Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was signifi cantly longer and quality of life was signifi cantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a signifi cant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insuffi cient biliary decompression, the benefi t of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment.

# Introduction
Chemotherapy in patients with biliary tract cancer is indicated in those with unresectable advanced cancer and patients with recurrence after resection. However, no standard chemotherapy for biliary tract cancer has yet been established, because few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date. There are a number of studies regarding chemotherapy for biliary tract cancer, but many of these studies were prospective clinical trials with small numbers of patients, corresponding to phase II studies, or retrospective studies, so high-level evidence in this area is limited. According to the "Classification of Biliary Tract Carcinoma", bile duct cancer, gallbladder cancer, and ampullary cancer are classifi ed as biliary tract cancer, and there are some clinical trials and articles in which treatment results that include those in intrahepatic bile duct cancer are also reported. If clinical trials are conducted for individual diseases separately, diffi culties are encountered in view of effi ciency and implementation, and so far, clinical trials of chemotherapy have been carried out only for biliary tract cancer in general. However, because treatment policy, sensitivity to chemotherapy, and prognosis differ widely from disease to disease, the treatment results of chemotherapy in biliary tract cancer should be evaluated on the basis of a full understanding of individual background factors.
In the present guidelines, chemotherapy for unresectable biliary tract cancer and postoperative adjuvant chemotherapy has been described based on results from clinical trials and retrospective studies performed up to now. In order that effective chemotherapy for biliary tract cancer may be developed, active implementation of clinical trials is recommended. Also, large multiinstitutional RCTs (phase III) should be conducted to establish standard treatment as soon as possible.
The only procedure in biliary cancer that confers a cure is curative surgical resection, so a diagnosis of incurability should be made with caution. Lest the cancer be benign, surgical treatment should be administered as a rule only after pathological diagnosis (such as cytological and histological diagnoses) has been made. The chemotherapy described in the these Guidelines is concerned with adenocarcinoma, which has the highest frequency of occurrence, so pertinent literature should be referred to in selecting treatment methods for other specifi c pathological types of cancer. In these Guidelines, clinical questions (CQs) are posed, with responses in the form of recommendations (grades of the recommendations are defi ned in [fig_ref] Table 1: Strength of recommendations 1 [/fig_ref]. Also, levels of evidence are given (in parentheses) for fi ndings in reference citations (see defi nitions of levels in [fig_ref] Table 1: Strength of recommendations 1 [/fig_ref].

## Chemotherapy is recommended in patients with good general physical condition (recommendation c1).
To assess the effi cacy of chemotherapy in achieving prolonged survival in biliary tract cancer, verifi cation is necessary by comparing it with supportive treatment

## Cq 1 does chemotherapy have any benefi ts in patients with unresectable biliary tract cancer?
alone. To date, only two small RCTs (level II) have been published. [bib_ref] Chemotherapy improves survival and quality of life in advanced pancreatic and biliary..., Glimelius [/bib_ref] [bib_ref] Prospective randomized trial of 5-fl uorouracil, doxorubicin, and mitomycin C for non-resectable..., Takada [/bib_ref] An RCT on chemotherapy and supportive treatment was conducted in patients with unresectable pancreas cancer and biliary tract cancer. [bib_ref] Chemotherapy improves survival and quality of life in advanced pancreatic and biliary..., Glimelius [/bib_ref] In this study, fl uorouracil (5-FU) + leucovorin or 5-FU + leucovorin + etoposide were used for chemotherapy. For all the patients, signifi cantly prolonged survival was observed in the group who received chemotherapy (median survival time [MST], 6.0 months) compared with the group who received supportive treatment alone (MST, 2.5 months). However, due to the small number of patients with biliary tract cancer (37 patients), no signifi cant difference was established between the groups (chemotherapy group MST, 6.5 months; supportive treatment group, 2.5 months; P = 0.1). The rate of improvement in quality of life (QOL) was also examined in this trial, and a signifi cant difference was found in the chemotherapy group compared with the supportive treatment group (P < 0.01); an improvement of 36% was observed in the chemotherapy group (pancreas cancer, 38%; biliary tract cancer, 33%) and an improvement of 10% (pancreas cancer, 13%; biliary tract cancer, 5%) was shown in the supportive treatment group.
