Optimization of treatment strategies and prognostication for patients with esophageal cancer Anderegg, M.C.J.

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1 UvA-DARE (Digital Academic Repository) Optimization of treatment strategies and prognostication for patients with esophageal cancer Anderegg, M.C.J. Link to publication Citation for published version (APA): Anderegg, M. C. J. (2018). Optimization of treatment strategies and prognostication for patients with esophageal cancer General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 30 Jun 2018

2 CHAPTER 7 Minimally invasive surgery for esophageal cancer MCJ Anderegg, SS Gisbertz, MI van Berge Henegouwen Best Practice & Research Clinical Gastroenterology 2014 Feb;28(1):41-52

3 Chapter 7 ABSTRACT Worldwide an increasing part of oncologic esophagectomies is performed in a minimally invasive way. Over the past decades multiple reports have addressed the perioperative outcomes and oncologic safety of minimally invasive esophageal surgery. Although many of these (retrospective) case-control studies identified minimally invasive esophagectomy as a safe alternative to open techniques, the clear benefit remained subject to debate. Recently, this controversy has partially resolved due to the results of the first randomized controlled trial that compared both techniques. In this trial shortterm benefits of minimally invasive esophagectomy were demonstrated in terms of lower incidence of pulmonary infections, shorter hospital stay and better postoperative quality of life. However, the current lack of long-term data on recurrence rate and overall survival precludes a comprehensive comparison of minimally invasive and open esophagectomy. Proclaiming minimally invasive esophagectomy as the standard of care for patients with resectable esophageal cancer would therefore be a premature decision. 136

4 Minimally invasive surgery for esophageal cancer INTRODUCTION Due to a steadily increasing incidence, esophageal cancer is by now the eighth most common malignancy in the world amounting to nearly half a million new patients annually [1]. Since the majority has advanced, inoperable or metastatic disease at the time of diagnosis, less than 50% of patients are eligible for curative treatment [2, 3]. Esophagectomy is the mainstay of this curative treatment, but the procedure is associated with a considerable risk of (severe) complications and the highest mortality rate among all elective gastrointestinal surgical interventions [4]. In an attempt to reduce complicationand mortality rates progress has been made in patient selection, perioperative care and surgical techniques. Among the technical advances minimally invasive esophagectomy represents the most important one in terms of utilization and scientific foundation. Minimally invasive esophagectomy was introduced in 1992, when the first report on thoracoscopic esophagectomy was published by Cuschieri et al [5]. From that moment, new developments in the field of esophageal surgery rapidly succeeded each other. A laparoscopic transhiatal approach was introduced in 1994 by Sadanga et al. [6] and in 1999 Kawahara et al. demonstrated the feasibility of combining an esophageal resection with an extended lymphadenectomy in a video-assisted thoracoscopic surgical (VATS) setting [7]. By now, multiple minimally invasive ways to perform an esophageal resection have been developed for both the transthoracic and the transhiatal approach. The extent to which they are used has increased dramatically, as was clearly shown by a nationwide study from England in This review of 18,673 esophagectomies performed over 12 years revealed that the use of minimally invasive techniques had risen from 0.6% in 1996 to 24.7% in 2009 [8]. In the Netherlands, the national upper gastrointestinal cancer registry has shown that in % (37% in 2011) of the oncologic esophageal resections was performed in a minimally invasive way [9]. Along with this rise in utilization came a steady increase in scientific output on this topic resulting in the embracement of minimally invasive techniques in national guidelines on esophageal cancer [10, 11]. 7 Despite the growing interest in minimally invasive esophagectomy, concern about clinical safety and oncologic efficacy are still under discussion. In this review we address this concern by providing an overview of the literature on minimally invasive surgery for esophageal cancer with respect to commonly used techniques, patient selection and (post)operative outcomes. 137

