Determinants of eligibility for second-line chemotherapy following gemcitabine plus nab-paclitaxel therapy in patients with unresectable pancreatic cancer: A retrospective study

Determinants of eligibility for second-line chemotherapy following gemcitabine plus nab-paclitaxel therapy in patients with unresectable pancreatic cancer: A retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Determinants of eligibility for second-line chemotherapy following gemcitabine plus nab-paclitaxel therapy in patients with unresectable pancreatic cancer: A retrospective study Tsuyoshi Ueda, Koichiro Miyagawa, Michihiko Shibata, Yasuhisa Mori, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9285193/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Background: Second-line chemotherapy (2L) is recommended after gemcitabine plus nab-paclitaxel (GnP) first-line chemotherapy (1L) for unresectable pancreatic cancer (UR-PC). However, in routine clinical practice, not all patients proceed to 2L. This retrospective study aimed to identify baseline clinical and biological factors associated with 2L eligibility. Methods: We retrospectively reviewed the data of 124 consecutive patients with UR-PC who received 1L GnP between 2016 and 2024 at a single center, excluding those with postoperative recurrence. Patients were grouped by 2L receipt [2L(+), n = 63] or non-receipt [2L(−), n = 61]. Overall survival (OS) and progression-free survival (PFS) from 1L (baseline) were assessed by Kaplan–Meier and Cox regression analyses. Predictors of 2L eligibility were evaluated by logistic regression. Results: The 2L(+) group less frequently had baseline ascites and better Eastern Cooperative Oncology Group performance status. Median OS was 15.5 vs. 4.7 months (p < 0.001) and median PFS was 5.9 vs. 3.0 months (p = 0.004) for 2L(+) vs. 2L(−). Multivariate Cox analysis identified 2L (hazard ratio [HR] 0.262), disease control (HR 0.398), and neutrophil-to-lymphocyte ratio (HR 0.530) as independent factors for longer OS. Multivariate logistic regression revealed that the absence of ascites independently predicted 2L eligibility (adjusted odds ratio 4.435, 95% confidence interval 1.583−12.423, p = 0.005). Conclusions: Baseline ascites was a barrier to 2L initiation after 1L GnP in patients with UR-PC. Nevertheless, 2L was associated with improved survival regardless of ascites status. This supports individualized reassessment and proactive supportive care to maximize opportunities for sequential chemotherapy. Ascites Drug therapy Pancreatic Neoplasm Patient Selection Survival Analysis Figures Figure 1 Figure 2 Figure 3 Background Pancreatic cancer (PC) is associated with high mortality and poor therapeutic outcomes. The 5-year overall survival (OS) rate of PC is approximately 12%, and the recurrence rate is high [ 1 , 2 ]. Around 51% of patients with PC are diagnosed with distant metastatic disease at presentation, and the 5-year relative survival for distant disease is only 3.2% [ 1 , 3 ]. According to the 2019 Japanese Clinical Practice Guidelines for Pancreatic Cancer, gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are recommended as first-line chemotherapy (1L) regimens for PC [ 4 ]. In clinical practice, GnP is frequently selected as 1L owing to its favorable balance between efficacy and tolerability [ 4 ]. Previous studies have demonstrated that patients with PC receiving second-line chemotherapy (2L) achieved significantly longer OS than those who received best supportive care (BSC) [ 5 – 7 ]. It has been reported that the median OS (mOS) of patients who received 2L after 1L failure was 5.6 months, significantly longer than in the BSC group (1.9 months) [ 7 ]. Moreover, 2L was identified as an independent prognostic factor [ 7 ]. Despite the reported survival benefits of 2L, the proportion of patients who can proceed to 2L remains limited, equating to approximately 46.0%–53.7% of the overall population [ 8 – 10 ]. Previous studies have suggested that Eastern Cooperative Oncology Group performance status (PS) and the presence of ascites are pragmatic clinical indicators of chemotherapy feasibility [ 11 , 12 ]. In addition, systemic inflammatory response (SIR) markers, such as the neutrophil-to-lymphocyte ratio (NLR), have been reported to be associated with PC prognosis [ 13 , 14 ]. Furthermore, the 2017 International Consensus Guidelines proposed a carbohydrate antigen 19 − 9 (CA19-9) concentration ≥ 500 U/mL as a biological high-risk feature, which has been associated with advanced disease and poor prognosis [ 15 , 16 ]. However, no established biomarkers or clinical indicators are currently available to predict eligibility for 2L initiation. Identifying factors that can predict transition to subsequent treatment is therefore important for optimizing treatment sequencing and improving overall treatment strategies. This study aimed to identify baseline clinical and laboratory factors associated with 2L initiation in patients with unresectable PC (UR-PC) who received 1L GnP. Methods Patients and study design In this retrospective single-center study, the data of 164 patients with UR-PC who received 1L GnP from January 2016 to December 2024 were analyzed. As shown in the flowchart (Fig. 1 ), patients with postoperative recurrence of PC (n = 22), conversion surgery (n = 4), ongoing 1L GnP (n = 9), and insufficient clinical data (n = 5) were excluded. Finally, 124 patients were enrolled. The patients were divided into two groups based on 2L receipt [2L (+)] or non-receipt [2L (−)]. The end of the follow-up period was defined as the date of the last visit for surviving patients and the date of death for deceased patients. This study was censored on 31 December 2024. The diagnosis of PC was established based on contrast-enhanced computed tomography findings and/or histopathological confirmation using endoscopic ultrasound-guided tissue acquisition or cytology obtained during endoscopic retrograde cholangiopancreatography. Clinical data at 1L (baseline) were obtained from the patients’ medical records, including demographics (age and sex), PS, presence or absence of ascites assessed by imaging (without quantitative assessment). Study endpoints The primary endpoint was the identification of factors associated with eligibility for 2L initiation. The administration of 2L was defined as the initiation of any chemotherapy after completion or discontinuation of 1L GnP. The secondary endpoints included OS, progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), incidence of grade ≥ 3 adverse events (AEs), and reasons for not receiving 2L. OS was defined as the time from 1L GnP initiation to death from any cause or final follow-up. PFS was measured from 1L GnP initiation to the first occurrence of disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ 17 ] or death, whichever occurred first. Patients without documented progression who were lost to follow-up were censored at their final radiological tumor assessment. Treatment protocol and therapeutic response evaluation GnP initiation was determined based on the Japanese Clinical Practice Guidelines for Pancreatic Cancer 2019 [ 4 ]. Locally advanced unresectable (UR-LA) PC and unresectable metastatic (UR-M) PC were defined according to the criteria established in the 8th edition of the Japan Pancreas Society classification [ 18 ]. UR-LA was defined as tumor involvement of the portal vein and/or superior mesenteric vein that was considered unreconstructible due to occlusion, and/or arterial involvement characterized by tumor abutment of ≥ 180° with the superior mesenteric artery, hepatic artery, or celiac artery. UR-M was defined as PC with distant metastasis, including hepatic, peritoneal, pulmonary, or other extra-pancreatic organ involvement, as confirmed by imaging or intraoperative findings. The therapeutic response was assessed according to RECIST version 1.1. A complete response (CR) was defined as the complete disappearance of all target lesions. A partial response (PR) was defined as a decrease of ≥ 30% in the sum of the diameters of target lesions compared with baseline measurements. Progressive disease (PD) was defined as an increase of ≥ 20% in the sum of target lesion diameters from the lowest value recorded during the study (including baseline if lowest), with a minimum absolute increase of 5 mm. The appearance of new lesions was also classified as PD. Stable disease (SD) was defined as tumor changes that did not meet the criteria for either PR or PD. The ORR was defined as the proportion of patients with CR or PR. The DCR was defined as the proportion of patients achieving CR, PR, or SD. Laboratory tests Hematology and chemistry tests were performed using standard methods. Baseline laboratory values at 1L initiation included serum albumin (Alb), C-reactive protein (CRP), and CA19-9, and peripheral blood cell counts. SIR, reflecting cancer-related inflammation, was assessed using established inflammation-based prognostic parameters (IBPSs). These IBPSs included Alb-to-globulin ratio (AGR), NLR, lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR). These indices were calculated using Alb, globulin, CRP, and the absolute counts of neutrophils, monocytes, lymphocytes, and platelets from peripheral blood samples. The modified Glasgow Prognostic Score (mGPS) is an established IBPS reflecting systemic inflammation and nutritional status [ 13 ]. The mGPS was calculated according to the method of Toiyama et al., as follows: patients with both elevated CRP (> 0.5 mg/dL) and hypoalbuminemia (< 3.5 g/dL) were assigned a score of 2 (mGPS 2); those with either abnormality were assigned a score of 1 (mGPS 1); and those with neither were assigned a score of 0 (mGPS 0) [ 19 ]. The Geriatric Nutritional Risk Index (GNRI) was calculated using serum Alb and body weight according to the following formula: GNRI = [1.489 × Alb (g/L)] + [41.7 × present body weight ÷ ideal body weight]. Body mass index (BMI) was calculated using the body weight, and ideal body weight was estimated based on a BMI of 22 and patient height [ 20 ]. The Prognostic Nutritional Index (PNI) was calculated using the following formula [ 21 , 22 ]: PNI = [10 × Alb (g/dL) + 0.005 × lymphocyte count (/mm 3 )]. The Controlling Nutritional Status score was not assessed because total cholesterol concentration was unavailable for some patients. Assessment of AEs associated with GnP therapy AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE version 5.0) and