Adenocarcinoma of the Gastroesophageal Junction, Esophageal Cancer, Gastric Cancer
Conditions
Keywords
adenocarcinoma of the esophagus, adenocarcinoma of the gastroesophageal junction, stage IIIA gastric cancer, stage IIIB gastric cancer, stage IIIC gastric cancer, stage IIIA esophageal cancer, stage IIIB esophageal cancer, stage IIIC esophageal cancer
Brief summary
This randomized phase II trial studies how well docetaxel, oxaliplatin, capecitabine, fluorouracil, and radiation therapy works compared with fluorouracil when given together with oxaliplatin and radiation therapy in treating patients with cancer of the esophagus or gastroesophageal junction that has spread from where it started to nearby tissue or lymph nodes. Drugs used in chemotherapy, such as docetaxel, oxaliplatin, capecitabine, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving more than one drug (combination chemotherapy) together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
Detailed description
PRIMARY OBJECTIVES: I. To assess and compare the pathologic complete response (PCR) rate of patients in Arm A receiving the sequence docetaxel, oxaliplatin, and capecitabine (DOC) followed by 5-fluorouracil (5-FU), oxaliplatin, and radiation therapy (RT) with patients in Arm B receiving only 5-FU, oxaliplatin and RT in patients with potentially resectable adenocarcinoma (ACA) of the esophagus, gastroesophageal junction (GEJ), or gastric cardia. SECONDARY OBJECTIVES: I. To assess the adverse event (AE) profile and safety of the proposed treatment in this population. II. To assess and compare the overall survival (OS) between treatment arms. III. To assess and compare the disease-free survival between treatment arms. IV. To assess and compare the clinical tumor response rate of the proposed regiments when administered before surgery between treatment arms. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive docetaxel intravenously (IV) over 1 hour and oxaliplatin IV over 2 hours on day 1. Patients also receive capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of the second course, patients receive fluorouracil\* IV continuously on days 1-5 and oxaliplatin IV over 2 hours on days 1, 15, and 29. Patients also undergo radiotherapy\*\* 5 days a week for 5.5 weeks in the absence of disease progression or unacceptable toxicity. Approximately 4-12 weeks after completion of radiotherapy, patients undergo surgery. ARM II: Patients receive fluorouracil IV continuously on days 1-5 and oxaliplatin IV over 2 hours on days 1, 15, and 29. Patients also undergo radiotherapy and then surgery as in Arm I. * NOTE: \* Fluorouracil continuous IV infusion begins within 24 hours of radiotherapy and ends within 24 hours of radiotherapy completion. * NOTE: \*\* Radiotherapy should begin within 2-6 weeks after completion of 2 courses of docetaxel, oxaliplatin, and capecitabine. After completion of study treatment, patients are followed up every 3 months for 2 years.
Interventions
DRUGcapecitabine
Given PO
DRUGdocetaxel
Given IV
DRUGfluorouracil
Given IV
DRUGoxaliplatin
Given IV
RADIATIONradiation therapy
Undergo radiation therapy
PROCEDUREtherapeutic conventional surgery
Undergo surgery
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological confirmation of adenocarcinoma of the esophagus, gastroesophageal (GE) junction, or gastric cardia * Tumor must be considered surgically resectable; Note: patients with T4N0M0 tumors that are potentially resectable are also eligible * Nodal involvement: patients with involvement of celiac nodes, (stations 15-20) are eligible if the primary lesion is mid-thoracic, distal esophagus or GE junction; patients with supraclavicular node involvement are eligible with upper thoracic esophagus primary lesions * Capable of swallowing pills * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 * Absolute neutrophil count (ANC) \>= 1500 * Peripheral platelet count \>= 100,000 * Hemoglobin \>= 9.0 g/dL * Total bilirubin =\< 1.5 x upper normal limit (UNL) * Serum glutamic oxaloacetic transaminase (SGOT) (alanine aminotransferase \[AST\]) =\< 3 x UNL * Creatinine =\< 1.5 x UNL * Negative pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only * Provide informed written consent * Willingness to return to NCCTG enrolling institution for follow-up * Patient willing to provide mandatory tissue and blood samples for research purposes * Patient willing to allow use of FDG PET/CT scans for mandatory research purposes
Exclusion criteria