5 Chapter 7 TECHNIQUES Traditionally, a distinction in open techniques is drawn between the transhiatal esophagectomy and the two main transthoracic esophagectomies: the 2-incisional Ivor- Lewis approach and the 3-incisional McKeown approach [3, 12]. Choice of technique depends on tumor location, extent of lymphadenectomy and surgeon s preference. Despite the theoretical advantage of transthoracic resection regarding extended (mediastinal) lymphadenectomy and a wider circumferential resection margin, consensus on the ideal approach has not been reached yet. In the largest randomized trial on this issue Hulscher et al. assigned 220 patients with an adenocarcinoma of the mid/distal esophagus or gastric cardia (involving the gastroesophageal junction) to open transhiatal esophagectomy or open transthoracic esophagectomy with extended en-bloc lymph node dissection [13, 14]. Transhiatal resection was associated with a shorter operative time, lower median blood loss, fewer pulmonary complications, decreased chylous leaks, shorter duration of mechanical ventilation and shorter stay in the intensive care unit and hospital. No significant difference in in-hospital mortality was observed [13]. In a followup study of this trial including the complete 5-year survival data no significant survival benefit of the transthoracic resection was observed. However, in subgroup analyses based on tumor location and number of positive lymph nodes a 5-year survival benefit of 14% (51% vs. 37%, P = 0.33) and 41% (23% vs. 64%, P = 0.02) was seen with the transthoracic approach for patients with mid/distal esophageal malignancies and patients with 1 to 8 positive lymph nodes in the resection specimen, respectively [14]. Based on these results we currently consider transthoracic resection as the standard surgical treatment for all esophageal tumors with the exception of gastroesophageal junction tumors without intrathoracic lymphadenopathy or patients that are unfit to undergo a transthoracic dissection. As shown in table 1, minimally invasive alternatives exist for the three open techniques. In this section we will discuss these minimally invasive techniques after a brief recapitulation of the traditional open procedure. 138

6 Minimally invasive surgery for esophageal cancer Table 1: Overview of surgical techniques in the treatment of esophageal cancer Technique Indication Thoracic part Abdominal part Location of anastomosis n/a Open Cervical Open transhiatal - Gastroesophageal junction tumors without intrathoracic lymphadenopathy Open Open Intrathoracic - Distal esophageal tumors - Gastroesophageal junction tumors with intrathoracic lymphadenopathy Open transthoracic (Ivor-Lewis) Open Open Cervical - Esophageal tumors - Gastroesophageal junction tumors with intrathoracic lymphadenopathy Open transthoracic (McKeown) n/a Laparoscopic Cervical Minimally invasive transhiatal - Gastroesophageal junction tumors without intrathoracic lymphadenopathy Thoracoscopic Laparoscopic Intrathoracic - Distal esophageal tumors - Gastroesophageal junction tumors with intrathoracic lymphadenopathy Minimally invasive transthoracic (Ivor-Lewis) Thoracoscopic Laparoscopic Cervical - Esophageal tumors - Gastroesophageal junction tumors with intrathoracic lymphadenopathy Minimally invasive transthoracic (McKeown) 7 139

7 Chapter 7 Transhiatal esophagectomy Classic transhiatal esophagectomy involves an upper midline laparotomy to mobilize the stomach and to dissect paracardial, lesser-curvature, left-gastric-artery, celiac trunc, common-hepatic-artery and splenic artery lymph nodes. Subsequently, the thoracic esophagus and the distal paraesophageal lymph nodes are bluntly dissected through the diaphragmatic hiatus. Further mobilization of the esophagus is performed through a left neck incision after which a cervical anastomosis is created with a gastric pull-up approach. During the minimally invasive variant of this procedure the patient is operated in supine position with a 5-port laparoscopy set-up. Through the diaphragmatic hiatus dissection of the esophagus and paraesophageal lymph nodes is performed up to the level of the inferior pulmonary vein. After mobilization of the stomach and the described lymphadenectomy a left cervical incision is made to dissect the proximal esophagus. As soon as the cervical esophagus is divided the resection specimen is stripped en retrieved via a 5-6 cm accessory supra-umbilical incision. The next step is extracorporeal generation of the gastric conduit, which is brought up prevertebrally to the cervical region where a hand-sewn or stapled anastomosis is created. Ivor-Lewis transthoracic esophagectomy During the traditional Ivor-Lewis esophagectomy a midline laparotomy is combined with a right posterolateral thoracotomy in the lateral decubitus position. This approach permits direct visualization of the thoracic esophagus and allows the surgeon to perform a full thoracic lymphadenectomy. Since an intrathoracic anastomosis is created, this technique is only indicated for distal tumors because of the limited proximal margin that can be achieved in case of tumors of the mid-esophagus. Comparable to the described transhiatal technique the minimally invasive Ivor-Lewis esophagectomy starts with 5-port laparoscopy in supine position. After gastric mobilization and identical abdominal lymphadenectomy, the gastric conduit is created by use of an endoscopic linear stapler (Figure 1 a-c). As soon as the phrenoesophageal ligament is divided, the abdominal part of the procedure is completed and the patient is repositioned in either the left lateral decubitus position or the prone position (see below). The procedure is continued with 4 port thoracoscopy. The first thoracic step is the division of the pulmonary ligament followed by circumferential mobilization of the esophagus, division of the azygos vein and dissection of paraesophageal, lower and middle mediastinal, subcarinal and rightsided paratracheal lymph nodes (Figure 1 e-f). When the gastric conduit has been brought 140

