Advanced Biliary Cancer Research Articles

Systemic therapy in younger and elderly patients with advanced biliary cancer: sub-analysis of ABC-02 and twelve other prospective trials

BackgroundOutcomes in younger (<40 years) and elderly (≥70 years) patients with advanced biliary cancer (ABC) receiving palliative chemotherapy are unclear. This study assessed outcomes in those receiving monotherapy or combination therapy in thirteen prospective systemic-therapy trials.MethodsMultivariable analysis explored the impact of therapy on progression-free (PFS) and overall survival (OS) in two separate age cohort groups: <70 years and ≥70 years, and <40 years and ≥40 years.ResultsOverall, 1163 patients were recruited (Jan 1997-Dec 2013). Median age of entire cohort: 63 years (range 23–85); 36 (3%) were <40, 260 (22%); ≥70. Combination therapy was platinum-based in nine studies. Among patients <40 and ≥70 years, 23 (64%) and 182 (70%) received combination therapy, respectively. Median follow-up was 42 months (95%-CI 37–51). Median PFS for patients <40 and ≥40 years was 3.5 and 5.9 months (P = 0.12), and OS was 10.8 and 9.7 months, respectively (P = 0.55). Median PFS for those <70 and ≥70 years was 6.0 and 5.0 months (P = 0.53), and OS was 10.2 and 8.8 months, respectively (P = 0.08). For the entire cohort, PFS and OS were significantly better in those receiving combination therapy: Hazard Ratio [HR]-0.66, 95%-CI 0.58–0.76, P < 0.0001 and HR-0.72, 95%-CI 0.63–0.82, P < 0.0001, respectively; and in patients ≥70 years: HR-0.54 (95%-CI 0.38–0.77, P = 0.001) and HR-0.60 (95%-CI 0.43–0.85, P = 0.004), respectively. There was no evidence of interaction between age and treatment for PFS (P = 0.58, P = 0.66) or OS (P = 0.18, P = 0.75).ConclusionsIn ABC, younger patients are rare, and survival in elderly patients in receipt of systemic therapy for advanced disease, whether monotherapy or combination therapy, is similar to that of non-elderly patients, therefore age alone should not influence decisions regarding treatment.

Chemotherapy in patients with hepatobiliary cancers and abnormal hepatic function.

Sorafenib and cisplatin plus gemcitabine currently represent first-line treatment standards in advanced hepatocellular carcinoma and biliary cancer, respectively. Conventional cytotoxic agents (monotherapy or combination therapy) have demonstrated activity in the second-line setting or in those in which first-line agents are contraindicated. A strategy for safe yet effective administration of such systemic therapies in patients with advanced hepatobiliary cancer and abnormal liver function needs to be strongly considered. Here, we highlight the safety and tolerability of systemic therapies routinely used for the treatment of advanced hepatobiliary cancer in patients with hepatic dysfunction. Based on data from available clinical studies, we review dosing strategies recommended for chemotherapy and targeted therapy in those with liver dysfunction. Dose modifications for many agents in this population remain empiric due to limited clinical evidence. Future dedicated phase I studies are needed to provide further dosing considerations for combination therapy in those with abnormal liver function in which data is lacking.

Outcomes of second line treatment in patients with advanced and metastatic biliary cancers.

