Effect of biliary drainage and biliary tract infection in unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: a multicenter, prospective cohort study (NAPOLEON-2)

Effect of biliary drainage and biliary tract infection in unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: a multicenter, prospective cohort study (NAPOLEON-2) | 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 Effect of biliary drainage and biliary tract infection in unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: a multicenter, prospective cohort study (NAPOLEON-2) Wataru Yoshioka, Tsuyoshi Shirakawa, Mototsugu Shimokawa, Taiga Otsuka, and 26 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8972664/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: The effectiveness and safety of nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) in patients with unresectable or recurrent pancreatic cancer with or without prior biliary drainage (BD) or on-treatment biliary tract infection (BTI) in the real world are unclear. Therefore, we analyzed the clinical outcomes of this condition in a multicenter, prospective study (NAPOLEON-2). Methods: We evaluated 150 patients with unresectableor recurrent pancreatic cancer who received NFF as second- or later-line therapy. The patients were categorized into the pre-treatment BD group (37 patients) and the non-BD group (113 patients). The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), the objective response rate (ORR), the disease control rate (DCR), relative dose intensity, and adverse events (AEs). BTI was estimated using landmark analysis at 2 and 3 months to reduce immortal bias. Results: There was no difference in OS between the two groups (hazard ratio, 1.25; 95% confidence interval, 0.83–1.89), and PFS was not different between the groups. Hematological AEs of grade ≥ 3 were observed in 34% of patients in the non-BD group and 38% in the BD group, while nonhematological AEs of grade ≥ 3 were observed in 40% and 68%, respectively. The BTI rate was higher in the BD group than in the non-BD group (30% vs 4%). On-treatment BTI showed no clinically meaningful difference in OS at the 2- and 3-month landmark analyses. Conclusions: BD has little effect on survival in patients treated with NFF. Physicians need to pay attention to BTI in NFF treatment. Biliary drainage Biliary tract infection Landmark analysis Pancreatic cancer Nanoliposomal irinotecan Figures Figure 1 Figure 2 Figure 3 Background Pancreatic cancer (PC) remains one of the most lethal malignancies, and is characterized by delayed diagnosis, rapid progression, and limited treatment options. PC is currently the seventh leading cause of cancer-related death worldwide and ranks fourth in Japan [1, 2, 3]. This finding is due in part to the difficulty in diagnosing PC early. Surgical resection is the only curative treatment for PC, but 80% of patients are estimated to be unresectable at the time of diagnosis [4]. Moreover, PC frequently causes local complications, such as biliary and duodenal obstruction due to tumor invasion. These complications can cause cholangitis, delay the proper timing for chemotherapy or surgery, and impair quality of life [5]. In patients with unresectable PC (urPC), systemic chemotherapy is the mainstay of treatment. Recently, some combination regimens, such as FOLFIRINOX and gemcitabine plus nab-paclitaxel, have been established as first-line treatments for urPC [6, 7]. Nanoliposomal irinotecan (Nal-IRI) in combination with fluorouracil, leucovorin, and oxaliplatin (NALIRIFOX) has become a possible reference regimen for first-line chemotherapy [8]. Additionally, a phase III trial (NAPOLI-1) showed that Nal-IRI in combination with fluorouracil and folinic acid (NFF) provided a considerable survival benefit over fluorouracil and folinic acid alone as a second-line chemotherapy subsequent to gemcitabine-based regimens [9]. Biliary drainage (BD) is often essential for the administration of chemotherapy because of the high frequency of biliary obstruction in PC. However, re-obstruction frequently occurs followed by BD, which may disrupt the continuation of chemotherapy. Despite this clinical relevance, no established data are available comparing the prognosis between patients with and without BD. A subgroup analysis of the NAPOLI-1 trial showed no significant difference in overall survival (OS) between patients with and without biliary stents who were treated with NFF (6.2 vs 6.1 months; hazard ratio [HR], 0.91; P = 0.785). However, the number of patients with biliary stents in the NFF arm was relatively small (15/117, 12.8%) [9, 10]. A recent study of patients treated with nab-paclitaxel plus gemcitabine ± capecitabine/cisplatin showed that biliary events could interfere with chemotherapy and negatively affect survival [11]. Additionally, an observational study in patients with PC reported that biliary infections were increased in long-term survivors who received chemotherapy [12]. Recently, the retrospective cohort analysis of NAPOLEON-2 reported that no significant difference in OS was observed between the non-BD and BD groups in the NFF setting [13]. Nevertheless , real-world evidence regarding the clinical effect of biliary events in patients receiving NFF therapy remains insufficient. T herefore, this study aimed to evaluate the clinical effect of BD and biliary tract infections (BTIs) on survival and treatment outcomes in patients with urPC receiving NFF therapy. Methods Study design The NAPOLEON-2 study was a multicenter observational study conducted in Japan by specialists in gastroenterology and medical oncology, consisting of retrospective and prospective cohorts to evaluate the efficacy and safety of NFF [14, 15]. In this study, we prospectively collected the data of consecutive patients with urPC treated with NFF who had received at least one previous chemotherapy in 17 hospitals in Japan from June 2021 to October 2023. Data on baseline characteristics, treatment exposure, efficacy outcomes, and adverse events (AEs) were prospectively recorded and analyzed. NFF was given on a 14-day cycle. On day 1, nal-IRI (70 mg/m²) was infused intravenously over 90 min, followed by levofolinate (200 mg/m²) over 2 h and fluorouracil (2400 mg/m²) as a 46 h continuous infusion. Dose reductions and schedule modifications were permitted according to toxicity and clinical judgment. Treatment was continued until disease progression, unacceptable toxicity despite dose modification, or patient request. The protocol was approved by the institutional review board/ethics committee at each participating institution and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. The study was registered in the UMIN Clinical Trials Registry (UMIN000043939), which meets ICMJE requirements. Assessments This analysis was a pre-planned analysis of the NAPOLEON-2 study. The primary endpoint was OS. The secondary endpoints were progression-free survival (PFS), the overall response rate (ORR), the disease control rate (DCR), relative dose intensity, and AEs. OS was measured from the date of NFF administration to the date of death from any cause or censored at the last follow-up examination. PFS was measured from the date of NFF administration to the date of progression or death from any cause, whichever was earlier, or censored at the last follow-up examination. We analyzed the prementioned endpoints between the BD and non-BD groups treated with NFF. Subsequently, we compared the clinical data between the BTI and non-BTI groups after initiating NFF. Taking into account the immortal time bias due to the time-dependent nature of biliary tract infections, we performed a 2-month landmark analysis from the initiation of NFF. This time point was selected according to the observed mean time to BTI onset, which was 2.2 months. Additionally, a 3-month landmark analysis was performed as a complementary evaluation. Statistical analyses Missing data were imputed using the method of multiple imputation with predictive mean matching [16]. Statistical analyses were performed using R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria). Data were collected by clinicians with expertise in clinical research under the supervision of a statistician and managed centrally. The patients’ characteristics were compared between groups using the standardized mean difference to assess group balance. OS and PFS were estimated using the Kaplan–Meier method, and were compared using the log-rank test and Cox proportional hazards model. HRs are expressed as 95% confidence intervals (95% CIs). Statistical significance was set at P < 0.05. The DCR and ORR were evaluated using computed tomography or magnetic resonance imaging and calculated according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [17]. The DCR was defined as a complete or partial response with stable disease as the best response, and the ORR was defined as a complete or partial response. Safety was analyzed using the common terminology criteria for AEs (CTCAE v5.0) [18]. Results Patients’ characteristics We enrolled 150 patients with urPC who received the NFF regimen prospectively (Figure 1). The median follow-up period was 7.2 months (95% CI, 6.3–8.8). Table 1 shows the patients’ baseline characteristics. All patients received gemcitabine before NFF. One-hundred thirteen patients were included in the non-BD group, and 37 were in the BD group. There were several clinically significant differences in the patients’ characteristics, such as the tumor location and duration time of previous chemotherapy. Patients with pancreatic head cancer were more frequently observed in the BD group than in the non-BD group (95% vs 24%). The duration of previous chemotherapy was longer