Study of Docetaxel or Vinorelbine Plus Cisplatin in Neoadjuvant Chemoradiotherapy for Esophageal Cancer

Study Overview
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Brief Summary
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The primary objective is to compare docetaxel plus cisplatin (DP) versus vinorelbine plus cisplatin (NP) in neoadjuvant chemoradiotherapy, in terms of the overall survival and toxicity 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 456,000 new cases and 400,000 deaths occurred annually worldwide. Every year in China, 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). Preoperative chemoradiotherapy (CRT) followed by surgery can hopefully improve the survival of ESCC. The CROSS trial has demonstrated that preoperative chemoradiotherapy can significantly increase the overall survival of patients with EC compared with surgery alone. The therapeutic effects were also found in 84 ESCC cases enrolled in this trial. Previously, the investigators performed a phase III, randomized clinical trial (NCT01216527) to compare the overall survival of stage IIB-III ESCC patients treated with or without neoadjuvant CRT, in which vinorelbine plus cisplatin was used as chemotherapy regime. The enrollment was completed in 2014. The outcomes will hopefully prove the survival benefit of neoadjuvant CRT to ESCC. However, the investigators also observed that some patients suffer from the toxic response of neoadjuvant therapy, such as myelosuppression (45.2%), pulmonary toxicity (42.9%), and esophagitis (59.5%). The toxicity caused by CRT will decrease the patient compliance; moreover increase the perioperative complications and deaths, which may totally offset the survival benefit. Therefore, it is important to improve chemoradiotherapy effect and reduce toxicity, so as to achieve better survival in ESCC patients. Docetaxel draws increasing attentions with its high effective rate and low toxicity. Several Phase II clinical trials and retrospective studies suggested that docetaxel showed better survival benefits in both monotherapy and combined-therapy in EC patients. Therefore, the investigators intended to conduct a phase III, randomized clinical trial to further explore whether docetaxel plus cisplatin would be an effective therapy with lower toxicity. The investigators are to carry out a phased III clinical trial to compare the effect and toxicity of docetaxel plus cisplatin with vinorelbine plus cisplatin in neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma.

Official Title
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A Phase III Clinical Trial of Docetaxel Plus Cisplatin Versus Vinorelbine Plus Cisplatin in Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma

Conditions
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Esophageal Squamous Cell Carcinoma, Esophageal Cancer, Oesophageal Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Cisplatin
* Radiation: Radiation
* Procedure: Surgery
* Drug: Vinorelbine
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of squamous cell thoracic esophageal carcinoma of Stage T1-4aN1-3M0 or T4aN0M0, according to 7th edition of Union for International Cancer Control (UICC) staging system. 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. WHO performance status (PS) of 0-1 Signed informed consent document on file Exclusion Criteria: Patients have received any prior anticancer therapy Patients with advanced inoperable or metastatic esophageal carcinoma Patients with concomitant hemorrhagic disease Patients with other uncontrollable status that cannot tolerate surgery Pregnant or breast feeding Patients cannot signed the informed consent document because of psychological quality, family and social factors 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 Have a history of diabetes over 10 years and with poorly controlled blood sugar level patients with serious cardiac, respiratory, hepatic, renal, hematologic, immunological disease or cachexy, who cannot tolerate chemoradiotherapy or surgery

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A (DP-RT)<br>• Arm A consists of the concurrent chemoradiotherapy prior to surgery. The patient will receive 4 weeks of radiation therapy and 4 weekly cycles of chemotherapy. The radiation will generally commence on the 1st day of treatment and will run for 4 weeks. Chemotherapy is given by intravenous infusion on days 1, 8, 15, and 22. Interventions: Radiation: (44 Gy/20 fractions) Drug: Docetaxel Drug: Cisplatin | Drug: Docetaxel<br>* 25mg/ m2 Docetaxel dose administered on days 1, 8, 15, and 22.<br>* Other names: Docetaxel in Arm A;Drug: Cisplatin<br>* 25mg/ m2 on days 1, 8, 15 and 22.<br>* Other names: Cisplatin in Arm A;Radiation: Radiation<br>* Patient will receive 4 weeks of radiation therapy (44 Gy/20 fractions).<br>* Other names: IMRT;Procedure: Surgery<br>* McKeown esophagectomy, Ivor Lewis esophagectomy or minimally invasive esophagectomy will be performed 4-8 weeks after chemoradiotherapy. Two-field lymphadenectomy with total mediastinal lymph node dissection is performed during surgery.<br>* Other names: Esophagectomy;|
| Experimental: B (NP-RT)<br>• Arm B consists of the concurrent chemoradiotherapy followed by surgery. The patient will receive 4 weeks of radiation therapy and 2 cycles of chemotherapy. The radiation will generally commence on the 1st day of treatment and will run for 4 weeks. Each cycle of chemotherapy lasts 21 days/3 weeks. The drugs include Vinorelbine and Cisplatin. Interventions: Radiation: (44 Gy/20 fractions) Drug: Vinorelbine Drug: Cisplatin | Radiation: Radiation<br>* Patient will receive 4 weeks of radiation therapy (44 Gy/20 fractions).<br>* Other names: IMRT;Procedure: Surgery<br>* McKeown esophagectomy, Ivor Lewis esophagectomy or minimally invasive esophagectomy will be performed 4-8 weeks after chemoradiotherapy. Two-field lymphadenectomy with total mediastinal lymph node dissection is performed during surgery.<br>* Other names: Esophagectomy;Drug: Vinorelbine<br>* 25mg/ m2 on days 1, 8 of each cycle (i.e. every 21 days).<br>* Other names: Vinorelbine in Arm B;Drug: Cisplatin<br>* 75mg/ m2 on day 1 of each cycle only (i.e. every 21 days).<br>* Other names: Cisplatin in Arm B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival will be calculated from the date of randomisation and an event registered on the date of death from any cause. Patients lost to follow up, or those with no death recorded on the day the database is frozen, will be censored on the date of last follow up. | At end of trial- up to 3 years in follow up | 
| Toxicities of neo-adjuvant chemoradiotherapy | All symptoms of toxicity will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) Version. 3.0. | Within the first 56 days after the start of chemoradiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival |  | At end of trial- up to 3 years in follow up | 
| Clinical response rate |  | 4-6 weeks after completion of chemoradiotherapy | 
| R0 resection rate |  | One week after the operation | 
| Number of Participants who withdraw the treatment |  | Within the first 84 days after the start of chemoradiotherapy | 
| Perioperative complication |  | Within the first 90 days after the start of surgery | 
| Pathological complete response rate |  | One week after the operation | 
| Health Related Quality of Life |  | Within the first 84 days after the start of chemoradiotherapy |