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Outcomes in patients receiving palliative chemotherapy for advanced biliary tract cancer

Open AccessPublished:December 15, 2021DOI:https://doi.org/10.1016/j.jhepr.2021.100417

      Highlights

      • This study provides important real-world data on the clinical outcomes of patients with ABTC.
      • Patients may benefit from later lines of chemotherapy beyond second line.
      • The use of FOLFIRINOX was associated with a promising overall survival of 23.8 months in our study.
      • Many prognostically relevant factors, such as pre-therapeutic albumin, bilirubin or CA19-9 levels, were identified.
      • Targeted therapies will become an integral part of the standard of care for patients with ABTC.

      Background & Aims

      Advanced biliary tract cancer (ABTC) is associated with a poor prognosis. Real-world data on the outcome of patients with ABTC undergoing sequential chemotherapies remain scarce, and little is known about treatment options beyond the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX. This study aimed to evaluate the outcome of patients with regard to different oncological therapies and to identify prognostic factors.

      Methods

      From January 2010 until December 2019, 142 patients started palliative chemotherapy at our tertiary care liver center. Overall survival (OS) was calculated using Kaplan-Meier plots. Prognostic factors were evaluated using cox proportional-hazards.

      Results

      Patients received a median number of 2 lines of chemotherapy. Median OS was 6.7, 15.2 and 18.2 months for patients who received 1, 2 and 3 lines of chemotherapy, respectively. Patients treated with FOLFIRINOX had a significantly extended OS of 23.8 months (log-rank test: p = 0.018). The univariate cox regression analysis identified several clinical parameters associated with survival (e.g. albumin, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9 levels).

      Conclusions

      Our study provides real-world data on the prognosis of ABTC including survival times for patients receiving third and later lines of chemotherapy.

      Lay summary

      Real-world data depicting the outcome of patients with advanced biliary tract cancer outside the framework of controlled trials remain rare despite being extremely important for clinical decision-making. This study therefore provides important real-world data on the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX, as well as on other chemotherapy regimens or later lines of chemotherapy. It further demonstrates that the use of FOLFIRINOX is associated with promising survival and that there is an association between various clinical parameters such as pre-therapeutic albumin, bilirubin or carbohydrate antigen 19-9 levels and survival.

      Graphical abstract

      Keywords

      Abbreviations:

      ABTC (advanced biliary tract cancer), CA19-9 (carbohydrate antigen 19-9), CEA (carcinoembryonic antigen), CT1 (first-line chemotherapy), CT2 (second-line chemotherapy), CT3 (third-line chemotherapy), ECOG PS (Eastern Cooperative Oncology Group performance status), FGFR (fibroblast growth factor receptor), GBC (gallbladder cancer), GemCis (gemcitabine + cisplatin), GemOx (gemcitabine + oxaliplatin), IDH (isocitrate dehydrogenase), iCCA (intrahepatic cholangiocarcinoma), OS (overall survival), pCCA (perihilar cholangiocarcinoma), UICC (Union for International Cancer Control)

      Introduction

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      ). However, most patients with ABTC will receive established treatments, and for them and their treating physicians real-world data on their prognosis can present valuable information. Furthermore, survival data for chemotherapies beyond the second-line are lacking. Therefore, the objective of this study was to retrospectively evaluate the outcome of patients with ABTC undergoing palliative chemotherapy at our institution and to identify prognostic factors.

      Patients and methods

      Patients

      We performed a retrospective analysis of 142 patients with histologically confirmed malignancies who started treatment with palliative chemotherapy at our center between January 01, 2010 and December 31, 2019. Data were retrieved from our institution’s electronic clinical information system and prepared for analysis. Patients were followed up until December 31, 2020. All patients provided informed consent.

      Ethical statement

      The study was conducted according to the guidelines of the Declaration of Helsinki 1975 and approved by the Ethics Committee of the state of Rhineland-Palatinate (permit number 2018-13618, October 15th, 2018).

