Impact of biliary drainage for unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: retrospective results from the NAPOLEON-2 study

Impact of biliary drainage for unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: retrospective results from the NAPOLEON-2 study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of biliary drainage for unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: retrospective results from the NAPOLEON-2 study Kazuo Nishikawa, Taiga Otsuka, Mototsugu Shimokawa, Takashi Inagaki, and 26 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6755345/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Oct, 2025 Read the published version in BMC Cancer → Version 1 posted 11 You are reading this latest preprint version Abstract Background Nanoliposomal irinotecan plus fluorouracil with leucovorin (NFF) is the standard treatment regimen after gemcitabine-based therapy in patients with unresectable pancreatic cancer. However, data on the efficacy and safety of NFF in terms of the presence or absence of biliary drainage (BD) or serum bilirubin levels prior to NFF are limited. Therefore, we analyzed whether these factors affect the efficacy and safety of NFF in the real world (NAPOLEON-2). Methods We evaluated 161 consecutive patients who received NFF as second-line treatment. The primary endpoint was overall survival (OS); other endpoints included progression-free survival, response rate, disease control rate, dose intensity, and adverse events (AEs). We compared the endpoints between the non-BD group and BD group first, and then between the serum total bilirubin ≥ 1.0 mg/dL group and < 1.0 mg/dL group. Results All patients received gemcitabine prior to NFF. No significant difference in OS was observed between the non-BD and BD groups (9.1 vs 7.6 months; hazard ratio (HR), 1.09; 95% confidence interval (CI), 0.72–1.66; P = 0.69). The rates of severe hematological AEs and biliary tract infections were higher in the BD group than in the non-BD group. A significant difference in OS was noted between the bilirubin ≥ 1.0 mg/dL and < 1.0 mg/dL groups (5.4 vs 8.9 months; HR, 2.13; 95%CI, 1.18–3.84; P = 0.01). In addition, the rate of severe hematological AE was higher in the high bilirubin group (56% vs. 26%). Conclusions BD had little effect on the efficacy of NFF in daily practice. Patients with total bilirubin ≥ 1.0 mg/dL had shorter OS than those with total bilirubin < 1.0 mg/dL. pancreatic cancer nanoliposomal irinotecan fluorouracil folinic acid biliary drainage Figures Figure 1 Figure 2 Figure 3 Background Pancreatic cancer is the seventh leading cause of cancer-related death worldwide. It is currently the third leading cause of cancer-related deaths in the United States, with approximately 48,800 deaths in the United States annually ( 1 , 2 ). In Japan, pancreatic cancer is the fourth leading cause of cancer-related death, with approximately 38,579 deaths reported in the 2021 Japanese Cancer Registry ( 3 , 4 ). The number of patients with pancreatic cancer continues to increase globally, and their prognosis is poor. Only 15% of patients present with resectable pancreatic cancer, and local or systemic recurrence is common ( 5 ). Chemotherapy is the primary treatment for unresectable pancreatic cancer (UrPC) is chemotherapy. Gemcitabine (GEM), GEM plus nab-paclitaxel (GnP) ( 6 ) or fluorouracil (FU), leucovorin (LV), irinotecan, and oxaliplatin (FOLFIRINOX) ( 7 ) are used in the first treatments. Platinum-based anticancer drugs are effective, and the poly adenosine diphosphate–ribose polymerase inhibitor olaparib is also effective for UrPC with BRCA gene mutations ( 8 ). Pembrolizumab is also effective against high microsatellite instability and/or tumor mutation burden in pancreatic cancer ( 9 ). Additionally, the results of the JCOG1611 trial showed that GnP is a possible reference regimen for first-line treatment ( 10 ). Nanoliposomal irinotecan (nal-IRI) and FU with LV (NFF) are superior to FU with LV therapy in terms of overall survival (OS) for UrPC refractory to GEM-based chemotherapy ( 11 , 12 ). Pancreatic cancer often causes biliary obstruction ( 13 ). In such cases, endoscopic retrograde cholangiography followed by the placement of a biliary drainage stent or percutaneous transhepatic biliary drainage tube is required. A prospective randomized phase III study (NAPOLI-1) has reported a subgroup analysis based on the presence or absence of biliary stents. However, the number of cases with biliary stents was small (15 of 117 patients, 12.8%) in the NFF arm ( 11 ). In clinical practice, data regarding the effectiveness, prognosis, and safety of NFF treatment, including the presence or absence of biliary drainage or serum bilirubin levels before NFF are limited. Therefore, we conducted the NAPOLEON-2 study to investigate these in the real world. Methods Study design The NAPOLEON-2 study was a multicenter observational study comprising a retrospective part ( 14 ) and a prospective study of patients with UrPC treated with NFF after previous GEM-based therapy to investigate the efficacy and safety of specialists in gastroenterology and medical oncology in Japan. In this study, we retrospectively reviewed the medical records of 161 consecutive patients with UrPC. We analyzed patient characteristics, treatment efficacy, and adverse events (AEs). NFF was administered as follows: 90 min intravenous (i.v.) infusion of nal-IRI (70 mg/m 2 ), 46 h continuous intravenous infusion of FU (2400 mg/m 2 ), and 2 h intravenous infusion of levofolinate (200 mg/m 2 ) every 2 weeks. At the discretion of the physician in charge, dose reduction at initiation and modification during treatment owing to toxicity were allowed. Treatment was discontinued when disease progression or unacceptable AEs occurred, even after dose adjustment, or at the patient’s request. Continuation of the NFF treatment regimen after disease progression was permitted, if deemed feasible by the physician. This study was conducted with the approval of each participating institution’s institutional review board or ethics committee and in accordance with the Declaration of Helsinki. Assessments The primary endpoint of this study was OS. The other endpoints included progression-free survival (PFS), the proportion of patients achieving objective response and disease control, dose intensity (DI), and AEs. First, we analyzed the endpoints between biliary drainage group and nonbiliary drainage group treated by NFF (Analysis 1), and then between the patients’ serum total bilirubin ≥ 1.0 mg/dL group and < 1.0 mg/dL group at the initiation of NFF (Analysis 2). OS was calculated from the date of NFF administration to the date of death from any cause or censored at the final follow-up examination. PFS was calculated from the date of NFF administration to the date of progression or death from any cause, whichever was earlier, or censored at the final follow-up examination. Statistical analyses To evaluate the efficacy, PFS and OS were estimated using the Kaplan–Meier method, and the probability of survival was compared using the log-rank test and Cox proportional hazards model. Hazard ratios (HRs) are expressed as 95% confidence intervals (95% CI). Statistical significance was set at P < 0.05. The overall response rate (ORR) and disease control rate (DCR) were evaluated using computed tomography or magnetic resonance imaging and calculated according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ( 15 ). ORR was defined as complete or partial response, and DCR was defined as complete or partial response with stable disease as the best response. Safety was analyzed using the common terminology criteria for AEs (CTCAE v5.0) ( 16 ). Patient characteristics were compared using standardized mean differences. Data were collected by clinicians with expertise in clinical research under the supervision of a statistician and managed centrally. Statistical analyses were performed using the R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria). Results Patient characteristics Between March 2020 and May 2021, 161 patients with UrPC who received the NFF regimen were retrospectively enrolled (Fig. 1 ). Table 1 summarizes baseline patient characteristics. The median follow-up period was 7.3 months (95% CI, 5.6–8.9), and all patients had received GEM previously. The nonbiliary and biliary drainage groups comprised 100 and 41 patients, respectively. Meanwhile, the total bilirubin ≥ 1.0 mg/dL and < 1.0 mg/dL groups comprised 16 and 144 patients, respectively, and one patient’s total bilirubin data were missing. Table 1 Patient characteristics ( n = 161) Analysis 1 Analysis 2 Nondrainage group n = 120 Biliary drainage group n = 41 SMD Total bilirubin < 1.0 mg/dL group n = 144 Total bilirubin ≧ 1 mg/dL group n = 16 SMD Age Median (range) 68 (38–85) 66 (47–78) 0.33 67 (38–82) 67 (47–85) 0.21 Sex, n (%) Male 65 (54) 23 (56) 0.04 76 (53) 12 (75) 0.48 ECOG PS, n (%) 0 1 2~ 55 (46) 60 (50) 5 ( 4 ) 19 (46) 16 (39) 6 ( 15 ) 0.39 67 (47) 67 (47) 10 ( 7 ) 6 (38) 9 (56) 1 ( 6 ) 0.20 Previous pancreatic surgery Yes No or unknown 32 ( 27 ) 88 (73) 8 ( 20 ) 33 (81) 0.17 37 ( 26 ) 107 (74) 3 ( 19 ) 13 (81) 0.17 Biliary drainage Yes 0 (0) 41 (100) n/a 35 ( 24 ) 5 (31) 0.16 Pancreatic tumor location, n (%) Head Body or tail 34 (28) 86 (72) 33 (81) 8 ( 20 ) 1.23 61 (42) 83 (58) 5 (31) 11 (69) 0.23 