Esophageal Cancer
Conditions
Keywords
adenocarcinoma of the esophagus, squamous cell carcinoma of the esophagus, stage III esophageal cancer
Brief summary
RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also stop the growth of esophageal cancer by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin and irinotecan, 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 cetuximab together with combination chemotherapy and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cetuximab together with combination chemotherapy and radiation therapy works in treating patients with locally advanced esophageal cancer that cannot be removed by surgery.
Detailed description
OBJECTIVES: Primary * Determine the 2-year overall survival of patients with previously untreated, clinically unresectable, locally advanced squamous cell carcinoma or adenocarcinoma of the esophagus treated with cetuximab, cisplatin, irinotecan, and thoracic radiotherapy. Secondary * Determine the toxicity profile of this regimen in these patients. * Determine the probability of objective response (confirmed and unconfirmed, complete and partial) in patients with measurable disease treated with this regimen. * Determine the time to progression in patients with measurable disease treated with this regimen. * Correlate, preliminarily, gene expression (RNA) levels and germline polymorphisms of genes involved in DNA repair (e.g., ECRCC-1 and XRCC-1), drug metabolism (e.g., UGT1A1), and the epidermal growth factor receptor (EGFR) pathway (e.g., EGFR, interleukin-8, and vascular endothelial growth factor) with response, time to progression, overall survival, and toxicity in patients treated with this regimen. (This will not be completed as this study was closed due to poor accrual.) OUTLINE: This is a multicenter study. Patients receive cetuximab intravenous (IV) over 1-2 hours on days 1, 8, and 15. Patients also receive cisplatin IV and irinotecan IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of course 3, patients undergo thoracic radiotherapy once daily 5 days a week for 5-6 weeks (total of 28 treatments). After completion of study treatment, patients are followed at 4 weeks and then every 3-6 months for up to 5 years after study entry. PROJECTED ACCRUAL: A total of 75-100 patients (75 with adenocarcinoma and 25 with squamous cell carcinoma) will be accrued for this study.
Interventions
BIOLOGICALcetuximab
400mg/m\^2 loading dose, intravenous (IV) over 120 min, day 1 of cycle 1 only. 250mg/m\^2 maintenance dose, IV over 60 min, Days 8 & 15 of Cycle 1 and Days 1, 8, and 15 of subsequent cycles.
DRUGcisplatin
30mg/m\^2, bolus intravenous (IV), on Days 1 & 8 of each cycle.
DRUGirinotecan hydrochloride
65mg/m\^2, intravenous (IV) over 30 min, on Days 1 & 8 of each cycle.
RADIATIONradiation therapy
The total dose to the prescription point will be 5,040 cGy given in 28 fractions. The patient will be treated with one fraction per day with all fields treated per day. 180 cGy will be delivered to the isocenter. The dose variation in the planning target volume (PTV) will be +7% and -5% of the prescription point dose.