      Statistical analysis

      Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) version 27.0.1.0 (SPSS, Chicago, IL, USA). Categorical variables were tested for statistical significance using the chi-square test. Kaplan-Meier plots were generated to estimate OS from either the time of diagnosis or the time of unresectability until the time of death or last follow-up. The log-rank test was used to assess the statistical significance of the difference between strata. Univariate Cox proportional-hazards regression models assessing hazard ratios (HRs) and corresponding 95% CIs were employed to determine the relationship between several risk factors and OS (HR >1: potentially harmful; HR <1: potentially protective). p values <0.05 were considered statistically significant. A significance-adjusting Bonferroni correction was not applied despite the multiple testing as the study aimed to identify new research hypotheses.

      Results

      Baseline characteristics

      Baseline clinical, laboratory and treatment characteristics are summarized in Table 1. The median age at diagnosis was 63.8 years and the sex distribution was balanced. The most frequent subtype was iCCA (51.4%), followed by GBC (21.1%) and pCCA (13.4%). Carcinomas originating from the distal bile duct (8.5%) or the Vateri ampulla (4.2%) were rarely observed. The majority of patients (63.2%) had Union for International Cancer Control (UICC)-stage 3 (14.8%) or 4 (48.4%) disease at diagnosis. Over half of the patients (54.5%) had lymph node metastases and over a third had distant metastases (39.1%). Histopathological grading was available for 92 patients with the majority being moderately (G2 = 55.4%) or poorly (G3 = 43.5%) differentiated. More than half (59.3%) of patients presented with an Eastern Cooperative Oncology Group – performance status (ECOG PS) of 0 at the start of palliative chemotherapy and 34.5% had an ECOG PS of 1. Only a minority (6.2%) had an ECOG PS of 2 or 3. Median baseline carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels were 122 U/ml and 2.6 ng/dl, respectively. CA19-9 and CEA levels over 1,000 U/ml and 4.5 ng/dl, respectively, could be detected in a third of patients (34.6% and 37.9%). Median bilirubin and albumin levels were 0.7 mg/dl and 33 mg/dl.
      Table 1Baseline characteristics.
      Baseline characteristicsPatients
      Age at diagnosis (years)63.8 (54.9-73.1)
      Age at start of CT1 (years)64.8 (55.5-73.5)
      Male sex71 (50%)
      BMI (kg/m2)25.1 (22.5-28.6)
       Underweight (<18.5)4 (3%)
       Normal weight (18.5-24.9)62 (46.6%)
       Overweight (25-29.9)42 (31.6%)
       Obese (≥30)25 (18.8%)
      ABTC-subtype
       iCCA73 (51.4%)
       pCCA19 (13.4%)
       dCCA12 (8.5%)
       GBC30 (21.1%)
       Ampullary cancer6 (4.2%)
       Mixed2 (1.4%)
      T-stage
       T111 (9.2%)
       T269 (58.0%)
       T334 (28.6%)
       T45 (4.2%)
       Lymph node metastases55 (54.5%)
       Distant metastases45 (39.1%)
      UICC-stage
       I12 (9.4%)
       II35 (27.3%)
       III19 (14.8%)
       IV62 (48.4%)
      Tumor grading
       G11 (1.1%)
       G251 (55.4%)
       G340 (43.5%)
      ECOG PS
       067 (59.3%)
       139 (34.5%)
       2 or 37 (6.2%)
      Serological markers
       CEA (ng/ml)2.6 (1.6-8.7)
       CA19-9 (U/ml)122 (18.0-1600.2)
       Bilirubin (mg/dl)0.73 (0.5-1.27)
       Albumin (mg/dl)33 (26.0-37.5)
      Clinical parameters
       Initially resectable60 (42.3%)
       Recurrence after resection60 (100%)
       Neoadjuvant chemotherapy2 (1.4%)
       Adjuvant chemotherapy13 (9.2%)
      Recurrence localization
       Lymph node3 (5%)
       Intrahepatic29 (48.3%)
       Peritoneal metastases13 (21.7%)
       Distant metastases15 (25%)
       Resectable recurrence5 (8.3%)
      Continuous variables are expressed as median (IQR), categorical variables as n (%).
      ABTC, advanced biliary tract cancer; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CT1, first-line chemotherapy; dCCA, distal cholangiocarcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; GBC, gallbladder cancer; iCCA, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma; UICC, Union for International Cancer Control.