graded from 1 to 5 [ 23 ]. In patients who experienced grade ≥ 3 AEs associated with GnP therapy, the treatment strategies were modified as appropriate, including dose reduction, temporary interruption, or discontinuation of chemotherapy. Statistical analysis Statistical analyses were performed using the Statistical Package for the Social Sciences Software Program (SPSS) version 25.0 (IBM, Tokyo, Japan). Categorical variables are presented as numbers and percentages and were compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables are summarized as the median with interquartile range (IQR) or mean ± standard deviation, depending on the distribution normality. Comparisons between continuous variables were performed using the Student’s t-test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. ORR and DCR were compared using the chi-square test or Fisher’s exact test. OS and PFS following GnP initiation were estimated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Prognostic factors for OS were analyzed by Cox proportional-hazards regression analysis. Factors associated with eligibility for 2L were analyzed using binomial logistic regression analysis. Based on prior studies, PS ≥ 1 [ 24 ] and mGPS ≥ 1 [ 25 , 26 ] were used as predefined poor prognostic factors in this study. The cutoff values for CA19-9 were set at ≥ 500 U/mL, in accordance with the 2017 International Consensus Guidelines [ 15 , 16 ]. Cutoff values for the other variables were determined around the median values. The prognostic factors analyzed were age (≥ 70 vs. <70 years), sex (male vs. female), PS (≥ 1 vs. 0), ascites (yes vs. no), 2L (yes vs. no), tumor location (body and tail vs. head), disease extension (UR-M vs. UR-LA), whether grade ≥ 3 AEs occurred (yes vs. no), DCR (yes vs. no), CA19-9 (≥ 500 vs. <500 U/mL), GNRI (≥ 97.0 vs. <97.0), PNI (≥ 46.0 vs. <46.0), mGPS (≥ 1 vs. 0), NLR (≥ 3.2 vs. <3.2), LMR (≥ 3.8 vs. <3.8), PLR (≥ 168.0 vs. <168.0), and AGR (≥ 1.3 vs. <1.3). All statistical tests were two-sided. To analyze the factors associated with OS, a significance threshold of p < 0.05 was applied in the univariate analyses, and variables meeting this criterion were subsequently included in the multivariate Cox proportional-hazards regression model. To analyze the determinants of 2L eligibility, variables with p < 0.05 in the univariate analyses were included in the multivariate logistic regression analysis. Multicollinearity was assessed using variance inflation factors (VIFs). Results Patient characteristics The baseline characteristics of the patients within 1 month from the diagnosis of PC to 1L initiation are summarized in Table 1. The median follow-up period, from the date of 1L initiation to the date of the final follow-up, was 10.0 months. The median age was 71 years (IQR 66−75), and 70 patients (56.5%) were male. Compared with the 2L(−) group, the 2L(+) group was significantly less likely to present with ascites at 1L initiation (p < 0.001) and exhibited better PS (p = 0.036). There was no statistically significant difference between the two groups in the incidence of grade ≥ 3 AEs associated with GnP therapy, as assessed by CTCAE version 5.0 (p = 0.108). Among the 2L(−) group, the reasons for GnP discontinuation were primarily GnP-related AEs and PS decline. The 2L(+) group had a significantly longer duration of GnP therapy (p < 0.001), higher serum Alb concentration (p = 0.020), lower serum CRP concentration (p = 0.047), lower serum carcinoembryonic antigen (p = 0.049), and more favorable LMR (p = 0.048). Efficacy of GnP therapy The efficacy outcomes are summarized in Table 2. Both the ORR and the DCR were significantly higher in the 2L(+) group than in the 2L(−) group (ORR: 31.7% vs. 16.4%; p = 0.046; DCR: 57.1% vs. 36.1%; p = 0.011) (Table 2). The mOS in the 2L(+) group was 15.5 months (95% confidence interval [CI] 11.51–19.49), significantly longer than in the 2L(−) group (4.7 months, 95% CI 3.24–6.16) (log-rank p < 0.001) (Figure 2a). A similar trend was observed for median PFS [2L(+): 5.9 months (95% CI 4.49–7.37) vs. 2L(−) group: 3.0 months (95% CI 1.96–3.97); log-rank p = 0.004] (Figure 2b). Prognostic factors for OS Univariate and multivariate Cox regression analyses were performed to identify the prognostic factors associated with OS (Table 3). In the univariate analysis, the following factors were significantly associated with longer OS: absence of ascites, receipt of 2L, disease extension (UR-LA), better DCR, lower mGPS, and LMR ≥ 3.8. Multivariate analysis identified 2L administration (HR 0.262, 95% CI 0.169–0.408; p < 0.001), better DCR (vs. poor DCR; HR 0.398, 95% CI 0.258–0.614; p < 0.001), better NLR (vs. worse NLR; HR 0.530, 95% CI 0.301–0.934; p = 0.028) as independent determinants of longer OS. In the multivariable Cox model for OS, the maximum VIF among the covariates entered into the model was 1.92, indicating no clinically relevant multicollinearity. Predictive factors for 2L eligibility We conducted univariate and multivariate binomial logistic regression analyses to identify the factors associated with 2L eligibility (Table 4). The univariate analyses identified better PS, absence of ascites, disease extension (UR-LA), and higher LMR as factors associated with 2L eligibility. Multivariate analysis identified that the absence of ascites remained independently associated with 2L eligibility (adjusted odds ratio [aOR] 4.435, 95% CI 1.583–12.423; p = 0.005). In contrast, PS 0 showed only a trend toward increased eligibility for 2L but did not reach statistical significance (aOR 2.385, 95% CI 0.979–5.815; p = 0.056) in our cohort. In the multivariable logistic regression model for 2L initiation, all covariates showed low VIFs, and the maximum VIF was approximately 1.25, indicating no clinically relevant multicollinearity. Subgroup analyses stratified by ascites In the subgroup with baseline ascites, mOS was longer in the 2L(+) group (10.2 months, 95% CI 5.84–14.50) than in the 2L(−) group (2.5 months, 95% CI 1.40–3.60) (log-rank p = 0.014) (Figure 3). In the Cox proportional-hazards regression analysis within this subgroup, receipt of 2L was associated with longer OS (HR 0.263, 95% CI 0.086–0.807; p = 0.019). Discussion In this cohort of patients with UR-PC treated with GnP, the presence of ascites was an important clinical factor associated with difficulty in initiating 2L. In addition, even among patients with ascites at baseline of 1L, those who were able to receive 2L tended to have better survival outcomes. These findings indicate that ascites may influence the transition to subsequent treatment rather than being an absolute indicator of poor prognosis. In the present study, GnP efficacy and safety were generally consistent with previous pivotal clinical trials [ 25 , 27 ]. Survival outcomes in the 2L(+) group were comparable to those observed in the GnP arms of both the MPACT and JCOG1611/GENERATE trials [ 25 , 27 ]. In addition, the incidence of AEs, including neutropenia and fatigue, was comparable to previous studies [ 25 , 27 ]. In contrast, patients who did not transition to 2L had markedly poorer outcomes, with an mOS of 4.7 months and an mPFS of 3.0 months. These findings are consistent with previous reports demonstrating the survival benefit of appropriate sequential chemotherapy and underscore the clinical importance of maintaining treatment continuity beyond 1L [ 28 ]. The proportion of patients who successfully proceeded to 2L in the present study was comparable to that reported in previous real-world studies (46.0%–53.7%) [ 8 – 10 ]. Notably, GnP discontinuation in the 2L(−) group was frequently attributable to treatment-related AEs or PS decline, suggesting that reduced GnP tolerability may represent a major barrier to 2L initiation. In the analysis of factors associated with eligibility for 2L initiation, neither PS nor inflammatory and nutritional markers, previously reported as important predictors, were identified as independent determinants, and only the presence of ascites remained significantly associated with the transition to 2L in our cohort. Although limited data are available specifically in PC, emerging evidence suggests several factors that may predict 2L eligibility after 1L failure. A multicenter retrospective study in UR-PC reported that age (< 70 years), baseline CRP, and 1L regimen category (combination therapy vs. monotherapy) were significant predictors of 2L eligibility [ 29 ]. Another study focusing on elderly patients with UR-PC reported that elevated inflammatory-nutritional markers, such as NLR, were associated with ineligibility for nanoliposomal irinotecan plus 5-fluorouracil and leucovorin therapy [ 30 ]. In addition, in other tumor types, PS has consistently been reported as a key determinant of 2L receipt. For example, in advanced non-small cell lung cancer, better baseline PS was significantly associated with an increased likelihood of receiving 2L [ 31 ]. Compared with these previous reports, a notable finding of the present study is that a clinical condition such as ascites may have a more direct impact on treatment transition than commonly used global condition or prognostic indicators. Moreover, patients who successfully proceeded to 2L tended to have higher serum Alb, PNI, and LMR, along with lower CRP and mGPS values. These findings suggest that nutritional status and systemic inflammation may represent underlying factors associated with ascites development. Consistent with this interpretation, ascites likely reflects multiple adverse disease-related processes, including advanced tumor burden, malnutrition, and chronic systemic inflammation, which contribute to functional decline and reduced tolerance to chemotherapy. Previous reports have shown that ascites develops in approximately 20% of patients with metastatic PC [ 32 ] and is associated with poor quality of life and a dismal prognosis, with median survival after ascites diagnosis ranging from 27 to 92 days [ 33 , 34 ]. In a previous report [ 32 ], although ascites severity was not quantified at baseline, serial paracentesis was required in 90.2% of the patients, and the median volume removed at the first paracentesis was approximately 5 L, suggesting that many patients had clinically substantial fluid accumulation. In contrast, ascites in the present study was assessed only at baseline and analyzed simply as present or absent, without considering volume or symptom severity. Therefore, patients with massive or symptomatic