Nab-paclitaxel plus cisplatin versus gemcitabine plus cisplatin as first-line treatment in advanced biliary tract cancer: results of a multicentre, randomised, phase II trial

Nab-paclitaxel plus cisplatin versus gemcitabine plus cisplatin as first-line treatment in advanced biliary tract cancer: results of a multicentre, randomised, phase II trial | 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 Nab-paclitaxel plus cisplatin versus gemcitabine plus cisplatin as first-line treatment in advanced biliary tract cancer: results of a multicentre, randomised, phase II trial xiao Yang, Liang Zhuang, Heng hui Cheng, Yu Hong Dai, Ming-Sheng Zhang, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5762910/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Aug, 2025 Read the published version in BMC Cancer → Version 1 posted 4 You are reading this latest preprint version Abstract Background: the efficacy and safety of conventional first-line chemotherapeutic regimens for the treatment of advanced biliary tract carcinomas (ABTCs) have been unsatisfactory. Objectives: We aimed to explore alternative chemotherapeutic regimens capable of providing a better efficacy and fewer side effects. Design: Multicentre, randomised, phase II clinical trial Methods : Eligible patients with unresectable, recurrent, or metastatic biliary system tumours diagnosed by pathology or cytology between January 2021 and November 2022 were included. The participants were randomised to either a gemcitabine-cisplatin group (GC) or an albumin-paclitaxel-cisplatin group (NC). Progression-free survival (PFS) was the primary outcome, whereas overall survival (OS), and objective response rate (ORR) were the secondary outcomes. Results : The trial enrolled 75 patients and had a median follow-up period of 11 months. The median PFS (mPFS) was 7.8 m (95% confidence interval [CI]: 5.4–14.0 m) in the NC group, and 7.0 m (95%CI: 3.9–10.1 m) in the GC group (p=0.0034, hazard ratio [HR]=0.5136, 95%CI: 0.3136–0.8411). Median OS for the NC group was 12.4 m (95%CI: 7.3–22.3 m) and for the GC group was 12.1 m (95%CI: 6.7–20.7 m), with no significant differences (p=0.4592, HR=0.811, 95%CI: 0.463–1.442). PFS rates at 6 and 8 months were 48.24% vs. 70.8% and 8.51% vs. 32.0% for the NC and the GC group, respectively (p < 0.05). Regarding safety, although patients from both groups experienced thrombocytopenia, those in the NC group demonstrated significantly lower rates (p < 0.05). Conclusion: Compared with the GC group, the NC group showed a significantly increased mPFS, in addition to higher PFS rates at 6 and 8 months. Furthermore, the NC group showed lower haematological toxicity. This suggests that paclitaxel-based regimens may be a viable alternative for first-line treatment of ABTCs. Registration: Clinical Trials.gov identifiers: NCT04692051. Registered October 31, 2018 (Web Links -https://www.chictr.org.cn/showproj.html?proj=38440) biliary tract carcinomas advanced stage chemotherapy albumin-paclitaxel first-line treatment cisplatin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1 Introduction Malignant biliary tract cancer (BTC) or cholangiocarcinoma, primarily an adenocarcinoma with relatively high mortality compared to other malignancies, originates from gallbladder cells or epithelial cells from the bile duct( 1 , 2 ). Although the exact aetiology of cholangiocarcinoma is unknown, most researchers believe that gallstones, infections, hepatic fibrosis, and congenital abnormalities in bile duct formation may be involved in its development ( 3 , 4 ). Currently, surgery is the only possible cure ( 5 ). However, less than one-third of patients undergo surgery, and they have a poor prognosis due to the high rate of disease progression, sepsis caused by localised tumours, bile duct obstruction, cholangitis or abscesses, and early-stage detection challenges ( 6 , 7 ),Approximately half of untreated individuals pass away from the disease within three to four months after diagnosis ( 8 ). The current first-line standard treatment for advanced biliary malignancies is gemcitabine plus cisplatin with immunotherapy (with or without durvalumab/pembrolizumab). This regimen increases the patients' chances of survival and quality of life compared to supportive care alone( 9 ). Considering the mechanism underlying the anti-tumour activity of paclitaxel, albumin-bound paclitaxel has gained wide recognition as a novel class of anti-microtubule drug ( 10 ). This drug exerts inhibitory effects on the proliferation and division of malignancies by interfering with the polymerisation and depolymerisation of microtubules within the cellular environment. Consequently, the synthesis of spindle bodies and filaments is impeded, thereby hindering the proliferation of tumour cells and ultimately leading to apoptosis. Notably, unlike conventional paclitaxel, albumin-bound paclitaxel possesses an additional tumour-targeting attribute. This characteristic not only enhances treatment efficacy but also diminishes adverse effects, such as neurotoxicity and haematological toxicity( 11 , 12 ). Several clinical trials have demonstrated nab-paclitaxel (use albumin to carry paclitaxel) superior efficacy in the management of oesophageal, ovarian, and bladder cancers ( 13 ) ( 14 – 18 ). Additionally, it offers the advantage of enhancing overall or progression-free survival compared with conventional paclitaxel formulations (e.g., castor-oil-coated paclitaxel), with fewer adverse effects and higher patient acceptance ( 19 ) ( 20 – 22 ). In a previous study aiming to evaluate nab-paclitaxel as a potential first-line therapy for BTC, patients were categorised into two groups: a test group that received paclitaxel treatment with albumin and a control group ( 23 ). Although the primary endpoint was not achieved, the results suggested that combination chemotherapy with nab-paclitaxel is well tolerated and may be an alternative to existing treatments for advanced cholangiocarcinoma. A clinical trial carried out evaluate the efficacy of combining S-1 with nab-paclitaxel as first-line treatment for (Advanced Bile tract cancer, ABTC) compared with a gemcitabine-cisplatin combination showed that the combination therapy had good anti-tumour activity and was safe ( 24 ). The feasibility of utilising capecitabine in combination with nab-paclitaxel as a viable option for second-line treatment in ABTC was also confirmed by another study ( 25 ). Most ongoing studies investigating the efficacy of nab-paclitaxel in ABTC treatment have incorporated gemcitabine. Some researchers have explored a triple combination therapy consisting of nab-paclitaxel, gemcitabine, and cisplatin as initial treatment for advanced BTC, with positive outcomes( 5 , 26 ). However, this triple combination therapy also carries an elevated risk of adverse effects, leading to a higher incidence of grade 3–4 side effects rarely reported in the existing literature on this topic ( 13 , 18 ). We designed this study to compare the effectiveness and safety of a combination of gemcitabine plus cisplatin (GC) or nab-paclitaxel plus cisplatin (NC) as first-line therapies for ABTC, and to provide alternatives for first-line chemotherapy regimens in BTC. 2 Patients and methods The present study constituted a multicentre, open-label, randomised, phase II trial aimed at evaluating and comparing the effectiveness and safety of the GC and NC regimens as initial therapies for individuals diagnosed with ABTC. Patients were recruited from four cancer centres in China. In accordance with the Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1), individuals between the ages of 18 and 70 years who had received histological or cytological confirmation of unresectable, recurrent or metastatic advanced biliary malignancies (intra/extrahepatic cholangiocarcinoma, gallbladder cancer) and had at least one measurable lesion were considered suitable for inclusion in the study. The inclusion criteria for patients encompassed having an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, a minimum life expectancy of at least 3 months, and normal haematologic and organ function. Participants were also required to have pre-admission serum bilirubin levels below the upper limit of the normal value multiplied by three, transaminase levels not higher than five times the upper limit of normality, serum creatinine levels not higher than 1.5 times the upper limit of normal values or creatinine clearance ≥ 45 mL/min, an absolute neutrophil count (ANC) ≥ 1.5 ×10^9/L, platelet concentration ≥ 75×10^9/L, haemoglobin concentration ≥ 90 g/L, white blood cells (WBC) ≥ 3.0× 10^9/L, and no indication of propensity for bleeding. The exclusion criteria included patients who exhibited treatment-related toxicity, This toxicity had to be successfully rectified and resolved. Participants were deemed ineligible for inclusion in the investigation if they met any of the following criteria: presence of unmanageable infection or recent administration of systemic antibiotic therapy within 72 hours prior to chemotherapy, presence of haematological disorders, previous diagnosis of untreated malignancies other than those under investigation or brain metastases, documented allergy to the chemotherapeutic agents being evaluated, presence of psychiatric or neurological disorders that hindered their ability to cooperate, being pregnant or breastfeeding, and presence of other medical conditions that rendered them ineligible for participation, including active tuberculosis, active pneumonia, unresolvable electrolyte imbalances, unmanageable tumour-induced pain, or uncontrollable pleural effusion or peritoneal effusion. Patients being treated with alternative antineoplastic agents, those that had received previous treatment with experimental drugs, those who had engaged in interventional clinical trials within a month prior to the screening phase, and those deemed unsuitable for enrolment by the investigators for any other reason were also excluded from the study. 3 Procedures Basis of Grouping: Using a series of computerized randomization methods, patients who met the requirements were randomized (1:1) to either the GC or NC group. Neither investigators nor patients were blinded to group allocation. A total of 75 individuals were enrolled(Fig. 1 ). Those allocated to the NC group received ( 1 ) Intravenous (IV) infusion of nab-paclitaxel (125 mg/m2) on days 1 and 8, and ( 2 ) IV infusion of cisplatin (25 mg/m2) on days 1 to 3. The treatment cycle was repeated every 3 weeks (Q21d), for a total of six cycles. Those allocated to the GC group received ( 1 ) IV infusion of gemcitabine (1000 mg/m2) on days 1 and 8, and ( 2 ) IV infusion of cisplatin (25 mg/m2) on days 1 to 3, with the same cycle length and number of cycles. First-line treatment was administered until disease progression or intolerable adverse effects up to six cycles of treatment in total. Thereafter, six cycles of oral maintenance therapy with S-1 were administered. Toxicity/adverse reactions were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03, and patients were managed by discontinuation or reduction of medication. Treatment cycles were delayed until non-haematologic (≥ Grade 1) and haematologic toxicity subsided. Drug reductions were permitted in the presence of one of the following conditions: ( 1 ) ANC < 0.5 × 109/L; ( 2 ) Fever with neutropenia; ( 3 ) ANC within the 0.5-1.0 × 109/ L range with PLT within the 25–50 × 109 /L range; ( 4 ) PLT < 25 × 109/L with bleeding tendency or need for blood transfusion; ( 5 ) Anaemia grade 3 or higher; or ( 6 ) Neuropathy grade 2 or higher. A maximum of two dose reductions (25% of the initial dose) was allowed if the dose reduction criteria were met. Patients were withdrawn from the clinical study if drug administration needed to be interrupted for more than 3 weeks or reduced for more than 2 weeks during the course of the trial. No dose re-escalation was permitted between the cycles. To prevent serious side effects, colony-stimulating factor (CSF) and erythropoietin (EPO) was used for prophylaxis throughout the treatment phase. 