Chemotherapy, Radiation Therapy, and Cetuximab Followed by Surgery, Docetaxel, and Cetuximab in Treating Patients With Esophageal Cancer or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, fluorouracil, and docetaxel, 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. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving docetaxel and cetuximab after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving chemotherapy and radiation therapy together with cetuximab followed by surgery, docetaxel and cetuximab works in treating patients with esophageal cancer or gastroesophageal junction cancer.

Detailed Description
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OBJECTIVES: Primary To determine the pathologic complete response (pCR) rate of neoadjuvant chemoradiotherapy with OX/5-FU/radiotherapy (RT) plus cetuximab in patients with resectable adenocarcinoma of the esophagus. Secondary To evaluate the safety of neoadjuvant chemoradiotherapy with OX/5-FU/RT plus cetuximab in patients with resectable adenocarcinoma of the esophagus. To evaluate the safety and tolerability of adjuvant therapy comprising cetuximab and docetaxel in these patients. To carry out exploratory studies to determine if activity of this regimen correlates with epidermal growth factor receptor (EGFR)-related genetic and pathway activation markers and circulating endothelial and tumor cells. OUTLINE: This is a multicenter study. Neoadjuvant chemoradiotherapy and cetuximab: Patients receive oxaliplatin intravenously (IV) over 2 hours on days 1, 15, and 29, cetuximab IV over 1-2 hours on days 1, 8, 15, 22, and 29, and 5-FU IV continuously over 24 hours on days 1-35. Patients also undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33. Patients then proceed to surgery. Surgery: Patients undergo surgical resection within 4-8 weeks after completion of neoadjuvant chemoradiotherapy and cetuximab. Patients with an R0 or R1 resection proceed to adjuvant therapy. Patients whose tumors have not been completely resected or who have metastatic disease discontinue protocol therapy and receive further therapy at the discretion of the treating physician. Adjuvant therapy: Within 4-8 weeks after surgery, patients receive docetaxel IV over 1 hour on days 1, 8, 15, 22, and 29 and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, and then every 6 months for 3-5 years.

Official Title
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A Phase II Study to Measure Response Rate and Toxicity of Neo-adjuvant Chemoradiotherapy With Oxaliplatin (OX) and Infusional 5-Fluorouracil (5-FU) Plus Cetuximab Followed by Post-Operative Docetaxel and Cetuximab in Patients With Operable Adenocarcinoma of the Esophagus

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: 5-Fluorouracil
* Drug: Oxaliplatin
* Drug: Cetuximab
* Drug: Docetaxel
* Procedure: Surgery
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed adenocarcinoma of the esophagus (> 20 cm below the incisors) or gastroesophageal (GE) junction, untreated with chemotherapy, radiation therapy, and surgery. Endoscopy with biopsy and dilation was permitted. Tumor stage T2N0M0, T3N0M0, T1-3N+M0, or T1-3N0-1M1A as determined by imaging studies performed no greater than 4 weeks prior to registration, and biopsy, where appropriate. Celiac nodal metastasis (M1A disease) was permitted if other eligibility criteria were met. Data from endoscopic ultrasound and endoscopy were required for staging. The following imaging was required: CT scan with IV contrast and PET or PET+CT. If the PET/CT incorporates CT with IV contrast, then a separate CT is not required. If laparoscopy or other relevant procedures were performed, the data were to be incorporated into stage assignment. Any lesion suspicious for metastasis had to have been biopsied to prove eligibility. Tumor extension into cardia, if present, must have been no more than 2 cm. Tumors must have been considered surgically resectable (T1-3, not T4). Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Granulocytes > 1,000/ mm³ Platelets > 100,000 μL Creatinine normal or creatinine clearance > 60 mL/min Total serum bilirubin < 1.5 mg/dL Fertile patients must use effective contraception History of a curatively treated malignancy from which the patient has been disease-free for ≥ 2 years and has a survival prognosis of > 5 years Exclusion Criteria: Pregnant or breast-feeding. Prior severe infusion reaction to a monoclonal antibody prior therapy specifically and directly targeting the epidermal growth factor receptor (EGFR) pathway Hypertension Uncontrolled diabetes Intercurrent illness that would likely interfere with protocol therapy or prevent surgical resection Any of the following within the past 6 months: New York Heart Association class III-IV congestive heart failure Cerebrovascular accident or transient ischemic attack Unstable angina or myocardial infarction

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant therapy, Surgery, adjuvant therapy<br>Neoadjuvant chemoradiotherapy and cetuximab: Patients (pts) receive oxaliplatin IV over 2 hours on days 1, 15, and 29, cetuximab IV over 1-2 hours on days 1, 8, 15, 22, and 29, and 5-FU IV over 24 hours on days 1-35. Pts also undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33. Pts then proceed to surgery. Surgery: Pts undergo surgical resection within 4-8 weeks after completion of neoadjuvant chemoradiotherapy and cetuximab. Pts with an R0 or R1 resection proceed to adjuvant therapy. Pts whose tumors have not been completely resected or who have metastatic disease discontinue protocol therapy and receive further therapy at the discretion of the treating physician. Adjuvant therapy: Within 4-8 weeks after surgery, pts receive docetaxel IV over 1 hour on days 1, 8, 15, 22, and 29 and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: 5-Fluorouracil<br>* given IV<br>* Other names: Efudex;Drug: Oxaliplatin<br>* given IV<br>* Other names: 5R96669;Drug: Cetuximab<br>* given IV<br>* Other names: C225;Drug: Docetaxel<br>* given IV<br>* Other names: RP 56976;Procedure: Surgery<br>* Patients underwent surgical resection within 4-8 weeks after completion of neoadjuvant chemoradiotherapy and cetuximab.<br>Radiation: Radiotherapy<br>* Patients underwent radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Pathologic Complete Response | After neoadjuvant therapy, participants underwent surgical resection. The excised tumor was examined by a pathologist. A pathologic complete response is defined as the absence of any histopathologic evidence of tumor in the resected esophageal and nodal tissue specimen. | At time of surgery (which occurred 63 to 91 days after study entry) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the esophagus, chemoradiotherapy, oxaliplatin, cetuximab, docetaxel