Smoking, Alcohol Consumption, and Risks for Biliary Tract Cancer and Intrahepatic Bile Duct Cancer

Abstract Background Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. Methods We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. Results Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. Conclusions Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

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Adjuvant and neoadjuvant therapy for biliary tract cancer: a review of clinical trials

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa170 ◽

2020 ◽

Vol 50 (12) ◽

pp. 1353-1363 ◽

Cited By ~ 1

Author(s):

Satoshi Nara ◽

Minoru Esaki ◽

Daisuke Ban ◽

Takeshi Takamoto ◽

Kazuaki Shimada ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Bile Duct ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Tract Cancer ◽

Adjuvant And Neoadjuvant Therapy ◽

Duct Cancer

Abstract Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.

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A randomized study of gemcitabine/cisplatin versus single-agent gemcitabine in patients with biliary tract cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4579 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4579-4579 ◽

Cited By ~ 1

Author(s):

J. Furuse ◽

T. Okusaka ◽

M. Miyazaki ◽

H. Taniai ◽

Y. Nimura ◽

...

Keyword(s):

Bile Duct ◽

Biliary Tract ◽

Bile Duct Cancer ◽

Extrahepatic Bile Duct ◽

Performance Status ◽

Single Agent ◽

Intrahepatic Bile Duct ◽

Extrahepatic Bile Duct Cancer ◽

Duct Cancer ◽

Grade 3

4579 Background: Biliary tract cancers (BTC) are not common but increasing in the US and Europe, and more prevalent in South America and Asia including Japan. Gemcitabine (G) and cisplatin (C) are now deemed as key drugs based on the accumulated literature. This is the first study to compare GC combination with G alone in Japan, even though one phase 3 trial (ABC-02) is ongoing in UK. Methods: 84 Japanese pts, aged ≥ 20 years, with histologically or cytologically confirmed advanced BTC, Performance Status 0 - 1, with adequate bone-marrow, hepatic and renal function were randomized. 83 pts received either C 25 mg/m2 plus G 1000 mg/m2 on days 1, and 8 of each 21-day cycle (GC-arm) or G 1000 mg/m2 on days 1, 8 and 15 of each 28-day cycle (G-arm). Treatments were repeated up to a maximum of 16 cycles of GC or 12 of G until disease progression or unacceptable toxicity occurred. Tumor response was evaluated using RECIST criteria by an independent review committee. The primary end-point of the study was 1- year survival rate. Safety, response rate, duration of progression-free survival were also evaluated. Results: A total of 83 pts (19 extrahepatic bile duct cancer, 28 intrahepatic bile duct cancer, 32 gallbladder cancer and 4 ampullary carcinoma) were eligible for the study protocol defined analysis set (Full Analysis Set, FAS); GC-arm n=41 and G-arm n=42. Baseline characteristics were similar between the two arms: median ages were 65.0 vs 66.5, females were 56.1 vs 50.0%. All pts completed at least one cycle of therapy, yielding a total of 247 cycles (median 6) in GC vs 203 (median 4) in G. The overall response rates were 19.5% (95% CI: 8.8, 34.9) vs 11.9 (95% CI: 4.0, 25.6). The results on survival will be determined and presented at the meeting. The most commonly reported grade 3 or 4 toxicities were: neutropenia (56.1 vs 38.1%), thrombocytopenia (39.0 vs 7.1%), leukopenia (29.3 vs 19.0%), hemoglobin decrease (36.6 vs 16.7%) and γ-GTP increase (29.3 vs 35.7%). Grade 3 acute renal failure was reported in 1 pt on GC. Conclusions: The combination therapy of GC would be an effective and well-tolerated chemotherapy regimen for Japanese pts with advanced BTC. [Table: see text]

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Frequency of severe neutropenia occurring as an adverse events of gemcitabine plus cisplatin chemotherapy in patients with recurrent biliary tract cancer compared to those with unresectable biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.488 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 488-488

Author(s):

Noriko Fujishiro ◽

Shuichi Mitsunaga ◽

Akira Shinohara ◽

Misaki K Takeno ◽

Hideki Funazaki ◽

...

