Extrahepatic Bile Duct Cancer, Gallbladder Cancer
Conditions
Keywords
unresectable gallbladder cancer, recurrent gallbladder cancer, unresectable extrahepatic bile duct cancer, recurrent extrahepatic bile duct cancer, adenocarcinoma of the gallbladder, adenocarcinoma with squamous metaplasia of the gallbladder, squamous cell carcinoma of the gallbladder, adenocarcinoma of the extrahepatic bile duct, cholangiocarcinoma of the gallbladder, cholangiocarcinoma of the extrahepatic bile duct
Brief summary
RATIONALE: Drugs used in chemotherapy, such as gemcitabine and capecitabine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining gemcitabine with capecitabine in treating patients who have locally advanced or metastatic gallbladder cancer or cholangiocarcinoma.
Detailed description
OBJECTIVES: * Determine the response rates (confirmed complete and partial responses) in patients with unresectable, locally advanced or metastatic gallbladder cancer or cholangiocarcinoma treated with gemcitabine and capecitabine. * Determine the overall survival of patients treated with this regimen. * Determine the quantitative and qualitative toxic effects of this regimen in these patients. * Determine the feasibility of accruing patients with these disease sites. * Evaluate, preliminarily, relevant prognostic markers in these disease sites and the prognostic implications as predictors of survival in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive oral capecitabine twice daily on days 1-14 and gemcitabine IV over 100 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 3 years. PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study within approximately 10-20 months.
Interventions
DRUGcapecitabine
650 mg/m\^2 twice daily (BID), by mouth (PO) at 12 hour intervals, Days 1-14, every 21 days
DRUGgemcitabine hydrochloride
1000 mg/m\^2, intravenous (IV) over 100 minutes, Days 1,8, every 21 days
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed gallbladder cancer or cholangiocarcinoma * Locally advanced or metastatic disease that is unresectable * Eligible subtypes: * Adenocarcinoma, intestinal type * Adenocarcinoma, not otherwise specified (NOS) * Papillary carcinoma * Clear cell adenocarcinoma * Mucinous carcinoma * Signet ring cell carcinoma * Squamous cell carcinoma * Adenosquamous carcinoma * Small cell carcinoma * Undifferentiated carcinoma * Carcinoma, NOS OR * Histologically confirmed adenocarcinoma of a metastatic site with clinical documentation\* of gallbladder or bile duct involvement and no evidence of another primary NOTE: \*If clinical documentation of gallbladder or bile duct involvement is not possible due to removal of the organ, a clinically and/or radiographically consistent picture plus pathologic findings from the metastatic site consistent with cholangiocarcinoma are allowed * Measurable disease located outside prior radiotherapy port * No carcinoid tumors or sarcomas PATIENT CHARACTERISTICS: Age: * 18 and over Performance status: * Zubrod 0-2 Life expectancy: * Not specified Hematopoietic: * Absolute granulocyte count at least 1,500/mm\^3 * Platelet count at least 100,000/mm\^3 Hepatic: * Bilirubin no greater than 3 times upper limit of normal (ULN) * Serum glutamic oxaloacetic transaminase (SGOT) or Serum glutamic pyruvic transaminase (SGPT) no greater than 2.5 times ULN (5 times ULN if liver metastasis is present) Renal: * Creatinine clearance at least 30 mL/min Cardiovascular: * No clinically significant cardiac disease that is not well controlled by medication * No congestive heart failure * No symptomatic coronary artery disease * No cardiac arrhythmias * No myocardial infarction within the past 12 months Gastrointestinal: * Able to swallow and/or receive medications via gastrostomy feeding tube * No intractable nausea or vomiting * No malabsorption syndrome Other: * No severe reaction to fluoropyrimidine therapy or known hypersensitivity to fluorouracil * No other malignancy within the past 5 years except: * Adequately treated basal cell or squamous cell skin cancer * Carcinoma in situ of the cervix * Adequately treated stage I or II cancer currently in complete remission * Not pregnant or nursing * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: * Prior neoadjuvant or adjuvant immunotherapy allowed provided therapy was completed at least 1 year before documented recurrence or metastatic disease * No concurrent immunotherapy Chemotherapy: * Prior neoadjuvant or adjuvant chemotherapy or chemoradiotherapy allowed provided therapy was completed at least 1 year before documented recurrence or metastatic disease * No other concurrent chemotherapy Endocrine therapy: * Prior neoadjuvant or adjuvant hormonal therapy allowed provided therapy was completed at least 1 year before documented recurrence or metastatic disease * No concurrent hormonal therapy Radiotherapy: * See Disease Characteristics * See Chemotherapy * Recovered from prior radiotherapy * Prior neoadjuvant or adjuvant radiotherapy allowed provided therapy was completed at least 1 year before documented recurrence or metastatic disease * No prior radiotherapy to 25% or more of bone marrow * No concurrent radiotherapy