Histology, n (%) Adenocarcinoma Other Unknown 111 (93) 5 ( 4 ) 4 ( 3 ) 37 (90) 2 ( 5 ) 2 ( 5 ) 0.09 133 (92) 7 ( 5 ) 4 ( 3 ) 14 (88) 0 (0) 2 ( 13 ) 0.49 Stage, n (%) Metastatic 110 (92) 32 (78) 0.39 128 (89) 13 (81) 0.22 Site of metastatic disease, n (%) Liver Peritoneum Lung 70 (58) 33 (28) 24 ( 20 ) 19 (46) 11 ( 27 ) 4 ( 10 ) 0.24 0.02 0.29 81 (56) 39 ( 27 ) 26 ( 18 ) 7 (44) 5 (31) 2 ( 13 ) 0.25 0.09 0.16 Ascites, n (%) Yes 19 ( 16 ) 5 ( 12 ) 0.11 23 ( 16 ) 1 ( 6 ) 0.31 Previous chemotherapy duration Median months (range) 9.1 (1.4–45.0) 11.2 (2.8–36.2) 0.34 9.4 (1.4–45.0) 15.3 (1.8–36.2) 0.43 nal-IRI treatment line, n (%) Second line Third line Forth or later line 79 (66) 30 ( 25 ) 11 ( 9 ) 25 (61) 11 ( 27 ) 5 ( 12 ) 0.12 97 (67) 38 ( 26 ) 9 ( 6 ) 6 (38) 3 ( 19 ) 7 (44) 0.97 Previous chemotherapy Fluorouracil Platinum Irinotecan 38 (32) 16 ( 13 ) 15 ( 13 ) 14 (34) 4 ( 10 ) 3 ( 7 ) 0.05 0.11 0.17 43 (30) 16 ( 11 ) 14 ( 10 ) 9 (56) 4 ( 25 ) 4 ( 25 ) 0.55 0.37 0.41 CA19-9 Median [U/mL] (range) 888 (0.6–543522) 1146 (0.6–129646) 0.16 880 (0.6–543522) 2079 (0.6–489500) 0.37 UGT1A1 genotype, n (%) Homozygous or heterocomplex 7 ( 6 ) 1 ( 2 ) 0.17 4 ( 3 ) 4 ( 25 ) 0.68 Abbreviations: SMD , standardized mean difference; ECOG PS , Eastern Cooperative Oncology Group Performance Statu s , n/a not applicable; nal-IRI , nanoliposomal irinotecan; CA19-9 , carbohydrate antigen 19 − 9; UGT1A1 , uridine diphosphate glucuronosyltransferase family 1 member A1 Analysis 1 revealed several significant differences in patient characteristics, such as tumor location, stage, and duration of previous chemotherapy. Similarly, significant differences were observed in the NFF treatment line, previous history of FU, and uridine diphosphate glucuronosyltransferase family 1 member A1 ( UGT1A1 ) status in Analysis 2. Analysis 1: biliary drainage and nonbiliary drainage groups We compared the efficacy and safety between the nonbiliary drainage and drainage groups in all patients. The median OS (mOS) was 9.1 months in the nonbiliary drainage group and 7.6 months in the biliary drainage group (HR for death, 1.09; 95% CI, 0.72–1.66; P = 0.69; Fig. 2 a). The two groups had the same median PFS of 3.4 months (HR, 0.80; 95% CI, 0.54–1.16; P = 0.24; Fig. 2 b). No significant differences in OS or PFS were observed between the two groups. The ORR were 5% and 5% in the nonbiliary and biliary drainage groups, respectively. The DCR were 50% and 59% in the nonbiliary and biliary drainage groups, respectively (Table 2 ). The median number of treatment cycles was six (range, 1–36) in the nonbiliary drainage group and 4 (range, 1–38) in the biliary drainage group. The median relative DIs (RDIs) for nal-IRI were 82.9% in the nonbiliary drainage group, 81.1% in the biliary drainage group, and 91.4% and 88.1% in the nonbiliary drainage and drainage groups, respectively (Supplementary Table 1). Table 2 Response to NFF in analyses 1 and 2 Analysis 1 Analysis 2 n (%) Non-BD n = 120 BD n = 41 SMD T-Bil < 1.0 n = 144 T-Bil ≧ 1.0 n = 16 SMD CR + PR (ORR) 6 ( 5 ) 2 ( 5 ) < 0.01 7 ( 5 ) 1 ( 6 ) 0.06 CR + PR + SD (DCR) 60 (50) 24 (59) 0.17 76 (53) 8 (50) 0.06 Abbreviations: NFF , nanoliposomal irinotecan and fluorouracil with folinic acid; BD , biliary drainage; SMD , standardized mean difference; T-Bil , total bilirubin; CR , complete response; PR , partial response; SD , stable disease; ORR , overall response rate; DCR , disease control rate The reasons for termination of the NFF treatment are summarized in Supplementary Table 2. Both groups experienced tumor progression and clinically progressive disease (PD) most frequently. The treatments followed by NFF are shown in Supplementary Table 3. Seventy (62%) patients in the nonbiliary drainage group and 25 (71%) in the biliary drainage group received the best supportive care alone. Treatment-related AEs affecting ≥ 10% of patients are summarized in Table 3 . As for ≥ grade 3 AEs, leukopenia was the most frequent one in both the nonbiliary drainage and biliary drainage groups, followed by leukopenia in the biliary drainage group and anorexia in the nonbiliary drainage group, respectively. The rate of biliary tract infection was higher in the biliary drainage group than in the nonbiliary drainage group. Table 3 All-grades and grade ≥ 3 AEs during NFF in analyses 1 and 2 Analysis 1 Analysis 2 n (%) Any grade Grade 3 or 4 Any grade Grade 3 or 4 Non-BD n = 120 BD n = 41 Non-BD n = 120 BD n = 41 T-Bil < 1.0 n = 144 T-Bil ≧ 1.0 n = 16 T-Bil < 1.0 n = 144 T-Bil ≧ 1.0 n = 16 Leukopenia 44 (37) 22 (54) 10 ( 8 ) 9 ( 22 ) 59 (41) 7 (44) 14 ( 10 ) 5 (31) Neutropenia 45 (38) 23 (56) 25 ( 21 ) 13 (32) 61 (42) 7 (44) 31 ( 22 ) 7 (44) Anemia 66 (55) 20 (49) 9 ( 8 ) 6 ( 15 ) 78 (54) 8 (50) 12 ( 8 ) 3 ( 19 ) Thrombocytopenia 15 ( 13 ) 5 ( 12 ) 1 ( 1 ) 1 ( 2 ) 16 ( 11 ) 4 ( 25 ) 1 ( 1 ) 1 ( 6 ) Anorexia 88 (73) 30 (73) 16 ( 13 ) 4 ( 10 ) 107 (74) 11 (69) 19 ( 13 ) 1 ( 6 ) Malaise 69 (58) 25 (61) 4 ( 3 ) 1 ( 2 ) 85 (59) 8 (50) 4 ( 3 ) 1 ( 6 ) Fatigue 55 (46) 24 (59) 2 ( 2 ) 3 ( 7 ) 69 (48) 9 (56) 4 ( 3 ) 1 ( 6 ) Nausea 49 (41) 19 (46) 7 ( 6 ) 2 ( 5 ) 61 (42) 7 (44) 8 ( 6 ) 1 ( 6 ) Vomiting 23 ( 19 ) 9 ( 22 ) 0 (0) 2 ( 5 ) 29 ( 20 ) 3 ( 19 ) 1 ( 1 ) 1 ( 6 ) Diarrhea 36 (30) 15 (37) 3 ( 3 ) 2 ( 5 ) 46 (32) 4 ( 25 ) 3 ( 2 ) 1 ( 6 ) Constipation 39 (33) 11 ( 27 ) 0 (0) 0 (0) 45 (31) 5 (31) 0 (0) 0 (0) Weight loss 9 ( 8 ) 1 ( 2 ) 1 ( 1 ) 0 (0) 8 ( 6 ) 2 ( 13 ) 1 ( 1 ) 0 (0) AST/ALT increased 29 ( 24 ) 12 (29) 2 ( 2 ) 0 (0) 38 ( 26 ) 3 ( 19 ) 1 ( 1 ) 1 ( 6 ) Creatinine increased 2 ( 2 ) 2 ( 5 ) 0 (0) 0 (0) 2 ( 1 ) 2 ( 13 ) 0 (0) 0 (0) Mucositis oral 16 ( 13 ) 4 ( 10 ) 0 (0) 1 ( 2 ) 20 ( 14 ) 0 (0) 1 ( 1 ) 0 (0) Alopecia 26 ( 22 ) 10 ( 24 ) – – 32 ( 22 ) 3 ( 19 ) – – Rash 6 ( 5 ) 3 ( 7 ) 1 ( 1 ) 0 (0) 6 ( 4 ) 2 ( 13 ) 1 ( 1 ) 0 (0) Fever 7 ( 6 ) 3 ( 7 ) 0 (0) 0 (0) 7 ( 5 ) 3 ( 19 ) 0 (0) 0 (0) Biliary tract or Gallbladder infection 1 ( 1 ) 4 ( 10 ) 1 ( 1 ) 3 ( 7 ) 1 ( 1 ) 1 ( 6 ) 1 ( 1 ) 1 ( 6 ) Peripheral motor neuropathy 3 ( 3 ) 3 ( 7 ) 0 (0) 0 (0) 4 ( 3 ) 1 ( 6 ) 0 (0) 0 (0) Peripheral sensory neuropathy 48 (40) 15 (37) 0 (0) 1 ( 2 ) 54 (38) 9 (56) 1 ( 1 ) 0 (0) Abdominal pain 2 ( 2 ) 0 (0) 1 ( 1 ) 0 (0) 1 ( 1 ) 1 ( 6 ) 1 ( 1 ) 0 (0) Hematologic AE 81 (68) 28 (68) 31 ( 26 ) 16 (39) 98 (70) 11 (69) 38 ( 26 ) 9 (56) Non-hematologic AE 117 (98) 40 (98) 27 ( 23 ) 15 (37) 140 (97) 16 (100) 36 ( 25 ) 5 (31) Abbreviations: AE , adverse event; NFF , nanoliposomal irinotecan and fluorouracil with folinic acid; BD , biliary drainage; T-Bil , total bilirubin; AST , aspartate transaminase; ALT , alanine transaminase Analysis 2: serum total bilirubin ≥ 1.0 mg/dL group and < 1.0mg/dL group We then analyzed the patients between the serum total bilirubin ≥ 1.0 mg/dL group and < 1.0 mg/dL group at the initiation of NFF. The median OS was 5.4 months in the bilirubin ≥ 1.0 mg/dL group and 8.9 months in the < 1.0 mg/dL group (HR, 2.13; 95% CI, 1.18–3.84; P = 0.01; Fig. 3 a). The median PFS was 2.7 months in the bilirubin ≥ 1.0 mg/dL group and 3.6 months in the < 1.0 mg/dL group (HR, 1.71; 95% CI, 1.01–2.89; P = 0.046; Fig. 3 b). Significant differences in OS and PFS were observed between the two groups. The ORR was 6% and 5% in the bilirubin ≥ 1.0 mg/dL group and < 1.0 mg/dL group, respectively. The DCR was 50% and 53% in the bilirubin ≥ 1.0 mg/dL group and < 1.0 mg/dL group, respectively (Table 2 ). The median number of treatment cycles was 4 (range, 1–14) in the bilirubin ≥ 1.0 mg/dL group and 6 (1–38) in the < 1.0 mg/dL group, respectively. The median RDIs for nal-IRI were 80.9% in the bilirubin ≥ 1.0 mg/dL group and 82.3% in the < 1.0 mg/dL group, respectively, and for FU were 91.3% in the bilirubin ≥ 1.0 mg/dL group and 90.8% in the < 1.0 mg/dL group, respectively (Supplementary Table 1). The reasons for the termination of the NFF treatment are summarized in Supplementary Table 2. The rate of tumor progression was higher in the < 1.0 mg/dL group (76%) than in the bilirubin ≥ 1.0 mg/dL group (50%). Supplementary Table 3 shows the post-treatment results after the NFF. Regarding ≥ grade 3 treatment-related AEs (Table 3 ), the rate of hematologic AE was higher in the ≥ 1.0 mg/dL group (56%) than in the bilirubin < 1.0 mg/dL group (26%). The rates of leukopenia and neutropenia of ≥ grade 3 were 31% and 44% in the bilirubin ≥ 1.0 mg/dL group, respectively. Discussion We conducted this study to analyze whether biliary drainage or serum bilirubin levels before NFF therapy affected the efficacy and safety of NFF treatment. In our data, the presence or absence of biliary drainage had little effect on prognosis or safety. However, a significant difference in prognosis was observed between the serum total bilirubin ≥ 1.0 mg/dL group and < 1.0 mg/dL group at NFF initiation. The median follow-up period of this study was 7.3 months, which was slightly shorter than the mOS of nonbiliary drainage or total bilirubin < 1.0 mg/dL group. However, this might be influenced by the fact that the mOS for confirmed deaths was 6.5 months. NFF showed a similar mOS to that reported previously ( 11 , 17 – 23 ). In our data, no significant difference in OS or PFS was observed between the nonbiliary and biliary drainage groups. The NAPOLI-1 study showed that prospective trials of NFF included the presence or absence of biliary stents in a pre-specified subgroup analysis of OS ( 11 ). In that trial, regardless of the presence