Accepted Manuscript Systemic therapy of cholangiocarcinoma: From chemotherapy to targeted therapies N. Schweitzer, Prof. Dr. med. A. Vogel
PII:
S1521-6918(15)00028-1
DOI:
10.1016/j.bpg.2015.01.002
Reference:
YBEGA 1335
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 19 December 2014 Accepted Date: 6 January 2015
Please cite this article as: Schweitzer N, Vogel A, Systemic therapy of cholangiocarcinoma: From chemotherapy to targeted therapies, Best Practice & Research Clinical Gastroenterology (2015), doi: 10.1016/j.bpg.2015.01.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Systemic therapy of cholangiocarcinoma: from chemotherapy to targeted therapies
N. Schweitzer, A. Vogel* Department of Gastroenterology, Hepatology and Endcrinology, Carl-Neuberg-Straße 1,
RI PT
30625 Hannover, Germany
*Corresponding Author: Prof. Dr. med. Arndt Vogel, Hannover Medical School, Department
SC
of Gastroenterology, Hepatology and Endcrinology, Carl-Neuberg-Straße 1, 30625
M AN U
Hannover, Germany; E-Mail: [email protected]
Abstract: Cholangiocarcinomas (CCA) are rare tumors of the liver with poor prognosis. The standard of care in patients with unresectable tumors or metastatic disease is combination chemotherapy (CT) with gemcitabine and cisplatin. Targeted therapies inhibiting EGFR, VEGF, MEK and others are broadly tested in CCA but to date, the existing data from
TE D
randomized and nonrandomized trials do not justify the application of small molecules outside of clinical trials. In clinical practice, many patients receive second-line CT after failure of gemcitabine/cisplatin, although there is so far no evidence to support second-line CT. This
EP
review summarizes current chemotherapy protocols and ongoing studies, including
AC C
conventional chemotherapy and targeted therapies.
Key words: Cholangiocarcinoma; Biliary tract cancer; Chemotherapy; Gemcitabine; Targeted therapy
ACCEPTED MANUSCRIPT Introduction Cholangiocarcinoma (CCA), including intrahepatic CCA, extrahepatic CCA and gallbladder carcinoma (GBC), is the second most common primary liver cancer. The incidence in western countries increases and currently up to 1/ 100.000 people are diagnosed with CCA
RI PT
per year [1-3]. Radical resection is the treatment of choice whenever possible. However, high rates of unresectable tumors and recurrence after resection result in a poor prognosis [4]. Furthermore, CCA is frequently diagnosed when metastases or advanced local tumor infiltration are already present and prevent tumor resection. Even in patients who are
SC
deemed to be curable, there is a probability of about 35% that during surgical exploration it turns out that resection is not possible (own data). Finally, only a minority of 25-35% of all
M AN U
patients undergoes resection [5;6]. Liver transplantation is currently no standard for patients with CCA, but can be a promising option for cure in very well selected patients and after neoadjuvant chemoradiation [7].
Consequently, most patients with CCA receive non-curative treatment sooner or later.
TE D
Despite a relative chemo-resistance of CCA [8-10], and a low number of phase III trials, the role of chemotherapy (CT) is best investigated in advanced CCA compared to other treatment options. The role of radiotherapy, chemoradiation, transarterial chemotherapy or ablative
treatments
such
as
photodynamic
therapy
(PDT)
or
intraductal
EP
locally
radiofrequency ablation (RFA) has only been investigated in small, mostly retrospective trials
AC C
[11-17], but larger and randomized studies are ongoing. Besides the anti-tumoral treatment, endoscopical or percutaneous biliary drainage have a great impact to reduce morbidity and mortality and to enhance quality of life by the prevention of cholangitis and jaundice, thereby often being a prerequisite to apply palliative anti-tumoral treatment [18-20].