in the non-BD group than in the BD group (median, 10.0 vs 8.0 months). Comparison between the biliary drainage and non-biliary drainage groups We analyzed the efficacy and safety of NFF in patients between the non-BD and BD groups. OS appeared to be more favorable in the non-BD group than in the BD group, but this difference was not significant (8.6 vs 6.8 months; HR, 1.25; 95% CI, 0.83–1.89; P = 0.29; Figure 2a). There was no significant difference in PFS between these two groups (3.7 vs 3.6 months; HR, 1.05; 95% CI, 0.71–1.55; P = 0.81; Figure 2b). The ORR was 11% and 11% in the non-BD and BD groups, respectively. The DCR was 58% and 51% in the non-BD and BD groups, respectively (Table 2). The median number of treatment cycles was seven (range, 1–44) in the non-BD group and six (1–30) in the BD group. The median relative dose intensity for Nal-IRI was 72.7% in the non-BD group and 75.0% in the BD group, and that for fluorouracil was 78.4% in the non-BD group and 82.7% in the BD group (Table 3). The reasons for termination of NFF treatment were most commonly tumor progression and clinical progressive disease in both groups. After NFF, 55 (54%) patients in the non-BD group and 25 (76%) patients in the BD group received best supportive care alone. Treatment-related AEs that occurred in ≥ 5% of patients are shown in Table 4. Hematological AEs of grade ≥ 3 were observed in 34% of patients in the non-BD group and in 38% in the BD group, while nonhematological AEs of grade ≥ 3 were observed in 40% and 68% of patients, respectively. The rate of BTI was clinically higher in the BD group than in the non-BD group (30% vs 4%). In the subgroup analysis of 62 patients with pancreatic head cancer, there was no significant difference in OS between non-BD and BD groups (9.7 vs 7.1 months; HR, 1.33; 95% CI, 0.76–2.34; P = 0.32). Analysis of patients with biliary tract infections Sixteen patients experienced BTI and/or gallbladder infection. The characteristics of the BTI group are shown in Table 5. Biliary stent placement had been performed in 10 of these patients, including 9 with covered self-expandable metallic stents and 1 with a plastic stent. The mean time from initiation of NFF to the onset of BTI was 2.2 months. The ORR was 12% and 0% in the non-BTI and BTI group, respectively. The DCR was 57% and 50% in the non-BTI and BTI group, respectively. The rate of febrile neutropenia was higher in the BTI group than in the non-BTI group (19% vs 3%). The data of landmark analysis at 2 months from the induction of NFF showed that there was no significant difference in OS between the non-BTI and BTI groups (8.8 vs 6.8 months; HR, 1.19; 95% CI, 0.62–2.28; P = 0.61; Figure 3a). A similar result was obtained at the 3-month landmark analysis (Figure 3b). Discussion We examined the clinical effects of pre-treatment BD and on-treatment BTI on the efficacy and safety of NFF in patients with urPC in this study. To the best of our knowledge, this is the first observational study to analyze such effects based on a multicentered prospective cohort in the real world. In this study, biliary events had no notable effect on treatment outcomes in patients who received NFF. The median OS was not significantly different between the non-BD and BD groups (8.6 vs 6.8). There was no also significant difference in PFS between these two groups. Pathophysiologically, hepatic impairment and obstruction of biliary excretion can expose systemic organs to anticancer drugs. Therefore, dose adjustment of chemotherapy may be required. Additionally, drug accumulation in systemic organs might cause hepatocellular damage [19]. Consequently, biliary stent placement is the standard initial management for patients with obstructive jaundice, especially in those indicated for subsequent chemotherapy. This stent placement can be initiated after a decrease in serum bilirubin concentrations [20]. However, there is no established consensus on whether biliary AEs during chemotherapy affect the prognosis of urPC. Our results for pre-treatment BD are similar to those of the retrospective cohort analysis of NAPOLEON-2 [13]. We also evaluated the impact of on-treatment BTI prospectively in this multicenter real-world cohort. Three previous studies need to be taken into consideration to comprehensively compare our efficacy data with previous relevant literature [9, 10, 20, 21]. In the NAPOLI-1 trial, 37 of 417 patients included in the intention-to-treat population had a biliary stent at baseline. Of these, 15 of 117 patients in the NFF arm had a biliary stent; and there was no significant difference in median OS between the two arms (6.2 vs 6.1 months; P = 0.78). Furthermore, despite the limited data on first-line chemotherapy, we reported in the NAPOLEON study that BD did not affect prognosis in urPC treated with FOLFIRINOX or gemcitabine plus nab-paclitaxel, and that there were no clinical differences in efficacy or safety between the two regimens [21]. In contrast, in a retrospective study of modified FOLFIRINOX, the biliary stent group had a shorter median OS than the non-stent group (10.3 vs 24.9 months; P < 0.01) [22]. Higher rates of AEs, such as febrile neutropenia, obstructive jaundice, and cholangitis, were observed in the stent group. This finding indicate that AEs can cause shorter survival through treatment delays and deterioration in the general condition. Importantly, the timing of biliary stent placement was not only before modified FOLFIRINOX initiation but also during treatment in this previous report, which is different from the procedure used in the present study. In our study of urPC treated with NFF, BD appeared to have little effect on the prognosis. The following reasons could explain for this finding. The BD group had a higher rate of pancreatic head cancer and a shorter duration of prior chemotherapy than the non-BD group. Regarding the anti-tumor effect, there was no clinical difference in the ORR between the non-BD and BD groups, which suggested that reduction of jaundice by BD did not weaken anti-tumor activity. We speculated that the tumor location might affect the indication of BD. Therefore, we performed a subgroup analysis limited to pancreatic head cancer, and showed that the median OS showed no clinically meaningful difference between the BD and non-BD groups. The relative dose intensity was also similar between the groups, indicating that BD is unlikely to impair the feasibility of NFF. However, we observed a modest separation of the OS curves of the non-BD and BD groups (Figure 2b), whereas the PFS curves generally overlapped (Figure 2a). Median post-discontinuation survival, which was defined as the interval from NFF discontinuation to death, was 3.3 months in the non-BD group and 2.4 months in the BD group, and BD was clinically associated with shorter post-discontinuation survival (HR, 1.63; 95% CI, 1.07–2.48; P = 0.02). The reason for this finding could be that the difference in subsequent therapy and deterioration in Eastern Cooperative Oncology Group performance status due to AEs played a large role. In fact, the rate of worsening of Eastern Cooperative Oncology Group performance status from baseline was higher in the BD group than in the non-BD group (62% vs 48%; standardized mean difference, 0.29). Additionally, more patients received best supportive care after NFF in the BD group than in the non-BD group. Collectively, these findings suggest that small clinical differences in OS are affected by post-discontinuation survival, regardless of the anti-tumor response, relative dose intensity, or PFS. Regarding AEs, biliary stents are prone to form microbial colonization and biofilm after their placement, and occlusion is associated with a higher risk of cholangitis [23]. Recurrent biliary-source bloodstream infections are associated with delays in chemotherapy among patients with cancer [24]. In the NAPOLI-1 trial, patients with a biliary stent at baseline tended to have a more frequent incidence of neutropenia, but there was no apparent increase in infection-related complications [10]. However, hematological AEs were similar between the BD and non-BD groups in the present study, but febrile neutropenia was more frequent in the BD group. Additionally, the incidence rate of nonhematological AEs was higher in the BD group than in the non-BD group, especially BTIs. This finding could be important for deciding whether to perform NFF for patients with BD. We performed a subanalysis to determine whether BTI affected the efficacy and safety of NFF. BTI is a time-dependent event that occurs after initiating chemotherapy, and it may introduce immortal time bias. To avoid such bias, we performed landmark analyses, with 2- and 3-month landmark points after initiating NFF because the mean time to BTI onset was 2.2 months. The median OS showed no clinically meaningful difference between the non-BTI and BTI groups. In both groups, disease progression was the main reason for discontinuing treatment, which suggested that appropriate management of BTI and febrile neutropenia could slightly affect the continuation of NFF. There are several limitations to this study. First, this was an observational study, and thus residual cannot be fully excluded. Second, the sample sizes of the BD and BTI groups were small. Nevertheless, to the best of our knowledge, this prospective, multicenter cohort is the largest to specifically evaluate biliary events in the NFF setting, and we consider that these findings are clinically relevant. Third, NFF was administered in second- and third- or later-line settings, and heterogeneity in the treatment line could have affected outcomes and AEs. Therefore, we conducted a subgroup analysis and confirmed the safety