ascites may have been underrepresented in our cohort, which should be acknowledged when interpreting our results. Importantly, although ascites emerged as a negative determinant of 2L initiation in the multivariate analysis, it should not be interpreted as an indicator of treatment futility. In the subgroup analyses, 2L initiation was associated with improved OS regardless of ascites status, provided that treatment could be started. Consistent with this finding, a previous report demonstrated that continuation of systemic therapy after ascites development was associated with significantly longer OS than BSC alone (HR 0.35, 95% CI 0.20–0.61; p < 0.001), with a median survival of 62 versus 16 days [ 34 ]. This apparent discrepancy can be explained by differences in the analytical populations, as the multivariate analysis evaluated factors associated with the ability to initiate 2L, whereas the subgroup analysis assessed outcomes only among patients who actually received 2L. Taken together, the findings suggest that ascites is an important clinical marker of advanced disease burden and a major barrier to treatment transition in UR-PC. However, selected patients may still derive meaningful survival benefit from 2L if treatment initiation is feasible. This study had several limitations. First, it was a retrospective single-center analysis and may have been influenced by selection bias and unmeasured confounding factors related to treatment allocation and clinical outcomes. Therefore, the association between 2L and survival should be evaluated in a prospective study. Although propensity score matching was considered to mitigate treatment selection bias, it was not feasible because only a small number of patients with baseline ascites proceeded to 2L. Second, the relatively small sample size limited detailed subgroup analyses according to 2L regimen types. The estimate for ascites had limited precision because only six patients with baseline ascites received 2L, resulting in imprecise estimates with wide CIs. Residual confounding related to disease burden and treatment decision making also cannot be excluded. Furthermore, 2L and DCR are time-dependent variables that occur during follow-up and may be subject to immortal bias. Accordingly, their associations with OS should be interpreted as correlational rather than causal. Third, some continuous variables were dichotomized using median or literature-based thresholds, which may reduce generalizability. Fourth, ascites was assessed only at baseline and treated as a binary variable based solely on imaging findings. The severity and volume of ascites were not quantitatively evaluated, and changes during therapy were not captured. Patients with massive ascites at baseline may have been excluded before the initiation of GnP therapy. Finally, this study included only Japanese patients treated between 2016 and 2024. Given recent advances in molecular targeted therapy and immunotherapy, caution is warranted when extrapolating these findings to other ethnic populations or evolving treatment settings. Conclusion Receipt of 2L was associated with improved survival among patients with UR-PC, and the absence of ascites was a key determinant of eligibility for subsequent treatment. However, once treatment was initiated, 2L was associated with prolonged OS regardless of baseline ascites status, suggesting that ascites represents a barrier to treatment transition rather than an indicator of treatment futility. These findings support proactive supportive care and individualized reassessment to maximize opportunities for sequential chemotherapy. Prospective studies are warranted to validate these results and establish strategies that improve eligibility for multiline treatment. Abbreviations 1L: first-line chemotherapy 2L: second-line chemotherapy 2L(+): received second-line chemotherapy 2L(−): did not receive second-line chemotherapy aOR: adjusted odds ratio AEs: adverse events AGR: albumin-to-globulin ratio Alb: albumin BMI: body mass index BSC: best supportive care CA19-9: carbohydrate antigen 19-9 CEA: carcinoembryonic antigen CI: confidence interval CR: complete response CRP: C-reactive protein CTCAE: Common Terminology Criteria for Adverse Events DCR: disease control rate ECOG PS: Eastern Cooperative Oncology Group performance status FOLFIRINOX: fluorouracil, leucovorin, irinotecan, and oxaliplatin GEM: gemcitabine GnP: gemcitabine plus nab-paclitaxel GNRI: Geriatric Nutritional Risk Index HR: hazard ratio IBPSs: inflammation-based prognostic parameters IQR: interquartile range JCOG: Japan Clinical Oncology Group LMR: lymphocyte-to-monocyte ratio mFOLFIRINOX: modified fluorouracil, leucovorin, irinotecan, and oxaliplatin mGPS: modified Glasgow Prognostic Score mOS: median overall survival MPACT: Metastatic Pancreatic Adenocarcinoma Clinical Trial NA: not available nal-IRI/FF: nanoliposomal irinotecan with fluorouracil and folinic acid NLR: neutrophil-to-lymphocyte ratio OR: odds ratio ORR: objective response rate OS: overall survival PC: pancreatic cancer PD: progressive disease PFS: progression-free survival PLR: platelet-to-lymphocyte ratio PNI: Prognostic Nutritional Index PR: partial response RECIST: Response Evaluation Criteria in Solid Tumors S-1: tegafur/gimeracil/oteracil SD: stable disease SD (statistics): standard deviation SIR: systemic inflammatory response SPSS: Statistical Package for the Social Sciences UR-LA: locally advanced unresectable UR-M: metastatic unresectable UR-PC: unresectable pancreatic cancer VIFs: variance inflation factors Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the University of Occupational and Environmental Health, Japan (approval no. UOEHCRB20-027). The requirement for written informed consent was waived due to the retrospective design, and an opt-out consent procedure was implemented as approved by the Institutional Review Board (IRB). Consent for publication Not applicable. Data availability statement The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors and Affiliations 1) Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan Tsuyoshi Ueda, Koichiro Miyagawa, Michihiko Shibata, Shinji Oe, Kenta Kajitani, Daiki Uchihara, Nobuhiko Shinohara, Noriyoshi Ogino, Shinsuke Kumei, Yuichi Honma, Tatsuyuki Watanabe, and Masaru Harada 2) Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan Yasuhisa Mori Author contributions Tsuyoshi Ueda: Conceptualization, Methodology, Formal analysis, Writing - Original Draft. Koichiro Miyagawa: Conceptualization, Supervision, Writing - Review & Editing. Michihiko Shibata: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Yasuhisa Mori: Writing - Review & Editing. Shinji Oe: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Kenta Kajitani: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Daiki Uchihara: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Nobuhiko Shinohara: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Noriyoshi Ogino: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Shinsuke Kumei: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Yuichi Honma: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Tatsuyuki Watanabe: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Masaru Harada: Formal analysis, Investigation, Data Curation, Writing - Review & Editing. Acknowledgements We thank all the participants and staff who cooperated with the surveys. 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Bockhorn M, Uzunoglu FG, Adham M, Imrie C, Milicevic M, Sandberg AA, et al; International Study Group of Pancreatic Surgery. Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2014;155(6):977-88. Eisenhauer 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(2):228-47. Ishida M, Fujii T, Kishiwada M, Shibuya K, Satoi S, Ueno M, et al. Japanese classification of pancreatic carcinoma by the Japan Pancreas Society: eighth edition. J Hepatobiliary Pancreat Sci. 2024;31(11):755-68. Toiyama Y, Miki C, Inoue Y, Tanaka K, Mohri Y, Kusunoki M. Evaluation of an inflammation-based prognostic score for the identification of patients requiring postoperative adjuvant chemotherapy for stage II colorectal cancer. Exp Ther Med. 2011;2(1):95-101. Bouillanne O, Morineau G, Dupont C, Coulombel I, Vincent JP, Nicolis I, et al. Geriatric Nutritional Risk Index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr. 2005;82(4):777-83. Geng Y, Qi Q, Sun M, Chen H, Wang P, Chen Z. Prognostic nutritional index predicts survival and correlates with systemic inflammatory response in advanced pancreatic cancer. Eur J Surg Oncol. 2015;41(11):1508-14. Lee SH, Chung MJ, Kim B, Lee HS, Lee HJ, Heo JY, et al. The significance of the prognostic nutritional index for all stages of pancreatic cancer. Nutr Cancer. 2017;69(3):512-9. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Bethesda (MD): National Cancer Institute; 2017 [cited 2024 Dec 31]. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm Colloca G. Performance status as prognostic factor in phase III trials of first-line chemotherapy of unresectable or metastatic pancreatic cancer: a trial-level meta-analysis. Asia Pac J Clin Oncol. 2022;18:232-9. Von 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(18):1691-703. Fu W, Wang K, Yan S, Wang X, Tang B, Chang J, et al. Prognostic significance of the modified Glasgow Prognostic Score in patients with pancreatic cancer: a meta-analysis. Dose Response. 2020;18(3):1559325820942065. Ohba A, Ozaka M, Mizusawa J, Okusaka T, Kobayashi S, Yamashita T, et al; Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG-HBPOG). Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin or S-1, irinotecan, and oxaliplatin versus nab-paclitaxel plus gemcitabine in metastatic or recurrent pancreatic cancer (GENERATE, JCOG1611): a randomized, open-label, phase II/III trial. J Clin Oncol. 2025;43(31):3345-54. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al; NAPOLI-1 Study Group. 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(10018):545-57. Sato K, Suzuki R, Konno N, Irie H, Watanabe KO, Imaizumi H, et al. Development and validation of a nomogram to predict eligibility for second-line chemotherapy in pancreatic cancer. Anticancer Res. 2025;45(10):4509-18. Ikoma T, Matsumoto T, Boku S, Yasuda T, Masuda M, Ito T, et al. A retrospective study investigating the safety and efficacy of nanoliposomal irinotecan in elderly patients with unresectable pancreatic cancer. J Clin Med. 2023;12(10):3477. Hensing TA, Schell MJ, Lee JH, Socinski MA. Factors associated with the likelihood of receiving second line therapy for advanced non-small cell lung cancer. Lung Cancer. 