Comparison of clinical features by primary site in patients with biliary tract cancer who received gemcitabine-based chemotherapy: an exploratory analysis of JCOG1113

Comparison of clinical features by primary site in patients with biliary tract cancer who received gemcitabine-based chemotherapy: an exploratory analysis of JCOG1113 | 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 Comparison of clinical features by primary site in patients with biliary tract cancer who received gemcitabine-based chemotherapy: an exploratory analysis of JCOG1113 Yuko Suzuki, Masafumi Ikeda, Junki Mizusawa, Yusuke Sano, Chigusa Morizane, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5483078/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jul, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Biliary tract cancers (BTCs) are heterogenous malignancies including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AVC). The reported data about the differences between the primary sites are limited to data that has just evaluated the efficacy of the treatment arms by primary site in randomized controlled trials. We aimed to compare the clinical features and treatment efficacy among the primary sites of BTCs using data from JCOG1113, a randomized trial. Methods Among the 354 patients enrolled in JCOG1113, 352 patients were included in this analysis. We compared the patient characteristics, and efficacy outcomes among the primary sites. Results There were more women, and more patients with metastatic disease and multiple organs involving metastases in GBC compared to other primary sites (female: 58.4% vs 35.3% ; metastatic disease: 78.1% vs 41.6% ; multiple metastases: 49.3% vs 26.5%). The median progression-free survival (PFS) was 5.7 months, 6.2 months, 8.7 months and 4.1 months for GBC, IHCC, EHCC and AVC, respectively. The median OS was 12.6 months, 15.7 months, 16.3 months and 11.5 months for GBC, IHCC, EHCC and AVC, respectively. Multivariable analysis revealed that primary site was identified as one of prognostic factors for PFS, but not significant for OS. Conclusions Patients with GBC were more likely to have metastatic disease and multiple metastases and more likely to show a poorer prognosis compared with those with the other primary sites; the primary sites were independent prognostic factors for PFS, but not for OS. biliary tract cancer chemotherapy primary sites prognostic factor Figures Figure 1 Figure 2 Introduction Biliary tract cancers (BTCs) are uncommon malignant tumors and have dismal prognoses because they are generally diagnosed at an advanced stage of disease, by which time surgical resection is no longer applicable [ 1 , 2 ]. Therefore, systemic chemotherapy plays an important role in the treatment of unresectable or recurrent BTCs. In 2019, the Japan Clinical Oncology Group (JCOG) Hepatobiliary and Pancreatic Oncology Group demonstrated the non-inferiority of the combined gemcitabine plus S-1 (GS) therapy to gemcitabine plus cisplatin (GC) therapy, which was the standard regimen at that time [ 3 ], in terms of the overall survival (OS) outcome (median OS, 13.4 months with GC and 15.1 months with GS; hazard ratio [HR], 0.945; 90% confidence interval [CI], 0.78–1.15; P = 0.046 for non-inferiority) in a randomized phase III trial (JCOG1113, UMIN000010667) [ 4 ]. Therefore, GS also became one of the first-line chemotherapy options for patients with advanced BTCs. BTCs are known as a heterogeneous group of cancers, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AVC) [ 1 , 2 ]. It is considered that there might be many differences among the primary sites in clinical features and treatment efficacies, as well as the prognosis individually. In previous studies, it was reported that GBC shows female dominance, while the other primary sites show male dominance. Furthermore, GBC has a poor prognosis despite its high sensitivity for systemic chemotherapy [ 1 , 5 , 6 ]. However, there are not enough evaluations about the differences in the clinical features and treatment efficacy by primary site. Although there are several studies concerning this issue, almost of them are retrospective studies [ 7 – 9 ], and few studies have included all four primary sites. Retrospective studies have the strength of reflecting daily practice; however, they have limitations such as inevitable bias and missing data. In most previous randomized phase III trials, including those for therapies combined with an immune checkpoint inhibitor (ICI), the primary site was just used as a factor for stratification on randomization and sub-group analyses for OS or PFS. Despite the heterogeneity of BTCs, they were treated as one kind of tumor. Our study was able to include patients who were adequate for evaluating efficacy and received a unified treatment, and it assessed efficacy with a unified modality and unified periods, according to the protocol. Therefore, we aimed to compare the clinical features, treatment efficacies, and prognoses among the primary sites of BTCs using reliable data from a randomized phase III trial, JCOG1113. Materials and methods Summary of JCOG1113 JCOG1113 was a multicenter randomized phase III trial conducted to confirm the non-inferiority of GS to GC in patients with advanced or recurrent BTCs. Patients were enrolled from 33 institutions in Japan. In brief, the eligibility criteria for it were as follows: histologically proven BTC, including adenocarcinoma and adenosquamous carcinoma (GBC, IHCC, EHCC, or AVC); unresectable or recurrent disease; age 20–79 years old; Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; adequate self-supported nutritional intake; no previous chemotherapy for BTC; adequate function of the major organs; and written informed consent to participate, including secondary use of data. Patients were allocated randomly to either the GC or GS arm using the minimization method with a random component to balance the primary tumor (GBC versus others), history of tumor resection (yes versus no), and institution. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and the objective response rate (ORR) and adverse events (AEs). This exploratory analysis of JCOG1113 [Patients] Between May 2013 and March 2016, 354 patients were enrolled into JCOG1113. Out of those 354 patients, 352 patients were included in this analysis, excluding two patients who were histologically revealed to not have BTCs after their registration. Although both patients were enrolled as patients with IHCC, one patient was diagnosed with an epithelioid hemangioendothelioma after surgery was performed, and the other patient was revealed to have breast cancer with liver metastasis. [Comparison of the clinical features and treatment outcomes among the primary sites of BTCs] We compared the patient characteristics and treatment efficacies (ORR, PFS) and the prognosis (OS) among the four primary sites: GBC, IHCC, EHCC, and AVC. We also performed univariable and multivariable analyses to identify independent factors associated with an unfavorable PFS and OS from among 9 potential factors: age, sex, ECOG performance status, extent of disease, treatment regimen, serum CA 19 − 9, albumin, CRP levels, and the primary sites. [Statistical analysis] ORR was defined as the proportion of patients with complete response (CR) or partial response (PR) and disease control rate (DCR) was defined as the proportion of patients with CR or PR or stable disease (SD) in RECIST in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. PFS was calculated as the interval of time from the date of randomization in the trial to the date of documentation of disease progression or death from any cause. OS was calculated as the interval of time from the date of randomization in the trial to the date of death from any cause or date of final follow-up. The time-to-event distribution (PFS and OS) by primary site was estimated by the Kaplan-Meier method. To assess the prognostic difference of each variable for PFS and OS in the univariable and multivariable analyses, the HR and 95% CI were calculated using the Cox proportional hazards model, and P -values were calculated using wald test. All tests were two-sided, and P < 0.05 was considered to denote statistical significance. The cutoff values of continuous variables were determined to be the median value of each variable. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) at the JCOG Data Center. Results Patient characteristics Baseline patient characteristics by primary site are shown in Table 1 . GBC was more common in females than males (58.4% and 41.6%, respectively), in contrast to the other primary sites. The percentages of patients with metastatic disease and the numbers of organs involving metastases were greater for those with GBC (78.1% and 41.6%, respectively) than for those with the other primary sites. Patients with EHCC were more likely to have recurrent disease (43.5%) and the percentage of metastatic diseases were lowest in the patients with EHCC (32.4%) compared with the other primary sites. Patients with GBC and IHCC were more likely to have an ECOG performance status score of 1 than those with the other primary sites. There were no differences in median age or laboratory data such as serum CA 19 − 9, albumin, and CRP levels among the primary sites. Table 1 Baseline patient characteristics Variable GBC (n = 137) IHCC (n = 94) EHCC (n = 108) AVC (n = 13) Total (n = 352) Age, years Median 66 67 69 70 67 Range 41–79 45–78 27–79 51–78 27–79 Sex, n (%) Male 57 (41.6) 56 (59.6) 72 (66.7) 11 (84.6) 196 (55.7) Female 80 (58.4) 38 (40.4) 36 (33.3) 2 (15.4) 156 (44.3) ECOG performance status, n (%) 0 91 (66.4) 65 (69.1) 84 (77.8) 12 (92.3) 252 (71.6) 1 46 (33.6) 29 (30.9) 24 (22.2) 1 (0.7) 100 (28.4) Extent of disease, n (%) Locally advanced 18 (13.1) 19 (20.2) 26 (24.1) 0 (0) 63 (17.9) Metastatic 107 (78.1) 61 (64.9) 35 (32.4) 10 (76.9) 213 (60.5) Recurrent 12 (8.8) 14 (14.9) 47 (43.5) 3 (23.1) 76 (21.6) Metastatic organs ≥ 2, n (%) 57 (41.6) 29 (30.9) 26 (24.1) 2 (1.5) 114 (32.4) Metastatic or recurrent organ, n (%) Local 2 (1.7) 1 (1.3) 12 (14.6) 1 (0.8) 16 (5.5) Liver 55 (46.2) 6 (8.0) 33 (40.2) 6 (46.2) 100 (34.6) Lung 12 (10.1) 18 (24.0) 8 (9.8) 0 (0) 38 (13.1) Lymph node 81 (68.1) 57 (76.0) 42 (51.2) 6 (46.2) 186 (64.4) Peritoneum 29 (24.4) 19 (25.3) 10 (12.2) 2 (15.4) 60 (20.8) CA 19 − 9, U/mL Median 183.0 138.7 195.1 32.7 170.6 Range 0.9-62525 0.0-1367000 2.0-193950 1.0-8255 0.0-1367000 Albumin, g/dL Median 3.8 3.9 3.8 3.6 3.8 Range 2.1–4.9 2.2–4.7 2.4–4.9 2.8–4.3 2.1–4.9 CRP, mg/dL Median 0.56 0.59 0.38 0.34 0.50 Range 0.00-19.72 0.00-13.40 0.01–12.63 0.05–3.60 0.00-19.72 Treatment regimen, n (%) GC 68 (49.6) 50 (53.1) 49 (45.4) 7 (53.8) 174 (49.4) GS 69 (50.4) 44 (46.9) 59 (54.6) 6 (46.2) 178 (50.6) GBC , gallbladder cancer; IHCC , intrahepatic cholangiocarcinoma; EHCC , extrahepatic cholangial carcinoma; AVC ampulla of Vater cancer; ECOG , Eastern Cooperative Oncology Group; CA 19 − 9 , carbohydrate antigen 19 − 9; CRP , C-reactive protein; GC , gemcitabine plus cisplatin; GS , gemcitabine plus S-1 Treatment efficacies and prognosis Regarding treatment efficacy, the ORRs were 34.4%, 28.9%, 34.4%, and 0.0% and the DCRs were 83.6%, 86.7%, 84.4%, and 54.6% for GBC, IHCC, EHCC, and AVC respectively (Table 2 ). The median PFS was 5.7 months, 6.2 months, 8.7 months and 4.1 months for GBC, IHCC, EHCC and AVC, respectively: compared with GBC, the HR was 0.843 (95% CI, 0.644–1.104), 0.636 (95% CI, 0.489–0.826), 1.506 (95% CI, 0.851–2.665) for IHCC, EHCC and AVC, respectively (Fig. 1 , Table 3 ). Regarding the prognosis, the median OS was 12.6 months, 15.7 months, 16.3 months and 11.5 months for GBC, IHCC, EHCC and AVC, respectively: compared with GBC, the HR was 0.749 (95% CI, 0.559–1.005), 0.704 (95% CI, 0.532–0.934) and 1.148 (95% CI, 0.633–2.080) for IHCC, EHCC and AVC, respectively (Fig. 2 , Table 4 ). Table 2 Overall response rate according to RECIST version 1.1 GBC (n = 137) IHCC (n = 94) EHCC (n = 108) AVC (n = 13) Total (n = 352) n = 122 n = 90 n = 64 n = 11 n = 287 ORR (CR + PR), % 34.4 28.9 34.4 0 31.4 (95% CI) (26.1–43.6) (19.8–39.4) (23.0-47.3) (0.0-28.5) (26.0-37.1) DCR (CR + PR + SD), % 83.6 86.7 84.4 54.6 83.6 (95% CI) (75.8–89.7) (77.9–92.9) (73.1–92.2) (23.4–83.3) (78.8–87.7) GBC , gallbladder cancer; IHCC , intrahepatic cholangiocarcinoma; EHCC , extrahepatic cholangial carcinoma; AVC , ampulla of Vater cancer; ORR , overall response rate, CR , complete response; PR , partial response; DCR , disease control rate; SD, stable disease; CI , confidence interval Table 3 Univariable and multivariable analysis for progression free survival Variable n median PFS, month (95% CI) Univariable analysis Multivariable analysis HR 95% CI P value HR 95% CI P value Age < 65 years 124 6.0 (5.4–8.9) 1 1 ≥ 65 years 228 6.3 (5.5–7.1) 0.897 (0.717–1.122) 0.341 0.842 (0.668–1.063) 0.149 Sex Male 196 6.5 (5.5–7.4) 1 1 Female 156 5.8 (5.5–6.9) 1.112 (0.896–1.381) 0.335 0.991 (0.784–1.253) 0.942 ECOG performance status 0 252 6.8 (5.6–7.4) 1 1 