Esophageal Cancer
Conditions
Keywords
adenocarcinoma of the esophagus, stage II esophageal cancer, stage III esophageal cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, work in 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. Oxaliplatin and fluorouracil may make tumor cells more sensitive to radiation therapy and may kill more tumor cells. Giving chemotherapy and radiation therapy before surgery may shrink the tumor so that it can be removed. PURPOSE: This phase II trial is studying how well giving oxaliplatin together with fluorouracil and radiation therapy works in treating patients who are undergoing surgery for stage II or stage III cancer of the esophagus or gastroesophageal junction.
Detailed description
OBJECTIVES: Primary * Determine the pathologic complete response probability in patients with stage II or III adenocarcinoma of the esophagus or gastroesophageal junction treated with neoadjuvant oxaliplatin, fluorouracil, and radiotherapy followed by definitive surgical resection. Secondary * Determine the frequency and severity of toxic effects associated with this neoadjuvant regimen in these patients. * Determine the overall survival and progression-free survival of patients treated with this regimen. Exploratory Analyses (subject to funding availability) * Correlate, preliminarily, initial messenger ribonucleic acid (mRNA) levels of the genes for thymidylate synthase (TS), γ-glutamyl transpeptidase (γGT), γ-glutamyl cysteine (γ-GCS), DNA excision repair cross-complementing (ERCC-1), and xeroderma pigmentosum (XPA) with response and survival of patients treated with this regimen. * Correlate, preliminarily, the mRNA levels of TS, γGT, γ-GCS, ERCC-1, and XPA before and after treatment with this regimen with survival of these patients. * Correlate, preliminarily, specific genetic polymorphisms of TS and ERCC-1 with tumor response and overall survival of patients treated with this regimen. OUTLINE: This is a multicenter study. * Neoadjuvant chemoradiotherapy: Patients receive oxaliplatin IV over 2 hours on days 1, 15, and 29 and fluorouracil (5-FU) IV continuously on days 8-43. Beginning on day 8, patients also undergo radiotherapy once daily, 5 days a week, for 5 weeks. * Surgery: Patients with stable disease or better undergo surgical resection 4-10 weeks after completion of chemoradiotherapy. * Adjuvant chemotherapy: Beginning 4-10 weeks after surgery, patients receive chemotherapy comprising oxaliplatin IV over 2 hours on days 1, 15, and 29 and 5-FU IV continuously on days 1-36. Treatment continues in the absence of unacceptable toxicity or disease progression. Patients are followed every 3 months for 1 year and then every 6 months for 2 years. PROJECTED ACCRUAL: A total of 45-85 patients will be accrued for this study within 17-21 months.
Interventions
DRUGfluorouracil
Before surgery: 180 mg/m2/day by 24-hour infusion days 8 through 43. After surgery:180 mg/m2/day by 24-hour infusion days 1 through 36.
DRUGoxaliplatin
Before surgery: 85 mg/m2 by 2-hour IV infusion days 1, 15, and 29. After surgery: 85 mg/m2 by 2-hour IV infusion days 1, 15, and 29.
PROCEDUREconventional surgery
The surgical technique will depend upon the location and extent of tumor and individual surgeon preference.
RADIATIONradiation therapy
Starting Day 8, patients will be treated 5 days/week at 180 centigray (cGy)/day times 25 fractions to a total dose of 4,500 cGy.
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 confirmed primary adenocarcinoma of the thoracic esophagus or gastroesophageal junction * No recurrent disease * Primary esophageal tumor at least 20 cm below the incisors (if \< 26 cm below the incisors, a bronchoscopy must be performed and cytology must be negative) * Esophageal disease confined to esophagus and peri-esophageal soft tissue * Gastroesophageal junction disease extending ≤ 2 cm into the gastric cardia * Clinical stage II or III disease by CT scan or MRI * If no esophageal mass is detected by these methods, esophageal endoscopic ultrasound is required to determine stage * Positron-emission tomography scan is required to confirm stage * Measurable or non-measurable disease by x-ray, scanning, or physical examination * No celiac axis nodes ≥ 1.5 cm * Measurable regional lymph nodes ≥ 1.5 cm at stations 2-10=N1 OR subdiaphragmatic lymph nodes at stations 15-19 ≤ 1.5 cm by CT scan or MRI allowed * Palpable supraclavicular lymph nodes must be free of metastatic esophageal cancer by biopsy PATIENT CHARACTERISTICS: Age * Over 18 Performance status * Zubrod 0-2 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count ≥ 1,500/mm\^3 * White blood cell (WBC) count ≥ 3,000/mm\^3 * Hemoglobin ≥ 10.0 g/dL (transfusion allowed) Hepatic * Albumin ≥ 3 g/dL * Bilirubin normal Renal * Creatinine ≤ 1.5 times upper limit of normal Cardiovascular * No myocardial infarction or cerebrovascular event within the past 6 months Pulmonary * No active pneumonia or inflammatory lung infiltrate Other * No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix * No peripheral neuropathy ≥ grade 2 * Not pregnant or nursing * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * No prior chemotherapy for esophageal cancer Endocrine therapy * Not specified Radiotherapy * No prior radiotherapy for esophageal cancer * No concurrent intensity-modulated radiotherapy Surgery * No prior surgical resection or attempted surgical resection of esophageal cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response | 10-16 weeks after beginning study treatment | Complete pathologic response assessed after chemoradiotherapy and surgery, defined as no evidence of residual disease on path review. Patients who did not receive surgery are assumed to have not responded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 0-5 years | Measured from time of registration to death, or last contact date |
| Progression-free Survival | 0-3 years | measured from date of registration to time of first documentation of progression by Response Evaluation Criteria in Solid Tumors (RECIST), death, or last contact date. |
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Up to 3 years | Only adverse events that are possibly, probably or definitely related to study drug are reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemo Plus RT, Surgery, Chemo Neoadjuvant fluorouracil, oxaliplatin and radiation therapy followed by conventional surgery and adjuvant fluoruracil and oxaliplatin | 93 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 29 |
| Overall Study | Death | 4 |
| Overall Study | not eligible | 5 |
| Overall Study | Other | 6 |
| Overall Study | progression/relapse | 7 |
| Overall Study | Withdrawal by Subject | 13 |
Baseline characteristics
| Characteristic | Chemo Plus RT, Surgery, Chemo |
|---|---|
| Age Continuous | 62.2 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 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 | 3 Participants |
| Race (NIH/OMB) White | 86 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 93 / 93 |
| serious Total, serious adverse events | 7 / 93 |
Outcome results
Primary
Pathological Complete Response
Complete pathologic response assessed after chemoradiotherapy and surgery, defined as no evidence of residual disease on path review. Patients who did not receive surgery are assumed to have not responded.
