Esophageal Cancer, Gastric Cancer
Conditions
Keywords
adenocarcinoma of the esophagus, adenocarcinoma of the stomach, stage III esophageal cancer, stage IV esophageal cancer, stage III gastric cancer, stage IV gastric cancer, stage II esophageal cancer, stage II gastric cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as epirubicin, oxaliplatin, fluorouracil, and cisplatin, 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 before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy and radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving combination chemotherapy, surgery, and radiation therapy works in treating patients with locoregionally advanced cancer of the esophagus, gastroesophageal junction, or stomach.
Detailed description
OBJECTIVES: Primary * To assess the feasibility and tolerability of induction chemotherapy comprising epirubicin hydrochloride, oxaliplatin, and fluorouracil (EOF), followed by surgical resection and postoperative concurrent chemoradiotherapy comprising fluorouracil and cisplatin in patients with locoregionally advanced adenocarcinoma of the esophagus, gastroesophageal junction, or gastric cardia. Secondary * To determine the rate of complete and partial response to three courses of EOF induction chemotherapy. * To compare the recurrence-free and overall survival of patients treated with this regimen vs historical controls at this institution. * To compare patterns of failure in patients treated with this regimen vs historical controls at this institution. OUTLINE: * Induction chemotherapy: Patients receive epirubicin hydrochloride IV over 3-15 minutes and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV continuously on days 1-21. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. * Surgery: Four weeks after completion of induction chemotherapy, patients with locoregionally confined disease (T0-4, N0-1, M0-1a) undergo transthoracic esophagogastrectomy or total gastrectomy with Roux-en-Y esophagojejunostomy, depending on the location and extent of the tumor at the time of surgery. * Postoperative chemoradiotherapy: Beginning 6-10 weeks after surgery, patients undergo radiotherapy 5 days a week for approximately 6 weeks. Patients also receive fluorouracil IV continuously and cisplatin IV continuously over 96 hours in weeks 1 and 4 of radiotherapy. After completion of study treatment, patients are followed every 8-12 weeks for 3 years.
Interventions
DRUGcisplatin
20 mg/m2/day IV continuous infusion over 24 hours for 96 total hours.
DRUGepirubicin hydrochloride
50 mg/m2 IV bolus
DRUGfluorouracil
200 mg/m2/day will be given as a continuous intravenous infusion for all 9 weeks, beginning on day 1.
DRUGoxaliplatin
130 mg/m2 IV infusion over 2 hours
PROCEDUREadjuvant therapy
Between 6-10 weeks after surgery patients will begin postoperative chemoradiotherapy. Daily radiation therapy fractions of 180-200 cGy will be given to the esophago-gastric bed and draining lymphatic regions to a total dose of 50-55 Gy (60 Gy in the event of an R1 or R2 resection). Concurrent with this radiation, two cycles of chemotherapy will be given, during the first and fourth weeks of the radiation
PROCEDUREneoadjuvant therapy
Three weeks after discontinuing the fluorouracil (12 weeks after study entry) patients will be fully restaged to assess for a clinical response, and to ensure that there is no contraindication to surgical resection, which will be scheduled for approximately one week later (13 weeks after study entry). Surgery will consist of a transthoracic esophagogastrectomy or a total gastrectomy with Roux-en-Y esophagojejunostomy depending on the location and extent of the tumor at surgery. An appropriate lymphadenectomy will be performed. Immediate reconstruction is anticipated if possible.