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 squamous cell carcinoma or adenocarcinoma of the thoracic esophagus (≥ 20 cm from the incisors\*) or the gastroesophageal junction (confined to ≤ 2 cm into the gastric cardia) * Disease confined to the esophagus or peri-esophageal soft tissue * T4, M0 disease * Surgically unresectable disease by esophageal endoscopic ultrasonography OR medically unresectable disease NOTE: \*Patients with primary disease \< 26 cm from the incisors must undergo bronchoscopy AND have negative cytology within the past 4 weeks * Measurable or non-measurable disease by x-ray, CT scan and/or MRI, or physical examination within the past 4 weeks (for measurable disease) or within the past 6 weeks (for non-measurable disease) * Tumor specimens available * No recurrent disease PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Zubrod 0-2 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count (ANC) ≥ 1,500/mm\^3 * White Blood Cell (WBC) count ≥ 3,000/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 10.0 g/dL Hepatic * Albumin normal * Bilirubin normal * Alkaline phosphatase normal * Serum glutamic oxaloacetic transaminase (SGOT) or Serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 times upper limit of normal Renal * Creatinine clearance \> 50 mL/min Other * Not pregnant or nursing * Fertile patients must use effective contraception * No prior severe reaction to monoclonal antibodies * 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 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 * No concurrent cobalt-60 Surgery * No prior surgical resection or attempted surgical resection of esophageal cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival at 2 Years | 0-2 years | Measured from time of registration to date of death due to any cause, or last contact date |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Patients were assessed for adverse events after every two cycles of chemotherapy. | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. |
| Objective Response (Confirmed and Unconfined, Complete and Partial) | at week 16, then every 3 months until progression | Complete response (CR) is complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Normalization of markers and other abnormal lab values. Partial response (PR) applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Confirmation of CR or PR means a repeat scan at least 4 weeks apart documented before progression or symptomatic deterioration. |
| Progression Free Survival | 0 - 5 years | Measured from date of registration to date of first observation of progression or symptomatic deterioration. Patients last known to be alive and progression-free are censored at date of last contact. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Cetuximab+Cisplatin+Irinotecan followed by radiation therapy (RT) in Cycle 3 | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 2 |
| Overall Study | Ineligible | 1 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Continuous | 61.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 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 | 15 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 3 / 21 |
Outcome results
Primary
Overall Survival at 2 Years
Measured from time of registration to date of death due to any cause, or last contact date
Time frame: 0-2 years
Population: All eligible patients who started treatment were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Overall Survival at 2 Years | 33.3 percentage of participants |
Secondary
Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug
Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Time frame: Patients were assessed for adverse events after every two cycles of chemotherapy.
Population: Eligible patients who had received any treatment were included in the adverse event summaries. Any CTCAE 3.0 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) |
|---|---|---|---|
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Albumin, serum-low (hypoalbuminemia) | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Anorexia | 4 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | CNS cerebrovascular ischemia | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Calcium, serum-low (hypocalcemia) | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Creatinine | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Death not associated w/CTCAE term - Sudden death | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dehydration | 4 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dermatology/Skin-Other (Specify) | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Diarrhea | 5 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Dysphagia (difficulty swallowing) | 3 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Esophagitis | 2 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Fatigue (asthenia, lethargy, malaise) | 5 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Febrile neutropenia | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Glucose, serum-high (hyperglycemia) | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Hemoglobin | 3 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Leukocytes (total WBC) | 9 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Lymphopenia | 4 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Magnesium, serum-low (hypomagnesemia) | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Nausea | 4 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Necrosis, GI - Colon/cecum/appendix | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Neuropathy: sensory | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Neutrophils/granulocytes (ANC/AGC) | 6 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Abdomen NOS | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Pain - Esophagus | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Perforation, GI - Colon | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Potassium, serum-low (hypokalemia) | 2 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Rash: acne/acneiform | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Renal failure | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Sodium, serum-low (hyponatremia) | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Thrombosis/thrombus/embolism | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Typhlitis (cecal inflammation) | 1 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Vomiting | 3 Participants |
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Weight loss | 1 Participants |
Secondary
Objective Response (Confirmed and Unconfined, Complete and Partial)
Complete response (CR) is complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Normalization of markers and other abnormal lab values. Partial response (PR) applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Confirmation of CR or PR means a repeat scan at least 4 weeks apart documented before progression or symptomatic deterioration.
Time frame: at week 16, then every 3 months until progression
Population: All eligible patients who started treatment and were evaluable for response were included in assessing response estimates.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Objective Response (Confirmed and Unconfined, Complete and Partial) | 17.6 percentage of participants |
Secondary
Progression Free Survival
Measured from date of registration to date of first observation of progression or symptomatic deterioration. Patients last known to be alive and progression-free are censored at date of last contact.
Time frame: 0 - 5 years
Population: All eligible patients who started treatment were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab+Cisplatin+Irinotecan Followed by Radiation Therapy | Progression Free Survival | 6.4 months |