except for palliation of metastatic sites not considered target lesions Surgery: * At least 2 weeks since prior surgery for this malignancy and recovered Other: * No prior treatment for metastatic disease * No other concurrent therapy for this cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response | Patients assessed at least every six weeks while on protocol treatment | Complete Response (CR) is complete disappearance of all measurable and non-measurable disease. No new lesions, no disease related symptoms. Normalization of markers and other abnormal lab values. Partial Response (PR) is greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Confirmation of CR or PR means a repeat scan at least 4 weeks apart documented before progression or symptomatic deterioration. Progression is 20% increase in sum of longest diameters of target measurable lesions over smallest sum observed and/or unequivocal progression of non-measurable disease and/or appearance of new lesion/site or death due to disease without prior documentation of progression and without symptomatic deterioration. Symptomatic deterioration is global deterioration of health status requiring discontinuation of treatment without objective evidence of progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | All patients will be followed until death or three years after registration, whichever is first. | Measured from time of registration to death, or last contact date |
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Patients were assessed for adverse events 3 weeks after starting treatment. Assessments for adverse events continued every 3 weeks for the duration of protocol treatment. | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Any CTCAE 3.0 event of Grade 3 (severe), Grade 4 (life threatening) or Grade 5 (fatal) which were deemed to be related to protocol treatment are included. For each patient, worst grade of each event type is reported. |
| Accrual of Patients With This Disease Site | 1-20 months | Only eligible patients who received treatment were evaluable for response and survival outcomes. |
| Median Survival Time for Participants With Relevant Biologic Markers | All patients will be followed until death or three years after registration, whichever is first. | To evaluate in a preliminary fashion relevant prognostic markers in gallbladder and cholangiocarcinoma which may have prognostic implications as predictors of survival. Overall survival measured from time of registration to death, or last contact date. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Capecitabine + Gemcitabine Capecitabine 650 mg/m\^2 twice daily (BID), by mouth (PO) at 12 hour intervals, Days 1-14, every 21 days; Gemcitabine 1000 mg/m\^2, intravenous (IV) over 100 minutes, Days 1, 8, every 21 days | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 14 |
| Overall Study | Death | 1 |
| Overall Study | Ineligible | 3 |
| Overall Study | Never received treatment | 2 |
| Overall Study | Other | 5 |
| Overall Study | Progression | 26 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Capecitabine + Gemcitabine |
|---|---|
| Age, Continuous | 58.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 37 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 51 / 51 |
| serious Total, serious adverse events | 7 / 51 |
Outcome results
Primary
Response
Complete Response (CR) is complete disappearance of all measurable and non-measurable disease. No new lesions, no disease related symptoms. Normalization of markers and other abnormal lab values. Partial Response (PR) is greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Confirmation of CR or PR means a repeat scan at least 4 weeks apart documented before progression or symptomatic deterioration. Progression is 20% increase in sum of longest diameters of target measurable lesions over smallest sum observed and/or unequivocal progression of non-measurable disease and/or appearance of new lesion/site or death due to disease without prior documentation of progression and without symptomatic deterioration. Symptomatic deterioration is global deterioration of health status requiring discontinuation of treatment without objective evidence of progression.
Time frame: Patients assessed at least every six weeks while on protocol treatment
Population: All eligible patients who started treatment were included in assessing response estimates.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Capecitabine + Gemcitabine | Response | Confirmed Partial Response | 7 participants |
| Capecitabine + Gemcitabine | Response | Unconfirmed Partial Response | 6 participants |
| Capecitabine + Gemcitabine | Response | Stable Disease | 12 participants |
| Capecitabine + Gemcitabine | Response | Progression | 15 participants |
| Capecitabine + Gemcitabine | Response | Symptomatic Deterioration | 3 participants |
| Capecitabine + Gemcitabine | Response | Early Death | 1 participants |
| Capecitabine + Gemcitabine | Response | Inadequate Assessment | 8 participants |
Secondary
Accrual of Patients With This Disease Site
Only eligible patients who received treatment were evaluable for response and survival outcomes.