Sponsors
National Cancer Institute (NCI)
Case Comprehensive Cancer Center
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
* Patients must have a histologic diagnosis of adenocarcinoma of the esophagus, gastroesophageal junction or gastric cardia, based on biopsy material or adequate cytologic exam. * Patients must be clinically staged according to the AJCC 2002 staging system and must have either T3-4, or N1 or M1a disease. Staging should include at least an upper endoscopy with endoscopic ultrasound and an FDG-PET/CT scan. * Patients must have an ECOG performance status of 0-1. * Patients must have adequate bone marrow function as evidenced by: Absolute neutrophil count \> 1,500/uL Platelet count \> 100,000/uL * Patients must have adequate renal function as evidenced by serum creatinine \< 1.6 mg/dL * Patients must have adequate hepatic function as evidenced by:Serum total bilirubin \< 1.5 mg/dL Alkaline phosphatase \< 3X the institutional ULN AST/ALT \< 3X the institutional ULN * Patients must have adequate pulmonary function as evidenced by an FEV1 \> 50% predicted. * Patients or their legal representatives must be able to read, understand, provide and sign informed consent to participate in the trial. * Patients of childbearing potential agree to use an effective form of contraception during the study and for 90 days following the last dose of study medication (an effective form of contraception is an oral contraceptive or a double barrier method) * Age \> 18 years
Exclusion criteria
* Patients with any other diagnosis except for adenocarcinoma (squamous cell carcinoma, small cell carcinoma, mixed adenosquamous, lymphoma, sarcoma etc,) will be ineligible. * Patients with any evidence of distant hematogenous or distant nodal disease (M1b) will be ineligible. * No prior chemotherapy, radiation therapy or surgery for this malignancy will be allowed. Prior endoscopic debulking, laser therapy or dilatation will not exclude a patient. * Patients with another active malignancy will not be eligible except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current PSA of \< 1.0 mg/dL on 2 successive evaluations at least 3 months apart, with the most recent evaluation within 4 weeks of entry * Patients with an active infection will not be eligible. * Patients with known hypersensitivity to any of the components of oxaliplatin, epirubicin, fluorouracil or cisplatin will not be eligible. * Patients who are receiving any other concurrent investigational therapy, or who have received investigational therapy within 30 days of the first scheduled day of protocol treatment (investigational therapy is defined as treatment for which there is currently no regulatory authority approved indication) will not be eligible. * Patients with a baseline peripheral neuropathy greater than or equal Grade 2 will not be eligible. * Patients who are pregnant or lactating will not be eligible. * Patients with any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results, will not be eligible. * Patients with any history of an allogeneic transplant will not be eligible. * Patients with known infection with HIV, Hepatitis B or C (active, previously treated or both) will not be eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Induction Chemoradiotherapy as Measured by Resectability Rate | at 12 weeks from on study | Feasibility of induction chemoradiotherapy as measured by resectability in greater than 75% of participants. The number of participants that were resectable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response Rate | at 12 weeks from on study | Percent of participants with a clinical response: Complete clinical response is defined as the complete disappearance of all clinical evidence of tumor. Partial clinical response is defined as any improvement in the clinically determined T or N stage (without reciprocal deterioration in N or T) or a resolution of M1a disease, when compared to the pretreatment clinical stage. A partial response will not be defined based only on shrinkage of a measurable lesion unless there is improvement in the TNM stage. Stable clinical disease is defined as no change in the clinical TNM stage when compared to the pretreatment clinical stage. Progressive clinical disease is defined as any increase in the T or N stage irrespective of any reciprocal improvement in N or T, or as the development of new areas of malignancy or metastases. |
| Pathological Response Rate | after completion of study at 35 weeks | Percent of participants with a clinical response: Complete pathologic response is defined as the complete disappearance of all viable tumor in the surgical specimen. Partial pathologic response is defined as any improvement in the pathologically determined T or N stage (without reciprocal deterioration in N or T) or a resolution of M1a disease, when compared to the pretreatment esophageal ultrasound-determined clinical stage. A partial response will not be defined based only on shrinkage of a measurable lesion unless there is improvement in the TNM stage. Stable pathologic disease is defined as no change in the pathologically determined TNM stage when compared to the pretreatment esophageal ultrasound. Progressive pathologic disease is defined as any increase in the T or N stage irrespective of any reciprocal improvement in N or T, or as the development of new areas of malignancy or metastases. |
| Overall Survival | at 3 years from on study | Percent of participants with a 3-year survival. A survival rate greater than 50% would suggest efficacy and justify further study. |
| Locoregional Control and Distant Metastatic Control | at 3 years from on study | A distant metastatic control rate of greater than 55 % would suggest efficacy for this treatment protocol. A locoregional control rate of less than 75% would suggest inefficacy. Locoregional control (LRC) defined by recurrence at the primary site or in regional lymph nodes and distant metastatic control (DMC), defined by recurrence in a distant site. |
| Postoperative Adjuvant Chemoradiotherapy Feasibility | Between 6 to 10 weeks postoperatively | Ability to complete postoperative chemoradiotherapy. A threshold level of 65% was set and if less than this percentage completed the phase, it would be deemed unacceptable. The anticipation was that 53-patients would be evaluable for this end point. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery Subjects received epirubicin (50-mg/m\^2), oxaliplatin (130-mg/m\^2), 5-fluorouracil (5FU; 200mg/m\^2/d), and surgery, which took place 4 to 5 weeks after the completion of preoperative chemotherapy. Epirubicin and oxaliplatin were given on day 1, while 5FU was intravenously infused for 21-days. Surgery was conducted 4 to 5-weeks after chemotherapy. Six to ten-weeks after surgery chemoradiotherapy was initiated. With radiotherapy, patients received two cycles of cisplatin and 5FU during the first and fourth weeks after surgery; they were administered intravenously over 96-hours. Specifically, cisplatin and 5FU total dose was 80-mg/m\^2 (20-mg/m\^2/d) and 4000 mg/m\^2 (1000-mg/m\^2/d), respectively. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery |
|---|---|
| Age, Continuous | 60 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 58 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 41 / 60 |
| other Total, other adverse events | 60 / 60 |
| serious Total, serious adverse events | 24 / 60 |
Outcome results
Primary
Feasibility of Induction Chemoradiotherapy as Measured by Resectability Rate
Feasibility of induction chemoradiotherapy as measured by resectability in greater than 75% of participants. The number of participants that were resectable.