of biliary stents, the NFF therapy group (15 of 102 patients with biliary stents) had better OS than the fluorouracil and folinic acid therapy group (8 of 111 patients with biliary stents). In a prospective trial of FOLFIRINOX, biliary stents were analyzed as a variable for OS ( 7 ), and the FOLFIRINOX group (27 of 171 patients with biliary stents) had superior OS compared to the GEM group (22 of 171 patients with biliary stents). In addition, a retrospective study of 278 patients examined whether placement of a biliary stent (self-expanding metallic stent or plastic stent) was a prognostic factor for survival in patients with UrPC ( 13 ). In that report, multivariate analysis showed that biliary stent use was not a prognostic factor, and only the presence of distant metastasis was an independent prognostic factor. Biliary drainage did not affect the prognosis of patients with UrPC treated with FOLFIRINOX or GnP and no statistically significant differences in efficacy or safety were observed between the biliary drainage-treated FOLFIRINOX and GnP groups ( 24 , 25 ). The current study showed similar results for NFF in patients with UrPC, suggesting that biliary drainage had little effect on prognosis. In addition, no clinical differences in terms of reasons for discontinuing NFF therapy, types of subsequent treatment, response rates, or RDI were observed between the two groups. Our data suggest that NFF might have similar efficacy not only for nonbiliary cases but also for biliary cases; however, we need to pay attention to the fact that the incidence of grade 3 or higher leukopenia, biliary tract infection, and any grade of neutropenia increased in the biliary drainage group in daily clinical practice. We also conducted a stratified analysis, which classified patients into two groups based on normal value or high total bilirubin value precisely before NFF, and increased toxicity and shorter mOS were observed in the bilirubin ≥ 1.0 mg/dL group. Clinically significant differences in the treatment line for NFF, history of FU, and UGT1A1 genotype frequency were observed between the two groups. The patients with bilirubin levels ≥ 1.0 mg/dL showed severe hematological AEs in NFF treatment. Thus, patients with high total bilirubin levels may require careful medical treatment during NFF chemotherapy. In the retrospective report on treatment results in actual clinical practice for 1085 patients with UrPC, the prognosis was analyzed using a bilirubin cutoff value of 0.85 mg/dL, and the report identified no difference in efficacy ( 25 ). In that report, the regimens GnP, FOLFIRINOX, GEM, erlotinib, tegafur, S-1, GEM, S-1, and GEM were analyzed; however, NFF was not analyzed. Thus, toxicity should be considered for patients with total bilirubin levels ≥ 1.0 mg/dL in NFF, regardless of the biliary drainage. This study had some limitations. First, this study was retrospective, so our results could have been affected by a selection bias. Moreover, the differences in patient characteristics in analyses 1 and 2 need to be considered. Second, because our study included patients treated with NFF chemotherapy, we analyzed NFF cases irrespective of their therapeutic lines. Third, the number of patients with high serum total bilirubin levels was insufficient. Classically, the upper standard value for the serum total bilirubin level is 1.0 mg/dl ( 26 ). Then, 1.2 mg/dL is often used as the upper limit ( 27 ), whereas in the NAPOLI-1 study, patients were enrolled within the facility’s standard range of total bilirubin ( 11 ). We used the cutoff of total bilirubin as 1.0 mg/dL considering that the number of bilirubin ≥ 1.0 mg/dL group was 16. To overcome these limitations, we are now prospectively analyzing other cohorts to confirm repeatability. Lastly, a total of six cases had no histological diagnosis (unknown). In clinical practice, diagnosing cancer histologically in some cases is difficult, and chemotherapy may be administered based on imaging and clinical diagnosis. Thus, further studies are warranted to provide stronger evidence to support the findings of this study. Conclusions In this study, biliary drainage might not affect prognosis, and the biliary drainage group experienced more AEs than the nonbiliary drainage group. Additionally, patients with higher total bilirubin levels at NFF initiation had more severe hematological AEs and shorter survival. Therefore, more frequent follow-ups and adequate prognostic information may be desirable. Abbreviations NFF: Nanoliposomal irinotecan plus fluorouracil with leucovorin BD: Biliary drainage OS: Overall survival AE: Adverse event HR: Hazard ratio CI: Confidence interval UrPC: Unresectable pancreatic cancer GEM: Gemcitabine GnP: Gemcitabine plus nab-paclitaxel FU: Fluorouracil LV: Leucovorin FOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin nal-IRI: Nanoliposomal irinotecan PFS: Progression-free survival DI: Dose intensity ORR: Overall response rate DCR: Disease control rate RECIST: Response Evaluation Criteria in Solid Tumors CTCAE: Common terminology criteria for adverse events UGT1A1: Uridine diphosphate glucuronosyltransferase family 1 member A1 RDI: Relative dose intensity PD: Progressive disease Declarations Ethics approval and consent to participate This study was conducted in accordance with the ethical guideline of the Declaration of Helsinki and was centrally approved by the Institutional Review Board of Sasebo Kyosai Hospital (study ID 2021-08), and also approved by the Institutional Review Boards or Ethics Committee of the following institutions: Kagoshima City Hospital, National Cancer Center Hospital East, Kagoshima University Hospital, Kurume University Hospital, Saga Medical Center Koseikan, Japanese Red Cross Kumamoto Hospital, Karatsu Red Cross Hospital, Japan Community Healthcare Organization Kyushu Hospital, Japanese Red Cross Nagasaki Genbaku Hospital, Oita University Hospital, University of Miyazaki Hospital, National Hospital Organization Kumamoto Medical Center, Saiseikai Kumamoto Hospital, Kagoshima Kouseiren Hospital, Miyazaki Prefectural Miyazaki Hospital, Nagasaki University Hospital, Izumi General Medical Center, Asakura Medical Association Hospital, and Saiseikai Sendai Hospital prior to the study. Because this study was a retrospective observational study conducted in Japan, informed consent was obtained using the opt-in/opt-out approach according to each participating institution’s policy. Clinical trial number: not applicable. 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 The authors declare that they have no competing interests. Funding This study did not receive any funding. Authors’ contributions 1. TS4, TO, MS, TM, and KM2 conceptualized the study. 2. KN, TO, TS4, MS, JN, TS1, SA1, FK, TM, and KM2 designed the study. 3. KN, TI, AK, AT, SO, TS1, JN, SA1, KM1, FK, YU, YK, HS, ST, AH, TS2, HO, MK, SA2, TH, HT, KT, TF, TS3, YK, and KM2 obtained clinical data. 4. TS4, TO, MS, and KM2 were involved in the quality control of the data and algorithms. 5. KN, TO, TS4, MS, TM, and KM2 analyzed and interpreted data. 6. KN, TO, TS4, MS, and KM2 performed statistical analysis. 7. KN prepared the manuscript, and TS4, TO, MS, TM, and KM2 edited it. 8. All the authors read and approved the final manuscript. Acknowledgments We thank all the patients and their families, and all of the investigators at the 21 institutions that participated in the NAPOLEON-2 study. We would also like to thank the Saga Study Group of Liver Disease (SASLD) for their cooperation. We are grateful and indebted to the clinical research coordinators and medical office assistants of the NAPOLEON study group for their assistance with the data collection. We also thank Editage for providing the medical writing support. 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Chun JW, Woo SM, Lee SH, Choi JH, Park N, Kim JS, et al. A real-world analysis of nanoliposomal-irinotecan with 5-fluorouracil and folinic acid as third- or later-line therapy in patients with metastatic pancreatic adenocarcinoma. Ther Adv Med Oncol. 2022;14:17588359221119539. Tezuka S, Ueno M, Kobayashi S, Hamaguchi T, Yamachika Y, Oishi R, et al. Nal-IRI/5-FU/LV versus modified FOLFIRINOX and FOLFIRI as second-line chemotherapy for unresectable pancreatic cancer: A single center retrospective study. Pancreatology. 2022;22:789–96. Honda T, Takayuki O, Shimokawa M, Koga F, Ueda Y, Nakazawa J, et al. PD-5 Impact of biliary drainage for unresectable pancreatic cancer treated with folfirinox or gemcitabine plus nab-paclitaxel: Results from the Napoleon study. Ann Oncol. 2020 Jul;31 3:S213. Terashima T, Yamashita T, Sakai A, Ohta H, Hinoue Y, Toya D, et al. Treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice: A region-wide analysis. Jpn J Clin Oncol. 2018 Nov 1;48:966-73. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333:1171-5. Pausawasdi N, Termsinsuk P, Charatcharoenwitthaya P, Limsrivilai J, Kaosombatwattana U. Development and validation of a risk score for predicting clinical success after endobiliary stenting for malignant biliary obstruction. PLOS One. 2022 Aug 19;17:e0272918. Additional Declarations No competing interests reported. Supplementary Files SupplementalInformation.docx Cite Share Download PDF Status: Published Journal Publication published 21 Oct, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 07 Aug, 2025 Reviews received at journal 06 Aug, 2025 Reviewers agreed at journal 03 Aug, 2025 Reviewers agreed at journal 29 Jul, 2025 Reviews received at journal 30 Jun, 2025 Reviewers agreed at journal 10 Jun, 2025 Reviewers invited by journal 30 May, 2025 Editor invited by journal 30 May, 2025 Editor assigned by journal 30 May, 2025 Submission checks completed at journal 30 May, 2025 First submitted to journal 27 May, 2025 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. 