Radiation Therapy, Paclitaxel, and Carboplatin With or Without Trastuzumab in Treating Patients With Esophageal Cancer

• Pathologic complete response [ Time Frame: Within 4 weeks after surgical resection ] [ Designated as safety issue: No ]
  Pathologic complete response is defined as no viable residual tumor cells.
• Overall survival (OS) [ Time Frame: From the date of randomization to the date of first failure or last follow-up, assessed up to 8 years ] [ Designated as safety issue: No ]
  OS will be estimated by the Kaplan-Meier method. The distribution of OS estimates between the 2 arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with OS.
• Adverse events [ Time Frame: From the start of chemoradiation up to the earlier date of surgery or 6 weeks after completion of chemoradiation ] [ Designated as safety issue: Yes ]
  Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
• Health-related quality of life (QOL) as measured by FACT-E [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  Distributions of QOL data collection patterns over all collection points in each treatment arm will be described. To inspect the missing data mechanism for each tool, at least a graphical method will be used.
• Quality-adjusted survival [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  The EQ-5D will be used to assess quality-adjusted survival. Quality-adjusted survival is calculated as the weighted sum of different time in different health states added up to a total quality-adjusted survival time [U=sum of quality (qi) of health states K times the duration (si) spent in each health state].
• Molecular correlates of efficacy [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
• Predictors of cardiotoxicity [ Time Frame: Up to 8 years ] [ Designated as safety issue: Yes ]

• Pathologic complete response [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Adverse events [ Designated as safety issue: Yes ]
• Health-related quality of life as measured by FACT-E [ Designated as safety issue: No ]
• Quality-adjusted survival [ Designated as safety issue: No ]
• Molecular correlates of efficacy [ Designated as safety issue: No ]
• Predictors of cardiotoxicity [ Designated as safety issue: Yes ]

This randomized phase III trial is studying how well giving radiation therapy, paclitaxel, and carboplatin together with or without trastuzumab works in treating patients with esophageal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, 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. It is not yet known whether giving radiation therapy and combination chemotherapy together with or without trastuzumab is more effective in treating esophageal cancer.

PRIMARY OBJECTIVES:

l. To determine if trastuzumab increases disease-free survival when combined with trimodality treatment (radiation plus chemotherapy followed by surgery) for patients with HER2-overexpressing esophageal adenocarcinoma.

SECONDARY OBJECTIVES:

I. To evaluate if the addition of trastuzumab to trimodality treatment increases the pathologic complete response rate and overall survival for patients with HER2-overexpressing esophageal adenocarcinoma.

II. To develop a tissue bank of tumor tissue from patients with non-metastatic esophageal adenocarcinoma.

III. To determine molecular correlates of complete pathologic response, disease-free survival, and overall survival for patients with HER2-overexpressing esophageal adenocarcinoma treated with neoadjuvant and maintenance trastuzumab.

IV. To evaluate predictors of cardiotoxicity in patients with esophageal cancer treated with trastuzumab and chemoradiation.

V. To evaluate adverse events associated with the addition of trastuzumab to trimodality treatment for patients with non-metastatic esophageal adenocarcinoma.

TERTIARY OBJECTIVES:

I. To determine if the addition of trastuzumab to trimodality treatment improves the patient-reported Functional Assessment of Cancer Therapy for Esophageal Cancer (FACT-E) Esophageal Cancer Subscale (ECS) score.

II. To determine if an improvement in the FACT-E ECS score at 6-8 weeks post completion of neoadjuvant chemoradiation correlates with pathologic complete response.

III. To determine if pathologic complete response correlates with the FACT-E ECS score at 1 year and/or 2 years from the start of chemoradiation.

IV. To determine if the addition of trastuzumab to trimodality treatment improves the Swallow Index and Eating Index Subscale scores of the FACT-E.

V. To determine if the addition of trastuzumab to paclitaxel, carboplatin, and radiation impacts quality-adjusted survival.

OUTLINE: This is a multicenter study. Patients are stratified according to presence of adenopathy (yes vs no), and involved celiac nodes (absent vs presence ≤ 2 cm). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV over 60 minutes and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 and trastuzumab IV over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and 57. Beginning 21-56 days after surgery, patients receive trastuzumab IV over 30-90 minutes. Treatment repeats every 21 days for 13 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV over 60 minutes and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 36.

Within 5-8 weeks after completion of radiotherapy, all patients undergo surgery.

Patients may undergo blood and tumor tissue samples collection (during surgery) for correlative studies and tissue bank. Patients may complete the Functional Assessment of Cancer Therapy for Esophageal Cancer (FACT-E) and the EuroQol (EQ-5D) questionnaires at baseline and periodically during study.

