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DCK expression, a potential predictive biomarker in the adjuvant gemcitabine chemotherapy for biliary tract cancer after surgical resection: results from a phase II study.

ABSTRACT: The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. This clinical phase II trial was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patients were started on intravenous infusions of gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of every 28-day cycle. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry. This study enrolled 72 patients with BTC (26 with gallbladder cancer, 33 with extrahepatic cholangiocarcinoma, and 13 with intrahepatic cholangiocarcinoma). The 2-year recurrence-free survival (RFS) rate was 43% (95% CI, 33-57%). Multivariable analysis showed that DCK expression, vascular invasion, and lymph node metastasis were significantly associated with RFS. Twenty-one (31.8%) were positive for DCK immunoreactivity. The median RFS was 34.95 months for DCK-positive patients, compared with 11.41 months for DCK-negative patients. Although the primary hypothesis of this study, defined as a 2-year RFS of 60%, was not met, intratumoral DCK expression was significantly associated with RFS in patients with resected BTC treated with postoperative gemcitabine chemotherapy. Future randomized controlled trials are warranted.

SUBMITTER: Woo SM

PROVIDER: S-EPMC5655294 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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DCK expression, a potential predictive biomarker in the adjuvant gemcitabine chemotherapy for biliary tract cancer after surgical resection: results from a phase II study.

Woo Sang Myung SM Yoon Kyong-Ah KA Hong Eun Kyung EK Park Weon Seo WS Han Sung-Sik SS Park Sang-Jae SJ Joo Jungnam J Park Eun Young EY Lee Ju Hee JH Kim Yun-Hee YH Kim Tae Hyun TH Lee Woo Jin WJ

Oncotarget 20170706 46

The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. This clinical phase II trial was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patients were started on intravenous infusions of gemcitabine 1000 mg/m<sup>2</sup> over 30 min on days 1, 8, and 15 of every 28-day cycle. Intratumoral expression of cyti ...[more]

PMID: 29113399

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Project description:Gemcitabine is a principal chemotherapeutic agent for biliary tract cancer (BTC). Expression of human equilibrative nucleoside transporter 1 (hENT1) is regarded as a potential predictive biomarker for a gemcitabine response in some cancers. This study was conducted to investigate the association between hENT1 expression and the effects of gemcitabine on BTC cell lines and on patients with advanced BTC receiving gemcitabine-based chemotherapy. A total of four BTC cell lines, HuCCT1, SNU-478, SNU-1079, and SNU-1196, were tested. mRNA and protein expression levels of hENT1 were measured by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively. Cell viability after gemcitabine treatment was measured in a chemosensitivity assay. For clinical assessment, 40 patients with unresectable or recurrent BTC who were treated with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) between June 2012 and May 2014 were enrolled. Among the four cell lines, SNU1196 showed the highest mRNA and protein levels of hENT1. Expression of hENT1 showed a linear correlation with the log value of the half-maximal inhibitory concentration of gemcitabine. During incubation with gemcitabine, pretreatment with hENT1-specific small interfering RNA (siRNA) resulted in higher cell viability than that in samples pretreated with control siRNA. In a clinical evaluation, the median progression-free survival was 24 and 11 weeks among patients with strong and weak intratumoral hENT1 immunohistochemical staining (P = 0.05), and the median overall survival was 52 and 26 weeks (P = 0.15), respectively. In conclusion, this study showed that increased hENT1 expression is associated with a stronger toxic effect of gemcitabine on BTC cell lines. The clinical outcomes in this study suggest that increased intratumoral hENT1 immunohistochemical staining is a possible biomarker predicting better therapeutic effects of gemcitabine on patients with advanced BTC. Further studies are needed to determine the precise role of hENT1 in BTC.

Project description:BackgroundComplete 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.ObjectivesTo understand the real-world proportions and reason for treatment failure in resected biliary tract cancers.Design and methodsWe 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.ResultsIn 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.ConclusionComplete 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.

Project description:ImportanceThe association of adjuvant chemotherapy (AC) with survival in the general population of patients with resected biliary tract cancer (BTC) remains controversial. As such, the role of this treatment in the treatment of older adult patients (aged ≥70 years) needs to be evaluated.ObjectiveTo describe the patterns of use of AC and compare survival outcomes of AC and observation in older adult patients following resection of BTC.Design, setting, and participantsThis retrospective cohort study included 8091 older adult patients with resected BTC with data available in the National Cancer Database from January 1, 2004, to December 31, 2019. Patients were divided into 2 cohorts: AC and observation. The AC cohort was subdivided into single-agent and multiagent AC treatment.ExposuresAdjuvant chemotherapy vs observation following BTC resection.Main outcomes and measuresThe primary outcome was overall survival (OS) of patients who received AC compared with observation following resection of BTC as evaluated using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Inverse probability of treatment weighting and propensity score matching were performed to address indication bias.ResultsBetween 2004 and 2019, of 8091 older adult patients with resected BTC identified (median [range] age, 77 [70-90] years; 5136 women [63.5%]; 2955 men [36.5%]), only one-third (2632 [32.5%]) received AC. There was an increase in the use of AC across the study period from 20.7% (n = 495) in 2004 to 2009 to 41.2% (n = 856) in 2016 to 2019. Age 80 years or older (odds ratio, 0.29; 95% CI, 0.25-0.33; P < .001) and gallbladder primary site (odds ratio, 0.71; 95% CI, 0.61-0.83; P < .001) were associated with a lower odds of AC. Following inverse probability of treatment weighting, as a composite, AC was not associated with improved survival (median OS, 20.5 months; 95% CI, 19.2-21.7 months) compared with observation (median OS, 19.0 months; 95% CI, 18.1-20.3 months). A longer median OS was associated with single-agent AC (21.5 months; 95% CI, 19.9-24.0 months) but not multiagent AC (19.1 months; 95% CI, 17.5-21.1 months) compared with observation (median OS, 17.3 months; 95% CI, 16.1-18.4 months). This improvement in OS with single-agent AC was not apparent on multivariable analysis (hazard ratio [HR], 0.97; 95% CI, 0.89-1.05; P = .44). However, age at diagnosis of 80 years or older (HR, 1.35; 95% CI, 1.28-1.42; P < .001) and treatment at nonacademic centers (HR, 1.14; 95% CI, 1.07-1.20, P < .001) were associated with worse OS.Conclusions and relevanceIn this cohort study of older adult patients, AC was not associated with an improvement in survival compared with observation following BTC resection. These findings suggest the need for further study of AC for older adult patients who may benefit after curative intent surgery for BTC.

Dataset Information

DCK expression, a potential predictive biomarker in the adjuvant gemcitabine chemotherapy for biliary tract cancer after surgical resection: results from a phase II study.

Publications

DCK expression, a potential predictive biomarker in the adjuvant gemcitabine chemotherapy for biliary tract cancer after surgical resection: results from a phase II study.

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