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1","display":"","copyAsset":false,"role":"figure","size":282353,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the NAPOLEON-2 study.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6755345/v1/af47d7ab941319ffabe19790.png"},{"id":83815685,"identity":"e630ad96-38e0-4077-b307-332a98275438","added_by":"auto","created_at":"2025-06-03 07:38:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":288887,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival curves for nanoliposomal irinotecan and fluorouracil with leucovorin.\u003c/p\u003e\n\u003cp\u003e(a) Comparison of overall survival between the nonbiliary drainage and drainage groups. (b) Comparison of progression-free survival between the nonbiliary drainage and biliary drainage groups.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6755345/v1/37ee625029fa430ad0b35015.png"},{"id":83815680,"identity":"8cfcf07f-21c3-4a60-8101-76782ccdf019","added_by":"auto","created_at":"2025-06-03 07:38:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":225000,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival curves for nanoliposomal irinotecan and fluorouracil with leucovorin.\u003c/p\u003e\n\u003cp\u003e(a) Comparison of overall survival between the serum total bilirubin ≥1.0 mg/dL group and \u0026lt;1.0 mg/dL group at NFF initiation. (b) Comparison of progression-free survival between the serum total bilirubin ≥1.0 mg/dL and \u0026lt;1.0 mg/dL groups.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6755345/v1/1b41dd77404b6db2b5a0ef81.png"},{"id":94490188,"identity":"c0115fbe-368c-404e-ac2a-0afd4813c455","added_by":"auto","created_at":"2025-10-27 17:08:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1843488,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6755345/v1/2fba0f87-c242-416c-9f8f-0eae16ce37b9.pdf"},{"id":83814708,"identity":"41f397f0-4158-4045-a9dc-c90cc82aa3fd","added_by":"auto","created_at":"2025-06-03 07:30:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20398,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-6755345/v1/3a9732a3f83eb4f28707da21.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of biliary drainage for unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: retrospective results from the NAPOLEON-2 study","fulltext":[{"header":"Background","content":"\u003cp\u003ePancreatic cancer is the seventh leading cause of cancer-related death worldwide. It is currently the third leading cause of cancer-related deaths in the United States, with approximately 48,800 deaths in the United States annually (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In Japan, pancreatic cancer is the fourth leading cause of cancer-related death, with approximately 38,579 deaths reported in the 2021 Japanese Cancer Registry (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The number of patients with pancreatic cancer continues to increase globally, and their prognosis is poor. Only 15% of patients present with resectable pancreatic cancer, and local or systemic recurrence is common (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eChemotherapy is the primary treatment for unresectable pancreatic cancer (UrPC) is chemotherapy. Gemcitabine (GEM), GEM plus nab-paclitaxel (GnP) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) or fluorouracil (FU), leucovorin (LV), irinotecan, and oxaliplatin (FOLFIRINOX) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) are used in the first treatments. Platinum-based anticancer drugs are effective, and the poly adenosine diphosphate\u0026ndash;ribose polymerase inhibitor olaparib is also effective for UrPC with \u003cem\u003eBRCA\u003c/em\u003e gene mutations (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Pembrolizumab is also effective against high microsatellite instability and/or tumor mutation burden in pancreatic cancer (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Additionally, the results of the JCOG1611 trial showed that GnP is a possible reference regimen for first-line treatment (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Nanoliposomal irinotecan (nal-IRI) and FU with LV (NFF) are superior to FU with LV therapy in terms of overall survival (OS) for UrPC refractory to GEM-based chemotherapy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePancreatic cancer often causes biliary obstruction (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In such cases, endoscopic retrograde cholangiography followed by the placement of a biliary drainage stent or percutaneous transhepatic biliary drainage tube is required. A prospective randomized phase III study (NAPOLI-1) has reported a subgroup analysis based on the presence or absence of biliary stents. However, the number of cases with biliary stents was small (15 of 117 patients, 12.8%) in the NFF arm (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In clinical practice, data regarding the effectiveness, prognosis, and safety of NFF treatment, including the presence or absence of biliary drainage or serum bilirubin levels before NFF are limited. Therefore, we conducted the NAPOLEON-2 study to investigate these in the real world.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe NAPOLEON-2 study was a multicenter observational study comprising a retrospective part (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and a prospective study of patients with UrPC treated with NFF after previous GEM-based therapy to investigate the efficacy and safety of specialists in gastroenterology and medical oncology in Japan. In this study, we retrospectively reviewed the medical records of 161 consecutive patients with UrPC. We analyzed patient characteristics, treatment efficacy, and adverse events (AEs).\u003c/p\u003e \u003cp\u003eNFF was administered as follows: 90 min intravenous (i.v.) infusion of nal-IRI (70 mg/m\u003csup\u003e2\u003c/sup\u003e), 46 h continuous intravenous infusion of FU (2400 mg/m\u003csup\u003e2\u003c/sup\u003e), and 2 h intravenous infusion of levofolinate (200 mg/m\u003csup\u003e2\u003c/sup\u003e) every 2 weeks. At the discretion of the physician in charge, dose reduction at initiation and modification during treatment owing to toxicity were allowed. Treatment was discontinued when disease progression or unacceptable AEs occurred, even after dose adjustment, or at the patient\u0026rsquo;s request. Continuation of the NFF treatment regimen after disease progression was permitted, if deemed feasible by the physician. This study was conducted with the approval of each participating institution\u0026rsquo;s institutional review board or ethics committee and in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAssessments\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of this study was OS. The other endpoints included progression-free survival (PFS), the proportion of patients achieving objective response and disease control, dose intensity (DI), and AEs. First, we analyzed the endpoints between biliary drainage group and nonbiliary drainage group treated by NFF (Analysis 1), and then between the patients\u0026rsquo; serum total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and \u0026lt;\u0026thinsp;1.0 mg/dL group at the initiation of NFF (Analysis 2). OS was calculated from the date of NFF administration to the date of death from any cause or censored at the final follow-up examination. PFS was calculated from the date of NFF administration to the date of progression or death from any cause, whichever was earlier, or censored at the final follow-up examination.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eTo evaluate the efficacy, PFS and OS were estimated using the Kaplan\u0026ndash;Meier method, and the probability of survival was compared using the log-rank test and Cox proportional hazards model. Hazard ratios (HRs) are expressed as 95% confidence intervals (95% CI). Statistical significance was set at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The overall response rate (ORR) and disease control rate (DCR) were evaluated using computed tomography or magnetic resonance imaging and calculated according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). ORR was defined as complete or partial response, and DCR was defined as complete or partial response with stable disease as the best response. Safety was analyzed using the common terminology criteria for AEs (CTCAE v5.0) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Patient characteristics were compared using standardized mean differences. Data were collected by clinicians with expertise in clinical research under the supervision of a statistician and managed centrally. Statistical analyses were performed using the R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eBetween March 2020 and May 2021, 161 patients with UrPC who received the NFF regimen were retrospectively enrolled (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes baseline patient characteristics. The median follow-up period was 7.3 months (95% CI, 5.6\u0026ndash;8.9), and all patients had received GEM previously. The nonbiliary and biliary drainage groups comprised 100 and 41 patients, respectively. Meanwhile, the total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL and \u0026lt;\u0026thinsp;1.0 mg/dL groups comprised 16 and 144 patients, respectively, and one patient\u0026rsquo;s total bilirubin data were missing.