Chemotherapy

The phase III ABC-02 study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive either cisplatin plus gemcitabine or gemcitabine alone for up to 6 months.[5][Level of evidence A1]

The phase III ABC-02 study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive either cisplatin plus gemcitabine or gemcitabine alone for up to 6 months.[5][Level of evidence A1]

The median overall survival (OS) was prolonged in the cisplatin-gemcitabine group (11.7 months) compared with the gemcitabine-alone group (8.1 months) (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.52−0.80; P < .001).[5]

The phase III ABC-02 study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive either cisplatin plus gemcitabine or gemcitabine alone for up to 6 months.[5][Level of evidence A1]

A similar median OS benefit was demonstrated in all subgroups, including 73 patients with extrahepatic bile duct cancer and 57 patients with hilar tumors.

The phase III ABC-02 study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive either cisplatin plus gemcitabine or gemcitabine alone for up to 6 months.[5][Level of evidence A1]

Grades 3 and 4 toxicities occurred with similar frequencies in both study groups, with the exception of increased hematologic toxicity in the cisplatin-gemcitabine group and increased hepatic toxicity in the gemcitabine-alone group.

A phase II study (NCT03044587) included 91 patients with advanced cholangiocarcinoma. Patients were randomly assigned to receive the combination of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin (arm A) or the ABC-02 study regimen of cisplatin plus gemcitabine (arm B). The primary end point was a prespecified benchmark of a 4-month progression-free survival (PFS) rate of 40%.[6][Level of evidence B3]

A phase II study (NCT03044587) included 91 patients with advanced cholangiocarcinoma. Patients were randomly assigned to receive the combination of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin (arm A) or the ABC-02 study regimen of cisplatin plus gemcitabine (arm B). The primary end point was a prespecified benchmark of a 4-month progression-free survival (PFS) rate of 40%.[6][Level of evidence B3]

The 4-month PFS rate was 51% in arm A. The median PFS was 6 months (95% CI, 2.4–9.6) in arm A and 6.9 months (95% CI, 2.5–7.9) in arm B.

A phase II study (NCT03044587) included 91 patients with advanced cholangiocarcinoma. Patients were randomly assigned to receive the combination of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin (arm A) or the ABC-02 study regimen of cisplatin plus gemcitabine (arm B). The primary end point was a prespecified benchmark of a 4-month progression-free survival (PFS) rate of 40%.[6][Level of evidence B3]

The median OS was 15.9 months (95% CI, 10.6–20.3) in arm A and 13.6 months (95% CI, 6.5–17.7) in arm B.

A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX). The primary end point was 6-month PFS.[7][Level of evidence B1]

A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX). The primary end point was 6-month PFS.[7][Level of evidence B1]

OS was not significantly different between treatment groups. It was 10.4 months (95% CI, 8.0−12.6) in the GEMOX group and 10.6 months (95% CI, 7.3−15.5) in the XELOX group (P = .131).

A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX). The primary end point was 6-month PFS.[7][Level of evidence B1]

The PFS rate was 44.6% in the GEMOX group and 46.7% in the XELOX group (95% CI of difference in 6-month PFS rate, -12% to 16%, meeting criteria for noninferiority).

A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX). The primary end point was 6-month PFS.[7][Level of evidence B1]

A predefined subgroup analysis based on primary site of disease did not reveal a difference in objective response rate between the two arms in patients with gallbladder cancer (P = .598).

A multicenter phase III trial in the United Kingdom (ABC-06 [NCT01926236]) included 162 patients with locally advanced or metastatic biliary tract cancer and documented radiological disease progression on first-line cisplatin and gemcitabine. Patients were randomly assigned to receive either FOLFOX (folinic acid, 5-FU, and oxaliplatin) with active symptom control (ASC) or ASC alone. The following results were observed after a median follow-up of 21.7 months:[8][Level of evidence A1]Two phase II trials have evaluated 5-FU and leucovorin with or without liposomal irinotecan, but results differed.

A multicenter phase III trial in the United Kingdom (ABC-06 [NCT01926236]) included 162 patients with locally advanced or metastatic biliary tract cancer and documented radiological disease progression on first-line cisplatin and gemcitabine. Patients were randomly assigned to receive either FOLFOX (folinic acid, 5-FU, and oxaliplatin) with active symptom control (ASC) or ASC alone. The following results were observed after a median follow-up of 21.7 months:[8][Level of evidence A1]Two phase II trials have evaluated 5-FU and leucovorin with or without liposomal irinotecan, but results differed.