* Evidence of distant metastases * Palpable supraclavicular nodes, biopsy-proven involvement of supraclavicular nodes, or radiographically involved supraclavicular nodes (\> 1.5 cm in greatest dimension) for lesions in mid-thoracic, distal thoracic or GE junction * T1N0M0 or T2N0M0 tumor stage * Any of the following * Pregnant women * Nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception * Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Uncontrolled diabetes (i.e., will interfere with the performance of the FDG PET/CT scans) * Receiving current treatment or prior treatment for this malignancy * Other active malignancy 5 years prior to registration, except non-melanotic skin cancer or carcinoma-in-situ of the cervix; if there is a history of prior malignancy, patient must not be receiving other specific treatment (other than hormonal therapy) for cancer * Prior radiation to \> 30% of the marrow cavity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Pathologic Complete Response (PCR) | Up to 2 years | Pathologic complete response was defined as no gross or microscopic tumor identified with the surgical specimen. All lymph nodes should be free of tumor to document a PCR. If no gross tumor is visible, section around the area of inflammation (nodularity) should be made every 2-3 cm and specimens examined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 2 years | Overall survival was defined as the time from randomization to the time of death from any cause. Overall survival was censored at the date of last follow-up visit for patients who are still alive or loss of follow-up. |
| Disease-free Survival | Up to 2 years | Disease-free survival was defined as the time from randomization to the date of recurrent or death, whichever comes first. |
| Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Up to 2 years | Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |
| Percentage of Participants With Overall Clinical Tumor Response (CR or PR) | Up to 2 years | Overall clinical tumor response rate was defined as the percentage of evaluable participants who achieved either complete response (CR) or partial response (PR) noted on the objective status from pre-surgical staging (for arm II) or either from pre-RT or pre-surgical staging (for arm I).\> CR was defined as disappearance of all non-target lesion (TL) and normalization of tumor biomarker level, all lymph nodes (LN) must be non-pathological in size (\<1 cm short axis); or disappearance of all TL and normalization of tumor biomarkers, any pathological LN (whether target or non-target) must have reduction in short axis to \<1 cm; or \>=30% decrease in the sum of the diameters of TL taking as reference the baseline sum of the diameters. |
Countries
United States
Participant flow
Recruitment details
Seventy-three participants were enrolled between January 2010 and July 2012.
Pre-assignment details
Seven participants from arm I were enrolled in the early toxicity evaluation portion. Additional sixty-six participants were randomized to arm I or II on the phase II portion of the study. There were 11 cancellations (5 arm I, 6 arm II) and these participants were excluded in all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (DOC, 5FU/O/RT, Surgery) Patients receive 60mg/m\^2 docetaxel (D) IV over 1 hour and 85mg/m\^2 oxaliplatin (O) IV over 2 hours on day 1. Patients also receive 625 mg/m\^2/dose twice a day of capecitabine (C) PO BID on days 1-14. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of the second course, patients receive 180 mg/m\^2 per day of fluorouracil (5FU) IV continuously on days 1-5 and 85 mg/m\^2 oxaliplatin (O) IV over 2 hours on days 1, 15, and 29. Patients also undergo radiation therapy (RT) 5 days a week for 5.5 weeks in the absence of disease progression or unacceptable toxicity. Approximately 4-12 weeks after completion of radiation therapy, patients undergo surgery. | 28 |
| Arm II (5FU/O/RT, Surgery) Patients receive 180 mg/m\^2 per day of fluorouracil (5FU) IV continuously on days 1-5 and 85 mg/m\^2 of oxaliplatin (O) IV over 2 hours on days 1, 15, and 29. Patients also undergo radiation therapy (RT) and then surgery. | 27 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Alternate Treatment | 1 | 0 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Disease Progression | 3 | 0 |
| Overall Study | Other Reason | 0 | 1 |
Baseline characteristics
| Characteristic | Arm II (5FU/O/RT, Surgery) | Total | Arm I (DOC, 5FU/O/RT, Surgery) |
|---|---|---|---|
| Age, Continuous | 65 years | 63 years | 62.5 years |
| ECOG Performance Status 0-1 | 27 Participants | 55 Participants | 28 Participants |
| Measurable Disease No | 16 Participants | 33 Participants | 17 Participants |
| Measurable Disease Yes | 11 Participants | 22 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 27 Participants | 55 Participants | 28 Participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 5 Participants |
| Sex: Female, Male Male | 23 Participants | 46 Participants | 23 Participants |
| Site of Tumor Esophagus | 11 Participants | 27 Participants | 16 Participants |
| Site of Tumor Gastric Cardia | 2 Participants | 2 Participants | 0 Participants |
| Site of Tumor Gastroesophageal Junction | 14 Participants | 26 Participants | 12 Participants |
| Tumor Stage II | 9 Participants | 15 Participants | 6 Participants |
| Tumor Stage III | 18 Participants | 40 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 34 / 34 | 28 / 28 |
| serious Total, serious adverse events | 7 / 34 | 7 / 28 |
Outcome results
Primary
Percentage of Participants With Pathologic Complete Response (PCR)
Pathologic complete response was defined as no gross or microscopic tumor identified with the surgical specimen. All lymph nodes should be free of tumor to document a PCR. If no gross tumor is visible, section around the area of inflammation (nodularity) should be made every 2-3 cm and specimens examined.