The other small RCT 3 was conducted in Japan, comparing chemotherapy with 5-FU + doxorubicin + mitomycin C (FAM) and palliative treatment, such as bypass, in patients with unresectable pancreatic cancer, gallbladder cancer, and bile duct cancer. No signifi cant improvement in prognosis was achieved in either group, but in the patients with gallbladder cancer, a good prognosis was achieved in the chemotherapy group (level II).
A retrospective analysis comparing chemotherapy and supportive treatment in patients with gallbladder cancer was carried out. No survival benefi t owing to chemotherapy was observed in patients with a performance status of 2, while prolonged survival in the chemotherapy group was observed in patients with a performance status of 0 or 1 4 (level IV).
Concerning the effi cacy of chemotherapy for unresectable biliary tract cancer, no evidence based on an RCT with a large number of patients is available, but there are reports demonstrating the effi cacy of chemotherapy in achieving improved QOL and prolonged survival. Thus, the strength of the recommendation for chemotherapy was determined as C1. [bib_ref] Chemotherapy improves survival and quality of life in advanced pancreatic and biliary..., Glimelius [/bib_ref] [bib_ref] Prospective randomized trial of 5-fl uorouracil, doxorubicin, and mitomycin C for non-resectable..., Takada [/bib_ref] [bib_ref] Chemotherapy in the treatment of advanced gallbladder cancer, Ishii [/bib_ref] 

## As chemotherapy for unresectable advanced biliary tract carcinoma, gemcitabine or tegafur/gimeracil/ oteracil potassium is recommended (recommendation c1).
The use of chemotherapy for biliary tract cancer should be limited to patients with unresectable, locally advanced disease and distant metastasis, or those with recurrence after resection. Chemotherapy is recommended in patients with a good general condition. However, in patients with general deterioration (performance status of 2 or 3) or those with insuffi cient biliary decompression, the benefi t of chemotherapy is small, so care should be taken in considering its indications. In these patients, palliative treatment targeting the maintenance of QOL should be administered, including pain control and the placement of stents in the bile duct. [fig_ref] Table 3: Systemic chemotherapy with single agents for biliary tract cancer [/fig_ref] shows the results of systemic chemotherapy with a single agent for biliary tract cancer. The single use of fl uoropyrimidines such as 5-FU, or a combination of 5-FU with interferon, leucovorin, or hydroxyurea as biochemical modulators, was often used for advanced biliary tract cancer. A favorable response rate of more than 30% has been reported with the combined use of a single agent with these modulators, but no difference was observed in MST, which ranged from 7 to 12 months, in studies in patients undergoing chemotherapy for unresectable biliary tract cancer, compared with patients who received best supportive care (level III). In Japan, uracil-tegafur (UFT) is approved by the Ministry of Health, Labor, and Welfare for biliary tract cancer. However, regimens of UFT alone or UFT plus leucovorin were reported to have objective responses of 5% and 0%, respectively, and more than 60% patients were evaluated as having progressive disease in these regimen. Therefore, UFT should not be used alone for biliary tract cancer (level III).
A clinical trial of tegafur/ gimeracil/oteracil potassium (S-1), which is an oral anticancer drug that consists of tegafur (FT) as a prodrug of 5-FU, 5-chloro-2, 4dihydroxypyridine (CDHP), and potassium oxonate (Oxo), was conducted in Japan. S-1 was orally administered at a dose of 80 mg/m 2 per day for 28 days, followed by 14 days of rest. In a late phase II trial, a favorable result was reported, with a success rate of 35% and MST of 9.4 months in 40 patients. Because of this result, insurance coverage for the use of this agent for biliary tract cancer was endorsed in August, 2007 (level III).
There are also some reports of the use of mitomycin C, cisplatin, taxanes, and irinotecan (CPT-11) [fig_ref] Table 3: Systemic chemotherapy with single agents for biliary tract cancer [/fig_ref] , but no satisfactory result has been achieved (level III).
For biliary tract cancer, there is a limitation in treatment effects brought about by chemotherapy with the use of a single agent, so many modalities of combination chemotherapy have been carried out [fig_ref] Table 4: Combination chemotherapy for biliary tract cancer [/fig_ref]. Compared with single-agent chemotherapy, the response rate of combination chemotherapy is generally high and the survival period is also inclined to be long. Although a regimen of a combination of 5-FU, anthracycline, and platinum has often been employed, no standard regimen has been established. An attempt at a regimen focusing [fig_ref] Table 3: Systemic chemotherapy with single agents for biliary tract cancer [/fig_ref].
