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Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, GermanyDepartment of Medicine I, University Hospital Schleswig-Holstein, Lübeck, Germany
Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, GermanyDepartment of Medicine I, University Hospital Schleswig-Holstein, Lübeck, Germany
Corresponding author. Address: Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckst. 1, 55131 Mainz, Germany; Tel.: +49-6131-17-6077.
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.
). The term ABTC encompasses various cancer entities that originate in the bile ducts, the gallbladder (GBC) and the ampulla of Vater. Bile duct carcinomas are also termed cholangiocarcinoma (CCA) and are categorized as intrahepatic (iCCA), perihilar (pCCA) and distal CCA depending on their primary site of origin.
Recurrences are frequent even after successful surgical resection, which makes the use of adjuvant chemotherapy a subject of current research (reviewed in
Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin.
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.
Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial.
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.
FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).
Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial.
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).
). 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 characteristics
Patients
Age at diagnosis (years)
63.8 (54.9-73.1)
Age at start of CT1 (years)
64.8 (55.5-73.5)
Male sex
71 (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
iCCA
73 (51.4%)
pCCA
19 (13.4%)
dCCA
12 (8.5%)
GBC
30 (21.1%)
Ampullary cancer
6 (4.2%)
Mixed
2 (1.4%)
T-stage
T1
11 (9.2%)
T2
69 (58.0%)
T3
34 (28.6%)
T4
5 (4.2%)
Lymph node metastases
55 (54.5%)
Distant metastases
45 (39.1%)
UICC-stage
I
12 (9.4%)
II
35 (27.3%)
III
19 (14.8%)
IV
62 (48.4%)
Tumor grading
G1
1 (1.1%)
G2
51 (55.4%)
G3
40 (43.5%)
ECOG PS
0
67 (59.3%)
1
39 (34.5%)
2 or 3
7 (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 resectable
60 (42.3%)
Recurrence after resection
60 (100%)
Neoadjuvant chemotherapy
2 (1.4%)
Adjuvant chemotherapy
13 (9.2%)
Recurrence localization
Lymph node
3 (5%)
Intrahepatic
29 (48.3%)
Peritoneal metastases
13 (21.7%)
Distant metastases
15 (25%)
Resectable recurrence
5 (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.
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
Deceased
127 (90.1%)
Number of received chemotherapy lines
1
58 (43.0%)
2
43 (31.9%)
3
25 (18.5%)
≥4
9 (6.6%)
Number of received cycles
Cycles of CT1
4.5 (2-8)
Cycles of CT2
4 (2-6)
Cycles of CT3
3 (2-5.25)
Cycles of CT4
4 (1.75-5.25)
Palliative oncological treatments
FOLFIRINOX as CT1
11 (7.7%)
FOLFIRINOX in any line
25 (17.6%)
FOLFOX/CAPOX as CT1
14 (9.9%)
Targeted therapy
17 (12%)
Treatment with TACE
15 (10.6%)
Treatment with SIRT
13 (9.2%)
Treatment with radiotherapy
11 (7.7%)
Ongoing oncological treatment at data cut-off
6 (4.2%)
Survival times
OS since diagnosis of ABTC
18.4 (8.1-31.9)
OS since resection (in case of resectability)
27.9 (19.5-45.7)
Recurrence-free survival
10.5 (4.9-15.4)
OS since unresectability
14.5 (7.1-23.1)
Time from unresectability until the start of CT1
1.1 (0.7-2.0)
OS since start of CT1
11.4 (4.8-21.0)
OS since start of CT2
8.0 (4.1-17.3)
OS since start of CT3
6.2 (4.2-13.2)
Duration of CT1
2.9 (1.1-6.4)
Duration of CT2
2.8 (1.4-5.2)
Duration of CT3
2.0 (1.0-2.8)
OS since last CTX application
1.8 (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).
(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.
Fig. 2Flow chart illustrating first-, second- and third-line palliative chemotherapies.
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.
Factor
Hazard ratio (95% CI)
p value
Age at diagnosis (years)
1.017 (1.002-1.033)
0.029
Age over 65 years at diagnosis
1.756 (1.236-2.496)
0.002
Gallbladder cancer
1.797 (1.174-2.749)
0.007
T-stage
T1+T2 vs. T3+T4
1.181 (0.788-1.771)
0.421
Lymph node metastases
1.627 (1.067-2.482)
0.024
Distant metastases
1.817 (1.213-2.723)
0.004
UICC-stage
I+II vs. III+V
1.580 (1.069-2.337)
0.022
Tumor grading
G1+G2 vs. G3
1.853 (1.192-2.882)
0.006
Number of received chemotherapy lines
<0.001
1
Reference
2
0.444 (0.294-0.671)
<0.001
3
0.334 (0.202-0.553)
<0.001
≥4
0.258 (0.126-0.530)
<0.001
Treatment with FOLFIRINOX
0.574 (0.360-0.914)
0.019
ECOG PS
0.045
0
Reference
1
1.516 (0.981-2.383)
0.061
2 or 3
2.443 (1.047-5.841)
0.039
Serological markers
CEA >4.5 ng/ml
1.859 (1.167-2.962
0.009
CA19-9 >1,000 U/ml
1.580 (1.030-2.425)
0.036
Bilirubin >1.2 mg/dl
1.649 (1.059-2.566)
0.027
Albumin >33 mg/dl
0.456 (0.281-0.738)
0.001
Initially resectable
0.760 (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.
(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.
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.
Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial.
Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin.
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.
Second-line chemotherapy prolongs survival in real world patients with advanced biliary tract and gallbladder cancers: a multicenter retrospective population-based cohort study.
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.
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.
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.
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.
Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial.
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.
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.
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.
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,
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.
). 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.
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.
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.
FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).
Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial.
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.
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.
Currently, checkpoint inhibitors are evaluated in combination with established chemotherapies such as GemCis (EORTC-1607-GITCG [NCT03260712], Keynote-966 [NCT04003636] or TOPAZ-1[NCT03875235])
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.
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.
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.
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.
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”.
Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin.
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.
Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial.
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.
FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).
Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial.
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).
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.
Second-line chemotherapy prolongs survival in real world patients with advanced biliary tract and gallbladder cancers: a multicenter retrospective population-based cohort study.
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.
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.
Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial.
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.
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.
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.
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.
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.
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