Time frame: 1-20 months
Population: Patients with advanced disease accrued between September 2003 to April 2005
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Capecitabine + Gemcitabine | Accrual of Patients With This Disease Site | Eligible | 54 participants |
| Capecitabine + Gemcitabine | Accrual of Patients With This Disease Site | Eligible and Analyzable | 52 participants |
Secondary
Median Survival Time for Participants With Relevant Biologic Markers
To evaluate in a preliminary fashion relevant prognostic markers in gallbladder and cholangiocarcinoma which may have prognostic implications as predictors of survival. Overall survival measured from time of registration to death, or last contact date.
Time frame: All patients will be followed until death or three years after registration, whichever is first.
Population: Eligible patients who received genotyping were included in this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | CDA A79C - A/C (N=12) | 7 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | TS 3' +/+ (N=14) | 7 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | TS 3' +/- (N=6) | 7 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | TS 3' -/- (N=2) | 9 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | TS 5' Low functional significance (N=16) | 9 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | TS 5' Intermediate functional significance (N=16) | 7 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | MTHFR C677T - C/C (N=11) | 6 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | MTHFR C677T - C/T (N=11) | 7 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | MTHFR A1298C - A/A (N=11) | 7 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | MTHFR A1298C - A/C (N=8) | 4 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | MTHFR A1298C - C/C (N=3) | 9 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | RRMI G/A - G/G (N=9) | 7 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | RRMI G/A - G/A (N=10) | 9 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | RRMI G/A - A/A (N=3) | 5 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | CDA A79C - A/A (N=8) | 4 months |
| Capecitabine + Gemcitabine | Median Survival Time for Participants With Relevant Biologic Markers | CDA A79C - C/C (N=1) | NA months |
Secondary
Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug
Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Any CTCAE 3.0 event of Grade 3 (severe), Grade 4 (life threatening) or Grade 5 (fatal) which were deemed to be related to protocol treatment are included. For each patient, worst grade of each event type is reported.
Time frame: Patients were assessed for adverse events 3 weeks after starting treatment. Assessments for adverse events continued every 3 weeks for the duration of protocol treatment.
Population: Eligible patients who received any treatment and were assessed for toxicity were included in the adverse event summaries. Any CTCAE 3.0 event of Grade 3 (severe), Grade 4 (life threatening) or Grade 5 (fatal) which were deemed to be related to protocol treatment are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | ALT, SGPT (serum glutamic pyruvic transaminase) | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | AST,SGOT (serum glutamic oxaloacetic transaminase) | 5 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Anorexia | 2 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Albumin, serum-low (hypoalbuminemia) | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Alkaline phosphatase | 5 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Ascites (non-malignant) | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Bilirubin (hyperbilirubinemia) | 4 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Constipation | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Creatinine | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dehydration | 3 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Diarrhea | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dysphagia (difficulty swallowing) | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Fatigue (asthenia, lethargy, malaise) | 8 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Hemoglobin | 6 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Hemolysis | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Hemorrhage, GI - Esophagus | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Infection w/Grade 3-4 neutrophils - Upper airway | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Infection with normal ANC or Grade 1-2 neutrophils | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Leukocytes (total WBC) | 9 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Mucositis/stomatitis (clinical exam) - Oral cavity | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Mucositis/stomatitis (function/symp)-Oral cavity | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Muscle weakness (not due to neuropathy) | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Nausea | 3 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Neutrophils/granulocytes (ANC/AGC) | 16 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Abdomen NOS | 2 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Joint | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Muscle | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Tumor pain | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Platelets | 12 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Potassium, serum-low (hypokalemia) | 2 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Rash: hand-foot skin reaction | 4 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Supraventricular nodal arrhythmia | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Thrombosis/thrombus/embolism | 1 Participants |
| Capecitabine + Gemcitabine | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Vomiting | 2 Participants |
Secondary
Overall Survival
Measured from time of registration to death, or last contact date
Time frame: All patients will be followed until death or three years after registration, whichever is first.
Population: All eligible patients who started treatment were included in assessing response estimates.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Capecitabine + Gemcitabine | Overall Survival | 7 months |