Keyword(s):

Bile Duct ◽

Adverse Events ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Intrahepatic Bile Duct ◽

Severe Neutropenia ◽

Primary Tumor Site ◽

Tract Cancer ◽

Significant Difference ◽

Grade 3

488 Background: In patients (pts) with biliary tract cancer (BTC), relapse occurs at a high frequency even after curative resection. It remains unclear whether in pts with postoperative recurrence receiving chemotherapy, the surgery exerts any influence on the risk of development of toxicities. The aim of this study was to compare the outcomes and incidences of adverse events between recurrent BTC (rBTC) pts and unresectable BTC (uBTC) pts receiving gemcitabine plus cisplatin chemotherapy (GC). Methods: Data of pts with rBTC or uBTC receiving GC as the first-line chemotherapy were analyzed. The GC regimen consisted of gemcitabine 1000 mg/m2 plus cisplatin 25 mg/m2on days 1 and 8, administered every 3 weeks. All adverse events occurring during the first 180 days of GC were evaluated according to CTCAE, version 4.0. Results: A total of 151 pts, including 55 pts with rBTC and 96 pts with uBTC, were enrolled. In regard to the baseline characteristics, no significant differences between the rBTC and uBTC groups were found in the gender distribution [male: 69% vs. 57%], age [median: 68 vs. 68], or ECOG performance status (PS) [PS0: 67%vs. 55%]. The distribution of the primary tumor site (intrahepatic bile duct [27% vs. 33%] / extrahepatic bile duct [45% vs. 20%] / gallbladder [20% vs. 44%] / ampulla [7% vs. 3%]) was unbalanced between the two groups ( p < 0.01). The overall survival (OS) was significantly longer in the rBTC group than that in the uBTC group [median 15.8 months vs. 10.0 months, p = 0.02], however, there was no significant difference in the progression-free survival [median 6.8 months vs. 5.8 months] between the two groups. Grade 3-4 neutropenia was more frequent in the rBTC group [69%] as compared to that in the uBTC group [44%, p < 0.01], whereas Grade 3-4 cholangitis was significantly less frequent in the rBTC [5%] group than that in the uBTC group [21%, p = 0.02]. Conclusions: The incidence of Grade 3-4 neutropenia developing during GC was significantly higher in the rBTC group as compared to that in the uBTC group.

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Neutrophil/lymphocyte ratio (NLR) may predict prognostic factor with gemcitabine, cisplatin (GC) for patients with advanced biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.410 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 410-410

Author(s):

Toru Otsuru ◽

Daisuke Sakai ◽

Akie Kimura ◽

Chiaki Inagaki ◽

Naohiro Nishida ◽

...

Keyword(s):

Overall Survival ◽

Survival Rate ◽

Bile Duct ◽

Prognostic Factor ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Intrahepatic Bile Duct ◽