Time frame: Up to 2 years
Population: Eligible randomized participants who initiated first cycle of protocol treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (DOC, 5FU/O/RT, Surgery) | Percentage of Participants With Pathologic Complete Response (PCR) | 28.6 percentage of participants |
| Arm II (5FU/O/RT, Surgery) | Percentage of Participants With Pathologic Complete Response (PCR) | 40.7 percentage of participants |
Secondary
Disease-free Survival
Disease-free survival was defined as the time from randomization to the date of recurrent or death, whichever comes first.
Time frame: Up to 2 years
Population: Eligible randomized participants who initiated first cycle of protocol treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (DOC, 5FU/O/RT, Surgery) | Disease-free Survival | 31.2 months |
| Arm II (5FU/O/RT, Surgery) | Disease-free Survival | 17.0 months |
Secondary
Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event
Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time frame: Up to 2 years
Population: Eligible randomized participants who initiated first cycle of protocol treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (DOC, 5FU/O/RT, Surgery) | Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Grade 3=Severe | 10 Participants |
| Arm I (DOC, 5FU/O/RT, Surgery) | Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Grade 5=Death | 4 Participants |
| Arm I (DOC, 5FU/O/RT, Surgery) | Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Grade 4=Life threatening | 10 Participants |
| Arm II (5FU/O/RT, Surgery) | Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Grade 3=Severe | 12 Participants |
| Arm II (5FU/O/RT, Surgery) | Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Grade 4=Life threatening | 7 Participants |
| Arm II (5FU/O/RT, Surgery) | Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Grade 5=Death | 4 Participants |
Secondary
Overall Survival
Overall survival was defined as the time from randomization to the time of death from any cause. Overall survival was censored at the date of last follow-up visit for patients who are still alive or loss of follow-up.
Time frame: Up to 2 years
Population: Eligible randomized participants who initiated first cycle of protocol treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (DOC, 5FU/O/RT, Surgery) | Overall Survival | NA months |
| Arm II (5FU/O/RT, Surgery) | Overall Survival | 18.8 months |
Secondary
Percentage of Participants With Overall Clinical Tumor Response (CR or PR)
Overall clinical tumor response rate was defined as the percentage of evaluable participants who achieved either complete response (CR) or partial response (PR) noted on the objective status from pre-surgical staging (for arm II) or either from pre-RT or pre-surgical staging (for arm I).\> CR was defined as disappearance of all non-target lesion (TL) and normalization of tumor biomarker level, all lymph nodes (LN) must be non-pathological in size (\<1 cm short axis); or disappearance of all TL and normalization of tumor biomarkers, any pathological LN (whether target or non-target) must have reduction in short axis to \<1 cm; or \>=30% decrease in the sum of the diameters of TL taking as reference the baseline sum of the diameters.
Time frame: Up to 2 years
Population: Eligible randomized participants who initiated first cycle of protocol treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (DOC, 5FU/O/RT, Surgery) | Percentage of Participants With Overall Clinical Tumor Response (CR or PR) | 32.1 percentage of participants |
| Arm II (5FU/O/RT, Surgery) | Percentage of Participants With Overall Clinical Tumor Response (CR or PR) | 33.3 percentage of participants |