Chemotherapy for biliary (gallbladder) cancer – pro

Lay Summary: Chemotherapy can be tried in glabladder and bibliary cancers but it is not particularly effective. There is no combination that is proven better than another. There is no credible medical literature that second line chemo is beneficial in gallbladder cancer.

Chemotherapy has a role in metastatic disease in biliary cancers. In advanced disease, one randomised study of combination chemotherapy versus best supportive care reported a significantly improved survival (four months of benefit) and quality of life to the chemotherapy arm. (The study also included pancreatic cancers with a positive result although the analysis was separate.) Conclusions from predominately phase II studies suggest that cholangiocarcinomas are relatively chemosensitive, with most studies being 5-fluorouracil (5-FU) based, and 10–20% partial response rates to (older) single agents, partial response rates to newer single agents, such as gemcitabine, vary from 20% to 30% and partial response rates to recent phase II combinations vary from 20 to 40%.

Gemcitabine in combination with cisplatin shows 30–50% partial response rates. It is encouraging that several patients have been clearly documented as being down staged and converted to operability in some phase II studies, with occasional long term survivors. In advanced disease, one randomised study of combinatins. The chance of responding appears to be correlated with performance status at the outset. Quality of life is significantly improved, particularly in responders. This regimen is recommended by NCCN as “gemcitabine based regimen”, with a note that refers specifically to gemcitabine/cisplatin (p. 19). There is still an ongoing trial: Gemcitabine With or Without Cisplatin in Treating Patients With Unresectable Locally Advanced or Metastatic Cholangiocarcinoma or Other Biliary Tract Tumors, NCT00262769 . This randomized phase III trial is studying gemcitabine and cisplatin to see how well they work compared to gemcitabine alone in treating patients with unresectable locally advanced or metastatic cholangiocarcinoma or other biliary tract tumors.

Targeted chemotherapy through the hepatic artery or portal vein has been shown to achieve greater local drug concentrations and improved response rates (44% in one phase II study) but because of the patterns of relapse, it is unlikely to replace systemic chemotherapy entirely. NCCN recommends 5FU or gemcitabine.Xeloda with oxaliplatin is in a current phase II trial, NCT00338988; however, there are at least two prior published phase II trials of this regimen. Folfox has been presented in abstract form with a recommendation for more studies.

A small study evaluated cetuximab in combination with gemcitabine and oxaliplatin (GEMOX) in nine GEMOX-resistant patients with advanced, metastatic and unresectable intrahepatic cholangiocarcinoma. Cetuximab was well tolerated, the median time to progression (TTP) was 4 months and the median OS was 7 months. Therefore, the addiction of cetuximab seemed to reverse the resistance to GEMOX.

A multicenter, randomized Phase II trial in patients with advanced BTC (BINGO trial) is evaluating the efficacy of GEMOX alone or in combination with biweekly cetuximab in first-line. The primary end point is PFS at 4 months. Secondary end points are response rate (RR), PFS, OS, toxicity, early response assessment by positron emission tomography (PET) and blood/tumor EGFR signaling pathway member analyses. From October 2007 to October 2008, 101 patients were enrolled. At the interim analysis, the 4-month PFS rate was 44% versus 61% in the arm with cetuximab, so the addition of cetuximab to GEMOX showed promising activity. We awiat the final results. NCCN  Choalngiocarcinoma EXTRA-2 does not recommend it.

S A Khan et al, Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document Gut 2002;51:

S A Khan, A Miras, M Pelling, and S D Taylor-Robinson
Cholangiocarcinoma and its management
Gut, December 1, 2007; 56(12): 1755 – 1756.

Paule B, Bralet M, Herelle M et al.: Cetuximab plus gemcitabine/oxaliplatin (GEMOX) for patients with unresectable/recurrent intrahepatic cholangiocarcinoma refractory to GEMOX. J. Clin. Oncol. 24(Suppl. 18),14084 (2007).

Sakurai N, Okada T, Iizawa H.A case of recurrent cholangiocarcinoma responding to weekly paclitaxel]. Gan To Kagaku Ryoho. 2010 Jul;37(7):1333-5. Aram F. Hezel and Andrew X. Zhu, Systemic Therapy for Biliary Tract Cancers. The Oncologist April 2008 vol. 13 no. 4 415-423

Natalia Ramírez-Merino, Santiago Ponce Aix, and Hernán Cortés-Funes, Chemotherapy for cholangiocarcinoma: An update.  World J Gastrointest Oncol. 2013 Jul 15; 5(7): 171–176.

Chemotherapy has a role in metastatic disease in biliary cancers. In advanced disease, one randomised study of combination chemotherapy versus best supportive care reported a significantly improved survival (four months of benefit) and quality of life to the chemotherapy arm. (The study also included pancreatic cancers with a positive result although the analysis was separate.) Conclusions from predominately phase II studies suggest that cholangiocarcinomas are relatively chemosensitive, with most studies being 5-fluorouracil (5-FU) based, and 1020% partial response rates to (older) single agents, partial response rates to newer single agents, such as gemcitabine, vary from 20% to 30% and partial response rates to recent phase II combinations vary from 20 to 40%.

 

Irinotecan 2nd line

Gemcitabine in combination with cisplatin shows 30-50% partial response rates. Little is know of second line chemotherapy. Fofiri has been explored in phase II studies, with some efficacy and responses of around 30-40%. I did not find studies of irinotecan and 5FU or irinotecan alone.

Jane E. Rogers,corresponding author Lindsey Law Van D. Nguyen, Wei Qiao, Milind M. Javle, Ahmed Kaseb, and Rachna T. Shroff,Second-line systemic treatment for advanced cholangiocarcinoma. J Gastrointest Oncol. 2014 Dec; 5(6): 408413.

Natalia Ramírez-Merino, Santiago Ponce Aix, and Hernán Cortés-Funes, Chemotherapy for cholangiocarcinoma: An update. World J Gastrointest Oncol. 2013 Jul 15; 5(7): 171176.

Jean-Florian Guion-Dusserre, Veronique Lorgis, Julie Vincent, Leila Bengrine, and Francois Ghiringhelli, FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. World J Gastroenterol. 2015 Feb 21; 21(7): 20962101.

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