8 Minimally invasive surgery for esophageal cancer into the thorax, the esophagus is divided just superior to the level of the carina and an intrathoracic anastomosis can be generated. In order to do so transoral and transthoracic staplers have been developed. Based on a recent review comparing these two methods in terms of anastomotic leakage- and anastomotic stenosis rates both techniques can be considered equally safe and effective [15]. Figure 1: Thoraco-laparoscopic Ivor-Lewis esophagectomy A B C D 7 E F -a- Dissection of the celiac trunk. A: hepatic artery. B: splenic artery. C: left gastric artery. D: caval vein. E: caudate lobe of the liver. F: pancreas. G: esophageal hiatus. -b- Dissection of the esophageal hiatus. A: esophagus. B: esophageal hiatus. -c- Formation of the gastric conduit using a linear stapler. -d- Right thoracoscopic view in prone position. Dorsally the aorta is visible (A). B: clipped thoracic duct at diaphragm level. C: left main bronchus. D: esophageal specimen. -e- View of the carina (A) after lymphadenectomy of the subcarinal nodes (B). The resected subcarinal nodes are retracted and visible at the right sight of the picture (C). D: left atrium. -f- Creation of the endto-side intrathoracic anastomosis using a circular stapler. 141

9 Chapter 7 In the described procedure both the abdominal and thoracic stage are performed in a minimally invasive way. However, the combination of open and endoscopic techniques for transthoracic resection has also been described. When a combination of open and endoscopic approaches is used the procedure is classified as a hybrid minimally invasive technique [16]. McKeown transthoracic esophagectomy The 3-incisional McKeown esophagectomy combines features of the transhiatal- and the Ivor-Lewis transthoracic technique. The abdominal and thoracic stage of the procedure are comparable to previously described Ivor-Lewis technique and allow the surgeon to perform the same two-field (upper abdominal and mediastinal) lymphadenectomy under direct vision. The main difference however, is the addition of a left cervical incision in order to generate a cervical anastomosis. Although robust scientific evidence is lacking, cervical reconstruction is considered to be associated with clinical advantages compared to an intrathoracic anastomosis like easier management of leakage and wider proximal resection margins. Supposed disadvantages include a higher rate of anastomotic leakage because of an extended gastric conduit and a higher rate of anastomotic stenosis [17, 18]. The thoracoscopic and laparoscopic part of the minimally invasive McKeown technique are comparable to the descriptions above. However, the procedure usually starts with a thoracic stage to avoid the need for extra repositioning. Removal of the resection specimen and construction of the gastric conduit usually occurs through an accessory upper midline incision of 5 cm. Subsequently the gastric conduit is delivered to the cervical region where again a hand-sewn or stapled anastomosis can be generated. Parallel to the minimally invasive Ivor-Lewis approach, hybrid minimally invasive McKeown procedures can be performed. Robot-assisted esophagectomy A striking example of ongoing technical advances in minimally invasive surgery is the introduction of robot-assisted esophagectomy, allowing three-dimensional visualization, improved magnification, and a greater range of instrument motion [19]. Robotic assistance has been described for gastric mobilization (in both transhiatal and transthoracic resections), mediastinal lymphadenectomy, dissection of the esophagus and generation of an intrathoracic anastomosis [20]. A potential pitfall of robot-assisted thoracic surgery is the need for single-lung ventilation (see below). However, preliminary studies showing equality with above mentioned techniques in terms of safety and efficacy have 142

