{"paper_id":"36b4e6ac-508b-4fcd-a22f-b012d413b8f4","body_text":"Third-line S-1 or FOLFOX treatment in advanced pancreatic cancer who received gemcitabine+nab-paclitaxel and nanoliposomal-irinotecan+5-fluorouracil/leucovorin | 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 Third-line S-1 or FOLFOX treatment in advanced pancreatic cancer who received gemcitabine+nab-paclitaxel and nanoliposomal-irinotecan+5-fluorouracil/leucovorin Tomomi Sanomachi, Akihiro Ohba, Chigusa Morizane, Nozomu Ogura, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5801148/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract BACKGROUND: To examine the efficacies of S-1 and FOLFOX as third-line treatment for patients with advanced pancreatic cancer. METHODS: We retrospectively analyzed the electronic medical record data of patients who received nanoliposomal-irinotecan+5-fluorouracil/leucovorin (nal-IRI+5FU/LV) as second-line treatment after first-line gemcitabine+nab-paclitaxel (GEM+nab-PTX) at the National Cancer Center Hospital (Tokyo, Japan) between June 2020 and May 2023. RESULTS: In total, 100 patients were included, 41 of whom received S-1 (n=19) or FOLFOX (n=22) as third-line therapy. The median age of patients who received S-1 and FOLFOX was 74 (range: 56–85) and 76 (46–81) years. The number of females, those with performance status (PS) 0, those with PS 1, and those with adenocarcinoma histology who received S-1/FOLFOX were 8/14, 6/11, 13/11, and 18/20. Median progression-free survival (PFS), median overall survival (OS), objective response rate, and disease control rate for S-1/FOLFOX were 2.8/2.2 months, 4.4/5.1 months, 0/0%, and 36.8/27.3%, the most common grade ≥3 adverse events were anemia (4/1) and elevated alanine transaminase levels (1/3). Adverse events were consistent with the known limits, and there were no treatment-related deaths. CONCLUSIONS: In patients with advanced pancreatic cancer treated with GEM+nab-PTX, followed by nal-IRI+5FU/LV, third-line treatment with S-1 or FOLFOX was tolerable. However, further therapeutic development is warranted because these regimens have only modest activities. Oncology Adverse Effects Drug Tolerance Overall Survival Pancreatic Neoplasms Progression-Free Survival Figures Figure 1 Figure 2 Introduction Pancreatic cancer is cause of cancer-related deaths with a projection to become the second by 2030 [ 1 ]. The 5-year survival rate of patients with pancreatic cancer is approximately ≤ 15% [ 2 ], palliative chemotherapy is the standard treatment for unresectable pancreatic cancer. It is suggested that FOLFIRINOX, which showed, in terms of overall survival (OS), superiority to gemcitabine (GEM) in the PRODIGE4-ACCORD11 trial (median OS: 11.1 months vs. 6.8 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.45–0.73, P < 0.001) [ 3 ], or GEM + nab-paclitaxel (GEM + nab-PTX), which showed superiority to GEM in the MPACT trial (median OS: 8.5 months vs. 6.7 months, HR: 0.72, 95%CI: 0.62–0.83, P < 0.001) [ 4 ], should be considered as first-line standard therapy for unresectable pancreatic cancer when the overall health status, including performance status (PS), is preserved. In the international multicenter phase III NAPOLI3 trial [ 5 ], in which the efficacy and safety of NALIRIFOX and GEM + nab-PTX as first-line therapies for metastatic pancreatic cancer were compared, the OS was higher in the NALIRIFOX than in the GEM + nab-PTX (median OS: 11.1 months vs. 9.2 months, HR: 0.83, 95%CI: 0.70–0.99, P = 0.036). In the future, NALIRIFOX may be preferred for patients with metastatic pancreatic cancer in good general condition. However, whether NALIRIFOX is superior to modified FOLFIRINOX (mFOLFIRINOX) remains unclear. In the phase II/III JCOG1611 trial, in which mFOLFIRINOX, S-IROX, and GEM + nab-PTX as first-line treatments for metastatic pancreatic cancer were compared, the median OS in the GEM + nab-PTX was 17.0, mFOLFIRINOX was 14.0 (HR: 1.31, 95%CI: 0.97–1.77) and S-IROX was 13.6 (HR: 1.35, 95%CI: 1.00–1.82) months. Median progression-free survival (PFS) was 6.7, 5.8 (HR: 1.15, 95%CI: 0.91–1.45), and 6.7 (HR: 1.07, 95%CI: 0.84–1.35) months. The trial was designed to confirm the superiority of mFOLFIRINOX or S-IROX over GEM + nab-PTX, but the planned interim analysis indicated a tendency toward better OS for GEM + nab-PTX and the statistical predictive probability of achieving superiority in the final analysis estimates as extremely low. Therefore, the Data and Safety Monitoring Committee recommended that the trial be terminated early because of futility, and investigators accepted this recommendation; GEM + nab-PTX is suitable as a standard regimen as a first-line therapy for unresectable advanced pancreatic cancer, at least in Japan populations. In the phase III NAPOLI-1 trial for metastatic pancreatic cancer that progressed after GEM-containing chemotherapy, the nanoliposomal-irinotecan + 5-fluorouracil/leucovorin (nal-IRI + 5FU/LV) showed an advantage over 5-FU/LV in terms of OS (6.1 months vs. 4.2 months, HR: 0.67, 95%CI: 0.49–0.92, P = 0.012) [ 6 ], making it a guideline recommendation to suggest nal-IRI + 5FU/LV after second-line treatment with GEM-related regimens. However, these guidelines do not specify a third-line treatment regimen, and the survival benefits of third-line treatments remain unclear. In Japanese clinical practice, S-1 or FOLFOX is used as third-line therapy for patients with preserved PS; however, no reports exist on these regimens’ benefit in such patients. Therefore, in this retrospective study, we aimed to examine the efficacies of S-1 and FOLFOX as third-line therapies for patients with advanced pancreatic cancer. Patients and methods In this study, we retrospectively analyzed the electronic medical record data of patients with advanced pancreatic cancer who received nal-IRI + 5FU/LV as second-line therapy after first-line GEM + nab-PTX at the National Cancer Center Hospital (NCCH) (Tokyo, Japan) between June 2020 and May 2023. All information was obtained from the electronic medical records. Information regarding patients’ just before the start of third-line treatment baseline characteristics (age, sex, PS, histological classification, primary site, tumor markers, disease extent, number of metastatic sites and locations) and the efficacy and safety of S-1 and FOLFOX was collected, and PFS and OS during each treatment period were retrospectively evaluated. Response rates were classified as complete response (CR), partial response (PR), stable disease (SD), or disease progression (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) [ 7 ]. Treatment S-1 was administered at 120 mg/day for surface area ≧ 1.5 m 2 , 100 mg/day for ≧ 1.25 – <1.5 m 2 , and 80 mg/day for < 1.25 m 2 on days 1–28, every 6 weeks for one cycle. FOLFOX consisted of oxaliplatin (85 mg/m 2 on day 1), l-LV (200 mg/m 2 on day 1), 5FU (400 mg/m 2 on day 1 via intravenous bolus injection, 2400 mg/m 2 on day 1 via 46 hours continuous intravenous infusion), every 2 weeks for one cycle. In cases of adverse events, the dose and dosing interval were reduced or withdrawn as appropriate. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). Treatment was continued until disease progression, unacceptable toxicity, or patient refusal. Treatment efficacy was reviewed and determined according to RECIST (version 1.1) in this study. Statistical analysis OS was defined as the interval from the date of the third-line first treatment to the date of a related event, such as death or loss to follow-up. PFS was defined as the interval from the date of the third-line first treatment to death or disease progression. For patients who could not be followed up, the end date was the date of the last known survival. Survival analysis was performed by plotting Kaplan–Meier curves using the log-rank test. Statistical significance was set at P = 0.05. SPSS (version 28.0.1.0 (142) [IBM]) was used for statistical analysis. Ethical review This study was conducted in accordance with the research protocol established by the Department of Hepatobiliary and Pancreatic Oncology at the NCCH approved by the Ethics Review Committee (No. 2018 − 149) and conducted in full compliance with the Declaration of Helsinki. Results The study flow diagram is shown in Figure 1 . Forty-one patients who received S-1 or FOLFOX as third-line therapy were finally analyzed. The baseline characteristics of the 41 eligible patients are presented in Table 1 . The median age of patients who received S-1/FOLFOX was 74 (range: 56–85) and 76 (46-81) years. The proportion of females, those with PS 0, those with PS 1, and