A Phase III Trial Evaluating the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for Patients With Esophageal Cancer Who Are Treated Without Surgery
Overview
- Phase
- Phase 3
- Intervention
- cetuximab
- Conditions
- Esophageal Cancer
- Sponsor
- Radiation Therapy Oncology Group
- Enrollment
- 344
- Locations
- 175
- Primary Endpoint
- Overall Survival (24-month Rate Reported)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as paclitaxel 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. 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 stop the growth of esophageal cancer by blocking blood flow to the tumor. It is not yet known whether giving paclitaxel and cisplatin together with radiation therapy is more effective with or without cetuximab in treating esophageal cancer.
PURPOSE: This randomized phase III trial is comparing how well giving paclitaxel and cisplatin together with radiation therapy works with or without cetuximab in treating patients with locally advanced esophageal cancer.
Detailed Description
OBJECTIVES: Primary * To evaluate whether the addition of cetuximab to chemotherapy comprising paclitaxel, cisplatin, and radiotherapy improves overall survival compared with paclitaxel, cisplatin, and radiotherapy alone in patients with esophageal cancer treated without surgery. Secondary * To evaluate whether the addition of cetuximab to paclitaxel, cisplatin, and radiotherapy improves local control by increasing the clinical complete response and decreasing local recurrence in these patients. * To evaluate adverse events in these patients. * To evaluate endoscopic complete response rates in these patients. * To evaluate if the addition of cetuximab to paclitaxel, cisplatin, and radiotherapy improves the Esophageal Cancer Subscale (ECS) score of the Functional Assessment of Cancer Therapy - Esophagus (FACT-E) quality of life tool. * To evaluate the quality-adjusted survival of each treatment arm using EQ-5D if the primary endpoint supports the primary hypothesis. OUTLINE: This is a multicenter study. Patients are stratified according to histology (adenocarcinoma vs squamous), cancer lesion size (\< 5 cm vs ≥ 5 cm), and disease status of celiac nodes (present vs absent). Patients are randomized to 1 of 2 treatment arms.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Pathologically (histologic or cytologic) proven diagnosis of primary squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction within 12 weeks prior to registration. Patients with involvement of the gastroesophageal junction with Siewert type I or II tumors (tumors arising from the distal esophagus and involving the esophagogastric junction or tumors starting at the esophagogastric junction and involving the cardia) are eligible.
- •1.1 Disease must be encompassed in a radiotherapy field.
- •1.2 Patients with celiac, perigastric, mediastinal or supraclavicular adenopathy are eligible.
- •1.3 Patients with cervical esophageal carcinoma are eligible.
- •Stage T1N1M0; T2-4, Any N, M0; Any T, Any N, M1a, based upon the following minimum diagnostic work-up:
- •2.1 History/physical examination within 6 weeks prior to registration
- •2.2 Positron emission tomography (PET)/positron emission tomography-computed tomography (PET-CT) scan (strongly recommended) or chest/abdominal CT within 6 weeks prior to registration
- •2.3 Electrocardiogram (EKG) within 6 weeks of study entry
- •2.4 Endoscopy with biopsy or cytology by fine needle aspiration (FNA) (must be able to document histologic subtype) within 12 weeks of study entry. Patients with T3-4 proximal thoracic esophageal tumors (15-25 cm) must undergo bronchoscopy to exclude fistula. (NOTE: Any images from endoscopic procedures up to the time of progression must be kept in the patient's confidential study file.)
- •Zubrod performance status 0-2
Exclusion Criteria
- •Evidence of tracheoesophageal fistula, or invasion into the trachea or major bronchi. Patients with T3-4 proximal thoracic esophageal tumors (15-25 cm) must undergo bronchoscopy to exclude fistula.
- •Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 2 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
- •Prior systemic chemotherapy for esophageal cancer; note that prior chemotherapy for a different cancer is allowable.
- •Prior radiation therapy that would result in overlap of planned radiation therapy fields.
- •Prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR) pathway.
- •Prior platinum-based and/or paclitaxel-based therapy.
- •Prior allergic reaction to the study drugs involved in this protocol.
- •Prior severe infusion reaction to a monoclonal antibody.
- •Severe, active comorbidity, defined as follows:
- •9.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months
Arms & Interventions
Chemoradiation + Cetuximab
External beam radiation therapy (RT) with concurrent weekly paclitaxel, cisplatin, and cetuximab
Intervention: cetuximab
Chemoradiation + Cetuximab
External beam radiation therapy (RT) with concurrent weekly paclitaxel, cisplatin, and cetuximab
Intervention: cisplatin
Chemoradiation + Cetuximab
External beam radiation therapy (RT) with concurrent weekly paclitaxel, cisplatin, and cetuximab
Intervention: paclitaxel
Chemoradiation + Cetuximab
External beam radiation therapy (RT) with concurrent weekly paclitaxel, cisplatin, and cetuximab
Intervention: radiation therapy
Chemoradiation
External beam radiation therapy with concurrent weekly paclitaxel, and cisplatin
Intervention: cisplatin
Chemoradiation
External beam radiation therapy with concurrent weekly paclitaxel, and cisplatin
Intervention: paclitaxel
Chemoradiation
External beam radiation therapy with concurrent weekly paclitaxel, and cisplatin
Intervention: radiation therapy
Outcomes
Primary Outcomes
Overall Survival (24-month Rate Reported)
Time Frame: From randomization to last follow-up. Analysis was planned to occur after at least 281 deaths had been observed. Maximum follow-up at time of analysis was 74.5 months.
Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur after at least 281 deaths have been observed, unless an early stopping rule was satisfied.
Secondary Outcomes
- Percentage of Patients With Acute Grade 4 or 5 Non-hematologic Treatment-related Adverse Events(From start of treatment to 90 days from end of treatment)
- Endoscopic Complete Response Rate(From randomization to 6-8 weeks after completion of chemoradiation (11-14 weeks))
- Local Failure (24-month Rate Reported)(From randomization to last follow-up. Analysis was planned to occur after at least 281 deaths had been observed. Maximum follow-up at time of analysis was 74.5 months.)
- Quality-adjusted Survival (Using EQ-5D), Only if Primary Hypothesis is Supported(Baseline, 6-8 weeks after completion of chemoradiation, 1 year and 2 years from treatment start.)
- Percentage of Patients With Improvement in the Functional Assessment of Cancer Therapy - Esophagus (FACT-E) Esophageal Cancer Subscale (ECS) Subscale After Treatment(Baseline, 6-8 weeks after completion of chemoradiation , 1 year and 2 years from treatment start.)