and efficacy of NFF in second- and third- or later-line settings. In fact, the efficacy and safety were similar between the second-line and third- or later-line groups [15]. Fourth, BD approach tools, such as percutaneous transhepatic BD, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasound-guided BD, and the stent type (metal or plastic) were not included in the analyses. With only 37 patients in BD group and no data on the drainage approach or stent type, approach- or stent-specific analyses were not feasible. Finally, 11 patients had no histological diagnosis. In clinical practice, histological confirmation is sometimes infeasible, and systemic chemotherapy may be initiated on the basis of imaging and clinical judgment. Conclusions BD did not materially affect NFF efficacy or survival. Therefore, NFF is considered feasible in patients with prior BD. However, BD may affect AEs and subsequent therapy, and particular caution regarding BTI is warranted. Abbreviations AE, adverse event; BD, biliary drainage; BTI, biliary tract infection; CI, confidence interval; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; Nal-IRI, nanoliposomal irinotecan; NFF, nanoliposomal irinotecan with fluorouracil and folinic acid; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RDI, relative dose intensity; RECIST, Response Evaluation Criteria in Solid Tumors; urPC, unresectable pancreatic cancer. Declarations Ethics approval and consent to participate The NAPOLEON-2 study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of each participating institution. Written informed consent was obtained from all participants. Consent for publication Consent for publication was obtained using the opt-in/opt-out approach according to each participating institution’s policy. Availability of data and materials All data generated or analyzed in this study were stored in a secured research database. Although not publicly available, they are available from the corresponding author upon reasonable request. Competing interests Satoshi Otsu declares speaker engagements from Ono Pharmaceutical, Daiichi-Sankyo Company, Eli Lilly Japan K.K., Bristol-Myers Squibb Company, and Taiho Pharmaceutical. Kazuo Nishikawa declares speaker engagements from Teijin Pharma, Takeda Pharmaceutical Company, Daiichi-Sankyo Company, Novartis Pharma, Bristol-Myers Squibb Company, and Nihon Servier. The remaining authors have no competing interests or financial disclosures to declare. Funding This study did not receive any funding. Authors' contributions Conceptualization: TS1, MS, TO, TM, and KM; Methodology: WY, TS1, MS, TO, SA1, FK, JN, TM, and KM; Formal analysis and investigation: WY, MS, TO, TS1, TM, and KM; Writing - original draft preparation: WY, TS1, and TO; Writing - review and editing: MS, HT1, TM, and KM; Resources: WY, TS1, TO, FK, NO, MK1, JN, HS1, YS, HO, ST, SA1, SA2, YK, KN1, SO, HT2, KJ, TS2, YU, TS3, NA, HS2, YI, MK2, and KN2. Acknowledgements We thank all of the patients and their families, investigators, and colleagues at the 17 institutions that were members of the NAPOLEON study group. We would like to thank the Saga Study Group of Liver Disease (SASLD) for their cooperation. We thank Ellen Knapp, PhD, from Edanz for editing a draft of this manuscript. Moreover, we are indebted to clinical research coordinators and medical office assistants of the NAPOLEON study group for their assistance in data collection: Mrs. Ishito (Sasebo Kyosai Hospital), Mrs. Yasutake (Saiseikai Kumamoto Hospital), and Mrs. Ookubo (Oita University Faculty of Medicine). References Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics. 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. Egawa S, Toma H, Ohigashi H, et al. Japan Pancreatic Cancer Registry;30th year anniversary:Japan Pancreas Society. Pancreas. 2012;41:985–992. De La Cruz MS, Young AP, Ruffin MT. Diagnosis and management of pancreatic cancer. Am Fam Physician. 2014 Apr 15;89:626–32. Boulay BR, et al. Managing malignant biliary obstruction in pancreas cancer:choosing the appropriate strategy. 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Epidemiology and Resistance Patterns of Bacterial and Fungal Colonization of Biliary Plastic Stents:A Prospective Cohort Study. PLoS One. 2016;11:e0155479. doi:10.1371/journal. pone.0155479. Grafia I, Chumbita M, Seguí E, et al. Epidemiology and risk factors for recurrence in biliary source bloodstream infection episodes in oncological patients. Microbiol Spectr. 2023;11. doi:10.1128/spectrum.02142–23. Tables Table 1. Baseline characteristics BD (n=37) Non-BD (n=113) SMD BTI (n=16) Non-BTI (n=134) SMD Age Years, median (range) 71 (48–81) 72 (45–85) 0.25 72 (55–81) 72 (45-85) 0.04 Sex, n (%) Male 14 (38) 67 (59) 0.44 9 (56) 72 (54) 0.05 ECOG PS, n (%) 0 8 (22) 38 (34) 0.42 4 (25%) 42 (31%) 0.16 1 28 (76) 65 (58) 11 (69) 82 (61) 2–3 1 (3) 10 (9) 1 (6) 10 (8) Pancreatectomy, n (%) Yes 7 (19) 34 (30) 0.26 3 (19) 38 (28) 0.23 Biliary drainage history, n (%) Yes 37 (100) 0 n/a 11 (69) 26 (19) 1.15 Pancreatic tumor location, n (%) Head 35 (95) 27 (24) 2.07 12 (75) 50 (37) 0.82 Body or tail 2 (5) 86 (76) 4 (25) 84 (63) Histology, n (%) Adenocarcinoma 36 (97) 95 (84) 0.51 15 (94) 116 (87) 0.36 Others 1 (3) 7 (6) 0 8 (6) Unknown 0 11 (10) 1 (6) 10 (8) Stage, n (%) Metastatic 32 (86) 102 (90) 0.12 15 (94) 119 (89) 0.18 Site of metastatic disease, n (%) Liver 22 (60) 55 (49) 0.22 10 (63) 67 (50) 0.25 Peritoneum 8 (22) 39 (35) 0.29 2 (12) 45 (34) 0.52 Lung 6 (16) 37 (33) 0.39 4 (25) 39 (29) 0.09 Ascites, n (%) Yes 9 (24) 34 (30) 0.13 6 (38) 37 (28) 0.21 Time to NFF from 1st-line Months, median (range) 8.0 (2.3–22.3) 10.0 (2.1–42.8) 0.50 7.7 (2.1–24.7) 8.9 (2.3–42.8) 0.41 Treatment line of NFF, n (%) 2nd-line 23 (62) 64 (57) 0.24 13 (81) 74 (55) 0.63 3rd-line 13 (35) 40 (35) 2 (13) 51 (38) 4th- or later-line 1 (3) 9 (8) 1 (6) 9 (7) Previous agent except for GEM, n (%) Fluoropyrimidine 12 (32) 40 (35) 0.06 2 (13) 50 (37) 0.60 Platinum 4 (11) 15 (13) 0.08 2 (13) 17 (13) <0.01 CPT-11 4 (11) 15 (13) 0.08 2 (13) 17 (13) <0.01 CA19-9 concentration† U/mL, median (range) 1413 (2–418458) 390 (2–718508) 0.12 2729 (8–418458) 403 (2–718508) 0.40 UGT1A1 genotype, n (%) Homo or double hetero 2 (5) 7 (6) 0.03 0 9 (7) 0.38 †Two missing data points were imputed using the method of multiple imputation. Abbreviations: GEM , gemcitabine; CPT-11 , irinotecan; CA19-9 , carbohydrate antigen 19-9; UGT1A1 , uridine diphosphate glucuronosyltransferase family 1 member A1; n/a not applicable; SMD, standardized mean difference. Table 2. Response to NFF according to the biliary drainage status Response, n (%) BD (n=37) Non-BD (n=113) CR 0 0 PR 4 (11) 12 (11) SD 15 (41) 53 (47) PD 16 (43) 44 (39) NE 2 (5) 4 (4) ORR (CR + PR) 4 (11) 12 (11) DCR (CR + PR + SD) 19 (51) 65 (58) Abbreviations: CR , complete response; PR , partial response; SD , stable disease; PD , progressive disease; NE , SMD , standardized mean difference. Table 3. Relative dose intensity according to the biliary drainage status %, median (range) BD (n=37) Non-BD (n=113) Nal-IRI 75.0 (51.9-100.8) 72.7 (30.1-102.6) FU 82.7 (54.2-104.7) 78.4 (41.2-103.2) Abbreviations: FU , fluorouracil; SMD , standardized mean difference. Table 4. Adverse events according to the biliary drainage status n (%) Any grade Grade 3 or 4 BD (n=37) Non-BD (n=113) BD (n=37) Non-BD (n=113) WBC count decreased 16 (43) 38 (34) 6 (16) 18 (16) Neutrophil count decreased 16 (43) 55 (49) 10 (27) 31 (27) Anemia 28 (76) 68 (61) 6 (16) 9 (8) Platelet count decreased 9 (24) 31 (27) 2 (5) 1 (1) Febrile neutropenia 4 (11) 3 (3) 4 (11) 3 (3) Anorexia 26 (70) 72 (64) 7 (19) 21 (19) Malaise 24 (65) 64 (57) 3 (8) 7 (6) Fatigue 19 (51) 47 (42) 5 (14) 5 (4) Nausea 15 (41) 51 (45) 1 (3) 3 (3) Vomiting 8 (22) 19 (17) 1 (3) 1 (1) Diarrhea 13 (35) 42 (37) 1 (3) 4 (4) Constipation 11 (30) 29 (26) 0 0 Weight loss 8 (22) 16 (14) 0 0 AST, ALT increased 10 (27) 38 (34) 2 (5) 7 (6) Mucositis oral 6 (16) 7 (6) 1 (3) 1 (1) Alopecia 5 (14) 15 (13) - - Fever 11 (30) 15 (13) 0 0 Biliary tract infection 11 (30) 4 (4) 11 (30) 3 (3) Peripheral sensory neuropathy 8 (22) 32 (28) 0 2 (2) Hematological 14 (38) 38 (34) Nonhematological 25 (68) 45 (40) Abbreviations: SMD , standardized mean difference; WBC , white blood cell; AST , aspartate transaminase; ALT , alanine transaminase. Table 5. Characteristics of the BTI group (n = 16) Stage Age Sex Baseline BD Time to BTI (week) CTCAE grade Response Post-BTI NFF MPC 55 F Plastic stent 1 3 SD Continued MPC 75 M Metal stent 32 3 SD Continued MPC 81 M Metal stent 10 3 PD Stopped MPC 64 M None 9 3 PD Stopped MPC 79 F Metal stent 9 3 SD Continued MPC 71 F Metal stent 38 3 SD Stopped MPC 60 M Metal stent 10 3 SD Continued LAPC 75 M Metal stent 10 3 SD Continued MPC 64 M Metal stent 1 3 PD Continued MPC 72 M None 2 3 PD Continued MPC 71 F None 4 3 PD Continued MPC 72 M Metal stent 6 3 PD Continued MPC 73 F Metal stent 6 3 SD Continued MPC 71 F Unknown Unknown 3 PD Unknown MPC 63 F Unknown Unknown 3 PD Unknown MPC 73 M None 5 2 SD Continued Abbreviations: MPC , metastatic pancreatic cancer; LAPC , locally advanced pancreatic cancer; F , female; M , male; SD , stable disease; PD , progressive disease. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Apr, 2026 Reviews received at journal 22 Apr, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviews received at journal 10 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers invited by journal 05 Mar, 2026 Editor assigned by journal 05 Mar, 2026 Editor invited by journal 03 Mar, 2026 Submission checks completed at journal 02 Mar, 2026 First submitted to journal 02 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8972664","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":601740925,"identity":"fe5cc513-238c-476c-8a0c-fcd918553d3e","order_by":0,"name":"Wataru Yoshioka","email":"","orcid":"","institution":"Saga Medical Center Koseikan","correspondingAuthor":false,"prefix":"","firstName":"Wataru","middleName":"","lastName":"Yoshioka","suffix":""},{"id":601740926,"identity":"21d2f856-993e-4a9f-99c0-09aedf26554e","order_by":1,"name":"Tsuyoshi Shirakawa","email":"","orcid":"","institution":"Eikoh 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toshihiko","middleName":"","lastName":"Mizuta","suffix":""},{"id":601740955,"identity":"5a05de64-8cd5-4277-b3d4-1d34566971b0","order_by":29,"name":"Kenji Mitsugi","email":"","orcid":"","institution":"Sasebo Kyosai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Mitsugi","suffix":""}],"badges":[],"createdAt":"2026-02-26 03:08:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8972664/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8972664/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104343278,"identity":"fe028983-9a7c-4380-ab84-ba034115e0b5","added_by":"auto","created_at":"2026-03-10 17:10:13","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":654762,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the patients.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e \u003cem\u003eBD\u003c/em\u003e, biliary drainage; \u003cem\u003eBTI\u003c/em\u003e, biliary tract infection\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8972664/v1/3a662091e33521d655bef8eb.jpg"},{"id":104343342,"identity":"28c67706-fd8d-4f3b-9c1e-3a9f5be51eac","added_by":"auto","created_at":"2026-03-10 17:10:29","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":232306,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival curves of patients who were administered nanoliposomal irinotecan and fluorouracil with leucovorin. (a) Comparison of overall survival between the non-biliary drainage group and the drainage group. (b) Comparison of progression-free survival between the non-biliary drainage group and the biliary drainage group.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: HR\u003c/em\u003e, hazard ratio; \u003cem\u003eCI\u003c/em\u003e, confidence interval\u003c/p\u003e","description":"","filename":"Fig2a.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8972664/v1/3fdc5c1b0f88121c7246fd18.jpg"},{"id":104343338,"identity":"9264d611-c968-4caf-a858-3fed4b3c91d6","added_by":"auto","created_at":"2026-03-10 17:10:29","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":221924,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival curves of overall survival by landmark analysis. (a) Comparison of overall survival between the biliary tract infection group and the non-biliary tract infection group at 2 months. (b) Comparison of overall survival between the biliary tract infection group and the non-biliary tract infection group at 3-months.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: BT\u003c/em\u003e, biliary tract; \u003cem\u003eHR\u003c/em\u003e, hazard ratio; \u003cem\u003eCI\u003c/em\u003e, confidence interval\u003c/p\u003e","description":"","filename":"Fig3a.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8972664/v1/7f1b0c3b580b4b3d17ab934e.jpg"},{"id":104343411,"identity":"5f517a26-cf46-4f51-9d4b-7359d86a283d","added_by":"auto","created_at":"2026-03-10 17:10:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2267387,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8972664/v1/873d3e69-0ef9-4d92-a9c0-56bbafcc4ba7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of biliary drainage and biliary tract infection in unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: a multicenter, prospective cohort study (NAPOLEON-2)","fulltext":[{"header":"Background","content":"\u003cp\u003ePancreatic cancer (PC) remains one of the most lethal malignancies, and is characterized by delayed diagnosis, rapid progression, and limited treatment options. PC is currently the seventh leading cause of cancer-related death worldwide and ranks fourth in Japan [1, 2, 3]. This finding is due in part to the difficulty in diagnosing PC early. Surgical resection is the only curative treatment for PC, but 80% of patients are estimated to be unresectable at the time of diagnosis [4]. Moreover, PC frequently causes local complications, such as biliary and duodenal obstruction due to tumor invasion. These complications can cause cholangitis, delay the proper timing for chemotherapy or surgery, and impair quality of life\u0026nbsp;[5].\u003c/p\u003e\n\u003cp\u003eIn patients with unresectable PC (urPC), systemic chemotherapy is the mainstay of treatment. Recently, some combination regimens, such as FOLFIRINOX and gemcitabine plus nab-paclitaxel, have been established as first-line treatments for urPC [6, 7]. Nanoliposomal irinotecan (Nal-IRI) in combination with\u0026nbsp;fluorouracil, leucovorin, and oxaliplatin (NALIRIFOX) has become a possible reference regimen for first-line chemotherapy [8]. Additionally, a phase III trial (NAPOLI-1) showed that Nal-IRI in combination with fluorouracil and folinic acid (NFF) provided a considerable survival benefit over fluorouracil and folinic acid alone as a second-line chemotherapy subsequent to gemcitabine-based regimens [9].\u003c/p\u003e\n\u003cp\u003eBiliary drainage (BD) is often essential for the administration of chemotherapy because of the high frequency of biliary obstruction in PC. However, re-obstruction frequently occurs followed by BD, which may disrupt the continuation of chemotherapy. Despite this clinical relevance, no established data are available comparing the prognosis between patients with and without BD. A subgroup analysis of the NAPOLI-1 trial showed no significant difference in overall survival (OS) between patients with and without biliary stents who were treated with NFF (6.2 vs 6.1 months; hazard ratio [HR], 0.91; \u003cem\u003eP\u003c/em\u003e = 0.785). However, the number of patients with biliary stents in the NFF arm was relatively small (15/117, 12.8%) [9, 10]. A recent study of patients treated with nab-paclitaxel plus gemcitabine \u0026plusmn; capecitabine/cisplatin showed that biliary events could interfere with chemotherapy and negatively affect survival [11]. Additionally, an observational study in patients with PC reported that biliary infections were increased in long-term survivors who received chemotherapy [12]. Recently, the retrospective cohort analysis of NAPOLEON-2 reported that no significant difference in OS was observed between the non-BD and BD groups in the NFF setting [13]. Nevertheless\u003cstrong\u003e, real-world evidence regarding the clinical effect of biliary events in patients receiving NFF therapy remains insufficient. T\u003c/strong\u003eherefore, this study aimed to evaluate the clinical effect of BD and biliary tract infections (BTIs) on survival and treatment outcomes in patients with urPC receiving NFF therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NAPOLEON-2 study was a multicenter observational study conducted in Japan by specialists in gastroenterology and medical oncology, consisting of retrospective and prospective cohorts to evaluate the efficacy and safety of NFF [14, 15]. In this study, we prospectively collected the data of consecutive patients with urPC treated with NFF who had received at least one previous chemotherapy in 17 hospitals in Japan from June 2021 to October 2023.\u0026nbsp;Data on baseline characteristics, treatment exposure, efficacy outcomes, and adverse events (AEs) were prospectively recorded and analyzed. NFF was given on a 14-day cycle. On day 1, nal-IRI (70 mg/m²) was infused intravenously over 90 min, followed by levofolinate (200 mg/m²) over 2 h and fluorouracil (2400 mg/m²) as a 46 h continuous infusion. Dose reductions and schedule modifications were permitted according to toxicity and clinical judgment. Treatment was continued until disease progression, unacceptable toxicity despite dose modification, or patient request. The protocol was approved by the institutional review board/ethics committee at each participating institution and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. The study was registered in the UMIN Clinical Trials Registry (UMIN000043939), which meets ICMJE requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis analysis was a pre-planned analysis of the NAPOLEON-2 study.\u0026nbsp;The primary endpoint was OS. The secondary endpoints were progression-free survival (PFS), the overall response rate (ORR), the disease control rate (DCR), relative dose intensity, and AEs.\u0026nbsp;OS was measured from the date of NFF administration to the date of death from any cause or censored at the last follow-up examination. PFS was measured from the date of NFF administration to the date of progression or death from any cause, whichever was earlier, or censored at the last follow-up examination. We analyzed the prementioned endpoints between the BD and non-BD groups treated with NFF. Subsequently, we compared the clinical data between the BTI and non-BTI groups after initiating NFF. Taking into account the immortal time bias due to the time-dependent nature of biliary tract infections, we performed a 2-month landmark analysis from the initiation of NFF. This time point was selected according to the observed mean time to BTI onset, which was 2.2 months. Additionally, a 3-month landmark analysis was performed as a complementary evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMissing data were imputed using the method of multiple imputation with predictive mean matching [16]. Statistical analyses were performed using R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria). Data were collected by clinicians with expertise in clinical research under the supervision of a statistician and managed centrally. The patients’ characteristics were compared between groups using the standardized mean difference to assess group balance. OS and PFS were estimated using the Kaplan–Meier method, and were compared using the log-rank test and Cox proportional hazards model. HRs are expressed\u0026nbsp;as 95% confidence intervals (95% CIs). Statistical significance was set at \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05. The DCR and ORR were evaluated using computed tomography or magnetic resonance imaging and calculated according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [17]. The DCR was defined as a complete or partial response with stable disease as the best response, and the ORR was defined as a complete or partial response. Safety was analyzed using the common terminology criteria for AEs (CTCAE v5.0) [18].