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Chemotherapy with Gemcitabine plus Cisplatin in Patients with Advanced Biliary Tract Carcinoma at Chang Gung Memorial Hospital: A Retrospective Analysis  [PDF]
Chiao-En Wu,Hung-Chih Hsu,Wen-Chi Shen,Yang-Chung Lin
Chang Gung Medical Journal , 2012,
Abstract: Background: A gemcitabine-cisplatin combination is a standard treatment option for patients with advanced biliary tract carcinoma (BTC). We assessed the efficacy and safety of this regimen at Chang Gung Memorial Hospital.Methods: Between April 2009 and December 2010, 30 chemotherapy-na ve patients (13 men and 17 women; median age: 61.5 years) with advanced BTC were retrospectively analyzed. Treatment consisted of gemcitabine (Gemmis ; TTY, Taipei, Taiwan) 1000 mg/m2, followed by cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria every 2–3 cycles. The toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.Results: At the end of July, 2011, 27 patients were evaluated using the RECIST criteria. According to the intent to treat analysis of response, 5 patients (16.7%) had a partial response, 10 patients (33.3%) had stable disease and 12 patients (40.0%) had progressive disease. The median time to progression (TTP) and median overall survival (OS) of the 30 patients were 4.8 months and 13.4 months, respectively. The patients with biliary obstruction requiring drainagebefore treatment had a significantly shorter OS than those without biliary obstruction (p = 0.02) even though the TTP showed no statistically significant difference (p = 0.69) between groups. The major grade III/IV adverse events in the 30 patients included infection (n = 8, 26.7%), anemia (n = 5, 16.7%), neutropenia (n = 4, 13.3%), and elevated alanine aminotransferase (n = 2, 6.7%). There were no treatment-related deaths.Conclusions: Gemcitabine plus cisplatin is a feasible chemotherapy regimen with manageable toxicity in patients with advanced BTC. Maintaining good biliary drainage is essential for these patients.
Targeted Therapy for Biliary Tract Cancer  [PDF]
Junji Furuse,Takuji Okusaka
Cancers , 2011, DOI: 10.3390/cancers3022243
Abstract: It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine was reported to show survival benefits over gemcitabine alone in randomized clinical trials conducted in the United Kingdom and Japan. Thus, the combination of cisplatin plus gemcitabine is now recognized as the standard therapy for unresectable biliary tract cancer. One of the next issues that need to be addressed is whether molecular targeted agents might also be effective against biliary tract cancer. Although some targeted agents have been investigated as monotherapy for first-line chemotherapy, none were found to exert satisfactory efficacy. On the other hand, monoclonal antibodies such as bevacizumab and cetuximab have also been investigated in combination with a gemcitabine-based regimen and have been demonstrated to show promising activity. Furthermore, clinical trials using new targeted agents for biliary tract cancer are also proposed. This cancer is a relatively rare and heterogeneous tumor consisting of cholangiocarcinoma and gallbladder carcinoma. Therefore, a large randomized clinical trial is necessary to confirm the efficacy of chemotherapy, and international collaboration is important.
Recent progress and limitations of chemotherapy for pancreatic and biliary tract cancers  [cached]
Minoru Tada, Yousuke Nakai, Takashi Sasaki, Tsuyoshi Hamada, Rie Nagano, Dai Mohri, Koji Miyabayashi, Keisuke Yamamoto, Hirofumi Kogure, Kazumichi Kawakubo, Yukiko Ito, Natsuyo Yamamoto, Naoki Sasahira, Kenji Hirano, Hideaki Ijichi, Keishuke Tateishi, Hi
World Journal of Clinical Oncology , 2011,
Abstract: Gemcitabine chemotherapy has been the standard for advanced pancreatic cancer for more than a decade. New oral fluoropyrimidines such as S-1 and capecitabine are other key drugs. Gemcitabine plus erlotinib was the only combination therapy that significantly prolonged survival, although the effect was minimal. Little or no improvement in survival with recent molecular-targeted drugs might be attributed to the very high incidence of K-ras gene mutation in pancreatic cancer. Recently, the non-gemcitabine-based-regimen of FOLFIRINOX showed significantly greater overall survival compared with gemcitabine for the first time. For biliary tract cancer, gemcitabine plus cisplatin combination chemotherapy has been proved to significantly prolong survival and will become the standard therapy. Further improvement in survival is expected by the addition of cetuximab.
Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas
Ymera Pignochino, Ivana Sarotto, Caterina Peraldo-Neia, Junia Y Penachioni, Giuliana Cavalloni, Giorgia Migliardi, Laura Casorzo, Giovanna Chiorino, Mauro Risio, Alberto Bardelli, Massimo Aglietta, Francesco Leone
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-631
Abstract: Immunohistochemistry, FISH and mutational analysis were performed on 49 BTC samples of intrahepatic (ICCs), extrahepatic (ECCs), and gallbladder (GBCs) origin. The effect on cell proliferation of different EGFR/HER2 pathway inhibitors as single agents or in combination with gemcitabine was investigated on BTC cell lines. Western blot analyses were performed to investigate molecular mechanisms of targeted drugs.EGFR is expressed in 100% of ICCs, 52.6% of ECCs, and in 38.5% of GBCs. P-MAPK and p-Akt are highly expressed in ICCs (>58% of samples), and to a lower extent in ECCs and GBCs (<46%), indicating EGFR pathway activation. HER2 is overexpressed in 10% of GBCs (with genomic amplification), and 26.3% of ECCs (half of which has genomic amplification). EGFR or its signal transducers are mutated in 26.5% of cases: 4 samples bear mutations of PI3K (8.2%), 3 cases (6.1%) in K-RAS, 4 (8.2%) in B-RAF, and 2 cases (4.1%) in PTEN, but no loss of PTEN expression is detected. EGI-1 cell line is highly sensitive to gemcitabine, TFK1 and TGBC1-TKB cell lines are responsive and HuH28 cell line is resistant. In EGI-1 cells, combination with gefitinib further increases the antiproliferative effect of gemcitabine. In TFK1 and TGBC1-TKB cells, the efficacy of gemcitabine is increased with addiction of sorafenib and everolimus. In TGBC1-TKB cells, lapatinib also has a synergic effect with gemcitabine. HuH28 becomes responsive if treated in combination with erlotinib. Moreover, HuH28 cells are sensitive to lapatinib as a single agent. Molecular mechanisms were confirmed by western blot analysis.These data demonstrate that EGFR and HER2 pathways are suitable therapeutic targets for BTCs. The combination of gemcitabine with drugs targeting these pathways gives encouraging results and further clinical studies could be warranted.Biliary tract carcinomas (BTCs) are rare primary malignancies originating from the epithelium of the biliary tree and lead to intrahepatic (ICCs), extrahepatic (E
Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma
Stefan von Delius, Christian Lersch, Ewert Schulte-Frohlinde, Martina Mayr, Roland M Schmid, Florian Eckel
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-61
Abstract: Nineteen consecutive eligible patients were enrolled. All patients were required to have histologically confirmed diagnosis and measurable disease. Gemcitabine was infused over 24 hours at a dose of 100 mg/m2 on days 1, 8, and 15. Treatment was repeated every 28 days until progression of disease or limiting toxicity. Tumor response was evaluated every second course by computed tomography (CT) scans.Eighteen patients were evaluable for response. A total of 89 cycles of therapy were administered. One partial response was observed (6%; 95% confidence interval (CI): 0–27%) and ten additional patients had stable disease for at least two months (disease control rate 61%; 95% CI: 36–83%). The therapy was well tolerated, with moderate myelosuppression as the main toxicity. The median time to tumor progression and median overall survival was 3.6 months (95% CI 2.6–4.6 months) and 7.5 months (95% CI 6.5–8.5 months), respectively.Weekly 24-hour gemcitabine at a dose of 100 mg/m2 is well tolerated. There was a relatively high rate of disease control for a median duration of 5.3 months (range 2.8–18.8 months). However, the objective response rate of this regimen in gallbladder and biliary tract carcinomas was limited.Adenocarcinomas of the gallbladder and the biliary tract are relatively uncommon in the western world, with approximately 5,000 cases of gallbladder carcinoma and 2,500 cases of cholangiocarcinoma annually in the USA [1,2]. Worldwide, the highest prevalence of gallbladder cancer is seen in Israel, Mexico, Chile, Japan, and among Native American women, particularly those living in New Mexico. Incidence of cholangiocarcinoma is highest in Israel, Japan, among Native Americans, and in Southeast Asia, where it can reach 87 per 100,000 [3].Biliary tract tumors can occur anywhere in the hepatobiliary system. Cholangiocarcinoma may be further classified as intrahepatic or extrahepatic (hilar and distal bile duct) carcinomas. Hilar tumors, so called Klatskin's tumors, usual
Gemcitabine-based versus fluoropyrimidine-based chemotherapy with or without platinum in unresectable biliary tract cancer: a retrospective study
Mi-Jung Kim, Do-Youn Oh, Se-Hoon Lee, Dong-Wan Kim, Seock-Ah Im, Tae-You Kim, Dae Heo, Yung-Jue Bang
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-374