those with adenocarcinoma who received S-1/FOLFOX were 8 (42.1%)/14 (63.6%), 6 (31.6%)/11 (50.0%), 13 (68.4%)/11 (50.0%), and 18 (94.7%)/20 (90.9%). The sites of pancreatic head lesions in the S-1/FOLFOX were 7 (36.8%) and 9 (40.9%). More than half of patients who received S-1 and FOLFOX (10 [52.6%] and 14 (63.6%]) had carbohydrate antigen 19-9 (CA19-9) levels higher than 59 times the institutional upper limit. In the S-1 and FOLFOX, distant metastases were observed in 14 (73.7%) and 16 (72.8%) patients, whereas single organ metastases were observed in 11 (57.8%) and 13 (59.2%) patients. The median PFS for S-1 and FOLFOX was 2.8 and 2.2 months (HR: 1.20, 95%CI: 0.61–2.38, P=0.59) ( Figure 2A ). The median OS for S-1 and FOLFOX was 4.4 and 5.1 months (HR: 1.19, 95%CI: 0.53–2.69, P=0.67) ( Figure 2B ). The best overall responce of S-1 and FOLFOX are presented in Table 2 . In the S-1 and FOLFOX, the overall response rate (ORR) was 0% and 0%, whereas the disease control rate (DCR) was 36.8% and 27.3%. The most common grade ≥3 adverse events in the S-1 and FOLFOX were anemia (4 [21.1%] and 1 [4.5%]) and elevated alanine transaminase levels (1 [5.3%] and 3 [13.6%]). Adverse events were within known limits, and there were no treatment-related deaths ( Table 3 ). Discussion Our study is the first report to examine the efficacy and safety of S-1 and FOLFOX as third-line therapies for patients with advanced pancreatic cancer who received nal-IRI+5FU/LV as second-line therapy after first-line GEM+nab-PTX. Guidelines for treatment strategies for advanced pancreatic cancer vary among countries and regions based on the drug approval status. However, 5-FU-related regimens are recommended as second-line therapy when GEM-related regimens are refractory or intolerable. Nevertheless, there are no clear guidelines for third-line therapy following the use of these regimens. Therefore, in clinical practice, drugs other than those used in first- and second-line therapies may be administered to patients with preserved PS at the physician's discretion. Based on previous clinical trials and clinical feasibility, GEM, the metabolic antagonists, and nab-PTX, a microtubule polymerization inhibitor, were used as first-line therapies, whereas the 5-FU and nal-IRI, a topoisomerase Ⅰ inhibitor, were used as second-line therapies in our study. Then, the cytotoxic chemotherapeutic agents, S-1 and FOLFOX, were administered as third-line therapies to patients with preserved PS. S-1, an oral fluoropyrimidine antimetabolite, has been used in perioperative and palliative chemotherapy for pancreatic cancer in Japan and has been the subject of several clinical trials, including the phase III trial for chemotherapy-naïve locally advanced or metastatic pancreatic cancer. In the GEST trial [8], the median OS for GEM, S-1, and GEM+S-1 was 8.8, 9.7, and 10.1 months. S-1 is well tolerated and non-inferior to GEM in terms of OS. Notably, S-1 is widely used to treat pancreatic cancer, at least in Asia. Regarding the late-line benefit of S-1, in patients with advanced pancreatic cancer [9], 21 patients (6.3%) received an S-1-containing regimen as third-line therapy, and patients with advanced pancreatic cancer who received S-1 had significantly higher OS and stable disease rate than those who did not receive S-1. However, no pretreatment regimen was specified in the study, and the efficacy and safety of S-1 as a third-line therapy after first-line GEM+nab-PTX and second-line nal-IRI+5FU/LV remain unknown. FOLFOX, which consists of 5-FU, folinic acid, and oxaliplatin has been the subject of several clinical trials as a second-line treatment for advanced pancreatic cancer. In a randomized, open-label, phase III trial (CONKO-003) [10], in which the efficacies of oxaliplatin, folinic acid and fluorouracil (OFF) and folinic acid and fluorouracil (FF) in patients with GEM-resistant advanced pancreatic cancer were compared, the OFF was significantly better than the FF (median OS: 5.9 months vs. 3.3 months, HR: 0.66, 95%CI: 0.48–0.91, P=0.010). The PANCREOX trial [11] comparing mFOLFOX6 and infusional FU/LV in second-line therapy in advanced pancreatic cancer patients previously treated with GEM showed no benefit with the addition of oxaliplatin compared to FU/LV infusion. Thus, as a second-line treatment after GEM, both positive and negative data are available and controversial. Although information about the efficacy of FOLFOX as third-line setting is even more lacking, in the case of patients who have already exhausted other agents, FOLFOX is often chosen as the third-line therapy in daily practice. Therefore, the efficacy and safety of S-1 and FOLFOX as third-line treatments were evaluated in our study. FOLFOX, a two-drug combination therapy including platinum as a key agent in pancreatic cancer, was expected to be more effective than S-1; however, there were no significant differences in PFS and OS between these two regimens. Reports on third-line treatment for advanced pancreatic cancer are scarce. Lu H.R. et al. [12] compared various treatment approaches, including chemotherapy, chemotherapy combined with targeted or immunotherapy, chemotherapy-free antitumor therapy, and palliative care. Chemotherapy regimens in their report included FOLFIRINOX, FOLFIRI, nab-PTX, GEM+S-1, capecitabine+oxaliplatin, GEM +capecitabine, nab-PTX+S-1, GEM, and S-1, as well as pembrolizumab and apatinib. Their report is a retrospective study with a small number of patients (n=72) and should be interpreted taking into account the effects of selection bias, the median PFS ranged from 0.80 to 5.20 months, treatment effect is significant differences between the palliative care group and others (median OS: P < 0.001, median PFS: P < 0.001, DCR: P < 0.001). In our study, the median PFS for S-1 and FOLFOX were 2.8 and 2.2 months, within the range of median PFS for the third-line treatment cohort of their report, however we consider our results were not clinically sufficient to be determined effective. Other mechanisms of action explored for third-line treatment of advanced pancreatic cancer include hydroxychloroquine or CDK4/6 inhibitors combined with trametinib [13] and the phase II trial of ganetespib [14]. However, these regimens showed limited efficacy and tolerability ( Supplementary Table1 ). Additionally, a phase I trial on third-line low-dose paclitaxel in advanced pancreatic cancer patients [15] reported a DCR of 40.0%, targeting patients who had progressed GEM and S-1. Since PTX and nab-PTX may exhibit cross-resistance, the efficacy of PTX as a third-line therapy following first-line GEM+nab-PTX and second-line nal-IRI+5FU/LV is likely limited. Besides these agents, other treatments targeting different mechanisms are under development for pancreatic cancer. However, due to the robust and dense fibroplastic stroma, tumor vasculature, and immunosuppressive tumor microenvironment that promote tumor progression and metastasis[16] [17], the response to chemotherapy remains limited. In our study, S-1 and FOLFOX have advantages in terms of safety and management with fewer grade 3 or 4 adverse events and 22 (53.7%) patients were aged ≥75 years. A retrospective study [18] in which S-1 was compared with GEM showed a better OS with S-1 than with GEM monotherapy, even though approximately 50% of the patients were aged ≥80 years. Data on the safety and tolerance of FOLFOX in older patients with advanced pancreatic cancer are limited; however, its efficacy has been demonstrated in patients with other cancer types, such as colorectal cancer [19], and the same efficacy is expected to be demonstrated in the future in elderly patients with pancreatic cancer. Late-line S-1 and FOLFOX may be feasible treatment options for older patients, who are considered \"vulnerable\" under the guidelines. Furthermore, the proportion of older patients with pancreatic cancer is expected to increase annually with respect to the increasing incidence of pancreatic cancer worldwide. When these factors are considered, both S-1 and FOLFOX can be considered feasible and tolerable third-line treatment options for pancreatic cancer in the current and future real-world settings. This study has three limitations. First, our study was a single-center retrospective study, and the number of cases was limited by the small number of patients with pancreatic cancer requiring tertiary treatment owing to the poor prognosis of pancreatic cancer. Second, our study compared S-1 and FOLFOX as third-line therapies but did not compare them to best supportive care (BSC), and the survival benefit of these regimens compared