\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients’ characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe enrolled 150 patients with urPC who received the NFF regimen prospectively (Figure 1). The median follow-up period was 7.2 months (95% CI, 6.3–8.8). Table 1 shows the patients’ baseline characteristics. All patients received gemcitabine before NFF. One-hundred thirteen patients were included in the non-BD group, and 37 were in the BD group. There were several clinically significant differences in the patients’ characteristics, such as the tumor location and duration time of previous chemotherapy. Patients with pancreatic head cancer were more frequently observed in the BD group than in the non-BD group (95% vs 24%). The duration of previous chemotherapy was longer in the non-BD group than in the BD group (median, 10.0 vs 8.0 months).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparison between the biliary drainage and non-biliary drainage groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed the efficacy and safety of NFF in patients between the non-BD and BD groups. OS appeared to be more favorable in the non-BD group than in the BD group, but this difference was not significant (8.6 vs 6.8 months; HR, 1.25; 95% CI, 0.83–1.89; \u003cem\u003eP\u003c/em\u003e = 0.29; Figure 2a). There was no significant difference in PFS between these two groups (3.7 vs 3.6 months; HR, 1.05; 95% CI, 0.71–1.55; \u003cem\u003eP\u003c/em\u003e = 0.81; Figure 2b). The ORR was 11% and 11% in the non-BD and BD groups, respectively. The DCR was 58% and 51% in the non-BD and BD groups, respectively (Table 2). The median number of treatment cycles was seven (range, 1–44) in the non-BD group and six (1–30) in the BD group. The median relative dose intensity for Nal-IRI was 72.7% in the non-BD group and 75.0% in the BD group, and that for fluorouracil was 78.4% in the non-BD group and 82.7% in the BD group (Table 3). The reasons for termination of NFF treatment were most commonly tumor progression and clinical progressive disease in both groups. After NFF, 55 (54%) patients in the non-BD group and 25 (76%) patients in the BD group received best supportive care alone. Treatment-related AEs that occurred in ≥ 5% of patients are shown in Table 4. Hematological AEs of grade ≥ 3 were observed in 34% of patients in the non-BD group and in 38% in the BD group, while nonhematological AEs of grade ≥ 3 were observed in 40% and 68% of patients, respectively. The rate of BTI was clinically higher in the BD group than in the non-BD group (30% vs 4%). In the subgroup analysis of 62 patients with pancreatic head cancer, there was no significant difference in OS between non-BD and BD groups (9.7 vs 7.1 months; HR, 1.33; 95% CI, 0.76–2.34; \u003cem\u003eP\u003c/em\u003e = 0.32).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis of patients with biliary tract infections\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSixteen patients experienced BTI and/or gallbladder infection. The characteristics of the BTI group are shown in Table 5. Biliary stent placement had been performed in 10 of these patients, including 9 with covered self-expandable metallic stents and 1 with a plastic stent. The mean time from initiation of NFF to the onset of BTI was 2.2 months. The ORR was 12% and 0% in the non-BTI and BTI group, respectively. The DCR was 57% and 50% in the non-BTI and BTI group, respectively. The rate of febrile neutropenia was higher in the BTI group than in the non-BTI group (19% vs 3%). The data of landmark analysis at 2 months from the induction of NFF showed that there was no significant difference in OS between the non-BTI and BTI groups (8.8 vs 6.8 months; HR, 1.19; 95% CI, 0.62–2.28; \u003cem\u003eP\u003c/em\u003e = 0.61; Figure 3a). A similar result was obtained at the 3-month landmark analysis (Figure 3b).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe examined the clinical effects of pre-treatment BD and on-treatment BTI on the efficacy and safety of NFF in patients with urPC in this study. To the best of our knowledge, this is the first observational study to analyze such effects based on a multicentered prospective cohort in the real world.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this study, biliary events had no notable effect on treatment outcomes in patients who received NFF. The median OS was not significantly different between the non-BD and BD groups (8.6 vs 6.8). There was no also significant difference in PFS between these two groups. Pathophysiologically, hepatic impairment and obstruction of biliary excretion can expose systemic organs to anticancer drugs. Therefore, dose adjustment of chemotherapy may be required. Additionally, drug accumulation in systemic organs might cause hepatocellular damage [19]. Consequently, biliary stent placement is the standard initial management for patients with obstructive jaundice, especially in those indicated for subsequent chemotherapy. This stent placement can be initiated after a decrease in serum bilirubin concentrations [20]. However, there is no established consensus on whether biliary AEs during chemotherapy affect the prognosis of urPC.\u0026nbsp;Our results for pre-treatment BD are similar to those of the retrospective cohort analysis of NAPOLEON-2 [13]. We also evaluated the impact of on-treatment BTI prospectively in this multicenter real-world cohort.\u003c/p\u003e\n\u003cp\u003eThree previous studies need to be taken into consideration to comprehensively compare our efficacy data with previous relevant literature [9, 10, 20, 21]. In the NAPOLI-1 trial, 37 of 417 patients included in the intention-to-treat population had a biliary stent at baseline. Of these, 15 of 117 patients in the NFF arm had a biliary stent; and there was no significant difference in median OS between the two arms (6.2 vs 6.1 months;\u003cem\u003e\u0026nbsp;P\u0026nbsp;\u003c/em\u003e= 0.78). Furthermore, despite the limited data on first-line chemotherapy, we reported in the NAPOLEON study that BD did not affect prognosis in urPC treated with FOLFIRINOX or gemcitabine plus nab-paclitaxel, and that there were no clinical differences in efficacy or safety between the two regimens [21]. In contrast, in a retrospective study of modified FOLFIRINOX, the biliary stent group had a shorter median OS than the non-stent group (10.3 vs 24.9 months;\u003cem\u003e\u0026nbsp;P\u0026nbsp;\u003c/em\u003e\u0026lt; 0.01) [22]. Higher rates of AEs, such as febrile neutropenia, obstructive jaundice, and cholangitis, were observed in the stent group. This finding indicate that AEs can cause shorter survival through treatment delays and deterioration in the general condition. Importantly, the timing of biliary stent placement was not only before modified FOLFIRINOX initiation but also during treatment in this previous report, which is different from the procedure used in the present study.\u003c/p\u003e\n\u003cp\u003eIn our study of urPC treated with NFF, BD appeared to have little effect on the prognosis. The following reasons could explain for this finding. The BD group had a higher rate of pancreatic head cancer and a shorter duration of prior chemotherapy than the non-BD group. Regarding the anti-tumor effect, there was no clinical difference in the ORR between the non-BD and BD groups, which suggested that reduction of jaundice by BD did not weaken anti-tumor activity. We speculated that the tumor location might affect the indication of BD. Therefore, we performed a subgroup analysis limited to pancreatic head cancer, and showed that the median OS showed no clinically meaningful difference between the BD and non-BD groups. The\u0026nbsp;relative dose intensity\u0026nbsp;was also similar between the groups, indicating that BD is unlikely to impair the feasibility of NFF. However, we observed a modest separation of the OS curves of the non-BD and BD groups (Figure 2b), whereas the PFS curves generally overlapped (Figure 2a). Median post-discontinuation survival, which was defined as the interval from NFF discontinuation to death, was 3.3 months in the non-BD group and 2.4 months in the BD group, and BD was clinically associated with shorter post-discontinuation survival (HR, 1.63; 95% CI, 1.07\u0026ndash;2.48; \u003cem\u003eP\u003c/em\u003e = 0.02). The reason for this finding could be that the difference in subsequent therapy and deterioration in Eastern Cooperative Oncology Group performance status due to AEs played a large role. In fact, the rate of worsening of Eastern Cooperative Oncology Group performance status from baseline was higher in the BD group than in the non-BD group (62% vs 48%; standardized mean difference, 0.29). Additionally, more patients received best supportive care after NFF in the BD group than in the non-BD group. Collectively, these findings suggest that small clinical differences in OS are affected by post-discontinuation survival, regardless of the anti-tumor response,\u0026nbsp;relative dose intensity, or PFS.