Chemotherapy

A multicenter phase III study in the United Kingdom (BILCAP) included 447 patients with cholangiocarcinoma or muscle-invasive gallbladder cancer who underwent a macroscopically complete resection with curative intent. Patients were randomly assigned to receive eight cycles of capecitabine (1,250 mg/m2 twice a day on days 1−14 of a 21-day cycle) or observation.[13][Level of evidence B1] At a median follow-up of 106 months, the following results were observed:

A multicenter phase III study in the United Kingdom (BILCAP) included 447 patients with cholangiocarcinoma or muscle-invasive gallbladder cancer who underwent a macroscopically complete resection with curative intent. Patients were randomly assigned to receive eight cycles of capecitabine (1,250 mg/m2 twice a day on days 1−14 of a 21-day cycle) or observation.[13][Level of evidence B1] At a median follow-up of 106 months, the following results were observed:

There was no statistically significant difference in OS in the intention-to-treat analysis (median OS, 49.6 months in the capecitabine group vs. 36.1 months in the observation group; adjusted hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.67−1.06; P > .05).

A multicenter phase III study in the United Kingdom (BILCAP) included 447 patients with cholangiocarcinoma or muscle-invasive gallbladder cancer who underwent a macroscopically complete resection with curative intent. Patients were randomly assigned to receive eight cycles of capecitabine (1,250 mg/m2 twice a day on days 1−14 of a 21-day cycle) or observation.[13][Level of evidence B1] At a median follow-up of 106 months, the following results were observed:

In the intention-to-treat analysis, the median recurrence-free survival (RFS) was 24.3 months (95% CI, 18.6–34.6) in the capecitabine group and 17.4 months (95% CI, 11.8–23) in the observation group. An adjusted Cox proportional hazards model suggested potential improvement in RFS in the first 24 months from randomization (HR, 0.74; 95% CI, 0.57–0.96), but with no significant difference in the period after 24 months (HR, 1.57; 95% CI, 0.90–2.74).

The open-label, randomized, phase II STAMP study (NCT03079427), presented in abstract form, included 101 patients with perihilar or distal bile duct cancer, at least one regional lymph node metastasis (N1 or greater), and complete macroscopic (R0 or R1) resection within 12 weeks. Patients were assigned to receive either eight cycles of capecitabine (1,250 mg/m2) twice a day on days 1–14 of a 21-day cycle (based on the BILCAP trial) or eight cycles of cisplatin (25 mg/m2) and gemcitabine (1,000 mg/m2) on days 1 and 8 of a 21-day cycle. The primary end point was disease-free survival (DFS).[14][Level of evidence B1] At a median follow-up of 28.7 months, the following results were observed:

The open-label, randomized, phase II STAMP study (NCT03079427), presented in abstract form, included 101 patients with perihilar or distal bile duct cancer, at least one regional lymph node metastasis (N1 or greater), and complete macroscopic (R0 or R1) resection within 12 weeks. Patients were assigned to receive either eight cycles of capecitabine (1,250 mg/m2) twice a day on days 1–14 of a 21-day cycle (based on the BILCAP trial) or eight cycles of cisplatin (25 mg/m2) and gemcitabine (1,000 mg/m2) on days 1 and 8 of a 21-day cycle. The primary end point was disease-free survival (DFS).[14][Level of evidence B1] At a median follow-up of 28.7 months, the following results were observed:

The median DFS was 14.3 months (1-sided 90% CI, 10.7–16.5) in the cisplatin-and-gemcitabine group and 11.1 months in the capecitabine group (1-sided 90% CI, 8.4–12.7).

