Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-analysis Based on Individual Patient-Level Data of Randomized Trials

Jaewon Hyung; Minsu Kang; Ilhwan Kim; Kyu-pyo Kim; Baek-Yeol Ryoo; Jaekyung Cheon; Hyewon Ryu; Ji Sung Lee; Ji-Won Kim; In Sil Choi; Jin Hyun Park; Ghassan K. Abou-Alfa; Jin Won Kim; Changhoon Yoo

doi:10.4143/crt.2024.652

Articles

Page Path: HOME > Cancer Res Treat > Volume 57(2); 2025 > Article

Original Article Gastrointestinal cancer Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-analysis Based on Individual Patient-Level Data of Randomized Trials: Jaewon Hyung¹, Minsu Kang², Ilhwan Kim³, Kyu-pyo Kim¹, Baek-Yeol Ryoo¹, Jaekyung Cheon^1,4, Hyewon Ryu⁵, Ji Sung Lee^6,7, Ji-Won Kim², In Sil Choi⁸, Jin Hyun Park⁸, Ghassan K. Abou-Alfa^9,10,11, Jin Won Kim^2,, Changhoon Yoo^1,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2025;57(2):519-527.
DOI: https://doi.org/10.4143/crt.2024.652
Published online: October 17, 2024

¹Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

³Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

⁴Division of Hematology and Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea

⁵Division of Hematology and Oncology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea

⁶Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

⁷Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

⁸Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University Colledge of Medicine, Seoul, Korea

⁹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

¹⁰Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA

¹¹Department of Medicine, Trinity College Dublin Medical School, Dublin, Ireland

Correspondence: Jin Won Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173 Beon-gil, Bungdang-gu, Seongnam 13602, Korea
Tel: 82-31-787-7053 E-mail: kimjw05@snu.ac.kr

Co-correspondence: Changhoon Yoo, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-1727 E-mail: yooc@amc.seoul.kr

*Jaewon Hyung and Minsu Kang contributed equally to this work.

• Received: July 16, 2024 • Accepted: October 15, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

1,440 Views
136 Download
1 Crossref

prev next

Full Article

Download PDF

Abstract

Purpose
While fluoropyrimidine-based chemotherapy regimens are recommended second-line treatment for patients with advanced biliary tract cancer (BTC), there have been no studies comparing different regimens head-to-head.
Materials and Methods
We performed individual patient-level meta-analysis based on data from the intention-to-treat population of the phase 2b NIFTY trial (liposomal irinotecan [nal-IRI] plus fluorouracil and leucovorin [5-FU/LV] vs. 5-FU/LV; NCT03542508) and the phase 2 FIReFOX trial (modified oxaliplatin plus 5-FU/LV [mFOLFOX] vs. modified irinotecan plus 5-FU/LV [mFOLFIRI]; NCT03464968). Pairwise log-rank tests and multivariable analysis using Cox proportional hazards modeling with shared frailty to account for the trial's effect were used to compare overall survival (OS) between regimens.
Results
A total of 277 patients were included. The nal-IRI plus 5-FU/LV group (n=88) showed significantly better OS compared to the mFOLFOX group (n=49, pairwise log-rank, p=0.02), and mFOLFIRI group (n=50, p=0.03). Multivariable analysis showed consistent trends in OS with adjusted hazard ratios of 1.39 (mFOLFOX vs. nal-IRI plus 5-FU/LV: 95% confidence interval [CI], 0.93 to 2.07; p=0.11) and 1.36 (mFOLFIRI vs. nal-IRI plus 5-FU/LV: 95% CI, 0.92 to 2.03; p=0.13), respectively. Compared to the 5-FU/LV group, the mFOLFOX group and the mFOLFIRI group did not show differences in terms of OS (pairwise log-rank p=0.83 and p=0.58, respectively). The nal-IRI plus 5-FU/LV group experienced more frequent diarrhea, while the mFOLFOX group experienced peripheral neuropathy.
Conclusion
Nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV. The safety profiles of these regimens should be considered along with efficacy.
Key words: Biliary tract neoplasms, Fluoropyrimidine, Liposomal irinotecan

Introduction

Biliary tract cancer (BTC) is an epithelial malignancy that arises from the intra- and extrahepatic bile ducts and gallbladder [1]. It is a complex disease with diverse clinical and molecular characteristics, often leading to a poor prognosis, and majority of patients are diagnosed at an advanced stage [1,2]. Systemic treatment is the primary approach for managing unresectable or metastatic BTC. In the first-line treatment setting, recent randomized phase 3 trials have shown clinical benefits of adding anti–programmed death-1 (pembrolizumab) or programmed death-ligand 1 (durvalumab) to gemcitabine plus cisplatin (GemCis) [3,4]. However, the majority of patients eventually experience disease progression on these treatments and require subsequent therapy. Based on the results of previous randomized trials, fluoropyrimidine-based regimens are recommended as second-line treatment in the global guidelines if actionable targets such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2) gene fusion, or human epidermal growth factor receptor 2 (HER2) amplification are not identified in the tumors [5-13].

Fluorouracil and leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is recommended based on the results of the phase 3 ABC-06 study, which demonstrated a significantly improved overall survival (OS) compared to active symptom control [14]. Liposomal irinotecan (nal-IRI) plus 5-FU/LV was investigated in the phase 2b NIFTY trial and has shown significant benefits in terms of both progression-free survival (PFS) and OS compared to 5-FU/LV alone [15,16]. In the phase 2 FIReFOX study, modified FOLFOX (mFOLFOX) was compared with modified 5-FU/LV plus irinotecan (mFOLFIRI) as second-line therapy, and there were no significant differences in PFS and OS between the two regimens [17]. Although nal-IRI plus 5-FU/LV, mFOLFOX, mFOLFIRI, and 5-FU/LV are suggested for second-line therapy in the global guidelines, there have been no studies that compared these regimens head-to-head [5,6].

Here, we conducted an individual patient-level pooled analysis of the NIFTY (NCT03524508) and FIReFOX (NCT03464968) trials to compare the efficacy outcomes of second-line 5-FU–based chemotherapy regimens after progression on first-line GemCis in patients with advanced BTC.