\u003c/p\u003e\n\u003cp\u003eRegarding AEs, biliary stents are prone to form microbial colonization and biofilm after their placement, and occlusion is associated with a higher risk of cholangitis [23]. Recurrent biliary-source bloodstream infections are associated with delays in chemotherapy among patients with cancer [24]. In the NAPOLI-1 trial, patients with a biliary stent at baseline tended to have a more frequent incidence of neutropenia, but there was no apparent increase in infection-related complications [10]. However, hematological AEs were similar between the BD and non-BD groups in the present study, but febrile neutropenia was more frequent in the BD group. Additionally, the incidence rate of nonhematological AEs was higher in the BD group than in the non-BD group, especially BTIs. This finding could be important for deciding whether to perform NFF for patients with BD.\u003c/p\u003e\n\u003cp\u003eWe performed a subanalysis to determine whether BTI affected the efficacy and safety of NFF. BTI is a time-dependent event that occurs after initiating chemotherapy, and it may introduce immortal time bias. To avoid such bias, we performed landmark analyses, with 2- and 3-month landmark points after initiating NFF because the mean time to BTI onset was 2.2 months. The median OS showed no clinically meaningful difference between the non-BTI and BTI groups. In both groups, disease progression was the main reason for discontinuing treatment, which suggested that appropriate management of BTI and febrile neutropenia could slightly affect the continuation of NFF.\u003c/p\u003e\n\u003cp\u003eThere are several limitations to this study. First, this was an observational study, and thus residual cannot be fully excluded. Second, the sample sizes of the BD and BTI groups were small. Nevertheless, to the best of our knowledge, this prospective, multicenter cohort is the largest to specifically evaluate biliary events in the NFF setting, and we consider that these findings are clinically relevant. Third, NFF was administered in second- and third- or later-line settings, and heterogeneity in the treatment line could have affected outcomes and AEs. Therefore, we conducted a subgroup analysis and confirmed the safety and efficacy of NFF in second- and third- or later-line settings. In fact, the efficacy and safety were similar between the second-line and third- or later-line groups [15]. Fourth, BD approach tools, such as percutaneous transhepatic BD, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasound-guided BD, and the stent type (metal or plastic) were not included in the analyses. With only 37 patients in BD group and no data on the drainage approach or stent type, approach- or stent-specific analyses were not feasible. Finally, 11 patients had no histological diagnosis. In clinical practice, histological confirmation is sometimes infeasible, and systemic chemotherapy may be initiated on the basis of imaging and clinical judgment.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eBD did not materially affect NFF efficacy or survival. Therefore, NFF is considered feasible in patients with prior BD. However, BD may affect AEs and subsequent therapy, and particular caution regarding BTI is warranted.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAE, adverse event; BD, biliary drainage; BTI, biliary tract infection; CI, confidence interval; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; Nal-IRI, nanoliposomal irinotecan; NFF, nanoliposomal irinotecan with fluorouracil and folinic acid; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RDI, relative dose intensity; RECIST, Response Evaluation Criteria in Solid Tumors; urPC, unresectable pancreatic cancer.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NAPOLEON-2 study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of each participating institution. Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication was obtained using the opt-in/opt-out approach according to each participating institution’s policy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed in this study were stored in a secured research database. Although not publicly available, they are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSatoshi Otsu declares speaker engagements from Ono Pharmaceutical, Daiichi-Sankyo Company, Eli Lilly Japan K.K., Bristol-Myers Squibb Company, and Taiho Pharmaceutical. Kazuo Nishikawa declares speaker engagements from Teijin Pharma, Takeda Pharmaceutical Company, Daiichi-Sankyo Company, Novartis Pharma, Bristol-Myers Squibb Company, and Nihon Servier. The remaining authors have no competing interests or financial disclosures to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: TS1, MS, TO, TM, and KM; Methodology: WY, TS1, MS, TO, SA1, FK,\u003c/p\u003e\n\u003cp\u003eJN, TM, and KM; Formal analysis and investigation: WY, MS, TO, TS1, TM, and KM;\u003c/p\u003e\n\u003cp\u003eWriting - original draft preparation: WY, TS1, and TO; Writing - review and editing: MS,\u003c/p\u003e\n\u003cp\u003eHT1, TM, and KM; Resources: WY, TS1, TO, FK, NO, MK1, JN, HS1, YS, HO, ST, SA1,\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SA2, YK, KN1, SO, HT2, KJ, TS2, YU, TS3, NA, HS2, YI, MK2, and KN2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all of the patients and their families, investigators, and colleagues at the 17 institutions that were members of the NAPOLEON study group. We would like to thank the Saga Study Group of Liver Disease (SASLD) for their cooperation. We thank Ellen Knapp, PhD, from Edanz for editing a draft of this manuscript. Moreover, we are indebted to clinical research coordinators and medical office assistants of the NAPOLEON study group for their assistance in data collection: Mrs. Ishito (Sasebo Kyosai Hospital), Mrs. Yasutake (Saiseikai Kumamoto Hospital), and Mrs. Ookubo (Oita University Faculty of Medicine).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17\u0026ndash;48.\u003c/li\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, et al. Global cancer statistics. 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209\u0026ndash;249.\u003c/li\u003e\n\u003cli\u003eEgawa S, Toma H, Ohigashi H, et al. Japan Pancreatic Cancer Registry;30th year anniversary:Japan Pancreas Society. Pancreas. 2012;41:985\u0026ndash;992.\u003c/li\u003e\n\u003cli\u003eDe La Cruz MS, Young AP, Ruffin MT. Diagnosis and management of pancreatic cancer. Am Fam Physician. 2014 Apr 15;89:626\u0026ndash;32.\u003c/li\u003e\n\u003cli\u003eBoulay BR, et al. Managing malignant biliary obstruction in pancreas cancer:choosing the appropriate strategy. World J Gastroenterol. 2014 Jul 28;20:9345\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eConroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817\u0026ndash;1825.\u003c/li\u003e\n\u003cli\u003eVon Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691\u0026ndash;1703.\u003c/li\u003e\n\u003cli\u003eWainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nabpaclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3):a randomised, open-label, phase 3 trial. Lancet. 2023;402:1272\u0026ndash;1281.\u003c/li\u003e\n\u003cli\u003eWang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (Napoli-1):A global, randomised, open-label, phase 3 trial. Lancet. (2016) 387:545\u0026ndash;57.\u003c/li\u003e\n\u003cli\u003eMacarulla Mercad\u0026eacute; T, Chen L-T, Li C-P, et al. Liposomal irinotecan + 5-FU/LV in metastatic pancreatic cancer:subgroup analyses of patient, tumor, and previous treatment characteristics in the pivotal NAPOLI-1 trial. Pancreas. 2020;49:62\u0026ndash;75.\u003c/li\u003e\n\u003cli\u003eGasparini G, Aleotti F, Palucci M, et al. The role of biliary events in treatment and survival of patients with advanced pancreatic ductal adenocarcinoma. Dig Liver Dis. 2023;55:1750\u0026ndash;1756. doi:10.1016/j. dld.2023.04.015\u003c/li\u003e\n\u003cli\u003eBuxbaum JL, Biggins SW, Bagatelos KC, et al. Inoperable pancreatic cancer patients who have prolonged survival exhibit an increased risk of cholangitis. JOP. 2011;12:377\u0026ndash;383.\u003c/li\u003e\n\u003cli\u003eNishikawa K, Otsuka T, Shimokawa M, Inagaki T, Komori A, Todaka A, et al. Impact of biliary drainage for unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: retrospective results from the NAPOLEON-2 study. BMC Cancer. 2025;25:1614. doi:10.1186/s12885-025-14992-2.\u003c/li\u003e\n\u003cli\u003eKodama T, Imajima T, Shimokawa M, et al. A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer. Sci Rep. 2024;14:12422. doi:10.1038/s41598\u0026ndash;024\u0026ndash;63172-y.\u003c/li\u003e\n\u003cli\u003eShirakawa T, Shimokawa M, Otsuka T, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable or recurrent pancreatic cancer:a multicenter observational study (NAPOLEON-2). ESMO Gastrointest Oncol. 2025;8(C):100150. doi:10.1016/j. esmogo.2025.100150.\u003c/li\u003e\n\u003cli\u003eMorris TP, White IR, Royston P. Tuning multiple imputation by predictive mean matching and local residual draws. BMC Med Res Methodol. 2014;14:75. doi:10.1186/1471\u0026ndash;2288\u0026ndash;14\u0026ndash;75.\u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours:Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228\u0026ndash;247. doi:10.1016/j.ejca.2008.10.026.\u003c/li\u003e\n\u003cli\u003eNational Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Bethesda, MD:U.S. Department of Health and Human Services, National Institutes of Health;2017.\u003c/li\u003e\n\u003cli\u003eKrens SD, Lassche G, Jansman FGA, et al. Dose recommendations for anticancer drugs in patients with renal or hepatic impairment. Lancet Oncol. 