Chemotherapy For Biliary Tract Cancer Research Articles

Real-world experience supporting the role of oncologic resection and adjuvant chemotherapy in biliary tract cancers.

Complete resection followed by adjuvant chemotherapy is the gold standard for patients with localized cholangiocarcinoma (CC) or gallbladder cancer (GBC). However, this is not always feasible, and recurrence rates remain high. To understand the real-world proportions and reason for treatment failure in resected biliary tract cancers. We performed a retrospective population-based review of patients with GBC or CC [intrahepatic (IHCC) or extrahepatic (EHCC)] resected between 2005 and 2019 using the BC Cancer provincial database. A chart review was conducted to characterize demographics, treatments received and outcomes. In total, 594 patients were identified of whom 416 (70%) had disease recurrence. Most GBCs (96%) were diagnosed incidentally, and repeat oncologic resection was performed in 45%. Adjuvant chemotherapy was received in 51% of patients diagnosed after 2017 (mostly capecitabine). Patient co-morbidities, disease progression and patient preference were the commonest reasons for not proceeding with adjuvant chemotherapy. One-third of patients did not complete all planned cycles. Median overall survival was significantly higher in those with complete (R0) versus incomplete (R1) resection [31.6 versus 18 months, hazard ratio (HR): 0.43, 95% confidence interval (CI): 0.35-0.53] and in those with versus without re-resection for GBC [29.4 versus 19 months, HR: 0.55, 95% CI: 0.41-0.73]. There was a trend towards improved survival with versus without adjuvant therapy (HR: 0.79, 95% CI: 0.61-1.02). Only 25% in the more contemporary cohort (2017-2019) had an R0 resection and completed adjuvant chemotherapy. Complete resection, including reresection for incidentally diagnosed GBCs, and adjuvant chemotherapy were associated with improved outcomes in this retrospective cohort, yet many patients were not able to complete these treatments. Neoadjuvant strategies may improve treatment delivery and ultimately, outcomes.

Feasibility of S-1 adjuvant chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202

IntroductionMajor hepatectomy (MH) may produce the impaired liver function and affect the feasibility of adjuvant chemotherapy in terms of early period after the surgery, but there have not been detailed investigations. JCOG1202 (UMIN000011688) is a randomized phase III trial demonstrating the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine the influence of MH for BTC on adjuvant S-1. Materials and methodsOf the total 424 patients, 207 received S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH) for BTC. ResultsIn the S-1 arm, 42 had undergone MH, and 165 had undergone NMH. MH had similar pretreatment features to NMH, including the proportion of biliary reconstruction, to NMH, except for a lower platelet count (17.7 vs. 23.4 × 104/mm3, p < 0.0001) and lower serum albumin level (3.5 vs. 3.8 g/dL, p < 0.0001). The treatment completion proportion tended to be lower for MH than for NMH (59.5 % vs. 75.8 %; risk ratio, 0.786 [95 % confidence interval, 0.603–1.023], p = 0.0733), and the median dose intensity was lower as well (88.7 % vs. 99.6 %, p = 0.0358). The major reasons for discontinuation were biliary tract infections and gastrointestinal disorders after MH. The frequency of grade 3–4 biliary tract infection was 19.0 % in MH vs. 4.2 % in NMH. ConclusionThe treatment completion proportion and dose intensity were lower in MH than in NMH. Caution should be exercised against biliary tract infections and gastrointestinal disorders during adjuvant S-1 after MH for BTC.

Unresectable intrahepatic cholangiocarcinoma: TARE or TACE, which one to choose?