with that of BSC in advanced pancreatic cancer is unknown. Finally, the mechanisms of action of S-1 and FOLFOX were similar to those of drugs used in previous regimens, which had similar mechanisms of action. Therefore, the efficacy of these regimens may have been inferior to that required for non-resistant cancer cells in the tumor cohort, and new treatment modalities should be developed to prolong the lives of patients with advanced pancreatic cancer. Our study is the first report to examine the efficacy and safety of S-1 and FOLFOX as third-line therapies. The survival benefits of third-line therapies and optimal regimens remain unclear. Further exploration of third-line therapies in prospective trials involving patients with advanced pancreatic cancer is warranted. Conclusions In patients with advanced pancreatic cancer treated with GEM+nab-PTX followed by nal-IRI+5FU/LV, S-1 and FOLFOX as third-line therapies were tolerable; however, the therapeutic efficacy of these regimens is limited, and further therapeutic development is needed. Declarations Twitter handle: I do not own a Twitter handle. Sources of support: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgment We want to thank Editage (www.editage.jp) for the English language editing. Statement of Ethics The study protocol was reviewed and approved by the National Cancer Center Hospital, Tokyo, Japan (approval number: 2018-149). Written informed consent was obtained from all participants. Conflict of Interest Statement Chigusa Morizane reports personal fees from Eisai, personal fees from Yakult Honsha, personal fees from ONO Pharmaceutical, personal fees from Taiho Pharmaceutical, personal fees from J-Pharma, personal fees from AstraZeneca, personal fees from Merck biopharma, personal fees from Daiichi Sankyo, personal fees from Boehringer Ingelheim, personal fees from Labcorp, personal fees from Hitachi, personal fees from MSD K.K., personal fees from SERVIER, personal fees from Novartis, personal fees from TORAY, personal fees from Guardant, personal fees from Myriad Genetics. Takuji Okusakareports personal fees from Chugai Pharmaceutical, personal fees from Eisai, personal fees from Novartis Pharma, personal fees from Bristol-Myers Squibb Company, personal fees from AstraZeneca, personal fees from MSD, personal fees from Chiome Bioscience, personal fees from Syneos, personal fees from Incyte jp, personal fees from SYSMEX, personal fees from Ono Pharmaceutica, personal fees from FUJIFILM, personal fees from Toyama Chemical, personal fees from Daiichi Sankyo, personal fees from Dainippon Sumitomo Pharma, personal fees from Nihon Servier, personal fees from Johnson & Johnson, personal fees from Taiho Pharmaceutical, personal fees from Myriad Genetics, personal fees from Yakult Honsha. Funding Sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contributions Conceptualization: Tomomi Sanomachi, Akihiro Ohba, and Nozomu Ogura; Investigation: Tomomi Sanomachi and Nozomu Ogura; Supervision: Akihiro Ohba and Mao Okada and Chigusa Morizane; Roles/Writing -Original draft: Tomomi Sanomachi; Writing - Review and Editing: Hidenobu Hara, Shin Yagi, Mao Okada, Yuta Maruki, Yoshikuni Nagashio, Shunsuke Kondo, Susumu Hijioka, Chigusa Morizane, Hideki Ueno, and Takuji Okusaka. Data Availability Statement: The data that support the findings of this study are available on request from the corresponding author, Akihiro Ohba. References Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21. Xing L, Lv L, Ren J, Yu H, Zhao X, Kong X, et al. Advances in targeted therapy for pancreatic cancer. Biomed Pharmacother 2023;168:115717. 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Gill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, et al. PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol 2016;34:3914-20. Lu HR, Zhu PF, Deng YY, Chen ZL, Yang L. Third-line treatment options in metastatic pancreatic cancer patients: a real-world study. Front Oncol 2023;13:1251258. Tang H, Ge Y, You T, Li X, Wang Y, Cheng Y, et al. A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma. BMC Cancer 2023;23:958. Cardin DB, Thota R, Goff LW, Berlin JD, Jones CM, Ayers GD, et al. A Phase II Study of Ganetespib as Second-line or Third-line Therapy for Metastatic Pancreatic Cancer. Am J Clin Oncol 2018;41:772-6. Tajima H, Okazaki M, Yamaguchi T, Ohbatake Y, Okamoto K, Nakanuma S, et al. 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Baseline characteristics S-1 (n=19) n (%) FOLFOX (n=22) n (%) Age, median (range) 74.0 (56.0-85.0) 76.0 (46.0-81.0) Sex Female Male 8 (42.1%) 11 (57.9%) 14 (63.6%) 8 (36.4%) Performance status 0 1 2 6 (31.6%) 13 (68.4%) 0 11 (50.0%) 11 (50.0%) 0 Pathology Adenocarcinoma Other 18 (94.7%) 1 (5.3%) 20 (90.9%) 2 (9.1%) Pancreatic tumor location Head Other 7 (36.8%) 12 (63.2%) 9 (40.9%) 13 (59.1%) CA19-9 levels Normal ULN to <59x ULN ≧59x ULN 5 (26.3%) 4 (21.1%) 10 (52.6%) 4 (18.2%) 4 (18.2%) 14 (63.6%) Disease status Locally advanced Metastatic Recurrent 3 (15.8%) 14 (73.7%) 2 (10.5%) 1 (4.5%) 16 (72.8%) 5 (22.7%) Number of metastatic site 0 1 2 3 3 (15.8%) 11 (57.8%) 4 (21.1%) 1 (5.3%) 1 (4.5%) 13 (59.2%) 7 (31.8%) 1 (4.5%) Liver metastasis No Yes 11 (57.9%) 8 (42.1%) 9 (40.9%) 13 (59.1%) The level of CA19-9 was divided into two groups with reference to the previous trial [3]. Abbreviations: upper limit of the normal range: ULN Table 2. Best treatment effects of S-1 and FOLFOX S-1 (n=19) n (%) FOLFOX (n=22) n (%) CR (Complete response) 0 0 PR (Partial response) 0 0 SD (Stable disease) 7 (36.8%) 6 (27.3%) PD (Progressive disease) 9 (47.4%) 13 (59.1%) NE (Not evaluate) 3 (15.8%) 3 (13.6%) ORR (Overall response rate) (CR+PR) 0 0 DCR (Disease control rate) (CR+PR+SD) 7 (36.8%) 6 (27.3%) Table 3. Grade ≥3 adverse events in the S-1 and FOLFOX S-1 (n=19) n (%) FOLFOX (n=22) n (%) Leucopenia 1 (5.3%) 0 Neutropenia 0 0 Anemia 4 (21.1%) 1 (4.5%) Thrombocytopenia 0 1 (4.5%) Febrile neutropenia 1 (5.3%) 0 Fatigue 0 1 (4.5%) Sensory neuropathy 0 0 Anorexia 1 (5.3%) 1 (4.5%) Nausea 0 0 Vomiting 0 0 Diarrhea 2 (10.5%) 0 Hypoalbuminemia 1 (5.3%) 1 (4.5%) Elevated AST levels 1 (5.3%) 2 (9.1%) Elevated ALT levels 1 (5.3%) 3 (13.6%) Elevated creatinine levels 0 0 Any adverse events 8 (42.1%) 6 (27.3%) Additional Declarations The authors declare potential competing interests as follows: Chigusa Morizane reports personal fees from Eisai, personal fees from Yakult Honsha, personal fees from ONO Pharmaceutical, personal fees from Taiho Pharmaceutical, personal fees from J-Pharma, personal fees from AstraZeneca, personal fees from Merck biopharma, personal fees from Daiichi Sankyo, personal fees from Boehringer Ingelheim, personal fees from Labcorp, personal fees from Hitachi, personal fees from MSD K.K., personal fees from SERVIER, personal fees from Novartis, personal fees from TORAY, personal fees from Guardant, personal fees from Myriad Genetics. Takuji Okusaka reports personal fees from Chugai Pharmaceutical, personal fees from Eisai, personal fees from Novartis Pharma, personal fees from Bristol-Myers Squibb Company, personal fees from AstraZeneca, personal fees from MSD, personal fees from Chiome Bioscience, personal fees from Syneos, personal fees from Incyte jp, personal fees from SYSMEX, personal fees from Ono Pharmaceutica, personal fees from FUJIFILM, personal fees from Toyama Chemical, personal fees from Daiichi Sankyo, personal fees from Dainippon Sumitomo Pharma, personal fees from Nihon Servier, personal fees from Johnson & Johnson, personal fees from Taiho Pharmaceutical, personal fees from Myriad Genetics, personal fees from Yakult Honsha. Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-5801148\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":400305725,\"identity\":\"93e1ff0e-af67-437a-b7cd-250e038bed1a\",\"order_by\":0,\"name\":\"Tomomi Sanomachi\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0002-1984-7741\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tomomi\",\"middleName\":\"\",\"lastName\":\"Sanomachi\",\"suffix\":\"\"},{\"id\":400305799,\"identity\":\"005a8643-a5b1-4d32-afa2-8c65566e578a\",\"order_by\":1,\"name\":\"Akihiro Ohba\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYFACHjYGhgo4h2gtZ0jWwthGirP423uPPfg57448fwP7xQcMMncIa5E4cy7dsHfbM8MZB3iKDRh4nhFhzY0cMwnebYcTgMrTJBh4DhPWIQ/UIvl3DilaDIBapHkbQFrYjxGnxfDMGXNjmWOHDWcc5mE2SCDGL3LHe8wevqk5LM/f3v7wwcceIkIMAZh5DBgSew6QooWB/QEDww/StIyCUTAKRsHIAAAH5TgrfFo09wAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Akihiro\",\"middleName\":\"\",\"lastName\":\"Ohba\",\"suffix\":\"\"},{\"id\":400306374,\"identity\":\"38aecf55-78be-4318-b535-68c9cf0b415a\",\"order_by\":2,\"name\":\"Chigusa Morizane\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Chigusa\",\"middleName\":\"\",\"lastName\":\"Morizane\",\"suffix\":\"\"},{\"id\":400306375,\"identity\":\"af753e8c-8ce6-443e-aad4-fc0f16550340\",\"order_by\":3,\"name\":\"Nozomu Ogura\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Nozomu\",\"middleName\":\"\",\"lastName\":\"Ogura\",\"suffix\":\"\"},{\"id\":400306376,\"identity\":\"f6ce2704-6a9b-4260-b3da-7998c1ab02d1\",\"order_by\":4,\"name\":\"Hidenobu Hara\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hidenobu\",\"middleName\":\"\",\"lastName\":\"Hara\",\"suffix\":\"\"},{\"id\":400306377,\"identity\":\"c229f12d-758c-4b65-88bd-ecb1f8287f0a\",\"order_by\":5,\"name\":\"Shin Yagi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shin\",\"middleName\":\"\",\"lastName\":\"Yagi\",\"suffix\":\"\"},{\"id\":400306378,\"identity\":\"c66728a5-5b40-46af-8628-1423a3531424\",\"order_by\":6,\"name\":\"Mao Okada\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mao\",\"middleName\":\"\",\"lastName\":\"Okada\",\"suffix\":\"\"},{\"id\":400306379,\"identity\":\"5acf04a3-3459-48cf-bd5b-3033dfba370b\",\"order_by\":7,\"name\":\"Yuta Maruki\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuta\",\"middleName\":\"\",\"lastName\":\"Maruki\",\"suffix\":\"\"},{\"id\":400306380,\"identity\":\"02195ff4-9e22-4248-bbd5-53f1707f6712\",\"order_by\":8,\"name\":\"Yoshikuni Nagashio\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yoshikuni\",\"middleName\":\"\",\"lastName\":\"Nagashio\",\"suffix\":\"\"},{\"id\":400306381,\"identity\":\"bea1b821-c8a2-4956-a23d-3620d60e04b7\",\"order_by\":9,\"name\":\"Shunsuke Kondo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shunsuke\",\"middleName\":\"\",\"lastName\":\"Kondo\",\"suffix\":\"\"},{\"id\":400306382,\"identity\":\"0a8ee748-3c51-4357-998e-b9df468bc05d\",\"order_by\":10,\"name\":\"Susumu Hijioka\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Susumu\",\"middleName\":\"\",\"lastName\":\"Hijioka\",\"suffix\":\"\"},{\"id\":400306383,\"identity\":\"0cc43504-e796-4955-a6d2-23900fcaf92e\",\"order_by\":11,\"name\":\"Hideki Ueno\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hideki\",\"middleName\":\"\",\"lastName\":\"Ueno\",\"suffix\":\"\"},{\"id\":400306384,\"identity\":\"0bf488e6-16bc-4c5d-bd3d-fcb5175b8a1d\",\"order_by\":12,\"name\":\"Takuji Okusaka\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Cancer Center Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Takuji\",\"middleName\":\"\",\"lastName\":\"Okusaka\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-01-10 06:44:19\",\"currentVersionCode\":1,\"declarations\":{\"humanSubjects\":true,\"vertebrateSubjects\":false,\"conflictsOfInterestStatement\":true,\"humanSubjectEthicalGuidelines\":true,\"humanSubjectConsent\":true,\"humanSubjectClinicalTrial\":false,\"humanSubjectCaseReport\":false,\"vertebrateSubjectEthicalGuidelines\":false},\"doi\":\"10.21203/rs.3.rs-5801148/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-5801148/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":73703152,\"identity\":\"46a46966-3cdf-43e4-aafa-4e6c5799858a\",\"added_by\":\"auto\",\"created_at\":\"2025-01-13 17:37:38\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":96249,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFlow diagram.\\u003c/p\\u003e\\n\\u003cp\\u003eIndicates patients inclusion in this study.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"241225Figure1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5801148/v1/bc4b7e560ada4452407f271b.jpg\"},{\"id\":73703151,\"identity\":\"b5ce57ce-7490-4c56-9d02-78ac0c3755dc\",\"added_by\":\"auto\",\"created_at\":\"2025-01-13 17:37:38\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":106262,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e(A) Kaplan–Meier curves of PFS for S-1 or FOLFOX; (B) Kaplan–Meier curves of OS for S-1 or FOLFOX.\\u003c/p\\u003e\\n\\u003cp\\u003eThe figure shows the Kaplan–Meier curves, median PFS, median OS, and 95%CI for patients who received S-1 and FOLFOX. The horizontal axis indicates the duration (months), whereas the vertical axis indicates the survival rate.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"241225Figure2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5801148/v1/2ccc86d077da378818cb9f08.jpg\"},{\"id\":73703851,\"identity\":\"7cf2d8a5-7b81-44d2-b5a1-76990dd056c9\",\"added_by\":\"auto\",\"created_at\":\"2025-01-13 17:45:43\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":804073,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5801148/v1/494d48bd-9b72-4a4b-830b-424cf8e37f5f.pdf\"},{\"id\":73703153,\"identity\":\"7dea040d-c74e-45f5-b6ac-f4c6fd5ee2d1\",\"added_by\":\"auto\",\"created_at\":\"2025-01-13 17:37:38\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":22142,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SupplementaryTable1.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5801148/v1/df1ba1646959ea415d5a3d72.docx\"}],\"financialInterests\":\"The authors declare potential competing interests as follows: Chigusa Morizane reports personal fees from Eisai, personal fees from Yakult Honsha, personal fees from ONO Pharmaceutical, personal fees from Taiho Pharmaceutical, personal fees from J-Pharma, personal fees from AstraZeneca, personal fees from Merck biopharma, personal fees from Daiichi Sankyo, personal fees from Boehringer Ingelheim, personal fees from Labcorp, personal fees from Hitachi, personal fees from MSD K.K., personal fees from SERVIER, personal fees from Novartis, personal fees from TORAY, personal fees from Guardant, personal fees from Myriad Genetics. \\nTakuji Okusaka reports personal fees from Chugai Pharmaceutical, personal fees from Eisai, personal fees from Novartis Pharma, personal fees from Bristol-Myers Squibb Company, personal fees from AstraZeneca, personal fees from MSD, personal fees from Chiome Bioscience, personal fees from Syneos, personal fees from Incyte jp, personal fees from SYSMEX, personal fees from Ono Pharmaceutica, personal fees from FUJIFILM, personal fees from Toyama Chemical, personal fees from Daiichi Sankyo, personal fees from Dainippon Sumitomo Pharma, personal fees from Nihon Servier, personal fees from Johnson \\u0026 Johnson, personal fees from Taiho Pharmaceutical, personal fees from Myriad Genetics, personal fees from Yakult Honsha.\",\"formattedTitle\":\"\\u003cp\\u003eThird-line S-1 or FOLFOX treatment in advanced pancreatic cancer who received gemcitabine+nab-paclitaxel and nanoliposomal-irinotecan+5-fluorouracil/leucovorin \\u003c/p\\u003e\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003ePancreatic cancer is cause of cancer-related deaths with a projection to become the second by 2030 [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. The 5-year survival rate of patients with pancreatic cancer is approximately\\u0026thinsp;\\u0026le;\\u0026thinsp;15% [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e], palliative chemotherapy is the standard treatment for unresectable pancreatic cancer.\\u003c/p\\u003e \\u003cp\\u003eIt is suggested that FOLFIRINOX, which showed, in terms of overall survival (OS), superiority to gemcitabine (GEM) in the PRODIGE4-ACCORD11 trial (median OS: 11.1 months vs. 6.8 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.45\\u0026ndash;0.73, P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e], or GEM\\u0026thinsp;+\\u0026thinsp;nab-paclitaxel (GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX), which showed superiority to GEM in the MPACT trial (median OS: 8.5 months vs. 6.7 months, HR: 0.72, 95%CI: 0.62\\u0026ndash;0.83, P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e], should be considered as first-line standard therapy for unresectable pancreatic cancer when the overall health status, including performance status (PS), is preserved. In the international multicenter phase III NAPOLI3 trial [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e], in which the efficacy and safety of NALIRIFOX and GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX as first-line therapies for metastatic pancreatic cancer were compared, the OS was higher in the NALIRIFOX than in the GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX (median OS: 11.1 months vs. 9.2 months, HR: 0.83, 95%CI: 0.70\\u0026ndash;0.99, P\\u0026thinsp;=\\u0026thinsp;0.036). In the future, NALIRIFOX may be preferred for patients with metastatic pancreatic cancer in good general condition. However, whether NALIRIFOX is superior to modified FOLFIRINOX (mFOLFIRINOX) remains unclear. In the phase II/III JCOG1611 trial, in which mFOLFIRINOX, S-IROX, and GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX as first-line treatments for metastatic pancreatic cancer were compared, the median OS in the GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX was 17.0, mFOLFIRINOX was 14.0 (HR: 1.31, 95%CI: 0.97\\u0026ndash;1.77) and S-IROX was 13.6 (HR: 1.35, 95%CI: 1.00\\u0026ndash;1.82) months. Median progression-free survival (PFS) was 6.7, 5.8 (HR: 1.15, 95%CI: 0.91\\u0026ndash;1.45), and 6.7 (HR: 1.07, 95%CI: 0.84\\u0026ndash;1.35) months. The trial was designed to confirm the superiority of mFOLFIRINOX or S-IROX over GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX, but the planned interim analysis indicated a tendency toward better OS for GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX and the statistical predictive probability of achieving superiority in the final analysis estimates as extremely low. Therefore, the Data and Safety Monitoring Committee recommended that the trial be terminated early because of futility, and investigators accepted this recommendation; GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX is suitable as a standard regimen as a first-line therapy for unresectable advanced pancreatic cancer, at least in Japan populations.