The open-label, randomized, phase II STAMP study (NCT03079427), presented in abstract form, included 101 patients with perihilar or distal bile duct cancer, at least one regional lymph node metastasis (N1 or greater), and complete macroscopic (R0 or R1) resection within 12 weeks. Patients were assigned to receive either eight cycles of capecitabine (1,250 mg/m2) twice a day on days 1–14 of a 21-day cycle (based on the BILCAP trial) or eight cycles of cisplatin (25 mg/m2) and gemcitabine (1,000 mg/m2) on days 1 and 8 of a 21-day cycle. The primary end point was disease-free survival (DFS).[14][Level of evidence B1] At a median follow-up of 28.7 months, the following results were observed:

The median OS was 35.7 months (1-sided 90% CI, 29.5–not estimated) in the cisplatin-and-gemcitabine group and 35.7 months (1-sided 90% CI, 30.9–not estimated) in the capecitabine group.

The open-label, randomized, phase II STAMP study (NCT03079427), presented in abstract form, included 101 patients with perihilar or distal bile duct cancer, at least one regional lymph node metastasis (N1 or greater), and complete macroscopic (R0 or R1) resection within 12 weeks. Patients were assigned to receive either eight cycles of capecitabine (1,250 mg/m2) twice a day on days 1–14 of a 21-day cycle (based on the BILCAP trial) or eight cycles of cisplatin (25 mg/m2) and gemcitabine (1,000 mg/m2) on days 1 and 8 of a 21-day cycle. The primary end point was disease-free survival (DFS).[14][Level of evidence B1] At a median follow-up of 28.7 months, the following results were observed:

The gemcitabine-and-cisplatin group had increased rates of toxicity. Grade 3 to 4 adverse events occurred in 84% of patients who received gemcitabine and cisplatin (most commonly neutropenia) and in 16% of patients who received capecitabine (most commonly hand-foot syndrome).

The open-label, randomized, phase II STAMP study (NCT03079427), presented in abstract form, included 101 patients with perihilar or distal bile duct cancer, at least one regional lymph node metastasis (N1 or greater), and complete macroscopic (R0 or R1) resection within 12 weeks. Patients were assigned to receive either eight cycles of capecitabine (1,250 mg/m2) twice a day on days 1–14 of a 21-day cycle (based on the BILCAP trial) or eight cycles of cisplatin (25 mg/m2) and gemcitabine (1,000 mg/m2) on days 1 and 8 of a 21-day cycle. The primary end point was disease-free survival (DFS).[14][Level of evidence B1] At a median follow-up of 28.7 months, the following results were observed:

Given the lack of significant difference in DFS and OS and the higher toxicity rate in the cisplatin-and-gemcitabine group, capecitabine remains the reference standard for adjuvant therapy.

A French multicenter phase III study (PRODIGE 12-ACCORD 18-UNICANCER GI) randomly assigned 196 patients with R0 or R1 resection of localized biliary tract cancer to 12 cycles of adjuvant gemcitabine plus oxaliplatin (GEMOX) or surveillance. The primary end point was RFS, and the secondary end point was OS.[15][Level of evidence B1] After a median follow-up of 46.5 months the following results were observed:

A French multicenter phase III study (PRODIGE 12-ACCORD 18-UNICANCER GI) randomly assigned 196 patients with R0 or R1 resection of localized biliary tract cancer to 12 cycles of adjuvant gemcitabine plus oxaliplatin (GEMOX) or surveillance. The primary end point was RFS, and the secondary end point was OS.[15][Level of evidence B1] After a median follow-up of 46.5 months the following results were observed:

There was no statistically significant difference in RFS (median, 30.4 months with GEMOX vs. 18.5 months with observation; HR, 0.88; 95% CI, 0.62–1.25, P = .48).

A French multicenter phase III study (PRODIGE 12-ACCORD 18-UNICANCER GI) randomly assigned 196 patients with R0 or R1 resection of localized biliary tract cancer to 12 cycles of adjuvant gemcitabine plus oxaliplatin (GEMOX) or surveillance. The primary end point was RFS, and the secondary end point was OS.[15][Level of evidence B1] After a median follow-up of 46.5 months the following results were observed:

There was also no statistically significant difference in OS (75.8 months with GEMOX vs. 50.8 months with observation; HR, 1.08; 95% CI, 0.7–1.66; P = .74).