The median OS was significantly longer in the FOLFOX group (6.2 months) than in the ASC-alone group (5.3 months) (adjusted HR, 0.69; 95% CI, 0.50−0.97; P = .031). In the FOLFOX group, the OS rate was 50.6% at 6 months and 25.9% at 12 months, compared with 35.5% at 6 months and 11.4% at 12 months in the ASC-alone group.

A multicenter phase III trial in the United Kingdom (ABC-06 [NCT01926236]) included 162 patients with locally advanced or metastatic biliary tract cancer and documented radiological disease progression on first-line cisplatin and gemcitabine. Patients were randomly assigned to receive either FOLFOX (folinic acid, 5-FU, and oxaliplatin) with active symptom control (ASC) or ASC alone. The following results were observed after a median follow-up of 21.7 months:[8][Level of evidence A1]Two phase II trials have evaluated 5-FU and leucovorin with or without liposomal irinotecan, but results differed.

Grade 3 to 5 adverse events were reported in 56 patients (69%) in the FOLFOX group, compared with 42 patients (52%) in the ASC-alone group. The most frequently reported grade 3 to 5 FOLFOX-related adverse events were neutropenia (12%), fatigue/lethargy (11%), and infection (10%). There were three chemotherapy-related deaths, one each due to infection, acute kidney injury, and febrile neutropenia.

A multicenter phase IIb trial in South Korea (NIFTY [NCT03524508]) randomly assigned 174 patients with metastatic biliary tract cancer that had progressed during first-line cisplatin and gemcitabine to receive 5-FU and leucovorin with or without liposomal irinotecan. The following was observed after a median follow-up of 6.1 months:[9][Level of evidence A1]

A multicenter phase IIb trial in South Korea (NIFTY [NCT03524508]) randomly assigned 174 patients with metastatic biliary tract cancer that had progressed during first-line cisplatin and gemcitabine to receive 5-FU and leucovorin with or without liposomal irinotecan. The following was observed after a median follow-up of 6.1 months:[9][Level of evidence A1]

The primary end point of median PFS was significantly longer in the group who received liposomal irinotecan (3.9 months) compared with the group who received 5-FU plus leucovorin alone (1.6 months) (HR, 0.38; 95% CI, not reported; P = .0001). A secondary end point of median OS was also significantly longer in the group who received liposomal irinotecan (8.6 months) compared with the group who received 5-FU plus leucovorin alone (5.3 months) (HR, 0.68; 95% CI, not reported; P = .024).

The German multicenter phase II NALIRICC trial (NCT03043547) included 100 patients with metastatic biliary tract cancer that progressed during gemcitabine-based therapy. Patients were randomly assigned to receive 5-FU plus leucovorin with or without liposomal irinotecan.[10][Level of evidence A1]

The German multicenter phase II NALIRICC trial (NCT03043547) included 100 patients with metastatic biliary tract cancer that progressed during gemcitabine-based therapy. Patients were randomly assigned to receive 5-FU plus leucovorin with or without liposomal irinotecan.[10][Level of evidence A1]

The median PFS in the liposomal irinotecan group was 2.6 months, compared with 2.3 months in the 5-FU–leucovorin-alone group (HR, 0.87; 95% CI, 0.56–1.35; P not reported). The median OS was 6.9 months in the liposomal irinotecan group and 8.2 months in the 5-FU–leucovorin-alone group (HR, 1.08; 95% CI, 0.68–1.72; P not reported).

The German multicenter phase II NALIRICC trial (NCT03043547) included 100 patients with metastatic biliary tract cancer that progressed during gemcitabine-based therapy. Patients were randomly assigned to receive 5-FU plus leucovorin with or without liposomal irinotecan.[10][Level of evidence A1]

Toxicity was significantly higher in the liposomal irinotecan group, with treatment-related serious adverse events occurring in 16 patients (33%), compared with one patient (2%) in the 5-FU–leucovorin-alone group. The most common grade 3 or higher adverse events in the liposomal irinotecan group were neutropenia (17%), diarrhea (15%), and nausea (8%).