Materials and Methods

1. Study design

The current study is an individual patient-level pooled analysis of two multicenter randomized trials conducted in Korea. The NIFTY trial included 178 patients between September 5, 2018 and February 18, 2020, while the FIReFOX trial enrolled 118 patients between August 24, 2015 and November 5, 2019. The study procedures and results of these trials were previously published elsewhere [15-17]. Briefly, in the NIFTY trial, patients in the 5-FU/LV group received 400 mg/m² of LV followed by 2,400 mg/m² of 5-FU intravenously every 2 weeks, while the nal-IRI plus 5-FU/LV group received 70 mg/m² of nal-IRI intravenously prior to LV and 5-FU [15]. In the FIReFOX trial, patients in the mFOLFOX group received 100 mg/m² of oxaliplatin, 100 mg/m² of LV followed by 2,400 mg/m² of 5-FU intravenously every 2 weeks, and patients in the mFOLFIRI group received 150 mg/m² of irinotecan, 100 mg/m² LV followed by 2,400 mg/m² of 5-FU every 2 weeks [17]. The study treatments in these trials were administered as second-line therapy after progression on first-line GemCis. Radiologic disease evaluation was performed every 6 weeks following the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 in both trials. While the radiologic evaluation was performed by both investigators and blinded independent central review in the NIFTY trial, the independent radiologic assessment was not performed in the FIReFOX trial.

2. Patient population and data collection

The intention-to-treat (ITT) population from the two trials was used to assess the efficacy outcomes of this study. For safety outcomes, all patients in the ITT population who had at least one follow-up visit to evaluate safety after receiving the study treatment were included in the analysis. Data on individual patient information from the two trials were collected from the database of each trial, including age, sex, baseline serum carbohydrate antigen 19-9 levels, primary tumor location, Eastern Cooperative Oncology Group (ECOG) performance status, disease setting (metastatic or recurrent after surgery), duration of first-line GemCis, post-study treatment, treatment regimens (nal-IRI plus 5-FU/LV, mFOLFOX, mFOLFIRI, and 5-FU/LV), overall tumor response by RECIST ver. 1.1 per investigator assessment, PFS per investigator assessment, and overall survival. Adverse events evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03 were also collected from each trial. In this study, an updated follow-up analysis dataset from the NIFTY trial was used [16].

Although the two trials shared major inclusion and exclusion criteria, there were discrepancies in terms of inclusion of ECOG performance status 2 and Ampulla of Vater cancer in the FIReFOX trial [15,17]. To minimize potential confounding effects, this study excluded patients with ECOG performance status 2 and Ampulla of Vater cancer from the FIReFOX trial for the current analysis.

3. Statistical analysis

The heterogeneity of the patient characteristics between the two trials was compared using the chi-square test or Fisher’s exact test, as appropriate. The primary endpoint was OS and the secondary endpoints included PFS and overall response rates (ORR) as assessed by the investigators. These outcomes were compared among the four regimens investigated in the two trials. Nal-IRI plus 5-FU/LV or 5-FU/LV were used as references in the univariate and multivariate analyses. In addition, as mFOLFOX and mFOLFIRI showed similar efficacy outcomes in the FIReFOX trial and were the commonly used doublet regimens [5,18], we conducted an independent analysis that included a combined group of mFOLFOX and mFOLFIRI in the FIReFOX trial for comparison with the nal-IRI plus 5-FU/LV group or 5-FU/LV group. The safety profiles of the four treatment regimens were compared using a descriptive method.

Survival curves were estimated using Kaplan-Meier methods and compared using the pairwise log-rank test. Multivariable analysis was conducted to estimate the hazard ratio (HR), adjusted for variables potentially associated with survival outcomes, using Cox proportional hazards modeling with shared frailty to account for the trial’s effect. Among the baseline clinical characteristics tested in the univariate analysis, those with a significance of p < 0.10 were included in the multivariable model. All statistical analyses were conducted using SAS ver. 9.4 (SAS Institute Inc.) and R ver. 4.1.2 (R Foundation for Statistical Computing). Two-sided p-values less than 0.05 were considered statistically significant.

Results

1. Patients

Among the ITT populations of both trials, all 178 patients from the NIFTY trial and 99 patients from the FIReFOX trial were included in the current analysis after excluding 19 patients due to primary Ampulla of Vater cancer (n=6) and ECOG performance status 2 (n=13) (Fig. 1). There were no significant differences in baseline characteristics between the two trials, except for the higher proportion of patients with ECOG performance status 0 in the nal-IRI plus 5-FU/LV group (26.1%) and the 5-FU/LV group (17.8%) compared to the mFOLFOX group (6.1%) and the mFOLFIRI group (8.0%) (p=0.006) (Table 1).

2. Nal-IRI plus 5-FU/LV vs. mFOLFOX or mFOLFIRI

Efficacy outcomes including ORR, PFS, and OS of the four treatment groups are summarized in the S1 Table. Tumor response according to RECIST v1.1 are shown in the S2 Table. The nal-IRI plus 5-FU/LV group showed significantly better PFS and OS compared to the mFOLFOX group (pairwise log-rank p=0.01 and p=0.02, respectively) and the mFOLFIRI group (p=0.04 and p=0.03, respectively) (Fig. 2). In the analysis involving the combined mFOLFOX or mFOLFIRI group, the nal-IRI plus 5-FU/LV group showed significantly better PFS (pairwise log-rank p=0.02) and OS (p=0.02) compared to the combined mFOLFOX or mFOLFIRI group (S3 Fig.). In the multivariable analysis adjusted for the effect of potential prognostic variables and each trial, similar trends for PFS and OS benefit of nal-IRI plus 5-FU were observed when compared with the mFOLFOX group (vs. nal-IRI plus 5-FU/LV, PFS; adjusted HR 1.46 [95% confidence interval (CI), 1.00 to 2.13; p=0.05], and OS; 1.39 [95% CI, 0.93 to 2.07; p=0.11]) and the mFOLFIRI group (vs. nal-IRI plus 5-FU/LV, PFS; 1.31 [95% CI, 0.89 to 1.92; p=0.17], and OS; 1.36 [95% CI, 0.92 to 2.03; p=0.13]), although these were not statistically significant (Table 2). In comparison involving the combined mFOLFOX or mFOLFIRI group, the nal-IRI plus 5-FU/LV group showed significantly better PFS (vs. nal-IRI plus 5-FU/LV, adjusted HR 1.38 [95% CI, 1.01 to 1.89; p=0.04]), and there was a marginal association with improved OS (adjusted HR 1.37 [95% CI, 0.99 to 1.91; p=0.06]) (S4 Table).