\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient characteristics (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;161)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eAnalysis 1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eAnalysis 2\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNondrainage group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBiliary drainage group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal bilirubin\u0026thinsp;\u0026lt;\u0026thinsp;1.0\u003c/p\u003e\n \u003cp\u003emg/dL group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal bilirubin\u0026thinsp;≧\u0026thinsp;1\u003c/p\u003e\n \u003cp\u003emg/dL group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (38\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66 (47\u0026ndash;78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (38\u0026ndash;82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (47\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG PS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2~\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (46)\u003c/p\u003e\n \u003cp\u003e60 (50)\u003c/p\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (46)\u003c/p\u003e\n \u003cp\u003e16 (39)\u003c/p\u003e\n \u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (47)\u003c/p\u003e\n \u003cp\u003e67 (47)\u003c/p\u003e\n \u003cp\u003e10 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (38)\u003c/p\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious pancreatic surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo or unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e88 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e33 (81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e107 (74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e13 (81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBiliary drainage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en/a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePancreatic tumor location, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003cp\u003eBody or tail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (28)\u003c/p\u003e\n \u003cp\u003e86 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (81)\u003c/p\u003e\n \u003cp\u003e8 (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (42)\u003c/p\u003e\n \u003cp\u003e83 (58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (31)\u003c/p\u003e\n \u003cp\u003e11 (69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistology, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111 (93)\u003c/p\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (90)\u003c/p\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e133 (92)\u003c/p\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (88)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110 (92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e128 (89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSite of metastatic disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003cp\u003ePeritoneum\u003c/p\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70 (58)\u003c/p\u003e\n \u003cp\u003e33 (28)\u003c/p\u003e\n \u003cp\u003e24 (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (46)\u003c/p\u003e\n \u003cp\u003e11 (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81 (56)\u003c/p\u003e\n \u003cp\u003e39 (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e26 (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003cp\u003e5 (31)\u003c/p\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAscites, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious chemotherapy duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian months (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.1 (1.4\u0026ndash;45.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.2 (2.8\u0026ndash;36.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.4 (1.4\u0026ndash;45.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.3 (1.8\u0026ndash;36.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enal-IRI treatment line, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond line\u003c/p\u003e\n \u003cp\u003eThird line\u003c/p\u003e\n \u003cp\u003eForth or later line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79 (66)\u003c/p\u003e\n \u003cp\u003e30 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e11 (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (61)\u003c/p\u003e\n \u003cp\u003e11 (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (67)\u003c/p\u003e\n \u003cp\u003e38 (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (38)\u003c/p\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFluorouracil\u003c/p\u003e\n \u003cp\u003ePlatinum\u003c/p\u003e\n \u003cp\u003eIrinotecan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (32)\u003c/p\u003e\n \u003cp\u003e16 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e15 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (34)\u003c/p\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (30)\u003c/p\u003e\n \u003cp\u003e16 (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e14 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCA19-9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian [U/mL] (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e888 (0.6\u0026ndash;543522)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1146 (0.6\u0026ndash;129646)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e880 (0.6\u0026ndash;543522)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2079 (0.6\u0026ndash;489500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUGT1A1 genotype, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHomozygous or heterocomplex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003e\u003cem\u003eAbbreviations: SMD\u003c/em\u003e, standardized mean difference; \u003cem\u003eECOG PS\u003c/em\u003e, Eastern Cooperative Oncology Group Performance Statu\u003cem\u003es\u003c/em\u003e, \u003cem\u003en/a\u003c/em\u003e not applicable; \u003cem\u003enal-IRI\u003c/em\u003e, nanoliposomal irinotecan; \u003cem\u003eCA19-9\u003c/em\u003e, carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; \u003cem\u003eUGT1A1\u003c/em\u003e, uridine diphosphate glucuronosyltransferase family 1 member A1\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eAnalysis 1 revealed several significant differences in patient characteristics, such as tumor location, stage, and duration of previous chemotherapy. Similarly, significant differences were observed in the NFF treatment line, previous history of FU, and uridine diphosphate glucuronosyltransferase family 1 member A1 (\u003cem\u003eUGT1A1\u003c/em\u003e) status in Analysis 2.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eAnalysis 1: biliary drainage and nonbiliary drainage groups\u003c/h2\u003e\n \u003cp\u003eWe compared the efficacy and safety between the nonbiliary drainage and drainage groups in all patients. The median OS (mOS) was 9.1 months in the nonbiliary drainage group and 7.6 months in the biliary drainage group (HR for death, 1.09; 95% CI, 0.72\u0026ndash;1.66; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.69; Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). The two groups had the same median PFS of 3.4 months (HR, 0.80; 95% CI, 0.54\u0026ndash;1.16; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.24; Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb). No significant differences in OS or PFS were observed between the two groups. The ORR were 5% and 5% in the nonbiliary and biliary drainage groups, respectively. The DCR were 50% and 59% in the nonbiliary and biliary drainage groups, respectively (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The median number of treatment cycles was six (range, 1\u0026ndash;36) in the nonbiliary drainage group and 4 (range, 1\u0026ndash;38) in the biliary drainage group. The median relative DIs (RDIs) for nal-IRI were 82.9% in the nonbiliary drainage group, 81.1% in the biliary drainage group, and 91.4% and 88.1% in the nonbiliary drainage and drainage groups, respectively (Supplementary Table 1).