420 Background: Advanced biliary cancers respond poorly to chemotherapy and have a dismal survival. Currently gemcitabine-cisplatin (GC) is the standard of care for patients with advanced disease. The efficacy of second line treatment options is not well-defined. We retrospectively evaluated outcomes of patients undergoing second line treatment for advanced biliary cancers at Mayo Clinic. Methods: After obtaining approval from the institutional board review (IRB), we identified 42 patients with advanced and metastatic biliary cancers that progressed after first line (GC) and received second line treatment from 2007-2014. All patients had adequate follow up data. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of &lt; 0.05 was considered significant. Results: The median age at diagnosis was 61.5 (range 26-87). The most common regimens used for second line settings were 5-FU-based (69%) followed by gemcitabine-based regimens (19%). The overall response rate (ORR) was 9.1%, while the disease control rate (DCR; stable disease and partial response) was 33%. The median overall survival (mOS) for the entire cohort from first line was 16.8 months (95% CI 12.7-21.7) and the progression-free survival (PFS) was 9.16 months (95% CI 7.3-14.7). From second line start the mOS was 10.4 months (95%; CI 7.3-23.7), and PFS was 2.8 months (95% CI 2.3-4.0). 73% of patients who received second line therapy were alive at 6 months and 50% at 12 months. 25 patients received third line treatment after progression. An univariate and multivariate analysis were performed including age, sex, stage at diagnosis, regimen used, CA19-9 and total body weight loss &gt; 5%, but no significant prognostic factors were identified. Conclusions: Patients with biliary cancers who progress after first line treatment have poor prognosis, but may benefit from second line regimens. 5-FU based regimens were the most commonly used in the second line setting, and 73% of patients who received second line therapy were alive at 6 months.

Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary cancer after failure of gemcitabine plus cisplatin: Retrospective analysis of 321 patients.

425 Background: In advanced biliary tract cancer (BTC), the role of 2nd line chemotherapy after failure of 1st line gemcitabine plus cisplatin (GEMCIS) has not been established. Fluoropyrimidine(FP)-based regimens are widely used as 2nd line treatment in clinical practice. We retrospectively analyzed the efficacy of 2nd line FP-based chemotherapy in patients(pts) with advanced BTC after failure of GEMCIS. Methods: Histologically confirmed advanced BTC pts who received 1st line GEMCIS at Asan Medical Center between December 2010 and June 2016 were identified. Among 748 pts treated with GEMCIS, 331 patients (44%) subsequently received 2nd line chemotherapy and FP-based regimens were used in 321 pts (97%). Results: The median age was 60 years (range, 27-82) and 57% of pts were male. Intrahepatic cholangiocarcinoma(IH-CCC) (44%) was the most common type, and followed by extrahepatic cholangiocarcinoma (32%). Most pts (n = 289, 89%) had metastatic/recurrent disease at the time of 1st line treatment. FP alone and FP plus platinum combination were used in 255 pts (79%) and 66 pts (21%), respectively. In pts with measurable disease, response rate (RR) was 3% (8/301) and disease control rate was 47% (142/301). After a median follow-up of 27.6 months (0.9-70.4 months), the median progression free survival (PFS) and overall survival (OS) were 1.9 months (95% CI, 1.6-2.2) and 6.5 months (95% CI, 5.9-7.0). RR was significantly higher in pts with combination of FP and platinum compared to FP alone (8% vs 1%, p = 0.009). However, there were no statistically significant differences in terms of PFS (p = 0.43) or OS (p = 0.88) between two groups. In the multivariate analysis for OS, IH-CCC, initially metastatic disease and elevated CA 19-9 level at the time of 1st line treatment, and time-to-progression at 1st line GEMCIS &gt; 4 months were independent poor prognostic factors. Conclusions: In this analysis, FP-based regimen showed modest efficacy as 2nd line chemotherapy for advanced BTC patients after failure of 1st line GEMCIS. Combination of FP and platinum was not associated with improved survival outcomes compared to FP monotherapy, despite of higher RR.

A phase I/II trial of MEK162 in combination with gemcitabine (G) and cisplatin (C) for patients (pts) with untreated advanced biliary cancer (ABC).