3. mFOLFOX or mFOLFIRI vs. 5-FU/LV monotherapy

Then, we performed the analysis using the 5-FU/LV group as the reference. The mFOLFOX group and the mFOLFIRI group showed trends toward better PFS compared to the 5-FU/LV group (pairwise log-rank p=0.13 and p=0.06, respectively); in contrast, there were no differences in terms of OS (p=0.83 and p=0.58, respectively) (Fig. 1). Similar trends were shown in the multivariable analysis (Table 2). The combined mFOLFOX or mFOLFIRI group showed significantly better PFS compared to the 5-FU/LV group (pairwise log-rank, p=0.04), with a consistent trend in the multivariable analysis (vs. 5-FU/LV, adjusted HR, 0.74 [95% CI, 0.54 to 1.01]; p=0.06); in contrast, OS did not significantly differ between the combined mFOLFOX or mFOLFIRI group and the 5-FU/LV group (pairwise log-rank, p=0.66 and adjusted HR, 0.91 [95% CI, 0.66 to 1.25; p=0.56]) (S3 Fig., S4 Table).

4. Safety profiles

After excluding four patients in the 5-FU/LV group, one patient in the mFOLFOX group, and one patient in the mFOLFIRI group who did not receive any study treatment after randomization, 271 patients in the ITT population were included in the safety analysis set (Fig. 1). Most patients experienced adverse events (n=87 [98.7%] in the nal-IRI plus 5-FU/LV group; n=47 [97.9%] in the mFOLFOX group; n=47 [95.9%] in the mFOLFIRI group; and n=77 [89.5%] in the 5-FU/LV group) (Table 3). Grade 3-4 adverse events occurred most frequently in the nal-IRI plus 5-FU/LV group (n=68, 77.3%) followed by the mFOLFOX group (n=29, 60.4%), the mFOLFIRI group (n=27, 55.1%) and the 5-FU/LV monotherapy group (n=29, 33.7%). Neutropenia was the most common grade 3 or higher adverse event among those who received doublet regimens (n=21, 23.9% in the nal-IRI plus 5-FU/LV group; n=13, 27.1% in the mFOLFOX group; and n=14, 28.6% in the mFOLFIRI group), while its incidence was 1.2% (n=1) in the 5-FU/LV group. Otherwise, the most common grade 3-4 adverse events were fatigue (n=11, 12.5%) and nausea (n=5, 5/7%) in the nal-IRI plus 5-FU/LV group, anemia (n=6, 12.5%), thrombocytopenia (n=6, 12.5%) and peripheral neuropathy (n=3, 6.3%) in the mFOLFOX group, and anemia (n=10, 20.4%), thrombocytopenia (n=5, 10.2%) and fatigue (n=3, 6.1%) in the mFOLFIRI group.

Discussion

Here, we conducted a pooled analysis using individual patient data from two randomized trials of fluoropyrimidine-containing second-line chemotherapy regimens for patients with unresectable or metastatic BTC after progression on first-line GemCis. Previously, in the NIFTY trial, nal-IRI plus 5-FU/LV showed significantly better PFS and OS than 5-FU/LV, while the FIReFOX trial showed similar PFS and OS for mFOLFOX and mFOLFIRI [15-17]. We compared the key efficacy outcomes of nal-IRI plus 5-FU/LV, mFOLFOX, mFOLFIRI, and 5-FU/LV, which are guideline-recommended and commonly used regimens in daily practice for biomarker-unselected patients who had previously failed on prior GemCis [5,6,19-23]. To the best of our knowledge, this is the first study to compare the efficacy outcomes of chemotherapy regimens, including nal-IRI plus 5-FU/LV and mFOLFOX. As these two trials share similarities in terms of region/ethnicity (South Korea), inclusion/exclusion criteria, and study period, it may be advantageous to compare the efficacy outcomes of these regimens with reduced unintended confounding biases, such as the pattern of daily practice for BTC.

In the current analysis, the nal-IRI plus 5-FU/LV group showed significantly better PFS and OS compared to both the mFOLFOX group and the mFOLFIRI group, as well as the combined mFOLFOX and mFOLFIRI group, according to the pairwise log-rank test. Consistent trends favoring nal-IRI plus 5-FU/LV for PFS and OS were observed in multivariable analyses, which were adjusted for the effect of potential prognostic variables and trials, although statistical significance (p < 0.05) was not achieved. There has been a lack of studies comparing the clinical outcomes of nal-IRI plus 5-FU/LV with those of other widely used fluorouracil doublets, such as mFOLFOX or mFOLFIRI. Due to the small sample size, especially for the mFOLFOX and mFOLFIRI groups, and the marginal significance in the multivariable analyses for nal-IRI plus 5-FU/LV vs. mFOLFIRI or mFOLFOX, the results of this analysis are not conclusive and further investigations are necessary.

The other key focus in the current analysis was the comparison of the efficacy outcomes between mFOLFOX or mFOLFIRI, and 5-FU/LV monotherapy. The mFOLFOX, mFOLFIRI, or combined mFOLFOX and mFOLFIRI groups showed trends for better PFS compared to the 5-FU/LV group. However, there was no difference in terms of OS among these regimens, which indicates that oxaliplatin- or irinotecan-containing doublet may provide benefit in terms of PFS but have a limited impact on OS compared to 5-FU/LV monotherapy. FOLFOX has been regarded as the global standard second-line therapy following progression on GemCis based on the results of the ABC-06 trial [14]. However, in this trial, FOLFOX was compared with active supportive care, and there are no other prospective data demonstrating the impact of adding oxaliplatin to 5-FU/LV monotherapy in the second-line setting [14]. Our findings are partially in line with previous retrospective studies. In a multicenter retrospective study conducted in France and Italy, which included 525 patients, OS did not show a significant difference among fluoropyrimidine monotherapy, irinotecan-fluoropyrimidine, and platinum-fluoropyrimidine doublets [19]. Furthermore, in a retrospective study in Korea (n=321), platinum-fluoropyrimidine doublets was associated with a higher ORR than fluoropyrimidine monotherapy, while there were no significant differences in PFS and OS [22]. The remaining issue is whether nal-IRI plus 5-FU/LV is superior to 5-FU/LV in global patient populations. In contrast to the positive results of the NIFTY trial, the recent phase 2 NALIRICC trial conducted in Germany showed similar PFS and OS between nal-IRI plus 5-FU/LV and 5-FU/LV monotherapy, despite an improved ORR with nal-IRI plus 5-FU/LV compared to 5-FU/LV monotherapy (14.3% vs. 3.9%) [24]. As this randomized study included a relatively small number of patients (n=100), its findings do not definitively exclude the potential effectiveness of nal-IRI plus 5-FU/LV over 5-FU/LV monotherapy in the Western patient population. Further investigation, such as meta-analysis and real-world evidence, is required [25].

