint was 2-year overall survival; secondary endpoints were recurrence-free survival and safety. The sample size was calculated assuming a 2-year survival rate of 65% with S-1 alone and 78% with S-1 plus metformin (hazard ratio: 0.58), providing 80% power with a one-sided α of 0.20. Glycemia-related safety was monitored using Common Terminology Criteria for Adverse Events-defined hyperglycemia and hypoglycemia. Results Seventy-six patients were randomized (38 per group). The 2-year survival rate was 66.7% in Group A and 66.1% in Group B (hazard ratio 1.09; 95% confidence interval 0.55–2.16; p = 0.93). Median overall survival was 53.8 versus 58.0 months, and median recurrence-free survival was 17.9 versus 12.6 months ( p = 0.78). No grade ≥ 4 adverse events occurred; Grade 3 toxicities were infrequent and comparable between groups. Conclusions Adding metformin to adjuvant S-1 did not improve survival in patients with resected pancreatic cancer. Pancreatic cancer adjuvant chemotherapy S-1 metformin Figures Figure 1 Figure 2 Figure 3 Introduction Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with poor long-term survival even after curative resection [ 1 ]. Although only a minority of patients present with resectable disease, recurrence within two years is common [ 2 ]. Adjuvant chemotherapy has demonstrated clear benefits, with ESPAC 1 and CONKO 001 establishing 5-fluorouracil and gemcitabine as effective therapies [ 3 , 4 ]. The JASPAC01 study further showed the superiority of S-1 over gemcitabine, making S-1 the standard adjuvant treatment in Japan [ 5 ]. Metformin, widely used for type 2 diabetes, has been proposed to exert anticancer effects through AMPK activation and downstream mTOR inhibition [ 6 ]. Observational data suggest reduced cancer incidence among metformin users [ 7 ], but prospective trials in advanced PDAC have not shown clinical benefit [ 8 ], and its role after curative resection remains unknown. Because metformin does not cause hypoglycemia when used as monotherapy [ 9 ], any antitumor benefit could extend to patients without diabetes. Standard adjuvant S-1 is administered in a 4-week on/2-week off schedule; however, adherence can be challenging [ 5 , 10 ]. A shorter 2-week on/1-week off regimen has been developed to improve tolerability while maintaining efficacy, supported by evidence that S-1–related toxicities commonly arise during week three [ 11 ]. This modified schedule was selected to facilitate combination treatment with metformin. Given the exploratory nature and feasibility constraints, a randomized Phase II design was chosen to detect a potential survival signal, using 2-year overall survival as an early indicator of treatment effect in resected PDAC, where recurrence and death commonly occur within this timeframe. Accordingly, this study was not powered to demonstrate a definitive survival benefit but was intended to provide preliminary data to inform the feasibility and rationale for future confirmatory trials. Patients and Methods Study design This was a multicenter, open-label, randomized Phase II trial designed to compare adjuvant chemotherapy with 6 months of S-1 alone versus 6 months of S-1 combined with 2 years of metformin in patients who had undergone pancreatic cancer resection. Participants Eligible patients had histologically confirmed PDAC according to the General Rules for the Study of Pancreatic Cancer [ 12 ]; pathological Stage I–III per the TNM Classification of Malignant Tumors [ 13 ]; no macroscopic residual tumor (R0) or only microscopic residual tumor (R1); and negative intraoperative peritoneal lavage cytology. Additional inclusion criteria were age ≥ 20 years; Eastern Cooperative Oncology Group performance status of 0 or 1 [ 14 ]; no prior chemotherapy or radiotherapy within 3 years; enrollment within 12 weeks after surgery; and adequate bone marrow, liver, and kidney function within 14 days before registration (leucocytes 3000–12,000/mm 3 ; platelets ≥ 100,000/mm 3 ; hemoglobin ≥ 8.0 g/dL; total bilirubin ≤ 2.0 mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 100 IU/L; and serum creatinine ≤ 1.2 mg/dL). Written informed consent was required. Patients with abnormal glucose tolerance before or within 12 weeks post-surgery were included. Abnormal glucose tolerance was defined as fasting blood glucose ≥ 126 mg/dL, random blood glucose ≥ 200 mg/dL, diabetes-type results on a 75 g oral glucose tolerance test, hemoglobin A1c (HbA1c; National Glycohemoglobin Standardization Program ≥ 6.5%, or Japan Diabetes Society ≥ 6.1%), or a clinical diagnosis of diabetes by the principal investigator. Exclusion criteria included prior use of S-1, metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, or glucagon-like peptide agonists, anticancer therapy within the past year, evidence of recurrence or active secondary malignancy (except early-stage cancers treated curatively); significant organ dysfunction (New York Heart Association Class III–IV heart failure, recent myocardial infarction, renal or hepatic impairment, pulmonary fibrosis, or severe metabolic disorders), conditions increasing the risk of hypoxemia or severe infection, pregnancy, breastfeeding, or plans to conceive, concurrent use of flucytosine, phenytoin, or warfarin, and any other condition deemed unsuitable by the investigator. Randomization Patients were initially enrolled and screened for eligibility. Those meeting all inclusion and exclusion criteria were formally registered in the study database. Randomization was performed only after registration using a modified minimization method to balance prespecified stratification factors. For clarity, \"enrollment\" refers to entry into screening, \"registration\" to confirmation of eligibility and inclusion in the database, and “randomization” to assignment to the treatment groups. Participants were allocated 1:1 to Group A (6 months of S-1 plus 2 years of metformin) or Group B (6 months of S-1 alone). Randomization was centralized using a modified minimization method adjusted for residual tumor status (R0 vs . R1), lymph node status (N0 vs . N1), and trial site. Investigators and patients were aware of the assigned treatments. Procedure In both Groups A and B, patients received oral S-1 at doses based on body surface area (BSA): BSA < 1.25 m 2 , 40 mg, BSA 1.25 < 1.5 m 2 : 50 mg, and BSA ≥ 1.5 m 2 : 60 mg. S-1 was administered twice daily for 2 weeks, followed by a 1-week break (1 cycle). From the second cycle onward, administration continued for 2 weeks with a 1-week break, adjusted as needed for toxicity. This regimen was repeated over a 6-month period. In Group A, metformin was initiated at 500 mg/day for the first 3 weeks, increased to 750 mg/day from the fourth week onward, and continued for up to 2 years. If hyperglycemia was not adequately controlled with metformin alone, additional antidiabetic medications (e.g., insulin, sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors) were permitted. To start each S-1 cycle, patients had to meet the following criteria: white blood cell count ≥ 3000/mm 3 , neutrophil count ≥ 1500/mm 3 , platelet count ≥ 100,000/mm 3 , hemoglobin ≥ 6.5 g/dL, absence of fever ≥ 38°C, serum creatinine ≤ 1.5 mg/dL, AST ≤ 150 IU/L, and ALT ≤ 150 IU/L. No other nonhematological adverse events (AEs) of Grade 2 or higher were permitted. In addition to the criteria for interrupting and restarting S-1 at each cycle, S-1 was discontinued during a cycle if the following AEs occurred: white blood cell count ≤ 1000/mm 3 , platelet count ≤ 50,000/mm 3 , fever ≥ 38°C, serum creatinine exceeding institutional limit, or Grade ≥ 2 nonhematological AEs. After discontinuation, the S-1 daily dose was reduced for the next cycle according to BSA (120 → 100 mg/day, 100 → 80 mg/day, or 80 → 50 mg/day) based on BSA. During treatment, subjective and objective symptoms and blood chemistry ​​were assessed every 3 weeks, tumor markers every 6 weeks, and abdominal computed tomography or magnetic resonance imaging every 3 months. After completion of the protocol treatment, tumor markers were measured every 3 months, and computed tomography or magnetic resonance imaging was performed every 3 months for the first 2 years and then every 6 months thereafter. Folate and vitamin B12 levels were assessed every 6 months. Evaluation methods The primary endpoint was 2-year OS, defined as the time from randomization to death from any cause. Secondary endpoints included recurrence-free survival (RFS) and incidence of AEs. RFS was defined as the time from enrollment to disease recurrence or death from any cause. AEs were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) [ 15 ]. Statistical analysis The JASPAC 01 trial demonstrated a 2-year survival rate of 70% with S-1 therapy. However, because most participating institutions were high-volume centers performing more than 20 pancreatic resections per year, and because the majority of cases were R0 or N0, case selection bias was likely. Accordingly, the 2-year survival rate for the S-1 adjuvant chemotherapy group after pancreatic cancer surgery was conservatively estimated at 65%. Assuming a 13% absolute improvement in survival over the 65% observed with S-1 monotherapy, the S-1 plus metformin combination group was expected to achieve a 2-year survival rate of 78%. Assuming an exponential survival distribution, this corresponds to a hazard ratio (HR) of 0.58. Using a log-rank test with a two-sided significance level of 20% and a statistical power of 80%, 61 events were required. Assuming a 3-year enrollment period, a 2-year follow-up period, no loss to follow-up, and a constant accrual rate, approximately 73 patients per group were required to achieve this number of events. Allowing for potential dropouts after enrollment, the target sample size was set at 80 patients per group, for a total of 160 patients. The primary analysis was performed in the Full Analysis Set, which included all randomized patients who received at least one dose of the study treatment, excluding those found ineligible after enrollment. OS and RFS were estimated using the Kaplan–Meier method and compared between groups using a stratified log-rank test, stratified by the randomization factors (excluding trial site). HRs and 95% confidence intervals (CIs) were estimated using a stratified Cox proportional hazards regression model with the same stratification factors. Confidence intervals for survival rates and median survival times were calculated using Greenwood’s formula and the Brookmeyer–Crowley method, respectively. All analyses and graphics were performed using SAS version 9.4 (SAS Institute, Inc.). All statistical tests were two-sided, with p -values less than 0.20 considered statistically significant for the primary endpoint; p -values for secondary analyses were exploratory. Results Enrollment and study conduct By the time enrollment closed on January 26, 2022, a total of 76 patients had been randomized. The enrollment rate declined over time due to protocol restrictions on concomitant medications, including DPP-4 inhibitors and sodium–glucose cotransporter 2 inhibitors, as well as evolving clinical practice, such as increased use of neoadjuvant chemotherapy for resectable pancreatic cancer [ 16 ]. The Coronavirus Disease 2019 pandemic and subsequent guidance from several academic societies