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and its incidence is rising in Western countries. Although surgical resection is considered the only curative treatment, up to 70% of patients are diagnosed at an advanced stage, which precludes surgical intervention. Those who are inoperable become candidates for systemic treatment. Currently, the combination of gemcitabine and cisplatin is the first-line chemotherapy, with a median overall survival (OS) of about one year. Recently, there has been a notable increase in evidence regarding chemotherapy for biliary tract cancer; however, the effectiveness of the new chemotherapy drugs still needs to be evaluated. Today, intra-arterial therapies (IAT), especially trans-arterial chemoembolization (TACE) and trans-arterial radioembolization (TARE), are widely used. Both TACE and TARE have demonstrated good efficacy in controlling localized disease and in improving survival. However, current literature does not conclusively show whether TACE is superior to TARE or vice versa. As recent meta-analyses have indicated, both TACE and TARE offer suboptimal objective response rates but yield similar positive outcomes. It’s important to note that these findings are based on single-center studies, which often include a small number of patients and lack a comparative design. Therefore, when comparing such studies, there’s an inevitable selection bias among the treatment groups (TACE or TARE) and significant heterogeneity. This review outlines the current evidence on the use of interventional IAT in managing ICC.

Adjuvant and neoadjuvant chemotherapy for biliary tract cancer: a review of randomized controlled trials.

The first randomized controlled trial of adjuvant chemotherapy for biliary tract cancer was reported in 2002. Since then, studies have continued, with efficacy reported for capecitabine in 2018 and S-1 in 2023. Oral fluoropyrimidines have become established as the standard of care. This article reviews the evidence from the randomized controlled trials reported to date and those that are ongoing or from which results have not yet been reported.

ADJUBIL: A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer.

TPS4187 Background: Despite improvements in multidisciplinary management, patients with biliary tract cancer (BTC) have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. Data regarding pure adjuvant chemotherapy in BTC’s are conflicting and the SOC of the western world is currently capecitabine according to the British BILCAP- trial, even though BILCAP was formally negative. Based on the positive data for durvalumab in the TOPAZ- 1 – trial in BTC and for STRIDE- regimen in HCC according to the Himalaya- data, evaluation of IO- combination in the adjuvant setting seems to be promising. Preclinical studies indicate that the antibody combination results in stronger and more durable anti-tumor effects than single therapies by synergistically modulating the immunosuppressive tumor microenvironment which is particularly rich in cholangiocarcinoma. The aim of this study is the assessment of the clinical activity of the anti-PD-L1 (programmed- death 1-ligand) antibody durvalumab and the anti-CTLA-4 (cytotoxic T- lymphocyte-associated antigen 4) antibody tremelimumab in combination with or without capecitabine in patients with respectable BTC in the adjuvant situation. This is a randomized phase II study as a proof-of-concept for a potentially larger research program. Methods: The ADJUBIL trial is an open-label, multicenter phase II study, including patients with BTC after curative surgery with no previous systemic treatment. Patients are randomly assigned to receive tremelimumab (300mg, one dose) plus durvalumab (1500mg every 4 weeks; STRIDE, for a maximum of 12 months), with or without capecitabine (for 8 cycles). Forty evaluable patients will be enrolled in the study (1:1) to receive anticancer treatment until disease recurrence or intolerable toxicities. Primary objective is to assess the anti-tumor activity of the treatment in both arms by the recurrence-free survival rate after 12 months (RFS@12). Secondary endpoints are recurrence-free survival, overall survival, toxicity, and quality of life. Exploratory endpoints: Explore predictive biomarkers for recurrence-free survival and overall survival. Study start of the ADJUBIL trial was in June 2021. By January 2023, 12 centers across Germany have been initiated and a total of 8 out of 40 planned patients (1:1) have been enrolled. The study is currently ongoing. Clinical trial information: EUCTR2021-002389-41 .

Current progress in perioperative chemotherapy for biliary tract cancer.

Biliary tract cancer (BTCs) is a heterogeneous malignancy divided into cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Due to little or no symptoms, most patients with BTCs are diagnosed with unresectable or metastatic disease. Only 20%-30% of all BTCs are suitable for potentially resectable diseases. Although radical resection with a negative surgical margin is the only potentially curative method for BTCs, most patients develop postoperative recurrence, which is associated with poor prognosis. Therefore, perioperative treatment is necessary to improve survival. There are very few randomized phase III clinical trials of perioperative chemotherapy due to the relative rarity of BTCs. Adjuvant chemotherapy with S-1 for patients with resected BTC significantly increased overall survival compared with upfront surgery in a recent ASCOT trial. In East Asia, S-1 is currently considered the standard adjuvant chemotherapy, while capecitabine may still be used in other areas. Since then, our phase III trial (KHBO1401), gemcitabine and cisplatin plus S-1 (GCS) has become the standard chemotherapy for advanced BTCs. GCS not only improved overall survival but demonstrated a high response rate. The efficacy of GCS as a preoperative neoadjuvant chemotherapy for resectable BTCs has been investigated in a randomized phase III trial (JCOG1920) in Japan. In this review, we summarize the current and ongoing clinical trials focusing on adjuvant and neoadjuvant chemotherapy for BTCs.