      Treatment outcome

      42.3% of patients were initially treated with curative surgical resection. Of these 21.6% (13/60) also received adjuvant chemotherapy (in most cases GemCis or capecitabine). Recurrence of ABTC occurred 10.5 months after surgery (median; Table 2). Patients whose malignancy was resected had superior OS of 27.9 months compared with 11.7 months in patients whose malignancy was not resected (log-rank test p <0.001; Fig. 1A). After recurrence, OS in patients who received an initial tumor resection was comparable to that of initially unresectable patients (log-rank test p = 0.130; Fig. 1B). Median time from unresectability until the start of first-line chemotherapy (CT1) was 1.1 months. In the palliative setting, 50.7% of patients received GemCis or gemcitabine/oxaliplatin (GemOx) as CT1. Gemcitabine monotherapy (13.4%), FOLFOX/CAPOX (10.6%) or FOLFIRINOX (7.7%) were used less frequently. More than half of patients (57%) were treated with a second-line chemotherapy (CT2) following disease progression. Regarding second-line therapy, most patients received FOLFOX/CAPOX (30.5%), followed by gemcitabine monotherapy (18.3%), GemCis/GemOx (17.1%), other capecitabine-based therapies (9.8%), FOLFIRI (4.9%) or FOLFIRINOX (4.9%). 25.1% received ≥3 lines of chemotherapy, while a 4th or 5th line could only be employed in 6.6% of patients. As third-line chemotherapy (CT3), FOLFIRI (18.4%), FOLFOX (18.4%), S1-based therapies (15.8%) and docetaxel (15.8%) were most commonly used. 27.5% of patients received additional locoregional therapy (transarterial chemoembolization [(10.6%)], selective internal radiation therapy [(9.2%)], radiotherapy [(7.7%)]).
      Table 2Treatment outcomes.
      Outcome
      Deceased127 (90.1%)
      Number of received chemotherapy lines
       158 (43.0%)
       243 (31.9%)
       325 (18.5%)
       ≥49 (6.6%)
      Number of received cycles
       Cycles of CT14.5 (2-8)
       Cycles of CT24 (2-6)
       Cycles of CT33 (2-5.25)
       Cycles of CT44 (1.75-5.25)
      Palliative oncological treatments
       FOLFIRINOX as CT111 (7.7%)
       FOLFIRINOX in any line25 (17.6%)
       FOLFOX/CAPOX as CT114 (9.9%)
       Targeted therapy17 (12%)
       Treatment with TACE15 (10.6%)
       Treatment with SIRT13 (9.2%)
       Treatment with radiotherapy11 (7.7%)
       Ongoing oncological treatment at data cut-off6 (4.2%)
      Survival times
       OS since diagnosis of ABTC18.4 (8.1-31.9)
       OS since resection (in case of resectability)27.9 (19.5-45.7)
       Recurrence-free survival10.5 (4.9-15.4)
       OS since unresectability14.5 (7.1-23.1)
       Time from unresectability until the start of CT11.1 (0.7-2.0)
       OS since start of CT111.4 (4.8-21.0)
       OS since start of CT28.0 (4.1-17.3)
       OS since start of CT36.2 (4.2-13.2)
       Duration of CT12.9 (1.1-6.4)
       Duration of CT22.8 (1.4-5.2)
       Duration of CT32.0 (1.0-2.8)
       OS since last CTX application1.8 (1.1-4.1)
      Continuous variables are expressed as median (IQR), categorical variables as n (%). Survival times are given in months and expressed as median (IQR).