advising caution regarding adjuvant chemotherapy [ 17 ] further slowed recruitment. Consequently, the trial was terminated without extension, and statistical analyses were performed on the available dataset. This early termination was approved by the ethics committee. No interim analyses were planned or conducted. Since fewer than 50% of the originally planned sample size was enrolled, all statistical comparisons should be considered exploratory and interpreted with caution, which may limit the robustness and generalizability of the findings. Patient demographics Of the 91 patients initially enrolled, 15 were not randomized, including nine who did not meet eligibility criteria and six who withdrew consent. Seventy-six patients were randomized equally to Group A (S-1 plus metformin, n = 38) and Group B (S-1 monotherapy, n = 38) (Fig. 1 ). Following randomization, one patient did not begin study treatment due to a sudden change in clinical status. By study completion, three patients (two in Group A, one in Group B) had significant protocol deviations, leaving 72 patients evaluable for efficacy and 75 evaluable for safety. Patient demographics are summarized in Table 1 . The median age was 69.5 years in Group A and 70 years in Group B. Regarding sex differences, Eastern Cooperative Oncology Group performance status, body mass index, surgical approach, disease stage, R0 resection rate, and lymph node metastasis, there were no significant differences between Group A and Group B, as shown in Table 1 . Median carcinoembryonic antigen, carbohydrate antigen 19 − 9, and HbA1c levels were 2.6 ng/mL, 32.8 ng/mL, and 6.2%, respectively, in Group A and 2.4 ng/mL, 39.3 U/mL, and 6.2%, respectively, in Group B. Regarding diabetes history, 18 patients in Group A and 13 in Group B had had diabetes for less than two years, while 18 patients in Group A and 23 in Group B were newly diagnosed during screening. Only two patients in Group A and one in Group B had diabetes for more than five years. Table 1 Demographics and baseline characteristics Age Group A ( n = 38) n (%) Group B ( n = 37) n (%) Median (range) 69.5 years (49–81) 70.0 years (52–83) Gender Male 23 (60.5) 20 (54.1) Female 15 (39.5) 17 (45.9) ECOG PS0 29 32 PS1 9 5 BMI Median (range) 20.3 (16.5–25.7) 20.2 (15.3–25.5) Surgical procedure PD 26 (68.4) 23 (62.2) DP 12 (31.6) 14 (37.8) Stage I -Ⅱ 37 (97.4) 37 (100) Ⅲ 1 (2.6) 0 (0) R status R0 37 (97.4) 35 (94.6) R1 1 (2.6) 2 (5.4) Nodal status N0 17 (44.7) 17 (45.9) N1 21 (55.3) 20 (54.1) CEA (ng/mL) Mean ± SD 2.6 ± 1.9 2.4 ± 1.0 CA19-9 (U/mL) 32.8 ± 66.8 39.3 ± 88.8 HbA1c (%) 6.2 ± 0.8 6.2 ± 0.7 DM duration 5–10 years 0 (0.0) 1 (2.7) 2–5 years 2 (5.3) 0 (0.0) 0–2 years 18 (47.4) 13 (35.1) 0 18 (47.4) 23 (62.2) The population in this table refers to the 75 patients who started study treatment after randomization. DM duration 0 refers to patients who were diagnosed with diabetes for the first time after pancreatectomy BMI, body mass index; CA19-9, carbohydrate antigen 19 − 9; CEA, carcinoembryonic antigen; DM, diabetes mellitus; ECOG, eastern cooperative oncology group performance status; HbA1c, hemoglobin A1c; Nodal status, lymph node status; R status, resection status Efficacy outcomes The primary endpoint, 2-year OS, was 66.7% in Group A and 66.1% in Group B (HR: 1.09, 95% CI: 0.55–2.16, p = 0.93). Median OS was 53.8 months in Group A and 58.0 months in Group B (Fig. 2 ). Median RFS, a secondary endpoint, was 17.9 months in Group A and 12.6 months in Group B (HR: 1.17, 95% CI: 0.66–2.09, p = 0.78; Fig. 3 ). No statistically significant differences in OS or RFS were observed between the groups. Adverse events AEs occurred in 76.3% of patients in Group A and 75.7% in Group B during the treatment and observation periods (Table 2 ). No Grade 4 or higher AEs were reported. Grade 3 hematologic toxicities included neutropenia (2.6% in Group A vs . 0% in Group B) and anemia (5.3% vs . 2.7%). Grade 3 nonhematologic toxicities included cholangitis (7.9% vs . 5.4%), decreased appetite (0% vs . 2.7%), nausea (2.6% vs . 0%), diarrhea (0% vs . 2.7%), and fatigue/general malaise (0% vs . 2.7%). Table 2 Adverse events Group A ( n = 38) Group B ( n = 37) Any (%) Grade 3 (%) Any (%) Grade 3 (%) Neutropenia 4 (10.5) 1 (2.6) 5 (13.5) 0 (0.0) Leukopenia 3 (7.9) 0 (0.0) 3 (8.1) 0 (0.0) Thrombocytopenia 1 (2.6) 0 (0.0) 2 (5.4) 0 (0.0) Anemia 8 (21.1) 2 (5.3) 8 (21.6) 1 (2.7) Anorexia 15 (39.5) 0 (0.0) 8 (21.6) 1 (2.7) Nausea 11 (28.9) 1 (2.6) 1 (2.7) 0 (0.0) Vomiting 4 (10.5) 0 (0.0) 0 (0.0) 0 (0.0) Diarrhea 8 (21.1) 0 (0.0) 5 (13.5) 1 (2.7) Fatigue 10 (26.3) 0 (0.0) 7 (18.9) 0 (0.0) Fever 6 (15.8) 0 (0.0) 0 (0.0) 0 (0.0) Oral mucositis 3 (7.9) 0 (0.0) 7 (18.9) 0 (0.0) Visual abnormalities 6 (15.8) 0 (0.0) 0 (0.0) 0 (0.0) Skin abnormalities 5 (13.2) 0 (0.0) 3 (8.1) 0 (0.0) Cholangitis 3 (7.9) 3 (7.9) 2 (5.4) 2 (5.4) Hypoalbuminemia 6 (15.8) 1 (2.6) 6 (16.2) 0 (0.0) Total bilirubin increased 6 (15.8) 1 (2.6) 7 (18.9) 0 (0.0) Elevated AST 7 (18.4) 1 (2.6) 13 (35.1) 0 (0.0) Elevated ALT 5 (13.2) 1 (2.6) 11 (29.7) 0 (0.0) Elevated ALP 5 (13.2) 0 (0.0) 10 (27.0) 2 (5.4) Hyponatremia 7 (18.4) 0 (0.0) 6 (16.2) 0 (0.0) Hypernatremia 0 (0.0) 0 (0.0) 2 (5.4) 0 (0.0) Hypokalemia 3 (7.9) 1 (2.6) 2 (5.4) 0 (0.0) Hyperkalemia 6 (15.8) 0 (0.0) 3 (8.1) 0 (0.0) Elevated serum creatinine 3 (7.9) 0 (0.0) 4 (10.8) 0 (0.0) Hypoglycemia 2 (10.5) 0 (0.0) 1 (2.7) 0 (0.0) Hyperglycemia 5 (13.2) 0 (0.0) 7 (18.9) 0 (0.0) The diagnosis of \"cholangitis\" was made by the principal investigator based on subjective and objective findings and test results, and the grade was determined in accordance with the CTCAE. ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Discussion In this randomized Phase II trial, we compared adjuvant S-1 chemotherapy with or without metformin in patients with resected pancreatic ductal adenocarcinoma and impaired glucose tolerance. Enrollment was closed with 76 randomized patients on January 26, 2022, and analyses were conducted on the available dataset (trial registration jRCTs031180270/UMIN000020681). The trial design and status are publicly archived in the Japanese clinical trial registries. To our knowledge, this is the first prospective randomized trial evaluating the combination of metformin and S-1 adjuvant chemotherapy in pancreatic cancer patients with diabetes who have undergone resection, directly addressing a long-standing clinical question: whether the antitumor effect of metformin is clinically significant. The design of this study reflects routine clinical practice in Japan and provides prospective safety data demonstrating that metformin does not enhance toxicity. Although preclinical and retrospective studies have suggested potential antitumor effects of metformin [ 18 ], our results did not demonstrate a survival benefit when metformin was added to standard S-1 therapy. Two-year OS and RFS were similar between the combination and monotherapy groups, indicating no significant additive effect. While these findings resemble previous trials in patients with unresectable or metastatic pancreatic cancer where metformin also failed to improve outcomes, direct comparisons should be made cautiously. The adjuvant setting differs from advanced disease in tumor biology, microenvironment, and treatment objectives, including lower tumor burden and different clinical priorities. Thus, although the lack of benefit aligns with prior negative results, these findings should not be extrapolated to other disease stages [ 19 – 21 ]. Overall, these findings suggest that metformin's antitumor activity may be limited in this clinical context and may not effectively synergize with cytotoxic chemotherapy in patients with resected pancreatic cancer. One possible explanation for the lack of observed efficacy is the pharmacokinetic profile of metformin. The drug has a relatively short half-life, and the plasma concentrations achieved with standard dosing are substantially lower than those required to induce apoptosis in vitro [ 22 ]. Consequently, while the dosing in this study was appropriate for glycemic control, it may have been insufficient for anticancer activity. Another important consideration is the nature of the diabetic population in this trial. Most patients developed diabetes in association with pancreatic cancer or following pancreatic resection, differing from populations in prior observational studies where metformin was used for longstanding type 2 diabetes. This difference in disease biology and metabolic background may have influenced the therapeutic response. Diabetes related to PDAC or pancreatic surgery is often classified as pancreatogenic, characterized primarily by impaired insulin secretion due to pancreatic endocrine insufficiency rather than the insulin resistance that predominates in type 2 diabetes. This distinction is critical because metformin mainly improves insulin sensitivity and suppress hepatic gluconeogenesis—mechanisms that may be less effective in the context of profound beta-cell dysfunction [ 23 ]. Regarding safety, the overall incidence of AEs was comparable between groups (76.3% in the S-1 plus metformin group versus 75.7% in the S-1 monotherapy group), with no Grade 4 or higher events reported. Grade 3 hematologic toxicities included neutropenia (2.6% vs . 0%) and anemia (5.3% vs . 2.7%), whereas grade 3 nonhematologic toxicities were infrequent and similar across groups. The addition of metformin did not increase the incidence or severity of AEs, indicating that the combination is generally well tolerated in patients with impaired glucose tolerance. Patients were monitored every three weeks, and no cases of lactic acidosis or vitamin B12 deficiency were observed (data not shown). Because the primary aim of the study was to evaluate the antitumor efficacy in the adjuvant setting, the protocol prioritized oncologic endpoints and safety monitoring according to Common Terminology Criteria for AEs rather than detailed longitudinal glycemic profiling. While this design limits metabolic inference, it does not compromise the internal validity of the randomized controlled trial for assessing oncological outcomes. This study also employed a modified S-1 dosing schedule of two weeks on followed by one week off, which demonstrated favorable safety and efficacy profiles compared with conventional regimens. These findings support the feasibility of alternative dosing schedules to enhance tolerability without compromising therapeutic outcomes [ 7 ]. It is important to consider the evolving treatment paradigm for resectable pancreatic cancer. Neoadjuvant chemotherapy is increasingly used to improve R0 resection rates and target micrometastatic disease [ 16 ]. However, recent trials, including NORPACT-1, have not demonstrated a clear survival advantage of neoadjuvant therapy over upfront surgery, and its role in truly resectable disease remains uncertain. Several limitations must also be acknowledged. First, enrollment reached less than half of the planned sample size, rendering all statistical comparison exploratory. Second, recurrence detection and safety assessments were conducted without a blinded independent review, potentially introducing observer and ascertainment bias. Third, the use of a fixed 2-year survival endpoint—prespecified to reflect durable benefit—may be less sensitive than time-to-event