4 Assessment Before each treatment cycle, a comprehensive physical examination was conducted along with routine laboratory tests, including routine and blood biochemistry, coagulation, and liver and renal function. Imaging by CT or MRI was carried out every two cycles from the initiation of treatment until disease progression. Further, survival follow-up was performed after disease progression, and alterations in the tumour were evaluated according to the assessment criteria outlined in RECIST version 1.1 5 Endpoints The main endpoint of the study was progression-free survival (PFS), defined as the time between allocation to the experimental group and the onset of disease progression or death from any cause. The secondary endpoints were overall survival (OS), defined as the time between allocation to the experimental group and death from any cause, objective response rate (ORR), defined as the sum of complete and partial remissions (CR + PR), and chemotherapy-related AEs. We used SPSS Statistics (version 26.0, IBM Corp., Armonk, N.Y., USA) for data analysis and GraphPad Prism (version 8.0, San Diego, CA, USA) for data visualisation, with statistical descriptions and analysis methods for the different indicators. The baseline indicators (e.g. medical history) and demographic characteristics were summarised, and the metrics were described by the number of patients, median, and other statistical analyses, such as the number of cases and minimum and maximum values. Numerical variables are described as numbers and percentages. The full analysis set (FAS) included all randomised participants. Efficacy and safety were assessed for patients who had received at least one administration of the drug and had had one follow-up visit. The null hypothesis was rejected, and the difference was statistically significant at the test level α = 0.05 level when the p-value was < 0.05. 6 Results 6.1Patient characteristics This study recruited a cohort of 75 participants (Table 1 ). The median age at diagnosis was 55 years, ranging from 27 to 67 years, with a balanced sex distribution (41 men, 54.6%; 34 women, 45.4%). Following randomisation, 38 patients received the GC regimen and 37 patients received the NC regimen. Statistical comparison of the demographic parameters between the two groups, including sex, age, tumour location, and metastasis, showed no significant differences. Table 1 Baseline levels and clinical characteristics of enrolled patients GC group (n = 38) NC group (n = 37) Sex Male 19 (50%) 22(59.4%) Female 19(50%) 15(40.6%) Age, years Median 58[40–70] 55[27–67] 60 16(42.1%) 10(27.0%) ECOG score, PS 0 29(76.3%) 26(70.3%) 1 9(23.7%) 11(29.7%) Tumour primary site Bile duct origin 25(65.8%) 24(64.9%) Gallbladder origin 10(26.3%) 10(27.0%) Unknown origin 3(7.9%) 3(8.1%) Degree of pathologic differentiation Highly differentiated 4(10.5%) 6(16.2%) Moderately differentiated 16(42.1%) 14(37.8%) Poorly differentiated 14(36.9%) 14(37.8%) Unknown 4(10.5%) 3(8.2%) Site of distant metastasis at enrolment Liver 35(92.1%) 33(89.2%) Lungs 4(10.5%) 5(13.5%) Bone 3(7.9%) 4(10.8%) Peritoneum 19(50%) 15(40.5%) Pelvis 7(18.4%) 8(21.6%) Lymph nodes 23(60.5%) 32(86.5%) Number of distantly metastasized organs 0ཞ1 21(55.3%) 21(56.8%) ≥ 2 17(44.7%) 16(43.2%) History of hepatitis B Yes 17(44.7%) 12(32.4%) No or not available 21(55.3%) 25(67.6%) Ki-67 index <50% 9(23.7%) 15(40.5%) ≥ 50%, <80% 14(36.8%) 15(40.5%) ≥ 80% 15(39.5%) 7(19.0%) Note: Data are presented as median (IQR) or n (%). GC, gemcitabine combined with cisplatin; NC, albumin paclitaxel combined with cisplatin; ECOG PS, Eastern Cooperative Oncology Group of the United States Performance Status; Ki-67, tumour proliferation index. 6.2 Efficacy Table 2 details the efficacy outcomes. One patient (2.7%) in the NC group attained complete response (CR), while none in the GC group did (0.0%). Partial response (PR) was achieved in 13 patients in each group, representing 34.2% and 35.1% of the patients included in the NC and GC groups, respectively. The majority of patients in both groups maintained a stable disease status. Eight (21.2%) and seven (18.9%) patients in the NC and GC group, respectively, showed disease progression (PD) after treatment. In terms of effectiveness, no significant differences were found between the two groups (p > 0.05). Table 2 Efficacy assessment variable values in both groups (according to RECIST 1.1 criteria) GC group (n = 38) NC group (n = 37) P CR 0(0.0%) 1(2.7%) >0.05 PR 13(34.2%) 13(35.1%) >0.05 SD 17(44.7%) 16(43.2%) >0.05 PD 8(21.1) 7(18.9%) >0.05 ORR 13(34.2%) 14(37.8%) >0.05 DCR 30(78.9%) 30(81.1%) >0.05 GC, gemcitabine combined with cisplatin; NC, albumin paclitaxel combined with cisplatin; CR, complete response; PR, partial response; SD, Stable Disease; PD, disease progression; ORR, objective response rate; DCR, Disease control rate Regarding PFS, the median PFS (mPFS) in the GC group was 7.0 m (95% confidence interval [CI]: 3.9–10.1 m), and that in the NC group was 7.8 m (95% CI: 5.4–14.0 m). The difference between the two groups was statistically significant (p = 0.0034, hazard ratio [HR]: 0.5136, 95% CI: 0.3136–0.8411; Fig. 2 ). The median OS (mOS) in the GC group was 12.1 m (95% CI: 6.7–20.7 m) and 12.4 m (95% CI: 7.3–22.3 m) in the NC group, with no significant differences between the groups (p:0.4592, HR: 0.811, 95% CI: 0.463–1.442; Fig. 2 ). The NC group exhibited a significantly higher PFS rate at 6 months (70.83%) compared to the GC group (48.24%, Z = 1.989, p = 0.047). The PFS rates at 8 months were 31.97% and 8.51% in the NC and GC groups, respectively (Z = 2.509, p = 0.012; Fig. 3 ). Patients in the NC group also showed favourable trends in OS rates at 6, 12 and 18 months, GC vs NC(94.7% vs. 96.3%), (48.3% vs. 58.5%), and (5.3% vs. 2.7%), respectively, with p > 0.05 in all cases (Fig. 3 ). 6.3 Safety The major treatment-induced adverse events are summarised in Table 3 . Twenty-nine of the 38 patients in the NC group (76.3%) and 27 of the 37 patients in the GC group (72.9%) experienced treatment-induced AEs of any grade. The discrepancies observed in the incidence of side effects between the two drug regimens, or in the rate of occurrence of adverse events of grade 3 or higher (31.5% vs. 27.5%) were not statistically significant. Most haematological adverse events were resolved after symptom treatment, with two (5.2%) and one (2.7%) patients in either group, respectively, experiencing granulocytopenia with fever that was resolved, after treatment with non-steroidal anti-inflammatory drugs (after exclusion of contraindications), anti-infectives, and leukocyte boosters. Patients who were administered gemcitabine in combination with cisplatin had a significantly higher risk of experiencing platelet count reduction compared with those that received nab-paclitaxel instead (50.0% vs. 32.4%, p = 0.041). The most common non-haematological AEs were weariness and malaise, which improved with rest. Numbness and pain in the hands and feet were the most common neurological adverse events, occurring in 14 (36.8%) and 23 (62.1%) of patients in the GC and NC group, respectively (p = 0.028). Neurological symptoms improved after treatment with drugs such as vitamin analogues and calcium channel blockers. Table 3 Treatment-related side effects discriminated by group GC group (n = 38) NC group (n = 37) P* Any ⩾3 Grade Any ⩾3 Grade Any ⩾3 Grade Haematological Anaemia 16(42.1%) 3(7.9%) 17(45.9%) 1(2.7%) 0.738 0.627 Red blood cell decreased 17(44.7%) 3(7.9%) 15(40.5%) 1(2.7%) 0.713 0.627 Neutropenia 22(57.9%) 4(10.5%) 20(54.1%) 1(2.7%) 0.738 0.371 Leukopenia 26(68.4%) 4(10.5%) 22(59.5%) 2(5.4%) 0.419 0.414 Thrombocytopenia 19(50%) 3(7.9%) 10(27.0%) 1(2.7%) 0.041 0.627 Non-haematological Fatigue 26(68.4%) 8(21.1%) 25(67.6%) 8(21.6%) 0.937 0.952 Anorexia 12(31.5%) 5(13.2%) 13(35.1%) 4(10.8%) 0.744 0.999 Fatigue 26(68.4%) 8(21.1%) 20(54.1%) 7(18.9%) 0.201 0.768 Constipation 3(7.9%) 0(0.0%) 2(5.2%) 0(0.0%) 0.666 - Diarrhoea 3(7.9%) 0(0.0%) 5(13.5%) 0(0.0%) 0.431 - Sensory neuropathy 14(36.8%) 0(0.0%) 23(62.1%) 0(0.0%) 0.028 - Liver dysfunction 13(34.2%) 2(5.3%) 9(24.3%) 1(2.7%) 0.347 0.999 Renal dysfunction 5(13.2%) 0(0.0%) 5(13.5%) 0(0.0%) 0.964 - Rash 9(23.7%) 0(0.0%) 3(8.1%) 0(0.0%) 0.066 - Any AEs 29(76.3%) - 27(72.9%) - 0.739 - ⩾3 Grade AEs - 12(31.2%) - 10(27.5%) - 0.665 Note: Data are n (%). *Bold font indicates P < 0.05, statistically significant. GC, gemcitabine combined with cisplatin; NC, albumin paclitaxel combined with cisplatin; AEs, adverse events 6.4 Subgroup analysis and multivariate analysis The subgroup analysis of PFS (Fig. 4 ) showed that patients with the gallbladder as primary site (p = 0.125, HR:0.622, 95%CI: 0.075–0.804), those aged under 50 years of age (p = 0.012, HR: 0.122 95%CI: 0.023–0.636), and those previously infected with hepatitis B (p = 0.002, HR:0.201, 95%CI: 0.074–0.542) had a lower risk of disease progression). The difference was not statistically significant for other subgroups (p > 0.05). Multifactorial analysis (Fig. 5 ) demonstrated that the probability of disease progression in patients with poorly differentiated tumours was 4.09 times higher than that in the group with well-differentiated tumours (p = 0.014, 95%CI: 1.334–12.560), and the probability of disease progression for those with moderately differentiated tumours was 2.53 times higher than that in the group with well-differentiated tumours. Patients with a Ki-67 index between 50% and 80% and those with a Ki-67 index ≥ 80% were 2.769 times (p = 0.011, 95%CI: 1.188–6.457) and 26.7 times (p < 0.01, 95% CI:7.482–95.871) more likely to exhibit disease progression compared to those with a Ki-67 index < 50%. In the subgroup analysis of OS (Fig. 6 ), patients with an ECOG score of 1 showed a significantly higher OS (p = 0.0006, HR:0.181, 95%CI: 0.053–0.619), and those with a high Ki-67 index (≥ 80%) had a higher chance of death (p = 0.049, HR:3.445, 95%CI: 1.055–12.430). No significant differences were identified for any other subgroup. Multivariate analysis showed that, compared with the patient subpopulation under 50 years of age, patients that were between 51 and 60 years old had a risk of death that was more than nine times higher (Fig. 7 ). Relative to the patient population with high differentiation, the probability of death in the patients with medium differentiation was also significantly higher (approximately 4.3 times that of the high differentiation group). Furthermore, the forest chart demonstrates that older participants (50–60 years old, > 60 years old), those with an ECOG score of 1 point (compared with ECOG score of 0 points), and those with moderate differentiation (compared with those with poorly differentiation) were at increased risk of death caused by the disease. No obvious effect on OS was observed for any other subgroup (p > 0.05). 