2019;20:e200-e207. doi:10.1016/S1470\u0026ndash;204530145\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eNoventa S, Cherri S, Zaniboni A. Chemotherapy in advanced pancreatic cancer with hyperbilirubinemia. Dig Med Res. 2020;3:18. doi:10.21037/dmr.2020.04.04.\u003c/li\u003e\n\u003cli\u003eHonda T, Takayuki O, Shimokawa M, et al. PD-5 Impact of biliary drainagefor unresectable pancreatic cancer treated with folfirinox or gemcitabine plus nab-paclitaxel:Results from the Napoleon study. Ann Oncol. 2020 Jul;31:S213.\u003c/li\u003e\n\u003cli\u003eYoshikawa-Kimura A, Taira K, Maruyama H, et al. Influence of a biliary stent in patients with advanced pancreatic cancer treated with modified FOLFIRINOX. Medicine (Baltimore). 2022;101.\u003c/li\u003e\n\u003cli\u003eL\u0026uuml;bbert C, Wendt K, Feisthammel J, et al. Epidemiology and Resistance Patterns of Bacterial and Fungal Colonization of Biliary Plastic Stents:A Prospective Cohort Study. PLoS One. 2016;11:e0155479. doi:10.1371/journal. pone.0155479.\u003c/li\u003e\n\u003cli\u003eGrafia I, Chumbita M, Segu\u0026iacute; E, et al. Epidemiology and risk factors for recurrence in biliary source bloodstream infection episodes in oncological patients. Microbiol Spectr. 2023;11. doi:10.1128/spectrum.02142\u0026ndash;23.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eBD (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eNon-BD (n=113)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eSMD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eBTI (n=16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eNon-BTI (n=134)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003eSMD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eYears, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e71 (48\u0026ndash;81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e72 (45\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e72 (55\u0026ndash;81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e72 (45-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e14 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e67 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e72 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eECOG PS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e8 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e38 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e42 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e28 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e65 (58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e11 (69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e82 (61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2\u0026ndash;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e10 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e10 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003ePancreatectomy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e34 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e3 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e38 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eBiliary drainage history, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e37 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003en/a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e11 (69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e26 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003ePancreatic tumor location, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e35 (95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e27 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e12 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e50 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBody or tail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e86 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e4 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e84 (63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eHistology, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e36 (97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e95 (84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e15 (94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e116 (87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e8 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e11 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e10 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eStage, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMetastatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e32 (86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e102 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e15 (94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e119 (89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eSite of metastatic disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e22 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e55 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e10 (63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e67 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ePeritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e8 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e39 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e2 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e45 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e6 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e37 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e4 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e39 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eAscites, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e34 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e6 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e37 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eTime to NFF from 1st-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMonths, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e8.0 (2.3\u0026ndash;22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e10.0 (2.1\u0026ndash;42.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e7.7 (2.1\u0026ndash;24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e8.9 (2.3\u0026ndash;42.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eTreatment line of NFF, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2nd-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e23 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e64 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e13 (81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e74 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3rd-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e13 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e40 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e51 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4th- or later-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e9 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003ePrevious agent except for GEM, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eFluoropyrimidine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e12 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e40 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e50 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ePlatinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e15 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e17 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eCPT-11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e15 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e17 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eCA19-9 concentration\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eU/mL, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1413 (2\u0026ndash;418458)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e390 (2\u0026ndash;718508)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e2729 (8\u0026ndash;418458)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e403 (2\u0026ndash;718508)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eUGT1A1 genotype, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eHomo or double hetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e9 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026dagger;Two missing data points were imputed using the method of multiple imputation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: GEM\u003c/em\u003e, gemcitabine; \u003cem\u003eCPT-11\u003c/em\u003e, irinotecan; \u003cem\u003eCA19-9\u003c/em\u003e, carbohydrate antigen 19-9; \u003cem\u003eUGT1A1\u003c/em\u003e\u003cem\u003e,\u003c/em\u003e uridine diphosphate glucuronosyltransferase family 1 member A1; n/a not applicable; SMD, standardized mean difference.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Response to NFF according to the biliary drainage status\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eResponse, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eBD (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eNon-BD (n=113)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e12 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e15 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e53 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e16 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e44 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e4 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eORR (CR + PR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e12 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDCR (CR + PR + SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e19 (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e65 (58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e \u003cem\u003eCR\u003c/em\u003e, complete response; \u003cem\u003ePR\u003c/em\u003e, partial response; \u003cem\u003eSD\u003c/em\u003e, stable disease; \u003cem\u003ePD\u003c/em\u003e, progressive disease; \u003cem\u003eNE\u003c/em\u003e, \u003cem\u003eSMD\u003c/em\u003e, standardized mean difference.