      ABTC, advanced biliary tract cancer; CT1, first-line chemotherapy; CT2, second-line chemotherapy; CT3, third-line chemotherapy; OS, overall survival; SIRT, selective internal radiation therapy; TACE, transarterial chemoembolization.
      Figure thumbnail gr1
      Fig. 1Kaplan-Meier plots comparing OS.
      (A) OS since diagnosis with regard to initial resectability; (B) OS since unresectability with regard to initial resecteability; (C) OS since unresectability with regard to the number of received chemotherapy lines; (D) OS since the start of CT1 with regard to the chosen CT1 regimen; (E) OS since the start of CT2 with regard to the chosen CT2 regimen; (F) OS after unresectability with regard to a treatment with FOLFOX / CAPOX as CT1; (G) OS after unresectability with regard to a treatment with FOLFIRINOX at any point. P values were generated by using log-rank tests. CT1, first-line chemotherapy; CT2, second-line chemotherapy; CT3, third-line chemotherapy; OS, overall survival.
      Median OS was 6.7, 15.2, 18.2 and 24.6 months for patients receiving 1, 2, 3, or ≥4 lines of chemotherapy, respectively (log-rank test p <0.001, Fig. 1C). The median number of received therapy lines was 2 (range 1-5). The duration of CT1, CT2 and CT3 was 2.9, 2.8 and 2.0 months, respectively.
      In patients receiving FOLFOX/CAPOX as CT1, median OS was significantly lower than in patients receiving GemCis/GemOx with a difference of approximately 8 months (12.3 vs. 4.8 months; log-rank test p = 0.07; Fig. 1D-F).
      In contrast, a comparison of patients who had received FOLFIRINOX at some point with those who never did revealed a significantly prolonged survival for the FOLFIRINOX group (11.9 vs. 23.8 months; log-rank test p = 0.018; Fig. 1G). A comparison of prognostically relevant factors revealed that patients treated with FOLFIRINOX received more lines of chemotherapy and had lower bilirubin levels than those who never did.
      Regardless of the chemotherapy regimen received, median OS after the start of CT1, CT2 and CT3 was 11.4, 8.0 and 6.2 months, respectively. Time from the last administration of chemotherapy until death was 1.8 months (median). At the end of follow-up, 127 patients (90.1%) had died.
      Reported treatment outcomes and palliative chemotherapy regimens are summarized in Table 2 and Fig. 2. The fractions of patients who received 1, 2, 3 or ≥4 chemotherapy lines and their associated OS are illustrated in Fig. 3.
      Figure thumbnail gr2
      Fig. 2Flow chart illustrating first-, second- and third-line palliative chemotherapies.
      CT1, first-line chemotherapy; CT2, second-line chemotherapy; CT3, third-line chemotherapy; GemCis, gemcitabine + cisplatin; GemOx, gemcitabine + oxaliplatin.
      Figure thumbnail gr3
      Fig. 3Outcome and fractions of patients with advanced biliary tract cancer receiving sequential chemotherapy lines.
      Survival times were calculated by using Kaplan-Meier plots. OS, overall survival.

