Trial Information

Definitive Chemoradiation With Gemcitabine and Continuous 5- FU (Fluorouracil)Followed by High Dose Rate Brachytherapy or Stereotactic Body Radiation Therapy Boost in Locally Advanced Intra or Extrahepatic Cholangiocarcinoma

Cholangiocarcinoma is an uncommon tumor arising from the biliary tract. It can be
stratified into two categories based on location, intrahepatic and extrahepatic. In the
United States, approximately 4,000-5,000 cases of cholangiocarcinoma are diagnosed each
year. The most common location is at the bifurcation of the common hepatic duct and is
classified as extrahepatic, also known as a Klatskin tumor. Approximately 60-80% of tumors
are found in this perihilar location. A history of primary sclerosing cholangitis confers
10% lifetime risk of developing cholangiocarcinoma. Other known risk factors include
ulcerative colitis, liver fluke infestations, hepatolithiasis, thorotrast exposure and
choledochal cysts. Cholecystectomy decreases the risk. Most patients are lymph node
positive at diagnosis, approaching 55-60%, and less than half are resectable at diagnosis.

Because of the rare nature of the tumor, there are limited prospective trials addressing the
roles for surgery, chemotherapy (CT) and radiation therapy (RT) in the treatment of
cholangiocarcinoma. Despite advances in surgical and radiotherapy techniques, the prognosis
for cholangiocarcinoma remains dismal. Historically, survival is poor with a 0-10% 5-year
survival. In more recent years, a median survival of 2-15 months is expected. Patients who
are able to undergo surgical resection at diagnosis have longer survival of approximately
20-24 months. Recent investigations in the area of neoadjuvant chemoradiation followed by
orthotopic liver transplant in a select group of patients report promising results, with 1-,
3- and 5-year overall survival of 92%, 82% and 82%, respectively. Although this approach
may be appropriate for select patients, namely younger patients with small tumors, no or
limited nodal involvement, and no encasement of the major vasculature, the majority of
patients presenting with cholangiocarcinoma will present with unresectable disease at
initial diagnosis, often due to nodal involvement.

Chemotherapy The role of chemotherapy (CT) in cholangiocarcinoma has not been established.
Most chemotherapy trials have been small single institution phase II trials, and there have
been no large prospective randomized trials. Additionally, most chemotherapy trials include
patients with intrahepatic, extrahepatic and gallbladder carcinomas, as well as patients
with locally advanced and metastatic disease. Response rates have ranged from 0-40% with no
complete remissions. The most extensively investigated CT agent has been 5-fluorouracil
(5-FU), which has disappointing response rates of 9% as a single agent. Response rates were
not improved by the addition of streptozotocin or methyl-CCNU (Semustine) to 5-FU in a
randomized trial performed by Eastern Cooperative Oncology Group (ECOG).6 Multiple
combination CT regimens have been investigated in small clinical trials, and none have shown
a survival benefit.

Gemcitabine has shown some promise as a potential chemotherapeutic agent in the treatment of
cholangiocarcinoma. A multicenter retrospective analysis out of Japan examining a multitude
of different CT regimens in patients with intrahepatic, extrahepatic or gallbladder
carcinomas reported gemcitabine was the most effective treatment, with a reduction in
mortality by about 50%.7 Fifty-eight patients of the 413 identified in this study were
treated with gemcitabine, 6.9% showed partial response, 50% remained stable, and 39.7%
progressed despite therapy. Median survival was 8.05 months with a hazard ratio (HR) of
0.50 (95% confidence interval 0.35-0.72). Sixteen out of the 58 patients treated with
gemcitabine had extrahepatic cholangiocarcinoma. In numerous phase II trials of gemcitabine
as a single agent, response rates have ranged from 6-30%, with greater than 50% of treated
patients having either a partial response or stable disease. 7-12 Median survival (MS) has
ranged from 6.5-14 months in these trials. In 2008, guidelines for CT in biliary tract
cancers were published in the Journal of Hepatobiliary and Pancreatic Surgery.13 Seven
trials using gemcitabine as a single agent were identified, with response rates ranging from
0-36% and MS ranging from 4.6-14 months. In this article the use of gemcitabine in
unresectable cancers of the biliary tract was given a recommendation level C1, meaning that
its use may be considered, although there is a lack of high-level evidence.13

The combination of 5-FU or it's oral analog capecitabine and gemcitabine chemotherapy alone
(without radiation) in the advanced metastatic setting has improved response rates and
median overall survivals from around 10% or 6.1 months to 10-36% and 9.7 to 14 months
respectively.13a Based on this data it likely should have synergy if both agents are given
concurrently with external beam RT. The combination of continuous 5-FU and gemcitabine
with external beam radiation in locally advanced pancreatic cancer has been shown to be safe
and resulted in a complete response in 2 patients (6.3%), a partial response in 18 patients
(56.3%), with an overall all response rate of 62.5% 13b. Based on this data and the similar
dose of external RT therapy it seems reasonable and safe to combine the two agents 5-FU and
gemcitabine with RT in advanced cholangiocarcinoma. We chose to use 5-FU rather than oral
capecitabine due to occasional problems obtaining prescription coverage for this more
expensive alternative and the prior available safety data and our own institutional
experience using 5-FU and gemcitabine combination with RT for pancreatic cancer.

Radiation Therapy Data for the use of radiation therapy (RT) alone in the setting of
unresectable disease is sparse. In a report from Johns Hopkins, a total of 23 patients were
treated with a surgical procedure followed by RT.14 Complete resection was accomplished in
14 of these patients and palliative stenting for 9. Postoperative RT doses ranging from
45-63 Gy delivered by external beam radiation therapy (EBRT) followed by brachytherapy boost
or EBRT with cone down boost. RT had no effect on overall survival of patients who had
undergone complete resection or on patients who were being treated with palliative intent.
Of note, none of the patients in this study were treated with concurrent chemotherapy. The
subgroup of patients who were stented and then treated with palliative RT applies to our
current investigational study group, and in this subset of patients there was no survival
benefit for RT alone.

Chemotherapy and Radiation Therapy Because of the success of combined CT and RT in other
gastrointestinal cancers, and the unsuccessful attempts at CT and RT alone, multimodality
treatment has been applied to cholangiocarcinoma. There is limited data on the use of EBRT
in combination with 5-FU specifically for extrahepatic cholangiocarcinoma. In a
retrospective review, Kim et al looked at ≥40 Gy EBRT with concomitant bolus 5-FU (500mg/m2)
for the first 3-days of each of two weeks of radiation, followed by monthly maintenance
chemo with 5-FU for one year.15 Eighty four patients were included, of which 72 had a gross
total resection (47 negative margins, 25 microscopically positive margins) and the remaining
12 had palliative procedures prior to the chemoradiation. The 5-year survival was 31%.
Although this trial was specifically looking at postoperative chemoradiotherapy, the subset
of patients that did not undergo gross total resection would apply to our study population.
The 5-year actuarial survival was 14% overall for this subgroup.