measures in early-phase studies with heterogeneous postrecurrence management. Additional factors limiting the robustness and generalizability of the findings should inform the design of future trials, which would benefit from centralized adjudication, standardized imaging schedules, and event-driven endpoints. However, important limitations must also be acknowledged. This study was underpowered due to delayed enrollment, influenced by external factors such as the widespread use of DPP-4 and sodium–glucose cotransporter 2 inhibitors, evolving criteria for prioritizing neoadjuvant therapy, and pandemic-related disruptions. These factors may limit the generalizability of the study findings and highlight the need for future trials with adaptive designs and broader eligibility criteria. In conclusion, this prospective randomized Phase II trial found no evidence that adding metformin to adjuvant S-1 chemotherapy improves OS or RFS in patients with resected pancreatic cancer and concurrent diabetes. Given the limited sample size, the study cannot definitively assess the effectiveness of metformin, and no significant efficacy signals were detected. As the trial evaluated metformin only in a defined patient subset—those with resected pancreatic cancer, diabetes, and a fixed S-1–based adjuvant regimen—the generalizability of these findings is limited and should not be extrapolated to other clinical settings, disease stages, or patient populations Declarations Acknowledgements We would like to thank Masafumi Nakamura (Kyushu University Hospital), Tetsuhide Itoh (International University of Health and Welfare), and Kunihisa Kobayashi (Fukuoka University Chikushi Hospital) for the data and safety monitoring. Conflicts of interest The authors have no competing interests to declare that are relevant to the content of this article. Data Availability statement The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and ethical restrictions but are available from the corresponding author on reasonable request. Author contribution Conceptualization: Dr. Masayuki Furukawa; Data collection: Dr. Masato Narita, Dr. Ichiro Sakamoto, Dr. Yutaka Itoh, Dr. Koji Ohta, Dr. Ichiro Onishi, Dr. Hiroshi Nakano, Dr. Noboru Yahara, Dr. Takuji Naka, Dr. Takeshi Sudo, Dr. Tomohiro Iguchi, Dr. Toshifumi Matsumoto, Dr. Masato Suzuoki, Dr. Hideki Aoki, Dr. Terumasa Hisano, Dr. Hideyasu Matsumura, Dr. Naoki Hama, Dr. Masaru Inagaki, Dr. Akira Saeki; Formal analysis and investigation: Prof. Mototsugu Shimokawa; Contributed data/analysis tools: Prof. Mototsugu Shimokawa; Writing – original draft preparation: Dr. Masayuki Furukawa; Writing – review and editing: All authors; Supervision: Prof. Mototsugu Shimokawa. All authors read and approved the final manuscript. Ethics approval The study protocol was approved by the National Hospital Organization Review Board for Clinical Trials (Approval number: 4180009). This trial was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labour, and Welfare of Japan. Consent to participate Informed consent was obtained from all participants prior to their inclusion in the study. Registration number This study was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000020681. Funding This study was supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization (multicenter clinical studies for EBM). References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660 Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, Bray F (2021) Cancer statistics for the year 2020: An overview. Int J Cancer. https://doi.org/10.1002/ijc.33588 Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger HG, Büchler MW (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200–1210. https://doi.org/10.1056/NEJMoa032295 Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H (2013) Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA 310:1473–1481. https://doi.org/10.1001/jama.2013.279201 Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Baba H, Sakamoto H, Morinaga S, Kinoshita T, Yamaue H, Sudo T, Sato A, Maeda A, Aoyama T, Eguchi H, Ishikawa O, Nakao A (2016) Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A Phase 3, open-label, randomised, noninferiority trial (JASPAC 01). Lancet 388:248–257. https://doi.org/10.1016/S0140 6736(16)30583-9 Yue W, Yang CS, DiPaola RS, Tan XL, Santella RM, Weinstein IB (2014) Repurposing metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res 7:388–397. https://doi.org/10.1158/1940-6207.CAPR-13-0337 Hu J, Fan HD, Gong JP, Mao QS (2023) The relationship between the use of metformin and the risk of pancreatic cancer in patients with diabetes: A systematic review and meta-analysis. BMC Gastroenterol 23:50. https://doi.org/10.1186/s12876-023-02671-0 Reni M, Dugnani E, Cereda S, Belli C, Balzano G, Nicoletti R, Liberati F, Pasquali C, Di Carlo V, Villa E (2016) (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: An open-label, randomized phase II trial. Clin Cancer Res 22:1076–1085. https://doi.org/10.1158/1078-0432.CCR-15-1722 Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334:574–579. https://doi.org/10.1056/NEJM199602293340906 Kayashima H, Itoh S, Shimokawa M, Fukutomi A, Yamada S, Honda G, Nakao A, Uesaka K (2023) Effect of duration of adjuvant chemotherapy with S-1 (6 versus 12 months) for resected pancreatic cancer: The PACS-1 trial. Int J Clin Oncol 28:1520–1529. https://doi.org/10.1007/s10147-023-02399-7 Kimura Y, Kikkawa N, Iijima S, Sakai K, Koike H, Tsuburaya A, Kono S (2003) A new regimen for S-1 therapy aiming at adverse reaction mitigation and prolonged medication by introducing a 1-week drug-free interval after each 2-week dosing session: Efficacy and feasibility in clinical practice. Gastric Cancer 6:34–39. https://doi.org/10.1007/s10120-003-0230-y Japanese Pancreas Society (2009) General rules for the study of pancreatic cancer. Kanehara, Tokyo Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumours. Wiley-Blackwell, Hoboken Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655 National Cancer Institute (2009) Common terminology criteria for adverse events v4.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 Unno M, Motoi F, Matsuyama Y, Mizuno T, Shimizu Y, Furuse J, Egawa S, Sudo T, Tanaka M, Yamada S, Yamaguchi K, Uesaka K (2026) Neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer: Results of the randomized Phase II/III Prep-02/JSAP05 trial. Ann Surg 283:57–64. https://doi.org/10.1097/SLA.0000000000006730 Japan Cancer Association, Japanese Society of Medical Oncology, Japanese Society of Clinical Oncology (2021) COVID-19 and cancer care q&a for healthcare professionals, 3rd ed. https://www.jsco.or.jp/covid19_med_qa/ Eibl G, Rozengurt E (2021) Metformin: Review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 40:865–878. https://doi.org/10.1007/s10555-021-09977-z Dong YW, Shi YQ, He LW, Liu XX, Zhang Y, Wang XX (2017) Effects of metformin on survival outcomes of pancreatic cancer: A meta-analysis. Oncotarget 8:55478–55488. https://doi.org/10.18632/oncotarget.18233 Yu OHY, Suissa S (2023) Metformin and cancer: Solutions to real-world evidence failure. Diabetes Care 46:904–912. https://doi.org/10.2337/dci22-0047 Lewis A, Williams K, Oroszi T (2024) Metformin—a pharmacokinetic and pharmacodynamic journey through the body. Pharmacol Pharm 15:466–477 Andersen DK, Ramirez-Zamora A, Chari ST, Brand RE, Hart PA, O’Connell PJ, Gelrud A (2017) Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66:1103–1110. https://doi.org/10.2337/db16-1477 Labori KJ, Bratlie SO, Anderson B, Grønningsaeter IS, Boggi U, Næs T, Pande R, Yaqub S, Gladhaug IP (2024) Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): A multicentre, randomised, Phase 2 trial. Lancet Gastroenterol Hepatol 9:205–217. https://doi.org/10.1016/S2468-1253(23)00405-3 Supplementary Files CONSORT2025editablechecklist.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 20 Apr, 2026 Reviewers invited by journal 20 Apr, 2026 Editor assigned by journal 18 Apr, 2026 First submitted to journal 16 Apr, 2026 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-9445035\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":626361675,\"identity\":\"82050acc-f921-4440-82ee-adbadb26bad8\",\"order_by\":0,\"name\":\"Masayuki Furukawa\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYDACCQYGZgYGGyCLsfEAKVrSQFoaSNJyGMwmTou5dPPBx4U55+3Wth8G2lJjE01Qi+WcY8nGM7fdTt52JhGo5VhabgMhLQY3csykeYFazA4AtTA2HCZKi/lv3m3nks3OPyReixkz77YDdmY3iLclLVl65rbkBLMbQFsSiPNL8sHPhdvs7M3Opz988KHGhrAWGEgEq0wgVjkI2JOieBSMglEwCkYYAAD+xkgZLYxrrQAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Kyushu Cancer Center\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Masayuki\",\"middleName\":\"\",\"lastName\":\"Furukawa\",\"suffix\":\"\"},{\"id\":626361676,\"identity\":\"c020f76e-b14b-4d61-8baf-59f1de1cb590\",\"order_by\":1,\"name\":\"Masato Narita\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organisation Kyoto Medical Center: Kokuritsu Byoin Kiko Kyoto Iryo Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Masato\",\"middleName\":\"\",\"lastName\":\"Narita\",\"suffix\":\"\"},{\"id\":626361677,\"identity\":\"ec52d08c-8a9b-4d98-9f11-647d54559d45\",\"order_by\":2,\"name\":\"Ichiro Sakamoto\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Takasaki General Medical Center Attached Takasaki School of Nursing: Kokuritsu Byoin Kiko Takasaki Sogo Iryo Center Fuzoku Takasaki Kango Gakko\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ichiro\",\"middleName\":\"\",\"lastName\":\"Sakamoto\",\"suffix\":\"\"},{\"id\":626361678,\"identity\":\"af1fb4e0-39b3-467e-a608-3847d827859b\",\"order_by\":3,\"name\":\"Yutaka Itoh\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Disaster Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yutaka\",\"middleName\":\"\",\"lastName\":\"Itoh\",\"suffix\":\"\"},{\"id\":626361679,\"identity\":\"601bfb13-e7db-45ab-85d6-f4d1748c0704\",\"order_by\":4,\"name\":\"Koji Ohta\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Shikoku Cancer Center: Kokuritsu Byoin Shikoku Gan Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Koji\",\"middleName\":\"\",\"lastName\":\"Ohta\",\"suffix\":\"\"},{\"id\":626361680,\"identity\":\"80a1532e-4352-4472-bac1-ad1858a7ca27\",\"order_by\":5,\"name\":\"Ichiro Onishi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Kanazawa Medical Center: Kokuritsu Byoin Kiko Kanazawa Iryo Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ichiro\",\"middleName\":\"\",\"lastName\":\"Onishi\",\"suffix\":\"\"},{\"id\":626361681,\"identity\":\"8090609f-b5b0-4d6c-a676-3797a4d0d301\",\"order_by\":6,\"name\":\"Hiroshi Nakano\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Shizuoka Medical Center Shizuoka Nursing School: Shizuoka Iryo Center Fuzoku Shizuoka Kango Gakko\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hiroshi\",\"middleName\":\"\",\"lastName\":\"Nakano\",\"suffix\":\"\"},{\"id\":626361682,\"identity\":\"0abed396-4b9f-4aac-86d3-36cdcb2958bd\",\"order_by\":7,\"name\":\"Noboru Yahara\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organisation Kanmon Medical Center: Kokuritsu Byoin Kiko Kanmon Iryo Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Noboru\",\"middleName\":\"\",\"lastName\":\"Yahara\",\"suffix\":\"\"},{\"id\":626361683,\"identity\":\"89a31dea-1960-4e77-9474-4cdf76915b1c\",\"order_by\":8,\"name\":\"Takuji