Time frame: 10-16 weeks after beginning study treatment
Population: Eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemo Plus RT, Surgery, Chemo | Pathological Complete Response | 26 participants |
Secondary
Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug
Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time frame: Up to 3 years
Population: Eligible patients who received any treatment and were assessed for toxicity were included in the adverse event summaries. Any Common Terminology Criteria for Adverse Events (CTCAE) v3.0 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) |
|---|---|---|---|
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Chyle or lymph leakage | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Confusion | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Cough | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dehydration | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Diarrhea | 12 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Distention/bloating, abdominal | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dysphagia (difficulty swallowing) | 4 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dyspnea (shortness of breath) | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Esophagitis | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Fatigue (asthenia, lethargy, malaise) | 14 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Leak (including anastomotic), GI - Esophagus | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Leukocytes (total WBC) | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Lymphopenia | 10 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Skin breakdown/decubitus ulcer | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Adult respiratory distress syndrome (ARDS) | 4 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Anorexia | 15 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | CNS cerebrovascular ischemia | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Calcium, serum-low (hypocalcemia) | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Cardiac troponin T (cTnT) | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Cardiac-ischemia/infarction | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Creatinine | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Febrile neutropenia | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Fever in absence of neutropenia, ANC lt1.0x10e9/L | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Fistula, GI - Oral cavity | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Gastrointestinal-Other (Specify) | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Glucose, serum-high (hyperglycemia) | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Heartburn/dyspepsia | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Hemoglobin | 4 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Hypotension | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Hypoxia | 6 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Inf (clin/microbio) w/Gr 3-4 neuts - Lung | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - Blood | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - Lung | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - Perit cav | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - Wound | 4 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Infection with unknown ANC - Blood | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Infection with unknown ANC - Lung (pneumonia) | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Infection with unknown ANC - Wound | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Mood alteration - anxiety | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Mucositis/stomatitis (clinical exam) - Esophagus | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Mucositis/stomatitis (clinical exam) - Oral cavity | 4 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Mucositis/stomatitis (functional/symp) - Esophagus | 5 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Mucositis/stomatitis (functional/symp) - Oral cav | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Muscle weakness, not d/t neuropathy - body/general | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Nausea | 11 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Necrosis, GI - Stomach | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Neutrophils/granulocytes (ANC/AGC) | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Obstruction, GI - Esophagus | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Abdomen NOS | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Pain NOS | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pericardial effusion (non-malignant) | 4 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Platelets | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pleural effusion (non-malignant) | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pneumonitis/pulmonary infiltrates | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Potassium, serum-low (hypokalemia) | 4 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pulmonary/Upper Respiratory-Other (Specify) | 3 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Renal failure | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | SVT and nodal arrhythmia - Atrial fibrillation | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | SVT and nodal arrhythmia - Sinus tachycardia | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Sodium, serum-low (hyponatremia) | 5 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Stricture/stenosis (incl anastomotic), Esophagus | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Syncope (fainting) | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Thrombosis/thrombus/embolism | 2 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Typhlitis (cecal inflammation) | 1 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Vomiting | 7 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Weight loss | 13 Participants |
| Chemo Plus RT, Surgery, Chemo | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Wound complication, non-infectious | 1 Participants |
Secondary
Overall Survival
Measured from time of registration to death, or last contact date
Time frame: 0-5 years
Population: eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemo Plus RT, Surgery, Chemo | Overall Survival | 28.3 months |
Secondary
Progression-free Survival
measured from date of registration to time of first documentation of progression by Response Evaluation Criteria in Solid Tumors (RECIST), death, or last contact date.
Time frame: 0-3 years
Population: eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemo Plus RT, Surgery, Chemo | Progression-free Survival | 19.7 months |