Gemcitabine With/Out Capecitabine in Locally Advanced, Unresectable, or Metastatic Biliary Cancer
Gemcitabine With/Out Capecitabine in Locally Advanced, Unresectable, or Metastatic Biliary Cancer
RATIONALE: Drugs used in chemotherapy, such as gemcitabine and capecitabine, work in
 different ways to stop the growth of tumor cells, either by killing the cells or by stopping
 them from dividing. It is not yet known whether gemcitabine is more effective when given
 together with or without capecitabine in treating patients with biliary cancer.

 PURPOSE: This randomized phase III trial is studying giving gemcitabine together with
 capecitabine to see how well it works compared with giving gemcitabine alone in treating
 patients with locally advanced, unresectable, or metastatic biliary cancer.
OBJECTIVES:

 Primary

 -  To compare overall survival (OS) rates in patients with locally advanced, unresectable
 or metastatic biliary tree cancer treated with combined gemcitabine hydrochloride and
 capecitabine vs. gemcitabine hydrochloride alone.

 Secondary

 -  To compare progression-free survival (PFS) in this patient group.

 -  To compare response rates (complete response [CR] and partial response [PR]) in this
 patient group.

 -  To compare stable disease (SD) rates in this patient group.

 -  To compare rate of disease control (CR, PR and SD) in this patient group.

 -  To estimate and compare response duration in this patient group.

 -  To compare the effects of these treatments on measures of quality of life in this
 patient group using the EORTC QLQ-C30.

 -  To compare the nature, severity and frequency of toxicities between the two arms.

 OUTLINE: This is a multicenter study. Patients are stratified according to tumour type
 (cholangiocarcinoma vs. gallbladder or biliary unknown), ECOG performance status (0-1 vs. 2),
 extent of disease (locally advanced vs. metastatic), and treatment center. Patients are
 randomized to 1 of 2 treatment arms.

 -  Arm I (Gemcitabine hydrochloride and capecitabine): Patients receive gemcitabine
 hydrochloride IV on days 1 and 8 and oral capecitabine twice daily on days 1-14.
 Treatment repeats every 21 days in the absence of disease progression or unacceptable
 toxicity.

 -  Arm II (Gemcitabine hydrochloride alone): Patients receive gemcitabine hydrochloride IV
 on days 1, 8, and 15. Treatment repeats every 28 days in the absence of disease
 progression or unacceptable toxicity.

 Quality of life is assessed at 12 weeks after randomization and 4 weeks after completion of
 study treatment.

 After completion of study treatment, patients are followed at 4 weeks and then every 12 weeks
 thereafter.
DISEASE CHARACTERISTICS:

 -  Histologically or cytologically proven adenocarcinoma of the biliary tree (intra- and
 extra-hepatic biliary ducts or gallbladder)

 -  Locally advanced, unresectable, or metastatic disease

 -  Patients with pathologically confirmed metastatic adenocarcinoma consistent with
 biliary primary with clinical documentation of gallbladder or biliary tree
 involvement and no evidence of another primary adenocarcinoma are eligible

 -  Must have evidence of disease but measurable disease is not required

 -  Chest x-ray and/or CT scan of the chest, CT scan or MRI of the abdomen, and other
 radiological examination to document all disease sites have been done within 28
 days prior to randomization

 -  No repeat scan needed if a negative scan was performed within 35 days prior
 to randomization

 -  Patients who have only one site of disease located inside a previous radiotherapy
 field are eligible

 -  Lesions within a previous radiotherapy field may be considered measurable if
 documented ≥ 20% increase in size

 -  If the lesion size increase has not been documented since the completion of
 radiotherapy, and the lesion is still present (i.e. not CR), the lesion is
 considered evaluable for this trial

 -  Patients with biliary duct obstruction are eligible provided all of the following
 criteria are met:

 -  Treatable, clinically relevant obstruction

 -  Obstruction has been relieved by internal endoscopic drainage/stenting,
 palliative bypass surgery or percutaneous drainage prior to trial entry

 -  No ampullary carcinomas (i.e., arising from the ampulla of Vater)

 -  No central nervous system (CNS) metastases, including active, progressive brain or
 leptomeningeal metastases

 -  Patients with focal neurological symptoms must have had a CT scan to rule out CNS
 metastases

 PATIENT CHARACTERISTICS:

 -  ECOG performance status 0-2

 -  Minimum life expectancy of 12 weeks

 -  Able (i.e. sufficiently fluent) and willing to complete the quality of life
 questionnaires in one of the validated languages

 -  Must be able to swallow and retain oral medication

 -  Hemoglobin > 90 g/L

 -  Absolute neutrophil count ≥ 1,500/mm³

 -  Platelet count ≥ 100,000/mm³

 -  Total bilirubin < 3 times upper limit of normal(ULN)

 -  AST and/or ALT ≤ 5 times ULN

 -  Liver function tests stable and < 3 times ULN

 -  Serum creatinine < 160 µmol/L OR creatinine clearance > 60 mL/min

 -  Negative pregnancy test

 -  Fertile patients and their partners must agree to use adequate contraception prior to
 study entry, throughout the study, and for a period of 4 weeks after cessation of
 protocol therapy

 -  Patients must be accessible for treatment and follow-up

 -  No known dihydropyrimidine dehydrogenase deficiency

 -  No known hypersensitivity to gemcitabine or capecitabine

 -  No other active medical condition which would render the protocol treatment dangerous
 or impair the ability of the patient to receive protocol therapy, including, but not
 limited to, any of the following:

 -  Unstable angina

 -  Uncontrolled arrhythmia

 -  Heart failure

 -  No other condition (e.g. psychological, geographical, etc.) that does not permit
 compliance with the protocol

 -  No other malignancies except adequately treated nonmelanoma skin cancer, curatively
 treated in-situ cancer of the cervix, or other solid tumors curatively treated with no
 evidence of disease for > 5 years

 PRIOR CONCURRENT THERAPY:

 -  No prior chemotherapy for advanced or metastatic disease unless used in the following
 circumstances:

 -  Fluorouracil or gemcitabine given concurrently with radiotherapy as a
 radiosensitizer, completed more than 3 months prior to randomization

 -  Fluorouracil given as adjuvant treatment following surgery, completed at least 1
 year prior to randomization

 -  No major surgery within 4 weeks of randomization

 -  No prior treatment with another investigational agent within 2 weeks of randomization

 -  At least 4 weeks from randomization since completion of prior radiotherapy and
 recovered

 -  Patients may be randomized within the required 4 weeks if short course (< 5
 fractions) of non-myelosuppressive radiotherapy was given

 -  Concurrent palliative radiation to a known site of bone metastasis allowed provided
 that the criteria for disease progression are otherwise not met

 -  No other concurrent anti-cancer therapy (cytotoxic, biological/immunotherapy or
 radiotherapy other than for known bone metastases as specified above)

 -  No other concurrent investigational drug therapy