Naka\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Yonago Medical Center School of Nursing: Kokuritsu Byoin Kiko Yonago Iryo Center Fuzoku Kango Gakko\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Takuji\",\"middleName\":\"\",\"lastName\":\"Naka\",\"suffix\":\"\"},{\"id\":626361684,\"identity\":\"90493c32-7513-42c4-a4c0-516e3436cf61\",\"order_by\":9,\"name\":\"Takeshi Sudo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Kure Medical Center and Chugoku Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Takeshi\",\"middleName\":\"\",\"lastName\":\"Sudo\",\"suffix\":\"\"},{\"id\":626361685,\"identity\":\"51ac67d9-5e3e-4920-8940-29d70530315f\",\"order_by\":10,\"name\":\"Tomohiro Iguchi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Fukokahigashi Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tomohiro\",\"middleName\":\"\",\"lastName\":\"Iguchi\",\"suffix\":\"\"},{\"id\":626361686,\"identity\":\"cc4ee4fb-bfc3-4a25-9f58-44d94edee34f\",\"order_by\":11,\"name\":\"Toshifumi Matsumoto\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Beppu Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Toshifumi\",\"middleName\":\"\",\"lastName\":\"Matsumoto\",\"suffix\":\"\"},{\"id\":626361687,\"identity\":\"b27e3c10-9f44-4c83-a6a0-79dac32e7c12\",\"order_by\":12,\"name\":\"Masato Suzuoki\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Hakodate Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Masato\",\"middleName\":\"\",\"lastName\":\"Suzuoki\",\"suffix\":\"\"},{\"id\":626361688,\"identity\":\"e4cda020-2dde-4b63-b15f-3833666c47dd\",\"order_by\":13,\"name\":\"Hideki Aoki\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Iwakuni Clinical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hideki\",\"middleName\":\"\",\"lastName\":\"Aoki\",\"suffix\":\"\"},{\"id\":626361689,\"identity\":\"53327a25-932b-485a-a052-60956232b161\",\"order_by\":14,\"name\":\"Terumasa Hisano\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Kyushu Cancer Center: Kokuritsu Byoin Kiko Kyushu Gan Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Terumasa\",\"middleName\":\"\",\"lastName\":\"Hisano\",\"suffix\":\"\"},{\"id\":626361690,\"identity\":\"51bbd019-63c4-4dd6-8ccd-508e1bca6bce\",\"order_by\":15,\"name\":\"Hideyasu Matsumura\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Matsumoto Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hideyasu\",\"middleName\":\"\",\"lastName\":\"Matsumura\",\"suffix\":\"\"},{\"id\":626361691,\"identity\":\"e8574e3f-d7b0-42b2-ac12-4a7d017fc77e\",\"order_by\":16,\"name\":\"Naoki Hama\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organization Osaka National Hospital: Kokuritsu Byoin Kiko Osaka Iryo Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Naoki\",\"middleName\":\"\",\"lastName\":\"Hama\",\"suffix\":\"\"},{\"id\":626361692,\"identity\":\"f052243b-0f4c-4e3c-8db7-8d1ce09a6500\",\"order_by\":17,\"name\":\"Masaru Inagaki\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organisation Fukuyama Medical Center: Kokuritsu Byoin Kiko Fukuyama Iryo Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Masaru\",\"middleName\":\"\",\"lastName\":\"Inagaki\",\"suffix\":\"\"},{\"id\":626361693,\"identity\":\"177034d0-7e65-4367-bdea-0eb39e8c4fc5\",\"order_by\":18,\"name\":\"Akira Saeki\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Hospital Organisation Nagasaki Medical Center: Kokuritsu Byoin Kiko Nagasaki Iryo Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Akira\",\"middleName\":\"\",\"lastName\":\"Saeki\",\"suffix\":\"\"},{\"id\":626361694,\"identity\":\"9c4bd47a-8f04-492a-8871-9c8dc7e98cbe\",\"order_by\":19,\"name\":\"Mototsugu Shimokawa\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Yamaguchi University School of Medicine Graduate School of Medicine: Yamaguchi Daigaku Igakubu Daigakuin Igakukei Kenkyuka\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mototsugu\",\"middleName\":\"\",\"lastName\":\"Shimokawa\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2026-04-17 06:45:53\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-9445035/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-9445035/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":108181649,\"identity\":\"9a200298-6a1e-4044-8322-39677303eb87\",\"added_by\":\"auto\",\"created_at\":\"2026-04-30 08:58:49\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":314155,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePatient disposition and treatment flow chart\\u003c/p\\u003e\\n\\u003cp\\u003eAfter enrollment, patients underwent eligibility confirmation and were formally registered in the study. Randomization was performed only after registration using a modified minimization method to balance key stratification factors: resection status (R0 versus R1), lymph node status (N0 versus N1), and study site (Institute).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1option.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9445035/v1/54c44512f4a8abe1baccd291.png\"},{\"id\":108072677,\"identity\":\"fafe2198-274d-42a1-a886-5396eeaaf3ba\",\"added_by\":\"auto\",\"created_at\":\"2026-04-29 06:14:56\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":307728,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eOverall survival (OS)\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e-values ​​were calculated using a stratified log‑rank test. The numbers at the bottom of the graph indicate the number of patients at risk. The 2-year survival rate after randomization was 66.7% in Group A (S-1 plus metformin) and 66.1% in Group B (S-1 alone). Median OS was 53.8 months in Group A and 58.0 months in Group B.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2option.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9445035/v1/0ba59d435cac9ac781eb5e41.png\"},{\"id\":108181371,\"identity\":\"09077bef-56f7-47cc-9668-c8d4290764cf\",\"added_by\":\"auto\",\"created_at\":\"2026-04-30 08:58:35\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":146624,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eRecurrence-free survival (RFS)\\u003c/p\\u003e\\n\\u003cp\\u003eKaplan–Meier curves were used to estimate median RFS (in months), and \\u003cem\\u003ep\\u003c/em\\u003e-values were calculated using a stratified log‑rank test.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure3option.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9445035/v1/75787bba36686a721d2e42b4.png\"},{\"id\":108490943,\"identity\":\"95cf7ce2-4d70-4615-b26d-9413d34bef27\",\"added_by\":\"auto\",\"created_at\":\"2026-05-05 09:50:18\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":962234,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9445035/v1/1fd03176-ecff-4b5a-a857-b0bb92514b2d.pdf\"},{\"id\":108072679,\"identity\":\"51704eed-fd77-4879-89da-faa4d6ef4f27\",\"added_by\":\"auto\",\"created_at\":\"2026-04-29 06:14:56\",\"extension\":\"docx\",\"order_by\":7,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":38587,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"CONSORT2025editablechecklist.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9445035/v1/dfef61ceb8aa74c355bdf34a.docx\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Adjuvant S-1 Plus Metformin after Pancreatic Cancer Resection: A Multicenter Randomized Phase II Trial\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003ePancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with poor long-term survival even after curative resection [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. Although only a minority of patients present with resectable disease, recurrence within two years is common [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Adjuvant chemotherapy has demonstrated clear benefits, with ESPAC 1 and CONKO 001 establishing 5-fluorouracil and gemcitabine as effective therapies [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. The JASPAC01 study further showed the superiority of S-1 over gemcitabine, making S-1 the standard adjuvant treatment in Japan [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eMetformin, widely used for type 2 diabetes, has been proposed to exert anticancer effects through AMPK activation and downstream mTOR inhibition [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. Observational data suggest reduced cancer incidence among metformin users [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e], but prospective trials in advanced PDAC have not shown clinical benefit [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e], and its role after curative resection remains unknown. Because metformin does not cause hypoglycemia when used as monotherapy [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e], any antitumor benefit could extend to patients without diabetes.\\u003c/p\\u003e \\u003cp\\u003eStandard adjuvant S-1 is administered in a 4-week on/2-week off schedule; however, adherence can be challenging [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. A shorter 2-week on/1-week off regimen has been developed to improve tolerability while maintaining efficacy, supported by evidence that S-1\\u0026ndash;related toxicities commonly arise during week three [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. This modified schedule was selected to facilitate combination treatment with metformin.\\u003c/p\\u003e \\u003cp\\u003eGiven the exploratory nature and feasibility constraints, a randomized Phase II design was chosen to detect a potential survival signal, using 2-year overall survival as an early indicator of treatment effect in resected PDAC, where recurrence and death commonly occur within this timeframe. Accordingly, this study was not powered to demonstrate a definitive survival benefit but was intended to provide preliminary data to inform the feasibility and rationale for future confirmatory trials.\\u003c/p\\u003e\"},{\"header\":\"Patients and Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy design\\u003c/h2\\u003e \\u003cp\\u003eThis was a multicenter, open-label, randomized Phase II trial designed to compare adjuvant chemotherapy with 6 months of S-1 alone versus 6 months of S-1 combined with 2 years of metformin in patients who had undergone pancreatic cancer resection.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eParticipants\\u003c/h3\\u003e\\n\\u003cp\\u003eEligible patients had histologically confirmed PDAC according to the General Rules for the Study of Pancreatic Cancer [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]; pathological Stage I\\u0026ndash;III per the TNM Classification of Malignant Tumors [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]; no macroscopic residual tumor (R0) or only microscopic residual tumor (R1); and negative intraoperative peritoneal lavage cytology. Additional inclusion criteria were age\\u0026thinsp;\\u0026ge;\\u0026thinsp;20 years; Eastern Cooperative Oncology Group performance status of 0 or 1 [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]; no prior chemotherapy or radiotherapy within 3 years; enrollment within 12 weeks after surgery; and adequate bone marrow, liver, and kidney function within 14 days before registration (leucocytes 3000\\u0026ndash;12,000/mm\\u003csup\\u003e3\\u003c/sup\\u003e; platelets\\u0026thinsp;\\u0026ge;\\u0026thinsp;100,000/mm\\u003csup\\u003e3\\u003c/sup\\u003e; hemoglobin\\u0026thinsp;\\u0026ge;\\u0026thinsp;8.0 g/dL; total bilirubin\\u0026thinsp;\\u0026le;\\u0026thinsp;2.0 mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT)\\u0026thinsp;\\u0026le;\\u0026thinsp;100 IU/L; and serum creatinine\\u0026thinsp;\\u0026le;\\u0026thinsp;1.2 mg/dL). Written informed consent was required.