Minimally invasive esophagectomy

Introduction

During the last 3 decades, minimally invasive surgical approaches for the treatment of esophageal cancer have been increasingly pursued. Whereas open esophagectomy has historically been the standard of care, the use of minimally invasive esophagectomy (MIE) has increased substantially during the last 10 years.¹ The introduction of laparoscopic and thoracoscopic approaches—to replace laparotomy and thoracotomy, respectively—is associated with reduced perioperative morbidity and excellent oncologic outcomes.^2,3 Although there is a significant learning curve required to master this technically challenging procedure, MIE is rapidly replacing traditional open esophagectomy and has arguably become the new gold standard, as postoperative outcomes continue to improve. Here, we review the current role and status of MIE in the treatment of esophageal cancer, with a focus on thoracoscopic-laparoscopic Ivor Lewis esophagectomy.

History of minimally invasive esophagectomy development

MIE was originally envisioned to replace thoracotomy and laparotomy with thoracoscopy/video-assisted thoracoscopic surgery (VATS) and laparoscopy, respectively. The goal of such approaches is to reduce the invasiveness of the procedure and thereby improve perioperative outcomes without sacrificing oncologic efficacy. Thoracoscopic esophagectomy was first described in 1992 by Cuschieri.⁴ In the nearly 30 years since this initial report, improvements in minimally invasive instrumentation and techniques, in concert with improved patient selection and perioperative management, have led to significant advancements in the treatment of patients with esophageal cancer. Several minimally invasive approaches to esophagectomy have been developed during the last 3 decades: laparoscopic transhiatal, laparoscopic-thoracoscopic Ivor Lewis, and laparoscopic-thoracoscopic McKeown (3-hole). The operative approach is largely dictated by surgeon preference; however, tumor location and patient comorbidities may influence the choice of technique. Most commonly, tumors of the mid and lower esophagus, as well as those of the gastroesophageal junction, are addressed with an Ivor Lewis/intrathoracic anastomosis, whereas tumors found more proximally are addressed with a McKeown technique with a cervical anastomosis. The side-effect profile and postoperative morbidity associated with the operation may further influence the choice. Many surgeons prefer to avoid a cervical anastomosis, owing to the risk of recurrent laryngeal nerve injury and pharyngoesophageal dysphagia. The combination of these 2 issues may lead to increased risk of aspiration pneumonia and may significantly affect quality of life.^5–7 Conversely, transthoracic approaches (both open and thoracoscopic) predispose patients to higher rates of postoperative pulmonary complications.⁸ Before the widespread use of covered esophageal stents, intrathoracic anastamotic leaks were typically quite morbid. Ivor Lewis–type esophagectomy (increasingly minimally invasive) has rapidly become the most common approach used for patients with distal esophageal or gastroesophageal junction tumors, which account for the majority of esophageal cancers seen in Western populations.^9,10 With acknowledgment of the limitations mentioned above, the Ivor Lewis approach allows for an unparalleled view of the thoracic esophagus, the ability to perform an extensive mediastinal lymphadenectomy, and minimization of the risk of recurrent laryngeal nerve injury, as cervical esophageal dissection is not required in this technique. Reflecting the dominant approach at present, this review will focus on minimally invasive Ivor Lewis esophagectomy.

Since the initial description of MIE, it has gained in popularity and is increasingly performed.¹ Although several small, single-institution studies have demonstrated the feasibility of this approach, the surgical and oncologic outcomes of MIE require further investigation.