Adjuvant chemotherapy for resected intrahepatic cholangiocarcinoma confers no survival advantage.

560 Background: Randomized data suggest improved survival with adjuvant chemotherapy for biliary tract cancers, but subset analyses of intrahepatic cholangiocarcinoma (ICC) show limited survival benefit. This study uses a large bi-institutional cohort of resected ICC patients to evaluate the impact of adjuvant therapy on recurrence patterns and overall survival (OS) and compares these findings to data from a national cancer registry. Methods: Patients with resected ICC were identified within a bi-institutional cohort (Duke and Memorial Sloan Kettering, 1997-2020) and the National Cancer Database (NCDB, 2010-2018). Patients were stratified by treatment with adjuvant chemotherapy (adj). Site of first recurrence was categorized as local (liver only), regional (liver and perihepatic nodes), nodal (perihepatic nodes only), distant, or mixed (both liver and distant). OS was compared with Kaplan-Meier methods. Results: 367 patients underwent resection for ICC, and 163 (44%) patients received adjuvant therapy. Median follow-up was 33 vs. 44 months (adj vs observation (obs), p=0.15). 263 (72%) patients had recurrent disease, most commonly in the liver (72%). There was no difference in recurrence patterns stratified by treatment with adjuvant chemotherapy (% recurrence, adj vs obs; local: 42 vs 42; regional: 2 vs 2; nodal: 0 vs 3; distant only: 27 vs 26; mixed: 29 vs 27, p=0.5). OS was the same between groups (adj vs obs; 42 vs 49 months, p=0.3) and when stratified by recurrence site (p=0.5). Similarly, in an NCDB cohort of 1,159 ICC patients over the same time period, there was no association between adjuvant therapy and OS (adj vs obs; 49 vs 57 months, p=0.1). Conclusions: In this retrospective dual registry analysis, corroborated by national data, adjuvant chemotherapy was not associated with an improvement in OS in ICC patients subjected to curative intent resection. Further, adjuvant therapy had no impact on the high rate of hepatic recurrence, suggesting that alternative strategies, such as liver directed therapies, are needed to improve recurrence rates and OS.

Effects of gene expression in 5-FU metabolic pathways in a phase III trial evaluating adjuvant S-1 therapy compared to surgery alone following curative resection for biliary tract cancer (JCOG1202A1).

732 Background: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy in Japanese patients with resected biliary tract cancer (BTC), based on the results of JCOG1202, a phase III trial evaluating adjuvant S-1 following curative resection for BTC compared to surgery alone. The efficacy of 5-FU-based therapy is related to the expression of enzymes involved in 5-FU metabolic pathways, such as thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD). The aim of this study was to evaluate the impact of messenger RNA (mRNA) levels of the four 5-FU metabolic pathway genes on the outcomes of patients enrolled in JCOG1202. Methods: Tumor cell RNA was isolated from formalin-fixed paraffin-embedded primary BTC specimens resected in 264 of 440 randomized patients in JCOG1202. The four 5-FU metabolic pathway genes were measured in 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89) who were randomly divided to training (n = 96) or validation set (n = 87). The endpoints of interest were the predictive values of the four genes for the efficacy of adjuvant S-1 on overall survival and relapse-free survival (RFS), and we here report the results regarding RFS. Cut-off levels for mRNA expression were selected in the training set which minimized the bootstrap p-values (2,000 samples) of an interaction term of treatment (surgery alone or S-1) and mRNA expression in a Cox regression model. Results: There were no obvious differences in each mRNA level and clinical characteristics between surgery alone and adjuvant S-1 groups. RFS tended to be better with adjuvant S-1 (hazard ratio [HR] = 0.790, [95% confidence interval: 0.524-1.192]) compared to surgery alone, which was maintained in the low DPD population (HR = 0.440 [0.216-0.898] in training set and 0.748 [0.334-1.675] in validation set), in the low TP population (HR = 0.709 [0.388-1.296] and 0.602 [0.287-1.262]), and in the high OPRT population (HR = 0.520 [0.152-1.779] and 0.609 [0.161-2.304]). Conclusions: The efficacy of adjuvant S-1 on RFS was representative in BTC patients with intratumoral gene expressions of low DPD, low TP, and high OPRT, which was disappeared in the population with high DPD, high TP, and low OPRT. These biomarkers might be useful to predict therapeutic benefits with S-1 containing chemotherapy for BTC.

