Paclitaxel, Cisplatin, and Radiation Therapy With or Without Cetuximab in Treating Patients With Locally Advanced Esophageal Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase III Trial Evaluating the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for Patients With Esophageal Cancer Who Are Treated Without Surgery

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: cetuximab
* Drug: cisplatin
* Drug: paclitaxel
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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 Age ≥ 18 and ≤ 74 (upper limit was set at 74 in an amendment) 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.) 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 Patient's total intake (oral/enteral) must be ≥ 1500 kCal/day Patient must provide study-specific informed consent prior to study entry Women of childbearing potential and male participants must practice adequate contraception 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 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. 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. Women who are nursing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemoradiation + Cetuximab<br>External beam radiation therapy (RT) with concurrent weekly paclitaxel, cisplatin, and cetuximab | Drug: cetuximab<br>* Weekly with external beam radiation therapy for a total of six doses. The initial dose of cetuximab is 400 mg/m^2 intravenously administered over 120 minutes on day 1, followed by weekly infusions of 250 mg/m^2 intravenously over 60 minutes on days 8, 15, 22, 29, and 36. The infusion rate of cetuximab must never exceed 5 mL/min.<br>Drug: cisplatin<br>* Weekly with external beam radiation therapy for a total of six doses. Patients receive 25 mg/m^2 as an intravenous infusion over 30-60 minutes on days 1, 8, 15, 22, 29 and 36.<br>Drug: paclitaxel<br>* Weekly with external beam radiation therapy for a total of six doses. Patients receive 50 mg/m^2 as an intravenous infusion over 1 hour on days 1, 8, 15, 22, 29 and 36.<br>Radiation: radiation therapy<br>* 1.8 Gy daily for 28 days (over 5-6 weeks) for a total dose of 50.4 Gy.<br>|
| Active Comparator: Chemoradiation<br>External beam radiation therapy with concurrent weekly paclitaxel, and cisplatin | Drug: cisplatin<br>* Weekly with external beam radiation therapy for a total of six doses. Patients receive 25 mg/m^2 as an intravenous infusion over 30-60 minutes on days 1, 8, 15, 22, 29 and 36.<br>Drug: paclitaxel<br>* Weekly with external beam radiation therapy for a total of six doses. Patients receive 50 mg/m^2 as an intravenous infusion over 1 hour on days 1, 8, 15, 22, 29 and 36.<br>Radiation: radiation therapy<br>* 1.8 Gy daily for 28 days (over 5-6 weeks) for a total dose of 50.4 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (24-month Rate Reported) | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Failure (24-month Rate Reported) | Local failure (LF) was defined as residual cancer on posttreatment biopsy findings or biopsy-proven recurrent primary disease and local failure time was measured from randomization to failure or last follow-up. Nonprotocol surgery to the primary site with gross residual disease was considered a LF as of the surgery date. Patients with no viable disease or microscopic residual disease at nonprotocol surgery were censored for LF as of the surgery date. Local failure was estimated by the cumulative incidence method with death considered a competing risk. | 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. | 
| Percentage of Patients With Acute Grade 4 or 5 Non-hematologic Treatment-related Adverse Events | Adverse events (AE) are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE | From start of treatment to 90 days from end of treatment | 
| Endoscopic Complete Response Rate | All patients were to undergo a repeat endoscopy (EUS) 6-8 weeks after the completion of chemoradiation. At the time of EUS a visual inspection of the site of the original primary disease would be documented. Those patients found to be free of disease were NOT required to undergo repeat biopsy. These patients would be scored as clinical complete responses (cCR). Patients deemed to have residual disease or suspicion of residual disease would undergo a biopsy in order to pathologically confirm findings. Any patient with pathologically confirmed residual disease would be scored as a local failure. Patients who were pathologically proven to have no evidence of disease would be scored as cCRs. | From randomization to 6-8 weeks after completion of chemoradiation (11-14 weeks) | 
| Percentage of Patients With Improvement in the Functional Assessment of Cancer Therapy - Esophagus (FACT-E) Esophageal Cancer Subscale (ECS) Subscale After Treatment | The ECS is a 17-item self-report instrument designed to measure multidimensional quality of life in patients with esophagus cancer. It is to be administered with the Functional Assessment of Cancer Therapy - General (FACT-G). There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score which ranges from 0-68. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-E including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicated better QOL. Improvement in FACT-E score is defined as an increase from baseline score of at least 5 points. | Baseline, 6-8 weeks after completion of chemoradiation , 1 year and 2 years from treatment start. | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IIA esophageal cancer, stage IIB esophageal cancer, stage IIIA esophageal cancer, stage IIIB esophageal cancer, stage IIIC esophageal cancer, stage IV esophageal cancer, squamous cell carcinoma of the esophagus