\\u003c/p\\u003e \\u003cp\\u003eIn the phase III NAPOLI-1 trial for metastatic pancreatic cancer that progressed after GEM-containing chemotherapy, the nanoliposomal-irinotecan\\u0026thinsp;+\\u0026thinsp;5-fluorouracil/leucovorin (nal-IRI\\u0026thinsp;+\\u0026thinsp;5FU/LV) showed an advantage over 5-FU/LV in terms of OS (6.1 months vs. 4.2 months, HR: 0.67, 95%CI: 0.49\\u0026ndash;0.92, P\\u0026thinsp;=\\u0026thinsp;0.012) [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e], making it a guideline recommendation to suggest nal-IRI\\u0026thinsp;+\\u0026thinsp;5FU/LV after second-line treatment with GEM-related regimens.\\u003c/p\\u003e \\u003cp\\u003e However, these guidelines do not specify a third-line treatment regimen, and the survival benefits of third-line treatments remain unclear. In Japanese clinical practice, S-1 or FOLFOX is used as third-line therapy for patients with preserved PS; however, no reports exist on these regimens\\u0026rsquo; benefit in such patients. Therefore, in this retrospective study, we aimed to examine the efficacies of S-1 and FOLFOX as third-line therapies for patients with advanced pancreatic cancer.\\u003c/p\\u003e\"},{\"header\":\"Patients and methods\",\"content\":\"\\u003cp\\u003eIn this study, we retrospectively analyzed the electronic medical record data of patients with advanced pancreatic cancer who received nal-IRI\\u0026thinsp;+\\u0026thinsp;5FU/LV as second-line therapy after first-line GEM\\u0026thinsp;+\\u0026thinsp;nab-PTX at the National Cancer Center Hospital (NCCH) (Tokyo, Japan) between June 2020 and May 2023. All information was obtained from the electronic medical records. Information regarding patients\\u0026rsquo; just before the start of third-line treatment baseline characteristics (age, sex, PS, histological classification, primary site, tumor markers, disease extent, number of metastatic sites and locations) and the efficacy and safety of S-1 and FOLFOX was collected, and PFS and OS during each treatment period were retrospectively evaluated. Response rates were classified as complete response (CR), partial response (PR), stable disease (SD), or disease progression (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eTreatment\\u003c/h2\\u003e \\u003cp\\u003eS-1 was administered at 120 mg/day for surface area\\u0026thinsp;≧\\u0026thinsp;1.5 m\\u003csup\\u003e2\\u003c/sup\\u003e, 100 mg/day for ≧\\u0026thinsp;1.25 \\u0026ndash; \\u0026lt;1.5 m\\u003csup\\u003e2\\u003c/sup\\u003e, and 80 mg/day for \\u0026lt;\\u0026thinsp;1.25 m\\u003csup\\u003e2\\u003c/sup\\u003e on days 1\\u0026ndash;28, every 6 weeks for one cycle. FOLFOX consisted of oxaliplatin (85 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e on day 1), l-LV (200 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e on day 1), 5FU (400 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e on day 1 via intravenous bolus injection, 2400 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e on day 1 via 46 hours continuous intravenous infusion), every 2 weeks for one cycle. In cases of adverse events, the dose and dosing interval were reduced or withdrawn as appropriate. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). Treatment was continued until disease progression, unacceptable toxicity, or patient refusal. Treatment efficacy was reviewed and determined according to RECIST (version 1.1) in this study.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eOS was defined as the interval from the date of the third-line first treatment to the date of a related event, such as death or loss to follow-up. PFS was defined as the interval from the date of the third-line first treatment to death or disease progression. For patients who could not be followed up, the end date was the date of the last known survival. Survival analysis was performed by plotting Kaplan\\u0026ndash;Meier curves using the log-rank test. Statistical significance was set at P\\u0026thinsp;=\\u0026thinsp;0.05. SPSS (version 28.0.1.0 (142) [IBM]) was used for statistical analysis.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eEthical review\\u003c/h3\\u003e\\n\\u003cp\\u003e This study was conducted in accordance with the research protocol established by the Department of Hepatobiliary and Pancreatic Oncology at the NCCH approved by the Ethics Review Committee (No. 2018\\u0026thinsp;\\u0026minus;\\u0026thinsp;149) and conducted in full compliance with the Declaration of Helsinki.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eThe study flow diagram is shown in \\u003cstrong\\u003eFigure 1\\u003c/strong\\u003e. Forty-one patients who received S-1 or FOLFOX as third-line therapy were finally analyzed. The baseline characteristics of the 41 eligible patients are presented in \\u003cstrong\\u003eTable 1\\u003c/strong\\u003e. The median age of patients who received S-1/FOLFOX was 74 (range: 56–85) and 76 (46-81) years. The proportion of females, those with PS 0, those with PS 1, and those with adenocarcinoma who received S-1/FOLFOX were 8 (42.1%)/14 (63.6%), 6 (31.6%)/11 (50.0%), 13 (68.4%)/11 (50.0%), and 18 (94.7%)/20 (90.9%). The sites of pancreatic head lesions in the S-1/FOLFOX were 7 (36.8%) and 9 (40.9%). More than half of patients who received S-1 and FOLFOX (10 [52.6%] and 14 (63.6%]) had carbohydrate antigen 19-9 (CA19-9) levels higher than 59 times the institutional upper limit. In the S-1 and FOLFOX, distant metastases were observed in 14 (73.7%) and 16 (72.8%) patients, whereas single organ metastases were observed in 11 (57.8%) and 13 (59.2%) patients. The median PFS for S-1 and FOLFOX was 2.8 and 2.2 months (HR: 1.20,\\u0026nbsp;95%CI: 0.61–2.38, P=0.59) (\\u003cstrong\\u003eFigure 2A\\u003c/strong\\u003e). The median\\u0026nbsp;OS for S-1 and FOLFOX was 4.4 and 5.1 months (HR: 1.19,\\u0026nbsp;95%CI: 0.53–2.69, P=0.67) (\\u003cstrong\\u003eFigure 2B\\u003c/strong\\u003e). The best overall responce of S-1 and FOLFOX are presented in \\u003cstrong\\u003eTable 2\\u003c/strong\\u003e. In the S-1 and FOLFOX, the overall response rate (ORR) was 0% and 0%, whereas the disease control rate (DCR) was 36.8% and 27.3%. The most common grade ≥3 adverse events in the S-1 and FOLFOX were anemia (4 [21.1%] and 1 [4.5%]) and elevated alanine transaminase levels (1 [5.3%] and 3 [13.6%]). Adverse events were within known limits, and there were no treatment-related deaths (\\u003cstrong\\u003eTable 3\\u003c/strong\\u003e).\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eOur study is the first report to examine the efficacy and safety of S-1 and FOLFOX as third-line therapies for patients with advanced pancreatic cancer who received nal-IRI+5FU/LV as second-line therapy after first-line GEM+nab-PTX.\\u003c/p\\u003e\\n\\u003cp\\u003eGuidelines for treatment strategies for advanced pancreatic cancer vary among countries and regions based on the drug approval status. However, 5-FU-related regimens are recommended as second-line therapy when GEM-related regimens are refractory or intolerable. \\u003c/p\\u003e\\n\\u003cp\\u003eNevertheless, there are no clear guidelines for third-line therapy following the use of these regimens. Therefore, in clinical practice, drugs other than those used in first- and second-line therapies may be administered to patients with preserved PS at the physician's discretion.