290 Background: Activating mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in ABC. MEK162 is an oral, selective small molecule inhibitor of MEK1/2; single agent activity of MEK162 in ABC has previously been observed. Preclinical data support anti-tumor synergy for MEK inhibition (MEKi) when combined with G &amp; C, only when MEKi is held for 2 days prior to and on day of each G and C infusion. Methods: A Single arm, non-randomized, open-label, phase I/II,evaluated oral MEK162 twice daily with G and C IV infusions day 8 and 15 of a 21 day cycle. MEK162 was. Eligibility criteria were: untreated ABC, with advanced measurable disease, ECOG 0-1, adequate hematologic, renal, hepatic and cardiac function. The primary endpoints were to determine the MTD (phase 1); and 6 month PFS and response rate (RR) (phase II). Tumor tissue for targeted somatic mutational sequencing was evaluated. Results: Between 09/13 and 09/15, 12 pts were enrolled on phase 1, the MTDs were MEK162 45mg PO BID, in combination with G 800 mg/m2 and C 20mg/m2. 35 pts evaluable for primary endpoint of phase II (29 treated on phase II &amp; 6 pts treated at MTD in phase 1): Male = 19, median age 63 years (range 48- 77). Cholangiocarcinoma (CC) = 24, and gallbladder adenocarcinoma (GB) = 11. Median overall survival was 21 months (95% CI 11- NA), median PFS 6 months (95% CI 4-14). Molecular profiling using MSK-IMPACT 410 gene panel was feasible in 29 pts; aberrations in the RAS-RAF-MEK-ERK pathway were notable in responding pts including mutations in PIK3CA, AKT2, PIK3CG, KRAS, BRAF and MAP3K1. Overall RR was 36%, GB 45%, CC 32%. Two pts had CR, two pts remain on study &gt; 24 months, currently on MEK162 alone. Conclusions: The MTDs were MEK162 45mg PO BID, in combination with G 800 mg/m2 and C 20mg/m2.. Significant activity of the combination was noted in select pts with prolonged and complete response to treatment. Molecular profiling of BTC may facilitate selection of pts for further development of the combination. Clinical trial information: NCT01828034.

Chemotherapy for Biliary Tract Cancer

The term of biliary tract cancer (BTC) refers to all tumors that arise from the biliary tract or the biliary drainage system, including the intra- and extra-hepatic bile ducts as well as the gallbladder. BTCs are aggressive tumors with limited treatment options and poor overall survival. Currently, surgery remains to be the only potentially curative treatment, and most patients develop recurrence. For advanced tumors, only limited effective treatment modalities exist today. Gemcitabine plus cisplatin is considered as a standard option for advanced biliary cancer. A randomized phase III trial (ABC-02 trial) showed superiority of gemcitabine plus cisplatin over gemcitabine alone. In that study, they showed that after a median follow-up of 8.2 months, the median overall survival was 8.1 months in the gemcitabine-only group and 11.7 months in the gemcitabine plus cisplatin group (p<0.001). However, while this is a definite advancement, a 3-month survival extension among patients with BTC is modest at best. Moreover, this regimen has not been compared head-to-head with other gemcitabine based combinations. Gemcitabine monotherapy, 5-fluorouracil plus leucovorin, and single-agent capecitabine are all reasonable options for patients with a borderline performance status. Recent advancements have provided new insight into the genomic landscape of BTCs, and thus, it remains unclear whether combined treatment with molecular targeted agents or other cytotoxic chemotherapeutic agents may also be effective against advanced BTC.

Clinical implications of APEX1 and Jagged1 as chemoresistance factors in biliary tract cancer