The profiles of adverse events in each regimen were in line with those in the previous studies [14,26,27]. Hematological adverse events were the most frequent, particularly in the doublet combination regimens. The incidences of grade 3-4 neutropenia (23.9%-28.6%) and anemia (9.1%-20.4%) were similar across the nal-IRI plus 5-FU/LV, mFOLFOX, and mFOLFIRI groups. In contrast, 5-FU/LV monotherapy exhibited a more favorable profile of hematological adverse events (grade 3-4 neutropenia, 1.2%; anemia, 3.5%). Among non-hematological adverse events, fatigue was the most common adverse event of any grade (30.7%-52.1%) in patients receiving doublet combination regimens. Diarrhea occurred more frequently in the nal-IRI plus 5-FU/LV group (any grade, 22.7%; grade 3-4, 4.6%), while peripheral neuropathy was more common in the mFOLFOX group (any grade, 41.7%; grade 3-4, 6.3%).

Because there is no large global phase 3 trial for head-to-head comparison among these agents, there still exists uncertainty about which regimen is the best chemotherapy option for patients who progress on first-line GemCis, if they are not biologically eligible for targeted therapy. As patients with advanced BTC who have progressed on first-line therapy are often medically fragile, the toxicity profile of each regimen should be the key consideration, along with efficacy data, when selecting fluoropyrimidine-based second-line therapy.

Our study has several limitations. This study is a analysis that exclusively included patients of East Asian ethnicity. The NIFTY and FIReFOX trials did not exclude patients with actionable genomic alterations as the studies were performed prior to the approval of targeted agents [15,17]. Although most patient characteristics were well balanced in each treatment group in this study, there was an imbalance in ECOG performance status between the two trials; however, ECOG performance status was not significantly associated with survival outcomes in the multivariable analysis, indicating limited impact on the results of the current analysis. Moreover, the sample sizes in the current analysis may be insufficient to yield sufficient statistical power for comparing each treatment regimen and subgroup analyses. Despite these limitations, the current individual patient-level pooled analysis compared the efficacy of second-line treatments based on two of the largest randomized trials, including the two active agents proven effective in previous randomized trials (FOLFOX and nal-IRI plus 5-FU/LV).

In conclusion, nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV alone. Although nal-IRI plus 5-FU/LV may be a preferable second-line cytotoxic chemotherapy regimen for medically fit patients with advanced BTC after progression on first-line GemCis, the safety profiles of these regimens should be considered along with efficacy outcomes when selecting second-line therapy for patients without targetable genetic alterations.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2024-652_S1_Table.pdf

crt-2024-652_S2_Table.pdf

crt-2024-652_S3_Fig.pdf

crt-2024-652_S4_Table.pdf

NOTES

Ethical Statement

This pooled analysis was approved by the Institutional Review Boards of Asan Medical Center (IRB No. 2023-1225), Seoul National University Bundang Hospital (IRB No. B-2305-828-107), and Seoul Metropolitan Government Seoul National University Boramae Medical Center (IRB No. 10-2023-64). The Institutional Review Boards of Asan Medical Center, Seoul National University Bundang Hospital, and Seoul Metropolitant Government Seoul National University Boramae Medical Center waived to receive informed consent as this study is a pooled analysis using dataset from prior clinical trials.

Author Contributions

Conceived and designed the analysis: Hyung J, Kang M, Lee JS, Kim JW (Jin Won Kim), Yoo C.

Collected the data: Kang M, Kim I, Kim KP, Ryoo BY, Cheon J, Ryu H, Kim JW (Ji-Won Kim), Choi IS, Park JH, Abou-Alfa GK, Kim JW (Jin Won Kim), Yoo C.

Contributed data or analysis tools: Lee JS.

Performed the analysis: Hyung J.

Wrote the paper: Hyung J, Kang M, Kim I, Kim KP, Ryoo BY, Cheon J, Ryu H, Lee JS, Kim JW (Ji-Won Kim), Choi IS, Park JH, Abou-Alfa GK, Kim JW (Jin Won Kim), Yoo C.

Conflict of Interest

CY received honoraria from Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol Myers Squibb, Ipsen, Novartis, Boehringer Ingelheim, Boryung Pharmaceuticals, Mundipharma, and Roche; and received research grants from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Ipsen, Boryung Pharmaceuticals, CKD Pharm, Lunit Inc., and Boehringer Ingelheim. All other authors have no competing interests to disclose.

Funding

This study was funded in part by Servier and the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea [grant number 2020IL0018]. The funder had no role in the study design; data collection, analysis, or interpretation; or writing of the report.

Acknowledgements

We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center (Seoul, South Korea) for providing editorial assistance, which was funded by Asan Medical Center.

Fig. 1.

Study flow. AoV, ampulla of Vater; ECOG PS, Eastern Cooperative Oncology Group performance status; mFOLFIRI, modified fluorouracil and leucovorin plus irinotecan; mFOLFOX, modified fluorouracil and leucovorin plus oxaliplatin; nal-IRI, nanoliposomal irinotecan; SNUBH, Seoul National University Bundang Hospital; 5-FU/LV, fluorouracil and leucovorin.

Fig. 2.

