This trial was a prospective, single-arm phase II study conducted at the University Hospital Zurich in Switzerland. At the time of study conduct, no standard adjuvant treatment was yet established for cholangiocarcinoma, but gemcitabine had been established as adjuvant standard of care for resected pancreatic cancer shortly before by Oettle and colleagues. Based on these data and some smaller and retrospective data describing a benefit for gemcitabine in advanced cholangiocarcinoma, we chose this single agent treatment initially. The primary endpoints were safety and feasibility of adjuvant chemotherapy with the first patient cohort receiving gemcitabine as single-agent treatment and, after protocol amendment, the second patient cohort receiving the combination of cisplatin plus gemcitabine. After treatment of the first 11 patients, an interim safety analysis was planned, and the trial would have been stopped prematurely based on safety evaluations. Secondary endpoints were completion of treatment, adverse events according to CTCAE version 3.0, disease-free survival (DFS), and overall survival (OS). In addition, a separate analysis of the outcome in patients treated with gemcitabine alone (single agent cohort) and patients treated with cisplatin and gemcitabine combined (combined regimen cohort) was performed (Fig. 1). The trial started during August 2008 with first resection of BTC and ended by the cut-off date of patient’s follow up at 31st December 2016.
Ethics approval and consent to participate
The study was conducted after obtaining approval from the local ethical committee (ethical number KEK Zurich 1442) at 15th January 2008 and Swissmedic by 2nd April 2008. First patient was included at 4th August 2008. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov, as it was not yet obligatory at the time of trial start according to national specifications (NCT01073839).
Eligibility criteria
Patients diagnosed with cholangiocellular carcinoma who underwent curative intent tumor resection were enrolled in this study at the Department of Oncology, University Hospital Zurich. The main eligibility criteria included the following: Histologically or cytologically confirmed adenocarcinoma of the biliary tract (intrahepatic, extrahepatic, gallbladder); resection of the tumor with curative intention up to 8 weeks before start of chemotherapy; written informed consent; health status: WHO performance status (PS) 0–1; age > 18 years; adequate renal function (creatinine clearance ≥60 ml/min, calculated according to the formula of Cockroft-Gault); adequate hepatic function (bilirubin ≤3 x LUN, AP ≤ 5 x LUN, ASAT ≤5 x LUN); adequate hematologic function: neutrophils ≥1.5 × 109/l, platelets ≥100 × 109/l, Hb ≥ 9,5 mg/dl.
Patients were excluded in case of: Pregnancy or breastfeeding women, previous malignancy within 5 years or concomitant malignancy except non-melanomatous skin cancer or adequately treated in situ cervical cancer, neutrophil count <1000/μl, platelet count <100,000/μl, hemoglobin level < 9,5 mg/dl, bilirubin >3 x LUN, ALAT >5 x LUN, ASAT >5 x LUN, creatinine clearance <60 ml/min, calculated according to the formula of Cockroft-Gault, prior chemotherapy with gemcitabine, severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmias), psychiatric disorder precluding understanding of information of trial related topics and giving informed consent, active uncontrolled infection, pre-existing peripheral neuropathy (> grade 1), serious underlying medical condition (judged by the investigator) which could impair the ability of the patient to participate in the trial (e.g. uncontrolled diabetes mellitus, active autoimmune disease), concurrent treatment with other experimental drugs or other anti-cancer therapy; treatment in a clinical trial within 30 days prior to trial entry, known hypersensitivity to the study drug.
Treatment schedule
According to the initial protocol version, the first patients enrolled received gemcitabine at a dose of 1000 mg/m2 as a 30-min infusion on days 1, 8 and 15 every 28 days for a total of 6 cycles (24 weeks in total). After treatment of 11 patients, the first interim analysis was performed in September 2010, and the study would continue with inclusion of additional 19 patients if feasibility could be shown. After this planned interim analysis, the protocol was amended on the evidence of new available data for the combination therapy with cisplatin and gemcitabine. In detail, the second cohort of patients received gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 every 21 days for a total of 8 cycles (24 weeks of treatment in total). The treatment was stopped ahead of schedule in case of unacceptable toxicities, tumor recurrence, or patient wish. If the administration of the planned chemotherapy was delayed for more than a month, the treatment was discontinued and the patient clinically followed thereafter. Blood examinations were performed on each day of treatment. To continue treatment as planned, a neutrophil count greater than 1000/μl, and a platelet count greater than 100,000/μl was required for each full dose of gemcitabine and cisplatin. Dose reductions were indicated at days 8 (combined regimen cohort) or 15 (single agent cohort) of each cycle in case of thrombocytopenia with platelets between 75,000 and 100,000/μl and/or absolute neutrophil counts between 500 and 1000/μl. The treatment was withheld if neutrophil count was below 500/μl or platelet count was below 75,000/μl. Treatment was restarted following hematologic recovery (neutrophil >1000/μl and/or platelets >100,000/μl, respectively. Administration of G-CSF was allowed, but discontinuation was required at least 2 days prior to the next administration of chemotherapy.
After end of treatment clinical visits and laboratory analyses were carried out every three months for the first two years, thereafter every 6 months for the next three years and thereafter at the discretion of the attending physician. Assessments with CT-scans of thorax and abdomen and/or MRI of the abdomen were performed after end of treatment and 6 months later, and thereafter at the discretion of the attending physician.
Statistical analysis
Patient recruitment followed a Simon’s two-stage design; a maximum of anticipated non-laboratory adverse events ≥ grade 3 in up to 45% of patients was considered acceptable, whereas non-laboratory adverse events ≥ grade 3 in more than 70% were considered unacceptable, resulting in the regimen being considered not feasible. Eleven patients had been planned to be recruited in the first phase; and if 4 or fewer patients experience at least one Grade 3 or 4 non-laboratory toxicity, a further 19 patients would be recruited for a total of 30 evaluable patients. This study had 80% power to discriminate between these two levels at the 5% level of significance.
The relative dose intensity (RDI) was calculated as the ratio of the actual dose given during the study to the planned dose in the protocol. DFS would be calculated from the day of resection until locoregional recurrence, the development of distant metastases, second primary cancer, death from the same or other cancer, or treatment-related death. Overall survival was calculated from the day of resection until death. Follow-up is also being reported from the day of surgery until the final cut-off date at 31st December 2016. Patients alive would be censored at that time point. Continuous and ordinal variables were presented as median with interquartile range (IQR). DFS and OS were determined by the Kaplan-Meier method and Cox-regression. Median time to event was reported with 95% confidence interval (CI). Estimates at 3 years were presented with standard error. Hazard ratios (HR) of gemcitabine plus cisplatin vs. gemcitabine monotherapy were presented with 95% CI. A post hoc comparison of the two patient groups receiving either gemcitabine alone or combination therapy with cisplatin and gemcitabine was performed by the log-rank test.