      Prognostic factors

      In the log-rank tests and univariate cox regression analyses, increasing age, gallbladder cancer, lymph node metastases, distant metastases, UICC-stage 3 or 4, poor differentiation (G3) and a poor ECOG PS were associated with a shorter OS (Table 3). The greatest differences in OS were found for ECOG PS (17.2 months OS for ECOG PS 0, 12.1 for ECOG PS 1 and 5.2 for ECOG PS ≥2; log-rank test p = 0.036; Fig. 4A), age at diagnosis (10 vs. 18.0 month OS for patients <65 years; log-rank test p = 0.001), distant metastases (10.8 vs. 17.6 month OS for patients without metastatic disease; log-rank test p = 0.003), tumor cell differentiation (10.3 vs. 16.5 months OS for patients with well or moderately differentiated tumor cells [G1, G2] compared with poorly differentiated tumor cells [G3]; log-rank test p = 0.005) and GBC (11.5 vs. 14.7 months OS for patients with other primary anatomic origins; log-rank test p = 0.006; Fig. 4B).
      Table 3Univariate cox proportional-hazards of death for selected factors.
      FactorHazard ratio (95% CI)p value
      Age at diagnosis (years)1.017 (1.002-1.033)0.029
      Age over 65 years at diagnosis1.756 (1.236-2.496)0.002
      Gallbladder cancer1.797 (1.174-2.749)0.007
      T-stage
       T1+T2 vs. T3+T41.181 (0.788-1.771)0.421
       Lymph node metastases1.627 (1.067-2.482)0.024
       Distant metastases1.817 (1.213-2.723)0.004
      UICC-stage
       I+II vs. III+V1.580 (1.069-2.337)0.022
      Tumor grading
       G1+G2 vs. G31.853 (1.192-2.882)0.006
      Number of received chemotherapy lines<0.001
       1Reference
       20.444 (0.294-0.671)<0.001
       30.334 (0.202-0.553)<0.001
       ≥40.258 (0.126-0.530)<0.001
       Treatment with FOLFIRINOX0.574 (0.360-0.914)0.019
      ECOG PS0.045
       0Reference
       11.516 (0.981-2.383)0.061
       2 or 32.443 (1.047-5.841)0.039
      Serological markers
       CEA >4.5 ng/ml1.859 (1.167-2.9620.009
       CA19-9 >1,000 U/ml1.580 (1.030-2.425)0.036
       Bilirubin >1.2 mg/dl1.649 (1.059-2.566)0.027
       Albumin >33 mg/dl0.456 (0.281-0.738)0.001
      Initially resectable0.760 (0.532-1.086)0.132
      The calculated p values and hazard ratios including a 95% CI are given. P values and hazard ratios were generated by using univariate cox proportional-hazards.
      CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ECOG PS, Eastern Cooperative Oncology Group performance status; UICC, Union for International Cancer Control.
      Figure thumbnail gr4
      Fig. 4Kaplan-Meier plots comparing OS based on prognostic factors.
      (A) OS since unresectability with regard to ECOG PS; (B) OS since unresectability with regard to the different biliary tract cancer subtypes; (C) OS since the start of CT1 with regard to pre-therapeutic CEA concentration; (D) OS since the start of CT1 with regard to pre-therapeutic CA19-9 concentration; (E) OS since the start of CT1 with regard to pre-therapeutic bilirubin concentration; (F) OS since the start of CT1 with regard to pre-therapeutic albumin concentration. P values were generated by using log-rank tests. CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CT1, first-line chemotherapy; dCCA, distal cholangiocarcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; GBC, gallbladder cancer; iCCA, intrahepatic cholangiocarcinoma; OS, overall survival; pCCA, perihilar cholangiocarcinoma.
      In addition, serological markers such as elevated CEA, CA19-9 or bilirubin levels were found to be associated with poor OS. In patients with CEA <4.5 ng/dl, CA19-9 <1,000 U/ml and bilirubin <1.2 mg/dl, OS was extended by 6.9, 3.8 and 7.3 months, respectively, in comparison to patients with higher levels (Fig. 4C-E). In contrast, an albumin level >33 mg/dl was associated with a 7.5 month extension in OS (Fig. 4F).
      Finally, no significant correlation with OS was found for BMI, T-stage and sex.

