Esophageal resection in Austria—preparing a national registry

Esophageal resection is a technically challenging procedure. Despite improvements in perioperative management and outcome, it is still associated with considerably high morbidity and mortality rates even if performed in high-volume centers. This study aimed to shed light on the results of routine patient care in three representative referral centers concerning caseload and surgical and oncological outcomes. This study is a retrospective, multicenter, national-wide analysis of a newly established database including perioperative and long-term outcome data from three referral centers in Austria. In a 6-year study period (2013–2018), 411 patients were eligible for analysis. The indication for esophageal resection was esophageal adenocarcinoma in 299 (72.7%) patients and esophageal squamous cell carcinoma in 90 (21.9%) patients. The abdominothoracic approach (70.1%) was the most common operation, followed by transhiatal extended gastrectomy (14.8%) and a thoracic-abdominal-cervical approach (8.5%). Most patients (77.9%) underwent neoadjuvant therapy (chemotherapy 45.3%, radiochemotherapy in 32.6%). A minimally invasive approach was chosen in 25.3%. Major complications and mortality were seen in 21.7% and 2.9%, respectively. The 1‑year survival rate was 84%, 3‑year survival 60%, and 5‑year survival was 52%. The pooled overall median survival was 110 months (95% CI 33.97–186.03). This first publication of the Austrian Society of Esophageal Surgery shows that the outcome of esophageal surgery for cancer in Austria compares well with that of renowned international centers. However, a more comprehensive approach including as many national centers as possible will improve outcome research, offer quality management, and improve patient safety. The study group invites all Austrian institutions performing esophagectomy to participate in the initiative.


Results
In a 6-year study period (2013-2018), 411 patients were eligible for analysis. The indication for esophageal resection was esophageal adenocarcinoma in 299 (72.7%) patients and esophageal squamous cell carcinoma in 90 (21.9%) patients. The abdominothoracic approach (70.1%) was the most common operation, followed by transhiatal extended gastrectomy (14.8%) and a thoracic-abdominal-cervical approach (8.5%). Most patients (77.9%) underwent neoadjuvant therapy (chemotherapy 45.3%, radiochemotherapy in 32.6%). A minimally invasive approach was chosen in 25.3%. Major complications and mortality were seen in 21.7% and 2.9%, respectively. The 1-year survival rate was 84%, 3-year survival 60%, and 5-year survival was 52%. The pooled overall median survival was 110 months (95% CI 33.97-186.03). Conclusion This first publication of the Austrian Society of Esophageal Surgery shows that the outcome of esophageal surgery for cancer in Austria compares well with that of renowned international centers. However, a more comprehensive approach including as many national centers as possible will improve outcome research, offer quality management, and improve patient safety. The study group invites all Austrian institutions performing esophagectomy to participate in the initiative.

Introduction
Surgery is still the mainstay for curative treatment of esophageal cancers [1]. Notably, for locally advanced stages, multimodal therapy has gained significant importance [2,3]. Although perioperative therapy does not impair morbidity after surgery, esophageal resection is still associated with high morbidity and mortality rates [4][5][6].
To improve morbidity and oncological outcome, esophageal surgery was suggested to be preferably performed in high-volume centers [7]. Implementation of such caseload requirements reduced the number of hospitals performing esophageal resections, expecting to improve outcomes [8]. In 2013 a caseload threshold of at least five esophagectomies per year was introduced in Austria, and elevated to a minimum of 10 procedures 1 year later on. Currently, there are ten Austrian centers performing esophagectomies regularly.
A minimally invasive approach in esophageal surgery was introduced to reduce the incisional trauma, improve the postoperative pulmonal condition, and allow faster recovery and possibly better quality of life at an equal oncological outcome [9][10][11]. Multiple trials demonstrated that minimally invasive esophagectomy (MIE) showed comparable oncological results with reduced postoperative morbidity and improved functional recovery [10,12,13]. Despite the beneficial aspects of MIE, many cases are required to overcome the learning curve [14].
This study aimed to assess the treatment numbers and the surgical and oncological outcome in three high-volume referral centers representative for esophageal cancer surgery in Austria. Moreover, implementation of MIE and centralization of surgery is assessed and compared with current evidence.

Registry
This study is a retrospective, multicenter, national analysis of a newly established database including patient data of three high-volume referral centers in Austria. The data were prospectively collected in each center and entered into the registry after pseudonymization. All consecutive patients who received esophageal surgery in the 6 years between 2013 to 2018 were included. One center started in 2014 and did not include transhiatal extended gastrectomies. The indication for surgery was either an esophageal malignancy (adenocarcinoma [AC], esophageal squamous cell carcinoma [ESCC], gastrointestinal stromal tumor [GIST], sarcoma, neuroendocrine carcinoma) or a benign indication such as leiomyoma or complex GERD. The tumor location of adenocarcinomas was classified following the Siewert classification of adenocarcinoma of the esophagogastric junction (AEG) [15]. All other tumors were classified into suprabifurcal, infrabifurcal, and cervical locations.

Surgery
An esophageal surgery was defined as either abdominothoracic resection (Ivor-Lewis procedure), thoracic-abdominal-cervical approach (McKeown procedure), transhiatal esophagectomy (Orringer procedure), jejunal interposition operation (Merendino procedure), transhiatal extended gastrectomy for AEG II tumors, or anastomotic resection with esophagojejunostomy. Hybrid minimally invasive esophagectomy (MIE) was defined as a laparoscopic formation of the gastric tube combined with an open thoracic approach. Total MIE was defined as laparoscopic gastric tube formation and thoracoscopy for the thoracic phase. Morbidity was classified according to the Clavien-Dindo (C/D) classification [16]. According to recent publications a Clavien-Dindo grade IIIb or higher was classified as a major complication [11]. For more details, see Table 2.
Patients were followed up on a 3-monthly basis for the first 2 years and then every 6 months until year 5 after surgery, followed by yearly visits. In order to optimize data accuracy and reduce the number of patients lost to follow-up, patients were contacted to evaluate the current status if the information was missing. Overall survival (OS) and recurrence-free interval (RFI) were defined as the period from the operation until death or recurrence of disease, respectively. For analysis of OS and RFI, only malignant indications were used.
The study was approved by the ethics committee (EK 1310/2018) of the Medical University of Vienna. Individual informed consent was not acquired due to the study design and national regulations.