2005;47(2):253-9. Berger JM, Alany A, Puhr R, Berchtold L, Friedrich A, Scheiner B, et al. Clinical risk factors for ascites in metastatic pancreatic cancer. ESMO Open. 2023;8(2):101200. Wang J, Cui Y, Osipov A, Gong J, Pandol S, Lo S, et al. Ascites is a poor prognostic factor in advanced pancreatic adenocarcinoma and may be undertreated: a prospective cohort study. Clin Transl Gastroenterol. 2024;15(7):e00719. Berger JM, Alany A, Berchtold L, Puhr R, Friedrich A, Scheiner B, et al. Prognosticators of survival in patients with metastatic pancreatic cancer and ascites. ESMO Open. 2023;8(6):102048. Tables Tables 1 to 4 are available in the supplementary files section Additional Declarations No competing interests reported. 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Miyagawa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYBACCQbGBmYGAwYGfjAHCAygMswEtUg2EK8FKmlwAE0LTiDZ3tz4uaDgnpzxtcMHbzC22ciZM/AYMPyoYWA3x6FFmudgs/QMg2Jjs9tpyRaMbWnGlg08Bow9xxiYLRuwa5GTSGxj5jFISNx2O8dMgrHtcOKG+28MGHgbGJhBTsWrZfPs/G8gLfUbDgBt+YtHizRMywbpHDaQlgQDoBZmfLZI9gD9AtRiLHE7zdgi4Vya4YYDbAWHZY5J4PSLxPH2h595/iTI8c9OfnjjQ5mNvMEB5o0P39TYJOMKMVSQAKWBTpJIJhhBGMCOdC2jYBSMglEwTAEApLFQBP+DCX8AAAAASUVORK5CYII=","orcid":"","institution":"University of Occupational and Environmental Health Japan","correspondingAuthor":true,"prefix":"","firstName":"Koichiro","middleName":"","lastName":"Miyagawa","suffix":""},{"id":619693622,"identity":"7a9b29a4-2e78-44ae-92fc-96c9335651ce","order_by":2,"name":"Michihiko Shibata","email":"","orcid":"","institution":"University of Occupational and Environmental Health 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Japan","correspondingAuthor":false,"prefix":"","firstName":"Noriyoshi","middleName":"","lastName":"Ogino","suffix":""},{"id":619693644,"identity":"534035b4-4814-4bbf-b08c-20986c168537","order_by":9,"name":"Shinsuke Kumei","email":"","orcid":"","institution":"University of Occupational and Environmental Health Japan","correspondingAuthor":false,"prefix":"","firstName":"Shinsuke","middleName":"","lastName":"Kumei","suffix":""},{"id":619693647,"identity":"0d7550f3-1843-4848-8971-c116b4843a55","order_by":10,"name":"Yuichi Honma","email":"","orcid":"","institution":"University of Occupational and Environmental Health Japan","correspondingAuthor":false,"prefix":"","firstName":"Yuichi","middleName":"","lastName":"Honma","suffix":""},{"id":619693649,"identity":"30d66bf4-3847-4a24-9930-75c51772e7ec","order_by":11,"name":"Tatsuyuki Watanabe","email":"","orcid":"","institution":"University of Occupational and Environmental Health Japan","correspondingAuthor":false,"prefix":"","firstName":"Tatsuyuki","middleName":"","lastName":"Watanabe","suffix":""},{"id":619693650,"identity":"1310852c-10fc-4fab-b4ad-43ac7770ff50","order_by":12,"name":"Masaru Harada","email":"","orcid":"","institution":"University of Occupational and Environmental Health Japan","correspondingAuthor":false,"prefix":"","firstName":"Masaru","middleName":"","lastName":"Harada","suffix":""}],"badges":[],"createdAt":"2026-04-01 01:38:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9285193/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9285193/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106636054,"identity":"76a5e7c3-3707-4b8c-adf3-2008aeba70ec","added_by":"auto","created_at":"2026-04-10 16:52:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":135505,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of the included patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: GnP, gemcitabine plus nab-paclitaxel; 2L(+), second-line chemotherapy; 2L(−), no second-line chemotherapy.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9285193/v1/9c2dce2a64c91115475249b5.png"},{"id":106636056,"identity":"eeba937b-36e5-4b6f-86d2-11232bc5c5fa","added_by":"auto","created_at":"2026-04-10 16:52:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":169667,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier survival analyses of OS (a) and PFS (b) in patients with UR-PC.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Patients were categorized into the 2L(+) group (red line) and the 2L(−) group (blue line). The median\u003cstrong\u003e \u003c/strong\u003eOS in the 2L(+) group was better than that in the 2L(−) group.\u003c/p\u003e\n\u003cp\u003e(b) Patients were categorized into the 2L(+) group (red line) and the 2L(−) group (blue line). The median\u003cstrong\u003e \u003c/strong\u003ePFS in the 2L(+) group was better than that in the 2L(−) group.\u003c/p\u003e\n\u003cp\u003eAbbreviations: OS, overall survival; PFS, progression-free survival; UR-PC, unresectable pancreatic cancer; 2L(+), second-line chemotherapy; 2L(−), no second-line chemotherapy.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9285193/v1/d8fad305bb1a2cb7205f3358.png"},{"id":106727081,"identity":"7e0fc0d9-556c-4191-8e74-1057af491b85","added_by":"auto","created_at":"2026-04-12 18:38:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":72630,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier survival analysis of OS stratified by the presence or absence of 2L among patients with ascites in the subgroup analysis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were categorized into the 2L(+) group (red line) and the 2L(−) group (blue line). The median\u003cstrong\u003e \u003c/strong\u003eOS in the 2L(+) group was better than that in the 2L(−) group.\u003c/p\u003e\n\u003cp\u003eAbbreviations: OS, overall survival; 2L(+), second-line chemotherapy; 2L(−), no second-line chemotherapy.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9285193/v1/0b687bda54d560629ee123d1.png"},{"id":107479136,"identity":"73e4f071-c9f7-4d6f-bf5a-413efdfd273e","added_by":"auto","created_at":"2026-04-22 01:19:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":782557,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9285193/v1/6cad7040-c878-4a48-a078-278f4fbbc9ab.pdf"},{"id":106726724,"identity":"81231014-6ce9-49b5-93d8-15760d592bb4","added_by":"auto","created_at":"2026-04-12 18:37:11","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":786982,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9285193/v1/33b9082ee4ce479511ba91bb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Determinants of eligibility for second-line chemotherapy following gemcitabine plus nab-paclitaxel therapy in patients with unresectable pancreatic cancer: A retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003ePancreatic cancer (PC) is associated with high mortality and poor therapeutic outcomes. The 5-year overall survival (OS) rate of PC is approximately 12%, and the recurrence rate is high [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Around 51% of patients with PC are diagnosed with distant metastatic disease at presentation, and the 5-year relative survival for distant disease is only 3.2% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to the 2019 Japanese Clinical Practice Guidelines for Pancreatic Cancer, gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are recommended as first-line chemotherapy (1L) regimens for PC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In clinical practice, GnP is frequently selected as 1L owing to its favorable balance between efficacy and tolerability [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Previous studies have demonstrated that patients with PC receiving second-line chemotherapy (2L) achieved significantly longer OS than those who received best supportive care (BSC) [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It has been reported that the median OS (mOS) of patients who received 2L after 1L failure was 5.6 months, significantly longer than in the BSC group (1.9 months) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Moreover, 2L was identified as an independent prognostic factor [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the reported survival benefits of 2L, the proportion of patients who can proceed to 2L remains limited, equating to approximately 46.0%\u0026ndash;53.7% of the overall population [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Previous studies have suggested that Eastern Cooperative Oncology Group performance status (PS) and the presence of ascites are pragmatic clinical indicators of chemotherapy feasibility [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In addition, systemic inflammatory response (SIR) markers, such as the neutrophil-to-lymphocyte ratio (NLR), have been reported to be associated with PC prognosis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, the 2017 International Consensus Guidelines proposed a carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (CA19-9) concentration\u0026thinsp;\u0026ge;\u0026thinsp;500 U/mL as a biological high-risk feature, which has been associated with advanced disease and poor prognosis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, no established biomarkers or clinical indicators are currently available to predict eligibility for 2L initiation. Identifying factors that can predict transition to subsequent treatment is therefore important for optimizing treatment sequencing and improving overall treatment strategies.\u003c/p\u003e \u003cp\u003eThis study aimed to identify baseline clinical and laboratory factors associated with 2L initiation in patients with unresectable PC (UR-PC) who received 1L GnP.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cem\u003ePatients and study design\u003c/em\u003e \u003c/p\u003e \u003cp\u003eIn this retrospective single-center study, the data of 164 patients with UR-PC who received 1L GnP from January 2016 to December 2024 were analyzed. As shown in the flowchart (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), patients with postoperative recurrence of PC (n\u0026thinsp;=\u0026thinsp;22), conversion surgery (n\u0026thinsp;=\u0026thinsp;4), ongoing 1L GnP (n\u0026thinsp;=\u0026thinsp;9), and insufficient clinical data (n\u0026thinsp;=\u0026thinsp;5) were excluded. Finally, 124 patients were enrolled. The patients were divided into two groups based on 2L receipt [2L (+)] or non-receipt [2L (\u0026minus;)]. The end of the follow-up period was defined as the date of the last visit for surviving patients and the date of death for deceased patients. This study was censored on 31 December 2024.