Trial Information

A Phase I Study of Adjuvant Chemotherapy With Gemcitabine Plus S-1 in Patients With Biliary Tract Cancer Undergoing Curative Resection Without Major Hepatectomy

Surgery currently remains the only potentially curative treatment for biliary tract cancer
(BTC), and most patients develop recurrence. Therefore, effective adjuvant chemotherapy is
required to increase the curability of surgery and to prolong the survival in these
patients. However, to date, no standard adjuvant chemotherapy has been established, and a
guideline for BTC treatment recommends that trials of adjuvant chemotherapy be carried out.

Recently, there are two reports about gemcitabine (GEM) + S-1 combination (GS)chemotherapy
after surgical resection for patients with BTC. At Iwate Medical University, Takahara, et
al., performed a phase I study using a regimen of repeating 28 days as 1 course. Patients
received GEM on day 1 and day 15, and S-1 from day 1 to day 14. The recommended dose is
1,000 mg/m² of GEM and S-1 80 mg/m² after a pancreatoduodenectomy. The 2-year survival rate
of the 34 patients that received the GS therapy was 78.6% (Cancer Chemother Pharmacol. 2012
May;69(5):1127-33). At Hiroshima University, a cycle of chemotherapy consisted of
intravenous GEM of 700 mg/m² on day 1 and oral S-1 of 50 mg/m² for 7 consecutive days,
followed by a 1-week break from chemotherapy (14days as 1 course). Fifty patients received
GS therapy and had a significantly better 3-year survival rate (57%) compared with 53 cases
of surgery alone (30%). The GS adjuvant chemotherapy was feasible and the adverse event was
minimal (Ann Surg. 2009 Dec;250(6):950-6).

Thus, the regimens of these two studies were 14 or 28 days as 1 course. There was no regimen
that consisted of GEM on day 1, 8 and S-1 for 14 consecutive days, followed by a 1-week
break from chemotherapy (21days as 1 course), which is frequently used for unresectable BTC
and pancreatic cancer.

Though a hepatectomy is frequently performed during surgery for BTC, it is unclear if the
effect of the anticancer agent is affected by a hepatectomy. Because GEM is metabolized by
cytidine deaminase primarily in the liver, the ability to metabolize GEM after a hepatectomy
is thought to decrease. Some clinical studies demonstrated that patients who had undergone a
hepatectomy could not tolerate the standard dose and schedule of GEM. For adjuvant
chemotherapy with GEM, it is necessary to separately examine whether or not the patient has
undergone a hepatectomy.

Considering these present conditions, we aimed to assess the safety and efficacy of GEM +
S-1 combination chemotherapy (21days as 1 course regimen, which is frequently used for
unresectable BTC) for BTC with the patients undergoing curative resection without a
hepatectomy.