A clinical trial (phase II) was carried out with gemcitabine alone in Japan. [bib_ref] Phase II study of single-agent gemcitabine in patients with advanced biliary tract..., Okusaka [/bib_ref] A response rate of 17.5% (95% confi dence intervals [CI], 7.3%-32.8%), and an MST of 7.6 months was achieved with the standard dosage, which was 1000 mg/m 2 as a 30-min intravenous infusion weekly, given for 3 consecutive weeks, followed by a week of rest, the results being roughly similar to those of reports from abroad. Toxicity inducing myelosuppression, such as leucopenia, as well as nausea and anorexia, was mainly observed, but tolerance was good. Based on these results, gemcitabine was approved by the Ministry of Health, Labour, and Welfare, in June, 2006, for use in biliary tract cancer (level III).

## Side memo
In Japan, none of the above modulators are approved by the Ministry of Health, Labour, and Welfare for use as chemotherapeutic drugs in biliary tract cancer.
on the use of gemcitabine is currently being made and a favorable result has been achieved, with the response rate being 21%-48% and MST, 4.6-11.0 months in patients treated with gemcitabine + cisplatin 10-13 (level III). Currently, a large controlled trial comparing gemcitabine alone and gemcitabine + cisplatin (CDDP) is being conducted chiefl y by an English group and it is drawing attention. Also, therapeutic drugs targeting molecular biological characteristics (molecular targeting therapy) are now under development. In view of a report suggesting the strong expression of epithelial growth factor receptor (EGFR) in biliary tract cancer, a phase II trial using erlotinib, which is an EGFRinhibiting drug, is being carried out. [bib_ref] Phase II study of erlotinib in patients with advanced biliary cancer, Philip [/bib_ref] In biliary tract cancer, treatment results differ widely depending upon the site of the cancer. In clinical trials, patients' backgrounds, particularly the proportions of those with gallbladder cancer, bile duct cancer, and ampullary cancer, have a big impact on treatment results, such as the survival period. [bib_ref] A phase II trial of Uracil-tegafur (UFT) in patients with advanced biliary..., Ikeda [/bib_ref] [bib_ref] Early phase II study of uracil-tegafur plus doxorubicin in patients with unresectable..., Furuse [/bib_ref] [bib_ref] Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase..., Knox [/bib_ref] In a phase II study of gemcitabine + capecitabine, the MST in patients with gallbladder cancer was 6.6 months and the MST in patients with bile duct cancer was 19 months; thus, this difference in MST was assumed to be due to a biological difference. [bib_ref] Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase..., Knox [/bib_ref] In overseas clinical trials of chemotherapy for biliary tract cancer, intrahepatic cholangiocarcinoma is often included. In Japan, The number of RCTs that have been conducted concerning chemotherapy for bile duct cancer is not so large. Outlined in [fig_ref] Table 5: Randomized clinical trials for unresectable biliary tract cancer [/fig_ref] are RCTs retrieved from a literature search. In Japan, comparisons were made by [bib_ref] Comparison of 5-fl uorouracil, doxorubicin and mitomycin C with 5-fl uorouracil alone..., Takada [/bib_ref] between FAM and 5-FU alone and between FAM and palliative treatment, such as bypass operation. No signifi cant difference in survival was confi rmed in these RCTs, and a standard chemotherapy has not been established yet (level II). of postoperative adjuvant therapy is suggested by such trials.
Todoroki summarized the results of clinical trials of chemotherapy for gallbladder cancer and verifi ed that postoperative chemotherapy was effi cacious. Most of these clinical trials were conducted using a single arm, so no regimen could be selected as a possible candidate for postoperative adjuvant therapy. [bib_ref] Chemotherapy for gallbladder carcinoma -a surgeon's perspective, Todoroki [/bib_ref] Recently, chemotherapy focusing on gemcitabine for unresectable biliary tract cancer has been conducted, and regimens with good anticancer effects have sometimes been observed. However, no large RCTs of postoperative adjuvant therapy have been carried out with the use of such regimens. RCTs of postoperative adjuvant therapy, using new agents including gemcitabine and S-1, should be conducted vigorously. At the present time, no recommendable postoperative adjuvant therapy has been discovered, so clinical trials of various forms of chemotherapy are anticipated in the future.