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e The diagnosis of PC was established based on contrast-enhanced computed tomography findings and/or histopathological confirmation using endoscopic ultrasound-guided tissue acquisition or cytology obtained during endoscopic retrograde cholangiopancreatography. Clinical data at 1L (baseline) were obtained from the patients\u0026rsquo; medical records, including demographics (age and sex), PS, presence or absence of ascites assessed by imaging (without quantitative assessment).\u003c/p\u003e \u003cp\u003e \u003cem\u003eStudy endpoints\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe primary endpoint was the identification of factors associated with eligibility for 2L initiation. The administration of 2L was defined as the initiation of any chemotherapy after completion or discontinuation of 1L GnP. The secondary endpoints included OS, progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events (AEs), and reasons for not receiving 2L. OS was defined as the time from 1L GnP initiation to death from any cause or final follow-up. PFS was measured from 1L GnP initiation to the first occurrence of disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] or death, whichever occurred first. Patients without documented progression who were lost to follow-up were censored at their final radiological tumor assessment.\u003c/p\u003e \u003cp\u003e \u003cem\u003eTreatment protocol and therapeutic response evaluation\u003c/em\u003e \u003c/p\u003e \u003cp\u003eGnP initiation was determined based on the Japanese Clinical Practice Guidelines for Pancreatic Cancer 2019 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Locally advanced unresectable (UR-LA) PC and unresectable metastatic (UR-M) PC were defined according to the criteria established in the 8th edition of the Japan Pancreas Society classification [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. UR-LA was defined as tumor involvement of the portal vein and/or superior mesenteric vein that was considered unreconstructible due to occlusion, and/or arterial involvement characterized by tumor abutment of \u0026ge;\u0026thinsp;180\u0026deg; with the superior mesenteric artery, hepatic artery, or celiac artery. UR-M was defined as PC with distant metastasis, including hepatic, peritoneal, pulmonary, or other extra-pancreatic organ involvement, as confirmed by imaging or intraoperative findings.\u003c/p\u003e \u003cp\u003eThe therapeutic response was assessed according to RECIST version 1.1. A complete response (CR) was defined as the complete disappearance of all target lesions. A partial response (PR) was defined as a decrease of \u0026ge;\u0026thinsp;30% in the sum of the diameters of target lesions compared with baseline measurements. Progressive disease (PD) was defined as an increase of \u0026ge;\u0026thinsp;20% in the sum of target lesion diameters from the lowest value recorded during the study (including baseline if lowest), with a minimum absolute increase of 5 mm. The appearance of new lesions was also classified as PD. Stable disease (SD) was defined as tumor changes that did not meet the criteria for either PR or PD. The ORR was defined as the proportion of patients with CR or PR. The DCR was defined as the proportion of patients achieving CR, PR, or SD.\u003c/p\u003e \u003cp\u003e \u003cem\u003eLaboratory tests\u003c/em\u003e \u003c/p\u003e \u003cp\u003eHematology and chemistry tests were performed using standard methods. Baseline laboratory values at 1L initiation included serum albumin (Alb), C-reactive protein (CRP), and CA19-9, and peripheral blood cell counts. SIR, reflecting cancer-related inflammation, was assessed using established inflammation-based prognostic parameters (IBPSs). These IBPSs included Alb-to-globulin ratio (AGR), NLR, lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR). These indices were calculated using Alb, globulin, CRP, and the absolute counts of neutrophils, monocytes, lymphocytes, and platelets from peripheral blood samples.\u003c/p\u003e \u003cp\u003eThe modified Glasgow Prognostic Score (mGPS) is an established IBPS reflecting systemic inflammation and nutritional status [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The mGPS was calculated according to the method of Toiyama et al., as follows: patients with both elevated CRP (\u0026gt;\u0026thinsp;0.5 mg/dL) and hypoalbuminemia (\u0026lt;\u0026thinsp;3.5 g/dL) were assigned a score of 2 (mGPS 2); those with either abnormality were assigned a score of 1 (mGPS 1); and those with neither were assigned a score of 0 (mGPS 0) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Geriatric Nutritional Risk Index (GNRI) was calculated using serum Alb and body weight according to the following formula: GNRI = [1.489 \u0026times; Alb (g/L)] + [41.7 \u0026times; present body weight\u0026thinsp;\u0026divide;\u0026thinsp;ideal body weight].\u003c/p\u003e \u003cp\u003eBody mass index (BMI) was calculated using the body weight, and ideal body weight was estimated based on a BMI of 22 and patient height [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The Prognostic Nutritional Index (PNI) was calculated using the following formula [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]: PNI = [10 \u0026times; Alb (g/dL)\u0026thinsp;+\u0026thinsp;0.005 \u0026times; lymphocyte count (/mm\u003csup\u003e3\u003c/sup\u003e)].\u003c/p\u003e \u003cp\u003eThe Controlling Nutritional Status score was not assessed because total cholesterol concentration was unavailable for some patients.\u003c/p\u003e \u003cp\u003e \u003cem\u003eAssessment of AEs associated with GnP therapy\u003c/em\u003e \u003c/p\u003e \u003cp\u003eAEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE version 5.0) and graded from 1 to 5 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In patients who experienced grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs associated with GnP therapy, the treatment strategies were modified as appropriate, including dose reduction, temporary interruption, or discontinuation of chemotherapy.\u003c/p\u003e \u003cp\u003e \u003cem\u003eStatistical analysis\u003c/em\u003e \u003c/p\u003e \u003cp\u003eStatistical analyses were performed using the Statistical Package for the Social Sciences Software Program (SPSS) version 25.0 (IBM, Tokyo, Japan). Categorical variables are presented as numbers and percentages and were compared using the chi-square test or Fisher\u0026rsquo;s exact test, as appropriate. Continuous variables are summarized as the median with interquartile range (IQR) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, depending on the distribution normality. Comparisons between continuous variables were performed using the Student\u0026rsquo;s t-test for normally distributed variables and the Mann\u0026ndash;Whitney U test for non-normally distributed variables.\u003c/p\u003e \u003cp\u003eORR and DCR were compared using the chi-square test or Fisher\u0026rsquo;s exact test. OS and PFS following GnP initiation were estimated using the Kaplan\u0026ndash;Meier method, and survival curves were compared using the log-rank test. Prognostic factors for OS were analyzed by Cox proportional-hazards regression analysis. Factors associated with eligibility for 2L were analyzed using binomial logistic regression analysis.\u003c/p\u003e \u003cp\u003eBased on prior studies, PS\u0026thinsp;\u0026ge;\u0026thinsp;1 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and mGPS\u0026thinsp;\u0026ge;\u0026thinsp;1 [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] were used as predefined poor prognostic factors in this study. The cutoff values for CA19-9 were set at \u0026ge;\u0026thinsp;500 U/mL, in accordance with the 2017 International Consensus Guidelines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Cutoff values for the other variables were determined around the median values.\u003c/p\u003e \u003cp\u003eThe prognostic factors analyzed were age (\u0026ge;\u0026thinsp;70 vs. \u0026lt;70 years), sex (male vs. female), PS (\u0026ge;\u0026thinsp;1 vs. 0), ascites (yes vs. no), 2L (yes vs. no), tumor location (body and tail vs. head), disease extension (UR-M vs. UR-LA), whether grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs occurred (yes vs. no), DCR (yes vs. no), CA19-9 (\u0026ge;\u0026thinsp;500 vs. \u0026lt;500 U/mL), GNRI (\u0026ge;\u0026thinsp;97.0 vs. \u0026lt;97.0), PNI (\u0026ge;\u0026thinsp;46.0 vs. \u0026lt;46.0), mGPS (\u0026ge;\u0026thinsp;1 vs. 0), NLR (\u0026ge;\u0026thinsp;3.2 vs. \u0026lt;3.2), LMR (\u0026ge;\u0026thinsp;3.8 vs. \u0026lt;3.8), PLR (\u0026ge;\u0026thinsp;168.0 vs. \u0026lt;168.0), and AGR (\u0026ge;\u0026thinsp;1.3 vs. \u0026lt;1.3).\u003c/p\u003e \u003cp\u003eAll statistical tests were two-sided. To analyze the factors associated with OS, a significance threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was applied in the univariate analyses, and variables meeting this criterion were subsequently included in the multivariate Cox proportional-hazards regression model. To analyze the determinants of 2L eligibility, variables with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in the univariate analyses were included in the multivariate logistic regression analysis. Multicollinearity was assessed using variance inflation factors (VIFs).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics of the patients within 1 month from the diagnosis of PC to 1L initiation are summarized in Table 1. The median follow-up period, from the date of 1L initiation to the date of the final follow-up, was 10.0 months. The median age was 71 years (IQR 66−75), and 70 patients (56.5%) were male. Compared with the 2L(−) group, the 2L(+) group was significantly less likely to present with ascites at 1L initiation (p \u0026lt; 0.001) and exhibited better PS (p = 0.036). There was no statistically significant difference between the two groups in the incidence of grade ≥ 3 AEs associated with GnP therapy, as assessed by CTCAE version 5.0 (p = 0.108). Among the 2L(−) group, the reasons for GnP discontinuation were primarily GnP-related AEs and PS decline. The 2L(+) group had a significantly longer duration of GnP therapy (p \u0026lt; 0.001), higher serum Alb concentration (p = 0.020), lower serum CRP concentration (p = 0.047), lower serum carcinoembryonic antigen (p = 0.049), and more favorable LMR (p = 0.048).