10 Minimally invasive surgery for esophageal cancer encouraged researchers to initiate the first randomized controlled trial comparing robotassisted thoracolaparoscopic esophagectomy and open transthoracic esophagectomy for resectable esophageal cancer (ROBOT trial) [21, 22]. Patient positioning: lateral decubitus position versus prone position The main advantage of the prone position is increased visualization because gravity causes the right lung to fall away from the surgical field without the need of additional retraction [23]. It has been suggested that the prone position is also associated with a lower incidence of pulmonary infection compared to the lateral decubitus position because total lung collapse resulting from single-lung ventilation can be avoided [24]. However, the downside is that putting the patient in prone position complicates airway management by the anaesthesiologist and could delay emergency conversion to open thoracotomy [25]. PATIENT SELECTION Given the relatively high risk of surgery related morbidity, adequate patient selection is essential in both conventional and minimally invasive esophagectomy. Pre-treatment staging using imaging techniques like endoscopic ultrasonography, computed tomography and positron emission tomography remains the mainstay of this process. One of the most important challenges in staging is the identification of patients with distant metastases, an absolute contraindication for esophagectomy [3]. If non-invasive diagnostic modalities do not provide a decisive answer on the question of resectablity and dissemination, minimally invasive techniques like laparoscopy and thoracoscopy are safe and effective alternatives [26-28]. 7 In general, minimally invasive esophagectomy is indicated in the same patients as the open techniques with a few exceptions. Relative contraindications to thoracoscopy and laparoscopy include prior thoracic/abdominal surgery with a risk of pleural/abdominal adhesions and locally infiltrative tumors, especially in case of airway involvement. Although some authors have recommended the use of open techniques after chemoradiotherapy because of the difficulty of radiation fibrosis [29, 30] recent literature does not provide evidence to consider neoadjuvant treatment as a contraindication for minimally invasive techniques [31, 32]. 143

11 Chapter 7 OUTCOMES OF MINIMALLY INVASIVE ESOPHAGECTOMY Currently four meta-analyses and one randomized controlled trial (RCT) comparing open- and minimally invasive esophagectomy have been published [33-36]. In order to determine to what extent minimally invasive resection should be considered standard of care for esophageal carcinoma, we will discuss the best available evidence focussing on surgical, postoperative and oncologic outcomes. Surgical outcomes Intraoperative outcomes were assessed in one meta-analysis by Nagpal et al (Table 2) [35]. Based on the five comparative studies included in the analysis a significantly lower amount of blood loss was observed in the minimally invasive group (weighted mean difference = ml), but there was significant heterogeneity in the studies reporting this outcome (P=0.02). This beneficial effect of minimally invasive surgery was confirmed by the recent TIME trial by Biere et al (summary of TIME trial results in Table 3) in which a significant difference in blood loss (200 vs. 475 ml) was found as well [32]. Table 3: Summary of outcomes of the first published randomised controlled trial comparing open and minimally invasive esophagectomy (TIME trial) [32] MI TTE (n=59) Open TTE (n=56) P value Blood loss (median) 200 ml 475 ml < 0.001* Operative time (median) 329 min 299 min 0.002* ICU stay (median) 1 day 1 day Pulmonary infection within two weeks primary outcome Pulmonary infection in-hospital primary outcome 9% 29% 0.005* 12% 34% 0.005* Anastomotic leakage 12% 7% Vocal cord paralysis 2% 14% 0.012* Reoperations 14% 11% Hospital stay (median) 11 days 14 days 0.044* In-hospital mortality 3% 2% Radicality radical (R0) resection non-radical (R1) resection 92% 2% 84% 9% Number of lymph nodes retrieved (median) ICU = Intensive Care Unit; MI = minimally invasive; TTE = transthoracic esophagectomy; R0 = microscopically radical; R1 = microscopically non-radical * significant result 144

12 Minimally invasive surgery for esophageal cancer Table 2: Overview of meta-analyses comparing operative and short-term outcomes between open and total minimally invasive esophagectomy 30 daymortality Hospital stay (WMD) ICU stay (WMD) RLNP (OR) Pulmonary complications (OR) Major mobidity (OR) Total morbidity (OR) Minimal number of patients Operative time (WMD) Blood loss (WMD) Number of included studies Study Surgical technique NR NR NR OR 0.58 (P=0.64) NR NR NR 0.88 (P=0.78) 1.05 (P=0.91) Biere-2009 MI TTE open TTE NR NR RR 1.45 (P= 0.47) 0.57 (P=0.52) NR 1.31 (P=0.73) NR NR 1.93* (P<0.05) Sgourakis-2010 MI TTE open TTE OR 0.55 (P=0.26) -2,75* (P=0.004) -0,97* (P<0.001) 0.76 (P=0.71) NR 0.58* (P=0.04) 0.52* (P=0.007) 5,91 (P=0.80)^ * (P<0.001)^ Nagpal-2010 MI E open E NR NR NR NR NR NR NR NR HR 0.87 (P=0.88) Dantoc-2012 MI TTE open TTE HR = hazard ratio; ICU = Intensive Care Unit; MI = minimally invasive; E = esophagectomy (both transthoracic and transhiatal); OR = odds ratio; NR = not registered; RLNP = recurrent laryngeal nerve palsy; TTE = transthoracic esophagectomy; RR = relative risk; WMD = weighted mean difference * significant result in favour of minimally invasive esophagectomy; ^ significant heterogeneity in the studies reporting this outcome 7 145