\\u0026nbsp;Based on previous clinical trials and clinical feasibility, GEM, the metabolic antagonists, and nab-PTX, a microtubule polymerization inhibitor, were used as first-line therapies, whereas the 5-FU and nal-IRI, a topoisomerase Ⅰ\\u0026nbsp;inhibitor, were used as second-line therapies in our study. Then, the cytotoxic chemotherapeutic agents, S-1 and FOLFOX, were administered as third-line therapies to patients with preserved PS.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eS-1, an oral fluoropyrimidine antimetabolite, has been used in perioperative and palliative chemotherapy for pancreatic cancer in Japan and has been the subject of several clinical trials, including the phase III trial for chemotherapy-naïve locally advanced or metastatic pancreatic cancer. In the GEST trial\\u0026nbsp;[8], the median OS for GEM, S-1, and GEM+S-1 was 8.8, 9.7, and 10.1 months. S-1 is well tolerated and non-inferior to GEM in terms of OS. Notably, S-1 is widely used to treat pancreatic cancer, at least in Asia. Regarding the late-line benefit of S-1, in patients with advanced pancreatic cancer\\u0026nbsp;[9], 21 patients (6.3%) received an S-1-containing regimen as third-line therapy, and\\u0026nbsp;patients with advanced pancreatic cancer who received S-1 had significantly higher OS and stable disease rate than those who did not receive S-1. However, no pretreatment regimen was specified in the study, and the efficacy and safety of S-1 as a third-line therapy after first-line GEM+nab-PTX and second-line nal-IRI+5FU/LV remain unknown.\\u003c/p\\u003e\\n\\u003cp\\u003eFOLFOX, which consists of 5-FU, folinic acid, and oxaliplatin has been the subject of several clinical trials as\\u0026nbsp;a second-line treatment for advanced pancreatic cancer. In a randomized, open-label, phase III trial (CONKO-003) [10], in which the efficacies of oxaliplatin, folinic acid and fluorouracil (OFF) and folinic acid and fluorouracil \\u0026nbsp;(FF) in patients with GEM-resistant advanced pancreatic cancer were compared, the OFF was significantly better than the FF (median OS: 5.9 months vs. 3.3 months, HR: 0.66, 95%CI: 0.48–0.91, P=0.010). The PANCREOX trial\\u0026nbsp;[11]\\u0026nbsp;comparing mFOLFOX6 and infusional FU/LV in second-line therapy in advanced pancreatic cancer patients previously treated with GEM showed no benefit with the addition of oxaliplatin compared to FU/LV infusion. Thus, as a second-line treatment after GEM, both positive and negative data are available and controversial.\\u0026nbsp;Although\\u0026nbsp;information about the efficacy of FOLFOX as third-line setting is even more lacking, in the case of patients who have already exhausted other agents, FOLFOX is often chosen as the third-line therapy in daily practice.\\u003c/p\\u003e\\n\\u003cp\\u003eTherefore, the efficacy and safety of S-1 and FOLFOX as third-line treatments were evaluated in our study. FOLFOX, a two-drug combination therapy including platinum as a key agent in pancreatic cancer, was expected to be more effective than S-1; however, there were no significant differences in PFS and OS between these two regimens.\\u003c/p\\u003e\\n\\u003cp\\u003eReports on third-line treatment for advanced pancreatic cancer are scarce. Lu H.R. et al.\\u0026nbsp;[12]\\u0026nbsp;compared various treatment approaches, including chemotherapy, chemotherapy combined with targeted or immunotherapy, chemotherapy-free antitumor therapy, and palliative care. Chemotherapy regimens in their report included FOLFIRINOX, FOLFIRI, nab-PTX, GEM+S-1, capecitabine+oxaliplatin, GEM +capecitabine, nab-PTX+S-1, GEM, and S-1, as well as pembrolizumab and apatinib.\\u0026nbsp;Their report is a retrospective study with a small number of patients (n=72) and should be interpreted taking into account the effects of selection bias,\\u0026nbsp;the median PFS ranged from 0.80 to 5.20 months, treatment effect is significant differences between the palliative care group and others (median OS: P \\u0026lt; 0.001, median PFS: P \\u0026lt; 0.001, DCR: P \\u0026lt; 0.001). In our study, the median PFS for S-1 and FOLFOX were 2.8 and 2.2 months, within the range of median PFS for the third-line treatment cohort of their report, however we consider our results were not clinically sufficient to be determined effective.\\u003c/p\\u003e\\n\\u003cp\\u003eOther mechanisms of action explored for third-line treatment of advanced pancreatic cancer include hydroxychloroquine or CDK4/6 inhibitors combined with trametinib\\u0026nbsp;[13]\\u0026nbsp;and the phase II trial of ganetespib\\u0026nbsp;[14]. However, these regimens showed limited efficacy and tolerability (\\u003cstrong\\u003eSupplementary Table1\\u003c/strong\\u003e). Additionally, a phase I trial on third-line low-dose paclitaxel in advanced pancreatic cancer patients\\u0026nbsp;[15]\\u0026nbsp;reported a DCR of 40.0%, targeting patients who had progressed GEM and S-1. Since PTX and nab-PTX may exhibit cross-resistance, the efficacy of PTX as a third-line therapy following first-line GEM+nab-PTX and second-line nal-IRI+5FU/LV is likely limited. Besides these agents, other treatments targeting different mechanisms are under development for pancreatic cancer. However, due to the robust and dense fibroplastic stroma, tumor vasculature, and immunosuppressive tumor microenvironment that promote tumor progression and metastasis[16] [17], the response to chemotherapy remains limited.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eIn our study, S-1 and FOLFOX have advantages in terms of safety and management with fewer grade 3 or 4 adverse events and 22 (53.7%) patients \\u0026nbsp; were aged ≥75 years.\\u0026nbsp;A retrospective study [18] in which S-1 was compared with GEM showed a better OS with S-1 than with GEM monotherapy, even though approximately 50% of the patients were aged ≥80 years. Data on the safety and tolerance of FOLFOX in older patients with advanced pancreatic cancer are limited; however, its efficacy has been demonstrated in patients with other cancer types, such as colorectal cancer [19], and the same efficacy is expected to be demonstrated in the future in elderly patients with pancreatic cancer. Late-line S-1 and FOLFOX may be feasible treatment options for older patients, who are considered \\\"vulnerable\\\" under the guidelines.\\u0026nbsp;Furthermore, the proportion of older patients with pancreatic cancer is expected to increase annually with respect to the increasing incidence of pancreatic cancer worldwide.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eWhen these factors are considered, both S-1 and FOLFOX can be considered feasible and tolerable third-line treatment options for pancreatic cancer in the current and future real-world settings.\\u003c/p\\u003e\\n\\u003cp\\u003eThis study has three limitations. First, our study was a single-center retrospective study, and the number of cases was limited by the small number of patients with pancreatic cancer requiring tertiary treatment owing to the poor prognosis of pancreatic cancer. Second, our study compared S-1 and FOLFOX as third-line therapies but did not compare them to best supportive care (BSC), and the survival benefit of these regimens compared with that of BSC in advanced pancreatic cancer is unknown. Finally, the mechanisms of action of S-1 and FOLFOX were similar to those of drugs used in previous regimens, which had similar mechanisms of action. Therefore, the efficacy of these regimens may have been inferior to that required for non-resistant cancer cells in the tumor cohort, and new treatment modalities should be developed to prolong the lives of patients with advanced pancreatic cancer.\\u003c/p\\u003e\\n\\u003cp\\u003eOur study is the first report to examine the efficacy and safety of S-1 and FOLFOX as third-line therapies. The survival benefits of third-line therapies and optimal regimens remain unclear. Further exploration of third-line therapies in prospective trials involving patients with advanced pancreatic cancer is warranted.\\u003c/p\\u003e\"},{\"header\":\"Conclusions\",\"content\":\"\\u003cp\\u003eIn patients with advanced pancreatic cancer treated with GEM+nab-PTX followed by nal-IRI+5FU/LV, S-1 and FOLFOX as third-line therapies were tolerable; however, the therapeutic efficacy of these regimens is limited, and further therapeutic development is needed.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eTwitter handle:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eI do not own a Twitter handle.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSources of support:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgment\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe want to thank Editage (www.editage.jp) for the English language editing.