\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eResponse to NFF in analyses 1 and 2\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eAnalysis 1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eAnalysis 2\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-BD\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBD\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-Bil\u0026thinsp;\u0026lt;\u0026thinsp;1.0\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-Bil\u0026thinsp;≧\u0026thinsp;1.0\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u0026thinsp;+\u0026thinsp;PR (ORR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;SD (DCR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003e\u003cem\u003eAbbreviations: NFF\u003c/em\u003e, nanoliposomal irinotecan and fluorouracil with folinic acid; \u003cem\u003eBD\u003c/em\u003e, biliary drainage; \u003cem\u003eSMD\u003c/em\u003e, standardized mean difference; \u003cem\u003eT-Bil\u003c/em\u003e, total bilirubin; \u003cem\u003eCR\u003c/em\u003e, complete response; \u003cem\u003ePR\u003c/em\u003e, partial response; \u003cem\u003eSD\u003c/em\u003e, stable disease; \u003cem\u003eORR\u003c/em\u003e, overall response rate; \u003cem\u003eDCR\u003c/em\u003e, disease control rate\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eThe reasons for termination of the NFF treatment are summarized in Supplementary Table 2. Both groups experienced tumor progression and clinically progressive disease (PD) most frequently. The treatments followed by NFF are shown in Supplementary Table 3. Seventy (62%) patients in the nonbiliary drainage group and 25 (71%) in the biliary drainage group received the best supportive care alone. Treatment-related AEs affecting\u0026thinsp;\u0026ge;\u0026thinsp;10% of patients are summarized in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. As for \u0026ge;\u0026thinsp;grade 3 AEs, leukopenia was the most frequent one in both the nonbiliary drainage and biliary drainage groups, followed by leukopenia in the biliary drainage group and anorexia in the nonbiliary drainage group, respectively. The rate of biliary tract infection was higher in the biliary drainage group than in the nonbiliary drainage group. \u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAll-grades and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs during NFF in analyses 1 and 2\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eAnalysis 1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eAnalysis 2\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGrade 3 or 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGrade 3 or 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-BD\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBD\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-BD\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBD\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-Bil\u0026thinsp;\u0026lt;\u0026thinsp;1.0\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-Bil\u0026thinsp;≧\u0026thinsp;1.0\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-Bil\u0026thinsp;\u0026lt;\u0026thinsp;1.0\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-Bil\u0026thinsp;≧\u0026thinsp;1.0\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLeukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e107 (74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMalaise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69 (58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAST/ALT increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCreatinine increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMucositis oral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlopecia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBiliary tract or\u003c/p\u003e\n \u003cp\u003eGallbladder infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeripheral motor\u003c/p\u003e\n \u003cp\u003eneuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeripheral sensory\u003c/p\u003e\n \u003cp\u003eneuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHematologic AE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-hematologic AE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e117 (98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e140 (97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003e\u003cem\u003eAbbreviations: AE\u003c/em\u003e, adverse event; \u003cem\u003eNFF\u003c/em\u003e, nanoliposomal irinotecan and fluorouracil with folinic acid; \u003cem\u003eBD\u003c/em\u003e, biliary drainage; \u003cem\u003eT-Bil\u003c/em\u003e, total bilirubin; \u003cem\u003eAST\u003c/em\u003e, aspartate transaminase; \u003cem\u003eALT\u003c/em\u003e, alanine transaminase\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eAnalysis 2: serum total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and \u0026lt;\u0026thinsp;1.0mg/dL group\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eWe then analyzed the patients between the serum total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and \u0026lt;\u0026thinsp;1.0 mg/dL group at the initiation of NFF. The median OS was 5.4 months in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and 8.9 months in the \u0026lt;\u0026thinsp;1.0 mg/dL group (HR, 2.13; 95% CI, 1.18\u0026ndash;3.84; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea). The median PFS was 2.7 months in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and 3.6 months in the \u0026lt;\u0026thinsp;1.0 mg/dL group (HR, 1.71; 95% CI, 1.01\u0026ndash;2.89; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb). Significant differences in OS and PFS were observed between the two groups. The ORR was 6% and 5% in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and \u0026lt;\u0026thinsp;1.0 mg/dL group, respectively. The DCR was 50% and 53% in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and \u0026lt;\u0026thinsp;1.0 mg/dL group, respectively (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The median number of treatment cycles was 4 (range, 1\u0026ndash;14) in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and 6 (1\u0026ndash;38) in the \u0026lt;\u0026thinsp;1.0 mg/dL group, respectively. The median RDIs for nal-IRI were 80.9% in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and 82.3% in the \u0026lt;\u0026thinsp;1.0 mg/dL group, respectively, and for FU were 91.3% in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and 90.8% in the \u0026lt;\u0026thinsp;1.0 mg/dL group, respectively (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003eThe reasons for the termination of the NFF treatment are summarized in Supplementary Table\u0026nbsp;2. The rate of tumor progression was higher in the \u0026lt;\u0026thinsp;1.0 mg/dL group (76%) than in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group (50%). Supplementary Table\u0026nbsp;3 shows the post-treatment results after the NFF. Regarding\u0026thinsp;\u0026ge;\u0026thinsp;grade 3 treatment-related AEs (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), the rate of hematologic AE was higher in the \u0026ge;\u0026thinsp;1.0 mg/dL group (56%) than in the bilirubin\u0026thinsp;\u0026lt;\u0026thinsp;1.0 mg/dL group (26%). The rates of leukopenia and neutropenia of \u0026ge;\u0026thinsp;grade 3 were 31% and 44% in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group, respectively.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe conducted this study to analyze whether biliary drainage or serum bilirubin levels before NFF therapy affected the efficacy and safety of NFF treatment. In our data, the presence or absence of biliary drainage had little effect on prognosis or safety. However, a significant difference in prognosis was observed between the serum total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and \u0026lt;\u0026thinsp;1.0 mg/dL group at NFF initiation. The median follow-up period of this study was 7.3 months, which was slightly shorter than the mOS of nonbiliary drainage or total bilirubin\u0026thinsp;\u0026lt;\u0026thinsp;1.0 mg/dL group. However, this might be influenced by the fact that the mOS for confirmed deaths was 6.5 months. NFF showed a similar mOS to that reported previously (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our data, no significant difference in OS or PFS was observed between the nonbiliary and biliary drainage groups. The NAPOLI-1 study showed that prospective trials of NFF included the presence or absence of biliary stents in a pre-specified subgroup analysis of OS (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In that trial, regardless of the presence of biliary stents, the NFF therapy group (15 of 102 patients with biliary stents) had better OS than the fluorouracil and folinic acid therapy group (8 of 111 patients with biliary stents). In a prospective trial of FOLFIRINOX, biliary stents were analyzed as a variable for OS (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), and the FOLFIRINOX group (27 of 171 patients with biliary stents) had superior OS compared to the GEM group (22 of 171 patients with biliary stents). In addition, a retrospective study of 278 patients examined whether placement of a biliary stent (self-expanding metallic stent or plastic stent) was a prognostic factor for survival in patients with UrPC (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In that report, multivariate analysis showed that biliary stent use was not a prognostic factor, and only the presence of distant metastasis was an independent prognostic factor. Biliary drainage did not affect the prognosis of patients with UrPC treated with FOLFIRINOX or GnP and no statistically significant differences in efficacy or safety were observed between the biliary drainage-treated FOLFIRINOX and GnP groups (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe current study showed similar results for NFF in patients with UrPC, suggesting that biliary drainage had little effect on prognosis. In addition, no clinical differences in terms of reasons for discontinuing NFF therapy, types of subsequent treatment, response rates, or RDI were observed between the two groups. Our data suggest that NFF might have similar efficacy not only for nonbiliary cases but also for biliary cases; however, we need to pay attention to the fact that the incidence of grade 3 or higher leukopenia, biliary tract infection, and any grade of neutropenia increased in the biliary drainage group in daily clinical practice.