      Discussion

      GemCis/GemOx as CT1 and FOLFOX as CT2 have been established for patients with ABTC.
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      and 6.7-7.2 months after CT2
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      obtained in previous studies. In our analysis, OS was significantly dependent on the number of received therapy lines. It is worth noting that in our cohort almost twice as many patients received CT2 (57% vs. 32.5%) and CT3 (25.1% vs. 13.9%) as reported in a meta-analysis by Brieau et al., which could be a reason for the prolonged survival times observed in our study.
      • Brieau B.
      • Dahan L.
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      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.
      Therefore, our data suggest that patients with ABTC who are still fit for chemotherapy might benefit from later lines of therapy, which should lead to further investigation and consideration in clinical decision-making.
      In light of the survival times reported by us and others, there is still an urgent and unmet medical need for more efficacious treatments for ABTC. In this regard, several previous studies have failed to identify new and more effective therapies.
      • Moehler M.
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      Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program.
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      Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme.
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      Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials.
      • Valle J.W.
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      • Backen A.C.
      • Palmer D.H.
      • Morris K.
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      Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
      • Lee J.K.
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      A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas.
      • Malka D.
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      • de la Fouchardière 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.
      • Kim S.T.
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      • et al.
      Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial.
      Therefore, a variety of new treatment regimens, such as triple therapies like FOLFIRINOX (NCT02591030) or gemcitabine/cisplatin/nab-paclitaxel (NCT03768414) are currently being investigated in clinical trials.
      • Shroff R.T.
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      ,
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      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.
      ,
      • Phelip J.-M.
      • Edeline J.
      • Blanc J.-F.
      • Barbier E.
      • Michel P.
      • Bourgeois V.
      • et al.
      Modified FOLFIRINOX versus CisGem first-line chemotherapy for locally advanced non resectable or metastatic biliary tract cancer (AMEBICA)-PRODIGE 38: study protocol for a randomized controlled multicenter phase II/III study.
      In a recent study, FOLFIRNIOX appeared to be a valid alternative for CT1 reaching an OS of 15 months.
      • Ulusakarya A.
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      A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer.
      Furthermore, even when FOLFIRINOX was used as salvage treatment after GemCis failure, an OS of 13.2 months was achieved.
      • Ye L.F.
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      • et al.
      Efficacy and safety of modified FOLFIRINOX as salvage therapy for patients with refractory advanced biliary tract cancer: a retrospective study.
      These observations support our finding of a significantly prolonged OS in patients who received FOLFIRINOX at some point. However, AMEBICA PRODIGE 38, a randomized controlled trial, which compared treatment with FOLFIRINOX against GemCis did not meet its primary endpoint,
      • Phelip J.
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      which should be taken into account when considering our study results and the role of selection bias in our study. In addition to survival, the quality of life should not be neglected in the evaluation of novel triple therapies, as increased toxicity can lead to a higher rate of adverse events. Recent studies, however, have not reported abnormalities in this regard.
      • Ulusakarya A.
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      • Ciacio O.
      • Pittau G.
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      • et al.
      A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer.
      • Ye L.F.
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      Efficacy and safety of modified FOLFIRINOX as salvage therapy for patients with refractory advanced biliary tract cancer: a retrospective study.
      • Phelip J.
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      • Michel P.
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      Modified FOLFIRINOX versus CISGEM chemotherapy for patients with advanced biliary tract cancer (PRODIGE 38 AMEBICA): a randomized phase II study.
      ,
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      Efficacy and safety of FOLFIRINOX as salvage treatment in advanced biliary tract cancer: an open-label, single arm, phase 2 trial.
      Molecular targeted therapies hold great promise for the treatment of ABTC (reviewed in