PurposeBiliary cancer is a highly malignant neoplasm with poor prognosis and most patients need to undergo palliative chemotherapy, however major clinical problem associated with the use of chemotherapy is chemoresistance. So far, we aimed at investigating clinical implications of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and Jagged1 as chemoresistance factors in biliary tract cancer.MethodsWe used 5 human biliary tract cancer cell lines (SNU-245, SNU-308, SNU-478, SNU-1079, and SNU-1196), and investigated the chemosensitivity of APEX1 and Jagged1 through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Western blot. Alternately, the 10 patients of advanced biliary cancer consist of 2 group according to the chemotherapy response examined by immunohistochemistry using APEX1 and Jagged1 antibody, and protein expression level was scored for staining intensity and percent positive cell.ResultsThe result of MTT assay after APEX1 knockdown showed that strong coexpression of APEX1 and Jagged1 cell line (SNU-245, SNU-1079, and SNU-1196) showed a greater decrease in IC50 of chemotherapeutic agent (5-fluorouracil, gemcitabine and cisplatin). The Western blot analysis of APEX1 and Jagged1 expression in biliary cancer cell lines after APEX1 knockdown definitively demonstrated decreased Jagged1 expression. The APEX1 and Jagged1expression level of immunohistochemistry represented that chemorefractory patients had higher than chemoresponsive patients.ConclusionThese results demonstrate that simultaneous high expression of APEX1 and Jagged1 is associated with chemoresistance in biliary cancer and suggest that is a potential therapeutic target for chemoresistance in advanced biliary cancer.

Systemic treatment in advanced biliary cancers: A multicenter Australian analysis and review.

While first-line palliative chemotherapy (CT1) improves survival and quality of life in advanced biliary cancer (ABC), there is no randomized evidence to support second-line chemotherapy (CT2) in ABC. We aim to explore to role of CT2 in ABC. We performed a retrospective review of all patients who received one or more lines of chemotherapy for ABC at four Australian cancer centers between 2008 and 2011. A Cox proportional hazard model was developed to determine the impact of clinicopathologic variables on overall survival (OS) from time of progression on CT1. We identified 73 patients who received palliative chemotherapy for ABC. Twenty-five patients (34%) received two or more lines of chemotherapy. Patients with a preserved performance status on progression on first-line chemotherapy (CT1) were more likely to receive second-line chemotherapy (CT2) (P < 0.001). Disease control rate with CT2 was 36%, and mean progression-free survival was 3.2 months (95% confidence interval 1.5-4.9 months). The following variables were significant in the univariate analysis of OS from time of progression on CT1: lines of chemotherapy (P = 0.0001), Eastern Cooperative Oncology Group performance status at progression on CT1 (P < 0.0001) and disease control with CT1 (P = 0.027). Lines of chemotherapy received and performance status remained significant in the multivariate analysis for OS from progression on CT1. Second-line chemotherapy is feasible in a subset of patients with ABC. Even after accounting for confounding variables, CT2 appears to increase OS in ABC, although we are unable to exclude other unmeasured factors such as tumor biology. These findings warrant further evaluation with prospective trials.

The rise of the FGFR inhibitor in advanced biliary cancer: the next cover of time magazine?

Cholangiocarcinomas (CCAs) are heterogeneous tumors arising from the biliary tract with features of cholangiocyte differentiation. CCAs are aggressive tumors with limited treatment options and poor overall survival. Only a subset of CCA patients with early stage disease can avail potentially curative treatment options. For advanced biliary tract tumors, currently there are limited effective treatment modalities. Recent advances have provided greater insight into the genomic landscape of CCAs. The fibroblast growth factor receptor (FGFR) pathway is involved in key cellular processes essential to survival and differentiation. Accordingly, aberrant FGFR signaling has significant oncogenic potential. Recent discovery of FGFR2 gene fusions in CCA has heightened interest in FGFR inhibition in advanced biliary tract cancer. These findings have served as a catalyst for ongoing clinical investigation of FGFR inhibition in CCA patients with various FGFR signaling abnormalities. Herein, we review FGFR aberrations in CCA and their prognostic implications, FGFR targeting as a viable therapeutic option in advanced biliary tract malignancies, and future directions for development of combination approaches utilizing FGFR inhibition.

698P - Phase I study of DKN-01 (D), an anti-DKK1 monoclonal antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) with advanced biliary cancer (ABC)

698P - Phase I study of DKN-01 (D), an anti-DKK1 monoclonal antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) with advanced biliary cancer (ABC)

Second-line chemotherapy (CTx) outcomes in advanced biliary cancers (ABC): A retrospective multicenter analysis.