1 100 5.7 (4.3–6.8) 1.283 (1.014–1.623) 0.038 1.123 (0.870–1.450) 0.374 Primary site GBC 137 5.7 (4.9–6.8) 1 1 IHCC 94 6.2 (4.9–7.1) 0.843 (0.644–1.104) 0.215 0.839 (0.637–1.105) 0.212 EHCC 108 8.7 (5.9–10.5) 0.636 (0.489–0.826) 0.0007 0.647 (0.483–0.865) 0.003 AVC 13 4.1 (1.6–6.8) 1.506 (0.851–2.665) 0.160 1.533 (0.838–2.804) 0.166 Extent of disease Locally advanced 63 6.9 (4.9–9.9) 1 1 Metastatic 213 5.7 (5.3–6.8) 1.440 (1.075–1.929) 0.015 1.146 (0.839–1.566) 0.392 Recurrent 76 7.8 (5.6–11.0) 1.029 (0.728–1.455) 0.871 1.188 (0.833–1.694) 0.341 Treatment regimen GC 174 5.9 (5.5-7.0) 1 1 GS 178 6.5 (5.4–7.5) 0.869 (0.701–1.077) 0.199 0.871 (0.699–1.086) 0.220 CA19-9 < 170.6 U/mL 176 6.9 (5.9–8.3) 1 1 ≥ 170.6 U/mL 176 5.6 (4.4–6.2) 1.427 (1.149–1.772) 0.001 1.398 (1.108–1.764) 0.005 Albumin < 3.8 g/dL 170 5.5 (4.4–5.8) 1 1 ≥ 3.8 g/dL 182 7.4 (6.3–8.5) 0.674 (0.543–0.836) 0.0003 0.747 (0.582–0.957) 0.021 CRP < 0.5 mg/dL 176 7.4 (6.2–8.7) 1 1 ≥ 0.5 mg/dL 176 5.4 (4.3–5.9) 1.441 (1.160–1.789) 0.0009 1.248 (0.980–1.588) 0.072 OS , overall survival; CI , confidence interval; HR , hazard ratio; ECOG , Eastern Cooperative Oncology Group; GBC , gallbladder cancer; IHCC , intrahepatic cholangiocarcinoma; EHCC , extrahepatic cholangial carcinoma; AVC , ampulla of Vater cancer; GC , gemcitabine plus cisplatin; GS gemcitabine plus S-1; CA 19 − 9 , carbohydrate antigen 19 − 9; CRP , C-reactive protein Table 4 Univariable and multivariable analysis for overall survival Variable n median OS, month (95% CI) Univariable analysis Multivariable analysis HR 95% CI P value HR 95% CI P value Age < 65 years 124 12.7 (11.3–15.6) 1 1 ≥ 65 years 228 14.7 (13.1–16.3) 1.010 (0.792–1.289) 0.934 0.940 (0.732–1.207) 0.628 Sex Male 196 14.9 (12.7–17.6) 1 1 Female 156 13.4 (11.5–15.2) 1.151 (0.912–1.452) 0.237 1.124 (0.876–1.442) 0.358 ECOG performance status 0 252 15.5 (13.5–17.3) 1 1 1 100 11.3 (9.6–13.4) 1.536 (1.196–1.973) 0.0008 1.254 (0.961–1.636) 0.095 Primary site GBC 137 12.6 (11.1–14.0) 1 1 IHCC 94 15.7 (11.8–17.8) 0.749 (0.559–1.005) 0.054 0.833 (0.619–1.122) 0.230 EHCC 108 16.3 (13.0-20.2) 0.704 (0.532–0.934) 0.015 0.839 (0.617–1.140) 0.262 AVC 13 11.5 (7.5–20.1) 1.148 (0.633–2.080) 0.650 1.410 (0.755–2.635) 0.281 Extent of disease Locally advanced 63 16.5 (13.3–20.2) 1 1 Metastatic 213 12.3 (11.2–13.5) 1.599 (1.154–2.216) 0.005 1.386 (0.985–1.951) 0.061 Recurrent 76 18.5 (14.2–23.8) 0.896 (0.604–1.330) 0.587 1.048 (0.697–1.574) 0.823 Treatment regimen GC 174 13.4 (12.3–15.5) 1 1 GS 178 15.0 (12.2–16.3) 0.950 (0.753–1.198) 0.665 0.936 (0.738–1.188) 0.586 CA 19 − 9 < 170.6 U/mL 176 16.5 (14.9–20.3) 1 1 ≥ 170.6 U/mL 176 11.3 (10.3–12.7) 1.688 (1.335–2.133) < 0.001 1.609 (1.253–2.066) 0.0002 Albumin < 3.8 g/dL 170 11.4 (9.7–13.1) 1 1 ≥ 3.8 g/dL 182 16.9 (15.1–19.4) 0.563 (0.446–0.711) < 0.001 0.710 (0.542–0.929) 0.013 CRP < 0.5 mg/dL 176 16.1 (14.2–19.4) 1 1 ≥ 0.5 mg/dL 176 11.9 (10.4–13.5) 1.710 (1.353–2.161) < 0.001 1.367 (1.055–1.771) 0.018 OS , overall survival; CI , confidence interval; HR , hazard ratio; ECOG , Eastern Cooperative Oncology Group; GBC gallbladder cancer, IHCC , intrahepatic cholangiocarcinoma; EHCC , extrahepatic cholangial carcinoma; AVC , ampulla of Vater cancer; GC , gemcitabine plus cisplatin; GS , gemcitabine plus S-1; CA 19 − 9 carbohydrate antigen 19 − 9; CRP , C-reactive protein Univariable and multivariable analyses for survival outcome The results of the univariable and multivariable analyses for 9 variables to evaluate whether the primary sites affect survival outcome are shown in Tables 3 and 4 . According to the multivariable analysis, serum albumin and CA 19 − 9 were identified as independent prognostic factors for PFS and GBC showed worse PFS than EHCC (Table 3 ). And serum albumin, CA 19 − 9, and CRP were identified as independent prognostic factors for OS (Table 4 ). Although the primary site was not identified as a prognostic factor for OS statistically, the patients with GBC tended to have shorter OS than the patients with EHCC. Discussion This is the first post-hoc analysis to compare the clinical features, treatment efficacy, and prognosis among the primary sites of unresectable BTCs using the data of JCOG1113, as there was no prospective study that had previously evaluated the differences in them by primary site in detail. In this study, there were several findings regarding the differences among the primary sites. We found patients with GBC were more likely to be female and have an advanced stage, such as a high number of metastatic organs involved. GBC and AVC showed poorer PFS than EHCC, and the multivariable analysis demonstrated the difference of PFS between GBC and EHCC was significant. Although GBC and AVC showed poorer OS than EHCC, the multivariable analysis revealed that the primary sites did not affect OS. Regarding the clinical features, there were some findings that were different or similar among the primary sites, but almost of those findings were consistent with previous reports. Firstly, there were more female patients than male patients for GBC compared with the other primary sites [ 1 , 5 ]. One of the reasons why GBC showed female dominance is generally thought to be that the anomalous pancreaticobiliary ductal junction, known as the biliopancreas maljunction or pancreaticobiliary maljunction and one of the great risk factors for GBC, shows female dominance [ 5 ]. According to previous studies, it was reported that premenopausal women with irregular or longer menstrual cycles may have an increased risk for GBC compared with postmenopausal women, but not for the other primary sites of BTCs [ 10 – 12 ]. The regularity of menstrual cycles depends on the amount of secreted female hormones, so there might be a slight association between female hormones and a higher risk of GBC [ 10 , 11 ]. This may be because female hormones can enhance the formation of biliary stones, one of the risk factors for GBC, by increasing biliary cholesterol secretion [ 11 , 13 ]. Although the exposure to female hormones might be associated with increased risk for GBC, the mechanisms explaining the female dominance of GBC remain unknown. Secondly, the patients with GBC tended to be detected with advanced disease. There were more GBC patients with metastases than patients with locally advanced or recurrent diseases, and the number of metastatic organs tended to be more than for the other primary sites. In addition, patients with GBC were more likely to have ECOG-PS of 1, although these differences were not so large. Because GBCs are rarely diagnosed with the onset of biliary obstructive jaundice, so most patients with GBC might be often detected at an advanced stage with some symptoms or ECOG-PS of 1. Patients with EHCC, on the other hand, were more likely to have locally advanced disease. Of the BTCs, EHCC and AVC are often diagnosed with the onset of biliary obstructive jaundice; therefore, patients with these tumors might be detected at a locally advanced stage or with fewer metastases compared with the other sites [ 14 ]. As for treatment efficacy, there were some differences in PFS among the primary sites, although the ORRs were comparable in our study. The result concerning PFS was consistent with a systematic review and meta-analysis showing that PFS in patients with GBC was worse than in patients with EHCC [ 6 ]. We speculated that PFS in the patients with EHCC was overestimated compared with that in the patients with GBC. In general, it is more difficult to assess efficacy in patients without a measurable lesion than in those with measurable lesion because we cannot assess the change of the tumor volume accurately, and the time used to determine disease progression tends to be delayed [ 6 , 15 ]. In fact, fewer patients with EHCC had measurable lesions than those with GBC in this study (59.3% vs. 89.1%). Therefore, PFS would be better in the patients with EHCC than in those with GBC despite comparable ORRs between the two primary sites. On the other hand, a previous study reported that ORR in patients with GBC was higher compared with those for the other primary sites [ 6 ]; however, this was not consistent with the results of this analysis. We suggest that ORR in the patients with EHCC would be increased because we calculated the numbers of measurable lesions as the denominator. Therefore, it is possible that the ORR for the patients with GBC might not be so much better than that for the patients with EHCC. Furthermore, it was also thought that the patients with GBC were more likely to include metastatic disease. Therefore, they were more likely to have poorer PFS than the patients with EHCC, even if they showed the same ORR. Patients with AVC did not show PR in this study, despite the other randomized control trials, such as the ABC-02 trial, showing some response [ 3 ]. The number of patients with AVC included in our study was too small to compare the ORR with that of another study. According to previous studies, GBC has generally a poorer prognosis than the other primary sites; however, the reason remains uncertain [ 5 , 16 ]. From the results of this study, it was demonstrated that the primary sites were not substantially associated with OS, as serum albumin, CRP, and CA 19 − 9 were stronger prognostic factors for OS than the primary sites. Indeed, in addition to our study, several previous studies have reported that these factors were identified as prognostic factors [ 17 – 20 ]. The reason why GBC was more likely to have a slightly shorter OS was thought to be that the patients with GBC were detected with advanced disease, which included the metastatic stage and multiple metastases, or had a poor PS, as described above, at least as far as patients with unresectable BTCs receiving palliative chemotherapy were concerned. Regarding AVC, the prognosis remains unclear according to previous reports. It has been reported that the prognosis of patients with AVC might not to be so dismal if they are diagnosed at an early stage [ 7 ]. However, the patients with AVC included in our study had metastatic or recurrent diseases, which could explain why the prognoses for the patients with AVC were comparable to those for other primary sites in our study. Nevertheless, we thought that the number of patients with AVC in our study was too small to analyze the prognosis as well as the ORR. This study had several limitations. Firstly, because all the patients with BTCs were divided into groups according to the primary sites, the numbers of patients in each group were smaller, and the AVC group in particular had few patients. Secondly, this study excluded the patients who were expected to have poor prognoses such as those with poor PS, inadequate function of the major organs, or massive ascites, and so on. Therefore, there might be the differences in the results between our clinical trial and the real world. Thirdly, this study did not include patients who received therapy using ICIs, such as GC plus durvalumab or pembrolizumab therapy, which has recently become one of the standard regimens [ 21 , 22 ]. Fourthly, this study did not include any information about the genomic alterations, although various genomic alterations have been found [ 23 – 29 ] and some therapeutic agents have recently been developed [ 30 – 34 ] in patients with BTCs. Considering these limitations, caution is necessary when attempting to simply apply our results to patients who receive the new standard of care in daily practice. In conclusion, patients with GBC are more likely to include metastatic disease and multiple metastases, and this is likely one of the causes of its poor prognosis. Although the primary sites were associated with PFS, there were some factors, such as serum albumin, CRP, CA 19 − 9, that had greater effects on OS than the primary sites. Therefore, the primary sites were not included as prognostic factor for OS. Further study is needed to determine whether the results of this study can be applied to patients with BTCs receiving treatments including ICIs or targeted therapies for genomic alterations. Declarations Acknowledgement The authors would like to thank all of the participating patients and families, as well as the investigators, and clinical research coordinators in JCOG1113. We also appreciate the members of the JCOG Data Center and JCOG Operations Office for their great and valuable support in preparing the manuscript, data management, and oversight of the management of the study. Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by Yuko Suzuki and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data availability statement Deidentified participant data can be shared upon reasonable request to the corresponding author. Individual participant data that underlie the results reported in this article, after deidentification will be shared if investigators whose proposed use of the data has been approved by the investigators from Hepatobiliary and Pancreatic Oncology Group of JCOG identified for this purpose. Proposals should be directed to corresponding author. The data will be available for achieving aims in the approved proposal. Funding statement The study was supported by the National Cancer Center Research and Development Fund [grant numbers 23-A-22, 26-A-4, 29-A-3, 2020-J-3, 2023-J-03]; Japan Agency for Medical Research and Development [grant numbers JP19ck0106350]; and the Grant-in-Aid for Clinical Cancer Research [H22-ganrinsho-ippan-013] from the Ministry of Health, Labor, and Welfare of Japan. Competing interests Y.S. reports research fundings from Chugai Pharmaceutical Co., Ltd. M.I. reports consulting fees from AstraZeneca K.K. and MSD K.K., honoraria from AstraZeneca K.K., Guardant Health Japan Corp., Incyte Biosciences Japan G.K., MSD K.K. and Taiho Pharmaceutical Co., Ltd., and research fundings from AstraZeneca K.K., Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, J-Pharma Co., Ltd., Merck Biopharma Co., Ltd. and Ono Pharmaceutical Co., Ltd. J.M. reports honoraria from Chugai Pharmaceutical Co., Ltd. and Taiho Pharmaceutical Co., Ltd., and his spouse is an employee of Pfizer Japan Inc. C.M. reports honoraria from AstraZeneca K.K., Eisai Co., Ltd., Guardant Health Japan Corp., MSD K.K., Myriad Genetic G.K., Novartis Pharma K.K., Nihon Servier Co., Ltd., Taiho Pharmaceutical Co., Ltd., Toray Industries, Inc., and Yakult Honsha Co., Ltd., and research fundings from AstraZeneca K.K., Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., J-Pharma Co., Ltd., Merck Biopharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Yakult Honsha Co., Ltd. T.O. reports grants from AstraZeneca K.K., Bristol Myers Squibb K.K., Chiome Bioscience Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Incyte Biosciences Japan G.K., MSD K.K., Novartis Pharma K.K., Syneos Health Clinical K.K. and Sysmex Corp., consulting fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., FUJIFILM Toyama Chemical Co., Ltd., Nihon Servier Co., Ltd., Novartis Pharma K.K. and Ono Pharmaceutical Co., Ltd., honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Johnson & Johnson, Myriad Genetic G.K., Nihon Servier Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Syneos Health Clinical K.K., Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. S.K. reports honoraria from AstraZeneca K.K. and MSD K.K. H.I. reports honoraria from AstraZeneca K.K., Boston Scientific Corp., Kaneka Medix Corp., Nihon Servier Co., Ltd., Novartis Pharma K.K., SB-KAWASUMI LABORATORIES, INC. and Yakult Honsha Co., Ltd., fees for promotional materials from Medico’s Hirata Inc., research fundings from Boehringer Ingelheim Co., Ltd., Nihon Servier Co., Ltd., Novartis Pharma K.K. and Ono Pharmaceutical Co., Ltd., and he is a participant on an advisory board of Nihon Servier Co., Ltd. T.T. reports honoraria from AstraZeneca K.K. and Chugai Pharmaceutical Co., Ltd. N.O. reports honoraria from AstraZeneca K.K. A.T. reports honoraria from AstraZeneca K.K., Nihon Servier Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Teijin Pharma, Ltd. and Yakult Honsha Co., Ltd. S.S. reports research fundings from AstraZeneca K.K., Delta-Fly Pharma, Inc., Incyte Biosciences Japan G.K. and Nihon Servier Co., Ltd. N.M. reports research fundings from AstraZeneca K.K., Boehringer Ingelheim Co., Ltd., Incyte Biosciences Japan G.K., MSD K.K., Nihon Servier Co., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc. and Seagen Inc. S.S. reports research fundings from Amino Up Co., Ltd., Boston Scientific Corp. and Nihon Servier Co., Ltd. M.O. reports honoraria from MSD K.K., Nihon Servier Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. M.U. reports honoraria from Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd., and fundings from Taiho Pharmaceutical Co., Ltd. The other authors have nothing to declare for this study. Ethic approval statement, patient consent statement, and permission to reproduce material from other sources JCOG1113 was conducted in accordance with the 1964 Declaration of Helsinki, its later amendments and Japanese Ethical Guidelines for Clinical Research, and the study protocol was approved by the institutional review board of each participating institution. The written informed consent was obtained from all participants of JCOG1113. Clinical trial registration JCOG1113 was registered with University hospital Medical Information Network Clinical Trials Regisry (UMIN000010667). References Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX: Biliary tract cancer . Lancet 2021, 397 (10272):428-444. Vogel A, Bridgewater J, Edeline J, Kelley RK, Klumpen HJ, Malka D, Primrose JN, Rimassa L, Stenzinger A, Valle JW et al : Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up . Ann Oncol 2023, 34 (2):127-140. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP et al : Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer . N Engl J Med 2010, 362 (14):1273-1281. Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A et al : Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: The FUGA-BT (JCOG1113) Randomized Phase III Clinical Trial . Ann Oncol 2019. Schmidt MA, Marcano-Bonilla L, Roberts LR: Gallbladder cancer: epidemiology and genetic risk associations . Chin Clin Oncol 2019, 8 (4):31. Azizi AA, Lamarca A, McNamara MG, Valle JW: Chemotherapy for advanced gallbladder cancer (GBC): A systematic review and meta-analysis . Crit Rev Oncol Hematol 2021, 163 :103328. Ishihara S, Horiguchi A, Miyakawa S, Endo I, Miyazaki M, Takada T: Biliary tract cancer registry in Japan from 2008 to 2013 . J Hepatobiliary Pancreat Sci 2016, 23 (3):149-157. Kang MJ, Lim J, Han SS, Park HM, Kim SW, Lee WJ, Woo SM, Kim TH, Won YJ, Park SJ: Distinct prognosis of biliary tract cancer according to tumor location, stage, and treatment: a population-based study . Sci Rep 2022, 12 (1):10206. Song BG, Park JK, Kim HS, Kim K, Park JK, Lee KH, Lee KT, Lee JK: Prognosis and prognostic factors in patients with advanced biliary tract cancer depending on its anatomical location . Scand J Gastroenterol 2019, 54 (6):740-745. Makiuchi T, Sobue T, Kitamura T, Sawada N, Iwasaki M, Sasazuki S, Yamaji T, Shimazu T, Tsugane S: Reproductive factors and gallbladder/bile duct cancer: a population-based cohort study in Japan . Eur J Cancer Prev 2017, 26 (4):292-300. Shin A, Cho S, Abe SK, Islam MR, Rahman MS, Saito E, Kazmi SZ, Katagiri R, Merritt M, Choi JY et al : Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium . Int J Cancer 2024, 155 (2):240-250. Jackson SS, Adami HO, Andreotti G, Beane-Freeman LE, de Gonzalez AB, Buring JE, Fraser GE, Freedman ND, Gapstur SM, Gierach G et al : Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project . J Hepatol 2020, 73 (4):863-872. Novacek G: Gender and gallstone disease . Wien Med Wochenschr 2006, 156 (19-20):527-533. Tsukada K, Takada T, Miyazaki M, Miyakawa S, Nagino M, Kondo S, Furuse J, Saito H, Tsuyuguchi T, Kimura F et al : Diagnosis of biliary tract and ampullary carcinomas . J Hepatobiliary Pancreat Surg 2008, 15 (1):31-40. Lamarca A, Frizziero M, McNamara MG, Valle JW: Clinical and Translational Research Challenges in Biliary Tract Cancers . Curr Med Chem 2020, 27 (29):4756-4777. Wernberg JA, Lucarelli DD: Gallbladder cancer . Surg Clin North Am 2014, 94 (2):343-360. Utsumi M, Inagaki M, Kitada K, Tokunaga N, Kondo M, Yunoki K, Sakurai Y, Hamano R, Miyasou H, Tsunemitsu Y et al : Preoperative C-reactive protein-to-albumin ratio as a prognostic factor in biliary tract cancer: A systematic review and meta-analysis . Medicine (Baltimore) 2023, 102 (22):e33656. Park HS, Park JS, Chun YJ, Roh YH, Moon J, Chon HJ, Choi HJ, Park JS, Lee DK, Lee SJ et al : Prognostic Factors and Scoring Model for Survival in Metastatic Biliary Tract Cancer . Cancer Res Treat 2017, 49 (4):1127-1139. Kim BJ, Hyung J, Yoo C, Kim KP, Park SJ, Lee SS, Park DH, Song TJ, Seo DW, Lee SK et al : Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients . Cancer Chemother Pharmacol 2017, 80 (1):209-215. Imaoka H, Ikeda M, Nomura S, Morizane C, Okusaka T, Ozaka M, Shimizu S, Yamazaki K, Okano N, Sugimori K et al : Development of a nomogram to predict survival in advanced biliary tract cancer . Sci Rep 2023, 13 (1):21548. Oh DY, Lee KH, Lee DW, Yoon J, Kim TY, Bang JH, Nam AR, Oh KS, Kim JM, Lee Y et al : Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study . Lancet Gastroenterol Hepatol 2022, 7 (6):522-532. Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klumpen HJ, Chan SL, Ozaka M et al : Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet 2023, 401 (10391):1853-1865. Chen X, Wang D, Liu J, Qiu J, Zhou J, Ying J, Shi Y, Wang Z, Lou H, Cui J et al : Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes . J Immunother Cancer 2021, 9 (11). Guo L, Zhou F, Liu H, Kou X, Zhang H, Chen X, Qiu J: Genomic mutation characteristics and prognosis of biliary tract cancer . Am J Transl Res 2022, 14 (7):4990-5002. Takada K, Kubo T, Kikuchi J, Yoshida M, Murota A, Arihara Y, Nakamura H, Nagashima H, Tanabe H, Sugita S et al : Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study . Front Oncol 2022, 12 :988527. Astier C, Ngo C, Colmet-Daage L, Marty V, Bawa O, Nicotra C, Ngo-Camus M, Italiano A, Massard C, Scoazec JY et al : Molecular profiling of biliary tract cancers reveals distinct genomic landscapes between circulating and tissue tumor DNA . Exp Hematol Oncol 2024, 13 (1):2. Tang TY, Nichetti F, Kaplan B, Lonardi S, Pietrantonio F, Salvatore L, Vivaldi C, Rimassa L, de Braud F, Rizzato MD et al : Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers . Clin Cancer Res 2023, 29 (23):4853-4862. Mavroeidi IA, Burghofer J, Kalbourtzis S, Taghizadeh H, Webersinke G, Piringer G, Kasper S, Schreil G, Liffers ST, Reichinger A et al : Understanding homologous recombination repair deficiency in biliary tract cancers: clinical implications and correlation with platinum sensitivity . ESMO Open 2024, 9 (8):103630. Kanai M: Current Clinical Practice of Precision Medicine Using Comprehensive Genomic Profiling Tests in Biliary Tract Cancer in Japan . Curr Oncol 2022, 29 (10):7272-7284. Subbiah V, Lassen U, Elez E, Italiano A, Curigliano G, Javle M, de Braud F, Prager GW, Greil R, Stein A et al : Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial . Lancet Oncol 2020, 21 (9):1234-1243. Bekaii-Saab TS, Valle JW, Van Cutsem E, Rimassa L, Furuse J, Ioka T, Melisi D, Macarulla T, Bridgewater J, Wasan H et al : FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements . Future Oncol 2020, 16 (30):2385-2399. Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DVT, Borad MJ, Bridgewater JA et al : Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial . JAMA Oncol 2021, 7 (11):1669-1677. Javle M, Borad MJ, Azad NS, Kurzrock R, Abou-Alfa GK, George B, Hainsworth J, Meric-Bernstam F, Swanton C, Sweeney CJ et al : Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study . Lancet Oncol 2021, 22 (9):1290-1300. Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, Morizane C, Karasic TB, Abrams TA, Furuse J, Kelley RK, Cassier PA et al : Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma . N Engl J Med 2023, 388 (3):228-239. Cite Share Download PDF Status: Published Journal Publication published 24 Jul, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Reviewers agreed at journal 13 Apr, 2025 Reviewers invited by journal 12 Apr, 2025 Editor assigned by journal 12 Apr, 2025 First submitted to journal 09 Apr, 2025 Editorial decision: Minor revisions 08 Feb, 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5483078","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":442160562,"identity":"0baa13d0-8019-472a-a778-e295e4e0048a","order_by":0,"name":"Yuko Suzuki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYFACNgjFD8QHIEweKCakRbIBqOUASVoMDsCtwascqPJGWuLDn211iZvPH354+EPNNnkG6d6DDxhk7uDTctiYt40tcduNNIMDB47dNmyQOZdswMDzDI+W9DZpxjYeoBag2w6w3WbcfyPHTIKB5zBeLZI/2yQSN/cf/3DgwL/b9g0SBLWkHZPgbTNI3MCQY3DgYNvtRIJaJM88SzbmOZdgPONGTsGBs323kxtkzhgbJODxC9/xNMOHP8rqZPv7j2/+UPHttm2DdI/hg489uENM4QCGkAQQJ/ZgisOAfANWLQw/cGsZBaNgFIyCEQcAXf5g2D57No4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0008-7362-5550","institution":"Saitama Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Suzuki","suffix":""},{"id":442160563,"identity":"576e6b4b-f61c-465b-bc92-b5bd63bdc7f3","order_by":1,"name":"Masafumi Ikeda","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Masafumi","middleName":"","lastName":"Ikeda","suffix":""},{"id":442160564,"identity":"0af710ac-21eb-494b-92f4-89a110ff60d4","order_by":2,"name":"Junki Mizusawa","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Junki","middleName":"","lastName":"Mizusawa","suffix":""},{"id":442160565,"identity":"a0d56de0-8fe9-4f50-b198-70891dbec527","order_by":3,"name":"Yusuke Sano","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Sano","suffix":""},{"id":442160566,"identity":"096af094-6044-4bbf-95ae-df5e2010f6af","order_by":4,"name":"Chigusa Morizane","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Chigusa","middleName":"","lastName":"Morizane","suffix":""},{"id":442160567,"identity":"d85914d0-45d7-4e60-98c8-8c4e2ced79bd","order_by":5,"name":"Takuji