A Phase III Trial Evaluating the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for Patients With Esophageal Cancer Who Are Treated Without Surgery
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.
- 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.
- 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.
18 Years to 74 Years
Accepting Healthy Volunteers?
1. 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.
2. 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.)
3. Zubrod performance status 0-2
4. Age ≥ 18 and ≤ 74 (upper limit was set at 74 in an amendment)
5. Complete blood count (CBC)/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function defined as follows:
- 5.1 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
- 5.2 Platelets ≥ 100,000 cells/mm3
- 5.3 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥8.0 g/dl is acceptable.)
6. Additional laboratory studies obtained within 2 weeks prior to registration on study
- 6.1 Creatinine ≤ 1.5 mg/dl
- 6.2 Bilirubin ≤ 1.5 x upper limit of normal
- 6.3 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 x upper limit of normal
- 6.4 Serum pregnancy test for women of childbearing potential
7. Patient's total intake (oral/enteral) must be ≥ 1500 kCal/day
8. Patient must provide study-specific informed consent prior to study entry
9. Women of childbearing potential and male participants must practice adequate contraception
1. 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.
2. 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).
3. Prior systemic chemotherapy for esophageal cancer; note that prior chemotherapy for a different cancer is allowable.
4. Prior radiation therapy that would result in overlap of planned radiation therapy fields.
5. Prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR) pathway.
6. Prior platinum-based and/or paclitaxel-based therapy.
7. Prior allergic reaction to the study drugs involved in this protocol.
8. Prior severe infusion reaction to a monoclonal antibody.
9. Severe, active comorbidity, defined as follows:
- 9.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months
- 9.2 Transmural myocardial infarction within the last 6 months
- 9.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
- 9.4 Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
- 9.5 Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immunocompromised patients.
10. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
11. Women who are nursing.