Gastric Cancer
Conditions
Keywords
stage II gastric cancer, stage III gastric cancer, stage IV gastric cancer, adenocarcinoma of the stomach
Brief summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy, radiation therapy, and surgery may kill more tumor cells. E7296 was conducted to study neoadjuvant chemotherapy and postoperative chemoradiation therapy in patients diagnosed with high-risk gastric cancer using a new neoadjuvant regimen: paclitaxel plus cisplatin. It was hypothesized that this new neoadjuvant chemotherapy followed by surgery and chemoradiation therapy would be well tolerated and would have a high curative resection rate.
Detailed description
OBJECTIVES: Primary objective: To evaluate the tolerability and toxicity of neoadjuvant cisplatin plus paclitaxel and postoperative chemoradiation therapy with fluorouracil plus leucovorin calcium in patients with high-risk gastric cancer. Secondary objectives: To assess the pathologic response of gastric tumors to neoadjuvant cisplatin plus paclitaxel chemotherapy, and preliminarily assess the patterns of failure and disease free and overall survival. OUTLINE: Patients receive 3 courses of preoperative neoadjuvant chemotherapy given on day 1 every 21 days. Courses consist of an intravenous infusion of cisplatin and a 3 hour intravenous infusion of paclitaxel on day 1. Patients then undergo surgery for tumor removal on day 63, followed 4-6 weeks later by one course of daily intravenous bolus leucovorin calcium and fluorouracil for 5 days. Chemotherapy is repeated 4-6 weeks later for the first 4 days of week 1 and the last 3 days of week 5 of radiation therapy given 5 days a week for 5 weeks. Patients receive two more courses, 4 weeks apart, of fluorouracil and leucovorin calcium for 5 days 4-6 weeks after completing radiation treatment. Patients are followed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter. PROJECTED ACCRUAL: Approximately 30-42 patients will be accrued over 18 months.
Interventions
DRUGcisplatin
Cisplatin was administered as part of the neoadjuvant regimen. It was given at a dose of 75 mg/m² via IV over approximately one hour, on day 1 of each cycle. Three cycles were given.
DRUGfluorouracil
Postoperative regimen 5-FU, along with Leucovorin, was given by IV bolus, with 5-FU given immediately after the Leucovorin
DRUGleucovorin calcium
Both 5-FU and Leucovorin will be given via IV bolus, with Leucovorin given immediately before 5-FU.
DRUGpaclitaxel
Paclitaxel was administered as part of the neoadjuvant regimen. It was given at a dose of 175 mg/m² as a 3 hour continuous intravenous infusion on day 1. Three cycles were given.
PROCEDUREsurgery
The surgical procedure performed involved a radical subtotal or total gastrectomy. A complete surgical resection was required
RADIATIONradiation therapy
Concomitant chemotherapy and radiation therapy course: 5-FU 400 mg/m²/day + Leucovorin 20 mg/m²/day on days 1-4 of week one and days 1-3 of week 5 of XRT. Combined chemotherapy and radiation therapy were to begin 4 weeks after day 1 of the initial course of chemotherapy
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
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
* Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction * Localized cancer that is potentially curable by surgery (T2, N1-2, M0 or T3-4, any N, M0) * No metastatic cancer to the ovaries * Age: 18 and over * Easter Cooperative Oncology Group (ECOG) performance status 0-2 * White blood cell (WBC) count at least 4,000 cells/mm3 * Platelet count at least 150,000/mm3 * Bilirubin less than 2 mg/dL * Creatinine no greater than 1.5 mg/dL * Creatinine clearance greater than 50 mL/min * Caloric intake must be at least 1500 kcal/day * No prior history of cancer within the past 5 years except for basal cell carcinoma of the skin or in situ carcinoma of the cervix * No prior radiation therapy, except for skin cancer * Fertile patients must use adequate contraception * Met criteria for re-registration after surgery * T1N1-2M0, T2N1-2M0 or T3-4NanyM0 at time of initial re-registration. * No evidence of metastatic disease from postoperative pathologic staging. * ECOG performance status of 0, 1, or 2 at re-registration * Curative resection performed * Re-registered 4 - 6 weeks from the date of surgery * WBC ≥ 4000 cells/mm³, platelets ≥ 150,000/mm³, creatinine ≤ 1.5 mg/dl or creatinine clearance of \> 50 ml/min (measured or calculated) and total serum bilirubin \< 2 mg/dl, all within four weeks prior to re-registration
Exclusion criteria
* Prior chemotherapy * Clinically significant auditory impairment * Significant heart disease * Pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3 or Higher Toxicity Incidence on Step 1 | assessed at the end of every cycle (cycle=21 days) during treatment (3 cycles in total) | Incidence is defined as proportion of patients with any grade 3 or higher treatment-related toxicities among all treated patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Confirmed Response to Neoadjuvant Therapy | Assessed at surgery time (surgery performed during week 8-10 after registration to the study) | Response was based on pathology at surgery. A patient achieved complete response if no gross or microscopic tumor were identified with the surgical specimen and nodal tissue. Stable response was defined as a response that did not qualify as complete response or progressive disease (PD), where PD indicated metastatic spread. Best confirmed response rate was defined as the proportion of patients with complete response (CR). A patient was considered unevaluable if the patient did not have surgery, the pathologist did not examine at least 15 lymph nodes, or the pathology report was unavailable. |