\\u003c/p\\u003e \\u003cp\\u003ePatients with abnormal glucose tolerance before or within 12 weeks post-surgery were included. Abnormal glucose tolerance was defined as fasting blood glucose\\u0026thinsp;\\u0026ge;\\u0026thinsp;126 mg/dL, random blood glucose\\u0026thinsp;\\u0026ge;\\u0026thinsp;200 mg/dL, diabetes-type results on a 75 g oral glucose tolerance test, hemoglobin A1c (HbA1c; National Glycohemoglobin Standardization Program\\u0026thinsp;\\u0026ge;\\u0026thinsp;6.5%, or Japan Diabetes Society\\u0026thinsp;\\u0026ge;\\u0026thinsp;6.1%), or a clinical diagnosis of diabetes by the principal investigator.\\u003c/p\\u003e \\u003cp\\u003eExclusion criteria included prior use of S-1, metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, or glucagon-like peptide agonists, anticancer therapy within the past year, evidence of recurrence or active secondary malignancy (except early-stage cancers treated curatively); significant organ dysfunction (New York Heart Association Class III\\u0026ndash;IV heart failure, recent myocardial infarction, renal or hepatic impairment, pulmonary fibrosis, or severe metabolic disorders), conditions increasing the risk of hypoxemia or severe infection, pregnancy, breastfeeding, or plans to conceive, concurrent use of flucytosine, phenytoin, or warfarin, and any other condition deemed unsuitable by the investigator.\\u003c/p\\u003e\\n\\u003ch3\\u003eRandomization\\u003c/h3\\u003e\\n\\u003cp\\u003ePatients were initially enrolled and screened for eligibility. Those meeting all inclusion and exclusion criteria were formally registered in the study database. Randomization was performed only after registration using a modified minimization method to balance prespecified stratification factors. For clarity, \\\"enrollment\\\" refers to entry into screening, \\\"registration\\\" to confirmation of eligibility and inclusion in the database, and \\u0026ldquo;randomization\\u0026rdquo; to assignment to the treatment groups. Participants were allocated 1:1 to Group A (6 months of S-1 plus 2 years of metformin) or Group B (6 months of S-1 alone). Randomization was centralized using a modified minimization method adjusted for residual tumor status (R0 \\u003cem\\u003evs\\u003c/em\\u003e. R1), lymph node status (N0 \\u003cem\\u003evs\\u003c/em\\u003e. N1), and trial site. Investigators and patients were aware of the assigned treatments.\\u003c/p\\u003e\\n\\u003ch3\\u003eProcedure\\u003c/h3\\u003e\\n\\u003cp\\u003eIn both Groups A and B, patients received oral S-1 at doses based on body surface area (BSA): BSA\\u0026thinsp;\\u0026lt;\\u0026thinsp;1.25 m\\u003csup\\u003e2\\u003c/sup\\u003e, 40 mg, BSA 1.25\\u0026thinsp;\\u0026lt;\\u0026thinsp;1.5 m\\u003csup\\u003e2\\u003c/sup\\u003e: 50 mg, and BSA\\u0026thinsp;\\u0026ge;\\u0026thinsp;1.5 m\\u003csup\\u003e2\\u003c/sup\\u003e: 60 mg. S-1 was administered twice daily for 2 weeks, followed by a 1-week break (1 cycle). From the second cycle onward, administration continued for 2 weeks with a 1-week break, adjusted as needed for toxicity. This regimen was repeated over a 6-month period.\\u003c/p\\u003e \\u003cp\\u003eIn Group A, metformin was initiated at 500 mg/day for the first 3 weeks, increased to 750 mg/day from the fourth week onward, and continued for up to 2 years. If hyperglycemia was not adequately controlled with metformin alone, additional antidiabetic medications (e.g., insulin, sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors) were permitted.\\u003c/p\\u003e \\u003cp\\u003eTo start each S-1 cycle, patients had to meet the following criteria: white blood cell count\\u0026thinsp;\\u0026ge;\\u0026thinsp;3000/mm\\u003csup\\u003e3\\u003c/sup\\u003e, neutrophil count\\u0026thinsp;\\u0026ge;\\u0026thinsp;1500/mm\\u003csup\\u003e3\\u003c/sup\\u003e, platelet count\\u0026thinsp;\\u0026ge;\\u0026thinsp;100,000/mm\\u003csup\\u003e3\\u003c/sup\\u003e, hemoglobin\\u0026thinsp;\\u0026ge;\\u0026thinsp;6.5 g/dL, absence of fever\\u0026thinsp;\\u0026ge;\\u0026thinsp;38\\u0026deg;C, serum creatinine\\u0026thinsp;\\u0026le;\\u0026thinsp;1.5 mg/dL, AST\\u0026thinsp;\\u0026le;\\u0026thinsp;150 IU/L, and ALT\\u0026thinsp;\\u0026le;\\u0026thinsp;150 IU/L. No other nonhematological adverse events (AEs) of Grade 2 or higher were permitted. In addition to the criteria for interrupting and restarting S-1 at each cycle, S-1 was discontinued during a cycle if the following AEs occurred: white blood cell count\\u0026thinsp;\\u0026le;\\u0026thinsp;1000/mm\\u003csup\\u003e3\\u003c/sup\\u003e, platelet count\\u0026thinsp;\\u0026le;\\u0026thinsp;50,000/mm\\u003csup\\u003e3\\u003c/sup\\u003e, fever\\u0026thinsp;\\u0026ge;\\u0026thinsp;38\\u0026deg;C, serum creatinine exceeding institutional limit, or Grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;2 nonhematological AEs. After discontinuation, the S-1 daily dose was reduced for the next cycle according to BSA (120 \\u0026rarr; 100 mg/day, 100 \\u0026rarr; 80 mg/day, or 80 \\u0026rarr; 50 mg/day) based on BSA.\\u003c/p\\u003e \\u003cp\\u003eDuring treatment, subjective and objective symptoms and blood chemistry ​​were assessed every 3 weeks, tumor markers every 6 weeks, and abdominal computed tomography or magnetic resonance imaging every 3 months. After completion of the protocol treatment, tumor markers were measured every 3 months, and computed tomography or magnetic resonance imaging was performed every 3 months for the first 2 years and then every 6 months thereafter. Folate and vitamin B12 levels were assessed every 6 months.\\u003c/p\\u003e\\n\\u003ch3\\u003eEvaluation methods\\u003c/h3\\u003e\\n\\u003cp\\u003eThe primary endpoint was 2-year OS, defined as the time from randomization to death from any cause. Secondary endpoints included recurrence-free survival (RFS) and incidence of AEs. RFS was defined as the time from enrollment to disease recurrence or death from any cause. AEs were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eThe JASPAC 01 trial demonstrated a 2-year survival rate of 70% with S-1 therapy. However, because most participating institutions were high-volume centers performing more than 20 pancreatic resections per year, and because the majority of cases were R0 or N0, case selection bias was likely. Accordingly, the 2-year survival rate for the S-1 adjuvant chemotherapy group after pancreatic cancer surgery was conservatively estimated at 65%. Assuming a 13% absolute improvement in survival over the 65% observed with S-1 monotherapy, the S-1 plus metformin combination group was expected to achieve a 2-year survival rate of 78%. Assuming an exponential survival distribution, this corresponds to a hazard ratio (HR) of 0.58. Using a log-rank test with a two-sided significance level of 20% and a statistical power of 80%, 61 events were required. Assuming a 3-year enrollment period, a 2-year follow-up period, no loss to follow-up, and a constant accrual rate, approximately 73 patients per group were required to achieve this number of events. Allowing for potential dropouts after enrollment, the target sample size was set at 80 patients per group, for a total of 160 patients.\\u003c/p\\u003e \\u003cp\\u003eThe primary analysis was performed in the Full Analysis Set, which included all randomized patients who received at least one dose of the study treatment, excluding those found ineligible after enrollment. OS and RFS were estimated using the Kaplan\\u0026ndash;Meier method and compared between groups using a stratified log-rank test, stratified by the randomization factors (excluding trial site). HRs and 95% confidence intervals (CIs) were estimated using a stratified Cox proportional hazards regression model with the same stratification factors. Confidence intervals for survival rates and median survival times were calculated using Greenwood\\u0026rsquo;s formula and the Brookmeyer\\u0026ndash;Crowley method, respectively.\\u003c/p\\u003e \\u003cp\\u003eAll analyses and graphics were performed using SAS version 9.4 (SAS Institute, Inc.). All statistical tests were two-sided, with \\u003cem\\u003ep\\u003c/em\\u003e-values less than 0.20 considered statistically significant for the primary endpoint; \\u003cem\\u003ep\\u003c/em\\u003e-values for secondary analyses were exploratory.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eEnrollment and study conduct\\u003c/h2\\u003e \\u003cp\\u003eBy the time enrollment closed on January 26, 2022, a total of 76 patients had been randomized. The enrollment rate declined over time due to protocol restrictions on concomitant medications, including DPP-4 inhibitors and sodium\\u0026ndash;glucose cotransporter 2 inhibitors, as well as evolving clinical practice, such as increased use of neoadjuvant chemotherapy for resectable pancreatic cancer [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. The Coronavirus Disease 2019 pandemic and subsequent guidance from several academic societies advising caution regarding adjuvant chemotherapy [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e] further slowed recruitment. Consequently, the trial was terminated without extension, and statistical analyses were performed on the available dataset. This early termination was approved by the ethics committee. No interim analyses were planned or conducted. Since fewer than 50% of the originally planned sample size was enrolled, all statistical comparisons should be considered exploratory and interpreted with caution, which may limit the robustness and generalizability of the findings.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatient demographics\\u003c/h2\\u003e \\u003cp\\u003eOf the 91 patients initially enrolled, 15 were not randomized, including nine who did not meet eligibility criteria and six who withdrew consent. Seventy-six patients were randomized equally to Group A (S-1 plus metformin, \\u003cem\\u003en\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;38) and Group B (S-1 monotherapy, \\u003cem\\u003en\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;38) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Following randomization, one patient did not begin study treatment due to a sudden change in clinical status. By study completion, three patients (two in Group A, one in Group B) had significant protocol deviations, leaving 72 patients evaluable for efficacy and 75 evaluable for safety.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003ePatient demographics are summarized in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. The median age was 69.5 years in Group A and 70 years in Group B. Regarding sex differences, Eastern Cooperative Oncology Group performance status, body mass index, surgical approach, disease stage, R0 resection rate, and lymph node metastasis, there were no significant differences between Group A and Group B, as shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. Median carcinoembryonic antigen, carbohydrate antigen 19\\u0026thinsp;\\u0026minus;\\u0026thinsp;9, and HbA1c levels were 2.6 ng/mL, 32.8 ng/mL, and 6.2%, respectively, in Group A and 2.4 ng/mL, 39.3 U/mL, and 6.2%, respectively, in Group B. Regarding diabetes history, 18 patients in Group A and 13 in Group B had had diabetes for less than two years, while 18 patients in Group A and 23 in Group B were newly diagnosed during screening. Only two patients in Group A and one in Group B had diabetes for more than five years.