Chemotherapy for biliary tract cancer -current status and future prospects

Chemotherapy for biliary tract cancer -current status and future prospects

Clinical Implications of BRCA Mutations in Advanced Biliary Tract Cancer

Introduction: Current standard chemotherapy for biliary tract cancer (BTC) has limited survival benefits, and the need for targeted therapies is increasing. This study investigated the genetic profiles and clinical implications of BRCA mutations in patients with advanced BTC. Methods: Targeted high-throughput sequencing was performed on samples obtained from 25 patients with advanced BTC who had received palliative first-line platinum-based chemotherapy. Results: Of the 25 patients, 16 (64.0%) were younger than 65 years of age and 16 (64.0%) were male. The BTC cases consisted of intrahepatic cholangiocarcinoma (9, 36.0%), extrahepatic cholangiocarcinoma (5, 20.0%), and gallbladder cancer (11, 44.0%). The median overall survival (OS) and progression-free survival (PFS) of all patients were 11.9 months (95% confidence interval [CI]: 9.2–14.6) and 5.6 months (95% CI: 3.8–7.3), respectively. Genomic alterations in TP53 (52.0%), BRCA (36.0%), ATM (32.0%), ERBB2 (24.0%), NOTCH1 (20.0%), and FGFR3 (20.0%) were frequently reported. TP53 and ATM mutations were associated with OS (TP53: hazard ratio [HR] 2.719, 95% CI: 1.074–6.881, p = 0.035; ATM: HR 2.780, 95% CI: 1.091–7.082, p = 0.032). Patients with BRCA mutations had a slightly improved PFS compared to those with intact BRCA (6.7 months [range, 2.7–10.7 months] vs. 5.3 months [range, 3.6–7.0 months], p = 0.090). However, there was no significant difference in OS between groups (BRCA mutant vs. intact: 10.6 months [range, 3.6–17.6 months] vs. 11.9 months [range, 7.5–16.3 months], p = 0.252). BRCA mutations were significantly associated with PFS in the multivariate analysis (HR 0.150, 95% CI: 0.034–0.655, p = 0.012). Conclusion: This study demonstrated that BRCA mutations might have a role as predictive biomarkers for palliative first-line platinum-based chemotherapy in patients with advanced BTC.

Health-related quality of life in patients treated with gemcitabine/cisplatin and durvalumab ± tremelimumab in chemotherapy-naïve advanced biliary tract cancer.