After completion of study therapy, patients are followed up every 4 months for 2 years and then yearly thereafter.

• Adenocarcinoma of the Esophagus
• Adenocarcinoma of the Gastroesophageal Junction
• Stage IB Esophageal Cancer
• Stage IIA Esophageal Cancer
• Stage IIB Esophageal Cancer
• Stage IIIA Esophageal Cancer
• Stage IIIB Esophageal Cancer

• Radiation: radiation therapy
  Undergo radiation therapy
  Other Names:

  • irradiation
  • radiotherapy
  • therapy, radiation
• Drug: paclitaxel
  Given IV
  Other Names:

  • Anzatax
  • Asotax
  • TAX
  • Taxol
• Drug: carboplatin
  Given IV
  Other Names:

  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
• Biological: trastuzumab
  Given IV
  Other Names:

  • anti-c-erB-2
  • Herceptin
  • MOAB HER2
• Procedure: therapeutic conventional surgery
  Undergo surgery
• Other: laboratory biomarker analysis
  Correlative studies
• Procedure: quality-of-life assessment
  Ancillary studies
  Other Name: quality of life assessment

• Experimental: Arm I (radiotherapy, chemotherapy, trastuzumab, surgery)
  Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV over 60 minutes and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 and trastuzumab IV over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and 57. Within 5-8 weeks after completion of radiotherapy, all patients undergo surgery. Beginning 21-56 days after surgery, patients receive trastuzumab IV over 30-90 minutes. Treatment repeats every 21 days for 13 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Radiation: radiation therapy
  • Drug: paclitaxel
  • Drug: carboplatin
  • Biological: trastuzumab
  • Procedure: therapeutic conventional surgery
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment
• Experimental: Arm II (radiotherapy and chemotherapy)
  Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV over 60 minutes and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 36. Within 5-8 weeks after completion of radiotherapy, all patients undergo surgery.
  Interventions:

  • Radiation: radiation therapy
  • Drug: paclitaxel
  • Drug: carboplatin
  • Procedure: therapeutic conventional surgery
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment

Inclusion Criteria:

• Pathologically confirmed primary adenocarcinoma of the esophagus meeting the following criteria:

  • Involvement of mid (up to 25 cm), distal, or esophagogastric junction

    • Involvement of the stomach up to 5 cm allowed
    • Patients with tumors at the level of the carina or above must undergo bronchoscopy to exclude fistula

  • Stage T1, N1-2 or T2-3, N0-2 disease by chest, abdominal, or pelvic CT scan or whole-body PET/CT scan

    • No T1,N0 or T4 disease
    • No metastatic disease
  • Regional adenopathy including para-esophageal, gastric, gastrohepatic, and celiac (≤ 2 cm) nodes allowed
  • No cervical esophageal or proximal esophageal (15-24 cm) carcinoma
• Intent to submit tissue for central HER2 testing
• Must have undergone endoscopy with biopsy
• HER2-overexpressing adenocarcinoma of the esophagus
• Disease must be encompassed in 1 radiotherapy field
• Able to undergo curative resection within 56 days after completion of chemoradiation
• No evidence of tracheoesophageal fistula or invasion into the trachea or major bronchi
• Zubrod performance status 0-2
• ANC ≥ 1,500 cells/mm³
• Platelet count ≥100,000 cells/mm³
• Hemoglobin (Hb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hb ≥ 8.0 g/dL allowed)
• Creatinine ≤ 2 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• AST ≤ 3.0 times ULN
• LVEF normal
• Negative pregnancy test
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for ≥ 60 days after completion of chemotherapy or trastuzumab
• No prior invasive malignancy except non-melanomatous skin cancer or curatively treated carcinoma in situ of the breast, oral cavity, or cervix with no evidence of disease within the past 2 years
• No medical contraindications to esophagectomy
• No prior allergic reaction to the study drugs involved in this protocol or to a monoclonal antibody
• No history of congestive heart failure

• No severe or active comorbidity defined as any of the following:

  • Unstable angina within the past 6 months
  • Transmural myocardial infarction within the past 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics

  • AIDS or immunocompromised patients

    • HIV testing is not required

• No prior systemic chemotherapy for esophageal cancer

  • Prior chemotherapy for a different cancer allowed
• No prior radiotherapy for esophageal cancer or prior chest radiotherapy
• No prior anthracycline or taxane
• No prior therapy with any agent targeting the HER2 pathway or HER1 (EGFR) pathway
• No prior trastuzumab
• No concurrent intensity-modulated radiotherapy
• No other concurrent radiotherapy
• No other concurrent investigational agents
• No other concurrent cytotoxic agents