Second-line chemotherapy (CTx) outcomes in advanced biliary cancers (ABC): A retrospective multicenter analysis.

Phase I study of DKN-01, an anti-DKK1 antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) with advanced biliary cancer.

e15603Background: DKK1 is an inhibitor of the canonical Wnt/β-catenin pathway and a direct modulator of non-canonical signaling. DKK1 is thought to enhance the invasive properties of cholangiocarci...

Major hepatopancreatoduodenectomy with simultaneous resection of the hepatic artery for advanced biliary cancer.

Major hepatopancreatoduodenectomy (HPD) with simultaneous resection of the hepatic artery (HA) for biliary cancer is the most extended surgery for obtaining curative resection, and its clinical significance is unclear. The aim of this study was to appraise the clinical value of this extended procedure as a treatment for biliary cancer. We retrospectively reviewed the medical records of 38 patients with biliary cancer who underwent major HPD from 1994 to 2014. Clinicopathological factors and survival following HPD were compared between patients with and without simultaneous resection of the HA. Of the 38 study patients, 12 patients (32%) underwent major HPD with HA. There was no significant difference in major complications between the two groups. The overall 2-year survival rate and the median survival time following major HPD with HA were 71% and 42.3months. The survival of the patients with gallbladder cancer was significantly worse than that of the patients with bile duct cancer (p = 0.001). Major HPD with simultaneous resection of the HA can be a preferable treatment option for bile duct cancer that offers acceptable perioperative morbidity and mortality, as well as long-term survival. However, this procedure for gallbladder cancer should not be performed.

Second-line chemotherapy (CTx) outcomes in advanced biliary cancers (ABC): A retrospective multicenter analysis.

437 Background: While gemcitabine in combination with platinum has been well established as first line systemic therapy for ABC, there remains no standard of care regimen in the second line setting. We evaluated current practice and outcomes for second line chemotherapy in patients with ABC across three geographically diverse, large US academic medical centers. Methods: 198 pts who received second line chemotherapy for ABC after 1/1/11 were identified from institutional databases following IRB approval. Records were reviewed for demographic, treatment and response data. Overall survival (OS) was calculated from start of second line chemotherapy and estimated using Kaplan-Meier methods. Results: Median follow up among survivors was 5 months and median OS for all patients from start of second line therapy was 11 months (mo) (95% CI 8.8-13.1): intrahepatic (61.1%): 13.4 mo (95%CI: 10.7-17.8); extrahepatic (14.1%): 6.8 mo (95%CI: 5-11); and gallbladder (24.8%): 9.4 mo (95%CI: 7.2-12.3). Median duration of second line chemotherapy was 2.2 mo (range 0-32.5). 103 pts (52%) received ≥ 3 lines of chemotherapy. Median OS from start of first line of gemcitabine plus cisplatin or oxaliplatin was 22.4 mo (95% CI 17.9 – 25.5). Conclusions: In highly selected pts with ABC treated at academic medical centers, survival following progression on first line chemotherapy was higher than previously reported, and patients received multiple lines of treatment. This multicenter collaboration provides a contemporary benchmark to inform the hypotheses and design of future clinical trials of second line chemotherapy in ABC. [Table: see text]

Molecular profiling of advanced biliary cancer: Lost in translation from bench to bedside.