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEfficacy of GnP therapy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe efficacy outcomes are summarized in Table 2. Both the ORR and the DCR were significantly higher in the 2L(+) group than in the 2L(−) group (ORR: 31.7% vs. 16.4%; p = 0.046; DCR: 57.1% vs. 36.1%; p = 0.011) (Table 2).\u003c/p\u003e\n\u003cp\u003eThe mOS in the 2L(+) group was 15.5 months (95% confidence interval [CI] 11.51–19.49), significantly longer than in the 2L(−) group (4.7 months, 95% CI 3.24–6.16) (log-rank p \u0026lt; 0.001) (Figure 2a). A similar trend was observed for median PFS [2L(+): 5.9 months (95% CI 4.49–7.37) vs. 2L(−) group: 3.0 months (95% CI 1.96–3.97); log-rank p = 0.004] (Figure 2b).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrognostic factors for OS\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate and multivariate Cox regression analyses were performed to identify the prognostic factors associated with OS (Table 3). In the univariate analysis, the following factors were significantly associated with longer OS: absence of ascites, receipt of 2L, disease extension (UR-LA), better DCR, lower mGPS, and LMR ≥ 3.8. Multivariate analysis identified 2L administration (HR 0.262, 95% CI 0.169–0.408; p \u0026lt; 0.001), better DCR (vs. poor DCR; HR 0.398, 95% CI 0.258–0.614; p \u0026lt; 0.001), better NLR (vs. worse NLR; HR 0.530, 95% CI 0.301–0.934; p = 0.028) as independent determinants of longer OS. In the multivariable Cox model for OS, the maximum VIF among the covariates entered into the model was 1.92, indicating no clinically relevant multicollinearity.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePredictive factors for 2L eligibility\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted univariate and multivariate binomial logistic regression analyses to identify the factors associated with 2L eligibility (Table 4). The univariate analyses identified better PS, absence of ascites, disease extension (UR-LA), and higher LMR as factors associated with 2L eligibility.\u003c/p\u003e\n\u003cp\u003eMultivariate analysis identified that the absence of ascites remained independently associated with 2L eligibility (adjusted odds ratio [aOR] 4.435, 95% CI 1.583–12.423; p = 0.005). In contrast, PS 0 showed only a trend toward increased eligibility for 2L but did not reach statistical significance (aOR 2.385, 95% CI 0.979–5.815; p = 0.056) in our cohort. In the multivariable logistic regression model for 2L initiation, all covariates showed low VIFs, and the maximum VIF was approximately 1.25, indicating no clinically relevant multicollinearity.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSubgroup analyses stratified by ascites\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the subgroup with baseline ascites, mOS was longer in the 2L(+) group (10.2 months, 95% CI 5.84–14.50) than in the 2L(−) group (2.5 months, 95% CI 1.40–3.60) (log-rank p = 0.014) (Figure 3). In the Cox proportional-hazards regression analysis within this subgroup, receipt of 2L was associated with longer OS (HR 0.263, 95% CI 0.086–0.807; p = 0.019).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this cohort of patients with UR-PC treated with GnP, the presence of ascites was an important clinical factor associated with difficulty in initiating 2L. In addition, even among patients with ascites at baseline of 1L, those who were able to receive 2L tended to have better survival outcomes. These findings indicate that ascites may influence the transition to subsequent treatment rather than being an absolute indicator of poor prognosis.\u003c/p\u003e \u003cp\u003eIn the present study, GnP efficacy and safety were generally consistent with previous pivotal clinical trials [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Survival outcomes in the 2L(+) group were comparable to those observed in the GnP arms of both the MPACT and JCOG1611/GENERATE trials [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In addition, the incidence of AEs, including neutropenia and fatigue, was comparable to previous studies [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In contrast, patients who did not transition to 2L had markedly poorer outcomes, with an mOS of 4.7 months and an mPFS of 3.0 months. These findings are consistent with previous reports demonstrating the survival benefit of appropriate sequential chemotherapy and underscore the clinical importance of maintaining treatment continuity beyond 1L [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The proportion of patients who successfully proceeded to 2L in the present study was comparable to that reported in previous real-world studies (46.0%\u0026ndash;53.7%) [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Notably, GnP discontinuation in the 2L(\u0026minus;) group was frequently attributable to treatment-related AEs or PS decline, suggesting that reduced GnP tolerability may represent a major barrier to 2L initiation.\u003c/p\u003e \u003cp\u003eIn the analysis of factors associated with eligibility for 2L initiation, neither PS nor inflammatory and nutritional markers, previously reported as important predictors, were identified as independent determinants, and only the presence of ascites remained significantly associated with the transition to 2L in our cohort. Although limited data are available specifically in PC, emerging evidence suggests several factors that may predict 2L eligibility after 1L failure. A multicenter retrospective study in UR-PC reported that age (\u0026lt;\u0026thinsp;70 years), baseline CRP, and 1L regimen category (combination therapy vs. monotherapy) were significant predictors of 2L eligibility [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother study focusing on elderly patients with UR-PC reported that elevated inflammatory-nutritional markers, such as NLR, were associated with ineligibility for nanoliposomal irinotecan plus 5-fluorouracil and leucovorin therapy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In addition, in other tumor types, PS has consistently been reported as a key determinant of 2L receipt. For example, in advanced non-small cell lung cancer, better baseline PS was significantly associated with an increased likelihood of receiving 2L [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Compared with these previous reports, a notable finding of the present study is that a clinical condition such as ascites may have a more direct impact on treatment transition than commonly used global condition or prognostic indicators. Moreover, patients who successfully proceeded to 2L tended to have higher serum Alb, PNI, and LMR, along with lower CRP and mGPS values. These findings suggest that nutritional status and systemic inflammation may represent underlying factors associated with ascites development.\u003c/p\u003e \u003cp\u003eConsistent with this interpretation, ascites likely reflects multiple adverse disease-related processes, including advanced tumor burden, malnutrition, and chronic systemic inflammation, which contribute to functional decline and reduced tolerance to chemotherapy. Previous reports have shown that ascites develops in approximately 20% of patients with metastatic PC [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and is associated with poor quality of life and a dismal prognosis, with median survival after ascites diagnosis ranging from 27 to 92 days [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In a previous report [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], although ascites severity was not quantified at baseline, serial paracentesis was required in 90.2% of the patients, and the median volume removed at the first paracentesis was approximately 5 L, suggesting that many patients had clinically substantial fluid accumulation. In contrast, ascites in the present study was assessed only at baseline and analyzed simply as present or absent, without considering volume or symptom severity. Therefore, patients with massive or symptomatic ascites may have been underrepresented in our cohort, which should be acknowledged when interpreting our results.\u003c/p\u003e \u003cp\u003eImportantly, although ascites emerged as a negative determinant of 2L initiation in the multivariate analysis, it should not be interpreted as an indicator of treatment futility. In the subgroup analyses, 2L initiation was associated with improved OS regardless of ascites status, provided that treatment could be started. Consistent with this finding, a previous report demonstrated that continuation of systemic therapy after ascites development was associated with significantly longer OS than BSC alone (HR 0.35, 95% CI 0.20\u0026ndash;0.61; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with a median survival of 62 versus 16 days [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This apparent discrepancy can be explained by differences in the analytical populations, as the multivariate analysis evaluated factors associated with the ability to initiate 2L, whereas the subgroup analysis assessed outcomes only among patients who actually received 2L. Taken together, the findings suggest that ascites is an important clinical marker of advanced disease burden and a major barrier to treatment transition in UR-PC. However, selected patients may still derive meaningful survival benefit from 2L if treatment initiation is feasible.