Time frame: at 12 weeks from on study
Population: All subjects that went on study and received treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Feasibility of Induction Chemoradiotherapy as Measured by Resectability Rate | 54 Participants |
Secondary
Clinical Response Rate
Percent of participants with a clinical response: Complete clinical response is defined as the complete disappearance of all clinical evidence of tumor. Partial clinical response is defined as any improvement in the clinically determined T or N stage (without reciprocal deterioration in N or T) or a resolution of M1a disease, when compared to the pretreatment clinical stage. A partial response will not be defined based only on shrinkage of a measurable lesion unless there is improvement in the TNM stage. Stable clinical disease is defined as no change in the clinical TNM stage when compared to the pretreatment clinical stage. Progressive clinical disease is defined as any increase in the T or N stage irrespective of any reciprocal improvement in N or T, or as the development of new areas of malignancy or metastases.
Time frame: at 12 weeks from on study
Population: Participants that complete induction therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Clinical Response Rate | Partial response | 48 percentage of participants |
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Clinical Response Rate | Complete response | 0 percentage of participants |
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Clinical Response Rate | Stable disease | 33 percentage of participants |
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Clinical Response Rate | Progressive disease | 19 percentage of participants |
Secondary
Locoregional Control and Distant Metastatic Control
A distant metastatic control rate of greater than 55 % would suggest efficacy for this treatment protocol. A locoregional control rate of less than 75% would suggest inefficacy. Locoregional control (LRC) defined by recurrence at the primary site or in regional lymph nodes and distant metastatic control (DMC), defined by recurrence in a distant site.
Time frame: at 3 years from on study
Population: All participants that went on study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Locoregional Control and Distant Metastatic Control | Locoregional Control | 4 Participants |
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Locoregional Control and Distant Metastatic Control | Distant Metastatic Control | 29 Participants |
Secondary
Overall Survival
Percent of participants with a 3-year survival. A survival rate greater than 50% would suggest efficacy and justify further study.
Time frame: at 3 years from on study
Population: All patients that went on study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Overall Survival | 47 percentage of participants |
Secondary
Pathological Response Rate
Percent of participants with a clinical response: Complete pathologic response is defined as the complete disappearance of all viable tumor in the surgical specimen. Partial pathologic response is defined as any improvement in the pathologically determined T or N stage (without reciprocal deterioration in N or T) or a resolution of M1a disease, when compared to the pretreatment esophageal ultrasound-determined clinical stage. A partial response will not be defined based only on shrinkage of a measurable lesion unless there is improvement in the TNM stage. Stable pathologic disease is defined as no change in the pathologically determined TNM stage when compared to the pretreatment esophageal ultrasound. Progressive pathologic disease is defined as any increase in the T or N stage irrespective of any reciprocal improvement in N or T, or as the development of new areas of malignancy or metastases.
Time frame: after completion of study at 35 weeks
Population: Participants that complete induction therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Pathological Response Rate | Complete response | 3 participants |
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Pathological Response Rate | Stable disease | 14 participants |
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Pathological Response Rate | Progressive disease | 20 participants |
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Pathological Response Rate | Partial response | 21 participants |
Secondary
Postoperative Adjuvant Chemoradiotherapy Feasibility
Ability to complete postoperative chemoradiotherapy. A threshold level of 65% was set and if less than this percentage completed the phase, it would be deemed unacceptable. The anticipation was that 53-patients would be evaluable for this end point.
Time frame: Between 6 to 10 weeks postoperatively
Population: All patients that went on study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Epirubicin, Oxaliplatin, 5-fluorouracil, and Surgery | Postoperative Adjuvant Chemoradiotherapy Feasibility | 48 Participants |