Adjuvant chemotherapy with gemcitabine and cisplatin compared to standard of care after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)

INTERVENTION: All patients eligible for the treatment phase will be randomised to adjuvant chemotherapy with either gemcitabine and cisplatin or capecitabine. Study treatment to be scheduled within 6‐16 weeks post‐surgery. Gemcitabine/cisplatin will be administered via IV infusion on day 1 and 8 every 3 weeks, with cisplatin (25mg per square meter of body‐surface area) and gemcitabine (1000mg per square meter), until progression, intolerable toxicity, or for a maximum of 8 cycles (24 weeks). Post‐resection evaluation of tumour recurrence will be conducted following current clinical standards (CT or MRI every 3 months for two years after randomisation followed by 6‐monthly abdominal ultrasound for further 3 years) until disease recurrence (radiological signs of recurrence or histological tumour detection by cytology or biopsy) in both groups. Adherence to treatment will be ensured by all dosing being administered at the study clinic CONDITION: cholangiocarcinoma muscle invasive gallbladder carcinoma PRIMARY OUTCOME: Disease free survival by review of 3 or 6 monthly CT/MRI/US SECONDARY OUTCOME: Composite outcome of rate and severity of biliary tract infections assessed by review of hospital records and assessment according to NCI CTCAE v4.03 Disease free survival by review of 3 or 6 monthly contrast enhanced CT/MRI/US. Diagnosis of recurrence could either be made by radiological imaging or by positive cytology or biopsy. Function of biliodigestive anastomosis assessed in terms of surgical revision, requirement for percutaneous transhepatic cholangiography (PTCD) Loco‐regional control will be assessed according to local recurrence or locoregional lymph node metastases and evaluated in regard of pathological stage according to TNM version 7 at resection. Overall survival by review of hospital records Pattern of disease recurrence Quality of life assessed by EORTC QLQ‐c30, QLQ‐BIL21, INFO25, PEF‐FB‐9 and PEF‐FB‐Doc Recurrence free survival by review of 3 or 6 monthly contrast enhanced CT/MRI/US. Diagnosis of recurrence could either be made by radiological imaging or by positive cytology or biopsy. Safety and tolerability of adjuvant chemotherapy. Safety assessment will include physical examinations including vital signs, ECOG performance status, clinical laboratory profile, concomitant medication and adverse events graded by NCI CTCAE v4.03, including the degree of association of each with the procedure assessed and summarized. ; Renal toxicity assessed by GFR ; Febrile neutropenia assessed by Temperature and ANC ; Neurotoxicity assessed by clinical laboratory profile ; Pneumonitis assessed by clinical laboratory profile and scans ; Ototoxicity assessed by clinical laboratory profile and audiometry INCLUSION CRITERIA: * Histologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma) after radical surgical therapy with macroscopically complete resection (mixed tumour entities (HCC/CCA) are excluded) * Macroscopically complete resection (R0/1) within 6 (‐16) weeks before scheduled start of chemotherapy *ECOG 0‐1 *Age greater than 18 years * Adequate liver function as measured by serum transaminases (AST and ALT) less than or equal to 5xULN and bilirubin less than or equal to 3xULN *Adequate renal function, ie. serum creatinine less than or equal to 1.5xULN, glomerular filtration rate greater than or equal to 60mL/min (MDRD) * No active uncontrolled infecti * Adequate hematologic function: ANC greater than or equal to 1.5 x 10*9/L, platelets greater than or equal to 100 x 10*9/L, haemoglobin greater than or equal to 9 grams/dl or greater than or equal to 5.59 mmol/L