\u003c/p\u003e \u003cp\u003eWe also conducted a stratified analysis, which classified patients into two groups based on normal value or high total bilirubin value precisely before NFF, and increased toxicity and shorter mOS were observed in the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group. Clinically significant differences in the treatment line for NFF, history of FU, and \u003cem\u003eUGT1A1\u003c/em\u003e genotype frequency were observed between the two groups. The patients with bilirubin levels\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL showed severe hematological AEs in NFF treatment. Thus, patients with high total bilirubin levels may require careful medical treatment during NFF chemotherapy. In the retrospective report on treatment results in actual clinical practice for 1085 patients with UrPC, the prognosis was analyzed using a bilirubin cutoff value of 0.85 mg/dL, and the report identified no difference in efficacy (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In that report, the regimens GnP, FOLFIRINOX, GEM, erlotinib, tegafur, S-1, GEM, S-1, and GEM were analyzed; however, NFF was not analyzed. Thus, toxicity should be considered for patients with total bilirubin levels\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL in NFF, regardless of the biliary drainage.\u003c/p\u003e \u003cp\u003eThis study had some limitations. First, this study was retrospective, so our results could have been affected by a selection bias. Moreover, the differences in patient characteristics in analyses 1 and 2 need to be considered. Second, because our study included patients treated with NFF chemotherapy, we analyzed NFF cases irrespective of their therapeutic lines. Third, the number of patients with high serum total bilirubin levels was insufficient. Classically, the upper standard value for the serum total bilirubin level is 1.0 mg/dl (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Then, 1.2 mg/dL is often used as the upper limit (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), whereas in the NAPOLI-1 study, patients were enrolled within the facility\u0026rsquo;s standard range of total bilirubin (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). We used the cutoff of total bilirubin as 1.0 mg/dL considering that the number of bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group was 16. To overcome these limitations, we are now prospectively analyzing other cohorts to confirm repeatability. Lastly, a total of six cases had no histological diagnosis (unknown). In clinical practice, diagnosing cancer histologically in some cases is difficult, and chemotherapy may be administered based on imaging and clinical diagnosis. Thus, further studies are warranted to provide stronger evidence to support the findings of this study.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this study, biliary drainage might not affect prognosis, and the biliary drainage group experienced more AEs than the nonbiliary drainage group. Additionally, patients with higher total bilirubin levels at NFF initiation had more severe hematological AEs and shorter survival. Therefore, more frequent follow-ups and adequate prognostic information may be desirable.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNFF:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNanoliposomal irinotecan plus fluorouracil with leucovorin\u003c/p\u003e\n\u003cp\u003eBD: Biliary drainage\u003c/p\u003e\n\u003cp\u003eOS: Overall survival\u003c/p\u003e\n\u003cp\u003eAE: Adverse event\u003c/p\u003e\n\u003cp\u003eHR: Hazard ratio\u003c/p\u003e\n\u003cp\u003eCI: Confidence interval\u003c/p\u003e\n\u003cp\u003eUrPC: Unresectable pancreatic cancer\u003c/p\u003e\n\u003cp\u003eGEM: Gemcitabine\u003c/p\u003e\n\u003cp\u003eGnP: Gemcitabine plus nab-paclitaxel\u003c/p\u003e\n\u003cp\u003eFU: Fluorouracil\u003c/p\u003e\n\u003cp\u003eLV: Leucovorin\u003c/p\u003e\n\u003cp\u003eFOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin\u003c/p\u003e\n\u003cp\u003enal-IRI: Nanoliposomal irinotecan\u003c/p\u003e\n\u003cp\u003ePFS:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eProgression-free survival\u003c/p\u003e\n\u003cp\u003eDI: Dose intensity\u003c/p\u003e\n\u003cp\u003eORR: Overall response rate\u003c/p\u003e\n\u003cp\u003eDCR: Disease control rate\u003c/p\u003e\n\u003cp\u003eRECIST: Response Evaluation Criteria in Solid Tumors\u003c/p\u003e\n\u003cp\u003eCTCAE: Common terminology criteria for adverse events\u003c/p\u003e\n\u003cp\u003eUGT1A1: Uridine diphosphate glucuronosyltransferase family 1 member A1\u003c/p\u003e\n\u003cp\u003eRDI: Relative dose intensity\u003c/p\u003e\n\u003cp\u003ePD: Progressive disease\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the ethical guideline of the Declaration of Helsinki and was centrally approved by the Institutional Review Board of Sasebo Kyosai Hospital (study ID 2021-08), and also approved by the Institutional Review Boards or Ethics Committee of the following institutions: Kagoshima City Hospital, National Cancer Center Hospital East, Kagoshima University Hospital, Kurume University Hospital, Saga Medical Center Koseikan, Japanese Red Cross Kumamoto Hospital, Karatsu Red Cross Hospital, Japan Community Healthcare Organization Kyushu Hospital, Japanese Red Cross Nagasaki Genbaku Hospital, Oita University Hospital, University of Miyazaki Hospital, National Hospital Organization Kumamoto Medical Center, Saiseikai Kumamoto Hospital, Kagoshima Kouseiren Hospital, Miyazaki Prefectural Miyazaki Hospital, Nagasaki University Hospital, Izumi General Medical Center, Asakura Medical Association Hospital, and Saiseikai Sendai Hospital prior to the study. Because this study was a retrospective observational study conducted in Japan, informed consent was obtained using the opt-in/opt-out approach according to each participating institution\u0026rsquo;s policy. Clinical trial number: not applicable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\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\u0026rsquo;s policy.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\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\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\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\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. TS4, TO, MS, TM, and KM2 conceptualized the study.\u003c/p\u003e\n\u003cp\u003e2. KN, TO, TS4, MS, JN, TS1, SA1, FK, TM, and KM2 designed the study.\u003c/p\u003e\n\u003cp\u003e3. KN, TI, AK, AT, SO, TS1, JN, SA1, KM1, FK, YU, YK, HS, ST, AH, TS2, HO, MK, SA2, TH, HT, KT, TF, TS3, YK, and KM2 obtained clinical data.\u003c/p\u003e\n\u003cp\u003e4. TS4, TO, MS, and KM2 were involved in the quality control of the data and algorithms.\u003c/p\u003e\n\u003cp\u003e5. KN, TO, TS4, MS, TM, and KM2 analyzed and interpreted data.\u003c/p\u003e\n\u003cp\u003e6. KN, TO, TS4, MS, and KM2 performed statistical analysis.\u003c/p\u003e\n\u003cp\u003e7. KN prepared the manuscript, and TS4, TO, MS, TM, and KM2 edited it.\u003c/p\u003e\n\u003cp\u003e8. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients and their families, and all of the investigators at the 21 institutions that participated in the NAPOLEON-2 study. We would also like to thank the Saga Study Group of Liver Disease (SASLD) for their cooperation. We are grateful and indebted to the clinical research coordinators and medical office assistants of the NAPOLEON study group for their assistance with the data collection. We also thank Editage for providing the medical writing support.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe used the R ver. 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria) for statistical analyses.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIlic I, Ilic M. International patterns in incidence and mortality trends of pancreatic cancer in the last three decades: A joinpoint regression analysis. World J Gastroenterol. 2022 Aug 28;28:4698-715.\u003c/li\u003e\n\u003cli\u003eStoffel EM, Brand RE, Goggins M. Pancreatic cancer: Changing epidemiology and new approaches to risk assessment, early detection, and prevention. Gastroenterology. 2023 Apr;164:752-65.\u003c/li\u003e\n\u003cli\u003eUshio J, Kanno A, Ikeda E, Ando K, Nagai H, Miwata T, et al. Pancreatic ductal adenocarcinoma: Epidemiology and risk factors. Diagnostics (Basel). 2021 Mar 20;11:562.\u003c/li\u003e\n\u003cli\u003eCancer Registry and Statistics Cancer Information Service, National Cancer Center. Japan (Ministry of Health, Labour and Welfare, National Cancer Registry) [(accessed on 1 February 2024)]. https://ganjoho.jp/reg_stat/statistics/stat/summary.html.\u003c/li\u003e\n\u003cli\u003eAnsari D, Gustafsson A, Andersson R. Update on the management of pancreatic cancer: Surgery is not enough. World J Gastroenterol. 2015 Mar 21;21:3157-65.\u003c/li\u003e\n\u003cli\u003eVon Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369:1691-703.