\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, it was a retrospective single-center analysis and may have been influenced by selection bias and unmeasured confounding factors related to treatment allocation and clinical outcomes. Therefore, the association between 2L and survival should be evaluated in a prospective study. Although propensity score matching was considered to mitigate treatment selection bias, it was not feasible because only a small number of patients with baseline ascites proceeded to 2L. Second, the relatively small sample size limited detailed subgroup analyses according to 2L regimen types. The estimate for ascites had limited precision because only six patients with baseline ascites received 2L, resulting in imprecise estimates with wide CIs. Residual confounding related to disease burden and treatment decision making also cannot be excluded. Furthermore, 2L and DCR are time-dependent variables that occur during follow-up and may be subject to immortal bias. Accordingly, their associations with OS should be interpreted as correlational rather than causal. Third, some continuous variables were dichotomized using median or literature-based thresholds, which may reduce generalizability. Fourth, ascites was assessed only at baseline and treated as a binary variable based solely on imaging findings. The severity and volume of ascites were not quantitatively evaluated, and changes during therapy were not captured. Patients with massive ascites at baseline may have been excluded before the initiation of GnP therapy. Finally, this study included only Japanese patients treated between 2016 and 2024. Given recent advances in molecular targeted therapy and immunotherapy, caution is warranted when extrapolating these findings to other ethnic populations or evolving treatment settings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eReceipt of 2L was associated with improved survival among patients with UR-PC, and the absence of ascites was a key determinant of eligibility for subsequent treatment. However, once treatment was initiated, 2L was associated with prolonged OS regardless of baseline ascites status, suggesting that ascites represents a barrier to treatment transition rather than an indicator of treatment futility. These findings support proactive supportive care and individualized reassessment to maximize opportunities for sequential chemotherapy. Prospective studies are warranted to validate these results and establish strategies that improve eligibility for multiline treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003e1L:\u003c/strong\u003e first-line chemotherapy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2L:\u003c/strong\u003e second-line chemotherapy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2L(+):\u003c/strong\u003e received second-line chemotherapy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2L(\u0026minus;):\u003c/strong\u003e did not receive second-line chemotherapy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eaOR:\u003c/strong\u003e adjusted odds ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAEs:\u003c/strong\u003e adverse events\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAGR:\u003c/strong\u003e albumin-to-globulin ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAlb:\u003c/strong\u003e albumin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI:\u003c/strong\u003e body mass index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBSC:\u003c/strong\u003e best supportive care\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCA19-9:\u003c/strong\u003e carbohydrate antigen 19-9\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCEA:\u003c/strong\u003e carcinoembryonic antigen\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI:\u003c/strong\u003e confidence interval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCR:\u003c/strong\u003e complete response\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRP:\u003c/strong\u003e C-reactive protein\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCTCAE:\u003c/strong\u003e Common Terminology Criteria for Adverse Events\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDCR:\u003c/strong\u003e disease control rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eECOG PS:\u003c/strong\u003e Eastern Cooperative Oncology Group performance status\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFOLFIRINOX:\u003c/strong\u003e fluorouracil, leucovorin, irinotecan, and oxaliplatin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGEM:\u003c/strong\u003e gemcitabine\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGnP:\u003c/strong\u003e gemcitabine plus nab-paclitaxel\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGNRI:\u003c/strong\u003e Geriatric Nutritional Risk Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHR:\u003c/strong\u003e hazard ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIBPSs:\u003c/strong\u003e inflammation-based prognostic parameters\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIQR:\u003c/strong\u003e interquartile range\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJCOG:\u003c/strong\u003e Japan Clinical Oncology Group\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLMR:\u003c/strong\u003e lymphocyte-to-monocyte ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003emFOLFIRINOX:\u003c/strong\u003e modified fluorouracil, leucovorin, irinotecan, and oxaliplatin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003emGPS:\u003c/strong\u003e modified Glasgow Prognostic Score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003emOS:\u003c/strong\u003e median overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMPACT:\u003c/strong\u003e Metastatic Pancreatic Adenocarcinoma Clinical Trial\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNA:\u003c/strong\u003e not available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003enal-IRI/FF:\u003c/strong\u003e nanoliposomal irinotecan with fluorouracil and folinic acid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNLR:\u003c/strong\u003e neutrophil-to-lymphocyte ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOR:\u003c/strong\u003e odds ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORR:\u003c/strong\u003e objective response rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOS:\u003c/strong\u003e overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePC:\u003c/strong\u003e pancreatic cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD:\u003c/strong\u003e progressive disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePFS:\u003c/strong\u003e progression-free survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePLR:\u003c/strong\u003e platelet-to-lymphocyte ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePNI:\u003c/strong\u003e Prognostic Nutritional Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePR:\u003c/strong\u003e partial response\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRECIST:\u003c/strong\u003e Response Evaluation Criteria in Solid Tumors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eS-1:\u003c/strong\u003e tegafur/gimeracil/oteracil\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSD:\u003c/strong\u003e stable disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSD (statistics):\u003c/strong\u003e standard deviation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSIR:\u003c/strong\u003e systemic inflammatory response\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSPSS:\u003c/strong\u003e Statistical Package for the Social Sciences\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUR-LA:\u003c/strong\u003e locally advanced unresectable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUR-M:\u003c/strong\u003e metastatic unresectable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUR-PC:\u003c/strong\u003e unresectable pancreatic cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVIFs:\u003c/strong\u003e variance inflation factors\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the University of Occupational and Environmental Health, Japan (approval no. UOEHCRB20-027). The requirement for written informed consent was waived due to the retrospective design, and an opt-out consent procedure was implemented as approved by the Institutional Review Board (IRB).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\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\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1) Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan\u003c/p\u003e\n\u003cp\u003eTsuyoshi Ueda, Koichiro Miyagawa, Michihiko Shibata, Shinji Oe, Kenta Kajitani, Daiki Uchihara, Nobuhiko Shinohara, Noriyoshi Ogino, Shinsuke Kumei, Yuichi Honma, Tatsuyuki Watanabe, and Masaru Harada\u003c/p\u003e\n\u003cp\u003e2) Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan\u003c/p\u003e\n\u003cp\u003eYasuhisa Mori\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTsuyoshi Ueda: Conceptualization, Methodology, Formal analysis, Writing - Original Draft. Koichiro Miyagawa: Conceptualization, Supervision, Writing - Review \u0026amp; Editing. Michihiko Shibata: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Yasuhisa Mori: Writing - Review \u0026amp; Editing. Shinji Oe: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Kenta Kajitani: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Daiki Uchihara: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Nobuhiko Shinohara: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Noriyoshi Ogino: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Shinsuke Kumei: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Yuichi Honma: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Tatsuyuki Watanabe: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing. Masaru Harada: Formal analysis, Investigation, Data Curation, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants and staff who cooperated with the surveys. We thank Emily Woodhouse, PhD, from Edanz (https://jp.edanz.com/ac)\u0026nbsp;for editing a draft of this manuscript, in accordance with the international guidelines for Good Publication Practice.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.\u003c/li\u003e\n\u003cli\u003e[dataset] Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Incidence\u0026mdash;SEER Research Data, 17 Registries, Nov 2022 Sub (2000-2020) - Linked To County Attributes\u0026mdash;Time Dependent (1990-2021) Income/Rurality, 1969-2021 Counties. National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program; 2023.\u003c/li\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63.\u003c/li\u003e\n\u003cli\u003eOkusaka T, Nakamura M, Yoshida M, Kitano M, Uesaka K, Ito Y, et al. Committee for Revision of Clinical Guidelines for Pancreatic Cancer of the Japan Pancreas Society. Clinical Practice Guidelines for Pancreatic Cancer 2019 From the Japan Pancreas Society: A synopsis. Pancreas. 2020;49(3):326-35.\u003c/li\u003e\n\u003cli\u003ePelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, D\u0026ouml;rken B, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011;47(11):1676-81.\u003c/li\u003e\n\u003cli\u003eFukahori M, Okabe Y, Shimokawa M, Otsuka T, Koga F, Ueda Y, et al. Efficacy of second-line chemotherapy after treatment with gemcitabine plus nab-paclitaxel or FOLFIRINOX in patients with metastatic pancreatic cancer. Sci Rep. 2023;13(1):19399.\u003c/li\u003e\n\u003cli\u003eLiu Y, Guo X, Xu P, Song Y, Huang J, Chen X, et al. Clinical outcomes of second-line chemotherapy in patients with advanced pancreatic adenocarcinoma: a real-world study. Cancer Biol Med. 2024;21(9):799-812.