283 Background: Advanced Biliary Cancer (ABC) is a collection of diseases which carry poor prognosis, and many patients derive limited benefit from chemotherapy. Identification of molecular drivers of ABC may help to predict treatment response and direct development of targeted therapy. Methods: Formalin fixed paraffin embedded (FFPE) tissue form patients with ABC treated at Princess Margaret Cancer Centre was analysed by MassARRAY Sequenom panel (23 genes, 279 mutations), or by next general sequencing (NGS) using Proton or Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage). Clinicopathologic and treatment data were collected from electronic health records. Results: Of 112 tested patients, 16 had insufficient DNA, and 96 had data for analysis: 13 with ampullary cancer (AC), 19 with hilar/distal bile duct (DBD), 43 with gallbladder (GBC), and 21 with intrahepatic (IHC). 13 patients had Sequenom testing, 85 had NGS with Miseq or Proton. 127 mutations were identified in 60 patients, 36 had no mutations detected: 23 in AC, 54 in GBC, 24 in IHC, 26 in DBD. The most frequent mutations were in TP53 (34%) and KRAS (20%). TP53 and SMAD4 mutations appeared most common in GBC, BRAF and KRAS mutations were most common in AC, and IDH1 and FGFR2mutations were seen only in IHC. 14 patients (15%) had a mutation for which targeted treatment could be applied. Conclusions: Profiling of patients with ABC is feasible and can identify some molecular drivers, with different tumour sites demonstrating distinct biological patterns. Only a limited number of patients are shown to have clinically relevant mutations with current NGS techniques, suggesting additional techniques (whole genome/RNA sequencing) may be required to fully characterise these diseases and identify new therapeutic targets. [Table: see text]

An institutional analysis of gemcitabine and capecitabine for advanced biliary cancer.

342 Background: The results of ABC-2 trial established gemcitabine and cisplatin (gem-cis) as a standard regimen for advanced biliary cancer. Although no randomized trial has been performed with gemcitabine and capecitabine (gem-cap), this regimen has reported benefits and has been a standard treatment at our institution. We report our experience with outcomes and toxicity. Methods: This is a single institution, retrospective study from 2005-2015 of patients with advanced biliary cancer, including intra and extrahepatic cholangiocarcinoma (IHCC/EHCC) and gallbladder carcinoma (GBC). Overall survival (OS) and progression-free survival (PFS) on gem-cap were reported using standard Kaplan-Meier methods. Comparisons were made using log-rank test. Results: A total of 372 patients were identified. Of these, 227 (61.0%) had chemotherapy data at our institution. A total of 153 patients (41.1%) received gem-cap, 133/153 (86.9%) received it in first line. The majority of patients (67.4%) had metastatic disease. Twenty-seven patients (17.6%) received it as adjuvant therapy, of which 16 (10.5%) also received adjuvant radiation. Forty-four patients (33.1%) received second line of chemotherapy and 12 (9.0%) received third line. Disease sites included 48.9% IHCC, 24.0% EHCC and 27.1% GBC. Median follow-up was 45.1 months (mo). The median OS and PFS for the entire cohort were 13.0 mo (95% CI 10.7-17.4) and 8.0 mo (6.0-9.3), respectively. Patients with metastatic disease had poorer OS and PFS compared to locally advanced disease: median OS – 11.4 vs 16.3 mo (p = 0.01); median PFS – 6.9 vs 10.4 mo (p &lt; 0.001). There was no statistically significant differences in OS/PFS by disease site. Overall, 69 patients (55.6%) experienced grade 3/4 toxicity. The most common (35.7%) was hematologic toxicity (neutropenia/thrombocytopenia). Other adverse events included elevated LFT’s (9.3%) and non-hematologic events (22.5%), including fatigue (6.8%) and hand-foot syndrome (6.0%). Conclusions: Gem-cap provides a similar PFS to gem-cis based on historical comparison with ABC-2 trial. Gem-cap may offer the advantage of fewer adverse events (55.6%) compared to the 70.7% reported in ABC-2. Prospective comparison of these two regimens is warranted.

Multi-institutional phase II trial of single agent regorafenib in refractory advanced biliary cancers.