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStatement of Ethics\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study protocol was reviewed and approved by the National Cancer Center Hospital, Tokyo, Japan (approval number: 2018-149). Written informed consent was obtained from all participants.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflict of Interest Statement\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eChigusa Morizane\\u0026nbsp;reports personal fees from\\u0026nbsp;Eisai, personal fees from Yakult Honsha, personal fees from ONO Pharmaceutical, personal fees from Taiho Pharmaceutical, personal fees from J-Pharma, personal fees from AstraZeneca, personal fees from Merck biopharma, personal fees from Daiichi Sankyo, personal fees from Boehringer Ingelheim, personal fees from Labcorp, personal fees from Hitachi, personal fees from MSD K.K., personal fees from SERVIER, personal fees from Novartis, personal fees from TORAY, personal fees from Guardant, personal fees from Myriad Genetics.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTakuji Okusakareports personal fees from\\u0026nbsp;Chugai Pharmaceutical,\\u0026nbsp;personal fees from\\u0026nbsp;Eisai,\\u0026nbsp;personal fees from\\u0026nbsp;Novartis Pharma,\\u0026nbsp;personal fees from\\u0026nbsp;Bristol-Myers Squibb Company,\\u0026nbsp;personal fees from\\u0026nbsp;AstraZeneca,\\u0026nbsp;personal fees from\\u0026nbsp;MSD,\\u0026nbsp;personal fees from\\u0026nbsp;Chiome Bioscience,\\u0026nbsp;personal fees from\\u0026nbsp;Syneos,\\u0026nbsp;personal fees from\\u0026nbsp;Incyte jp,\\u0026nbsp;personal fees from\\u0026nbsp;SYSMEX,\\u0026nbsp;personal fees from\\u0026nbsp;Ono Pharmaceutica,\\u0026nbsp;personal fees from\\u0026nbsp;FUJIFILM,\\u0026nbsp;personal fees from\\u0026nbsp;Toyama Chemical,\\u0026nbsp;personal fees from\\u0026nbsp;Daiichi Sankyo,\\u0026nbsp;personal fees from\\u0026nbsp;Dainippon Sumitomo Pharma,\\u0026nbsp;personal fees from\\u0026nbsp;Nihon Servier,\\u0026nbsp;personal fees from\\u0026nbsp;Johnson \\u0026amp; Johnson,\\u0026nbsp;personal fees from\\u0026nbsp;Taiho Pharmaceutical,\\u0026nbsp;personal fees from\\u0026nbsp;Myriad Genetics,\\u0026nbsp;personal fees from\\u0026nbsp;Yakult Honsha.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding Sources\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor Contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eConceptualization: Tomomi Sanomachi, Akihiro Ohba, and Nozomu Ogura; Investigation: Tomomi Sanomachi and Nozomu Ogura; Supervision: Akihiro Ohba and Mao Okada and Chigusa Morizane; Roles/Writing -Original draft: Tomomi Sanomachi; Writing - Review and Editing: Hidenobu Hara, Shin Yagi, Mao Okada, Yuta Maruki, Yoshikuni Nagashio, Shunsuke Kondo, Susumu Hijioka, Chigusa Morizane, Hideki Ueno, and Takuji Okusaka.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData Availability Statement:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data that support the findings of this study are available on request from the corresponding author, Akihiro Ohba.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n \\u003cli\\u003eRahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21.\\u003c/li\\u003e\\n \\u003cli\\u003eXing L, Lv L, Ren J, Yu H, Zhao X, Kong X, et al. Advances in targeted therapy for pancreatic cancer. Biomed Pharmacother 2023;168:115717.\\u003c/li\\u003e\\n \\u003cli\\u003eConroy T, Desseigne F, Ychou M, Bouch\\u0026eacute; O, Guimbaud R, B\\u0026eacute;couarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.\\u003c/li\\u003e\\n \\u003cli\\u003eVon Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703.\\u003c/li\\u003e\\n \\u003cli\\u003eWainberg ZA, Melisi D, Macarulla T, Pazo Cid R, Chandana SR, De La Fouchardi\\u0026egrave;re C, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet 2023;402:1272-81.\\u003c/li\\u003e\\n \\u003cli\\u003eWang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016;387:545-57.\\u003c/li\\u003e\\n \\u003cli\\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.\\u003c/li\\u003e\\n \\u003cli\\u003eUeno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 2013;31:1640-8.\\u003c/li\\u003e\\n \\u003cli\\u003eLai HL, Chen YY, Lu CH, Hung CY, Kuo YC, Chen JS, et al. Effect of S-1 on survival outcomes in 838 patients with advanced pancreatic cancer: A 7-year multicenter observational cohort study in Taiwan. Cancer Med 2019;8:2085-94.\\u003c/li\\u003e\\n \\u003cli\\u003eOettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014;32:2423-9.\\u003c/li\\u003e\\n \\u003cli\\u003eGill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, et al. PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol 2016;34:3914-20.\\u003c/li\\u003e\\n \\u003cli\\u003eLu HR, Zhu PF, Deng YY, Chen ZL, Yang L. Third-line treatment options in metastatic pancreatic cancer patients: a real-world study. Front Oncol 2023;13:1251258.\\u003c/li\\u003e\\n \\u003cli\\u003eTang H, Ge Y, You T, Li X, Wang Y, Cheng Y, et al. A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma. BMC Cancer 2023;23:958.\\u003c/li\\u003e\\n \\u003cli\\u003eCardin DB, Thota R, Goff LW, Berlin JD, Jones CM, Ayers GD, et al. A Phase II Study of Ganetespib as Second-line or Third-line Therapy for Metastatic Pancreatic Cancer. Am J Clin Oncol 2018;41:772-6.\\u003c/li\\u003e\\n \\u003cli\\u003eTajima H, Okazaki M, Yamaguchi T, Ohbatake Y, Okamoto K, Nakanuma S, et al. Phase I study of third-line palliative chemotherapy with low dose paclitaxel for pancreatic cancer. Mol Clin Oncol 2018;8:623-7.\\u003c/li\\u003e\\n \\u003cli\\u003eUrbanova M, Cihova M, Buocikova V, Slopovsky J, Dubovan P, Pindak D, et al. Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival. Biomed Pharmacother 2023;165:115179.\\u003c/li\\u003e\\n \\u003cli\\u003eAn YF, Pu N, Jia JB, Wang WQ, Liu L. Therapeutic advances targeting tumor angiogenesis in pancreatic cancer: Current dilemmas and future directions. Biochim Biophys Acta Rev Cancer 2023;1878:188958.\\u003c/li\\u003e\\n \\u003cli\\u003eHarano Y, Babazono A, Fujita T, Jiang P. Efficacy of S-1 monotherapy for older patients with unresectable pancreatic cancer: A retrospective cohort study. J Geriatr Oncol 2019;10:420-6.\\u003c/li\\u003e\\n \\u003cli\\u003eFiger A, Perez-Staub N, Carola E, Tournigand C, Lledo G, Flesch M, et al. FOLFOX in patients aged between 76 and 80 years with metastatic colorectal cancer: an exploratory cohort of the OPTIMOX1 study. Cancer 2007;110:2666-71.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTable 1. Baseline characteristics\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"564\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003eS-1 (n=19) n (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003eFOLFOX (n=22) n (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eAge, median (range)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e74.0 (56.0-85.0)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e76.0 (46.0-81.0)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eSex\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Female\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Male\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e8 (42.1%)\\u003c/p\\u003e\\n \\u003cp\\u003e11 (57.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e14 (63.6%)\\u003c/p\\u003e\\n \\u003cp\\u003e8 (36.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003ePerformance status\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;0\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;1\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e6 (31.6%)\\u003c/p\\u003e\\n \\u003cp\\u003e13 (68.4%)\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e11 (50.0%)\\u003c/p\\u003e\\n \\u003cp\\u003e11 (50.0%)\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003ePathology\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Adenocarcinoma\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Other\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e18 (94.7%)\\u003c/p\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e20 (90.9%)\\u003c/p\\u003e\\n \\u003cp\\u003e2 (9.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003ePancreatic tumor location\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Head\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Other\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e7 (36.8%)\\u003c/p\\u003e\\n \\u003cp\\u003e12 (63.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e9 (40.9%)\\u003c/p\\u003e\\n \\u003cp\\u003e13 (59.