Prophylactic combined chemotherapy for patients with cholangiocarcinoma after curative intent of carcinoma resection and muscle invasive gallbladder carcinoma.

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 781

Inclusion Criteria

Eligibility criteria for enrolment phase
1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma)
scheduled for radical surgical therapy
2. Written informed consent
3. No prior chemotherapy for biliary tract cancer
4. No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer
5. No 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 arrhythmia)
6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent
7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial
8. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile)
9. No pregnancy or lactation
Eligibility criteria for treatment phase (before randomization)
1.Histologically confirmed non metastatic adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma) after radical surgical therapy with macroscopically complete resection (mixed tumor entities (HCC/CCA) are excluded) (according to appendix H)
2.Macroscopically complete resection (R0/1) within 6 (-16) weeks before scheduled start of chemotherapy
3.ECOG 0-1
4.Age =18 years
5.Adequate hematologic function: ANC ¿1.5 x 109/L, platelets ¿100 x109/L, hemoglobin ¿9 g/dl or ¿5.59 mmol/L
6.Adequate liver function as measured by serum transaminases (AST and ALT) £5 x ULN and bilirubin £3 x ULN
7.Adequate renal function, i.e. serum creatinine £1.5 x ULN, glomerular filtration rate = 50 ml/min (determination of GFR according to local institutional standards, e.g. MDRD, (Appendix E))
8.No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy
9.No concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to randomization
10.Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause
Criteria for initial study enrolment
11.Written informed consent
12.No prior chemotherapy for biliary tract cancer
13.No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer
14.No severe or uncontrolled cardiovascular disease
15.Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent
16.No serious underlying medical conditions that could impair the ability of the patient to participate in the trial
17.Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of

Exclusion Criteria

Eligibility criteria for enrolment phase
1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma)
scheduled for radical surgical therapy
2. Written informed consent
3. No prior chemotherapy for biliary tract cancer
4. No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer
5. No 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 arrhythmia)
6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent
7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial
8. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile)
9. No pregnancy or lactation
Eligibility criteria for treatment phase (before randomization)
1.Histologically confirmed non metastatic adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma) after radical surgical therapy with macroscopically complete resection (mixed tumor entities (HCC/CCA) are excluded) (according to appendix H)
2.Macroscopically complete resection (R0/1) within 6 (-16) weeks before scheduled start of chemotherapy
3.ECOG 0-1
4.Age =18 years
5.Adequate hematologic function: ANC ¿1.5 x 109/L, platelets ¿100 x109/L, hemoglobin ¿9 g/dl or ¿5.59 mmol/L
6.Adequate liver function as measured by serum transaminases (AST and ALT) £5 x ULN and bilirubin £3 x ULN
7.Adequate renal function, i.e. serum creatinine £1.5 x ULN, glomerular filtration rate = 50 ml/min (determination of GFR according to local institutional standards, e.g. MDRD, (Appendix E))
8.No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy
9.No concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to randomization
10.Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause
Criteria for initial study enrolment
11.Written informed consent
12.No prior chemotherapy for biliary tract cancer
13.No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer
14.No severe or uncontrolled cardiovascular disease
15.Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent
16.No serious underlying medical conditions that could impair the ability of the patient to participate in the trial
17.Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is to evaluate the efficacy of gemcitabine and cisplatin compared with standard of care (observation alone in stage 1 and capecitabine and observation in stage 2) in patients with BTC after complete resection in terms of DFS.;Secondary Objective: Secondary objectives are safety and tolerability of the treatment as well as RFS and OS, quality of life, function of biliodigestive anastomoses, and evaluation of the quantity and quality of information patients have gained after the informed consent as well as of the involvement of patients in the decision-making process (shared decision making).;Primary end point(s): Disease free survival (DFS);Timepoint(s) of evaluation of this end point: Every 3 months up to 24 months

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Disease free survival rate at 24 months (DFSR@24)<br>• Recurrence free survival (RFS)<br>• Overall survival (OS)<br>• Safety and tolerability of adjuvant chemotherapy<br>• Quality of life (QoL)<br>• Function of biliodigestive anastomosis (in terms of surgical revision,<br>requirement for PTCD)<br>• Rate and severity of biliary tract infections<br>• Patterns of disease recurrence<br>• Locoregional control<br>• Local control rate at 24 months (primary end point radiotherapy substudy);Timepoint(s) of evaluation of this end point: Every 3 months for two years after randomization followed by 6 monthly for 3 years

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