Esophageal Cancer
Conditions
Keywords
adenocarcinoma of the esophagus, stage I esophageal cancer, stage II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying how well giving capecitabine and oxaliplatin together with radiation therapy works in treating patients with esophageal or gastroesophageal junction cancer.
Detailed description
OBJECTIVES: Primary * Determine the pathologic complete response in patients with adenocarcinoma of the esophagus or gastroesophageal junction treated with neoadjuvant therapy comprising capecitabine, oxaliplatin, and radiotherapy. Secondary * Determine the clinical response rate in patients treated with this regimen. * Determine the recurrence rate, time to progression, and patterns of failure in patients treated with this regimen. * Characterize the toxicity profile of this regimen in these patients. OUTLINE: * Induction therapy: Patients receive oral capecitabine twice daily on days 1-14 and oxaliplatin IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. * Combination chemoradiotherapy: Patients then receive oxaliplatin IV over 2 hours once weekly for 6 weeks. Patients also receive concurrent oral capecitabine twice daily and undergo radiotherapy once daily 5 days a week for 5½ weeks in the absence of disease progression or unacceptable toxicity. * Surgery: Patients undergo surgical resection at 4-8 weeks after completion of chemoradiotherapy. After completion of study treatment, patients are followed every 3 months.
Interventions
DRUGInduction Therapy - Oxaliplatin
Two 21-day cycles will be given as induction. Oxaliplatin will be given at 70 mg/m2 intravenously in 5% dextrose over two hours on days 1 and 8 of each cycle.
DRUGInduction Therapy - Capecitabine
Two 21-day cycles will be given as induction. Capecitabine will be given at 1000 mg/m2 twice daily approximately 12 hours apart for 14 days, followed by seven days off.
DRUGCombination Therapy - Capecitabine
Two 21-day cycles will be given for combination therapy. Capecitabine will be given at 825 mg/m2 twice daily approximately 12 hours apart for five days (Monday through Friday) followed by two days off for 51/2 weeks.
DRUGCombination Therapy - Oxaliplatin
Two 21-day cycles will be given. Oxaliplatin will be given at 50 mg/m2 intravenously in 5% dextrose over two hours on days 1, 8 and 15 of each cycle.
RADIATIONCombination Therapy - Radiation
1.8 Gy daily Monday through Friday to a total of 50.4 Gy for 6 weeks during combination therapy.
PROCEDUREEvaluation for response and surgery
Four to eight weeks following the completion of therapy subjects will undergo evaluation for response and surgical resection.
Sponsors
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction * Stage I-IVA disease * No distant metastatic disease (other than regional lymph nodes) * No evidence of CNS metastases * CNS metastases stable for \> 3 months allowed PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * Consuming ≥ 1,500 calories daily * ANC ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * SGOT ≤ 2.5 times ULN * Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 50 mL/min * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No pre-existing neuropathy * No prior unanticipated severe reaction to fluoropyrimidine therapy * No known hypersensitivity to fluorouracil * No known DPD deficiency * No known hypersensitivity to any of the components of oxaliplatin * No significant active infection or other severe complicated medical illness * No clinically significant cardiac disease (e.g., congestive heart failure, symptomatic coronary artery disease, or cardiac arrhythmias not well controlled with medication) * No myocardial infarction within the past 12 months * No history of uncontrolled seizures, CNS disorders, or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake * No malabsorption syndrome * No other active malignancy within the past 3 years except cervical carcinoma in situ or nonmelanoma skin cancer PRIOR CONCURRENT THERAPY: * More than 4 weeks since prior participation in any investigational drug study * No prior pelvic or thoracic radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine Pathologic Complete Response | At time of surgery | Pathologic response will be assessed semiquantitatively irrespective of lymph node status based on the estimated percentage of residual carcinoma in relation total carcinoma area, including amount of radiotherapy-induced tissue injury, in mural histologic sections. Pathologic response will be defined as: P0: 0% residual cancer P1: 1% to 50% residual cancer P2: more than 50% residual cancer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Rate | From the time of start of treatment until first documentation of disease recurrence, progression or death, whichever comes first until the end of the study, a maximum of 6 years and 7 months. | Recurrence rate will be defined as disease recurrence, progressive disease or death. Patients will be followed for disease recurrence or death until the end of the study. |
| Time to Progression | From start of first treatment until time of first documentation of progression of disease or death, whichever comes first, until the study closes, up to a maximum of 6 years and 7 months. | Time to Progression will be measured as time from the first day of therapy until death, disease progression or last contact. |
| Clinical Response Rate | four to six weeks following completion of 4 cycles (1 cycle = 21days) of chemotherapy treatment and prior to surgery | Clinical response Rate will be expressed as the proportion of patients demonstrating a complete and/or partial response based on all evaluable patients treated.Clinical response will be evaluated according to Response Evaluation Criteria In Solid Tumors 1.0 (RECIST) . Complete Response (CR) is defined as the disappearance of all target lesions Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions,taking as reference the baseline sum LD |
| Toxicity Profile | During chemotherapy treatment and up to 30 days post-last dose of chemotherapy. | Toxicity will be assessed at the beginning of every cycle during chemotherapy for a total of 4 cycles (1 cycle =21 days) and then 30 days post last dose of chemotherapy. All toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 3.0) In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE Only incidents of AEs determined to be related to chemotherapy are recorded here. |
| Correlate Proteomic and Pharmacologic Characteristics With Prognosis and Response to Therapy. | At time of sugery | — |
| Patterns of Failure | At time of surgery | — |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual on May 31, 2006 with an accrual goal of up to 43 patients. The study was designed to enroll 13 patients initially and do an interim efficacy assessment. Accrual was suspended on July 17, 2008 for this analysis and reopened on August 12, 2008. The study was closed permanently on february 24, 2009.