      • O'Rourke C.J.
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      • Andersen J.B.
      Molecular targets in cholangiocarcinoma.
      ). One novel mechanism of action is the inhibition of FGFR1-4. In this line, the FGFR inhibitor pemigatinib has demonstrated a survival benefit as second-line treatment in a phase II study in patients with advanced iCCA and a FGFR gene rearrangement which led to its approval by the Food and Drug Administration.
      • Abou-Alfa G.K.
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      • Melisi D.
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      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      Consequently, results from the FIGHT-302 phase III trial (NCT03656536) investigating the efficacy of pemigatinib as first-line treatment in patients with FGFR2 fusions are highly awaited.
      • Bekaii-Saab T.S.
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      • Rimassa L.
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      • Ioka T.
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      FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements.
      In addition to pemigatinib, various other FGFR inhibitors, such as derazantinib (FIDES-01 phase II trial, NCT03230318), futibatinib (FOENIX-CCA3 phase III trial, NCT04093362) and infigrantinib (PROOF study, NCT03773302), are being tested in clinical trials.
      • Javle M.M.
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      • Borad M.J.
      • Abou-Alfa G.K.
      • et al.
      FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).
      • Javle M.M.
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      • Borad M.J.
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      • Morizane C.
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      • Oh D.-Y.
      • Moehler M.H.
      • et al.
      A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3).
      Another target for personalized therapies involves mutations in the IDH gene. In this regard, the ClarIDHy phase III trial (NCT02989857) reported a significantly longer progression-free survival for pretreated patients with iCCA who received ivodesinib in comparison to placebo.
      • Abou-Alfa G.K.
      • Valle J.W.
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      • Goyal L.
      • Shroff R.T.
      • Javle M.M.
      • et al.
      ClarIDHy: a phase 3 multicenter randomized double-blind study of AG-120 versus placebo in patients with non-resectable or metastatic cholangiocarcinoma with an IDH1 mutation.
      Moreover, cancer immunotherapy will continue to be explored for the treatment of ABTC despite disappointing results from the first clinical trials testing checkpoint inhibitors as monotherapy.
      • Bang Y.-J.
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      Currently, checkpoint inhibitors are evaluated in combination with established chemotherapies such as GemCis (EORTC-1607-GITCG [NCT03260712], Keynote-966 [NCT04003636] or TOPAZ-1[NCT03875235])
      • Finn R.S.
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      Abstract CT283: KEYNOTE-966: a randomized, double-blind, placebo-controlled, phase 3 study of pembrolizumab in combination with gemcitabine and cisplatin for the treatment of advanced biliary tract carcinoma.
      ,
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      • et al.
      A phase III, randomized, double-blind, placebo-controlled, international study of durvalumab in combination with gemcitabine plus cisplatin for patients with advanced biliary tract cancers: TOPAZ-1.
      and other targeted agents.
      • Marin J.J.G.
      • Prete M.G.
      • Lamarca A.
      • Tavolari S.
      • Landa-Magdalena A.
      • Brandi G.
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      In this regard, the TOPAZ-1 trial, investigating a combination therapy with the PD-L1 inhibitor durvalumab and GemCis already showed promising results in an interim analysis in which it met its primary endpoint of a prolonged OS compared to GemCis. However, it remains to be seen how all these novel treatments will affect the overall outcome and management of patients with ABTC.
      Regarding prognostic factors, ECOG PS has been identified previously and is used in the current ESMO guidelines to select patients for an appropriate CT1 therapy regimen. Thus, patients with an ECOG PS of 0-1 should receive treatment with GemCis, while patients with an ECOG PS ≥2 should instead receive gemcitabine monotherapy.
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      Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials.
      In addition to ECOG PS,
      • Peixoto R.D.
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      A population based analysis of prognostic factors in advanced biliary tract cancer.
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      • Bridgewater J.
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      Prognostic factors for progression-free and overall survival in advanced biliary tract cancer.
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      several other factors such as old age at diagnosis,
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      lymph node metastases,
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      • Ito Y.
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      distant metastases,
