Traditional invasive vs. minimally invasive esophagectomy: a multi- centered, randomized trial (TIME-trial)

Background: There is a rise in incidence of esophageal carcinoma due to increasing incidence of adenocarcinoma. Probably the only curative option to date is the use of neoadjuvant therapy followed by surgical resection. Traditional open esophageal resection is associated with a high morbidity and mortality rate. Furthermore, this approach involves long intensive care unit stay, in-hospital stay and long recovery period. Minimally invasive esophagectomy could reduce the morbidity and accelerate the post-operative recovery. Methods/Design: Comparison between traditional open and minimally invasive esophagectomy in a multi-centered, randomized trial. Patients with a resectable intrathoracic esophageal carcinoma, including the gastro-esophageal junction tumors (Siewert I) are eligible for inclusion. Prior thoracic surgery and cervical esophageal carcinoma are indications for exclusion. The surgical technique involves a right thoracotomy with lung blockade and laparotomy either with a cervical or thoracic anastomosis for the traditional group. The minimally invasive procedure involves a right thoracoscopy in prone position with a single lumen tube and laparoscopy either with a cervical or thoracic anastomosis. All patients in both groups will undergo identical pre-operative and post-operative protocol. Primary endpoint of this study are post-operative respiratory complications within the first two post-operative weeks confirmed by clinical, radiological and sputum culture data. Secondary endpoints are the operative data, the post-operative data and oncological data such as quality of the specimen and survival. Operative data include duration of the operation, blood loss and conversion to open procedure. Post-operative data include morbidity (major and minor), quality of life tests and hospital stay. Based on current literature and the experience of all participating centers, an incidence of pulmonary complications for 57% in the traditional arm and 29% in the minimally invasive arm, it is estimated that per arm 48 patients are needed. This is based on a two-sided significance level (alpha) of 0.05 and a power of 0.80. Knowing that approximately 20% of the patients will be excluded, we will randomize 60 patients per arm. Discussion: The TIME-trial is a prospective, multi-centered, randomized study to define the role of minimally invasive esophageal resection in patients with resectable intrathoracic and junction esophageal cancer. Trial registration (Netherlands Trial Register): NTR TC 2452 BACKGROUND The incidence of esophageal cancer is increasing in the Western world. In the Netherlands, in the year 1990 some 807 patients were diagnosed with esophageal cancer, whereas in 2005, this number reached a staggering 1546 [1]. It is expected that this rise in incidence will continue in the years to come. This substantial increase in incidence can be accounted for by an increase in the number of adenocarcinomas diagnosed. Approximately one third of the patients are considered candidates for a curative approach. Surgical resection with radical lymphadenectomy, usually after neoadjuvant chemotherapy or chemo-radiotherapy, remains the only curative option for resectable esophageal cancer. Surgery is considered when the tumor is staged as cT1-3 N0-1 M0. Despite the curative intent, some 30% of all resections have microscopically residual disease (R1). Most patients present with stage III esophageal cancer, which has a 5-year survival of approximately 20-25 % [2]. In addition, the possible value of neoadjuvant chemoradiotherapy or chemotherapy is currently being investigated. However, a meta-analysis by Gebski et al. has shown that surgery following chemoradiotherapy for both squamous cell carcinoma and adenocarcinoma has a survival benefit of 13% after 2 years. For neoadjuvant chemotherapy this survival benefit was 7% after 2 years for adenocarcinomas [3]. The three main surgical approaches utilized worldwide for intrathoracic esophageal cancer are the following: (1) the three stage transthoracic resection (i.e. right postero-lateral thoracotomy, laparotomy and cervicotomy) with a cervical anastomosis; (2) the two stage transthoracic resection (i.e. laparotomy, and right postero-lateral thoracotomy, including the Ivor Lewis approach with an intrathoracic anastomosis); and (3) the two stage transhiatal resection (i.e. laparotomy and cervicotomy with cervical anastomosis) [4]. Transhiatal esophagectomy according to Orringer is generally performed for gastro-esophageal junction cancers [5]. Nevertheless, cancer of the lower esophagus metastasized, according to the Tumor-Node-Metastasis classification, in more than 45% to the lymph nodes in mediastinum and carina. Therefore patients with reasonable general condition are increasingly surgically approached transthoracically. In the randomized study by Hulscher et al. and long term follow-up, comparing the transhiatal and transthoracic esophageal resection, an important trend of better survival has been observed in the transthoracically approached patients [6, 7]. This transthoracic procedure is associated with a high morbidity and mortality rate of approximately 50-70% and 5% respectively [6]. Moreover, the extensive nature of this open approach has a significant negative impact on the quality of life of these patients and is associated with a long in-hospital recovery. Minimally invasive esophageal (MIE) resection for cancer avoiding the thoracotomy and laparotomy can reduce the amount of trauma of the required surgery with the same oncological value. This will imply a reduction of the post-operative morbidity, a shortening of the recovery time and an increase of quality of life. Evidence of the short term benefits of minimally invasive surgery over open procedures with similar oncological outcome is accumulating. Less perioperative complications, shorter hospital stay and faster post-operative recovery appear to be the main advantages. MIE involves a right thoracoscopy and laparoscopy, either with a cervical or intrathoracic anastomosis. The thoracic phase of this procedure can be performed through a lateral right thoracic approach with a right lung block by selective intubation or in prone position without selective lung block. This prone approach, with partial lung collapse, will result in lower percentage of pulmonary complications [8,9]. To date, no randomized trials have been performed comparing any modality of minimally invasive esophagectomy with an open traditional approach [10]. Given the values of postoperative morbidity, quality of life and quality of the specimen, the aim of this prospective randomized study is to compare the MIE by right thoracoscopy in prone position and laparoscopy with the open esophageal resection by right thoracotomy and laparotomy in left lateral decubitus, for those patients possessing intrathoracic resectable esophageal cancer. This comparison will provide further evidence supporting the minimally invasive and costeffective approach for esophageal cancer.