Kaplan-Meier estimates of survival outcomes in the nanoliposomal irinotecan (nal-IRI) plus fluorouracil and leucovorin (5-FU/LV), modified fluorouracil and leucovorin plus oxaliplatin (mFOLFOX), modified fluorouracil and leucovorin plus irinotecan (mFOLFIRI), and 5-FU/LV groups. (A) Progression-free survival (PFS). (B) Overall survival (OS). CI, confidence interval.

Table 1.

Baseline characteristics

	NIFTY (n=178)		FIReFOX (n=99)
	nal-IRI plus 5-FU/LV (n=88)	5-FU/LV (n=90)	mFOLFOX (n=49)	mFOLFIRI (n=50)	p-value
Age (yr)	64 (38-84)	64 (37-80)	63 (47-79)	63 (26-82)	0.87
Sex
Male	51 (58.0)	50 (55.6)	31 (63.3)	36 (72.0)	0.25
Female	37 (42.0)	40 (44.4)	18 (36.7)	14 (28.0)
Primary tumor location
Intrahepatic	35 (39.8)	40 (44.4)	22 (44.9)	21 (42.0)	0.90
Extrahepatic	22 (25.0)	27 (30.0)	13 (26.5)	13 (26.0)
Gallbladder	31 (35.2)	23 (25.6)	14 (28.6)	16 (32.0)
Disease setting
Initially metastatic	75 (85.2)	76 (84.4)	42 (85.7)	42 (84.0)	0.99
Recurrence after curative surgery	13 (14.8)	14 (15.6)	7 (14.3)	8 (16.0)
ECOG PS
0	23 (26.1)	16 (17.8)	3 (6.1)	4 (8.0)	0.006
1	65 (73.9)	74 (82.2)	46 (93.9)	46 (92.0)
First-line GEMCIS duration (3 months cut-off)
< 3	22 (25.0)	24 (26.7)	10 (20.4)	13 (26.0)
≥ 3	66 (75.0)	66 (73.3)	39 (79.6)	37 (74.0)
First-line GEMCIS duration (6 months cut-off)
< 6	58 (65.9)	58 (64.4)	31 (63.3)	27 (54.0)
≥ 6	30 (34.1)	32 (35.6)	18 (36.7)	23 (46.0)
Baseline serum CA 19-9 (IU/mL)		89
< 400	56 (63.6)	46 (51.7)	30 (61.2)	24 (48.0)	0.21
≥ 400	32 (36.4)	43 (48.3)	19 (38.8)	26 (52.0)
Post-study treatment
Yes	33 (37.5)	31 (34.4)	20 (40.8)	25 (50.0)
No	55 (62.5)	59 (65.6)	29 (59.2)	25 (50.0)

Values are presented as median (range) or number (%). CA 19-9, carbohydrate antigen 19-9; ECOG PS, Eastern Cooperative Oncology Group performance status; GEMCIS, gemcitabine plus cisplatin; mFOLFIRI, modified fluorouracil and leucovorin plus irinotecan; mFOLFOX, modified fluorouracil and leucovorin plus oxaliplatin; Nal-IRI, nanoliposomal irinotecan; 5-FU/LV, fluorouracil and leucovorin.

Table 2.

Cox proportional hazards modeling with shared frailty according to treatment groups and key prognostic variables

	Progression-free survival				Overall survival
	Univariable HR (95% CI)	p-value	Multivariable HR (95% CI)	p-value	Univariable HR (95% CI)	p-value	Multivariable HR (95% CI)	p-value
Treatment
Nal-IRI plus 5-FU/LV	1 (Ref)		1 (Ref)		1 (Ref)		1 (Ref)
mFOLFOX	1.40 (0.96-2.04)	0.09	1.46 (1.00-2.13)	0.05	1.46 (0.99-2.17)	0.06	1.39 (0.93-2.07)	0.11
mFOLFIRI	1.26 (0.86-1.84)	0.24	1.31 (0.89-1.92)	0.17	1.39 (0.94-2.06)	0.10	1.36 (0.92-2.03)	0.13
5-FU/LV	1.77 (1.30-2.39)	< 0.001	1.87 (1.37-2.54)	< 0.001	1.53 (1.11-2.09)	0.009	1.52 (1.09-2.10)	0.01
5-FU/LV	1 (Ref)		1 (Ref)		1 (Ref)		1 (Ref)
mFOLFOX	0.79 (0.54-1.15)	0.22	0.78 (0.53-1.14)	0.20	0.96 (0.65-1.41)	0.83	0.91 (0.62-1.35)	0.66
mFOLFIRI	0.71 (0.49-1.04)	0.08	0.70 (0.48-1.03)	0.07	0.91 (0.62-1.33)	0.64	0.90 (0.61-1.33)	0.60
Age (per 1-unit increase)	0.99 (0.98-1.00)	0.08	0.99 (0.97-1.00)	0.06	1.01 (0.99-1.02)	0.26	-	-
Sex
Female	1 (Ref)		-		1 (Ref)		1 (Ref)
Male	1.11 (0.86-1.42)	0.43	-	-	1.45 (1.11-1.89)	0.006	1.38 (1.05-1.81)	0.02
Primary tumor location
Intrahepatic	1 (Ref)		-		1 (Ref)		1 (Ref)
Extrahepatic	0.86 (0.64-1.17)	0.35	-	-	0.84 (0.61-1.15)	0.27	0.86 (0.62-1.18)	0.34
Gallbladder	0.79 (0.59-1.06)	0.12	-	-	0.75 (0.55-1.01)	0.06	0.84 (0.61-1.15)	0.27
Disease setting
Initially metastatic	1 (Ref)		-		1 (Ref)		-
Recurrence after curative surgery	0.90 (0.63-1.28)	0.55	-	-	0.86 (0.60-1.23)	0.41	-	-
ECOG PS
0	1 (Ref)		-		1 (Ref)		1 (Ref)
1	1.13 (0.81-1.56)	0.48	-	-	1.34 (0.95-1.90)	0.01	1.25 (0.88-1.78)	0.22
Duration of prior gemcitabine plus cisplatin (per 1-unit increase)	0.97 (0.94-0.99)	0.02	-	-	0.96 (0.93-0.99)	0.04	-	-
Baseline CA 19-9 level (per 10,000-unit increase)	1.12 (1.04-1.20)	0.002	1.12 (1.05-1.21)	0.002	1.17 (1.09-1.26)	< 0.001	1.18 (1.10-1.27)	< 0.001

CA 19-9, carbohydrate antigen 19-9; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; mFOLFIRI, modified fluorouracil and leucovorin plus irinotecan; mFOLFOX, modified fluorouracil and leucovorin plus oxaliplatin; Nal-IRI, nanoliposomal irinotecan; 5-FU/LV, fluorouracil and leucovorin.