7 Discussion This study aimed to evaluate the effectiveness and safety of two treatment regimens (GC and NC) as first-line therapy for patients with ABTC. During follow-up, we observed a significant difference between the groups regarding mPFS, with NC being superior to GC, although there were no significant differences for mOS. The differences in the ORR and the OS rates at 6, 12, and 18 months between the two groups were not statistically different either. However, the experimental data suggests that the PFS rates at 6 and 8 months were higher in the NC group. The research findings indicate that the combined treatment with nab-paclitaxel plus cisplatin offers an advantage for the treatment of advanced cholangiocarcinoma, resulting in increased PFS in these patients. In 2016, Cadamuro et al. demonstrated in CCA cell lines and in a severe combined immunodeficiency mouse xenograft model that small doses of paclitaxel (1.5 nM and 15 nM) decreased nuclear existence of the calcium-binding protein known as S100A4, a biomarker for CCA invasiveness, without altering its cytoplasmic levels, thereby inhibiting CCA invasion and metastatic spread( 27 ). A clinical study from 2019 reported an increase in mPFS in response to nab-paclitaxel treatment, An exploration of nab-paclitaxel combination with S-1 as an experimental regimen, compared with a conventional combination of gemcitabine with cisplatin as a first-line chemotherapy regimen for patients with ABTC, has also been conducted( 24 ). The difference in mOS between the experimental groups was considered statistically significant. The NAP-CAPABIL pilot study provided evidence that capecitabine plus nab-paclitaxel may be used as a viable therapy option for ABTC as second-line treatment ( 25 ). In most of the ongoing clinical trials on nab-paclitaxel for the treatment of ABTC, the drug is being tested in combination with gemcitabine, or with gemcitabine and cisplatin, at the same time, these combinations also increase the risk of side effects, including grade 3–4 adverse events. Furthermore, our results consistently showed that factors such as younger age, lower performance status score, and a higher degree of differentiation have a positive impact on patient survival. The subgroup analysis of the PFS data showed that tumours originating in the gallbladder posed a relatively lower risk compared to those originating in the bile ducts. The lower risk observed in patients infected with hepatitis B may be explained by the fact that certain patients with a history of hepatitis B infection are confounded within the subgroup of individuals with unknown infections. Additionally, the univariate analysis may have been influenced by other factors that required exclusion. Consequently, we conducted a multifactorial analysis of the PFS data to mitigate the potential influence of confounding factors. In this analysis, a higher degree of tumour differentiation was associated with a more favourable prognosis. These findings suggest a proactive correlation between the Ki-67 index and the disease progression rate. These findings align with the perspectives observed in our clinical practice and documented in the literature, substantiating the notion that characteristics such as a significant level of cellular differentiation and a low Ki-67 index may play a key role in extending PFS in these patients. Nevertheless, it is important to interpret the outcomes of this research with care because of the restricted sample size. Approximately 20–25% of patients in both groups were alive at the end of the, follow-up period, potentially impacting the calculation of the mOS. Survival was also evaluated in patients who experienced disease progression after initial chemotherapy with NC. Further treatment, regardless of the inclusion of nab-paclitaxel, tended to result in prolonged OS, while two of the four patients in the NC group who underwent retreatment with nab-paclitaxel exhibited an overall survival period exceeding 20 months. Therefore, it can be inferred that chemotherapy treatment based on nab-paclitaxel has the potential to provide enduring advantages for individuals whose tumours exhibit progression after the initial round of treatment. We evaluated the influence of the two chemotherapy protocols on the quality of life by comparing the occurrence of unfavourable events in the two groups. These were predominantly grade 1–2 events. No statistically significant differences were found between the two groups with regard to overall occurrence of AEs and occurrence of grade ≥ 3 AEs. Nevertheless, some variations were observed in the occurrence of specific adverse reactions and haematologic toxicities. Notably, patients administered gemcitabine in combination with cisplatin had a significantly higher likelihood of experiencing a reduction in platelet count than those receiving nab-paclitaxel (50% vs. 32.4%, p = 0.041). This phenomenon can be attributed to the pharmacological characteristics of gemcitabine. It can induce platelet antigen mutations, reduce platelet count, and impede platelet proliferation( 28 ). The NC group exhibited a higher incidence of peripheral neurotoxicity compared to the GC group. These results align with those of previous clinical trials investigating negative impact of these two regimens. In particular, the probability of peripheral neurotoxicity following nab-paclitaxel administration in previous clinical trials ranged from 60% to -70%( 23 ). The disparity in the incidence rates may due to the distinct pharmacological effects and adverse effect profiles associated with each regimen. The present investigation suggests that treatment regimens using nab-paclitaxel often exhibit a safety profile that is deemed acceptable and can be effectively managed when administered to patients with BTC. The AEs recorded in this study were highly consistent with the range of AEs documented in previous clinical studies( 29 – 31 ). In particular, neurotoxicity has been reported as a concern for nab-paclitaxel therapy. However, neuropathy caused by nab-paclitaxel can improve after the cessation of chemotherapy. Our findings are consistent with this, as we observed that a combination of neurotropic medications resulted in the relief of numbness in the hands and feet of most patients several months after stopping the medication. The median time to recovery in our study was determined to be 6.5 months after the cessation of medication. Our assessment of neurotoxicity during the COVID-19 pandemic was limited to a small number of patients. Nevertheless, we found evidence of neuropathy induced by nab-paclitaxel during the initial treatment cycles that did not significantly worsen during the subsequent cycles. Based on the data obtained from this study, in our current clinical practice, we observed that the administration of gemcitabine in patients with reduced platelet count led to delayed recovery of platelets compared with other blood cells. Consequently, this delay in platelet recovery may result in varying degrees of posNConement in subsequent treatment and potentially impact the effectiveness of the treatment. Notably, the majority of adverse events recorded in both groups were classified as grade 1 or 2. However, a minority of patients experienced severe adverse reactions (grade 3 or higher), which were ameliorated by supportive care and dosage modification. No deaths associated with the therapy were observed in either group. The comprehensive safety profile demonstrated satisfactory acceptability and feasibility. This study has some limitations. First, because of the COVID-19 pandemic, the number of patients enrolled was low, and the number of incidents we observed at the end of the study period did not correspond to the anticipated numerical value. This could have potentially affected the robustness and reliability of our results. Furthermore, during the development of the trial protocol, the focus was primarily on designing a chemotherapy regimen. However, owing to the notable efficacy of immunotherapy in the treatment of BTC, the study was terminated early due to the availability and accessibility of the PD-L1 monoclonal antibody (durvalumab). Therefore, we are currently planning a new clinical trial to identify a more appropriate immunotherapeutic modality for ABTC. This fell short of the initially projected number of participants to be recruited for the trial. Additionally, certain patients were unable to fulfil the necessary requirements for medication and efficacy assessments owing to quarantine measures and other related policies. Furthermore, a subset of patients opted to continue treatment at nearby hospitals, thereby disrupting our prospective evaluation of treatment effectiveness and follow-up procedures. Additionally, a minority of patients experienced worsening of their condition owing to contracting COVID-19, resulting in an earlier occurrence of the study endpoint. To enhance the comprehensiveness of the exploratory testing, other detectable indicators such as nutritional indicators and mutation status should have been included as well. An additional constraint of our study was its open-label approach, which carries the possibility of inadvertently introducing unconscious bias in favour of the experimental group. 8 Conclusion Biliary system tumours have an insidious onset, are difficult to detect in the early stages, and have a poor prognosis ( 32 , 33 ). We conducted a clinical trial of nab-paclitaxel plus cisplatin as a first-line treatment for patients with ABTC. The trial demonstrated that PFS was significantly increased in the NC group compared with the GC group when used as first-line therapy for ABTC. Additionally, PFS rates at 6 and 8 months were higher in the NC group compared to the GC group. However, OS and ORR were similar in both groups. The NC regimen had a different spectrum of side effects compared with the GC regimen, but it was generally safe and controllable. Notably, haematological toxicity reactions to AE are more advantageous. We are planning to extend the follow-up period and obtain additional data to provide more evidence for chemotherapy regimens used as first-line treatment options for malignant tumours of the biliary system. Declarations Ethics approval and consent to participate : This study has obtained informed consent from participants. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. This study was registered with the Ethics Committee of Registered Clinical Trials in China and has undergone ethical review under the ethical review symbol: ChiECRCT-20180167. Consent for publication : All authors have intellectually contributed to this manuscript and provided consent for submission and publication. Author contributions : Conceptualization: Zhuang L and Cheng H.H. Resources: Yang X, Dai Y.H, Peng H, Zhang M.S, Fu Q, Liu S. F, Sun L, Zou Y.M, Xu H.S, , Qiu P, Qiu H, Cheng H.H, Huang Q Writing-original draft: Zhuang L and Yang X; Writing – review & editing: Zhuang L Acknowledgements : We would like to thank Editage (www.editage.cn) for English language editing. Funding : Beijing Xisike Clinical Oncology Research Foundation (No. Y-SY201901-0074); the Natural Science Foundation of Hubei Province (2021CFB331); the Fund for Hepatobiliary and Pancreatic Malignant Tumours of the Hubei Chen Xiaoping Science and Technology Development Foundation (CXPJJH12000001-2020344); Competing interests : The authors declare that they have no competing interests. Availability of data and materials : The data that support the findings of this study are available on request from the first author, [Yang X]，upon reasonable request. References Brindley PJ, Bachini M, Ilyas SI, Khan SA, Loukas A, Sirica AE, et al. Cholangiocarcinoma. Nature reviews Disease primers. 2021;7(1):65. Massarweh NN, El-Serag HB. Epidemiology of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Cancer Control. 2017;24(3):1073274817729245. Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study. Br J Cancer. 2009;101(4):621-7. Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer. 2019;19(1):185. Kelley RK, Bridgewater J, Gores GJ, Zhu AX. Systemic therapies for intrahepatic cholangiocarcinoma. J Hepatol. 2020;72(2):353-63. Zaborowski A, Heneghan HM, Fiore B, Stafford A, Gallagher T, Geoghegan J, et al. Neoadjuvant Chemoradiotherapy and Liver Transplantation for Unresectable Hilar Cholangiocarcinoma: The Irish Experience of the Mayo Protocol. Transplantation. 2020;104(10):2097-104. Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and Prognosis for Patients With Intrahepatic Cholangiocarcinoma: Systematic Review and Meta-analysis. JAMA Surg. 2014;149(6):565-74. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvisé M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver international : official journal of the International Association for the Study of the Liver. 2019;39 Suppl 1:98-107. Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7(6):593-600. Oh DY, Lee KH, Lee DW, Yoon J, Kim TY, Bang JH, 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. The lancet Gastroenterology & hepatology. 2022;7(6):522-32. Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardiere C, Boucher E, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncology. 2014;15(8):819-28. Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov. 2012;2(3):260-9. Wang B, Sun T, Zhao Y, Wang S, Zhang J, Wang Z, et al. A randomized phase 3 trial of Gemcitabine or Nab-paclitaxel combined with cisPlatin as first-line treatment in patients with metastatic triple-negative breast cancer. Nat Commun. 2022;13(1):4025. Fan Y, Jiang Y, Zhou X, Chen Q, Huang Z, Xu Y, et al. Phase II study of neoadjuvant therapy with nab-paclitaxel and cisplatin followed by surgery in patients with locally advanced esophageal squamous cell carcinoma. Oncotarget. 2016;7(31):50624-34. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003;21(17):3194-200. de Jong LAW, Lambert M, van Erp NP, de Vries L, Chatelut E, Ottevanger PB. Systemic exposure to cisplatin and paclitaxel after intraperitoneal chemotherapy in ovarian cancer. Cancer Chemother Pharmacol. 2023;91(3):247-56. Choi SH, Kang I, Lee SH, Kang B, Cheon J, Kim DJ, et al. Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma. Surgery. 2023;173(2):280-8. Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, et al. Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial. JAMA Oncol. 2019;5(6):824-30. Li BX, Chen XJ, Ding TJ, Liu YH, Ma TT, Zhang GL, et al. Potentially Overestimated Efficacy of Nanoparticle Albumin-bound Paclitaxel compared with Solvent-based Paclitaxel in Breast Cancer: A Systemic Review and Meta-analysis. J Cancer. 2021;12(17):5164-72. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England journal of medicine. 2013;369(18):1691-703. Peng L, Bu Z, Ye X, Zhou Y, Zhao Q. Incidence and risk of peripheral neuropathy with nab-paclitaxel in patients with cancer: a meta-analysis. European journal of cancer care. 2017;26(5). Yasuda Y, Nomizo T, Ozasa H, Funazo T, Tsuji T, Yoshida H, et al. Retrospective analysis of acute exacerbation of interstitial lung diseases with nanoparticle albumin-bound paclitaxel in patients with advanced lung cancer with preexisting interstitial lung disease. Mol Clin Oncol. 2017;7(4):677-80. Sahai V, Catalano PJ, Zalupski MM, Lubner SJ, Menge MR, Nimeiri HS, et al. Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018;4(12):1707-12. Zhang W, Sun Y, Jiang Z, Qu W, Gong C, Zhou A. Nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) as first-line treatment for advanced biliary tract adenocarcinoma: a phase 2 clinical trial. Hepatobiliary Surg Nutr. 2023;12(1):37-44. Woodford R, Brungs D, Leighton C, Grimison P, Sjoquist KM, Becker T, et al. Combination chemotherapy with NAB(®) -paclitaxel and capecitabine for patients with advanced biliary tract cancer (NAP-CAPABIL Pilot Study). Asia Pac J Clin Oncol. 2022;18(5):e220-e6. Zhang J, Miao L, Guo S, Zhang Y, Zhang L, Satterlee A, et al. Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model. Journal of controlled release : official journal of the Controlled Release Society. 2014;182:90-6. Cadamuro M, Spagnuolo G, Sambado L, Indraccolo S, Nardo G, Rosato A, et al. Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma. Cancer Res. 2016;76(16):4775-84. Kuter DJ. Treatment of chemotherapy-induced thrombocytopenia in patients with non-hematologic malignancies. Haematologica. 2022;107(6):1243-63. Chen Y, Liu R, Li C, Song Y, Liu G, Huang Q, et al. Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator. American journal of cancer research. 2021;11(7):3445-60. Guo J, Zhao J, Gu M, Hou J, Xu T, Jiang Y, et al. Association between Body Composition and Peripheral Neurotoxicity in Cancer Patients from North China Taking Nab-Paclitaxel. Nutr Cancer. 2023;75(3):805-14. Ciruelos E, Apellániz-Ruiz M, Cantos B, Martinez-Jáñez N, Bueno-Muiño C, Echarri MJ, et al. A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer. The oncologist. 2019;24(11):e1024-e33. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. The oncologist. 2016;21(5):594-9. Jung SJ, Woo SM, Park HK, Lee WJ, Han MA, Han SS, et al. Patterns of initial disease recurrence after resection of biliary tract cancer. Oncology. 2012;83(2):83-90. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 16 Aug, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 13 Jan, 2025 Editor assigned by journal 06 Jan, 2025 Submission checks completed at journal 06 Jan, 2025 First submitted to journal 04 Jan, 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-5762910","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":398281580,"identity":"de5d0d93-0880-4d1f-9a75-64a691dbc88f","order_by":0,"name":"xiao Yang","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"xiao","middleName":"","lastName":"Yang","suffix":""},{"id":398281581,"identity":"1d42bf75-91d3-487c-bc74-c8c2915717a6","order_by":1,"name":"Liang Zhuang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYHACNjDJxwwiKyTk+InWwgbWcsbCWLKBaC0ggrGtInEDIS26s48/e8xTc8eujZ352cOv8yQYNzAwP3x0A48Ws3MJ6cY8x54ltzGzmRvLbpNgNmdgMzbOwaflDMMxaR62w8lAv5hJS26TYLNs4GGTxq+FsU2a5x9IC/s3ack5EjwGBwhqYWaT5m07bMfGzGMm+bFBQoIILWxsknP7DicAtZRJMxyTMJBsJugX9mcSb74dtufnP75N8kdNXX0/e/PDx/i0wEBiA5Bg5gExmYlQDgL2IILxB5GqR8EoGAWjYGQBANwlQR4JjoBOAAAAAElFTkSuQmCC","orcid":"","institution":"Tongji Hospital","correspondingAuthor":true,"prefix":"","firstName":"Liang","middleName":"","lastName":"Zhuang","suffix":""},{"id":398281582,"identity":"b0f03557-1779-4ead-a5e7-4fa630a6f1a6","order_by":2,"name":"Heng hui Cheng","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Heng","middleName":"hui","lastName":"Cheng","suffix":""},{"id":398281583,"identity":"92dc9c2b-b03a-44a2-ac64-1e42ce73be28","order_by":3,"name":"Yu Hong 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Qiu","email":"","orcid":"","institution":"Jingzhou Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Qiu","suffix":""},{"id":398281591,"identity":"b0956506-fbaf-435d-b9da-4acfa6b8a39d","order_by":11,"name":"Qiao Huang","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qiao","middleName":"","lastName":"Huang","suffix":""},{"id":398281592,"identity":"2b1819ed-6d03-442a-9f70-ab08f76e4d86","order_by":12,"name":"Hong Qiu","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Qiu","suffix":""}],"badges":[],"createdAt":"2025-01-04 10:23:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5762910/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5762910/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-025-14581-3","type":"published","date":"2025-08-16T15:57:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73317132,"identity":"3dce0ebf-ef26-4c34-94f7-1db269a67540","added_by":"auto","created_at":"2025-01-08 20:08:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":103037,"visible":true,"origin":"","legend":"\u003cp\u003eStudy Population\u003c/p\u003e\n\u003cp\u003eGC, Gemcitabine plus Cisplatin; NC, Nab-paclitaxel plus Cisplatin; ECOG PS, Eastern Cooperative Oncology Group of the United States Performance Status\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/1a3b8f140c12c0f7c737eacb.png"},{"id":73317138,"identity":"a770ac90-2f20-45b7-adb1-4d29b30ef908","added_by":"auto","created_at":"2025-01-08 20:08:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":125761,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival endpoints in the full analysis set population:(A) PFS (primary endpoint) and (B) OS\u003c/p\u003e\n\u003cp\u003e(secondary endpoint). GC, gemcitabine combined with cisplatin; NC, albumin paclitaxel combined with cisplatin; mOS, median survival; mPFS, median progression-free survival; CI, confidence interval; HR, hazard ratio\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/1017f26aad823510c4bb17c0.png"},{"id":73317131,"identity":"076a1152-e74c-48c8-95f9-69eaf5b0987c","added_by":"auto","created_at":"2025-01-08 20:08:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":153177,"visible":true,"origin":"","legend":"\u003cp\u003ePFS/OS rate over time for both groups (A) PFS (primary endpoint) and (B) OS\u003c/p\u003e\n\u003cp\u003e* represents a statistical difference\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/8bef4a92550c50f28b1494b7.png"},{"id":73317169,"identity":"bc7bd979-9538-4e50-9992-baae4557037e","added_by":"auto","created_at":"2025-01-08 20:08:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3574409,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses of PFS based on baseline characteristics.\u003c/p\u003e\n\u003cp\u003eGC, gemcitabine combined with cisplatin ; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; NC, albumin paclitaxel combined.* represents a statistical difference\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/15fa4679603c888b5806e361.png"},{"id":73317139,"identity":"f7ddb559-29b3-449d-9521-15bcd9b9ed76","added_by":"auto","created_at":"2025-01-08 20:08:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2992749,"visible":true,"origin":"","legend":"\u003cp\u003eMultifactorial analysis of PFS based on baseline characteristics.\u003c/p\u003e\n\u003cp\u003eGC, gemcitabine combined with cisplatin; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; NC, albumin paclitaxel combined. * represents a statistical difference\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/bf2707fa64c03eab577dbf6a.png"},{"id":73317135,"identity":"45fc69ac-49b8-4cda-9702-12ad5f499d7e","added_by":"auto","created_at":"2025-01-08 20:08:33","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":3507808,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses of OS based on baseline characteristics.\u003c/p\u003e\n\u003cp\u003eGC, gemcitabine combined with cisplatin; CI, confidence interval; HR, hazard ratio;\u003c/p\u003e\n\u003cp\u003eOS, overall survival; NC, albumin paclitaxel combined.* represents a statistical difference\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/2bd79df78ae51a276a4506ce.png"},{"id":73317136,"identity":"9c9956fd-bdc1-48b1-94e9-002fa05a9763","added_by":"auto","created_at":"2025-01-08 20:08:34","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":3165913,"visible":true,"origin":"","legend":"\u003cp\u003eMultifactorial analysis of OS based on baseline characteristics.