| Overall Survival | assessed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter up to year 10 | Overall survival was defined as the time from registration to death, where a subject was censored on date of last record alive. |
| Progression Free Survival | assessed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter up to year 10 | Progression-free survival (PFS) was defined as time from registration until progression, recurrence, or death, whichever occurred first. If date of death occurred beyond three months from the date of last disease assessment, then PFS was censored at date of last disease assessment. Patients who were alive and progression-free were censored at the date of last disease evaluation. |
Countries
United States
Participant flow
Recruitment details
E7296 was activated on February 25, 1999, accrued its first patient on June 1, 1999, and terminated on March 18, 2002 with a final accrual of 39 patients (accrual goal: 42 patients) enrolled by 13 ECOG affiliated institutions.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm Patients receive 3 courses of preoperative neoadjuvant chemotherapy (an intravenous infusion of cisplatin and a 3 hour intravenous infusion of paclitaxel) given on day 1 every 21 days. Patients then undergo surgery for tumor removal on day 63, followed 4-6 weeks later by one course of daily intravenous bolus leucovorin calcium and fluorouracil for 5 days. Chemotherapy is repeated 4-6 weeks later for the first 4 days of week 1 and the last 3 days of week 5 of radiation therapy given 5 days a week for 5 weeks. Patients receive two more courses, 4 weeks apart, of fluorouracil and leucovorin calcium for 5 days 4-6 weeks after completing radiation treatment. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Re-register to Step 2 After Surgery | Ineligible due to tumor staging | 3 |
| Re-register to Step 2 After Surgery | Less than 15 nodes examined | 7 |
| Re-register to Step 2 After Surgery | Other complications | 2 |
| Re-register to Step 2 After Surgery | Positive margins | 5 |
| Re-register to Step 2 After Surgery | Reason unknown | 1 |
| Step 1 (Neoadjuvant Therapy) | Adverse Event | 3 |
| Step 1 (Neoadjuvant Therapy) | Ineligible for step 1 | 1 |
| Step 2 (Adjuvant Therapy) | Death | 1 |
| Step 2 (Adjuvant Therapy) | Excessive complication | 1 |
| Step 2 (Adjuvant Therapy) | Ineligible | 1 |
| Step 2 (Adjuvant Therapy) | Progression before starting treatment | 1 |
| Step 2 (Adjuvant Therapy) | Withdrawal by Subject | 2 |
| Surgery | Progression before surgery | 2 |
| Surgery | Unevaluable and off study | 2 |
| Surgery | Unresectable at surgery | 3 |
Baseline characteristics
| Characteristic | Experimental Arm |
|---|---|
| Age, Continuous | 57 years |
| Region of Enrollment United States | 38 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 38 | 7 / 7 |
| serious Total, serious adverse events | 25 / 38 | 6 / 7 |
Outcome results
Primary
Grade 3 or Higher Toxicity Incidence on Step 1
Incidence is defined as proportion of patients with any grade 3 or higher treatment-related toxicities among all treated patients.
Time frame: assessed at the end of every cycle (cycle=21 days) during treatment (3 cycles in total)
Population: eligible and treated patients on step 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental Arm | Grade 3 or Higher Toxicity Incidence on Step 1 | 65.8 percentage of participants |
Secondary
Best Confirmed Response to Neoadjuvant Therapy
Response was based on pathology at surgery. A patient achieved complete response if no gross or microscopic tumor were identified with the surgical specimen and nodal tissue. Stable response was defined as a response that did not qualify as complete response or progressive disease (PD), where PD indicated metastatic spread. Best confirmed response rate was defined as the proportion of patients with complete response (CR). A patient was considered unevaluable if the patient did not have surgery, the pathologist did not examine at least 15 lymph nodes, or the pathology report was unavailable.
Time frame: Assessed at surgery time (surgery performed during week 8-10 after registration to the study)
Population: Eligible and treated patients on step 1. Since no patient had a complete response in the study, one-sided 95% confidence interval was provided here.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental Arm | Best Confirmed Response to Neoadjuvant Therapy | 0 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the time from registration to death, where a subject was censored on date of last record alive.
Time frame: assessed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter up to year 10
Population: eligible and treated patients on step 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Overall Survival | 1.55 years |
Secondary
Progression Free Survival
Progression-free survival (PFS) was defined as time from registration until progression, recurrence, or death, whichever occurred first. If date of death occurred beyond three months from the date of last disease assessment, then PFS was censored at date of last disease assessment. Patients who were alive and progression-free were censored at the date of last disease evaluation.
Time frame: assessed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter up to year 10
Population: eligible and treated patients on step 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Progression Free Survival | 0.68 years |