The Bile Duct Cancer Adjuvant Trial (BCAT), a Japanese, multicenter, phase III study, included 225 patients with resected bile duct cancer. Patients were randomly assigned to six cycles of adjuvant gemcitabine or observation. The primary end point was OS, and the secondary end point was RFS.[16][Level of evidence B1]

The Bile Duct Cancer Adjuvant Trial (BCAT), a Japanese, multicenter, phase III study, included 225 patients with resected bile duct cancer. Patients were randomly assigned to six cycles of adjuvant gemcitabine or observation. The primary end point was OS, and the secondary end point was RFS.[16][Level of evidence B1]

There was no significant difference in OS (median, 62.3 months with gemcitabine vs. 63.8 months with observation; HR, 1.01; 95% CI, 0.7–1.45; P = .964).

The Bile Duct Cancer Adjuvant Trial (BCAT), a Japanese, multicenter, phase III study, included 225 patients with resected bile duct cancer. Patients were randomly assigned to six cycles of adjuvant gemcitabine or observation. The primary end point was OS, and the secondary end point was RFS.[16][Level of evidence B1]

No OS differences were observed, even in subgroups stratified by lymph node status and surgical margin status.

The Bile Duct Cancer Adjuvant Trial (BCAT), a Japanese, multicenter, phase III study, included 225 patients with resected bile duct cancer. Patients were randomly assigned to six cycles of adjuvant gemcitabine or observation. The primary end point was OS, and the secondary end point was RFS.[16][Level of evidence B1]

There was also no significant difference in RFS (median, 36 months with gemcitabine vs. 39.9 months with observation; HR, 0.93; P = .693).

The European Study Group for Pancreatic Cancer (ESPAC-3 trial [NCT00058201]) enrolled 428 patients with periampullary cancer, which included 96 patients with bile duct cancers. Patients were randomly assigned to observation, 6 months of fluorouracil (5-FU)/leucovorin, or 6 months of gemcitabine.[17][Level of evidence B1]

The European Study Group for Pancreatic Cancer (ESPAC-3 trial [NCT00058201]) enrolled 428 patients with periampullary cancer, which included 96 patients with bile duct cancers. Patients were randomly assigned to observation, 6 months of fluorouracil (5-FU)/leucovorin, or 6 months of gemcitabine.[17][Level of evidence B1]

Among all patients, adjuvant chemotherapy was not associated with significant OS benefit when compared with observation. However, after adjusting for prognostic variables by multivariable analysis, a statistically significant OS benefit was associated with adjuvant chemotherapy (HR, 0.75; 95% CI, 0.57–0.98; P = .03).

The European Study Group for Pancreatic Cancer (ESPAC-3 trial [NCT00058201]) enrolled 428 patients with periampullary cancer, which included 96 patients with bile duct cancers. Patients were randomly assigned to observation, 6 months of fluorouracil (5-FU)/leucovorin, or 6 months of gemcitabine.[17][Level of evidence B1]

In a preplanned subgroup analysis of the 96 patients with bile duct cancer, no benefit was seen among patients treated with chemotherapy. Limitations of this subgroup analysis include limited statistical power and difficulty in differentiating ampullary versus distal common bile duct tumors as the pathological site of origin.

The European Study Group for Pancreatic Cancer (ESPAC-3 trial [NCT00058201]) enrolled 428 patients with periampullary cancer, which included 96 patients with bile duct cancers. Patients were randomly assigned to observation, 6 months of fluorouracil (5-FU)/leucovorin, or 6 months of gemcitabine.[17][Level of evidence B1]

The median survival was 27 months for the observation-alone group, 18 months for the 5-FU-leucovorin group, and 20 months for the gemcitabine-alone group.[17]

A multi-institutional Japanese study compared surgery alone with mitomycin and infusional 5-FU followed by 5-FU until disease progression.[18][Level of evidence B1]

A multi-institutional Japanese study compared surgery alone with mitomycin and infusional 5-FU followed by 5-FU until disease progression.[18][Level of evidence B1]

Among the subset of patients with bile duct cancer (n = 139), no survival benefit was seen.