      • Bridgewater J.
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      • Malka D.
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      Prognostic factors for progression-free and overall survival in advanced biliary tract cancer.
      poor tumor cell differentiation,
      • Lurje G.
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      • Czigany Z.
      • Lurje I.
      • Schlebusch I.K.
      • Boecker J.
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      gallbladder cancer
      • Okusaka T.
      • Nakachi K.
      • Fukutomi A.
      • Mizuno N.
      • Ohkawa S.
      • Funakoshi A.
      • et al.
      Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan.
      ,
      • Eckel F.
      • Schmid R.M.
      Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials.
      ,
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      • Lopes A.
      • Wasan H.
      • Malka D.
      • Goldstein D.
      • Shannon J.
      • et al.
      Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer.
      or levels of bilirubin,
      • Bridgewater J.
      • Lopes A.
      • Wasan H.
      • Malka D.
      • Jensen L.
      • Okusaka T.
      • et al.
      Prognostic factors for progression-free and overall survival in advanced biliary tract cancer.
      albumin, or CA19-9
      • Grunnet M.
      • Christensen I.J.
      • Lassen U.
      • Jensen L.H.
      • Lydolph M.
      • Knox J.J.
      • et al.
      Decline in CA19-9 during chemotherapy predicts survival in four independent cohorts of patients with inoperable bile duct cancer.
      have previously been reported to be associated with survival in ABTC and can therefore inform clinical decision-making. Our findings lend further support to their prognostic value. Taking these parameters one step further, prognostic scores can be employed to predict the outcome of patients, as has already been shown for the ALAN and Glasgow score.
      • Muller L.
      • Mahringer-Kunz A.
      • Jungmann F.
      • Tanyildizi Y.
      • Bartsch F.
      • Czauderna C.
      • et al.
      Risk stratification in advanced biliary tract cancer: validation of the A.L.A.N. Score.
      ,
      • Moriwaki T.
      • Ishige K.
      • Araki M.
      • Yoshida S.
      • Nishi M.
      • Sato M.
      • et al.
      Glasgow Prognostic Score predicts poor prognosis among advanced biliary tract cancer patients with good performance status.
      Regarding the limitations of our study, one major limitation is its retrospective and monocentric design. In addition, the possibility of selection bias must be considered. Thus, the superior OS of patients who received sequential therapy lines and those who received FOLFIRINOX at some point may have been due to a selection bias (patients in a generally better condition are more likely to receive both more lines of chemotherapy as well as FOLFIRINOX). Furthermore, the number of patients who received ≥3 lines of chemotherapy was comparatively small, which could influence the observed survival times as well. As molecular profiling is becoming increasingly important for successful therapy nowadays, it should also be mentioned that our study did not document patients’ mutational profiles, which could have additionally influenced the observed survival and should be considered in subsequent studies.
      Nevertheless, the reported survival times are an important guide for both patients and their treating physicians, precisely because the patient populations and conditions within controlled clinical trials can be very dissimilar from those of everyday clinical practice.
      Following the publication by Valle et al. in 2010, GemCis was quickly adopted as the new standard-of-care first-line chemotherapy in ABTC. Our study which covers the second decade of the 21st century, attests to this quick adoption and sets the benchmark for future oncological treatments. Analysis of clinical data provides an important pillar in addressing current knowledge gaps by generating hypotheses that can be confirmed in randomized controlled trials. Current problems such as the lack of first-line therapies besides GemCis or unclear evaluation regarding the efficacy of later lines can thus be addressed. In light of the currently ongoing clinical trials there is reason for optimism that the poor prognosis of patients with ABTC can be significantly improved in the coming years, whether by improving molecular profiling in combination with targeted therapies or by using immunotherapy in combination with classical chemotherapy.

      Financial support

      This research received no external founding.

      Authors’ contributions

      FF: conceptualization, methodology, project administration, supervision. FT, SJG and FF: writing-original draft preparation, validation. FT: formal analysis, visualization. FT, SJG, CC, TT, TG, YH, JV, JL, MMi, FB, LM, RK, PRG, MAW, JUM, MMo, AW and FF: writing-review and editing, data collection. All authors have read and agreed to the published version of the manuscript. This manuscript contains parts of the doctoral thesis of FT at the “Johannes Gutenberg-Universität Mainz”.

      Data availability statement

      Data is contained within the article or Supplementary Material.

      Conflicts of Interest

      The authors declare no conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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