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eDemographics and baseline characteristics\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eAge\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eGroup A (\\u003cem\\u003en\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;38) \\u003cem\\u003en\\u003c/em\\u003e (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eGroup B (\\u003cem\\u003en\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;37) \\u003cem\\u003en\\u003c/em\\u003e (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMedian (range)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e69.5 years (49\\u0026ndash;81)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e70.0 years (52\\u0026ndash;83)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGender\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e23 (60.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e20 (54.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eFemale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e15 (39.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e17 (45.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eECOG\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePS0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e32\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePS1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e5\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBMI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMedian (range)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e20.3 (16.5\\u0026ndash;25.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e20.2 (15.3\\u0026ndash;25.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSurgical procedure\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePD\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e26 (68.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e23 (62.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e12 (31.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e14 (37.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStage\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eI -Ⅱ\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e37 (97.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e37 (100)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eⅢ\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eR status\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eR0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e37 (97.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e35 (94.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eR1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNodal status\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eN0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e17 (44.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e17 (45.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eN1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e21 (55.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e20 (54.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCEA (ng/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2.4\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCA19-9 (U/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e32.8\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;66.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e39.3\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;88.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHbA1c (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6.2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6.2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDM duration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5\\u0026ndash;10 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1 (2.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2\\u0026ndash;5 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (5.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0\\u0026ndash;2 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e18 (47.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13 (35.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e18 (47.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e23 (62.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eThe population in this table refers to the 75 patients who started study treatment after randomization.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eDM duration 0 refers to patients who were diagnosed with diabetes for the first time after pancreatectomy\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eBMI, body mass index; CA19-9, carbohydrate antigen 19\\u0026thinsp;\\u0026minus;\\u0026thinsp;9; CEA, carcinoembryonic antigen; DM, diabetes mellitus; ECOG, eastern cooperative oncology group performance status; HbA1c, hemoglobin A1c; Nodal status, lymph node status; R status, resection status\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eEfficacy outcomes\\u003c/h2\\u003e \\u003cp\\u003eThe primary endpoint, 2-year OS, was 66.7% in Group A and 66.1% in Group B (HR: 1.09, 95% CI: 0.55\\u0026ndash;2.16, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.93). Median OS was 53.8 months in Group A and 58.0 months in Group B (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Median RFS, a secondary endpoint, was 17.9 months in Group A and 12.6 months in Group B (HR: 1.17, 95% CI: 0.66\\u0026ndash;2.09, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.78; Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). No statistically significant differences in OS or RFS were observed between the groups.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAdverse events\\u003c/h2\\u003e \\u003cp\\u003eAEs occurred in 76.3% of patients in Group A and 75.7% in Group B during the treatment and observation periods (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). No Grade 4 or higher AEs were reported. Grade 3 hematologic toxicities included neutropenia (2.6% in Group A \\u003cem\\u003evs\\u003c/em\\u003e. 0% in Group B) and anemia (5.3% \\u003cem\\u003evs\\u003c/em\\u003e. 2.7%). Grade 3 nonhematologic toxicities included cholangitis (7.9% \\u003cem\\u003evs\\u003c/em\\u003e. 5.4%), decreased appetite (0% \\u003cem\\u003evs\\u003c/em\\u003e. 2.7%), nausea (2.6% \\u003cem\\u003evs\\u003c/em\\u003e. 0%), diarrhea (0% \\u003cem\\u003evs\\u003c/em\\u003e. 2.7%), and fatigue/general malaise (0% \\u003cem\\u003evs\\u003c/em\\u003e. 2.7%).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eAdverse events\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003eGroup A (\\u003cem\\u003en\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;38)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eGroup B (\\u003cem\\u003en\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;37)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAny (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eGrade 3 (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAny (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eGrade 3 (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNeutropenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4 (10.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e5 (13.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLeukopenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3 (7.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 (8.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eThrombocytopenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAnemia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8 (21.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (5.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e8 (21.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1 (2.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAnorexia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e15 (39.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e8 (21.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1 (2.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNausea\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11 (28.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1 (2.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVomiting\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4 (10.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDiarrhea\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8 (21.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e5 (13.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1 (2.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFatigue\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10 (26.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7 (18.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFever\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (15.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOral mucositis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3 (7.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7 (18.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVisual abnormalities\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (15.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSkin abnormalities\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5 (13.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 (8.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCholangitis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3 (7.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3 (7.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHypoalbuminemia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (15.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6 (16.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTotal bilirubin increased\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (15.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7 (18.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eElevated AST\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e7 (18.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13 (35.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eElevated ALT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5 (13.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e11 (29.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eElevated ALP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5 (13.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10 (27.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHyponatremia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e7 (18.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6 (16.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHypernatremia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHypokalemia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3 (7.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHyperkalemia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (15.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 (8.