\u003c/p\u003e\n\u003cp\u003eGC, gemcitabine combined with cisplatin; CI, confidence interval; HR, hazard ratio;\u003c/p\u003e\n\u003cp\u003eOS, overall survival; NC, albumin paclitaxel combined. * represents a statistical difference\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/2d1ac52bb0aeca69d8ba5563.png"},{"id":89310642,"identity":"375a8244-7ffa-46a1-a357-a72a1a8a7fc7","added_by":"auto","created_at":"2025-08-18 16:09:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1410055,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5762910/v1/7ca31d6c-2d28-44c9-a7b8-f54e5fca0b7c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Nab-paclitaxel plus cisplatin versus gemcitabine plus cisplatin as first-line treatment in advanced biliary tract cancer: results of a multicentre, randomised, phase II trial","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eMalignant biliary tract cancer (BTC) or cholangiocarcinoma, primarily an adenocarcinoma with relatively high mortality compared to other malignancies, originates from gallbladder cells or epithelial cells from the bile duct(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Although the exact aetiology of cholangiocarcinoma is unknown, most researchers believe that gallstones, infections, hepatic fibrosis, and congenital abnormalities in bile duct formation may be involved in its development (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Currently, surgery is the only possible cure (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, less than one-third of patients undergo surgery, and they have a poor prognosis due to the high rate of disease progression, sepsis caused by localised tumours, bile duct obstruction, cholangitis or abscesses, and early-stage detection challenges (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e),Approximately half of untreated individuals pass away from the disease within three to four months after diagnosis (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The current first-line standard treatment for advanced biliary malignancies is gemcitabine plus cisplatin with immunotherapy (with or without durvalumab/pembrolizumab). This regimen increases the patients' chances of survival and quality of life compared to supportive care alone(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsidering the mechanism underlying the anti-tumour activity of paclitaxel, albumin-bound paclitaxel has gained wide recognition as a novel class of anti-microtubule drug (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). This drug exerts inhibitory effects on the proliferation and division of malignancies by interfering with the polymerisation and depolymerisation of microtubules within the cellular environment. Consequently, the synthesis of spindle bodies and filaments is impeded, thereby hindering the proliferation of tumour cells and ultimately leading to apoptosis. Notably, unlike conventional paclitaxel, albumin-bound paclitaxel possesses an additional tumour-targeting attribute. This characteristic not only enhances treatment efficacy but also diminishes adverse effects, such as neurotoxicity and haematological toxicity(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Several clinical trials have demonstrated nab-paclitaxel (use albumin to carry paclitaxel) superior efficacy in the management of oesophageal, ovarian, and bladder cancers (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) (\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Additionally, it offers the advantage of enhancing overall or progression-free survival compared with conventional paclitaxel formulations (e.g., castor-oil-coated paclitaxel), with fewer adverse effects and higher patient acceptance (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In a previous study aiming to evaluate nab-paclitaxel as a potential first-line therapy for BTC, patients were categorised into two groups: a test group that received paclitaxel treatment with albumin and a control group (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Although the primary endpoint was not achieved, the results suggested that combination chemotherapy with nab-paclitaxel is well tolerated and may be an alternative to existing treatments for advanced cholangiocarcinoma.\u003c/p\u003e \u003cp\u003eA clinical trial carried out evaluate the efficacy of combining S-1 with nab-paclitaxel as first-line treatment for (Advanced Bile tract cancer, ABTC) compared with a gemcitabine-cisplatin combination showed that the combination therapy had good anti-tumour activity and was safe (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The feasibility of utilising capecitabine in combination with nab-paclitaxel as a viable option for second-line treatment in ABTC was also confirmed by another study (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Most ongoing studies investigating the efficacy of nab-paclitaxel in ABTC treatment have incorporated gemcitabine. Some researchers have explored a triple combination therapy consisting of nab-paclitaxel, gemcitabine, and cisplatin as initial treatment for advanced BTC, with positive outcomes(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). However, this triple combination therapy also carries an elevated risk of adverse effects, leading to a higher incidence of grade 3\u0026ndash;4 side effects rarely reported in the existing literature on this topic (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). We designed this study to compare the effectiveness and safety of a combination of gemcitabine plus cisplatin (GC) or nab-paclitaxel plus cisplatin (NC) as first-line therapies for ABTC, and to provide alternatives for first-line chemotherapy regimens in BTC.\u003c/p\u003e"},{"header":"2 Patients and methods","content":"\u003cp\u003eThe present study constituted a multicentre, open-label, randomised, phase II trial aimed at evaluating and comparing the effectiveness and safety of the GC and NC regimens as initial therapies for individuals diagnosed with ABTC. Patients were recruited from four cancer centres in China. In accordance with the Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1), individuals between the ages of 18 and 70 years who had received histological or cytological confirmation of unresectable, recurrent or metastatic advanced biliary malignancies (intra/extrahepatic cholangiocarcinoma, gallbladder cancer) and had at least one measurable lesion were considered suitable for inclusion in the study. The inclusion criteria for patients encompassed having an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, a minimum life expectancy of at least 3 months, and normal haematologic and organ function. Participants were also required to have pre-admission serum bilirubin levels below the upper limit of the normal value multiplied by three, transaminase levels not higher than five times the upper limit of normality, serum creatinine levels not higher than 1.5 times the upper limit of normal values or creatinine clearance\u0026thinsp;\u0026ge;\u0026thinsp;45 mL/min, an absolute neutrophil count (ANC)\u0026thinsp;\u0026ge;\u0026thinsp;1.5 \u0026times;10^9/L, platelet concentration\u0026thinsp;\u0026ge;\u0026thinsp;75\u0026times;10^9/L, haemoglobin concentration\u0026thinsp;\u0026ge;\u0026thinsp;90 g/L, white blood cells (WBC)\u0026thinsp;\u0026ge;\u0026thinsp;3.0\u0026times; 10^9/L, and no indication of propensity for bleeding. The exclusion criteria included patients who exhibited treatment-related toxicity, This toxicity had to be successfully rectified and resolved. Participants were deemed ineligible for inclusion in the investigation if they met any of the following criteria: presence of unmanageable infection or recent administration of systemic antibiotic therapy within 72 hours prior to chemotherapy, presence of haematological disorders, previous diagnosis of untreated malignancies other than those under investigation or brain metastases, documented allergy to the chemotherapeutic agents being evaluated, presence of psychiatric or neurological disorders that hindered their ability to cooperate, being pregnant or breastfeeding, and presence of other medical conditions that rendered them ineligible for participation, including active tuberculosis, active pneumonia, unresolvable electrolyte imbalances, unmanageable tumour-induced pain, or uncontrollable pleural effusion or peritoneal effusion. Patients being treated with alternative antineoplastic agents, those that had received previous treatment with experimental drugs, those who had engaged in interventional clinical trials within a month prior to the screening phase, and those deemed unsuitable for enrolment by the investigators for any other reason were also excluded from the study.\u003c/p\u003e"},{"header":"3 Procedures","content":"\u003cp\u003eBasis of Grouping: Using a series of computerized randomization methods, patients who met the requirements were randomized (1:1) to either the GC or NC group. Neither investigators nor patients were blinded to group allocation. A total of 75 individuals were enrolled(Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Those allocated to the NC group received (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Intravenous (IV) infusion of nab-paclitaxel (125 mg/m2) on days 1 and 8, and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) IV infusion of cisplatin (25 mg/m2) on days 1 to 3. The treatment cycle was repeated every 3 weeks (Q21d), for a total of six cycles. Those allocated to the GC group received (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) IV infusion of gemcitabine (1000 mg/m2) on days 1 and 8, and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) IV infusion of cisplatin (25 mg/m2) on days 1 to 3, with the same cycle length and number of cycles.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFirst-line treatment was administered until disease progression or intolerable adverse effects up to six cycles of treatment in total. Thereafter, six cycles of oral maintenance therapy with S-1 were administered. Toxicity/adverse reactions were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03, and patients were managed by discontinuation or reduction of medication. Treatment cycles were delayed until non-haematologic (\u0026ge;\u0026thinsp;Grade 1) and haematologic toxicity subsided. Drug reductions were permitted in the presence of one of the following conditions: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.5 \u0026times; 109/L; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Fever with neutropenia; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) ANC within the 0.5-1.0 \u0026times; 109/ L range with PLT within the 25\u0026ndash;50 \u0026times; 109 /L range; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) PLT\u0026thinsp;\u0026lt;\u0026thinsp;25 \u0026times; 109/L with bleeding tendency or need for blood transfusion; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Anaemia grade 3 or higher; or (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Neuropathy grade 2 or higher. A maximum of two dose reductions (25% of the initial dose) was allowed if the dose reduction criteria were met. Patients were withdrawn from the clinical study if drug administration needed to be interrupted for more than 3 weeks or reduced for more than 2 weeks during the course of the trial. No dose re-escalation was permitted between the cycles. To prevent serious side effects, colony-stimulating factor (CSF) and erythropoietin (EPO) was used for prophylaxis throughout the treatment phase.\u003c/p\u003e"},{"header":"4 Assessment","content":"\u003cp\u003eBefore each treatment cycle, a comprehensive physical examination was conducted along with routine laboratory tests, including routine and blood biochemistry, coagulation, and liver and renal function. Imaging by CT or MRI was carried out every two cycles from the initiation of treatment until disease progression. Further, survival follow-up was performed after disease progression, and alterations in the tumour were evaluated according to the assessment criteria outlined in RECIST version 1.1\u003c/p\u003e"},{"header":"5 Endpoints","content":"\u003cp\u003eThe main endpoint of the study was progression-free survival (PFS), defined as the time between allocation to the experimental group and the onset of disease progression or death from any cause. The secondary endpoints were overall survival (OS), defined as the time between allocation to the experimental group and death from any cause, objective response rate (ORR), defined as the sum of complete and partial remissions (CR\u0026thinsp;+\u0026thinsp;PR), and chemotherapy-related AEs. We used SPSS Statistics (version 26.0, IBM Corp., Armonk, N.Y., USA) for data analysis and GraphPad Prism (version 8.0, San Diego, CA, USA) for data visualisation, with statistical descriptions and analysis methods for the different indicators. The baseline indicators (e.g. medical history) and demographic characteristics were summarised, and the metrics were described by the number of patients, median, and other statistical analyses, such as the number of cases and minimum and maximum values. Numerical variables are described as numbers and percentages. The full analysis set (FAS) included all randomised participants. Efficacy and safety were assessed for patients who had received at least one administration of the drug and had had one follow-up visit. The null hypothesis was rejected, and the difference was statistically significant at the test level α\u0026thinsp;=\u0026thinsp;0.05 level when the p-value was \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"6 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e6.1Patient characteristics\u003c/h2\u003e \u003cp\u003eThis study recruited a cohort of 75 participants (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median age at diagnosis was 55 years, ranging from 27 to 67 years, with a balanced sex distribution (41 men, 54.6%; 34 women, 45.4%). Following randomisation, 38 patients received the GC regimen and 37 patients received the NC regimen. Statistical comparison of the demographic parameters between the two groups, including sex, age, tumour location, and metastasis, showed no significant differences.