Participants by arm
| Arm | Count |
|---|---|
| Induction and Combination Treatment Induction Therapy: Two 21-day cycles will be given as induction. Weeks 1-6:
Capecitabine will be given at 1000 mg/m2 twice daily approximately 12 hours apart for 14 days, followed by seven days off.
Oxaliplatin will be given at 70 mg/m2 intravenously in 5% dextrose over 2 hours on days 1 and 8 of each cycle.
Combination Therapy: Two 21-day cycles will be given for combination therapy Weeks 7-12:
Capecitabine will be given at 825 mg/m2 twice daily approximately 12 hours apart for five days (Monday through Friday) followed by two days off for 51/2 weeks.
Oxaliplatin will be given at 50 mg/m2 intravenously in 5% dextrose over two hours on days 1, 8 and 15 of each cycle.
Radiation: 1.8 Gy daily Monday through Friday to a total of 50.4 Gy for 6 weeks during combination therapy.
4-6 weeks later subjects will undergo evaluation for response and surgical resection. | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Combination Treatment | Progressive Disease | 1 |
| Evaluated for Combination Treatment | Adverse Event | 2 |
| Evaluated for Combination Treatment | Death | 1 |
| Evaluated for Combination Treatment | Progressive disease | 2 |
| Evaluated for Combination Treatment | Withdrawal by Subject | 1 |
| Evaluation for Response and Surgery | Death | 1 |
| Evaluation for Response and Surgery | Progressive Disease | 2 |
| Evaluation for Response and Surgery | Too high risk for surgery | 2 |
| Evaluation for Response and Surgery | Withdrawal by Subject | 1 |
| Induction Treatment | Adverse Event | 1 |
| Induction Treatment | Death | 2 |
| Induction Treatment | Other | 1 |
| Survival Follow up Until Death | Other | 12 |
Baseline characteristics
| Characteristic | Induction and Combination Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 20 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 0 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Region of Enrollment United States | 44 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 28 / 44 |
| other Total, other adverse events | 43 / 43 |
| serious Total, serious adverse events | 10 / 43 |
Outcome results
Primary
Determine Pathologic Complete Response
Pathologic response will be assessed semiquantitatively irrespective of lymph node status based on the estimated percentage of residual carcinoma in relation total carcinoma area, including amount of radiotherapy-induced tissue injury, in mural histologic sections. Pathologic response will be defined as: P0: 0% residual cancer P1: 1% to 50% residual cancer P2: more than 50% residual cancer
Time frame: At time of surgery
Population: Patients analyzed were patients that reached and completed surgery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction, Combination and Surgery | Determine Pathologic Complete Response | 9 Participants |
Secondary
Clinical Response Rate
Clinical response Rate will be expressed as the proportion of patients demonstrating a complete and/or partial response based on all evaluable patients treated.Clinical response will be evaluated according to Response Evaluation Criteria In Solid Tumors 1.0 (RECIST) . Complete Response (CR) is defined as the disappearance of all target lesions Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions,taking as reference the baseline sum LD
Time frame: four to six weeks following completion of 4 cycles (1 cycle = 21days) of chemotherapy treatment and prior to surgery
Population: 1 patient was registered to the study but was not treated on study and was therefore not evaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction, Combination and Surgery | Clinical Response Rate | 28 Participants |
Secondary
Correlate Proteomic and Pharmacologic Characteristics With Prognosis and Response to Therapy.