4117 Background: In the phase 2 (NCT03046862), gemcitabine/cisplatin (GemCis) and durvalumab (D) ± tremelimumab (T) in chemotherapy-naïve advanced biliary tract cancer (BTC) showed a high objective response rate and durable clinical benefit. Based on this study, phase 3 trial (TOPAZ-1, NCT03875235) has been conducted and the positive result for adding D to GemCis has been reported. Health-related quality of life (HRQoL) for adding immunotherapy to cytotoxic chemotherapy in BTC has not been reported yet. We present HRQoL results from the phase 2 study. Methods: In this study, treatment-naïve patients with unresectable or recurrent BTC were enrolled into three cohorts. Patients received one cycle of GemCis followed by GemCis plus D and T (cohort 1) or, starting with the first cycle, received GemCis plus D (cohort 2) or GemCis plus D and T (cohort 3). The EORTC Quality of Life Questionnaire (QLQ)-C30 and BIL21 were administered at baseline and every cycle throughout treatment. Change from baseline to post-2 cycles and deterioration of HRQoL (≥10 points change) were analysed. Results: At data cut-off (March 22, 2021), 126 patients (32 in cohort 1, 47 in cohort 2, 47 in cohort 3) were included for this analysis. Compliance for QLQ was very high ( &gt; 90 %) at all time points. C30 global health status (GHS) scores remained stable at all time points and from baseline to post 2 cycles (mean [95% CI] change, 2.66 [-1.10‒6.42]), with greater improvements observed in patients with responder (a best response of complete response (CR) or partial response (PR)) (3.60 [-1.27 to 8.47]) compared to non-responder (stable disease (SD) or progressive disease (PD) (0.66 [-5.19 to 6.51]). For the overall cohort, functioning scales also remained stable from baseline to post 2 cycles. Nausea/vomiting (8.4 [4.45 to 12.36]), dyspnea (7.28 [2.17 to 12.4]), constipation (9.24 [3.35 to 15.13]), financial difficulties (5.53 [1.65 to 9.41]) in C30 and eating (5.53 [1.65 to 9.41]), tiredness (5.42 [1.23 to 9.6]), treatment side effects (7.98 [1.15 to 14.81] in BIL21 were worse at post 2 cycles. However, pain (-7.14 [-12.24 to -2.04]), diarrhea (-4.48 [-8.86 to -0.1]) in C30 and jaundice (-5.51 [-9.26 to -1.76]), pain (-6.02 [-9.7 to -2.34] in BIL21 were improved and more improvement was shown in responder compared to non-responder. Regarding deterioration of C30 GHS, median deterioration-free survival (months [95% CI]) was 4.14 (2.66-6.47) in all cohorts and there was no difference between responder (3.68 [2.27-7.92]) and non-responder (5.59 [2.73-9.46], Hazard ratio = 1.00 [95% CI, 0.62-1.61], p = 0.997). There was no difference among 3 cohorts. Conclusions: GemCis plus D ± T in chemotherapy-naïve advanced BTC generally preserved HRQoL and improved some symptom scales such as jaundice and pain although chemotherapy related symptom scales were worse.

Signal enhancement ratio of CE-MRI: a potential biomarker of survival after hepatic arterial infusion chemotherapy in biliary tract cancers

BackgroundThe association of contrast-enhanced MRI (CE-MRI) and the overall survival (OS) of biliary tract cancers (BTC) is ambiguous. Thus, the aim of this study is to evaluate the value of signal enhancement ratio (SER) and its early change in CE-MRI as biomarkers of survival after hepatic arterial infusion chemotherapy (HAIC) in BTC.ResultsOne hundred and two BTC patients treated via HAIC with 3cir-OFF regimen between January 2011 and June 2020 were enrolled in this retrospective study. The median progression-free survival (PFS) and OS were 9.8 months [range 1.5–83.3 months, 95% confidence interval (CI) 7.789–11.811] and 14.2 months (range 1.8–83.3 months, 95% CI: 11.106–17.294), respectively. The cutoff value of SER before HAIC (SER0) was 1.04, and both median PFS and OS in the SER0 ≥ 1.04 group were longer than in the SER0 < 1.04 group (median PFS: 10.5 vs. 8.5 months, p = 0.027; median OS: 23.9 vs. 12.3 months, p < 0.001). The median OS in the ΔSER > 0 group was longer than in the ΔSER < 0 group (17.3 versus 12.8 months, p = 0.029 (ΔSER means the change of SER after two cycles of HAIC). Multivariate analysis showed SER0 (p = 0.029) and HAIC treatment cycle (p = 0.002) were independent predictors of longer survival.ConclusionsSER in CE-MRI before HAIC (SER0) is a potential biomarker for the prediction of survival after HAIC in advanced BTC.