13 Chapter 7 With respect to operative time Nagpal et al did not find a convincing difference [35], but this could be caused by the fact that both transhiatal and transthoracic techniques were included in the analysis. So far comparative studies have not found significantly enhanced operating times for laparoscopically- versus open transhiatal esophagectomy [16, 25]. In fact, one study showed a decrease in operating time when transhiatal resections were performed using laparoscopy [37]. However, when the same comparison is made for transthoracic resections a difference becomes manifest. In a recent systematic review 7 out of 9 included studies (including the TIME trial) showed a significantly enhanced operative time in case of thoracoscopic resection [25]. Although a trend toward longer operating times for minimally invasive resections is visible, reports by Osugi et al and Nguyen et al show that increasing experience has a direct effect on this parameter and can lead eventually to operating times that are even lower in comparison to open surgery [38, 39]. Postoperative outcomes Two meta-analyses show a significantly lower overall morbidity in favour of minimally invasive esophagectomy [34, 35]. This result is mainly caused by a lower rate of mild complications (Clavien-Dindo [40] grade 1 and 2) in the minimally invasive group. When major postoperative morbidity (e.g. anastomotic leakage, chyle leakage, haemorrhage, pulmonary embolism, cardiac failure) - usually requiring re-intervention- and inhospital/30-day mortality are considered, no significant difference is found between open and minimally invasive esophagectomy (Table 2 & 3) [32, 33]. The most important cause of the lower overall morbidity after minimally invasive esophagectomy is the reduction in pulmonary complications. This is reflected by significant differences in the meta-analyses of Nagpal et al (Table 2) and the TIME trial (Table 3) and to a lesser extent by an observed trend in the meta-analysis by Sgourakis et al (Table 2) [32, 34, 35]. Besides the impact of placing the patient in prone postion this beneficial effect of minimally invasive esophagectomy is attributed to smaller incisions with lower associated pain resulting in faster mobilization and shorter hospital admission. The latter factors can explain why a reduction in respiratory complications was also observed in minimally invasive transhiatal approaches compared to their open equivalent (18% vs. 26%) [41]. Unlike the mentioned meta-analysis, but in accordance with a previous report by Schoppmann et al the TIME trail showed a significantly lower rate of recurrent laryngeal 146

14 Minimally invasive surgery for esophageal cancer nerve palsy after minimally invasive resection [32, 42]. There is no clear explanation for this, but pneumatic dissection by carbon dioxide from the thoracic cavity into the neck might simplify the neck dissection thereby reducing recurrent nerve lesions [32, 43]. Finally, the increasing attention for patient reported outcome measures is also visible in the latest studies comparing open- and minimally invasive esophagectomy. Patients treated in the minimally invasive arm of the TIME trial reported a significantly higher shortterm quality of life in terms of physical status, global health and in relation to common postoperative symptoms like pain and speech impediment [32]. The results of a recent comparative study by Parameswaran et al indicates that this effect could be abiding as patients from the minimally invasive group showed better physical recovery in the first 6 months after surgery with lower levels of fatique and higher activity patterns [44]. Based on the discussed literature minimally invasive esophagectomy should be regarded as a safe alternative to open resection with proven short-term advantages with respect to pulmonary status, vocal cord function and quality of life. Oncologic outcomes Probably the most controversial issue in the surgical treatment of esophageal cancer is the question whether minimally invasive techniques are a safe alternative to open procedures in terms of therapeutic efficacy. A first determinant of oncologic safety is the proportion of microscopically radical (R0) resections. Remarkably, comparisons of R0 resection rates between open- and minimally invasive esophagectomy have rarely been reported. In three recent comparative studies R0 resection rates were reported. In the TIME trial a non-significant difference of 8% (92% vs. 84%) in favour of minimally invasive esophagectomy was observed [32]. A similar non-significant difference was shown by Sihag et al (100% vs. 93.4%) and to a lesser extent by Sundaram et al (93.6% vs. 92.3%) [45, 46] 7 Contrary to R0 resection rates, the total number of retrieved lymph nodes is a very commonly reported outcome measure. One of the three meta-analyses on this topic resulted in a significant difference in median number of nodes, 16 vs. 10, in favour of minimally invasive esophagectomy (Table 4)[36]. In the same review the described increase in lymph node retrieval did not seem to translate to a survival benefit as no significant differences were found in 1-, 2-, 3- and 5-year survival [36]. 147