Neutrophil Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Tract Cancer

410 Background: There is little information available about prognostic markers of GC (gemcitabine, cisplatin) in patients with advanced biliary tract cancer (BTC). Neutrophil/lymphocyte ratio (NLR) in several cancers was might to be a prognostic factor associated with clinical outcomes, we examine NLR in patient with BTC underwent chemotherapy (GC). Methods: Retrospective chart review for consecutive patients who underwent GC for advanced BTC in our institute were performed. The patients who were enrolled in ongoing clinical trials were excluded. Gemcitabine and cisplatin were administered intravenously at doses of 1,000 or 25 mg/m2, on day one and eight, every three weeks. We divided these patients based on estimated NLR, and evaluated the clinicopathological factors and survival in the two groups (NLR ≥ 3 or < 3). Results: 57 patients from 2013 to 2017 were reviewed. 23 patients were in NLR ≥ 3 group and 34 patients were in NLR < 3 group. Patients characteristics were as follows; median age, 68 years old (range: 38-83) years: male 36 (63%); primary tumor lesion, intrahepatic bile duct 6 (10%)/extrahepatic bile duct 32 (56%)/gallbladder 18 (32%)/ampulla of vater 1 (2%); therapeutic purpose, palliative 50 (88%)/adjuvant 5 (8%)/neoadjuvant 2 (4%); PS, 0/1. Response rate of the patients who had measurable lesion according to RECIST v1.1 was 17% (8/46), and disease control rate was 70% (32/46). The progression-free survival rate between the two groups is not significantly different. Although, the median overall survival (OS) of NLR ≥ 3 group was 11.8 months, while OS of NLR < 3 group was 29.2 months. The overall survival rate in the NLR ≥ 3 group was significantly lower than that in the NLR < 3 group ( P = 0.0339). Conclusions: Our study confirmed that high NLR is associated with worse OS and PFS, and suggested it may be a predictive marker for GC chemotherapy in patients with BTC.

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A randomized phase III trial comparing adjuvant chemotherapy with S-1 vs. surgery alone in patients with resectable biliary tract cancer (JCOG1202: ASCOT).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps4144 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS4144-TPS4144 ◽

Cited By ~ 1

Author(s):

Masafumi Ikeda ◽

Kohei Nakachi ◽

Masaru Konishi ◽

Shuichi Mitsunaga ◽

Junki Mizusawa ◽

...

Keyword(s):

Overall Survival ◽

Bile Duct ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Residual Disease ◽

Extrahepatic Bile Duct ◽

Intrahepatic Bile Duct ◽

Phase Iii ◽

Phase Iii Trial ◽

Tract Cancer

TPS4144 Background: No standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer (BTC). S-1, which is one of the oral fluoropyrimidine derivatives, showed promising efficacy with a mild toxicity profiles in patients with advanced BTC, and the survival benefit of adjuvant S-1 therapy has been demonstrated in patients with resected gastric cancer and pancreatic cancer. The aim of this open-label, multicenter, randomized phase III trial is to assess whether adjuvant S-1 would prolong the overall survival in patients with resected BTC. Methods: The main eligibility criteria are as follows: 1) curatively resected carcinoma of the extrahepatic bile duct, gallbladder or ampulla of Vater (T2-4, N0, M0 or T1-4, N1, M0), or carcinoma of the intrahepatic bile duct (T1-4, N0-1, M0) (7th UICC classification), 2) histologically confirmed adeno (squamous) carcinoma, 3) R0 or R1 residual disease, 4) age 20 to 80 years, 5) ECOG performance status 0 or 1, 6) no prior chemotherapy or radiotherapy, 7) adequate organ functions, 8) written informed consent. Patients are randomly assigned to the surgery alone arm (arm A) or the adjuvant S-1 arm (arm B) by the minimization method for balancing institution, primary site of cancer and lymph node metastasis between the arms. Patients in arm A do not receive any anti-cancer treatment, while patients in arm B receive 4 cycles of oral S-1 chemotherapy at the dose of 40 mg/m2 twice daily for 4 weeks followed by 2 weeks of rest. The primary endpoint is overall survival, while the secondary endpoints are relapse-free survival, incidence of (serious) adverse events, and proportion of treatment completion. We assumed a 3-year survival in arm A of 47% and a 10% increase in the 3-year survival in arm B. The sample size was calculated as a total of 350, with a one-side alpha of 5% and power of 70%; planned accrual period is 4 years, and follow-up period, 3 years. Primary analysis will be conducted at 3 years and updated analysis will be conducted at 5 years after closing of accrual. As of Jan 31, 2016, a total of 285 patients have already been enrolled in this trial from Sep 2013. Clinical trial information: UMIN000011688.

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