\u003c/li\u003e\n\u003cli\u003eConroy T, Desseigne F, Ychou M, Bouch\u0026eacute; O, Guimbaud R, B\u0026eacute;couarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364:1817-25.\u003c/li\u003e\n\u003cli\u003eGolan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019 Jul 25;381:317-27.\u003c/li\u003e\n\u003cli\u003eSakakida T, Ishikawa T, Doi T, Morita R, Kataoka S, Miyake H, et al. Genomic profile and clinical features of MSI-H and TMB-high pancreatic cancers: Real-world data from C-CAT database. J Gastroenterol. 2024 Feb;59:145-56.\u003c/li\u003e\n\u003cli\u003eOhba A, Ozaka M, Ogawa G, Okusaka T, Kobayashi S, Yamashita T, et al. 1616O Nab-paclitaxel plus gemcitabine versus modified folfirinox or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): A multicentred, randomized, open-label, three-arm, phase II/III trial. Ann Oncol. 2023 Oct;34 Suppl 2:S894.\u003c/li\u003e\n\u003cli\u003eWang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): A global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387:545-57.\u003c/li\u003e\n\u003cli\u003eUeno M, Nakamori S, Sugimori K, Kanai M, Ikeda M, Ozaka M, et al. nal-IRI+5-FU/LV versus 5-FU/LV in post-gemcitabine metastatic pancreatic cancer: Randomized phase 2 trial in Japanese patients. Cancer Med. 2020 Dec;9:9396-408.\u003c/li\u003e\n\u003cli\u003eWeber A, Kehl V, Mittermeyer T, Herberich E, R\u0026ouml;thling N, Schmid RM, et al. Prognostic factors for survival in patients with unresectable pancreatic cancer. Pancreas. 2010 Nov;39:1247-53.\u003c/li\u003e\n\u003cli\u003eKodama T, Imajima T, Shimokawa M, Otsuka T, Kawahira M, Nakazawa J, 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 May 30;14:12422.\u003c/li\u003e\n\u003cli\u003eSchwartz LH, Seymour L, Liti\u0026egrave;re S, Ford R, Gwyther S, Mandrekar S, et al. RECIST 1.1\u0026mdash;Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group. Eur J Cancer. 2016 Jul;62:138-45.\u003c/li\u003e\n\u003cli\u003eCommon Terminology Criteria for Adverse Events (CTCAE) Version 5. Published: November 27. United States Department of Health and Human Services, National Institutes of Health \u0026ndash; National Cancer Institute; 2017.\u003c/li\u003e\n\u003cli\u003eKieler M, Unseld M, Bianconi D, Scheithauer W, Prager GW. A real-world analysis of second-line treatment options in pancreatic cancer: Liposomal-irinotecan plus 5-fluorouracil and folinic acid. Ther Adv Med Oncol. 2019 Jul 17;11:1758835919853196.\u003c/li\u003e\n\u003cli\u003eSu YY, Chiang NJ, Tsai HJ, Yen CJ, Shan YS, Chen LT. The impact of liposomal irinotecan on the treatment of advanced pancreatic adenocarcinoma: Real-world experience in a Taiwanese cohort. Sci Rep. 2020 May 4;10:7420.\u003c/li\u003e\n\u003cli\u003eGlassman DC, Palmaira RL, Covington CM, Desai AM, Ku GY, Li J, et al. Nanoliposomal irinotecan with fluorouracil for the treatment of advanced pancreatic cancer, a single institution experience. BMC Cancer. 2018 Jun 27;18:693.\u003c/li\u003e\n\u003cli\u003eYoo C, Im HS, Kim KP, Oh DY, Lee KH, Chon HJ, et al. Real-world efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin in patients with metastatic pancreatic adenocarcinoma: A study by the Korean Cancer Study Group. Ther Adv Med Oncol. 2019;11:1758835919871126.\u003c/li\u003e\n\u003cli\u003ePark SJ, Kim H, Shin K, Hong TH, Suh JH, Lee MA. Nanoliposomal irinotecan plus fluorouracil and folinic acid as a second-line treatment option in patients with metastatic pancreatic ductal adenocarcinoma: A retrospective cohort study. BMC Cancer. 2021 Nov 3;21:1176.\u003c/li\u003e\n\u003cli\u003eChun JW, Woo SM, Lee SH, Choi JH, Park N, Kim JS, et al. A real-world analysis of nanoliposomal-irinotecan with 5-fluorouracil and folinic acid as third- or later-line therapy in patients with metastatic pancreatic adenocarcinoma. Ther Adv Med Oncol. 2022;14:17588359221119539.\u003c/li\u003e\n\u003cli\u003eTezuka S, Ueno M, Kobayashi S, Hamaguchi T, Yamachika Y, Oishi R, et al. Nal-IRI/5-FU/LV versus modified FOLFIRINOX and FOLFIRI as second-line chemotherapy for unresectable pancreatic cancer: A single center retrospective study. Pancreatology. 2022;22:789\u0026ndash;96.\u003c/li\u003e\n\u003cli\u003eHonda T, Takayuki O, Shimokawa M, Koga F, Ueda Y, Nakazawa J, et al. PD-5 Impact of biliary drainage for unresectable pancreatic cancer treated with folfirinox or gemcitabine plus nab-paclitaxel: Results from the Napoleon study. Ann Oncol. 2020 Jul;31 3:S213.\u003c/li\u003e\n\u003cli\u003eTerashima T, Yamashita T, Sakai A, Ohta H, Hinoue Y, Toya D, et al. Treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice: A region-wide analysis. Jpn J Clin Oncol. 2018 Nov 1;48:966-73.\u003c/li\u003e\n\u003cli\u003eBosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert\u0026apos;s syndrome. N Engl J Med. 1995;333:1171-5.\u003c/li\u003e\n\u003cli\u003ePausawasdi N, Termsinsuk P, Charatcharoenwitthaya P, Limsrivilai J, Kaosombatwattana U. Development and validation of a risk score for predicting clinical success after endobiliary stenting for malignant biliary obstruction. PLOS One. 2022 Aug 19;17:e0272918.\u003c/li\u003e\n\u003c/ol\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":"pancreatic cancer, nanoliposomal irinotecan, fluorouracil, folinic acid, biliary drainage","lastPublishedDoi":"10.21203/rs.3.rs-6755345/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6755345/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNanoliposomal irinotecan plus fluorouracil with leucovorin (NFF) is the standard treatment regimen after gemcitabine-based therapy in patients with unresectable pancreatic cancer. However, data on the efficacy and safety of NFF in terms of the presence or absence of biliary drainage (BD) or serum bilirubin levels prior to NFF are limited. Therefore, we analyzed whether these factors affect the efficacy and safety of NFF in the real world (NAPOLEON-2).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe evaluated 161 consecutive patients who received NFF as second-line treatment. The primary endpoint was overall survival (OS); other endpoints included progression-free survival, response rate, disease control rate, dose intensity, and adverse events (AEs). We compared the endpoints between the non-BD group and BD group first, and then between the serum total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL group and \u0026lt;\u0026thinsp;1.0 mg/dL group.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAll patients received gemcitabine prior to NFF. No significant difference in OS was observed between the non-BD and BD groups (9.1 vs 7.6 months; hazard ratio (HR), 1.09; 95% confidence interval (CI), 0.72\u0026ndash;1.66; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.69). The rates of severe hematological AEs and biliary tract infections were higher in the BD group than in the non-BD group. A significant difference in OS was noted between the bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL and \u0026lt;\u0026thinsp;1.0 mg/dL groups (5.4 vs 8.9 months; HR, 2.13; 95%CI, 1.18\u0026ndash;3.84; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). In addition, the rate of severe hematological AE was higher in the high bilirubin group (56% vs. 26%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eBD had little effect on the efficacy of NFF in daily practice. Patients with total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;1.0 mg/dL had shorter OS than those with total bilirubin\u0026thinsp;\u0026lt;\u0026thinsp;1.0 mg/dL.\u003c/p\u003e","manuscriptTitle":"Impact of biliary drainage for unresectable pancreatic cancer treated with nanoliposomal irinotecan with fluorouracil and folinic acid: retrospective results from the NAPOLEON-2 study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 07:30:41","doi":"10.21203/rs.3.rs-6755345/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-07T11:30:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-07T03:22:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"84685006107221726004137330444286519452","date":"2025-08-03T21:25:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"283369457810357993404366157260877663215","date":"2025-07-29T22:03:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-30T20:55:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193016950798345605157086644351359780332","date":"2025-06-10T10:44:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-30T12:25:19+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-30T11:59:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-30T08:13:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-30T08:09:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-05-27T04:43:47+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":"97161c9d-40d9-4310-9e3d-0575ec26fd8e","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T16:35:03+00:00","versionOfRecord":{"articleIdentity":"rs-6755345","link":"https://doi.org/10.1186/s12885-025-14992-2","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-10-21 16:16:53","publishedOnDateReadable":"October 21st, 2025"},"versionCreatedAt":"2025-06-03 07:30:41","video":"","vorDoi":"10.1186/s12885-025-14992-2","vorDoiUrl":"https://doi.org/10.1186/s12885-025-14992-2","workflowStages":[]},"version":"v1","identity":"rs-6755345","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6755345","identity":"rs-6755345","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}