TPS468 Background: Currently, there is no standard second line treatment for patients with advanced biliary tract cancer (BC) who have failed prior systemic therapy. Aberrant activation of the Ras/Raf/MEK/ERK pathway occurs in more than 60% of BC indicating the importance of this pathway in biliary carcinogenesis. Furthermore anti-angiogenic agents such as the VEGF-antagonist bevacizumab, and the multikinase inhibitor sorafenib have been tested in BC in the first line setting with modest activity. Regorafenib is an oral multi-kinase inhibitor that targets multiple membrane-bound and intracellular kinases including VEGF, the Ras/Raf/MEK/ERK and PDGFR- ß pathways. Given the pivotal role of these pathways in biliary cancer biology, the clinical evaluation of regorafenib represents a novel and rational approach to treat this disease. Methods: This is a multi-institutional phase II single arm single-stage design trial using regorafenib as single agent. Patients with histologically or cytologically-proven locally advanced or metastatic biliary tract carcinomas that failed no more than 2 prior line of systemic chemotherapy are eligible for this study. Patients must have measurable disease per RECIST 1.1 criteria and never been treated with VEGF inhibitors. Patients will receive regorafenib 160 mg daily (21 days on and 7 days off) and will be evaluated for response every 2 cycles (1cycle = 28 days). The study’s primary endpoint is 6 month overall survival. Secondary endpoints are to define disease control, progression-free survival and toxicity related to treatment. Correlative biomarker studies using plasma samples will be performed to investigate levels of 40 relevant proteins associated with the above-mentioned pathways in the attempt to identify predictive markers of drug benefit. As per September 2015, twelve of the 39 planned patients have been accrued for the study. In addition to Moffitt Cancer Center, this trial will enroll patients at the UNC Lineberger Comprehensive Cancer Center and VCU Massey Cancer Center. Clinical trial information: NCT02115542.

Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data

BackgroundAfter progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far.MethodsWe collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings.ResultsA total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months).ConclusionsThe current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.

Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: the ABC-02 and BT-22 studies

The superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone in patients with advanced biliary tract cancer (ABC) has been demonstrated in two randomised trials; ABC02 and the Biliary Tract (BT) 22 study. We used a combined dataset from these two trials to investigate the derived neutrophil-to-lymphocyte ratio (dNLR), which is thought to be a prognostic factor associated with clinical outcomes in several solid tumours, including ABC. White blood cell (WBC) and absolute neutrophil count (ANC) were available for 379 of 410 patients from ABC-02 and all 83 patients in BT-22. The dNLR was calculated as ANC/(WBC-ANC), as previously specified. We examined the association between dNLR and overall survival (OS) and progression-free survival (PFS), as well as comparing the treatment effect in two patient groups defined by their dNLR level. A high dNLR was defined as ≥3.0, which was approximately the upper tertile value. A total of 462 individual patient records were analysed, 328 with baseline dNLR <3 and 134 with dNLR ≥3. There were 443 deaths in the cohort, and all surviving patients had a dNLR <3. There was strong evidence that dNLR was closely associated with both OS [hazard ratio (HR), 1.62; 95% confidence interval (CI) 1.32-2.01] and PFS (HR, 1.40; 95% CI 1.13-1.72). There was limited evidence (P = 0.10) of a differential effect of CisGem on OS between the two dNLR groups, but this was clearest in the ABC-02 dataset (P = 0.06). There was good evidence (P = 0.008) of an association between low baseline dNLR and long-term survival on a CisGem regimen. There was also good evidence of an association between ECOG performance status (split at 0 and 1 versus 2) on both OS (P < 0.001) and PFS (P = 0.01), but no evidence of a differential treatment effect, with both groups receiving benefit from the addition of cisplatin. These data confirm that high dNLR is associated with worse OS and PFS, and suggests it may also be predictive of benefit for the addition of cisplatin to gemcitabine in European patients with ABC. Incorporating dNLR into the clinical context may better inform prognosis and chemotherapy decisions in ABC patients.

2299 Nab-paclitaxel as second-line treatment in advanced biliary cancer

2299 Nab-paclitaxel as second-line treatment in advanced biliary cancer