Okusaka","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Takuji","middleName":"","lastName":"Okusaka","suffix":""},{"id":442160568,"identity":"a3a5bda6-6ce7-4eea-9c9c-a69427779f87","order_by":6,"name":"Satoshi Kobayashi","email":"","orcid":"","institution":"Kanagawa Cancer Center: Kanagawa Kenritsu Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Kobayashi","suffix":""},{"id":442160569,"identity":"d1b506e7-07de-471f-954b-56667a6001d5","order_by":7,"name":"Hiroshi Imaoka","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Imaoka","suffix":""},{"id":442160570,"identity":"6ba4b105-a925-4aa6-b5aa-55feea3633f7","order_by":8,"name":"Takeshi Terashima","email":"","orcid":"","institution":"Kanazawa University: Kanazawa Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Terashima","suffix":""},{"id":442160571,"identity":"71bbb9c1-b318-4cb1-87f7-700b954651b9","order_by":9,"name":"Naohiro Okano","email":"","orcid":"","institution":"Kyorin University Faculty of Medicine: Kyorin Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Naohiro","middleName":"","lastName":"Okano","suffix":""},{"id":442160572,"identity":"e13924b1-fba1-408f-b772-90a864bbc0cc","order_by":10,"name":"Haruo Miwa","email":"","orcid":"","institution":"Yokohama City University Medical Center: Yokohama Shiritsu Daigaku Fuzoku Shimin Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Haruo","middleName":"","lastName":"Miwa","suffix":""},{"id":442160573,"identity":"9376e7d9-c35e-4ba8-8f99-4d09eb99ee3f","order_by":11,"name":"Akiko Todaka","email":"","orcid":"","institution":"Shizuoka Cancer Center: Shizuoka Kenritsu Shizuoka Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Todaka","suffix":""},{"id":442160574,"identity":"ada2ea2d-b0f8-4704-9db5-760bf881c842","order_by":12,"name":"Satoshi Shimizu","email":"","orcid":"","institution":"Saitama Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Shimizu","suffix":""},{"id":442160575,"identity":"912d0591-5824-406e-9db4-b874ba7a3894","order_by":13,"name":"Nobumasa Mizuno","email":"","orcid":"","institution":"Aichi Cancer Center Hospital: Aichi-ken Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Nobumasa","middleName":"","lastName":"Mizuno","suffix":""},{"id":442160576,"identity":"11493ba5-3fda-43ec-8a0e-2cc9f3f88c5b","order_by":14,"name":"Sohei Satoi","email":"","orcid":"","institution":"Kansai Medical University: Kansai Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Sohei","middleName":"","lastName":"Satoi","suffix":""},{"id":442160577,"identity":"32f27712-0430-4945-9539-497cf31f3111","order_by":15,"name":"Keiji Sano","email":"","orcid":"","institution":"Teikyo University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Keiji","middleName":"","lastName":"Sano","suffix":""},{"id":442160578,"identity":"43394d24-da01-4b62-bb8e-89e6bcbd430a","order_by":16,"name":"Kazutoshi Tobimatsu","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kazutoshi","middleName":"","lastName":"Tobimatsu","suffix":""},{"id":442160579,"identity":"73e2a13a-ff1d-4a8a-8fcc-93e1a55d41b0","order_by":17,"name":"Akio Katanuma","email":"","orcid":"","institution":"Teine Keijinkai Hospital: Teine Keijinkai Byoin","correspondingAuthor":false,"prefix":"","firstName":"Akio","middleName":"","lastName":"Katanuma","suffix":""},{"id":442160580,"identity":"a820c447-dc45-4082-be57-cc50ff838efa","order_by":18,"name":"Masato Ozaka","email":"","orcid":"","institution":"Center Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Ozaka","suffix":""},{"id":442160581,"identity":"87d84db9-4f5a-4c1b-adca-936aca5a7369","order_by":19,"name":"Makoto Ueno","email":"","orcid":"","institution":"Kanagawa Cancer Center: Kanagawa Kenritsu Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Ueno","suffix":""}],"badges":[],"createdAt":"2024-11-19 11:27:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5483078/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5483078/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02834-x","type":"published","date":"2025-07-24T15:57:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80729057,"identity":"719b626c-a91f-4f70-9afb-78a533e57479","added_by":"auto","created_at":"2025-04-16 12:17:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":253754,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of PFS by primary site.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePFS, \u003c/em\u003eprogression-free survival;\u003cem\u003e GBC, \u003c/em\u003egallbladder cancer; \u003cem\u003eIHCC,\u003c/em\u003eintrahepatic cholangiocarcinoma; \u003cem\u003eEHCC,\u003c/em\u003e extrahepatic cholangial carcinoma; \u003cem\u003eAVC,\u003c/em\u003e ampulla of Vater cancer; \u003cem\u003eHR, \u003c/em\u003ehazard ratio; \u003cem\u003eCI,\u003c/em\u003econfidence interval.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5483078/v1/e92aa39427cfc7a9afbf1408.png"},{"id":80730152,"identity":"2faba7a3-733d-4eee-9300-3d451276508c","added_by":"auto","created_at":"2025-04-16 12:25:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":254499,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of OS by primary site.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOS, \u003c/em\u003eoverall survival;\u003cem\u003eGBC, \u003c/em\u003egallbladder cancer; \u003cem\u003eIHCC,\u003c/em\u003e intrahepatic cholangiocarcinoma; \u003cem\u003eEHCC,\u003c/em\u003e extrahepatic cholangial carcinoma; \u003cem\u003eAVC,\u003c/em\u003e ampulla of Vater cancer; \u003cem\u003eHR, \u003c/em\u003ehazard ratio; \u003cem\u003eCI,\u003c/em\u003e confidence interval.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5483078/v1/d2a1698b0d36e2f4f6871eca.png"},{"id":87757158,"identity":"58e1e2bc-5e8e-4ff8-8b96-9d1e4b3717c2","added_by":"auto","created_at":"2025-07-28 16:10:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3299404,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5483078/v1/02f3e612-8321-4e50-a696-d1b422e94fb7.pdf"}],"financialInterests":"","formattedTitle":"Comparison of clinical features by primary site in patients with biliary tract cancer who received gemcitabine-based chemotherapy: an exploratory analysis of JCOG1113","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBiliary tract cancers (BTCs) are uncommon malignant tumors and have dismal prognoses because they are generally diagnosed at an advanced stage of disease, by which time surgical resection is no longer applicable [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Therefore, systemic chemotherapy plays an important role in the treatment of unresectable or recurrent BTCs.\u003c/p\u003e \u003cp\u003eIn 2019, the Japan Clinical Oncology Group (JCOG) Hepatobiliary and Pancreatic Oncology Group demonstrated the non-inferiority of the combined gemcitabine plus S-1 (GS) therapy to gemcitabine plus cisplatin (GC) therapy, which was the standard regimen at that time [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], in terms of the overall survival (OS) outcome (median OS, 13.4 months with GC and 15.1 months with GS; hazard ratio [HR], 0.945; 90% confidence interval [CI], 0.78\u0026ndash;1.15; P\u0026thinsp;=\u0026thinsp;0.046 for non-inferiority) in a randomized phase III trial (JCOG1113, UMIN000010667) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Therefore, GS also became one of the first-line chemotherapy options for patients with advanced BTCs.\u003c/p\u003e \u003cp\u003eBTCs are known as a heterogeneous group of cancers, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AVC) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. It is considered that there might be many differences among the primary sites in clinical features and treatment efficacies, as well as the prognosis individually. In previous studies, it was reported that GBC shows female dominance, while the other primary sites show male dominance. Furthermore, GBC has a poor prognosis despite its high sensitivity for systemic chemotherapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, there are not enough evaluations about the differences in the clinical features and treatment efficacy by primary site. Although there are several studies concerning this issue, almost of them are retrospective studies [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and few studies have included all four primary sites. Retrospective studies have the strength of reflecting daily practice; however, they have limitations such as inevitable bias and missing data. In most previous randomized phase III trials, including those for therapies combined with an immune checkpoint inhibitor (ICI), the primary site was just used as a factor for stratification on randomization and sub-group analyses for OS or PFS. Despite the heterogeneity of BTCs, they were treated as one kind of tumor. Our study was able to include patients who were adequate for evaluating efficacy and received a unified treatment, and it assessed efficacy with a unified modality and unified periods, according to the protocol. Therefore, we aimed to compare the clinical features, treatment efficacies, and prognoses among the primary sites of BTCs using reliable data from a randomized phase III trial, JCOG1113.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSummary of JCOG1113\u003c/h2\u003e \u003cp\u003eJCOG1113 was a multicenter randomized phase III trial conducted to confirm the non-inferiority of GS to GC in patients with advanced or recurrent BTCs. Patients were enrolled from 33 institutions in Japan. In brief, the eligibility criteria for it were as follows: histologically proven BTC, including adenocarcinoma and adenosquamous carcinoma (GBC, IHCC, EHCC, or AVC); unresectable or recurrent disease; age 20\u0026ndash;79 years old; Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; adequate self-supported nutritional intake; no previous chemotherapy for BTC; adequate function of the major organs; and written informed consent to participate, including secondary use of data. Patients were allocated randomly to either the GC or GS arm using the minimization method with a random component to balance the primary tumor (GBC versus others), history of tumor resection (yes versus no), and institution. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and the objective response rate (ORR) and adverse events (AEs).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eThis exploratory analysis of JCOG1113\u003c/h3\u003e\n\u003cp\u003e[Patients]\u003c/p\u003e \u003cp\u003eBetween May 2013 and March 2016, 354 patients were enrolled into JCOG1113. Out of those 354 patients, 352 patients were included in this analysis, excluding two patients who were histologically revealed to not have BTCs after their registration. Although both patients were enrolled as patients with IHCC, one patient was diagnosed with an epithelioid hemangioendothelioma after surgery was performed, and the other patient was revealed to have breast cancer with liver metastasis.\u003c/p\u003e \u003cp\u003e[Comparison of the clinical features and treatment outcomes among the primary sites of BTCs]\u003c/p\u003e \u003cp\u003eWe compared the patient characteristics and treatment efficacies (ORR, PFS) and the prognosis (OS) among the four primary sites: GBC, IHCC, EHCC, and AVC. We also performed univariable and multivariable analyses to identify independent factors associated with an unfavorable PFS and OS from among 9 potential factors: age, sex, ECOG performance status, extent of disease, treatment regimen, serum CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, albumin, CRP levels, and the primary sites.\u003c/p\u003e \u003cp\u003e[Statistical analysis]\u003c/p\u003e \u003cp\u003eORR was defined as the proportion of patients with complete response (CR) or partial response (PR) and disease control rate (DCR) was defined as the proportion of patients with CR or PR or stable disease (SD) in RECIST in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. PFS was calculated as the interval of time from the date of randomization in the trial to the date of documentation of disease progression or death from any cause. OS was calculated as the interval of time from the date of randomization in the trial to the date of death from any cause or date of final follow-up. The time-to-event distribution (PFS and OS) by primary site was estimated by the Kaplan-Meier method. To assess the prognostic difference of each variable for PFS and OS in the univariable and multivariable analyses, the HR and 95% CI were calculated using the Cox proportional hazards model, and \u003cem\u003eP\u003c/em\u003e-values were calculated using wald test. All tests were two-sided, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to denote statistical significance. The cutoff values of continuous variables were determined to be the median value of each variable. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) at the JCOG Data Center.