Individual patient data meta-analysis of adjuvant gemcitabine-based chemotherapy for biliary tract cancer: combined analysis of the BCAT and PRODIGE-12 studies

BackgroundAlthough gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies. MethodsWe performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan–Meier curves and a Cox regression model stratified on the trial. ResultsTwo hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71–1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%–47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%–43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78–1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%–57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%–56.5%) for observation. ConclusionWith 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

Current status and future perspectives of chemotherapy for biliary tract cancer

Current status and future perspectives of chemotherapy for biliary tract cancer

Survival Outcomes of Gemcitabine Plus S-1 Adjuvant Chemotherapy after Surgical Resection for Advanced Biliary Tract Cancer

Introduction: The usefulness of adjuvant chemotherapy in biliary tract cancer (BTC) is poorly reported. This study aimed to evaluate the effectiveness and safety of adjuvant gemcitabine plus S-1 (GS) chemotherapy after curative surgical resection for BTC. Methods: 225 BTC patients who underwent surgical resection between January 2006 and May 2019 were enrolled in this study. Twenty-seven patients received adjuvant chemotherapy with GS (GS group), whereas 67 patients underwent surgery alone (S group). Twenty-three matching pairs were derived through propensity score (PS) matching analysis. Patients received 12 cycles of adjuvant chemotherapy (70 mg/m² oral S-1 for 7 consecutive days plus intravenous gemcitabine 1,000 mg/m² on day 7). The primary end point was recurrence-free survival (RFS). The secondary end points were the 1-, 2-, and 3-year RFS and overall survival (OS) rates, tolerability, and frequency of grade 3/4 toxicity. Results: The completion rate was 81.5%; no treatment-related deaths were observed. Grade 3/4 adverse events were seen in 40.7% of the patients. RFS (3-year RFS rate: 59.3% vs. 39.1%, p = 0.049) and OS (3-year OS rate: 71.7% vs. 53.4%, p = 0.008) were significantly better in the GS group than in the S group among PS-matched pairs. Discussion/Conclusion: GS chemotherapy after curative surgery was well tolerated, showed better clinical benefit in the adjuvant setting, and can effectively reduce BTC recurrence.

Chemotherapy for Biliary Tract Cancer in 2021.

Biliary tract cancer refers to a group of malignancies including cholangiocarcinoma, gallbladder cancer, and ampullary cancer. While surgical resection is considered the only curative treatment, postoperative recurrence can sometimes occur. Adjuvant chemotherapy is used to prolong prognosis in some cases. Many unresectable cases are also treated with chemotherapy. Therefore, systemic chemotherapy is widely introduced for the treatment of biliary tract cancer. Evidence on chemotherapy for biliary tract cancer is recently on the increase. Combination chemotherapy with gemcitabine and cisplatin is currently the standard of care for first-line chemotherapy in advanced cases. Recently, FOLFOX also demonstrated efficacy as a second-line treatment. In addition, efficacies of isocitrate dehydrogenase inhibitors and fibroblast growth factor receptor inhibitors have been shown. In the adjuvant setting, capecitabine monotherapy has become the standard of care in Western countries. In addition to conventional cytotoxic agents, molecular-targeted agents and immunotherapy have been evaluated in multiple clinical trials. Genetic testing is used to check for genetic alterations and molecular-targeted agents and immunotherapy are introduced based on tumor characteristics. In this article, we review the latest evidence of chemotherapy for biliary tract cancer.

ARID1A mutation to predict disease progression during first-line chemotherapy in biliary tract cancer patients.

