T1b – T3 tumors
Radical cholecystectomy: hepatic resection and lymph node dissection with or without common bile duct resection and reconstructive hepaticojejunostomy.
Consensus-based guidelines for adjuvant therapy after resection of bile duct cancer are available from two expert groups:
• National Comprehenisve Cancer Network (NCCN): Consider adjuvant fluoropyrimidine-based chemoradiotherapy, or chemotherapy alone with a single-agent fluoropyrimidine or gemcitabine should be considered after resection for all except T1 N0 tumors.
• European Society of Medical Oncology (ESMO): Consider postoperative chemoradiotherapy after complete surgical resection of any-stage disease.
Adjuvant therapy options/Supporting clinical trials
BILCAP trial (phase III)
Population: 447 patients with resected cholangiocarcinoma or GBC (n = 79)
Intervention: Capecitabine 1250 mg/m2 BID days 1–14 every 21 days × 8 cycles versus placebo
Outcome: Clinically but not statistically significant improvement in overall survival (OS) with capecitabine by intent to treat analysis (median OS 51 versus 36 months, HR 0.81, 95% CI 0.63–1.06, p = 0.097).
SWOG S0809 (phase II)
Population: 79 patients with resected extrahepatic biliary cancer (n = 54) or GBC (n = 25)
Intervention: Gemcitabine 1000 mg/m2 day 1 and day 8 + capecitabine 1500 mg/m2/day days 1–14 every 21 days × 4 cycles followed by concomitant capecitabine 1330 mg/m2/day and with RT (45 Gy to regional lymphatics, 54 to 59.4 Gy to tumor bed).
Outcome: Median overall survival 35 months.
PRODIGE 12-ACCORD 18 trial (phase III)
Population: 196 patients with resected biliary tract cancer including GBC (n = 37)
Intervention: Gemcitabine 1000 mg/m2 day 1 + oxaliplatin 85 mg/m2 day 2 every 21 days × 12 cycles versus surveillance
Outcome: Adjuvant gemcitabine + oxaliplatin did not significantly improve relapse-free survival, the primary endpoint (at four years, 39 versus 33%; HR 0.83, 95% CI 0.58–1.19, p = 0.31).
ACTICCA-1 trial (phase III)
Population: Open to patients with resected cholangiocarcinoma or GBC
Intervention: Cisplatin 25 mg/m2 + Gemcitabine 1000 mg/m2 days 1 and 8 every 21 days × 6 cycles versus Capecitabine 1250 mg/m2 BID days 1–14 every 21 days × 8 cycles versus observation
Not indicated: Although biliary or intestinal bypass can be considered, percutaneous or endoscopic approaches are generally preferred, given the limited median survival in patients with advanced disease.
Palliative therapy option/Supporting clinical trials
Any T, with distant metastatic disease
First line chemotherapy:
Population: 410 patients with locally advanced or metastatic bile duct, gallbladder (n = 148), or ampullary cancer.
Intervention: Cisplatin 25 mg/m2 + gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days versus single agent gemcitabine 1000 mg/m2 days 1, 8, 15 every 28 days.
Outcome: Median overall survival was significantly greater with combination therapy (11.7 versus 8.1 months, (P < 0.001).). Rate of tumor control among patients in the cisplatin-gemcitabine group was also significantly increased (81.4% vs. 71.8%, P = 0.049).
In select patients with unresectable disease and initial good systemic control, radiation therapy can be discussed on a case by case basis.
Second line chemotherapy:
No regimen can be considered standard after failure of an initial gemcitabine-based regimen. However, in patients who retain a good performance status oxaliplatin-based regimen, 5-FU/capecitabine, taxanes, or irinotecan based therapy may be considered.