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Relative dose intensity according to the biliary drainage status\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e%, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eBD (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNon-BD (n=113)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNal-IRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e75.0 (51.9-100.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e72.7 (30.1-102.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e82.7 (54.2-104.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e78.4 (41.2-103.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e \u003cem\u003eFU\u003c/em\u003e, fluorouracil; \u003cem\u003eSMD\u003c/em\u003e, standardized mean difference.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Adverse events according to the biliary drainage status\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"586\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eGrade 3 or 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eBD (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNon-BD (n=113)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eBD (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNon-BD (n=113)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eWBC count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e16 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e38 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e18 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNeutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e16 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e55 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e31 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e28 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e68 (61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e9 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003ePlatelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e31 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eFebrile neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e3 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e3 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e26 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e72 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e21 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMalaise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e24 (65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e64 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e7 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e19 (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e47 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e5 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e15 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e51 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e3 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e19 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e13 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e42 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e4 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e29 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eWeight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e16 (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eAST, ALT increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e38 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e7 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMucositis oral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e7 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eAlopecia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e15 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e15 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eBiliary tract infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e3 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003ePeripheral sensory neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e32 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eHematological\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e38 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNonhematological\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e25 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e45 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e \u003cem\u003eSMD\u003c/em\u003e, standardized mean difference; \u003cem\u003eWBC\u003c/em\u003e, white blood cell; \u003cem\u003eAST\u003c/em\u003e, aspartate transaminase; \u003cem\u003eALT\u003c/em\u003e, alanine transaminase.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Characteristics of the BTI group (n = 16)\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eStage\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSex\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eBaseline BD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eTime to BTI (week)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eCTCAE grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003ePost-BTI NFF\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003ePlastic stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eStopped\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eStopped\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eStopped\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eLAPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eMetal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eContinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e \u003cem\u003eMPC\u003c/em\u003e, metastatic pancreatic cancer; \u003cem\u003eLAPC\u003c/em\u003e, locally advanced pancreatic cancer; \u003cem\u003eF\u003c/em\u003e, female; \u003cem\u003eM\u003c/em\u003e, male; \u003cem\u003eSD\u003c/em\u003e, stable disease; \u003cem\u003ePD\u003c/em\u003e, progressive disease.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Biliary drainage, Biliary tract infection, Landmark analysis, Pancreatic cancer, Nanoliposomal irinotecan","lastPublishedDoi":"10.21203/rs.3.rs-8972664/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8972664/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: The effectiveness and safety of nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) in patients with unresectable or recurrent pancreatic cancer with or without prior biliary drainage (BD) or on-treatment biliary tract infection (BTI) in the real world are unclear. Therefore, we analyzed the clinical outcomes of this condition in a multicenter, prospective study (NAPOLEON-2).\u003c/p\u003e\n\u003cp\u003eMethods: We evaluated 150 patients with unresectableor recurrent pancreatic cancer who received NFF as second- or later-line therapy. The patients were categorized into the pre-treatment BD group (37 patients) and the non-BD group (113 patients). The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), the objective response rate (ORR), the disease control rate (DCR), relative dose intensity, and adverse events (AEs). BTI was estimated using landmark analysis at 2 and 3 months to reduce immortal bias.\u003c/p\u003e\n\u003cp\u003eResults: There was no difference in OS between the two groups (hazard ratio, 1.25; 95% confidence interval, 0.83–1.89), and PFS was not different between the groups. Hematological AEs of grade ≥ 3 were observed in 34% of patients in the non-BD group and 38% in the BD group, while nonhematological AEs of grade ≥ 3 were observed in 40% and 68%, respectively. The BTI rate was higher in the BD group than in the non-BD group (30% vs 4%). On-treatment BTI showed no clinically meaningful difference in OS at the 2- and 3-month landmark analyses.\u003c/p\u003e\n\u003cp\u003eConclusions: BD has little effect on survival in patients treated with NFF. Physicians need to pay attention to BTI in NFF treatment.\u003c/p\u003e","manuscriptTitle":"Effect of biliary drainage and biliary tract infection in unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: a multicenter, prospective cohort study (NAPOLEON-2)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 17:09:21","doi":"10.21203/rs.3.rs-8972664/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-23T14:15:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T15:43:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193832906066481441270254952596107800815","date":"2026-04-22T06:56:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-10T12:12:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"206978705764029658603741990579052318157","date":"2026-03-05T22:51:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-05T05:31:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-05T05:21:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-03T13:55:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-02T19:49:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-03-02T11:53:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"10435a75-1123-472e-a233-71975fef33b8","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T11:54:41+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 17:09:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8972664","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8972664","identity":"rs-8972664","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}