Acknowledgment. We would like to express our deep gratitude to the members of the the Japanese Association of Biliary Surgery, the Japanese Society of Hepato-Biliary-Pancreatic Surgery, and the Japan Society of Clinical Oncology, who provided us with great support and guidance in the preparation of the Guidelines. This process was conducted as part of the Integrated Research Project for Assessing Medical Technology 2005 and 2006 sponsored by the Japanese Ministry of Health, Labour, and Welfare.
We truly appreciate the following active working members who developed the draft of the evidencebased clinical practice Guidelines for the treatment of biliary tract cancer (Japanese version, 2007): Masahiro Kai (Miyazaki), Yasutoshi Kimura (Sapporo), Shigeaki Sawada (Toyama), Hiroaki Shimizu (Chiba), Hisatoshi Nakagawara (Kanazawa), Kohei Nakachi (Kashiwa), and Hiroyuki Yoshitome (Chiba). We also

## No recommendable regimen is available now, but it is hoped that adjuvant chemotherapy can be carried out as a clinical trial. (recommendation c1).
In gallbladder and bile duct cancers, early recurrence often occurs even if these patients have received curative resection; the prognosis in patients with recurrence is extremely poor. Therefore, further development of effective measures for preventing recurrence through postoperative adjuvant therapy is eagerly anticipated. In view of the low incidence of biliary tract cancer in Western countries, where a large number of clinical studies of postoperative adjuvant therapy have been conducted in other types of cancer, few RCTs of postoperative adjuvant therapy for biliary tract cancer have been carried out. On the other hand, in the East Asian region (including Japan), the incidence of biliary tract cancer is high so RCTs of postoperative adjuvant therapy have been carried out in Japan. From 1986 to 1992, Takada et al. performed an RCT in which 508 patients with pancreas cancer and biliary tract cancer were assigned to a group in which combination chemotherapy using 5-FU and mitomycin C (MMC) was administered (MF group) and a group for whom surgery alone was conducted (control group); the results were reported with a postoperative follow-up period of 5 years. [bib_ref] Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and..., Takada [/bib_ref] As eligible patients, 158 patients with pancreatic cancer, 118 patients with bile duct cancer, 112 patients with gallbladder cancer, and 48 patients with ampullary cancer were chosen. Analysis was done independently in the individual diseases, and the 5-year survival rate was found to be signifi cantly better in the MF group for gallbladder cancer [fig_ref] Table 6: Randomized clinical trial of adjuvant chemotherapy for pancreas and biliary tract cancer20 [/fig_ref] (level II). However, according to a review of the degree of cure due to resection, a signifi cant difference in survival rate was found only in patients with noncurative resection. On the basis of an intent-to-treat analysis, no signifi cant difference between the MF and the control group was observed in patients with gallbladder cancer. MF therapy has not yet been established as standard postoperative adjuvant therapy in biliary tract cancer, but the effi cacy CQ 3 Does adjuvant chemotherapy after surgery have a survival benefi t?
As chemotherapy for biliary tract cancer at the present time, gemcitabine or S-1, which is covered by insurance in Japan, is recommended on the basis of the results of many phase II trials, including those performed in Japan (level III). Evidence-based standard treatment should be established in the future by conducting controlled trials with the use of these agents. appreciate very much the following members who reviewed and approved the fi nal Japanese version of the guidelines: Hiromitsu Saisyo (Ichikawa), Munemasa Ryu (Chiba), Satoru Shikata (Kyoto), and Yuji Nimura (Nagoya).
[table] Table 1: Strength of recommendations 1 [/table]
[table] Table 3: Systemic chemotherapy with single agents for biliary tract cancer [/table]
[table] Table 4: Combination chemotherapy for biliary tract cancer [/table]
[table] Table 5: Randomized clinical trials for unresectable biliary tract cancer [/table]
[table] Table 6: Randomized clinical trial of adjuvant chemotherapy for pancreas and biliary tract cancer20 [/table]