\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\u003eBaseline levels and clinical characteristics of enrolled patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGC group (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNC group (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \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\u003e19 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(59.4%)\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\u003e19(50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(40.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \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\u003e58[40\u0026ndash;70]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55[27\u0026ndash;67]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(13.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(32.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50ཞ60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(44.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(40.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(42.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(27.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eECOG score, PS\u003c/p\u003e \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\u003e29(76.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26(70.3%)\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\u003e9(23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11(29.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTumour primary site\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBile duct origin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(65.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24(64.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGallbladder origin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(26.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(27.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown origin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(8.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDegree of pathologic differentiation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHighly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(16.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerately\u003c/p\u003e \u003cp\u003edifferentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(42.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(37.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoorly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(36.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(37.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(8.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eSite of distant metastasis at enrolment\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\u003e35(92.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33(89.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLungs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(13.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(10.8%)\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\u003e19(50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(40.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePelvis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(21.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph nodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(60.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32(86.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eNumber of distantly metastasized organs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0ཞ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(55.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21(56.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(44.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16(43.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eHistory of hepatitis B\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(44.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(32.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo or not available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(55.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25(67.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eKi-67 index\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(40.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;50%, \u0026lt;80%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(36.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(40.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;80%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(39.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(19.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNote: Data are presented as median (IQR) or n (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eGC, gemcitabine combined with cisplatin; NC, albumin paclitaxel combined with cisplatin; ECOG PS, Eastern Cooperative Oncology Group of the United States Performance Status; Ki-67, tumour proliferation index.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e6.2 Efficacy\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e details the efficacy outcomes. One patient (2.7%) in the NC group attained complete response (CR), while none in the GC group did (0.0%). Partial response (PR) was achieved in 13 patients in each group, representing 34.2% and 35.1% of the patients included in the NC and GC groups, respectively. The majority of patients in both groups maintained a stable disease status. Eight (21.2%) and seven (18.9%) patients in the NC and GC group, respectively, showed disease progression (PD) after treatment. In terms of effectiveness, no significant differences were found between the two groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\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\u003eEfficacy assessment variable values in both groups (according to RECIST 1.1 criteria)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\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\u003eGC group (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNC group (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(34.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13(35.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(44.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16(43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7(18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(34.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14(37.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30(78.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30(81.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eGC, gemcitabine combined with cisplatin; NC, albumin paclitaxel combined with cisplatin; CR, complete response; PR, partial response; SD, Stable Disease; PD, disease progression; ORR, objective response rate; DCR, Disease control rate\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding PFS, the median PFS (mPFS) in the GC group was 7.0 m (95% confidence interval [CI]: 3.9\u0026ndash;10.1 m), and that in the NC group was 7.8 m (95% CI: 5.4\u0026ndash;14.0 m). The difference between the two groups was statistically significant (p\u0026thinsp;=\u0026thinsp;0.0034, hazard ratio [HR]: 0.5136, 95% CI: 0.3136\u0026ndash;0.8411; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median OS (mOS) in the GC group was 12.1 m (95% CI: 6.7\u0026ndash;20.7 m) and 12.4 m (95% CI: 7.3\u0026ndash;22.3 m) in the NC group, with no significant differences between the groups (p:0.4592, HR: 0.811, 95% CI: 0.463\u0026ndash;1.442; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe NC group exhibited a significantly higher PFS rate at 6 months (70.83%) compared to the GC group (48.24%, Z\u0026thinsp;=\u0026thinsp;1.989, p\u0026thinsp;=\u0026thinsp;0.047). The PFS rates at 8 months were 31.97% and 8.51% in the NC and GC groups, respectively (Z\u0026thinsp;=\u0026thinsp;2.509, p\u0026thinsp;=\u0026thinsp;0.012; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Patients in the NC group also showed favourable trends in OS rates at 6, 12 and 18 months, GC vs NC(94.7% vs. 96.3%), (48.3% vs. 58.5%), and (5.3% vs. 2.7%), respectively, with p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 in all cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e6.3 Safety\u003c/h2\u003e \u003cp\u003eThe major treatment-induced adverse events are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Twenty-nine of the 38 patients in the NC group (76.3%) and 27 of the 37 patients in the GC group (72.9%) experienced treatment-induced AEs of any grade. The discrepancies observed in the incidence of side effects between the two drug regimens, or in the rate of occurrence of adverse events of grade 3 or higher (31.5% vs. 27.5%) were not statistically significant. Most haematological adverse events were resolved after symptom treatment, with two (5.2%) and one (2.7%) patients in either group, respectively, experiencing granulocytopenia with fever that was resolved, after treatment with non-steroidal anti-inflammatory drugs (after exclusion of contraindications), anti-infectives, and leukocyte boosters. Patients who were administered gemcitabine in combination with cisplatin had a significantly higher risk of experiencing platelet count reduction compared with those that received nab-paclitaxel instead (50.0% vs. 32.4%, p\u0026thinsp;=\u0026thinsp;0.041). The most common non-haematological AEs were weariness and malaise, which improved with rest. Numbness and pain in the hands and feet were the most common neurological adverse events, occurring in 14 (36.8%) and 23 (62.1%) of patients in the GC and NC group, respectively (p\u0026thinsp;=\u0026thinsp;0.028). Neurological symptoms improved after treatment with drugs such as vitamin analogues and calcium channel blockers.\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\u003eTreatment-related side effects discriminated by group\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\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eGC group (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eNC group (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eP*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e⩾3 Grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAny\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e⩾3 Grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAny\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e⩾3 Grade\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eHaematological\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e16(42.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e17(45.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRed blood cell decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e17(44.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e15(40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.713\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e22(57.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e20(54.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.371\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e26(68.