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eBaseline patient characteristics by primary site are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. GBC was more common in females than males (58.4% and 41.6%, respectively), in contrast to the other primary sites. The percentages of patients with metastatic disease and the numbers of organs involving metastases were greater for those with GBC (78.1% and 41.6%, respectively) than for those with the other primary sites. Patients with EHCC were more likely to have recurrent disease (43.5%) and the percentage of metastatic diseases were lowest in the patients with EHCC (32.4%) compared with the other primary sites. Patients with GBC and IHCC were more likely to have an ECOG performance status score of 1 than those with the other primary sites. There were no differences in median age or laboratory data such as serum CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, albumin, and CRP levels among the primary sites.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e Baseline patient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGBC\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;137)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIHCC\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;94)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEHCC\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;108)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVC\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;352)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u0026ndash;78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51\u0026ndash;78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (41.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (59.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (84.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e196 (55.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (58.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (40.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e156 (44.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG performance status, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91 (66.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (69.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84 (77.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (92.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e252 (71.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (33.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100 (28.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtent of disease, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocally advanced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63 (17.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (78.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (64.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (32.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (76.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e213 (60.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (14.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (43.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e76 (21.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (41.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e114 (32.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic or recurrent organ, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16 (5.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (40.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100 (34.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38 (13.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (68.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (76.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (51.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e186 (64.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (24.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (20.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e183.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e138.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e195.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e170.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.9-62525\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.0-1367000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0-193950\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.0-8255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0-1367000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1\u0026ndash;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2\u0026ndash;4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.4\u0026ndash;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.8\u0026ndash;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.1\u0026ndash;4.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.00-19.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00-13.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u0026ndash;12.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.05\u0026ndash;3.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.00-19.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment regimen, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (49.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (53.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (45.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e174 (49.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (50.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (46.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59 (54.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e178 (50.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eGBC\u003c/em\u003e, gallbladder cancer; \u003cem\u003eIHCC\u003c/em\u003e, intrahepatic cholangiocarcinoma; \u003cem\u003eEHCC\u003c/em\u003e, extrahepatic cholangial carcinoma; \u003cem\u003eAVC\u003c/em\u003e ampulla of Vater cancer; \u003cem\u003eECOG\u003c/em\u003e, Eastern Cooperative Oncology Group; \u003cem\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/em\u003e, carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; \u003cem\u003eCRP\u003c/em\u003e, C-reactive protein; \u003cem\u003eGC\u003c/em\u003e, gemcitabine plus cisplatin; \u003cem\u003eGS\u003c/em\u003e, gemcitabine plus S-1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment efficacies and prognosis\u003c/h3\u003e\n\u003cp\u003eRegarding treatment efficacy, the ORRs were 34.4%, 28.9%, 34.4%, and 0.0% and the DCRs were 83.6%, 86.7%, 84.4%, and 54.6% for GBC, IHCC, EHCC, and AVC respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median PFS was 5.7 months, 6.2 months, 8.7 months and 4.1 months for GBC, IHCC, EHCC and AVC, respectively: compared with GBC, the HR was 0.843 (95% CI, 0.644\u0026ndash;1.104), 0.636 (95% CI, 0.489\u0026ndash;0.826), 1.506 (95% CI, 0.851\u0026ndash;2.665) for IHCC, EHCC and AVC, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Regarding the prognosis, the median OS was 12.6 months, 15.7 months, 16.3 months and 11.5 months for GBC, IHCC, EHCC and AVC, respectively: compared with GBC, the HR was 0.749 (95% CI, 0.559\u0026ndash;1.005), 0.704 (95% CI, 0.532\u0026ndash;0.934) and 1.148 (95% CI, 0.633\u0026ndash;2.080) for IHCC, EHCC and AVC, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e Overall response rate according to RECIST version 1.1\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGBC (n\u0026thinsp;=\u0026thinsp;137)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIHCC (n\u0026thinsp;=\u0026thinsp;94)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEHCC (n\u0026thinsp;=\u0026thinsp;108)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVC (n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;352)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;287\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR (CR\u0026thinsp;+\u0026thinsp;PR), %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(26.1\u0026ndash;43.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(19.8\u0026ndash;39.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(23.0-47.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.0-28.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(26.0-37.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR (CR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;SD), %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e83.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(75.8\u0026ndash;89.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(77.9\u0026ndash;92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(73.1\u0026ndash;92.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(23.4\u0026ndash;83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(78.8\u0026ndash;87.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eGBC\u003c/em\u003e, gallbladder cancer; \u003cem\u003eIHCC\u003c/em\u003e, intrahepatic cholangiocarcinoma; \u003cem\u003eEHCC\u003c/em\u003e, extrahepatic cholangial carcinoma; \u003cem\u003eAVC\u003c/em\u003e, ampulla of Vater cancer; \u003cem\u003eORR\u003c/em\u003e, overall response rate, \u003cem\u003eCR\u003c/em\u003e, complete response; \u003cem\u003ePR\u003c/em\u003e, partial response; \u003cem\u003eDCR\u003c/em\u003e, disease control rate;\u003c/p\u003e \u003cp\u003e\u003cem\u003eSD, stable disease; CI\u003c/em\u003e, confidence interval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e Univariable and multivariable analysis for progression free survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003emedian PFS, month\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eUnivariable analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e \u003cp\u003eMultivariable analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0 (5.4\u0026ndash;8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.3 (5.5\u0026ndash;7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.897\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.717\u0026ndash;1.122)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.842\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.668\u0026ndash;1.063)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.149\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5 (5.5\u0026ndash;7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.8 (5.5\u0026ndash;6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.896\u0026ndash;1.381)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.784\u0026ndash;1.253)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.942\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG performance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.8 (5.6\u0026ndash;7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7 (4.3\u0026ndash;6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.014\u0026ndash;1.623)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.870\u0026ndash;1.450)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.374\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7 (4.9\u0026ndash;6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.2 (4.9\u0026ndash;7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.843\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.644\u0026ndash;1.104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.839\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.637\u0026ndash;1.105)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.212\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEHCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.7 (5.9\u0026ndash;10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.489\u0026ndash;0.826)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.647\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.483\u0026ndash;0.865)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.1 (1.6\u0026ndash;6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.851\u0026ndash;2.665)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.533\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.838\u0026ndash;2.804)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.166\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtent of disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocally advanced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.9 (4.9\u0026ndash;9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7 (5.3\u0026ndash;6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.440\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.075\u0026ndash;1.929)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.839\u0026ndash;1.566)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.392\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.8 (5.6\u0026ndash;11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.728\u0026ndash;1.455)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.833\u0026ndash;1.694)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.9 (5.5-7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e178\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5 (5.4\u0026ndash;7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.869\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.701\u0026ndash;1.077)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.199\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.699\u0026ndash;1.086)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.220\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA19-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;170.6 U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.9 (5.9\u0026ndash;8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;170.6 U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.6 (4.4\u0026ndash;6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.149\u0026ndash;1.772)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.398\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(1.108\u0026ndash;1.764)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3.8 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5 (4.4\u0026ndash;5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3.8 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.4 (6.3\u0026ndash;8.