Chemotherapy in unresectable cholangiocarcinoma It was demonstrated in two randomized trials that CT can improve the survival of patients with advanced CCA and GBC when compared to best supportive care (BSC) [21;22]. Glimelius et al. used 5- fluorouracil (5FU), folinic acid (FA) and etoposide and observed a
ACCEPTED MANUSCRIPT mean overall survival (OS) of 6 months vs. 2.5 months with BSC (p
PII:
S1521-6918(15)00028-1
DOI:
10.1016/j.bpg.2015.01.002
Reference:
YBEGA 1335
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 19 December 2014 Accepted Date: 6 January 2015
Please cite this article as: Schweitzer N, Vogel A, Systemic therapy of cholangiocarcinoma: From chemotherapy to targeted therapies, Best Practice & Research Clinical Gastroenterology (2015), doi: 10.1016/j.bpg.2015.01.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Systemic therapy of cholangiocarcinoma: from chemotherapy to targeted therapies
N. Schweitzer, A. Vogel* Department of Gastroenterology, Hepatology and Endcrinology, Carl-Neuberg-Straße 1,
RI PT
30625 Hannover, Germany
*Corresponding Author: Prof. Dr. med. Arndt Vogel, Hannover Medical School, Department
SC
of Gastroenterology, Hepatology and Endcrinology, Carl-Neuberg-Straße 1, 30625
M AN U
Hannover, Germany; E-Mail: [email protected]
Abstract: Cholangiocarcinomas (CCA) are rare tumors of the liver with poor prognosis. The standard of care in patients with unresectable tumors or metastatic disease is combination chemotherapy (CT) with gemcitabine and cisplatin. Targeted therapies inhibiting EGFR, VEGF, MEK and others are broadly tested in CCA but to date, the existing data from
TE D
randomized and nonrandomized trials do not justify the application of small molecules outside of clinical trials. In clinical practice, many patients receive second-line CT after failure of gemcitabine/cisplatin, although there is so far no evidence to support second-line CT. This
EP
review summarizes current chemotherapy protocols and ongoing studies, including
AC C
conventional chemotherapy and targeted therapies.
Key words: Cholangiocarcinoma; Biliary tract cancer; Chemotherapy; Gemcitabine; Targeted therapy
ACCEPTED MANUSCRIPT Introduction Cholangiocarcinoma (CCA), including intrahepatic CCA, extrahepatic CCA and gallbladder carcinoma (GBC), is the second most common primary liver cancer. The incidence in western countries increases and currently up to 1/ 100.000 people are diagnosed with CCA
RI PT
per year [1-3]. Radical resection is the treatment of choice whenever possible. However, high rates of unresectable tumors and recurrence after resection result in a poor prognosis [4]. Furthermore, CCA is frequently diagnosed when metastases or advanced local tumor infiltration are already present and prevent tumor resection. Even in patients who are
SC
deemed to be curable, there is a probability of about 35% that during surgical exploration it turns out that resection is not possible (own data). Finally, only a minority of 25-35% of all
M AN U
patients undergoes resection [5;6]. Liver transplantation is currently no standard for patients with CCA, but can be a promising option for cure in very well selected patients and after neoadjuvant chemoradiation [7].
Consequently, most patients with CCA receive non-curative treatment sooner or later.
TE D
Despite a relative chemo-resistance of CCA [8-10], and a low number of phase III trials, the role of chemotherapy (CT) is best investigated in advanced CCA compared to other treatment options. The role of radiotherapy, chemoradiation, transarterial chemotherapy or ablative
treatments
such
as
photodynamic
therapy
(PDT)
or
intraductal
EP
locally
radiofrequency ablation (RFA) has only been investigated in small, mostly retrospective trials
AC C
[11-17], but larger and randomized studies are ongoing. Besides the anti-tumoral treatment, endoscopical or percutaneous biliary drainage have a great impact to reduce morbidity and mortality and to enhance quality of life by the prevention of cholangitis and jaundice, thereby often being a prerequisite to apply palliative anti-tumoral treatment [18-20].
Chemotherapy in unresectable cholangiocarcinoma It was demonstrated in two randomized trials that CT can improve the survival of patients with advanced CCA and GBC when compared to best supportive care (BSC) [21;22]. Glimelius et al. used 5- fluorouracil (5FU), folinic acid (FA) and etoposide and observed a
ACCEPTED MANUSCRIPT mean overall survival (OS) of 6 months vs. 2.5 months with BSC (p