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eElevated serum creatinine\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3 (7.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4 (10.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHypoglycemia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2 (10.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1 (2.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHyperglycemia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5 (13.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7 (18.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003eThe diagnosis of \\\"cholangitis\\\" was made by the principal investigator based on subjective and objective findings and test results, and the grade was determined in accordance with the CTCAE.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003eALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this randomized Phase II trial, we compared adjuvant S-1 chemotherapy with or without metformin in patients with resected pancreatic ductal adenocarcinoma and impaired glucose tolerance. Enrollment was closed with 76 randomized patients on January 26, 2022, and analyses were conducted on the available dataset (trial registration jRCTs031180270/UMIN000020681). The trial design and status are publicly archived in the Japanese clinical trial registries. To our knowledge, this is the first prospective randomized trial evaluating the combination of metformin and S-1 adjuvant chemotherapy in pancreatic cancer patients with diabetes who have undergone resection, directly addressing a long-standing clinical question: whether the antitumor effect of metformin is clinically significant. The design of this study reflects routine clinical practice in Japan and provides prospective safety data demonstrating that metformin does not enhance toxicity.\\u003c/p\\u003e \\u003cp\\u003eAlthough preclinical and retrospective studies have suggested potential antitumor effects of metformin [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e], our results did not demonstrate a survival benefit when metformin was added to standard S-1 therapy. Two-year OS and RFS were similar between the combination and monotherapy groups, indicating no significant additive effect.\\u003c/p\\u003e \\u003cp\\u003eWhile these findings resemble previous trials in patients with unresectable or metastatic pancreatic cancer where metformin also failed to improve outcomes, direct comparisons should be made cautiously. The adjuvant setting differs from advanced disease in tumor biology, microenvironment, and treatment objectives, including lower tumor burden and different clinical priorities. Thus, although the lack of benefit aligns with prior negative results, these findings should not be extrapolated to other disease stages [\\u003cspan additionalcitationids=\\\"CR20\\\" citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. Overall, these findings suggest that metformin's antitumor activity may be limited in this clinical context and may not effectively synergize with cytotoxic chemotherapy in patients with resected pancreatic cancer.\\u003c/p\\u003e \\u003cp\\u003eOne possible explanation for the lack of observed efficacy is the pharmacokinetic profile of metformin. The drug has a relatively short half-life, and the plasma concentrations achieved with standard dosing are substantially lower than those required to induce apoptosis \\u003cem\\u003ein vitro\\u003c/em\\u003e [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. Consequently, while the dosing in this study was appropriate for glycemic control, it may have been insufficient for anticancer activity. Another important consideration is the nature of the diabetic population in this trial. Most patients developed diabetes in association with pancreatic cancer or following pancreatic resection, differing from populations in prior observational studies where metformin was used for longstanding type 2 diabetes. This difference in disease biology and metabolic background may have influenced the therapeutic response. Diabetes related to PDAC or pancreatic surgery is often classified as pancreatogenic, characterized primarily by impaired insulin secretion due to pancreatic endocrine insufficiency rather than the insulin resistance that predominates in type 2 diabetes. This distinction is critical because metformin mainly improves insulin sensitivity and suppress hepatic gluconeogenesis\\u0026mdash;mechanisms that may be less effective in the context of profound beta-cell dysfunction [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eRegarding safety, the overall incidence of AEs was comparable between groups (76.3% in the S-1 plus metformin group versus 75.7% in the S-1 monotherapy group), with no Grade 4 or higher events reported. Grade 3 hematologic toxicities included neutropenia (2.6% \\u003cem\\u003evs\\u003c/em\\u003e. 0%) and anemia (5.3% \\u003cem\\u003evs\\u003c/em\\u003e. 2.7%), whereas grade 3 nonhematologic toxicities were infrequent and similar across groups. The addition of metformin did not increase the incidence or severity of AEs, indicating that the combination is generally well tolerated in patients with impaired glucose tolerance. Patients were monitored every three weeks, and no cases of lactic acidosis or vitamin B12 deficiency were observed (data not shown).\\u003c/p\\u003e \\u003cp\\u003eBecause the primary aim of the study was to evaluate the antitumor efficacy in the adjuvant setting, the protocol prioritized oncologic endpoints and safety monitoring according to Common Terminology Criteria for AEs rather than detailed longitudinal glycemic profiling. While this design limits metabolic inference, it does not compromise the internal validity of the randomized controlled trial for assessing oncological outcomes.\\u003c/p\\u003e \\u003cp\\u003eThis study also employed a modified S-1 dosing schedule of two weeks on followed by one week off, which demonstrated favorable safety and efficacy profiles compared with conventional regimens. These findings support the feasibility of alternative dosing schedules to enhance tolerability without compromising therapeutic outcomes [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. It is important to consider the evolving treatment paradigm for resectable pancreatic cancer. Neoadjuvant chemotherapy is increasingly used to improve R0 resection rates and target micrometastatic disease [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. However, recent trials, including NORPACT-1, have not demonstrated a clear survival advantage of neoadjuvant therapy over upfront surgery, and its role in truly resectable disease remains uncertain.\\u003c/p\\u003e \\u003cp\\u003eSeveral limitations must also be acknowledged. First, enrollment reached less than half of the planned sample size, rendering all statistical comparison exploratory. Second, recurrence detection and safety assessments were conducted without a blinded independent review, potentially introducing observer and ascertainment bias. Third, the use of a fixed 2-year survival endpoint\\u0026mdash;prespecified to reflect durable benefit\\u0026mdash;may be less sensitive than time-to-event measures in early-phase studies with heterogeneous postrecurrence management. Additional factors limiting the robustness and generalizability of the findings should inform the design of future trials, which would benefit from centralized adjudication, standardized imaging schedules, and event-driven endpoints. However, important limitations must also be acknowledged. This study was underpowered due to delayed enrollment, influenced by external factors such as the widespread use of DPP-4 and sodium\\u0026ndash;glucose cotransporter 2 inhibitors, evolving criteria for prioritizing neoadjuvant therapy, and pandemic-related disruptions. These factors may limit the generalizability of the study findings and highlight the need for future trials with adaptive designs and broader eligibility criteria.\\u003c/p\\u003e \\u003cp\\u003eIn conclusion, this prospective randomized Phase II trial found no evidence that adding metformin to adjuvant S-1 chemotherapy improves OS or RFS in patients with resected pancreatic cancer and concurrent diabetes. Given the limited sample size, the study cannot definitively assess the effectiveness of metformin, and no significant efficacy signals were detected. As the trial evaluated metformin only in a defined patient subset\\u0026mdash;those with resected pancreatic cancer, diabetes, and a fixed S-1\\u0026ndash;based adjuvant regimen\\u0026mdash;the generalizability of these findings is limited and should not be extrapolated to other clinical settings, disease stages, or patient populations\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe would like to thank Masafumi Nakamura (Kyushu University Hospital), Tetsuhide Itoh (International University of Health and Welfare), and Kunihisa Kobayashi (Fukuoka University Chikushi Hospital) for the data and safety monitoring.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflicts of interest\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData Availability statement\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and ethical restrictions but are available from the corresponding author on reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contribution\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eConceptualization: Dr. Masayuki Furukawa; Data collection: Dr. Masato Narita, Dr. Ichiro Sakamoto, Dr. Yutaka Itoh, Dr. Koji Ohta, Dr. Ichiro Onishi, Dr. Hiroshi Nakano, Dr. Noboru Yahara, Dr. Takuji Naka, Dr. Takeshi Sudo, Dr. Tomohiro Iguchi, Dr. Toshifumi Matsumoto, Dr. Masato Suzuoki, Dr. Hideki Aoki, Dr. Terumasa Hisano, Dr. Hideyasu Matsumura, Dr. Naoki Hama, Dr. Masaru Inagaki, Dr. Akira Saeki; \\u0026nbsp;Formal analysis and investigation: Prof. Mototsugu Shimokawa; Contributed data/analysis tools: Prof. Mototsugu Shimokawa; Writing \\u0026ndash; original draft preparation: Dr. Masayuki Furukawa; Writing \\u0026ndash; review and editing: All authors; Supervision: Prof. Mototsugu Shimokawa. All authors read and approved the final manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study protocol was approved by the National Hospital Organization Review Board for Clinical Trials (Approval number: 4180009). This trial was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labour, and Welfare of Japan.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eInformed consent was obtained from all participants prior to their inclusion in the study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRegistration number\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000020681.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization (multicenter clinical studies for EBM).\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209\\u0026ndash;249. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.3322/caac.21660\\u003c/span\\u003e\\u003cspan address=\\\"10.3322/caac.21660\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFerlay J, Colombet M, Soerjomataram I, Parkin DM, Pi\\u0026ntilde;eros M, Znaor A, Bray F (2021) Cancer statistics for the year 2020: An overview. Int J Cancer. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1002/ijc.33588\\u003c/span\\u003e\\u003cspan address=\\\"10.1002/ijc.33588\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNeoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger HG, B\\u0026uuml;chler MW (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200\\u0026ndash;1210. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1056/NEJMoa032295\\u003c/span\\u003e\\u003cspan address=\\\"10.1056/NEJMoa032295\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Z\\u0026uuml;lke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H (2013) Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA 310:1473\\u0026ndash;1481. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1001/jama.2013.279201\\u003c/span\\u003e\\u003cspan address=\\\"10.1001/jama.2013.279201\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eUesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Baba H, Sakamoto H, Morinaga S, Kinoshita T, Yamaue H, Sudo T, Sato A, Maeda A, Aoyama T, Eguchi H, Ishikawa O, Nakao A (2016) Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A Phase 3, open-label, randomised, noninferiority trial (JASPAC 01). Lancet 388:248\\u0026ndash;257. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1016/S0140 6736(16)30583-9\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/S0140 6736(16)30583-9\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYue W, Yang CS, DiPaola RS, Tan XL, Santella RM, Weinstein IB (2014) Repurposing metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res 7:388\\u0026ndash;397. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1158/1940-6207.CAPR-13-0337\\u003c/span\\u003e\\u003cspan address=\\\"10.1158/1940-6207.CAPR-13-0337\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHu J, Fan HD, Gong JP, Mao QS (2023) The relationship between the use of metformin and the risk of pancreatic cancer in patients with diabetes: A systematic review and meta-analysis. BMC Gastroenterol 23:50. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1186/s12876-023-02671-0\\u003c/span\\u003e\\u003cspan address=\\\"10.1186/s12876-023-02671-0\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eReni M, Dugnani E, Cereda S, Belli C, Balzano G, Nicoletti R, Liberati F, Pasquali C, Di Carlo V, Villa E (2016) (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: An open-label, randomized phase II trial. Clin Cancer Res 22:1076\\u0026ndash;1085. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1158/1078-0432.CCR-15-1722\\u003c/span\\u003e\\u003cspan address=\\\"10.1158/1078-0432.CCR-15-1722\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBailey CJ, Turner RC (1996) Metformin. N Engl J Med 334:574\\u0026ndash;579. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1056/NEJM199602293340906\\u003c/span\\u003e\\u003cspan address=\\\"10.1056/NEJM199602293340906\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKayashima H, Itoh S, Shimokawa M, Fukutomi A, Yamada S, Honda G, Nakao A, Uesaka K (2023) Effect of duration of adjuvant chemotherapy with S-1 (6 versus 12 months) for resected pancreatic cancer: The PACS-1 trial. Int J Clin Oncol 28:1520\\u0026ndash;1529. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1007/s10147-023-02399-7\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/s10147-023-02399-7\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKimura Y, Kikkawa N, Iijima S, Sakai K, Koike H, Tsuburaya A, Kono S (2003) A new regimen for S-1 therapy aiming at adverse reaction mitigation and prolonged medication by introducing a 1-week drug-free interval after each 2-week dosing session: Efficacy and feasibility in clinical practice. Gastric Cancer 6:34\\u0026ndash;39. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1007/s10120-003-0230-y\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/s10120-003-0230-y\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJapanese Pancreas Society (2009) General rules for the study of pancreatic cancer. Kanehara, Tokyo\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumours. Wiley-Blackwell, Hoboken\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649\\u0026ndash;655\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Cancer Institute (2009) Common terminology criteria for adverse events v4.0. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40\\u003c/span\\u003e\\u003cspan address=\\\"http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eUnno M, Motoi F, Matsuyama Y, Mizuno T, Shimizu Y, Furuse J, Egawa S, Sudo T, Tanaka M, Yamada S, Yamaguchi K, Uesaka K (2026) Neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer: Results of the randomized Phase II/III Prep-02/JSAP05 trial. Ann Surg 283:57\\u0026ndash;64. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1097/SLA.0000000000006730\\u003c/span\\u003e\\u003cspan address=\\\"10.1097/SLA.0000000000006730\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJapan Cancer Association, Japanese Society of Medical Oncology, Japanese Society of Clinical Oncology (2021) COVID-19 and cancer care q\\u0026amp;a for healthcare professionals, 3rd ed. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://www.jsco.or.jp/covid19_med_qa/\\u003c/span\\u003e\\u003cspan address=\\\"https://www.jsco.or.jp/covid19_med_qa/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEibl G, Rozengurt E (2021) Metformin: Review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 40:865\\u0026ndash;878. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1007/s10555-021-09977-z\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/s10555-021-09977-z\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDong YW, Shi YQ, He LW, Liu XX, Zhang Y, Wang XX (2017) Effects of metformin on survival outcomes of pancreatic cancer: A meta-analysis. Oncotarget 8:55478\\u0026ndash;55488. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.18632/oncotarget.18233\\u003c/span\\u003e\\u003cspan address=\\\"10.18632/oncotarget.18233\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYu OHY, Suissa S (2023) Metformin and cancer: Solutions to real-world evidence failure. Diabetes Care 46:904\\u0026ndash;912. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.2337/dci22-0047\\u003c/span\\u003e\\u003cspan address=\\\"10.2337/dci22-0047\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLewis A, Williams K, Oroszi T (2024) Metformin\\u0026mdash;a pharmacokinetic and pharmacodynamic journey through the body. Pharmacol Pharm 15:466\\u0026ndash;477\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAndersen DK, Ramirez-Zamora A, Chari ST, Brand RE, Hart PA, O\\u0026rsquo;Connell PJ, Gelrud A (2017) Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66:1103\\u0026ndash;1110. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.2337/db16-1477\\u003c/span\\u003e\\u003cspan address=\\\"10.2337/db16-1477\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLabori KJ, Bratlie SO, Anderson B, Gr\\u0026oslash;nningsaeter IS, Boggi U, N\\u0026aelig;s T, Pande R, Yaqub S, Gladhaug IP (2024) Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): A multicentre, randomised, Phase 2 trial. Lancet Gastroenterol Hepatol 9:205\\u0026ndash;217. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1016/S2468-1253(23)00405-3\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/S2468-1253(23)00405-3\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"international-journal-of-clinical-oncology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ijco\",\"sideBox\":\"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)\",\"snPcode\":\"10147\",\"submissionUrl\":\"https://www.editorialmanager.com/ijco/default2.aspx\",\"title\":\"International Journal of Clinical Oncology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Pancreatic cancer, adjuvant chemotherapy, S-1, metformin\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-9445035/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-9445035/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eSix months of adjuvant S-1 is the standard treatment for resected pancreatic cancer in Japan. Metformin has demonstrated potential anticancer effects in preclinical and observational studies. This study aimed to evaluate whether adding metformin to S-1 improves 2-year survival after pancreatic cancer resection.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eThis multicenter, randomized, open-label Phase II trial enrolled patients with histologically confirmed Stage I\\u0026ndash;II invasive pancreatic ductal carcinoma who underwent curative resection. Patients were randomized to receive S-1 plus metformin (Group A) or S-1 alone (Group B). S-1 was administered for 6 months in both groups, and metformin for 2 years in Group A. The primary endpoint was 2-year overall survival; secondary endpoints were recurrence-free survival and safety. The sample size was calculated assuming a 2-year survival rate of 65% with S-1 alone and 78% with S-1 plus metformin (hazard ratio: 0.58), providing 80% power with a one-sided α of 0.20. Glycemia-related safety was monitored using Common Terminology Criteria for Adverse Events-defined hyperglycemia and hypoglycemia.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eSeventy-six patients were randomized (38 per group). The 2-year survival rate was 66.7% in Group A and 66.1% in Group B (hazard ratio 1.09; 95% confidence interval 0.55\\u0026ndash;2.16; \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.93). Median overall survival was 53.8 versus 58.0 months, and median recurrence-free survival was 17.9 versus 12.6 months (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.78). No grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;4 adverse events occurred; Grade 3 toxicities were infrequent and comparable between groups.\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003eAdding metformin to adjuvant S-1 did not improve survival in patients with resected pancreatic cancer.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Adjuvant S-1 Plus Metformin after Pancreatic Cancer Resection: A Multicenter Randomized Phase II Trial\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-04-29 06:14:52\",\"doi\":\"10.21203/rs.3.rs-9445035/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2026-04-20T14:04:49+00:00\",\"index\":0,\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2026-04-20T13:00:41+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2026-04-18T11:06:34+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"International Journal of Clinical Oncology\",\"date\":\"2026-04-17T02:41:27+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"international-journal-of-clinical-oncology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ijco\",\"sideBox\":\"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)\",\"snPcode\":\"10147\",\"submissionUrl\":\"https://www.editorialmanager.com/ijco/default2.aspx\",\"title\":\"International Journal of Clinical Oncology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"750c84b0-7806-44cf-8fce-b215d798f7d4\",\"owner\":[],\"postedDate\":\"April 29th, 2026\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-04-29T06:14:52+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2026-04-29 06:14:52\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-9445035\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-9445035\",\"identity\":\"rs-9445035\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}