4105 Background: Biliary tract cancer (BTC) is a retractable disease showing a dismal prognosis with therapeutic resistance. There are clinical unmet needs on predicting therapeutic response and precise strategy for the patient classification according to clinically relevant tumor biology in the patients with BTC. We aimed to identify clinically detectable genomic alteration predicting therapeutic response after first-line chemotherapy in BTC using real-world data. Methods: A comprehensive genomic analysis of multi-institutional cohorts of BTC cases was performed using next-generation sequencing (NGS) with targeted DNA panel and patients’ clinicopathologic data. Results: A total of 200 BTC patients with NGS panel tests from three cancer centers were included in this study. The genomic alteration of TP53 (55.5%), KRAS (23%), ARID1A (10%), and ERBB2 amplification (10%) were the most frequent alteration events in the BTC. Pathologically-proved BTC including extrahepatic (n = 52), ampulla of Vater (n = 4), gallbladder (n = 56), intrahepatic (n = 88) cancers showed a distinct pattern of genomic alterations in terms of ARID1A for extrahepatic BTC and ERBB2 amplification, RB1, ARID2 for GB cancer, and KRAS, IDH1, PBRM1, BAP1 for intrahepatic BTC respectively (chi-square test, P &lt; 0.05). The oncologic outcomes for progression-free and overall survival were significantly stratified according to the best response after the first-line chemotherapy (log-rank test, P &lt; 0.001). The logistic regression test revealed that ARID1A, BRCA2, and STK11 could significantly predict disease progression during first-line chemotherapy. ARID1A, especially, was the only independent predictive marker in the multivariate regression model in total BTC (OR 3.91, 95%CI 1.25-11.66, P = 0.015) and extrahepatic BTC (OR 5.71, 95%CI 1.23-28.98, P = 0.027). The predictive performance of significant genomic alteration was enhanced with the tumor marker CA19-9 (DeLong’s test, Z = 1.933, P = 0.053, AUC 0.73, 95%CI 0.623-0.837). Conclusions: Clinically available NGS test showed distinct genomic alterations in terms of different deterioration patterns for oncogenic molecular pathways according to the anatomic locations of BTC. Integrative analysis using the data for genomic alteration and therapeutic response for the first-line chemotherapy uncover that the patients with ARID1A mutation show a significant disease progression rate during initial treatment for BTC, especially in the extrahepatic BTC. Prospective translational studies revealing underlying biology and precision strategy should be followed to improve the therapeutic response of BTC.

Perioperative chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone in gallbladder carcinoma or in front of radical resection in BTC: The phase III GAIN trial.

TPS353 Background: Radical surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) and Gallbladder Carcinoma (GBC). Nevertheless, 5-year OS is only 20–40% after curatively intended resection. GBC is the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. The majority of gallbladder carcinoma cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication, so called incidental gallbladder carcinomas. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. Encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase management of GBC and intrahepatic as well extrahepatic cholangiocarcinoma, especially because data regarding pure adjuvant chemotherapy in BTC`s are currently conflicting. Methods: GAIN is a multicenter, randomized, controlled, open-label phase III trial, including pts with GBCs in front of radical liver resection and pts with resectable/borderline resectable intra- and extrahepatic cholangiocarcinomas (ICC/ECC). Pts. are randomized to either neoadjuvant systemic chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) followed by radical surgery or to direct surgery without neoadjuvant treatment. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has just started; first patient in was on December 6th, 2019. Clinical trial information: NCT03673072.

Prognostic Impact of Sarcopenia in Patients With Biliary Tract Cancer Undergoing Chemotherapy.

Sarcopenia affects the treatment of various cancer types but its impact on chemotherapy efficacy and prognosis in biliary tract cancer remains unclear. Thus, we evaluated whether sarcopenia independently affects the outcome of chemotherapy for biliary tract cancer. Data of 50 patients who underwent chemotherapy for biliary tract cancer at two affiliated centres were retrospectively analysed. The association of clinical factors, including sarcopenia, with overall survival and time to treatment failure was analysed. Sarcopenia was an independent factor negatively influencing overall survival and time to treatment failure in univariate and multivariate analyses (median overall survival, sarcopenic vs. non-sarcopenic patients: 10.6 vs. 16.6 months; hazard ratio=2.19, p=0.018; time to treatment failure: 5.3 vs. 13.1 months, hazard ratio=2.50, p=0.019). Sarcopenia may affect the efficacy of chemotherapy and prognosis in biliary tract cancer. Thus, improving sarcopenia may improve the prognosis of patients with biliary tract cancer undergoing chemotherapy.

PO-1044: Postoperative hypofractionated Image-Guided IMRT concomitant to chemotherapy in biliary tract cancer

PO-1044: Postoperative hypofractionated Image-Guided IMRT concomitant to chemotherapy in biliary tract cancer