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.674\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.543\u0026ndash;0.836)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.747\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.582\u0026ndash;0.957)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.5 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.4 (6.2\u0026ndash;8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;0.5 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.4 (4.3\u0026ndash;5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.160\u0026ndash;1.789)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.980\u0026ndash;1.588)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOS\u003c/em\u003e, overall survival; \u003cem\u003eCI\u003c/em\u003e, confidence interval; \u003cem\u003eHR\u003c/em\u003e, hazard ratio; \u003cem\u003eECOG\u003c/em\u003e, Eastern Cooperative Oncology Group; \u003cem\u003eGBC\u003c/em\u003e, gallbladder cancer; \u003cem\u003eIHCC\u003c/em\u003e, intrahepatic cholangiocarcinoma; \u003cem\u003eEHCC\u003c/em\u003e, extrahepatic cholangial carcinoma; \u003cem\u003eAVC\u003c/em\u003e, ampulla of Vater cancer; \u003cem\u003eGC\u003c/em\u003e, gemcitabine plus cisplatin; \u003cem\u003eGS\u003c/em\u003e gemcitabine plus S-1; \u003cem\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/em\u003e, carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; \u003cem\u003eCRP\u003c/em\u003e, C-reactive protein\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e Univariable and multivariable analysis for overall survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003emedian OS, month (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eUnivariable analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e \u003cp\u003eMultivariable analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.7 (11.3\u0026ndash;15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.7 (13.1\u0026ndash;16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.792\u0026ndash;1.289)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.934\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.940\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.732\u0026ndash;1.207)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.628\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.9 (12.7\u0026ndash;17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.4 (11.5\u0026ndash;15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.912\u0026ndash;1.452)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.876\u0026ndash;1.442)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG performance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.5 (13.5\u0026ndash;17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.3 (9.6\u0026ndash;13.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.536\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.196\u0026ndash;1.973)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.961\u0026ndash;1.636)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.6 (11.1\u0026ndash;14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.7 (11.8\u0026ndash;17.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.749\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.559\u0026ndash;1.005)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.619\u0026ndash;1.122)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.230\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEHCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.3 (13.0-20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.704\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.532\u0026ndash;0.934)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.839\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.617\u0026ndash;1.140)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.5 (7.5\u0026ndash;20.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.633\u0026ndash;2.080)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.650\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.755\u0026ndash;2.635)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.281\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtent of disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocally advanced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.5 (13.3\u0026ndash;20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.3 (11.2\u0026ndash;13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.154\u0026ndash;2.216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.386\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.985\u0026ndash;1.951)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.5 (14.2\u0026ndash;23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.896\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.604\u0026ndash;1.330)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.587\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.697\u0026ndash;1.574)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.823\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.4 (12.3\u0026ndash;15.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e178\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.0 (12.2\u0026ndash;16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.950\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.753\u0026ndash;1.198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.936\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.738\u0026ndash;1.188)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.586\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;170.6 U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.5 (14.9\u0026ndash;20.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;170.6 U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.3 (10.3\u0026ndash;12.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.688\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.335\u0026ndash;2.133)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(1.253\u0026ndash;2.066)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3.8 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.4 (9.7\u0026ndash;13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3.8 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.9 (15.1\u0026ndash;19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.446\u0026ndash;0.711)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.710\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.542\u0026ndash;0.929)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.5 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.1 (14.2\u0026ndash;19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;0.5 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.9 (10.4\u0026ndash;13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.710\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.353\u0026ndash;2.161)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.367\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(1.055\u0026ndash;1.771)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOS\u003c/em\u003e, overall survival; \u003cem\u003eCI\u003c/em\u003e, confidence interval; \u003cem\u003eHR\u003c/em\u003e, hazard ratio; \u003cem\u003eECOG\u003c/em\u003e, Eastern Cooperative Oncology Group; \u003cem\u003eGBC\u003c/em\u003e gallbladder cancer, \u003cem\u003eIHCC\u003c/em\u003e, intrahepatic cholangiocarcinoma; \u003cem\u003eEHCC\u003c/em\u003e, extrahepatic cholangial carcinoma; \u003cem\u003eAVC\u003c/em\u003e, ampulla of Vater cancer; \u003cem\u003eGC\u003c/em\u003e, gemcitabine plus cisplatin; \u003cem\u003eGS\u003c/em\u003e, gemcitabine plus S-1; \u003cem\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/em\u003e carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; \u003cem\u003eCRP\u003c/em\u003e, C-reactive protein\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eUnivariable and multivariable analyses for survival outcome\u003c/h2\u003e \u003cp\u003eThe results of the univariable and multivariable analyses for 9 variables to evaluate whether the primary sites affect survival outcome are shown in Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. According to the multivariable analysis, serum albumin and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 were identified as independent prognostic factors for PFS and GBC showed worse PFS than EHCC (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). And serum albumin, CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, and CRP were identified as independent prognostic factors for OS (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Although the primary site was not identified as a prognostic factor for OS statistically, the patients with GBC tended to have shorter OS than the patients with EHCC.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first post-hoc analysis to compare the clinical features, treatment efficacy, and prognosis among the primary sites of unresectable BTCs using the data of JCOG1113, as there was no prospective study that had previously evaluated the differences in them by primary site in detail. In this study, there were several findings regarding the differences among the primary sites. We found patients with GBC were more likely to be female and have an advanced stage, such as a high number of metastatic organs involved. GBC and AVC showed poorer PFS than EHCC, and the multivariable analysis demonstrated the difference of PFS between GBC and EHCC was significant. Although GBC and AVC showed poorer OS than EHCC, the multivariable analysis revealed that the primary sites did not affect OS.\u003c/p\u003e \u003cp\u003eRegarding the clinical features, there were some findings that were different or similar among the primary sites, but almost of those findings were consistent with previous reports. Firstly, there were more female patients than male patients for GBC compared with the other primary sites [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. One of the reasons why GBC showed female dominance is generally thought to be that the anomalous pancreaticobiliary ductal junction, known as the biliopancreas maljunction or pancreaticobiliary maljunction and one of the great risk factors for GBC, shows female dominance [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. According to previous studies, it was reported that premenopausal women with irregular or longer menstrual cycles may have an increased risk for GBC compared with postmenopausal women, but not for the other primary sites of BTCs [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The regularity of menstrual cycles depends on the amount of secreted female hormones, so there might be a slight association between female hormones and a higher risk of GBC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This may be because female hormones can enhance the formation of biliary stones, one of the risk factors for GBC, by increasing biliary cholesterol secretion [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although the exposure to female hormones might be associated with increased risk for GBC, the mechanisms explaining the female dominance of GBC remain unknown. Secondly, the patients with GBC tended to be detected with advanced disease. There were more GBC patients with metastases than patients with locally advanced or recurrent diseases, and the number of metastatic organs tended to be more than for the other primary sites. In addition, patients with GBC were more likely to have ECOG-PS of 1, although these differences were not so large. Because GBCs are rarely diagnosed with the onset of biliary obstructive jaundice, so most patients with GBC might be often detected at an advanced stage with some symptoms or ECOG-PS of 1. Patients with EHCC, on the other hand, were more likely to have locally advanced disease. Of the BTCs, EHCC and AVC are often diagnosed with the onset of biliary obstructive jaundice; therefore, patients with these tumors might be detected at a locally advanced