Table 3.

Adverse events that occurred in > 5% of patients regardless of causality

NCI CTCAE ver. 4.03	Nal-IRI plus 5-FU/LV (n=88)		mFOLFOX (n=48)		mFOLFIRI (n=49)		5-FU/LV (n=86)
NCI CTCAE ver. 4.03	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3
Any event	87 (98.7)	68 (77.3)	47 (97.9)	29 (60.4)	47 (95.9)	27 (55.1)	77 (89.5)	29 (33.7)
Hematologic
Anemia	13 (14.8)	8 (9.1)	9 (18.8)	6 (12.5)	15 (30.6)	10 (20.4)	5 (5.8)	3 (3.5)
Neutropenia	29 (33.0)	21 (23.9)	22 (45.8)	13 (27.1)	24 (50.0)	14 (28.6)	3 (3.5)	1 (1.2)
Thrombocytopenia	3 (3.4)	0	18 (37.5)	6 (12.5)	7 (14.3)	5 (10.2)	1 (1.2)	1 (1.2)
Febrile neutropenia	NA	2 (2.3)	NA	0	NA	2 (4.0)	NA	0
Non-hematologic
Nausea	22 (25.0)	5 (5.7)	17 (35.4)	1 (2.1)	14 (28.6)	1 (2.0)	14 (16.3)	1 (1.2)
Vomiting	9 (10.2)	0	2 (4.2)	0	8 (16.3)	2 (4.1)	4 (4.7)	1 (1.2)
Abdominal pain	22 (25.0)	4 (4.6)	9 (18.8)	2 (4.2)	12 (24.5)	1 (2.0)	14 (16.3)	3 (3.5)
Constipation	26 (29.5)	0	7 (14.6)	0	5 (10.2)	0	19 (22.1)	0
Diarrhea	20 (22.7)	4 (4.6)	3 (6.3)	0	0	0	9 (10.5)	0
Dyspepsia	20 (22.7)	0	3 (6.3)	0	2 (4.1)	0	12 (14.0)	0
Anorexia	24 (27.3)	1 (1.1)	21 (43.8)	0	18 (36.7)	0	16 (18.6)	0
Stomatitis	14 (15.9)	2 (2.3)	3 (6.3)	0	4 (8.2)	0	10 (11.6)	0
Peripheral neuropathy	10 (11.4)	0	20 (41.7)	3 (6.3)	2 (4.1)	1 (2.0)	2 (2.3)	0
Hemorrhage	2 (2.3)	2 (2.3)	2 (4.2)	0	0	0	0	0
Infection	1 (1.1)	1 (1.1)	1 (2.1)	0	3 (6.1)	2 (4.1)	1 (1.2)	1 (1.2)
Fatigue	27 (30.7)	11 (12.5)	25 (52.1)	1 (2.1)	19 (38.8)	3 (6.1)	17 (19.8)	3 (3.5)
Pyrexia	15 (17.1)	0	5 (10.4)	0	7 (14.3)	0	8 (9.3)	1 (1.2)

Values are presented as number (%). mFOLFIRI, modified fluorouracil and leucovorin plus irinotecan; mFOLFOX, modified fluorouracil and leucovorin plus oxaliplatin; NA, not available; nal-IRI, nanoliposomal irinotecan; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; 5-FU/LV, fluorouracil and leucovorin.

REFERENCES

1. Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397:428–44. Article PubMed
2. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557–88. Article PubMed PMC PDF
3. Oh DY, Ruth He A, Qin S, Chen LT, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1:EVIDoa2200015.PubMed
4. Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401:1853–65. PubMed
5. Vogel A, Bridgewater J, Edeline J, Kelley RK, Klumpen HJ, Malka D, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:127–40. Article PubMed
6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology biliary tract cancer (version 3.2023) [Internet]. National Comprehensive Cancer Network; c2023. [cited 2023 Nov 28]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
7. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796–807. Article PubMed PMC
8. Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy Trial. JAMA Oncol. 2021;7:1669–77. Article PubMed
9. Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671–84. Article PubMed PMC
10. Javle M, Borad MJ, Azad NS, Kurzrock R, Abou-Alfa GK, George B, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021;22:1290–300. Article PubMed
11. Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, Morizane C, Karasic TB, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med. 2023;388:228–39. PubMed
12. Harding JJ, Fan J, Oh DY, Choi HJ, Kim JW, Chang HM, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24:772–82. PubMed
13. Nakamura Y, Mizuno N, Sunakawa Y, Canon JL, Galsky MD, Hamilton E, et al. Tucatinib and trastuzumab for previously treated human epidermal growth factor receptor 2-positive metastatic biliary tract cancer (SGNTUC-019): a phase II basket study. J Clin Oncol. 2023;36:5569–78. Article
14. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690–701. Article PubMed PMC
15. Yoo C, Kim KP, Jeong JH, Kim I, Kang MJ, Cheon J, et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol. 2021;22:1560–72. Article PubMed
16. Hyung J, Kim I, Kim KP, Ryoo BY, Jeong JH, Kang MJ, et al. Treatment with liposomal irinotecan plus fluorouracil and leucovorin for patients with previously treated metastatic biliary tract cancer: the phase 2b NIFTY randomized clinical trial. JAMA Oncol. 2023;9:692–9. Article PubMed PMC
17. Choi IS, Kim KH, Lee JH, Suh KJ, Kim JW, Park JH, et al. A randomised phase II study of oxaliplatin/5-FU (mFOLFOX) versus irinotecan/5-FU (mFOLFIRI) chemotherapy in locally advanced or metastatic biliary tract cancer refractory to first-line gemcitabine/cisplatin chemotherapy. Eur J Cancer. 2021;154:288–95. Article PubMed
18. Lowery MA, Goff LW, Keenan BP, Jordan E, Wang R, Bocobo AG, et al. Second-line chemotherapy in advanced biliary cancers: a retrospective, multicenter analysis of outcomes. Cancer. 2019;125:4426–34. Article PubMed PDF
19. Neuzillet C, Casadei-Gardini A, Brieau B, Vivaldi C, Brandi G, Tougeron D, et al. Fluropyrimidine single agent or doublet chemotherapy as second line treatment in advanced biliary tract cancer. Int J Cancer. 2020;147:3177–88. Article PubMed PDF
20. Brieau B, Dahan L, De Rycke Y, Boussaha T, Vasseur P, Tougeron D, et al. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: a large multicenter study by the Association des Gastro-Enterologues Oncologues. Cancer. 2015;121:3290–7. Article PubMed
21. Schweitzer N, Kirstein MM, Kratzel AM, Mederacke YS, Fischer M, Manns MP, et al. Second-line chemotherapy in biliary tract cancer: outcome and prognostic factors. Liver Int. 2019;39:914–23. Article PubMed PDF
22. Kim BJ, Yoo C, Kim KP, Hyung J, Park SJ, Ryoo BY, et al. Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer after failure of gemcitabine plus cisplatin: retrospective analysis of 321 patients. Br J Cancer. 2017;116:561–7. Article PubMed PMC PDF
23. Lamarca A, Hubner RA, David Ryder W, Valle JW. Secondline chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol. 2014;25:2328–38. Article PubMed
24. Vogel A, Wenzel P, Folprecht G, Schutt P, Wege H, Kretzschmar A, et al. 53MO Nal-IRI and 5-FU/LV compared to 5-FU/LV in patients with cholangio- and gallbladder carcinoma previously treated with gemcitabine-based therapies (NALIRICC - AIO-HEP-0116). Ann Oncol. 2022;33(Suppl 7):S19–26. Article
25. Merz V, Messina C, Zecchetto C, Quinzii A, Frisinghelli M, Trentin C, et al. Is there room for liposomal irinotecan in biliary tract cancer? A meta-analysis of randomised trials. Clin Oncol (R Coll Radiol). 2024;36:87–97. Article PubMed
26. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387:545–57. PubMed
27. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25:1670–6. Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