Statistics
Age is described as mean and standard deviation (SD). Other continuous variables are described as medians and quartiles due to non-normal distributions. Interquartile range (IQR) was stated when applicable. Body mass index (BMI) was calculated by dividing weight in kilograms by height in meters squared. Categorical variables are described as counts and percentages. Overall survival and the recurrencefree interval were estimated using the Kaplan-Meier method. For comparison, the log-rank test was used.
Regarding non-TNM categories, there were significant differences in long-term survival: median overall survival and recurrence-free interval decreased significantly if a vascular, lymphatic, or perineural invasion was present (Fig. 7). For more tumor-related details, see Table 3. 208 Esophageal resection in three high-volume centers Austria-preparing a national registry K original article Fig. 1 Kaplan-Meier analysis of overall survival according to tumor histology. A p-value < 0.05 is considered statistically significant. n.s. non significant

Discussion
First and foremost, this study is the largest to demonstrate multicenter results of esophageal surgery in Austria. We show that the current treatment and surgical approach, morbidity, and oncological results are tantamount to international registries.
Ivor-Lewis esophagectomy (n = 70.1%) was the most commonly performed operation, in line with the recent development towards the abdominal-thoracic approach. There is still an ongoing debate about the best surgical approach to resect and reconstruct the esophagus [17]. A randomized trial showed favorable survival results after a transthoracic approach in patients with lymph node involvement compared to the Orringer procedure [18]. After growing evidence that an intrathoracic anastomotic leakage was no longer associated with increased mortality, the transtho-racic Ivor-Lewis approach was increasingly suggested for carcinoma localized in the distal esophagus [19]. However, transhiatal esophagectomy seemed to lead to less pulmonary morbidity and this without survival disadvantages [20]. New evidence, again, favors the transthoracic approach in a large retrospective cohort [21].
Addressing the highly relevant benchmarks of morbidity and mortality, the major complication rate (C/D > IIIa) in this study was 21.7%. This rate lies within published rates, which range from around 10% to up 34.9% [11,22]. In general, the definition of morbidity (major/minor) and the use of the classification is very inhomogeneous throughout the literature [23]. This also applies to reporting and classification of anastomotic leakage (AL). The participating centers did not use the Esophageal Complications Consensus Group definition for AL in this study [24]. However, K Esophageal resection in three high-volume centers Austria-preparing a national registry 209 original article the reported AL rate of 14.1% lies within the published rates from 5-25% for cervical anastomosis and 5-16% for thoracic anastomosis [23]. Still, the low rates published by Luketich et al. of 8.6% should be strived for [25]. Historically, esophageal resection was associated with a high mortality rate. Improvement of surgical technique as well as perioperative management could reduce mortality. However, the low rate of 2.9% is again comparable with other national data [26].
Centralization of esophageal surgery improves outcome [26,27]. In many European countries like Sweden, the Netherlands, or Switzerland, centralization has already taken place [8,26]. There is still an ongoing debate about caseload requirements in Austria, which led to different regional regulations. Nevertheless, current level 2a evidence showing the impact of centralization of cancer surgery on postoperative mortality supports this development towards caseload requirements [28].
In this study, around 25% of the esophagectomies were done with a minimally invasive approach. As there is growing evidence about the clear benefit of MIE, it is to expect that this number will rise. Still, it is crucial to implement new surgical techniques in a well-structured manner, without jeopardizing patient safety. Experts advise having adequate support, proctoring, and the appropriate infrastructure to over-210 Esophageal resection in three high-volume centers Austria-preparing a national registry K original article Fig. 5 Kaplan-Meier analysis of overall survival regarding lymph node yield > median number of 25. A p-value < 0.05 is considered statistically significant. n.s. non significant, LN lymph node Fig. 6 Kaplan-Meier analysis of recurrence-free interval regarding lymph node yield > median number of 25. A p-value < 0.05 is considered statistically significant. n.s. non significant, LN lymph node come a particular learning curve [14]. A recent multicenter study identified a substantial learning curve of 119 cases regarding anastomotic leakage in MIE [29].
The strength of this study is the multicenter approach and high treatment numbers. Furthermore, this work includes registry data exceeding the classical TNM categories. Such expanded oncological information like vascular, lymphatic, and perineural invasion and number of lymph nodes involved was also suggested for registries [30]. This will potentially refine prognostication and may direct future adjuvant therapy [30].
There are several limitations to address. First of all, this work is of a retrospective nature. The data extraction was performed locally in the particular centers and, therefore, challenging to standardize. Moreover, there are different approaches to classifying "soft" categories such as morbidity. To minimize this limitation, the centers used the Clavien-Dindo classification to categorize morbidity. A possible comprehensive registry should prospectively establish consensual reporting standards like those offered by the Esophageal Complications Consensus Group to overcome these limitations.

Conclusion
This first publication of this multicenter study group shows the current status of esophageal surgery in three high-volume centers in Austria. The outcome of esophageal surgery in this study is comparable with international benchmarks. However, a more comprehensive approach including as many national centers as possible will improve outcome research, offer quality management, and improve patient safety. Therefore, the study group aims to include all possible centers for esophageal surgery. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.