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e22(59.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2(5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.414\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e19(50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e10(27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-haematological\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\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\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e26(68.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(21.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e25(67.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8(21.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.937\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.952\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e12(31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(13.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e13(35.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4(10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.744\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e26(68.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(21.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e20(54.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7(18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.768\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstipation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3(7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2(5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.666\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3(7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e5(13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.431\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensory neuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e14(36.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e23(62.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e13(34.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e9(24.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.347\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5(13.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e5(13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.964\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e9(23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e3(8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e29(76.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e27(72.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.739\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e⩾3 Grade AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12(31.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10(27.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.665\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eNote: Data are n (%). *Bold font indicates P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, statistically significant.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eGC, gemcitabine combined with cisplatin; NC, albumin paclitaxel combined with cisplatin;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAEs, adverse events\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e6.4 Subgroup analysis and multivariate analysis\u003c/h2\u003e \u003cp\u003eThe subgroup analysis of PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) showed that patients with the gallbladder as primary site (p\u0026thinsp;=\u0026thinsp;0.125, HR:0.622, 95%CI: 0.075\u0026ndash;0.804), those aged under 50 years of age (p\u0026thinsp;=\u0026thinsp;0.012, HR: 0.122 95%CI: 0.023\u0026ndash;0.636), and those previously infected with hepatitis B (p\u0026thinsp;=\u0026thinsp;0.002, HR:0.201, 95%CI: 0.074\u0026ndash;0.542) had a lower risk of disease progression). The difference was not statistically significant for other subgroups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Multifactorial analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) demonstrated that the probability of disease progression in patients with poorly differentiated tumours was 4.09 times higher than that in the group with well-differentiated tumours (p\u0026thinsp;=\u0026thinsp;0.014, 95%CI: 1.334\u0026ndash;12.560), and the probability of disease progression for those with moderately differentiated tumours was 2.53 times higher than that in the group with well-differentiated tumours. Patients with a Ki-67 index between 50% and 80% and those with a Ki-67 index\u0026thinsp;\u0026ge;\u0026thinsp;80% were 2.769 times (p\u0026thinsp;=\u0026thinsp;0.011, 95%CI: 1.188\u0026ndash;6.457) and 26.7 times (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, 95% CI:7.482\u0026ndash;95.871) more likely to exhibit disease progression compared to those with a Ki-67 index\u0026thinsp;\u0026lt;\u0026thinsp;50%.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the subgroup analysis of OS (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e), patients with an ECOG score of 1 showed a significantly higher OS (p\u0026thinsp;=\u0026thinsp;0.0006, HR:0.181, 95%CI: 0.053\u0026ndash;0.619), and those with a high Ki-67 index (\u0026ge;\u0026thinsp;80%) had a higher chance of death (p\u0026thinsp;=\u0026thinsp;0.049, HR:3.445, 95%CI: 1.055\u0026ndash;12.430). No significant differences were identified for any other subgroup. Multivariate analysis showed that, compared with the patient subpopulation under 50 years of age, patients that were between 51 and 60 years old had a risk of death that was more than nine times higher (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Relative to the patient population with high differentiation, the probability of death in the patients with medium differentiation was also significantly higher (approximately 4.3 times that of the high differentiation group). Furthermore, the forest chart demonstrates that older participants (50\u0026ndash;60 years old, \u0026gt;\u0026thinsp;60 years old), those with an ECOG score of 1 point (compared with ECOG score of 0 points), and those with moderate differentiation (compared with those with poorly differentiation) were at increased risk of death caused by the disease. No obvious effect on OS was observed for any other subgroup (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"7 Discussion","content":"\u003cp\u003eThis study aimed to evaluate the effectiveness and safety of two treatment regimens (GC and NC) as first-line therapy for patients with ABTC. During follow-up, we observed a significant difference between the groups regarding mPFS, with NC being superior to GC, although there were no significant differences for mOS. The differences in the ORR and the OS rates at 6, 12, and 18 months between the two groups were not statistically different either. However, the experimental data suggests that the PFS rates at 6 and 8 months were higher in the NC group. The research findings indicate that the combined treatment with nab-paclitaxel plus cisplatin offers an advantage for the treatment of advanced cholangiocarcinoma, resulting in increased PFS in these patients.\u003c/p\u003e \u003cp\u003eIn 2016, Cadamuro et al. demonstrated in CCA cell lines and in a severe combined immunodeficiency mouse xenograft model that small doses of paclitaxel (1.5 nM and 15 nM) decreased nuclear existence of the calcium-binding protein known as S100A4, a biomarker for CCA invasiveness, without altering its cytoplasmic levels, thereby inhibiting CCA invasion and metastatic spread(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). A clinical study from 2019 reported an increase in mPFS in response to nab-paclitaxel treatment, An exploration of nab-paclitaxel combination with S-1 as an experimental regimen, compared with a conventional combination of gemcitabine with cisplatin as a first-line chemotherapy regimen for patients with ABTC, has also been conducted(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The difference in mOS between the experimental groups was considered statistically significant. The NAP-CAPABIL pilot study provided evidence that capecitabine plus nab-paclitaxel may be used as a viable therapy option for ABTC as second-line treatment (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In most of the ongoing clinical trials on nab-paclitaxel for the treatment of ABTC, the drug is being tested in combination with gemcitabine, or with gemcitabine and cisplatin, at the same time, these combinations also increase the risk of side effects, including grade 3\u0026ndash;4 adverse events. Furthermore, our results consistently showed that factors such as younger age, lower performance status score, and a higher degree of differentiation have a positive impact on patient survival.\u003c/p\u003e \u003cp\u003eThe subgroup analysis of the PFS data showed that tumours originating in the gallbladder posed a relatively lower risk compared to those originating in the bile ducts. The lower risk observed in patients infected with hepatitis B may be explained by the fact that certain patients with a history of hepatitis B infection are confounded within the subgroup of individuals with unknown infections. Additionally, the univariate analysis may have been influenced by other factors that required exclusion. Consequently, we conducted a multifactorial analysis of the PFS data to mitigate the potential influence of confounding factors. In this analysis, a higher degree of tumour differentiation was associated with a more favourable prognosis. These findings suggest a proactive correlation between the Ki-67 index and the disease progression rate. These findings align with the perspectives observed in our clinical practice and documented in the literature, substantiating the notion that characteristics such as a significant level of cellular differentiation and a low Ki-67 index may play a key role in extending PFS in these patients. Nevertheless, it is important to interpret the outcomes of this research with care because of the restricted sample size. Approximately 20\u0026ndash;25% of patients in both groups were alive at the end of the, follow-up period, potentially impacting the calculation of the mOS. Survival was also evaluated in patients who experienced disease progression after initial chemotherapy with NC. Further treatment, regardless of the inclusion of nab-paclitaxel, tended to result in prolonged OS, while two of the four patients in the NC group who underwent retreatment with nab-paclitaxel exhibited an overall survival period exceeding 20 months. Therefore, it can be inferred that chemotherapy treatment based on nab-paclitaxel has the potential to provide enduring advantages for individuals whose tumours exhibit progression after the initial round of treatment. We evaluated the influence of the two chemotherapy protocols on the quality of life by comparing the occurrence of unfavourable events in the two groups. These were predominantly grade 1\u0026ndash;2 events. No statistically significant differences were found between the two groups with regard to overall occurrence of AEs and occurrence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs. Nevertheless, some variations were observed in the occurrence of specific adverse reactions and haematologic toxicities. Notably, patients administered gemcitabine in combination with cisplatin had a significantly higher likelihood of experiencing a reduction in platelet count than those receiving nab-paclitaxel (50% vs. 32.4%, p\u0026thinsp;=\u0026thinsp;0.041). This phenomenon can be attributed to the pharmacological characteristics of gemcitabine. It can induce platelet antigen mutations, reduce platelet count, and impede platelet proliferation(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The NC group exhibited a higher incidence of peripheral neurotoxicity compared to the GC group. These results align with those of previous clinical trials investigating