Liposomal irinotecan for previously treated patients with biliary tract cancer: A pooled analysis of NIFTY and NALIRICC trials
Changhoon Yoo, Anna Saborowski, Jaewon Hyung, Patrick Wenzel, Ilhwan Kim, Henning Wege, Kyu-pyo Kim, Gunnar Folprecht, Baek-Yeol Ryoo, Phillip Schütt, Jaekyung Cheon, Thorsten Götze, Hyewon Ryu, Ji Sung Lee, Arndt Vogel
Journal of Hepatology.2025;[Epub] CrossRef

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-analysis Based on Individual Patient-Level Data of Randomized Trials

Cancer Res Treat. 2025;57(2):519-527. Published online October 17, 2024

DOI: https://doi.org/10.4143/crt.2024.652

XML Download

Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-analysis Based on Individual Patient-Level Data of Randomized Trials

Fig. 1. Study flow. AoV, ampulla of Vater; ECOG PS, Eastern Cooperative Oncology Group performance status; mFOLFIRI, modified fluorouracil and leucovorin plus irinotecan; mFOLFOX, modified fluorouracil and leucovorin plus oxaliplatin; nal-IRI, nanoliposomal irinotecan; SNUBH, Seoul National University Bundang Hospital; 5-FU/LV, fluorouracil and leucovorin.

Fig. 2. Kaplan-Meier estimates of survival outcomes in the nanoliposomal irinotecan (nal-IRI) plus fluorouracil and leucovorin (5-FU/LV), modified fluorouracil and leucovorin plus oxaliplatin (mFOLFOX), modified fluorouracil and leucovorin plus irinotecan (mFOLFIRI), and 5-FU/LV groups. (A) Progression-free survival (PFS). (B) Overall survival (OS). CI, confidence interval.

Fig. 1.

Fig. 2.

Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-analysis Based on Individual Patient-Level Data of Randomized Trials

	NIFTY (n=178)		FIReFOX (n=99)
	nal-IRI plus 5-FU/LV (n=88)	5-FU/LV (n=90)	mFOLFOX (n=49)	mFOLFIRI (n=50)	p-value
Age (yr)	64 (38-84)	64 (37-80)	63 (47-79)	63 (26-82)	0.87
Sex
Male	51 (58.0)	50 (55.6)	31 (63.3)	36 (72.0)	0.25
Female	37 (42.0)	40 (44.4)	18 (36.7)	14 (28.0)
Primary tumor location
Intrahepatic	35 (39.8)	40 (44.4)	22 (44.9)	21 (42.0)	0.90
Extrahepatic	22 (25.0)	27 (30.0)	13 (26.5)	13 (26.0)
Gallbladder	31 (35.2)	23 (25.6)	14 (28.6)	16 (32.0)
Disease setting
Initially metastatic	75 (85.2)	76 (84.4)	42 (85.7)	42 (84.0)	0.99
Recurrence after curative surgery	13 (14.8)	14 (15.6)	7 (14.3)	8 (16.0)
ECOG PS
0	23 (26.1)	16 (17.8)	3 (6.1)	4 (8.0)	0.006
1	65 (73.9)	74 (82.2)	46 (93.9)	46 (92.0)
First-line GEMCIS duration (3 months cut-off)
< 3	22 (25.0)	24 (26.7)	10 (20.4)	13 (26.0)
≥ 3	66 (75.0)	66 (73.3)	39 (79.6)	37 (74.0)
First-line GEMCIS duration (6 months cut-off)
< 6	58 (65.9)	58 (64.4)	31 (63.3)	27 (54.0)
≥ 6	30 (34.1)	32 (35.6)	18 (36.7)	23 (46.0)
Baseline serum CA 19-9 (IU/mL)		89
< 400	56 (63.6)	46 (51.7)	30 (61.2)	24 (48.0)	0.21
≥ 400	32 (36.4)	43 (48.3)	19 (38.8)	26 (52.0)
Post-study treatment
Yes	33 (37.5)	31 (34.4)	20 (40.8)	25 (50.0)
No	55 (62.5)	59 (65.6)	29 (59.2)	25 (50.0)