stage or with fewer metastases compared with the other sites [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs for treatment efficacy, there were some differences in PFS among the primary sites, although the ORRs were comparable in our study. The result concerning PFS was consistent with a systematic review and meta-analysis showing that PFS in patients with GBC was worse than in patients with EHCC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. We speculated that PFS in the patients with EHCC was overestimated compared with that in the patients with GBC. In general, it is more difficult to assess efficacy in patients without a measurable lesion than in those with measurable lesion because we cannot assess the change of the tumor volume accurately, and the time used to determine disease progression tends to be delayed [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In fact, fewer patients with EHCC had measurable lesions than those with GBC in this study (59.3% vs. 89.1%). Therefore, PFS would be better in the patients with EHCC than in those with GBC despite comparable ORRs between the two primary sites. On the other hand, a previous study reported that ORR in patients with GBC was higher compared with those for the other primary sites [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]; however, this was not consistent with the results of this analysis. We suggest that ORR in the patients with EHCC would be increased because we calculated the numbers of measurable lesions as the denominator. Therefore, it is possible that the ORR for the patients with GBC might not be so much better than that for the\u003c/p\u003e \u003cp\u003epatients with EHCC. Furthermore, it was also thought that the patients with GBC were more likely to include metastatic disease. Therefore, they were more likely to have poorer PFS than the patients with EHCC, even if they showed the same ORR. Patients with AVC did not show PR in this study, despite the other randomized control trials, such as the ABC-02 trial, showing some response [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The number of patients with AVC included in our study was too small to compare the ORR with that of another study.\u003c/p\u003e \u003cp\u003eAccording to previous studies, GBC has generally a poorer prognosis than the other primary sites; however, the reason remains uncertain [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. From the results of this study, it was demonstrated that the primary sites were not substantially associated with OS, as serum albumin, CRP, and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 were stronger prognostic factors for OS than the primary sites. Indeed, in addition to our study, several previous studies have reported that these factors were identified as prognostic factors [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The reason why GBC was more likely to have a slightly shorter OS was thought to be that the patients with GBC were detected with advanced disease, which included the metastatic stage and multiple metastases, or had a poor PS, as described above, at least as far as patients with unresectable BTCs receiving palliative chemotherapy were concerned. Regarding AVC, the prognosis remains unclear according to previous reports. It has been reported that the prognosis of patients with AVC might not to be so dismal if they are diagnosed at an early stage [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, the patients with AVC included in our study had metastatic or recurrent diseases, which could explain why the prognoses for the patients with AVC were comparable to those for other primary sites in our study. Nevertheless, we thought that the number of patients with AVC in our study was too small to analyze the prognosis as well as the ORR.\u003c/p\u003e \u003cp\u003eThis study had several limitations. Firstly, because all the patients with BTCs were divided into groups according to the primary sites, the numbers of patients in each group were smaller, and the AVC group in particular had few patients. Secondly, this study excluded the patients who were expected to have poor prognoses such as those with poor PS, inadequate function of the major organs, or massive ascites, and so on. Therefore, there might be the differences in the results between our clinical trial and the real world. Thirdly, this study did not include patients who received therapy using ICIs, such as GC plus durvalumab or pembrolizumab therapy, which has recently become one of the standard regimens [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Fourthly, this study did not include any information about the genomic alterations, although various genomic alterations have been found [\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and some therapeutic agents have recently been developed [\u003cspan additionalcitationids=\"CR31 CR32 CR33\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] in patients with BTCs. Considering these limitations, caution is necessary when attempting to simply apply our results to patients who receive the new standard of care in daily practice.\u003c/p\u003e \u003cp\u003eIn conclusion, patients with GBC are more likely to include metastatic disease and multiple metastases, and this is likely one of the causes of its poor prognosis. Although the primary sites were associated with PFS, there were some factors, such as serum albumin, CRP, CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, that had greater effects on OS than the primary sites. Therefore, the primary sites were not included as prognostic factor for OS. Further study is needed to determine whether the results of this study can be applied to patients with BTCs receiving treatments including ICIs or targeted therapies for genomic alterations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgement\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all of the participating patients and families, as well as the investigators, and clinical research coordinators in JCOG1113. We also appreciate the members of the JCOG Data Center and JCOG Operations Office for their great and valuable support in preparing the manuscript, data management, and oversight of the management of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by Yuko Suzuki and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeidentified participant data can be shared upon reasonable request to the corresponding author.\u003c/p\u003e\n\u003cp\u003eIndividual participant data that underlie the results reported in this article, after deidentification will be shared if investigators whose proposed use of the data has been approved by the investigators from Hepatobiliary and Pancreatic Oncology Group of JCOG identified for this purpose. Proposals should be directed to corresponding author. The data will be available for achieving aims in the approved proposal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the National Cancer Center Research and Development Fund [grant numbers 23-A-22, 26-A-4, 29-A-3, 2020-J-3, 2023-J-03]; Japan Agency for Medical Research and Development [grant numbers JP19ck0106350]; and the Grant-in-Aid for Clinical Cancer Research [H22-ganrinsho-ippan-013] from the Ministry of Health, Labor, and Welfare of Japan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY.S. reports research fundings from Chugai Pharmaceutical Co., Ltd. M.I. reports consulting fees from AstraZeneca K.K. and MSD K.K., honoraria from AstraZeneca K.K., Guardant Health Japan Corp., Incyte Biosciences Japan G.K., MSD K.K. and Taiho Pharmaceutical Co., Ltd., and research fundings from AstraZeneca K.K., Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, J-Pharma Co., Ltd., Merck Biopharma Co., Ltd. and Ono Pharmaceutical Co., Ltd. J.M. reports honoraria from Chugai Pharmaceutical Co., Ltd. and Taiho Pharmaceutical Co., Ltd., and his spouse is an employee of Pfizer Japan Inc. C.M. reports honoraria from AstraZeneca K.K., Eisai Co., Ltd., Guardant Health Japan Corp., MSD K.K., Myriad Genetic G.K., Novartis Pharma K.K., Nihon Servier Co., Ltd., Taiho Pharmaceutical Co., Ltd., Toray Industries, Inc., and Yakult Honsha Co., Ltd., and research fundings from AstraZeneca K.K., Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., J-Pharma Co., Ltd., Merck Biopharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Yakult Honsha Co., Ltd. T.O. reports grants from AstraZeneca K.K., Bristol Myers Squibb K.K., Chiome Bioscience Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Incyte Biosciences Japan G.K., MSD K.K., Novartis Pharma K.K., Syneos Health Clinical K.K. and Sysmex Corp., consulting fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., FUJIFILM Toyama Chemical Co., Ltd., Nihon Servier Co., Ltd., Novartis Pharma K.K. and Ono Pharmaceutical Co., Ltd., honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Johnson \u0026amp; Johnson, Myriad Genetic G.K., Nihon Servier Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Syneos Health Clinical K.K., Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. S.K. reports honoraria from AstraZeneca K.K. and MSD K.K. H.I. reports honoraria from AstraZeneca K.K., Boston Scientific Corp., Kaneka Medix Corp., Nihon Servier Co., Ltd., Novartis Pharma K.K., SB-KAWASUMI LABORATORIES, INC. and Yakult Honsha Co., Ltd., fees for promotional materials from Medico\u0026rsquo;s Hirata Inc., research fundings from Boehringer Ingelheim Co., Ltd., Nihon Servier Co., Ltd., Novartis Pharma K.K. and Ono Pharmaceutical Co., Ltd., and he is a participant on an advisory board of Nihon Servier Co., Ltd. T.T. reports honoraria from AstraZeneca K.K. and Chugai Pharmaceutical Co., Ltd. N.O. reports honoraria from AstraZeneca K.K. A.T. reports honoraria from AstraZeneca K.K., Nihon Servier Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Teijin Pharma, Ltd. and Yakult Honsha Co., Ltd. S.S. reports research fundings from AstraZeneca K.K., Delta-Fly Pharma, Inc., Incyte Biosciences Japan G.K. and Nihon Servier Co., Ltd. N.M. reports research fundings from AstraZeneca K.K., Boehringer Ingelheim Co., Ltd., Incyte Biosciences Japan G.K., MSD K.K., Nihon Servier Co., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc. and Seagen Inc. S.S. reports research fundings from Amino Up Co., Ltd., Boston Scientific Corp. and Nihon Servier Co., Ltd. M.O. reports honoraria from MSD K.K., Nihon Servier Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. M.U. reports honoraria from Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd., and fundings from Taiho Pharmaceutical Co., Ltd. The other authors have nothing to declare for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthic approval statement, patient consent statement, and permission to reproduce material from other sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJCOG1113 was conducted in accordance with the 1964 Declaration of Helsinki, its later amendments and Japanese Ethical Guidelines for Clinical Research, and the study protocol was approved by the institutional review board of each participating institution. The written informed consent was obtained from all participants of JCOG1113.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJCOG1113 was registered with University hospital Medical Information Network Clinical Trials Regisry (UMIN000010667).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eValle JW, Kelley RK, Nervi B, Oh DY, Zhu AX: \u003cstrong\u003eBiliary tract cancer\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2021, \u003cstrong\u003e397\u003c/strong\u003e(10272):428-444.\u003c/li\u003e\n\u003cli\u003eVogel A, Bridgewater J, Edeline J, Kelley RK, Klumpen HJ, Malka D, Primrose JN, Rimassa L, Stenzinger A, Valle JW\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eBiliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up\u003c/strong\u003e. \u003cem\u003eAnn Oncol \u003c/em\u003e2023, \u003cstrong\u003e34\u003c/strong\u003e(2):127-140.\u003c/li\u003e\n\u003cli\u003eValle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCisplatin plus gemcitabine versus gemcitabine for biliary tract cancer\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2010, \u003cstrong\u003e362\u003c/strong\u003e(14):1273-1281.\u003c/li\u003e\n\u003cli\u003eMorizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCombination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: The FUGA-BT (JCOG1113) Randomized Phase III Clinical Trial\u003c/strong\u003e. \u003cem\u003eAnn Oncol \u003c/em\u003e2019.\u003c/li\u003e\n\u003cli\u003eSchmidt MA, Marcano-Bonilla L, Roberts LR: \u003cstrong\u003eGallbladder cancer: epidemiology and genetic risk associations\u003c/strong\u003e. \u003cem\u003eChin Clin Oncol \u003c/em\u003e2019, \u003cstrong\u003e8\u003c/strong\u003e(4):31.\u003c/li\u003e\n\u003cli\u003eAzizi AA, Lamarca A, McNamara MG, Valle JW: \u003cstrong\u003eChemotherapy for advanced gallbladder cancer (GBC): A systematic review and meta-analysis\u003c/strong\u003e. \u003cem\u003eCrit Rev Oncol Hematol \u003c/em\u003e2021, \u003cstrong\u003e163\u003c/strong\u003e:103328.