Phase III Study of Neo-adjuvant Chemoradiotherapy Followed by Surgery for Squamous Cell Esophageal Cancer

Study Overview
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Brief Summary
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The primary objective is to compare neo-adjuvant chemoradiotherapy followed by surgery versus surgery, in terms of the overall survival time (OS) in patients with Stage IIB or III squamous cell esophageal carcinoma.

Detailed Description
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Esophageal cancer (EC) is the eighth most common cancers in the world, with more than 480,000 new cases and 400,000 deaths occurred annually worldwide. In China, every year, no matter new cases or deaths account for more than half of the world. Besides, over 90% of Chinese patients have esophageal squamous cell carcinoma (ESCC). Surgery is the main treatment of this disease, but the prognosis of patients with locally advanced esophageal cancer is rather poor. As a result of surgery alone, the 5-year survival rate of about 25% has not changed significantly in several decades. Preoperative chemoradiotherapy followed by surgery seems to hopefully improve the survival of EC. Nevertheless, the results of different studies were inconsistent. Recently, the CROSS trial has demonstrated that preoperative chemoradiotherapy can significantly increased the overall survival of patients with EC compared with surgery alone. It should be noticed that only 84 cases(23%) of ESCC were enrolled in this trial with potential minimal follow-up of 2 years, which may be not perfect to evaluate the effect of this combined therapy for this tumor type. Up till now, vinorelbine has no indications for esophageal cancer, although, some studied have reported its effect and feasibility to the therapy of EC. Vinorelbine has similar mechanism with paclitaxel and docetaxel, which are recommended for the chemotherapy of EC by NCCN. They are all classified as antimicrotubule agents, which cause mitotic arrest and eventual cell death through inhibition of microtubule dynamics. In comparison with the taxanes, vinorelbine has obvious advantage of few cardiac toxicity. This should be beneficial to prevent cardiac side effects of chemoradiotherapy, especially for the middle or lower thoracic EC, which account for over 70% of thoracic EC in China. For this group of patients, radiotherapy can hardly avoid cardiac toxicity. Based on our preliminary study, we have demonstrated the validity and safety of vinorelbine and cisplatin-based neoadjuvant chemoradiotherapy. We are to carry out a phased III clinical trial to investigate the effect of this multidisciplinary therapy for the overall survival of patients with locally advanced ESCC.

Official Title
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A Phase III, Multicenter Randomized Controlled Study of Neo-adjuvant Chemoradiotherapy Followed by Surgery Versus Surgery for Locally Advanced Squamous Cell Esophageal Carcinoma

Conditions
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Squamous Cell Esophageal Carcinoma

Intervention / Treatment
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* Procedure: Neo-adjuvant Chemoradiotherapy followed by Surgery
* Procedure: surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of squamous cell thoracic esophageal carcinoma of Stage IIB or III, which is potentially resectable. Patients must not have received any prior anticancer therapy. More than 6 months of expected survival. Age ranges from 18 to 70 years. Absolute white blood cells count ≥4.0×109/L, neutrophil ≥1.5×109/L, platelets ≥100.0×109/L, hemoglobin ≥90g/L, and normal functions of liver and kidney. Karnofsky performance status (KPS) of 90 or more. Signed informed consent document on file. Exclusion Criteria: Patients are diagnosed or suspected to be allergic to cisplatin or vinorelbine. Patients with concomitant hemorrhagic disease. Pregnant or breast feeding. Inability to use gastric conduit after esophagectomy because of a prior surgery. Patients with concomitant peripheral neuropathy, whose CTC status is 2 or even more. Have a prior malignancy other than esophageal carcinoma, carcinoma in situ of the cervix, nonmelanoma skin cancer or cured early stage of prostate cancer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: experimental group<br>Neo-adjuvant Chemoradiotherapy followed by Surgery | Procedure: Neo-adjuvant Chemoradiotherapy followed by Surgery<br>* Radiotherapy combined with concomitant chemotherapy: Radiotherapy Program:External radiation with a total dose of 40.0Gy is given in 20 fractions of 2.0Gy,5 fractions a week. neo-chemotherapy program: Vinorelbine 25mg/m2, IV (in the vein) on day 1 and day 8 of each 21 day cycle. Cisplatin 75mg/m2,IV DRIP on day 1 of each 21 day cycle;or Cisplatin 25mg/m2,IV DRIP on day 1 to day 4 of each 21 day cycle. Number of cycles:two surgery:Mckeown Modification Surgery and total two-field lymphadenectomy<br>|
| Active Comparator: control group<br>only Surgery | Procedure: surgery<br>* two field lymphadenectomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate |  | 3 and 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| toxicities of neo-adjuvant chemoradiotherapy | Evaluate the toxicities of neo-adjuvant chemoradiotherapy,according to National Cancer Institute Common Terminology Criteria for Adverse Event,Version 3.0(CTC AE3.0). | 56 days | 
| assessment in perioperation | Removal rate， Time of operation， Quantity of bleeding， Thoracic Drainage， Days of Hospitalization， Rate of Operative Complication， Mortality of perioperation， | perioperative period | 
| efficacy of neo-adjuvant chemoradiotherapy | Criteria:Response Evaluation Criteria in Solid Tumors，RECIST | 4 weeks after completion of radiotherapy | 
| Disease free survival rate |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage IIB or III squamous cell esophageal carcinoma.