	Progression-free survival				Overall survival
	Univariable HR (95% CI)	p-value	Multivariable HR (95% CI)	p-value	Univariable HR (95% CI)	p-value	Multivariable HR (95% CI)	p-value
Treatment
Nal-IRI plus 5-FU/LV	1 (Ref)		1 (Ref)		1 (Ref)		1 (Ref)
mFOLFOX	1.40 (0.96-2.04)	0.09	1.46 (1.00-2.13)	0.05	1.46 (0.99-2.17)	0.06	1.39 (0.93-2.07)	0.11
mFOLFIRI	1.26 (0.86-1.84)	0.24	1.31 (0.89-1.92)	0.17	1.39 (0.94-2.06)	0.10	1.36 (0.92-2.03)	0.13
5-FU/LV	1.77 (1.30-2.39)	< 0.001	1.87 (1.37-2.54)	< 0.001	1.53 (1.11-2.09)	0.009	1.52 (1.09-2.10)	0.01
5-FU/LV	1 (Ref)		1 (Ref)		1 (Ref)		1 (Ref)
mFOLFOX	0.79 (0.54-1.15)	0.22	0.78 (0.53-1.14)	0.20	0.96 (0.65-1.41)	0.83	0.91 (0.62-1.35)	0.66
mFOLFIRI	0.71 (0.49-1.04)	0.08	0.70 (0.48-1.03)	0.07	0.91 (0.62-1.33)	0.64	0.90 (0.61-1.33)	0.60
Age (per 1-unit increase)	0.99 (0.98-1.00)	0.08	0.99 (0.97-1.00)	0.06	1.01 (0.99-1.02)	0.26	-	-
Sex
Female	1 (Ref)		-		1 (Ref)		1 (Ref)
Male	1.11 (0.86-1.42)	0.43	-	-	1.45 (1.11-1.89)	0.006	1.38 (1.05-1.81)	0.02
Primary tumor location
Intrahepatic	1 (Ref)		-		1 (Ref)		1 (Ref)
Extrahepatic	0.86 (0.64-1.17)	0.35	-	-	0.84 (0.61-1.15)	0.27	0.86 (0.62-1.18)	0.34
Gallbladder	0.79 (0.59-1.06)	0.12	-	-	0.75 (0.55-1.01)	0.06	0.84 (0.61-1.15)	0.27
Disease setting
Initially metastatic	1 (Ref)		-		1 (Ref)		-
Recurrence after curative surgery	0.90 (0.63-1.28)	0.55	-	-	0.86 (0.60-1.23)	0.41	-	-
ECOG PS
0	1 (Ref)		-		1 (Ref)		1 (Ref)
1	1.13 (0.81-1.56)	0.48	-	-	1.34 (0.95-1.90)	0.01	1.25 (0.88-1.78)	0.22
Duration of prior gemcitabine plus cisplatin (per 1-unit increase)	0.97 (0.94-0.99)	0.02	-	-	0.96 (0.93-0.99)	0.04	-	-
Baseline CA 19-9 level (per 10,000-unit increase)	1.12 (1.04-1.20)	0.002	1.12 (1.05-1.21)	0.002	1.17 (1.09-1.26)	< 0.001	1.18 (1.10-1.27)	< 0.001

NCI CTCAE ver. 4.03	Nal-IRI plus 5-FU/LV (n=88)		mFOLFOX (n=48)		mFOLFIRI (n=49)		5-FU/LV (n=86)
NCI CTCAE ver. 4.03	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3
Any event	87 (98.7)	68 (77.3)	47 (97.9)	29 (60.4)	47 (95.9)	27 (55.1)	77 (89.5)	29 (33.7)
Hematologic
Anemia	13 (14.8)	8 (9.1)	9 (18.8)	6 (12.5)	15 (30.6)	10 (20.4)	5 (5.8)	3 (3.5)
Neutropenia	29 (33.0)	21 (23.9)	22 (45.8)	13 (27.1)	24 (50.0)	14 (28.6)	3 (3.5)	1 (1.2)
Thrombocytopenia	3 (3.4)	0	18 (37.5)	6 (12.5)	7 (14.3)	5 (10.2)	1 (1.2)	1 (1.2)
Febrile neutropenia	NA	2 (2.3)	NA	0	NA	2 (4.0)	NA	0
Non-hematologic
Nausea	22 (25.0)	5 (5.7)	17 (35.4)	1 (2.1)	14 (28.6)	1 (2.0)	14 (16.3)	1 (1.2)
Vomiting	9 (10.2)	0	2 (4.2)	0	8 (16.3)	2 (4.1)	4 (4.7)	1 (1.2)
Abdominal pain	22 (25.0)	4 (4.6)	9 (18.8)	2 (4.2)	12 (24.5)	1 (2.0)	14 (16.3)	3 (3.5)
Constipation	26 (29.5)	0	7 (14.6)	0	5 (10.2)	0	19 (22.1)	0
Diarrhea	20 (22.7)	4 (4.6)	3 (6.3)	0	0	0	9 (10.5)	0
Dyspepsia	20 (22.7)	0	3 (6.3)	0	2 (4.1)	0	12 (14.0)	0
Anorexia	24 (27.3)	1 (1.1)	21 (43.8)	0	18 (36.7)	0	16 (18.6)	0
Stomatitis	14 (15.9)	2 (2.3)	3 (6.3)	0	4 (8.2)	0	10 (11.6)	0
Peripheral neuropathy	10 (11.4)	0	20 (41.7)	3 (6.3)	2 (4.1)	1 (2.0)	2 (2.3)	0
Hemorrhage	2 (2.3)	2 (2.3)	2 (4.2)	0	0	0	0	0
Infection	1 (1.1)	1 (1.1)	1 (2.1)	0	3 (6.1)	2 (4.1)	1 (1.2)	1 (1.2)
Fatigue	27 (30.7)	11 (12.5)	25 (52.1)	1 (2.1)	19 (38.8)	3 (6.1)	17 (19.8)	3 (3.5)
Pyrexia	15 (17.1)	0	5 (10.4)	0	7 (14.3)	0	8 (9.3)	1 (1.2)

Table 1. Baseline characteristics

Table 2. Cox proportional hazards modeling with shared frailty according to treatment groups and key prognostic variables

Table 3. Adverse events that occurred in > 5% of patients regardless of causality