\u003c/li\u003e\n\u003cli\u003eKing G, Ittershagen S, He L, Shen Y, Li F, Villacorta R. Treatment patterns in US patients receiving first-line and second-line therapy for metastatic pancreatic ductal adenocarcinoma in the real world. Adv Ther. 2022;39(12):5433-52.\u003c/li\u003e\n\u003cli\u003eAseafan M, Alfakeeh AH, Tashkandi E, Mahrous M, Alghamdi M, Alshamsan B, et al. Real-world clinical outcome of unresectable locally advanced and de-novo metastatic pancreatic ductal adenocarcinoma: a multicentre retrospective study. BMC Cancer. 2025;25:7.\u003c/li\u003e\n\u003cli\u003eSinn M, D\u0026auml;lken L, Striefler JK, Bischoff S, Schweitzer N, Pelzer U, et al. Second-line treatment in pancreatic cancer patients: who profits? Results from the CONKO Study Group. Pancreas. 2016;45(4):601-5.\u003c/li\u003e\n\u003cli\u003eVienot A, Beinse G, Louvet C, de Mestier L, Meurisse A, Fein F, et al. Overall survival prediction and usefulness of second-line chemotherapy in advanced pancreatic adenocarcinoma. J Natl Cancer Inst. 2017;109(10):doi:10.1093/jnci/djx037.\u003c/li\u003e\n\u003cli\u003eGiordano G, Milella M, Landriscina M, Bergamo F, Tirino G, Santaniello A, et al. Prognostic analysis and outcomes of metastatic pancreatic cancer patients receiving nab-paclitaxel plus gemcitabine as second or later-line treatment. Cancer Med. 2024;13(12):e7345.\u003c/li\u003e\n\u003cli\u003eGao Y, Wang WJ, Zhi Q, Shen M, Jiang M, Bian X, et al. Neutrophil/lymphocyte ratio is a more sensitive systemic inflammatory response biomarker than platelet/lymphocyte ratio in the prognosis evaluation of unresectable pancreatic cancer. Oncotarget. 2017;8(51):88835-44.\u003c/li\u003e\n\u003cli\u003eMcMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12(3):223-6.\u003c/li\u003e\n\u003cli\u003eIsaji S, Mizuno S, Windsor JA, Bassi C, Fern\u0026aacute;ndez-Del Castillo C, Hackert T, et al. International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. Pancreatology. 2018;18(1):2-11.\u003c/li\u003e\n\u003cli\u003eBockhorn M, Uzunoglu FG, Adham M, Imrie C, Milicevic M, Sandberg AA, et al; International Study Group of Pancreatic Surgery. Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2014;155(6):977-88.\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(2):228-47.\u003c/li\u003e\n\u003cli\u003eIshida M, Fujii T, Kishiwada M, Shibuya K, Satoi S, Ueno M, et al. Japanese classification of pancreatic carcinoma by the Japan Pancreas Society: eighth edition. J Hepatobiliary Pancreat Sci. 2024;31(11):755-68.\u003c/li\u003e\n\u003cli\u003eToiyama Y, Miki C, Inoue Y, Tanaka K, Mohri Y, Kusunoki M. Evaluation of an inflammation-based prognostic score for the identification of patients requiring postoperative adjuvant chemotherapy for stage II colorectal cancer. Exp Ther Med. 2011;2(1):95-101.\u003c/li\u003e\n\u003cli\u003eBouillanne O, Morineau G, Dupont C, Coulombel I, Vincent JP, Nicolis I, et al. Geriatric Nutritional Risk Index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr. 2005;82(4):777-83.\u003c/li\u003e\n\u003cli\u003eGeng Y, Qi Q, Sun M, Chen H, Wang P, Chen Z. Prognostic nutritional index predicts survival and correlates with systemic inflammatory response in advanced pancreatic cancer. Eur J Surg Oncol. 2015;41(11):1508-14.\u003c/li\u003e\n\u003cli\u003eLee SH, Chung MJ, Kim B, Lee HS, Lee HJ, Heo JY, et al. The significance of the prognostic nutritional index for all stages of pancreatic cancer. Nutr Cancer. 2017;69(3):512-9.\u003c/li\u003e\n\u003cli\u003eNational Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Bethesda (MD): National Cancer Institute; 2017 [cited 2024 Dec 31]. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm\u003c/li\u003e\n\u003cli\u003eColloca G. Performance status as prognostic factor in phase III trials of first-line chemotherapy of unresectable or metastatic pancreatic cancer: a trial-level meta-analysis. Asia Pac J Clin Oncol. 2022;18:232-9.\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(18):1691-703.\u003c/li\u003e\n\u003cli\u003eFu W, Wang K, Yan S, Wang X, Tang B, Chang J, et al. Prognostic significance of the modified Glasgow Prognostic Score in patients with pancreatic cancer: a meta-analysis. Dose Response. 2020;18(3):1559325820942065.\u003c/li\u003e\n\u003cli\u003eOhba A, Ozaka M, Mizusawa J, Okusaka T, Kobayashi S, Yamashita T, et al; Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG-HBPOG). Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin or S-1, irinotecan, and oxaliplatin versus nab-paclitaxel plus gemcitabine in metastatic or recurrent pancreatic cancer (GENERATE, JCOG1611): a randomized, open-label, phase II/III trial. J Clin Oncol. 2025;43(31):3345-54.\u003c/li\u003e\n\u003cli\u003eWang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al; NAPOLI-1 Study Group. 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(10018):545-57.\u003c/li\u003e\n\u003cli\u003eSato K, Suzuki R, Konno N, Irie H, Watanabe KO, Imaizumi H, et al. Development and validation of a nomogram to predict eligibility for second-line chemotherapy in pancreatic cancer. Anticancer Res. 2025;45(10):4509-18.\u003c/li\u003e\n\u003cli\u003eIkoma T, Matsumoto T, Boku S, Yasuda T, Masuda M, Ito T, et al. A retrospective study investigating the safety and efficacy of nanoliposomal irinotecan in elderly patients with unresectable pancreatic cancer. J Clin Med. 2023;12(10):3477.\u003c/li\u003e\n\u003cli\u003eHensing TA, Schell MJ, Lee JH, Socinski MA. Factors associated with the likelihood of receiving second line therapy for advanced non-small cell lung cancer. Lung Cancer. 2005;47(2):253-9.\u003c/li\u003e\n\u003cli\u003eBerger JM, Alany A, Puhr R, Berchtold L, Friedrich A, Scheiner B, et al. Clinical risk factors for ascites in metastatic pancreatic cancer. ESMO Open. 2023;8(2):101200.\u003c/li\u003e\n\u003cli\u003eWang J, Cui Y, Osipov A, Gong J, Pandol S, Lo S, et al. Ascites is a poor prognostic factor in advanced pancreatic adenocarcinoma and may be undertreated: a prospective cohort study. Clin Transl Gastroenterol. 2024;15(7):e00719.\u003c/li\u003e\n\u003cli\u003eBerger JM, Alany A, Berchtold L, Puhr R, Friedrich A, Scheiner B, et al. Prognosticators of survival in patients with metastatic pancreatic cancer and ascites. ESMO Open. 2023;8(6):102048.\u003cbr clear=\"all\"\u003e \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the supplementary files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ascites, Drug therapy, Pancreatic Neoplasm, Patient Selection, Survival Analysis","lastPublishedDoi":"10.21203/rs.3.rs-9285193/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9285193/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eSecond-line chemotherapy (2L) is recommended after gemcitabine plus nab-paclitaxel (GnP) first-line chemotherapy (1L) for unresectable pancreatic cancer (UR-PC). However, in routine clinical practice, not all patients proceed to 2L. This retrospective study aimed to identify baseline clinical and biological factors associated with 2L eligibility.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe retrospectively reviewed the data of 124 consecutive patients with UR-PC who received 1L GnP between 2016 and 2024 at a single center, excluding those with postoperative recurrence. Patients were grouped by 2L receipt [2L(+), n = 63] or non-receipt [2L(−), n = 61]. Overall survival (OS) and progression-free survival (PFS) from 1L (baseline) were assessed by Kaplan–Meier and Cox regression analyses. Predictors of 2L eligibility were evaluated by logistic regression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe 2L(+) group less frequently had baseline ascites and better Eastern Cooperative Oncology Group performance status. Median OS was 15.5 vs. 4.7 months (p \u0026lt; 0.001) and median PFS was 5.9 vs. 3.0 months (p = 0.004) for 2L(+) vs. 2L(−). Multivariate Cox analysis identified 2L (hazard ratio [HR] 0.262), disease control (HR 0.398), and neutrophil-to-lymphocyte ratio (HR 0.530) as independent factors for longer OS. Multivariate logistic regression revealed that the absence of ascites independently predicted 2L eligibility (adjusted odds ratio 4.435, 95% confidence interval 1.583−12.423, p = 0.005).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eBaseline ascites was a barrier to 2L initiation after 1L GnP in patients with UR-PC. Nevertheless, 2L was associated with improved survival regardless of ascites status. This supports individualized reassessment and proactive supportive care to maximize opportunities for sequential chemotherapy.\u003c/p\u003e","manuscriptTitle":"Determinants of eligibility for second-line chemotherapy following gemcitabine plus nab-paclitaxel therapy in patients with unresectable pancreatic cancer: A retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 16:51:57","doi":"10.21203/rs.3.rs-9285193/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-27T06:04:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-26T01:12:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286868353345378495864838347706876142809","date":"2026-04-24T06:24:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T04:00:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92337602882560064989344463526189440196","date":"2026-04-20T13:45:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"116587748660303543589890910815120939285","date":"2026-04-19T09:25:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-18T15:58:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"15401289089955835126072561957113056719","date":"2026-04-11T15:28:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85571166991302972908604727590557058185","date":"2026-04-11T11:00:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49623604145477165949611180191280004685","date":"2026-04-06T17:26:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-06T08:54:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-03T11:47:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-02T11:24:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-02T11:23:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2026-04-01T01:28:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"07b33546-e7b7-4565-b97d-fb849d108a8c","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-07T02:23:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 16:51:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9285193","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9285193","identity":"rs-9285193","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}