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Patients with ≤50% viable tumor cells remaining in the surgical specimen will receive postoperative chemo-radiotherapy with the mFOLFOX6 regimen

Patients with \>50% viable tumor cells remaining in the surgical specimen, will receive postoperative chemo-radiotherapy with weekly carboplatin and paclitaxel.

oxaliplatin

leucovorin calcium

fluorouracil

therapeutic conventional surgery

radiation therapy

carboplatin

paclitaxel

Michael McNamara, MD

This phase II trial studies how well oxaliplatin, leucovorin calcium, and fluorouracil followed by surgery and response based concurrent chemotherapy and radiation therapy works in treating patients with cancer of the esophagus, gastroesophageal junction, or gastric cardia. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, 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. Radiation therapy uses high energy x rays to kill tumor cells. Giving chemotherapy followed by surgery and response based chemotherapy and radiation therapy may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To assess the ability of response adapted adjuvant chemoradiotherapy to improve the 1 year recurrence free survival (RFS) compared to historical data in patients with \> 50% remaining viable tumor after induction chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the rates of symptomatic, endoscopic, and pathologic response to induction chemotherapy.

II. To determine the rate of R0 resection after induction chemotherapy. III. To establish the toxicity profile of this tri-modality regimen. IV. To assess the recurrence free survival (RFS) and overall survival (OS) of this trimodality therapy regimen for the entire cohort and in patients who do and do not achieve a pathologic response.

V. To assess patterns of failure and assess the rates of distant metastatic control (DMC) and locoregional control (LRC) of this tri-modality therapy regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the pattern of Ki-67 expression in patients with LRA esophageal cancer before and after induction chemotherapy.

II. To explore the relationship of Ki-67 expression to clinical and pathologic response parameters as well as survival outcomes.

III. To evaluate the relationship between human epidermal growth factor receptor 2 (HER2) overexpression (based on immunohistochemistry) and gene amplification (based on fluorescence in situ hybridization) with clinical and pathologic response parameters and survival outcomes.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 44 hours on days 1-3. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Approximately 4-5 weeks after completion of induction chemotherapy, patients undergo a surgical procedure. The choice of surgical procedure is at the discretion of the operating physician.

ADJUVANT THERAPY: Within 6-12 weeks after surgery, patients undergo radiation therapy for 28 days. Patients with a positive pathological response also receive oxaliplatin, leucovorin calcium, and fluorouracil as in the induction chemotherapy, beginning days 1, 15, and 29 concurrent with radiation therapy. Patients with a negative pathological response receive paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36 in the absence of disease progression or unacceptable toxicity. Patients with locoregional disease only after induction therapy but do not undergo surgery may receive chemoradiotherapy with carboplatin and paclitaxel as determined by the primary oncologist.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 4-5 months for 3 years, and then annually thereafter.

FOLFOX-6 Induction Chemotherapy Followed by Esophagectomy and Post-operative Chemoradiotherapy in Patients With Esophageal Adenocarcinoma

A Phase II Trial of Modified FOLFOX-6 Induction Chemotherapy Followed by Esophagectomy and Post-operative Response Based Concurrent Chemoradiotherapy in Patients With Locoregionally Advanced Adenocarcinoma of the Esophagus, Gastro-esophageal Junction, and Gastric Cardia

Change in the amount of CTCs before and after induction chemotherapy will be assessed using either the paired t-test or Wilcoxon signed rank test.

Change in Ki-67 expression before and after induction chemotherapy will be assessed using either the paired t-test or Wilcoxon signed rank test.

HER2 overexpression will be described as frequency counts and percentages.

The prognostic effect of CTCs, KI-67, and HER2 overexpression on pathologic response will be assessed with logistic regression analysis, and the prognostic effect on OS and RFS with Cox proportional hazards analysis.

Compare the number of study patients who achieved RFS with \>50% remaining viable tumor after response adapted adjuvant chemoradiotherapy to historical data among patients with \>50% viable tumor after induction chemotherapy. A once sided test (p\<=0.05) will be used to describe significance of change.

Symptomatic response is defined as improvement in dysphagia by 1 grade from baseline. Level 1 - No dysphagia. Level 2 - Minimal dysphagia, able to swallow liquids and most solid foods, experiencing occasional difficulty. Level 3 - Moderate dysphagia, able to swallow liquids and very soft foods. Level 4 - Severe dysphagia, unable to swallow liquids or solids. Significance of change will be calculated using 95% confidence intervals.

Complete response = no residual abnormality (cyT0N0-Stage 0). Partial response = any improvement in the clinically determined T or N stage (without reciprocal deterioration in T or N) when compared to the pretreatment clinical stage as assessed by EGD/EUS. Stable disease = no change in the clinical T or N stage when compared to the pretreatment assessment. Progressive disease = any increase in the T or N stage (irrespective of any reciprocal improvement in the T or N stage) when compared to the pretreatment clinical stage as assessed by EGD/EUS. Endoscopic response will be estimated using exact 95% confidence intervals.

A positive pathologic response (+PR) will be defined as ≤ 50% residual tumor cells remaining. A negative pathologic response (-PR) will be defined as \>50% residual tumor cells remaining. Pathologic response will be described using exact 95% confidence intervals.

R0 resection is defined as the resection of all gross and microscopic tumor. R0 resections will be estimated using exact 95% confidence intervals.

Toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The number of toxicities will be estimated using exact 95% confidence intervals.

RFS will be compared between patients with ≤ 50% and \> 50% viable tumor using the log-rank test. Outcomes will be calculated relative to the start of therapy. Log rank tests will be used to estimate the hazard ratio for RFS for patients with \> 50% viable tumor relative to those with ≤ 50%. If there are a sufficient number of events, multivariable Cox analysis will be done to adjust for other prognostic factors.

OS will be compared between patients with ≤ 50% and \> 50% viable tumor using the log-rank test. Outcomes will be calculated relative to the start of therapy. Log rank tests will be used to estimate the hazard ratio for OS for patients with \> 50% viable tumor relative to those with ≤ 50%. If there are a sufficient number of events, multivariable Cox analysis will be done to adjust for other prognostic factors.

Kaplan Meier analysis will be used to estimate distant recurrence

Kaplan-Meier analysis will be used to estimate local recurrence

Spots Global Cancer Trial Database for adenocarcinoma of the gastric cardia