Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study

Lee, Jeeyun; Park, Se Hoon; Chang, Heung Moon; Kim, Jun Suk; Choi, Hye Jin; Lee, Myung Ah; Chang, Joung Soon; Jeung, Hei Cheul; Kang, Jung Hun; Lee, Hyun Woo; Shin, Dong Bok; Kang, Hye Jin; Sun, Jong Mu; Park, Joon Oh; Park, Young Suk; Kang, Won Ki; Lim, Ho Yeong

doi:10.1016/s1470-2045(11)70301-1

Cited by 405 publications

(335 citation statements)

References 22 publications

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“…However, other studies have also shown a trend toward better outcomes for IHC patients treated with anti-EGFR-targeted agents. 17,18 Is there any underlying biology that could explain why patients with IHC may benefit from EGFR inhibition? Our findings themselves do not justify the design of a new randomized clinical trial in this setting of patients; however, we think that data from available studies should be put together to draw more solid conclusions.…”

Section: Discussionmentioning

confidence: 99%

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Leone

Marino

Cereda

et al. 2015

Cancer

120

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BACKGROUND: Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression. METHODS: This open-label, randomized phase 2 trial recruited chemotherapy-naive patients with advanced BTC displaying a wild-type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m 2 ) and oxaliplatin (100 mg/m 2 ) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression-free survival (PFS) analyzed in an intention-to-treat fashion. RESULTS: Eighty-nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow-up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3-7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6-6.2 months) in arm B (P 5.27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P 5.42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P 5.13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A. CONCLUSIONS: These results confirm the marginal role of anti-EGFR therapy even for WT KRAS-selected BTC. Cancer 2016;122:574-81.

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Section: Discussionmentioning

confidence: 99%

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Leone

Marino

Cereda

et al. 2015

Cancer

120

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“…Due to the overall poor prognosis of metastatic cholangiocarcinoma and limited treatment options, there is a clear need for identification of novel treatment options (26)(27)(28)(29). The role of anti-angiogenics and other targeted therapies have been evaluated in first and second line treatment of cholangiocarcinoma either in combination with gemcitabine based chemotherapy or 5 fluorouracil based therapy (26,27,(29)(30)(31). In a phase 2 study, GEMOX with bevacizumab (GEMOX-B) showed tolerable safety in patients with advanced BTCs (26).…”

Section: Discussionmentioning

confidence: 99%

“…Whether these results are better than can be achieved with GEMOX alone or GC will require a randomized clinical trial. Agents targeting epidermal growth factor receptor (EGFR) have also been evaluated in cholangiocarcinoma patients (30)(31)(32). Cetuximab, an anti-EGFR monoclonal antibody showed some response in a single arm phase II study but the benefits were not found to be significant in a randomized clinical trial (30,32).…”

Section: Discussionmentioning

confidence: 99%

Advanced biliary tract cancer: clinical outcomes with ABC-02 regimen and analysis of prognostic factors in a tertiary care center in the United States

Agarwal

Sendilnathan

Siddiqi

et al. 2016

J. Gastrointest. Oncol.

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Background: Gemcitabine plus cisplatin (GC) is currently the standard regimen for advanced biliary tract cancers (BTC) based on the outcomes in ABC-02 trial. Multiple factors can affect outcomes in these patients. This retrospective review evaluates the University of Cincinnati experience with GC in advanced intrahepatic (IHC)/ extrahepatic cholangiocarcinoma (EHC) and gall bladder carcinoma (GBC). Methods: In this study approved by University of Cincinnati IRB, retrospective analysis of advanced BTC patients seen between 01/2008 and 01/2015 was done. Kaplan Meyer method was used to calculate progression free survival (PFS), and overall survival (OS). Cox model was used to test the association between baseline variables and OS/PFS, adjusting for gender and age at diagnosis. Patients were identified using ICD code for BT tumors, 26 patients met inclusion criteria: histologically proven advanced BTC that received GC as their initial chemotherapy. GC was given as per ABC-02 protocol with appropriate modifications until disease progression or unacceptable toxicities. Results: Median age at diagnosis was 62 years (range, 31-81 years). Eighteen (69%) were IHC, 5 EHC, 3 GBC, 61% male, 73% whites. Performance status (PS): 0-1: 69%, PS 2: 31%. Baseline CA19-9 data was available for 21 patients, (range 1 to 69,543), and abnormal CA19-9 was seen in 14 patients (54%). PFS was 4.5 months (95% CI: 3.1-8.9 months) and OS was 10.5 months (95 % CI: 7.9-18.8 months). OS at 6 and 12 months was 69% (18/26) and 42% (11/26). Thirty-eight percent (10/26) received 2nd line chemotherapy, of these 9/10 received 5FU based chemotherapy. Eleven percent (3/26) received 3rd line chemotherapy. Increase in baseline carcinoembryonic antigen (CEA), alanine aminotransferase, alkaline phosphatase (ALP) and total bilirubin was associated with increased risk of death while increase in baseline CEA and ALP was associated with increased risk of progression (P valve <0.05). In the group of patients who had all three major risk factors (PS ≥2, CEA >3, and stage IVb), the median survival was 2.9 months (95% CI: 2.6-9.3 months), which was significantly worse compared to rest of the population [median 18 months (95% CI: 5.4-19.5 months), P<0.01]. Conclusions: Our data supports the use of GC as a first line regimen for advance BTC in a non-clinical trial setting. Results are comparable to those reported in ABC-02 trial, despite inclusion of PS 2 patients whom constituted 31% of our population. In the patient population studied, baseline CEA and liver function test appeared able to predict response to GC in advanced BTC. Patients with all three high risk factors (PS ≥2, CEA >3, and stage IVb) did poorly and may need careful selection prior to initiating chemotherapy.

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“…The EGFR signaling pathway is integral in epithelial cell growth and proliferation, where preclinical studies have shown tumor regression with EGFR inhibition (28,30), forming the rationale for targeting EGFR for treatment. While initial small studies demonstrated promising antitumor activity with anti-EGFR therapy in combination with gemcitabine-based chemotherapy (31,32), these findings were unable to translate into a significant clinical benefit in larger randomized clinical trials (33,34 (35,36).…”

Section: Egfr Signaling Pathwaymentioning

confidence: 99%

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

Ahn

Bekaii‐Saab

2017

J. Gastrointest. Oncol.

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Biliary cancers (BCs) are a diverse group of tumors that arise from the bile duct epithelium and are divided into cholangiocarcinomas of the intrahepatic and extrahepatic cholangiocarcinoma (EHCC) and cancer of the gallbladder. Despite improvements in treatment and diagnosis, BCs are often diagnosed at an advanced stage and associated with poor prognosis and limited treatment options. Recent discoveries have allowed us to have a better understanding of the genomic diversity in BC, and identify genes that are likely contributing to its pathogenesis, proliferation and treatment resistance. Additionally, these advances have allowed us to reason that each anatomic group within BC behave as distinct diseases, with differences in prognosis and outcomes. Based on this knowledge, recent advances have allowed us to identify actionable mutations that form rational therapeutic targets with novel agents, where their relevance will be better understood through the completion of prospective clinical trials.

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Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study

Cited by 405 publications

References 22 publications

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Advanced biliary tract cancer: clinical outcomes with ABC-02 regimen and analysis of prognostic factors in a tertiary care center in the United States

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

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