15 Chapter 7 Table 4: Overview of meta-analyses comparing oncologic outcomes and survival between open and total minimally invasive esophagectomy Study Surgical technique Sgourakis-2010 MI TTE open TTE Nagpal-2010 MI E open E Dantoc-2012 MI TTE open TTE Number of included studies Minimal number of patients Number of lymph nodes retrieved (WMD) (P=0.65) (P=0.28) * (P=0.02) 1-year survival 2-year survival 3-year survival 5-year survival NR NR RR 0.73 NR (P=0.11) NR NR NR NR HR 0.71 (P=0.16) HR 0.75 (P=0.06) HR 0.81 (P=0.18) HR 0.88 (P=0.44) HR = hazard ratio; MI = minimally invasive; E = esophagectomy (both transthoracic and transhiatal); NR = not registered; TTE = transthoracic esophagectomy; RR = relative risk; WMD = weighted mean difference * significant result in favour of minimally invasive esophagectomy All in all, currently available data imply that oncologic outcomes of minimally invasive esophagectomy are not inferior to those of open esophagectomy. The suggested oncologic advantage of minimally invasive esophagectomy has to be confirmed in an RCT or in long term outcomes of recently published studies like the TIME trial [32]. IMPLEMENTATION OF MINIMALLY INVASIVE ESOPHAGECTOMY Two commonly expressed concerns during the introduction of minimally invasive techniques to daily practice are the surgeon s learning curve and the additional costs of the new procedure. We addressed the first issue in a report describing the introduction of minimally invasive esophagectomy to our tertiary referral center [47]. Using a standardized training program including hands-on courses, training visits and proctoring sessions, gastrointestinal surgeons became acquainted with the thoracolaparoscopic technique. Increased operator experience was shown to decrease operative time up to the level of the original open procedures [47]. The financial impact of using minimally invasive techniques in the treatment of esophageal carcinoma was described in a recent publication by Lee et al [48]. In this study the expected costs and outcomes of open- and minimally invasive esophagectomy were compared. Outcomes were calculated based on a pooled analysis of thirteen comparative studies including the TIME trial. The eventual decision-analysis model revealed minimally invasive esophagectomy to be cost-effective compared to open esophagectomy in patients with resectable esophageal cancer [48]. 148

16 Minimally invasive surgery for esophageal cancer PERSPECTIVES The field of (minimally invasive) esophageal surgery is stirring and innovations happen in rapid succession. At this moment, the most prominent question that has not been answered yet is related to long-term outcomes. Although the discussed studies provide no indication of oncologic inferiority of minimally invasive esophagectomy, long-term survival data of randomised trials is needed for a well-founded recommendation on this topic. In the meantime, studies on indications and contraindications are needed to define the right selection criteria for minimally invasive surgery. Doubt exists about the feasibility and safety of thoracoscopic surgery after radiotherapy, which is an increasingly important component of neoadjuvant treatment. At the same time, it has been proposed that selection criteria should be extended because especially high-risk patients could benefit from the mentioned short-term advantages of minimally invasive esophagectomy. However, we should not forget that there are also more fundamental unaddressed dilemmas like the choice between Ivor-Lewis and McKeown esophagectomy. Based on these scientific challenges we propose the following research agenda in order to maintain the pace in improving surgical care for patients with esophageal cancer. Research agenda The recurrence rate and long-term survival of open- vs. minimally invasive esophagectomy have to be investigated in an RCT Feasibility studies are needed to evaluate the safety of minimally invasive esophagectomy after chemoradiotherapy The left lateral decubitus position and the prone position should be compared in an RCT An RCT on the (short-term) outcomes of minimally invasive Ivor-Lewis- vs. minimally invasive McKeown esophagectomy could end the ongoing debate about the optimal transthoracic approach. Ongoing RCT: open transthoracic- vs. laparoscopically assisted transthoracic esophagectomy (MIRO trial) Ongoing RCT: open transthoracic- vs. robot-assisted thoracolaparoscopic esophagectomy (ROBOT trial) 7 149

17 Chapter 7 Practice points Both transthoracic and transhiatal esophagectomy can be performed in a minimally invasive way Minimally invasive esophagectomy is a safe and cost-effective alternative to open surgery for esophageal cancer Based on postoperative outcomes minimally invasive esophagectomy is preferable to open esophagectomy, but long-term data is needed to determine the (new) standard of care 150

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