Neoadjuvant Chemotherapy With Gemcitabine Plus Cisplatin Followed by Radical Liver Resection Versus Immediate Radical Liver Resection Alone With or Without Adjuvant Chemotherapy in Incidentally Detected Gallbladder Carcinoma After Simple Cholecystectomy or in Front of Radical Resection of BTC
Neoadjuvant Chemotherapy With Gemcitabine Plus Cisplatin Followed by Radical Liver Resection Versus Immediate Radical Liver Resection Alone With or Without Adjuvant Chemotherapy in Incidentally Detected Gallbladder Carcinoma After Simple Cholecystectomy or in Front of Radical Resection of BTC
Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection
 versus immediate radical liver resection alone with or without adjuvant chemotherapy in
 incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of
 radical resection of BTC (ICC/ECC)
The aim of the study is to investigate whether induction chemotherapy followed by radical
 re-resection (and - if possible - postoperative chemotherapy) in incidental gallbladder
 carcinoma (IGBC) or in front radical resection in biliary tract cancer (BTC) (intrahepatic
 cholangiocarcinoma (ICC)/ extrahepatic cholangiocarcinoma (ECC)) prolongs overall survival
 without impaired quality of life compared to immediate radical surgery alone with or without
 adjuvant chemotherapy (investigator's choice) in patients with IGBC, or BTC (ICC/ECC). One of
 the most important secondary objectives is to raise awareness for the necessity of a radical
 second surgery as well as to improve the adherence to the treatment guidelines in IGBC.
 Further secondary objectives are safety and tolerability of the treatment as well as quality
 of life.
Inclusion criteria

 1. Incidental gallbladder carcinoma (IGBC), gallbladder carcinoma (GBC) () or Biliary
 tract cancer (BTC) (intrahepatic, hilar or distal Cholangiocarcinoma (CCA)) scheduled
 for complete resection (mixed tumor entities with hepatocellular carcinoma are
 excluded).

 2. No prior partial or complete tumor resection for BTC (intrahepatic, hilar or distal
 CCA), and for IGBC/GBC prior Cholecystectomy is allowed.

 3. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan
 or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the
 infiltration of any adjacent organs or structures by CT or MRI, indicating an
 unresectable situation.

 4. ECOG performance status of 0, 1, or 2.

 5. Estimated life expectancy > 3 months.

 6. Female and male patients1 ≥18 years.

 7. Patient able and willing to provide written informed consent and to comply with the
 study protocol and with the planned surgical procedures

 8. No previous or preceding cytotoxic or targeted therapy for BTC or IGBC/GBC.

 9. No previous malignancy within two years or concomitant malignancy, except for
 curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix,
 and prostate cancer

 10. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or
 IV, unstable angina pectoris, history of myocardial infarction in the last three
 months, significant arrhythmia).

 11. Absence of psychiatric disorder precluding understanding of information of trial
 related topics and giving informed consent.

 12. No serious underlying medical conditions (judged by the investigator), that could
 impair the ability of the patient to participate in the trial.

 13. A) Females of childbearing potential must agree to remain abstinent (refrain from
 heterosexual intercourse) or use contraceptive methods that result in a failure rate
 of <1% per year during the treatment period and for at least 7 months after the last
 study treatment.

 A woman is considered to be of childbearing potential if she is postmenarcheal, has
 not reached a postmenopausal state (has not had ≥12 continuous months of amenorrhea
 with no identified cause other than menopause), and has not undergone surgical
 sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods
 with a failure rate of < 1% per year include bilateral tubal ligation, male
 sterilization, hormonal implants, established, proper use of combined oral or injected
 hormonal contraceptives, and certain intrauterine devices. The reliability of sexual
 abstinence should be evaluated in relation to the duration of the clinical trial and
 the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar,
 ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable
 methods of contraception.

 B) Males must agree to remain abstinent (refrain from heterosexual intercourse) or use
 contraceptive measures, and agree to refrain from donating sperm, as defined below:

 With female partners of childbearing potential or pregnant female partners, men must
 remain abstinent or use a condom plus an additional contraceptive method that together
 result in a failure rate of 1% per year during the treatment period and for at least 6
 months after the last dose of study treatment to avoid exposing the embryo. Men must
 refrain from donating sperm during this same period. Men with a pregnant partner must
 agree to remain abstinent or to use a condom for the duration of the pregnancy.

 14. No pregnancy or lactation.

 15. Adequate hematologic function: ANC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin
 ≥ 9 g/dl or ≥ 5.59 mmol/L; prior transfusions for patients with low hemoglobin are
 allowed

 16. Adequate liver function as measured by serum transaminases (AST and ALT) ≤ 5 x ULN and
 bilirubin ≤ 3 x ULN.

 17. Adequate renal function, i.e. serum creatinine ≤ 1.5 x institutional ULN, a calculated
 glomerular filtration rate ≥ 30 mL/min.

 18. Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤
 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless
 receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be
 switched to low molecular weight heparin and have achieved stable coagulation profile
 prior to randomization.

 19. No active uncontrolled infection, except chronic viral hepatitis under antiviral
 therapy (patients on long-term antibiotics are eligible provided signs of active
 infection have been resolved).

 20. No concurrent treatment with other experimental drugs or other anti-cancer therapy,
 treatment in a clinical trial within 30 days or five half-lives (whichever is longer)
 prior to randomization.

 21. Negative serum pregnancy test within 7 days of starting study treatment in
 pre-menopausal women and women <1 year after the onset of menopause Please note that
 after randomization for patients in Arm A the histological confirmation of BTC or GBC
 must be performed before administering chemotherapy. For IGBC histological
 confirmation should already have been performed.

 For Arm B patients the histological confirmation can be performed after surgery with
 material from the surgery.

 Exclusion criteria

 1. Known hypersensitivity against gemcitabine or cisplatin

 2. Other known contraindications to gemcitabine or cisplatin

 3. Clinically significant valvular defect

 4. Past or current history of other malignancies not curatively treated and without
 evidence of disease for more than two years, except for curatively treated basal cell
 carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer

 5. Locally unresectable tumor or metastatic disease:

 -  Radiological evidence suggesting inability to resect with curative intent whilst
 maintaining adequate vascular inflow and outflow, and sufficient future liver
 remnant

 -  Radiological evidence of direct invasion into adjacent organs

 -  Radiological evidence of extrahepatic metastatic disease

 6. Other severe internal disease or acute infection

 7. Chronic inflammatory bowel disease

 8. Receiving chronic antiplatelet therapy, including aspirin (Once-daily aspirin use
 (maximum dose 325 mg/day) is permitted), nonsteroidal anti-inflammatory drugs
 (including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar
 agents.

 9. History of deep vein thrombosis, pulmonary embolism, or any other significant
 thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis
 are not considered "significant") during 3 months prior to randomization.

 10. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a
 history of hepatic encephalopathy or ascites.

 11. On-treatment participation in another clinical study 30 days or five half-lives
 (whichever is longer) prior to inclusion and during the study

 12. Pregnant or breast feeding patient, or patient is planning to become pregnant within 7
 months after the end of treatment.

 13. Patients in a closed institution according to an authority or court decision (AMG §
 40, Abs. 1 No. 4)

 14. Any other concurrent antineoplastic treatment including irradiation