negative impact of these two regimens. In particular, the probability of peripheral neurotoxicity following nab-paclitaxel administration in previous clinical trials ranged from 60% to -70%(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The disparity in the incidence rates may due to the distinct pharmacological effects and adverse effect profiles associated with each regimen. The present investigation suggests that treatment regimens using nab-paclitaxel often exhibit a safety profile that is deemed acceptable and can be effectively managed when administered to patients with BTC. The AEs recorded in this study were highly consistent with the range of AEs documented in previous clinical studies(\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). In particular, neurotoxicity has been reported as a concern for nab-paclitaxel therapy. However, neuropathy caused by nab-paclitaxel can improve after the cessation of chemotherapy. Our findings are consistent with this, as we observed that a combination of neurotropic medications resulted in the relief of numbness in the hands and feet of most patients several months after stopping the medication. The median time to recovery in our study was determined to be 6.5 months after the cessation of medication. Our assessment of neurotoxicity during the COVID-19 pandemic was limited to a small number of patients. Nevertheless, we found evidence of neuropathy induced by nab-paclitaxel during the initial treatment cycles that did not significantly worsen during the subsequent cycles. Based on the data obtained from this study, in our current clinical practice, we observed that the administration of gemcitabine in patients with reduced platelet count led to delayed recovery of platelets compared with other blood cells. Consequently, this delay in platelet recovery may result in varying degrees of posNConement in subsequent treatment and potentially impact the effectiveness of the treatment. Notably, the majority of adverse events recorded in both groups were classified as grade 1 or 2. However, a minority of patients experienced severe adverse reactions (grade 3 or higher), which were ameliorated by supportive care and dosage modification. No deaths associated with the therapy were observed in either group. The comprehensive safety profile demonstrated satisfactory acceptability and feasibility.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, because of the COVID-19 pandemic, the number of patients enrolled was low, and the number of incidents we observed at the end of the study period did not correspond to the anticipated numerical value. This could have potentially affected the robustness and reliability of our results. Furthermore, during the development of the trial protocol, the focus was primarily on designing a chemotherapy regimen. However, owing to the notable efficacy of immunotherapy in the treatment of BTC, the study was terminated early due to the availability and accessibility of the PD-L1 monoclonal antibody (durvalumab). Therefore, we are currently planning a new clinical trial to identify a more appropriate immunotherapeutic modality for ABTC. This fell short of the initially projected number of participants to be recruited for the trial. Additionally, certain patients were unable to fulfil the necessary requirements for medication and efficacy assessments owing to quarantine measures and other related policies. Furthermore, a subset of patients opted to continue treatment at nearby hospitals, thereby disrupting our prospective evaluation of treatment effectiveness and follow-up procedures. Additionally, a minority of patients experienced worsening of their condition owing to contracting COVID-19, resulting in an earlier occurrence of the study endpoint. To enhance the comprehensiveness of the exploratory testing, other detectable indicators such as nutritional indicators and mutation status should have been included as well. An additional constraint of our study was its open-label approach, which carries the possibility of inadvertently introducing unconscious bias in favour of the experimental group.\u003c/p\u003e"},{"header":"8 Conclusion","content":"\u003cp\u003eBiliary system tumours have an insidious onset, are difficult to detect in the early stages, and have a poor prognosis (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). We conducted a clinical trial of nab-paclitaxel plus cisplatin as a first-line treatment for patients with ABTC. The trial demonstrated that PFS was significantly increased in the NC group compared with the GC group when used as first-line therapy for ABTC. Additionally, PFS rates at 6 and 8 months were higher in the NC group compared to the GC group. However, OS and ORR were similar in both groups. The NC regimen had a different spectrum of side effects compared with the GC regimen, but it was generally safe and controllable. Notably, haematological toxicity reactions to AE are more advantageous. We are planning to extend the follow-up period and obtain additional data to provide more evidence for chemotherapy regimens used as first-line treatment options for malignant tumours of the biliary system.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: This study has obtained informed consent from participants. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. This study was registered with the Ethics Committee of Registered Clinical Trials in China and has undergone ethical review under the ethical review symbol: ChiECRCT-20180167.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: All authors have intellectually contributed to this manuscript and provided consent for submission and publication. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e: \u003c/p\u003e\n\u003cp\u003eConceptualization: Zhuang L and Cheng H.H.\u003c/p\u003e\n\u003cp\u003eResources: Yang X, Dai Y.H, Peng H, Zhang M.S, Fu Q, Liu S. F, Sun L, Zou Y.M, Xu H.S, , Qiu P, Qiu H, Cheng H.H, Huang Q\u003c/p\u003e\n\u003cp\u003eWriting-original draft: Zhuang L and Yang X; \u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; review \u0026amp; editing: Zhuang L \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We would like to thank Editage (www.editage.cn) for English language editing.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: Beijing\u0026ensp;Xisike\u0026ensp;Clinical\u0026ensp;Oncology\u0026ensp;Research\u0026ensp;Foundation\u0026ensp;(No.\u0026ensp;Y-SY201901-0074);\u0026ensp;\u003c/p\u003e\n\u003cp\u003ethe Natural Science Foundation of Hubei Province (2021CFB331); \u003c/p\u003e\n\u003cp\u003ethe Fund for Hepatobiliary and Pancreatic Malignant Tumours of the Hubei Chen Xiaoping Science and Technology Development Foundation (CXPJJH12000001-2020344);\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e:\u0026ensp;The\u0026ensp;authors\u0026ensp;declare\u0026ensp;that\u0026ensp;they\u0026ensp;have\u0026ensp;no\u0026ensp;competing\u0026ensp;interests.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The data that support the findings of this study are available on request from the first author, [Yang X]，upon reasonable request.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBrindley PJ, Bachini M, Ilyas SI, Khan SA, Loukas A, Sirica AE, et al. 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Association between Body Composition and Peripheral Neurotoxicity in Cancer Patients from North China Taking Nab-Paclitaxel. Nutr Cancer. 2023;75(3):805-14.\u003c/li\u003e\n\u003cli\u003eCiruelos E, Apell\u0026aacute;niz-Ruiz M, Cantos B, Martinez-J\u0026aacute;\u0026ntilde;ez N, Bueno-Mui\u0026ntilde;o C, Echarri MJ, et al. A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer. The oncologist. 2019;24(11):e1024-e33.\u003c/li\u003e\n\u003cli\u003eSaha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. The oncologist. 2016;21(5):594-9.\u003c/li\u003e\n\u003cli\u003eJung SJ, Woo SM, Park HK, Lee WJ, Han MA, Han SS, et al. Patterns of initial disease recurrence after resection of biliary tract cancer. Oncology. 2012;83(2):83-90.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"biliary tract carcinomas, advanced stage, chemotherapy, albumin-paclitaxel, first-line treatment, cisplatin","lastPublishedDoi":"10.21203/rs.3.rs-5762910/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5762910/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: the efficacy and safety of conventional first-line chemotherapeutic regimens for the treatment of advanced biliary tract carcinomas (ABTCs) have been unsatisfactory.\u003c/p\u003e\n\u003cp\u003eObjectives: We aimed to explore alternative chemotherapeutic regimens capable of providing a better efficacy and fewer side effects.\u003c/p\u003e\n\u003cp\u003eDesign: Multicentre, randomised, phase II clinical trial\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Eligible patients with unresectable, recurrent, or metastatic biliary system tumours diagnosed by pathology or cytology between January 2021 and November 2022 were included. The participants were randomised to either a gemcitabine-cisplatin group (GC) or an albumin-paclitaxel-cisplatin group (NC). Progression-free survival (PFS) was the primary outcome, whereas overall survival (OS), and objective response rate (ORR) were the secondary outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The trial enrolled 75 patients and had a median follow-up period of 11 months. The median PFS (mPFS) was 7.8 m (95% confidence interval [CI]: 5.4–14.0 m) in the NC group, and 7.0 m (95%CI: 3.9–10.1 m) in the GC group (p=0.0034, hazard ratio [HR]=0.5136, 95%CI: 0.3136–0.8411). Median OS for the NC group was 12.4 m (95%CI: 7.3–22.3 m) and for the GC group was 12.1 m (95%CI: 6.7–20.7 m), with no significant differences (p=0.4592, HR=0.811, 95%CI: 0.463–1.442). PFS rates at 6 and 8 months were 48.24% vs. 70.8% and 8.51% vs. 32.0% for the NC and the GC group, respectively (p \u0026lt; 0.05). Regarding safety, although patients from both groups experienced thrombocytopenia, those in the NC group demonstrated significantly lower rates (p \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003eConclusion: Compared with the GC group, the NC group showed a significantly increased mPFS, in addition to higher PFS rates at 6 and 8 months. Furthermore, the NC group showed lower haematological toxicity. This suggests that paclitaxel-based regimens may be a viable alternative for first-line treatment of ABTCs.\u003c/p\u003e\n\u003cp\u003eRegistration: Clinical Trials.gov identifiers: NCT04692051. Registered October 31, 2018\u003c/p\u003e\n\u003cp\u003e(Web Links -https://www.chictr.org.cn/showproj.html?proj=38440)\u003c/p\u003e","manuscriptTitle":"Nab-paclitaxel plus cisplatin versus gemcitabine plus cisplatin as first-line treatment in advanced biliary tract cancer: results of a multicentre, randomised, phase II trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-08 20:08:28","doi":"10.21203/rs.3.rs-5762910/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-13T07:32:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-06T12:22:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-06T12:22:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-01-04T10:08:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1a1dfb02-cae6-46d3-bc50-c2f185e062e7","owner":[],"postedDate":"January 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-18T16:05:03+00:00","versionOfRecord":{"articleIdentity":"rs-5762910","link":"https://doi.org/10.1186/s12885-025-14581-3","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-08-16 15:57:01","publishedOnDateReadable":"August 16th, 2025"},"versionCreatedAt":"2025-01-08 20:08:28","video":"","vorDoi":"10.1186/s12885-025-14581-3","vorDoiUrl":"https://doi.org/10.1186/s12885-025-14581-3","workflowStages":[]},"version":"v1","identity":"rs-5762910","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5762910","identity":"rs-5762910","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}