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eCA19-9 levels\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Normal\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;ULN to \\u0026lt;59x ULN\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;≧59x ULN\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e5 (26.3%)\\u003c/p\\u003e\\n \\u003cp\\u003e4 (21.1%)\\u003c/p\\u003e\\n \\u003cp\\u003e10 (52.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e4 (18.2%)\\u003c/p\\u003e\\n \\u003cp\\u003e4 (18.2%)\\u003c/p\\u003e\\n \\u003cp\\u003e14 (63.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eDisease status\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Locally advanced\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Metastatic\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Recurrent\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e3 (15.8%)\\u003c/p\\u003e\\n \\u003cp\\u003e14 (73.7%)\\u003c/p\\u003e\\n \\u003cp\\u003e2 (10.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003cp\\u003e16 (72.8%)\\u003c/p\\u003e\\n \\u003cp\\u003e5 (22.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eNumber of metastatic site\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;0\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;1\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;2\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e3 (15.8%)\\u003c/p\\u003e\\n \\u003cp\\u003e11 (57.8%)\\u003c/p\\u003e\\n \\u003cp\\u003e4 (21.1%)\\u003c/p\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003cp\\u003e13 (59.2%)\\u003c/p\\u003e\\n \\u003cp\\u003e7 (31.8%)\\u003c/p\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eLiver metastasis\\u003c/p\\u003e\\n \\u003cp\\u003e No\\u003c/p\\u003e\\n \\u003cp\\u003e Yes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e11 (57.9%)\\u003c/p\\u003e\\n \\u003cp\\u003e8 (42.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 187px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e9 (40.9%)\\u003c/p\\u003e\\n \\u003cp\\u003e13 (59.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eThe level of CA19-9 was divided into two groups with reference to the previous trial [3].\\u003c/p\\u003e\\n\\u003cp\\u003eAbbreviations:\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eupper limit of the normal range: ULN\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 2. Best treatment effects of S-1 and FOLFOX\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"567\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003eS-1 (n=19) n (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003eFOLFOX (n=22) n (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003eCR (Complete response)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003ePR (Partial response)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003eSD (Stable disease)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003e7 (36.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e6 (27.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003ePD (Progressive disease)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003e9 (47.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e13 (59.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003eNE (Not evaluate)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003e3 (15.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e3 (13.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003eORR (Overall response rate)\\u003c/p\\u003e\\n \\u003cp\\u003e(CR+PR)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 198px;\\\"\\u003e\\n \\u003cp\\u003eDCR (Disease control rate)\\u003c/p\\u003e\\n \\u003cp\\u003e(CR+PR+SD)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 189px;\\\"\\u003e\\n \\u003cp\\u003e7 (36.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e6 (27.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eTable 3. Grade \\u0026ge;3 adverse events in the S-1 and FOLFOX\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"558\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;S-1 (n=19) n (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003eFOLFOX (n=22) n (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eLeucopenia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eNeutropenia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eAnemia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e4 (21.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eThrombocytopenia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eFebrile neutropenia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eFatigue\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eSensory neuropathy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eAnorexia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eNausea\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eVomiting\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eDiarrhea\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e2 (10.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e0\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eHypoalbuminemia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e1 (4.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eElevated AST levels\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 170px;\\\"\\u003e\\n \\u003cp\\u003e2 (9.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 236px;\\\"\\u003e\\n \\u003cp\\u003eElevated ALT levels\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 151px;\\\"\\u003e\\n \\u003cp\\u003e1 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 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\\u003c/tbody\\u003e\\n\\u003c/table\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"National Cancer Center Hospital\",\"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\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Adverse Effects, Drug Tolerance, Overall Survival, Pancreatic Neoplasms, Progression-Free Survival\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-5801148/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-5801148/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eBACKGROUND: To examine the efficacies of S-1 and FOLFOX as third-line treatment for patients with advanced pancreatic cancer.\\u003c/p\\u003e\\n\\u003cp\\u003eMETHODS: We retrospectively analyzed the electronic medical record data of patients who received nanoliposomal-irinotecan+5-fluorouracil/leucovorin (nal-IRI+5FU/LV) as second-line treatment after first-line gemcitabine+nab-paclitaxel (GEM+nab-PTX) at the National Cancer Center Hospital (Tokyo, Japan) between June 2020 and May 2023.\\u003c/p\\u003e\\n\\u003cp\\u003eRESULTS: In total, 100 patients were included, 41 of whom received S-1 (n=19) or FOLFOX (n=22) as third-line therapy. The median age of patients who received S-1 and FOLFOX was 74 (range: 56–85) and 76 (46–81) years. The number of females, those with performance status (PS) 0, those with PS 1, and those with adenocarcinoma histology who received S-1/FOLFOX were 8/14, 6/11, 13/11, and 18/20. Median progression-free survival (PFS), median overall survival (OS), objective response rate, and disease control rate for S-1/FOLFOX were 2.8/2.2 months, 4.4/5.1 months, 0/0%, and 36.8/27.3%, the most common grade ≥3 adverse events were anemia (4/1) and elevated alanine transaminase levels (1/3). Adverse events were consistent with the known limits, and there were no treatment-related deaths.\\u003c/p\\u003e\\n\\u003cp\\u003eCONCLUSIONS: In patients with advanced pancreatic cancer treated with GEM+nab-PTX, followed by nal-IRI+5FU/LV, third-line treatment with S-1 or FOLFOX was tolerable. However, further therapeutic development is warranted because these regimens have only modest activities.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Third-line S-1 or FOLFOX treatment in advanced pancreatic cancer who received gemcitabine+nab-paclitaxel and nanoliposomal-irinotecan+5-fluorouracil/leucovorin\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-01-13 17:37:33\",\"doi\":\"10.21203/rs.3.rs-5801148/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"3a570b77-17bc-4e49-b30b-eb6dafd7ab76\",\"owner\":[],\"postedDate\":\"January 13th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":42664233,\"name\":\"Oncology\"}],\"tags\":[],\"updatedAt\":\"2025-09-28T16:27:18+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-01-13 17:37:33\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-5801148\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-5801148\",\"identity\":\"rs-5801148\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}