\u003c/li\u003e\n\u003cli\u003eIshihara S, Horiguchi A, Miyakawa S, Endo I, Miyazaki M, Takada T: \u003cstrong\u003eBiliary tract cancer registry in Japan from 2008 to 2013\u003c/strong\u003e. \u003cem\u003eJ Hepatobiliary Pancreat Sci \u003c/em\u003e2016, \u003cstrong\u003e23\u003c/strong\u003e(3):149-157.\u003c/li\u003e\n\u003cli\u003eKang MJ, Lim J, Han SS, Park HM, Kim SW, Lee WJ, Woo SM, Kim TH, Won YJ, Park SJ: \u003cstrong\u003eDistinct prognosis of biliary tract cancer according to tumor location, stage, and treatment: a population-based study\u003c/strong\u003e. \u003cem\u003eSci Rep \u003c/em\u003e2022, \u003cstrong\u003e12\u003c/strong\u003e(1):10206.\u003c/li\u003e\n\u003cli\u003eSong BG, Park JK, Kim HS, Kim K, Park JK, Lee KH, Lee KT, Lee JK: \u003cstrong\u003ePrognosis and prognostic factors in patients with advanced biliary tract cancer depending on its anatomical location\u003c/strong\u003e. \u003cem\u003eScand J Gastroenterol \u003c/em\u003e2019, \u003cstrong\u003e54\u003c/strong\u003e(6):740-745.\u003c/li\u003e\n\u003cli\u003eMakiuchi T, Sobue T, Kitamura T, Sawada N, Iwasaki M, Sasazuki S, Yamaji T, Shimazu T, Tsugane S: \u003cstrong\u003eReproductive factors and gallbladder/bile duct cancer: a population-based cohort study in Japan\u003c/strong\u003e. \u003cem\u003eEur J Cancer Prev \u003c/em\u003e2017, \u003cstrong\u003e26\u003c/strong\u003e(4):292-300.\u003c/li\u003e\n\u003cli\u003eShin A, Cho S, Abe SK, Islam MR, Rahman MS, Saito E, Kazmi SZ, Katagiri R, Merritt M, Choi JY\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAssociation of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium\u003c/strong\u003e. \u003cem\u003eInt J Cancer \u003c/em\u003e2024, \u003cstrong\u003e155\u003c/strong\u003e(2):240-250.\u003c/li\u003e\n\u003cli\u003eJackson SS, Adami HO, Andreotti G, Beane-Freeman LE, de Gonzalez AB, Buring JE, Fraser GE, Freedman ND, Gapstur SM, Gierach G\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAssociations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project\u003c/strong\u003e. \u003cem\u003eJ Hepatol \u003c/em\u003e2020, \u003cstrong\u003e73\u003c/strong\u003e(4):863-872.\u003c/li\u003e\n\u003cli\u003eNovacek G: \u003cstrong\u003eGender and gallstone disease\u003c/strong\u003e. \u003cem\u003eWien Med Wochenschr \u003c/em\u003e2006, \u003cstrong\u003e156\u003c/strong\u003e(19-20):527-533.\u003c/li\u003e\n\u003cli\u003eTsukada K, Takada T, Miyazaki M, Miyakawa S, Nagino M, Kondo S, Furuse J, Saito H, Tsuyuguchi T, Kimura F\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDiagnosis of biliary tract and ampullary carcinomas\u003c/strong\u003e. \u003cem\u003eJ Hepatobiliary Pancreat Surg \u003c/em\u003e2008, \u003cstrong\u003e15\u003c/strong\u003e(1):31-40.\u003c/li\u003e\n\u003cli\u003eLamarca A, Frizziero M, McNamara MG, Valle JW: \u003cstrong\u003eClinical and Translational Research Challenges in Biliary Tract Cancers\u003c/strong\u003e. \u003cem\u003eCurr Med Chem \u003c/em\u003e2020, \u003cstrong\u003e27\u003c/strong\u003e(29):4756-4777.\u003c/li\u003e\n\u003cli\u003eWernberg JA, Lucarelli DD: \u003cstrong\u003eGallbladder cancer\u003c/strong\u003e. \u003cem\u003eSurg Clin North Am \u003c/em\u003e2014, \u003cstrong\u003e94\u003c/strong\u003e(2):343-360.\u003c/li\u003e\n\u003cli\u003eUtsumi M, Inagaki M, Kitada K, Tokunaga N, Kondo M, Yunoki K, Sakurai Y, Hamano R, Miyasou H, Tsunemitsu Y\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePreoperative C-reactive protein-to-albumin ratio as a prognostic factor in biliary tract cancer: A systematic review and meta-analysis\u003c/strong\u003e. \u003cem\u003eMedicine (Baltimore) \u003c/em\u003e2023, \u003cstrong\u003e102\u003c/strong\u003e(22):e33656.\u003c/li\u003e\n\u003cli\u003ePark HS, Park JS, Chun YJ, Roh YH, Moon J, Chon HJ, Choi HJ, Park JS, Lee DK, Lee SJ\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePrognostic Factors and Scoring Model for Survival in Metastatic Biliary Tract Cancer\u003c/strong\u003e. \u003cem\u003eCancer Res Treat \u003c/em\u003e2017, \u003cstrong\u003e49\u003c/strong\u003e(4):1127-1139.\u003c/li\u003e\n\u003cli\u003eKim BJ, Hyung J, Yoo C, Kim KP, Park SJ, Lee SS, Park DH, Song TJ, Seo DW, Lee SK\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePrognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients\u003c/strong\u003e. \u003cem\u003eCancer Chemother Pharmacol \u003c/em\u003e2017, \u003cstrong\u003e80\u003c/strong\u003e(1):209-215.\u003c/li\u003e\n\u003cli\u003eImaoka H, Ikeda M, Nomura S, Morizane C, Okusaka T, Ozaka M, Shimizu S, Yamazaki K, Okano N, Sugimori K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDevelopment of a nomogram to predict survival in advanced biliary tract cancer\u003c/strong\u003e. \u003cem\u003eSci Rep \u003c/em\u003e2023, \u003cstrong\u003e13\u003c/strong\u003e(1):21548.\u003c/li\u003e\n\u003cli\u003eOh DY, Lee KH, Lee DW, Yoon J, Kim TY, Bang JH, Nam AR, Oh KS, Kim JM, Lee Y\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study\u003c/strong\u003e. \u003cem\u003eLancet Gastroenterol Hepatol \u003c/em\u003e2022, \u003cstrong\u003e7\u003c/strong\u003e(6):522-532.\u003c/li\u003e\n\u003cli\u003eKelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klumpen HJ, Chan SL, Ozaka M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2023, \u003cstrong\u003e401\u003c/strong\u003e(10391):1853-1865.\u003c/li\u003e\n\u003cli\u003eChen X, Wang D, Liu J, Qiu J, Zhou J, Ying J, Shi Y, Wang Z, Lou H, Cui J\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes\u003c/strong\u003e. \u003cem\u003eJ Immunother Cancer \u003c/em\u003e2021, \u003cstrong\u003e9\u003c/strong\u003e(11).\u003c/li\u003e\n\u003cli\u003eGuo L, Zhou F, Liu H, Kou X, Zhang H, Chen X, Qiu J: \u003cstrong\u003eGenomic mutation characteristics and prognosis of biliary tract cancer\u003c/strong\u003e. \u003cem\u003eAm J Transl Res \u003c/em\u003e2022, \u003cstrong\u003e14\u003c/strong\u003e(7):4990-5002.\u003c/li\u003e\n\u003cli\u003eTakada K, Kubo T, Kikuchi J, Yoshida M, Murota A, Arihara Y, Nakamura H, Nagashima H, Tanabe H, Sugita S\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEffect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study\u003c/strong\u003e. \u003cem\u003eFront Oncol \u003c/em\u003e2022, \u003cstrong\u003e12\u003c/strong\u003e:988527.\u003c/li\u003e\n\u003cli\u003eAstier C, Ngo C, Colmet-Daage L, Marty V, Bawa O, Nicotra C, Ngo-Camus M, Italiano A, Massard C, Scoazec JY\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMolecular profiling of biliary tract cancers reveals distinct genomic landscapes between circulating and tissue tumor DNA\u003c/strong\u003e. \u003cem\u003eExp Hematol Oncol \u003c/em\u003e2024, \u003cstrong\u003e13\u003c/strong\u003e(1):2.\u003c/li\u003e\n\u003cli\u003eTang TY, Nichetti F, Kaplan B, Lonardi S, Pietrantonio F, Salvatore L, Vivaldi C, Rimassa L, de Braud F, Rizzato MD\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eComparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers\u003c/strong\u003e. \u003cem\u003eClin Cancer Res \u003c/em\u003e2023, \u003cstrong\u003e29\u003c/strong\u003e(23):4853-4862.\u003c/li\u003e\n\u003cli\u003eMavroeidi IA, Burghofer J, Kalbourtzis S, Taghizadeh H, Webersinke G, Piringer G, Kasper S, Schreil G, Liffers ST, Reichinger A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eUnderstanding homologous recombination repair deficiency in biliary tract cancers: clinical implications and correlation with platinum sensitivity\u003c/strong\u003e. \u003cem\u003eESMO Open \u003c/em\u003e2024, \u003cstrong\u003e9\u003c/strong\u003e(8):103630.\u003c/li\u003e\n\u003cli\u003eKanai M: \u003cstrong\u003eCurrent Clinical Practice of Precision Medicine Using Comprehensive Genomic Profiling Tests in Biliary Tract Cancer in Japan\u003c/strong\u003e. \u003cem\u003eCurr Oncol \u003c/em\u003e2022, \u003cstrong\u003e29\u003c/strong\u003e(10):7272-7284.\u003c/li\u003e\n\u003cli\u003eSubbiah V, Lassen U, Elez E, Italiano A, Curigliano G, Javle M, de Braud F, Prager GW, Greil R, Stein A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial\u003c/strong\u003e. \u003cem\u003eLancet Oncol \u003c/em\u003e2020, \u003cstrong\u003e21\u003c/strong\u003e(9):1234-1243.\u003c/li\u003e\n\u003cli\u003eBekaii-Saab TS, Valle JW, Van Cutsem E, Rimassa L, Furuse J, Ioka T, Melisi D, Macarulla T, Bridgewater J, Wasan H\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eFIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements\u003c/strong\u003e. \u003cem\u003eFuture Oncol \u003c/em\u003e2020, \u003cstrong\u003e16\u003c/strong\u003e(30):2385-2399.\u003c/li\u003e\n\u003cli\u003eZhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DVT, Borad MJ, Bridgewater JA\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eFinal Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial\u003c/strong\u003e. \u003cem\u003eJAMA Oncol \u003c/em\u003e2021, \u003cstrong\u003e7\u003c/strong\u003e(11):1669-1677.\u003c/li\u003e\n\u003cli\u003eJavle M, Borad MJ, Azad NS, Kurzrock R, Abou-Alfa GK, George B, Hainsworth J, Meric-Bernstam F, Swanton C, Sweeney CJ\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study\u003c/strong\u003e. \u003cem\u003eLancet Oncol \u003c/em\u003e2021, \u003cstrong\u003e22\u003c/strong\u003e(9):1290-1300.\u003c/li\u003e\n\u003cli\u003eGoyal L, Meric-Bernstam F, Hollebecque A, Valle JW, Morizane C, Karasic TB, Abrams TA, Furuse J, Kelley RK, Cassier PA\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eFutibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2023, \u003cstrong\u003e388\u003c/strong\u003e(3):228-239.\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"biliary tract cancer, chemotherapy, primary sites, prognostic factor","lastPublishedDoi":"10.21203/rs.3.rs-5483078/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5483078/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eBiliary tract cancers (BTCs) are heterogenous malignancies including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AVC). The reported data about the differences between the primary sites are limited to data that has just evaluated the efficacy of the treatment arms by primary site in randomized controlled trials. We aimed to compare the clinical features and treatment efficacy among the primary sites of BTCs using data from JCOG1113, a randomized trial.\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eAmong the 354 patients enrolled in JCOG1113, 352 patients were included in this analysis. We compared the patient characteristics, and efficacy outcomes among the primary sites.\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eThere were more women, and more patients with metastatic disease and multiple organs involving metastases in GBC compared to other primary sites (female: 58.4% vs 35.3% ; metastatic disease: 78.1% vs 41.6% ; multiple metastases: 49.3% vs 26.5%). The median progression-free survival (PFS) was 5.7 months, 6.2 months, 8.7 months and 4.1 months for GBC, IHCC, EHCC and AVC, respectively. The median OS was 12.6 months, 15.7 months, 16.3 months and 11.5 months for GBC, IHCC, EHCC and AVC, respectively. Multivariable analysis revealed that primary site was identified as one of prognostic factors for PFS, but not significant for OS.\u003c/p\u003e\n\u003cp\u003eConclusions\u003c/p\u003e\n\u003cp\u003ePatients with GBC were more likely to have metastatic disease and multiple metastases and more likely to show a poorer prognosis compared with those with the other primary sites; the primary sites were independent prognostic factors for PFS, but not for OS.\u003c/p\u003e","manuscriptTitle":"Comparison of clinical features by primary site in patients with biliary tract cancer who received gemcitabine-based chemotherapy: an exploratory analysis of JCOG1113","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-16 12:17:14","doi":"10.21203/rs.3.rs-5483078/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-04-13T22:32:57+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-13T02:35:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-12T07:14:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-04-09T22:02:45+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor revisions","date":"2025-02-09T04:39:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ea34d0f2-0253-47e8-ad90-d0ef9e7e462e","owner":[],"postedDate":"April 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T16:08:11+00:00","versionOfRecord":{"articleIdentity":"rs-5483078","link":"https://doi.org/10.1007/s10147-025-02834-x","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-07-24 15:57:50","publishedOnDateReadable":"July 24th, 2025"},"versionCreatedAt":"2025-04-16 12:17:14","video":"","vorDoi":"10.1007/s10147-025-02834-x","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02834-x","workflowStages":[]},"version":"v1","identity":"rs-5483078","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5483078","identity":"rs-5483078","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}