Abstract: Patients with unresectable BTC treated with palliative chemotherapy between Oct 2001 and Aug 2006 at Seoul National University Hospital were reviewed retrospectively. Histologically confirmed cases of intrahepatic cholangiocarcinoma, gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater carcinoma were enrolled. We analyzed the efficacy of regimens: gemcitabine (G) versus fluoropyrimidine (F) and with or without platinum (P).A total of 243 patients were enrolled. 159 patients (65%) were male and the median age of the patients was 60 years (range 26–81). Intrahepatic cholangiocarcinoma, gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater carcinoma were 92, 72, 58, and 21 cases, respectively. The median progression free survival (PFS) was 4.3 months (95% CI, 3.7–4.9) and median overall survival (OS) was 8.7 months (95% CI, 7.4–10.0). Ninety-nine patients received G-based chemotherapy (94 GP, 5 G alone), and 144 patients received F-based chemotherapy (83 FP, 61 F alone). The response rate (RR), disease control rate (DCR), PFS and OS of G-based chemotherapy versus F-based chemotherapy were 16.7% vs. 19.5% (P = 0.591), 52.8% vs. 58.9% (P = 0.372), 4.0 months vs. 4.3 months (P = 0.816), and 7.8 months vs. 9.1 months (P = 0.848), respectively. Sixty-six patients received F or G without P, and 177 patients received F or G with P. The RR, DCR, PFS and OS of chemotherapy without P versus chemotherapy including P were 12.7% vs. 20.6% (P = 0.169), 46.0% vs. 60.6% (P = 0.049), 3.3 months vs. 4.4 months (P = 0.887), and 10.6 months vs. 8.1 months (P = 0.257), respectively.In unresectable BTC, F-based and G-based chemotherapy showed similar efficacy in terms of RR, DCR, PFS and OS. The benefit of adding P to F or G was not significant except for DCR. Further prospective studies which define the efficacy of various chemotherapeutic regimens in BTC are warranted.Biliary tract cancers (BTC) are relatively rare tumors with a poor prognosis. BTC acc
A successful treatment by hepatic arterial infusion therapy for advanced, unresectable biliary tract cancer  [cached]
Masako Nishimura
World Journal of Hepatology , 2010,
Abstract: Biliary tract cancers (BTC) are relatively rare tumors, and the prognosis is extremely poor. There has been no standard chemotherapy for advanced BTC. However, recently, gemcitabine (GEM) have been used against BTC as the most active agent, and promising response rates and overall survival times with tolerable drug toxicities have been observed. In this article, two cases of advanced intrahepatic cholangiocarcinoma and unresectable metastatic gallbladder (GB) cancer are reported. They were treated with hepatic arterial infusion (HAI) chemotherapy using a combination of GEM and cisplatin, along with the systemic administration of GEM. As a consequence, multiple liver tumors, the GB cancer and metastatic lymph nodes regressed without severe drug toxicities, and favorable results (the overall survival times were 16 and 14 mo, respectively) were achieved. In conclusion, HAI therapy using GEM combined with cisplatin may be a useful and well-tolerated option for advanced BTC, especially in cases where multiple liver metastases are detected.
Comparison of 4-Weekly vs 3-Weekly Gemcitabine as Adjuvant Chemotherapy Following Curative Resection for Biliary Tract Cancer: A Prospective Randomized Controlled Trial  [PDF]
Shogo Kobayashi, Atsushi Miyamoto, Junzo Shimizu, Masaki Kashiwazaki, Yutaka Takeda, Shigeyuki Ueshima, Yongkook Kim, Toru Kitagawa, Keizo Dono, Masaki Mori, Yuichiro Doki, Hiroaki Nagano
Journal of Cancer Therapy (JCT) , 2011, DOI: 10.4236/jct.2011.25095
Abstract: Background: Surgery for biliary tract cancer, including pancreatoduodenectomy and major hepatectomy, is too aggressive and does not allow postoperative gemcitabine to be administered by the usual dosage protocol. We hypothesized that the feasibility of 3-weekly protocol (days 1 and 8, every 3 weeks) of adjuvant gemcitabine therapy may be superior to the usual 4-weekly protocol (days 1, 8, and 15 every 4 weeks). Method: We compared the outcomes of 6 cycles of the 4-weekly protocol and 9 cycles of the 3-weekly protocol in a prospective randomized setting. The primary endpoint was the completion rate, and the secondary endpoints were the adverse events and the recurrence-free survival rate. Results: Totally, 27 patients were enrolled. The protocol could be completed without any omittances and/or dose modifications in two patients (14%) of the 4-weekly protocol, and three patients (23%) of the 3-weekly protocol (p = 0.8099); grade 3/4 neutropenia occurred in almost all the remaining (70%) patients. The relative dose intensity was 72% in the 4-weekly protocol and 78% in the 3-weekly protocol. There was no significant difference in the recurrence-free survival rate. Conclusion: The 3-weekly protocol did not yield superior completion, adverse events or recurrence-free survival rates as compared to the 4-week protocol. Trial Registration: UMIN-CTR, UMIN000001020.
Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report
Kabir Mody, Edward Strauss, Robert Lincer, Richard C Frank
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-570
Abstract: A 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine (1000 mg/m2) on day 1 and 8 every 21 days as well as daily erlotinib (100 mg). After four cycles of therapy, the CA 19-9 normalized and a PET/CT showed a complete remission; this response was maintained by the end of 12 cycles of therapy. Gemcitabine was then discontinued and single agent erlotinib was continued as maintenance therapy. The disease remains in good control 18 months after initiation of therapy, including 6 months on maintenance erlotinib. The only grade 3 toxicity was a typical EGFR-related skin rash. Because of the remarkable response to erlotinib plus gemcitabine, we performed tumor genotyping of the EGFR gene for response predicting mutations in exons 18, 19 and 21. This disclosed the wild-type genotype with no mutations found.This case report demonstrates a patient with stage IV gallbladder cancer who experienced a rarely encountered complete, prolonged response after treatment with an oral EGFR-TKI plus chemotherapy. This response occurred in the absence of an EGFR gene mutation. These observations should inform the design of clinical trials using EGFR-TKIs to treat gallbladder and other biliary tract cancers; such trials should not select patients based on EGFR mutation status.Biliary tract cancers (BTC) include carcinomas of the gallbladder and intra- and extra-hepatic bile ducts (cholangiocarcinomas). Gallbladder cancer is the most common type worldwide, affects women more frequently than men and is considered to be the most aggressive form of BTC with the shortest survival [1]. In contrast to cholangiocarcioma, gallbladder cancer (GBC) has a distinct molecular pathogenesis and may require a different therapeutic approach [1,2].The majority of BTC present at an advanced, incurable stage and are typically treated with chemotherapy drugs such as 5-fluoruracil, gemcitabine and cisplatin, often in combination. Response ra
Improvement of prognosis for unresectable biliary tract cancer  [cached]
Takashi Sasaki,Hiroyuki Isayama,Yousuke Nakai,Naminatsu Takahara
World Journal of Gastroenterology , 2013, DOI: 10.3748/wjg.v19.i1.72
Abstract: AIM: To evaluate the chemotherapeutic outcomes and confirm the recent improvement of prognosis for unresectable biliary tract cancer. METHODS: A total of 186 consecutive patients with unresectable biliary tract cancer, who had been treated with chemotherapy between 2000 and 2009 at five institutions in Japan, were retrospectively analyzed. These patients were divided into three groups based on the year beginning chemotherapy: Group A (2000-2003), Group B (2004-2006), and Group C (2007-2009). The data were fixed at the end of December 2011. Overall survival and time-to-progression were analyzed and compared chronologically. RESULTS: No patient characteristics were significantly different among the three groups. The gallbladder was involved in about half of the patients in each group, and metastatic biliary tract cancer was present in three quarters of the enrollees. In Group A, 5-fluorouracil-based chemotherapies were primarily selected as first-line chemotherapy, and only 24% were treated with second-line chemotherapy. In Group B, gemcitabine or S-1 monotherapy was mainly introduced as first-line chemotherapy, and 51% of the patients who were refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with monotherapy. In Group C, the combination therapy with gemcitabine and S-1 was mainly chosen as first-line chemotherapy, and 53% of the patients refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with combination therapy. The median time-to-progressions were 4.4 mo, 3.5 mo and 5.9 mo in Groups A, B and C, respectively (4.4 mo vs 3.5 mo vs 5.9 mo, P < 0.01). The median overall survivals were 7.1, 7.3, and 11.7 mo in Groups A, B and C (7.1 mo vs 7.3 mo vs 11.7 mo, P = 0.03). Induction rates of all three drugs (gemcitabine, platinum analogs, and fluoropyrimidine) in Groups A, B and C were 4%, 2% and 27% (4% vs 2% vs 27%, P < 0.01). CONCLUSION: The prognosis of unresectable biliary tract cancer has improved recently. Using three effective drugs (gemcitabine, platinum analogs, and fluoropyrimidine) may improve the prognosis of this cancer.
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