Time frame: At time of sugery
Population: No data was collected for this outcome measure. There is no data to report on.
Secondary
Patterns of Failure
Time frame: At time of surgery
Population: No data collected for this outcome measure. There is no data to report on.
Secondary
Recurrence Rate
Recurrence rate will be defined as disease recurrence, progressive disease or death. Patients will be followed for disease recurrence or death until the end of the study.
Time frame: From the time of start of treatment until first documentation of disease recurrence, progression or death, whichever comes first until the end of the study, a maximum of 6 years and 7 months.
Population: 1 patient was registered but not treated on study and therefore was not evaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction, Combination and Surgery | Recurrence Rate | 23 Participants |
Secondary
Time to Progression
Time to Progression will be measured as time from the first day of therapy until death, disease progression or last contact.
Time frame: From start of first treatment until time of first documentation of progression of disease or death, whichever comes first, until the study closes, up to a maximum of 6 years and 7 months.
Population: Data collected was not analyzed before the study was terminated. Count of participants indicates the number of patients with progressive disease or death at the time the study closed permanently.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction, Combination and Surgery | Time to Progression | 28 Participants |
Secondary
Toxicity Profile
Toxicity will be assessed at the beginning of every cycle during chemotherapy for a total of 4 cycles (1 cycle =21 days) and then 30 days post last dose of chemotherapy. All toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 3.0) In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE Only incidents of AEs determined to be related to chemotherapy are recorded here.
Time frame: During chemotherapy treatment and up to 30 days post-last dose of chemotherapy.
Population: Toxicity data was collected and analysed for the first 40 patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction, Combination and Surgery | Toxicity Profile | Thrombocytopenia | 20 participants |
| Induction, Combination and Surgery | Toxicity Profile | Anemia | 17 participants |
| Induction, Combination and Surgery | Toxicity Profile | lymphopenia | 16 participants |
| Induction, Combination and Surgery | Toxicity Profile | Leukopenia | 15 participants |
| Induction, Combination and Surgery | Toxicity Profile | Neutropenia | 8 participants |
| Induction, Combination and Surgery | Toxicity Profile | Thrombosis | 5 participants |
| Induction, Combination and Surgery | Toxicity Profile | Nausea | 18 participants |
| Induction, Combination and Surgery | Toxicity Profile | Diarrhea | 15 participants |
| Induction, Combination and Surgery | Toxicity Profile | Dysphagia | 15 participants |
| Induction, Combination and Surgery | Toxicity Profile | Vomiting | 8 participants |
| Induction, Combination and Surgery | Toxicity Profile | Constipatation | 7 participants |
| Induction, Combination and Surgery | Toxicity Profile | Abdominal pain | 6 participants |
| Induction, Combination and Surgery | Toxicity Profile | Stomatitis | 6 participants |
| Induction, Combination and Surgery | Toxicity Profile | Esophgitis | 4 participants |
Post Hoc
Determine Progressive Free Survival
Time frame: After cycles 2, and 4 (pre-surgery) 30 days after surgery and then every 3 months until first documentation of progressive disease, death and up to a maximum of 24 months.
Population: The only data collected for this outcome measure was progression free survival rate at 3 months, 6 months, and 12 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction, Combination and Surgery | Determine Progressive Free Survival | 6 months | 67.44 percentage of patents progression free |
| Induction, Combination and Surgery | Determine Progressive Free Survival | 12 months | 62.62 percentage of patents progression free |
| Induction, Combination and Surgery | Determine Progressive Free Survival | 24 months | 51.83 percentage of patents progression free |
| Induction, Combination and Surgery | Determine Progressive Free Survival | 3 months | 86.05 percentage of patents progression free |
Post Hoc
Overall Survival
Time frame: From the start of treatment and then every 3 months until death or a maximum of 24 months.
Population: 1 patient was registered to the study, but was not treated on study and was therefore not evaluable. Data for overall surivival was collected at 3 months, 6 months, 12 months and 24 months. There was no further data analysis completed
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction, Combination and Surgery | Overall Survival | 3 months | 93.02 percentage of patients alive |
| Induction, Combination and Surgery | Overall Survival | 6 months | 83.72 percentage of patients alive |
| Induction, Combination and Surgery | Overall Survival | 12 months | 66.81 percentage of patients alive |
| Induction, Combination and Surgery | Overall Survival | 24 months | 58.51 percentage of patients alive |