Surgical, perioperative, and oncologic outcomes

Minimally invasive versus open esophagectomy

The MIE approach was first cultivated and championed by James Luketich at the University of Pittsburgh. The initial University of Pittsburgh experience, including 222 patients undergoing MIE, was described in 2003.¹¹ In this series, the first several cases were conducted as laparoscopic transhiatal esophagectomies; however, the technique evolved rapidly to a modified 3-hole esophagectomy with VATS esophageal mobilization with cervical anastomosis. The median length of stay for this cohort was approximately 7 days, and operative mortality was 1.4%, which was comparable to data for open esophagectomy, which was the standard at the time. Rates of postoperative pulmonary complications—namely, pneumonia—were lower (7.7%) than those from comparable contemporary open series.¹² This initial experience also demonstrated an acceptable rate of anastomotic leak—approximately 11.7%—which was also comparable to rates from previously published open experiences.¹³ In the subsequent follow-up to the study, published in 2012, the University of Pittsburgh group reported on more than 1000 patients who underwent MIE.¹⁴ This study also documented the group’s evolution from the initial laparoscopic transhiatal approach, to a laparoscopic 3-hole approach, to a minimally invasive Ivor Lewis esophagectomy, which is now their preferred technique. Slightly more than one half of the patients in this follow-up study underwent minimally invasive Ivor Lewis esophagectomy. This study, which included the largest cohort to date, demonstrated that MIE could be performed safely, with excellent overall operative mortality of 1.7% and a median hospital stay of 8 days. Furthermore, this study allowed for comparison between minimally invasive Ivor Lewis and 3-hole esophagectomy, which were shown to have similar median length of stay, morbidity, and mortality. Rates of anastomotic leak were also similar between the 2 techniques; however the rate of recurrent laryngeal nerve injury was markedly higher for minimally invasive 3-hole esophagectomy than for Ivor Lewis esophagectomy (8% vs 1%). R0 resection was accomplished in 98% of cases, and the median number of lymph nodes resected was 21, with both of these metrics comparable to those from similar series of open esophagectomy.

At around the same time, several other single-institution studies that advocated for the use of MIE were being published, although these were on a smaller scale. Given the technical challenges of learning and teaching MIE, there was concern that this technique may not be generalizable or feasible to perform at other centers. As a result, a prospective, multicenter, phase II cooperative group study was conducted by the Eastern Cooperative Oncology Group (E2202).³ The primary aim of this study was to assess the feasibility of MIE within a multi-institutional setting; the primary endpoint was 30-day mortality. Secondary endpoints include length of stay, complications, and 3-year outcomes. Of the 100 patients eligible for analysis, 95 successfully underwent MIE. Thirty-day mortality was 2.1%, and median length of stay was 9 days. Anastomotic leak occurred in 8.6% of patients, and the respiratory complications ARDS and pneumonitis occurred in 5.7% and 3.8% of patients, respectively. This adverse-events profile was similar to or better than those for previously reported open experiences. This study also demonstrated that MIE was successful from a technical standpoint, as 96% of cases included R0 resection, with a median lymph node count of 19. Similar to outcomes for open procedures, 3-year overall survival was 58.4%. Local regional recurrence occurred in 6.7% of patients, which was also comparable to outcomes from open procedures.

Following the publication of single-institution studies demonstrating short-term benefits and possibly reduced perioperative morbidity associated with MIE, a multicenter, open-label, randomized controlled trial comparing open esophagectomy with MIE (McKeown or Ivor Lewis) was performed (the TIME [traditional invasive vs. minimally invasive esophagectomy] study).¹⁵ In this study, 56 patients were randomly assigned to the open esophagectomy group, and 59 patients were randomly assigned to the MIE group. The primary outcome was pulmonary infection during the initial 2 weeks postoperatively and during the entire hospital stay. In total, 16 patients (29%) who underwent open esophagectomy and 5 patients (9%) who underwent MIE had pulmonary complications during the first 2 weeks (P = 0.005). Similarly, 19 patients (34%) in the open arm and 7 (12%) in the MIE arm had pulmonary infections during the entirety of their hospital stay (P = 0.005). Anastomotic leak rates were not significantly different between the 2 modalities (7% for open esophagectomy vs 12% for MIE; P = 0.39). In-hospital mortality was low in both study arms: 1 patient in the open esophagectomy arm (anastomotic leak) and 2 patients in the MIE arm (aspiration and mediastinitis from anastomotic leak) died in hospital from perioperative complications. In addition to lower rates of pulmonary complications, the hospital stay was also shorter in the MIE group (median, 14 vs 11 days; P = 0.044). On postoperative quality of life surveys, patients’ postoperative scores were significantly better among those who underwent MIE. Although operative time for MIE was statistically significantly longer (by 30 minutes), blood loss was lower for MIE. There were, however, a substantial number of conversions in the study: 6 had the thoracic portion converted from VATS to thoracotomy, and 2 had the abdominal portion of the procedure converted to laparotomy. Rates of reoperation after the index surgery were similar between groups as well: 11% for open versus 14% for MIE. Although this study was not initially powered to detect an oncologic difference, R0 resection rates were not significantly different between groups (84% vs 92%; P = 0.08). Furthermore, the total number of lymph nodes removed, as identified on final pathologic assessment, was not statistically different between groups (21 vs 20; P = 0.85). This study demonstrated excellent short-term benefits associated with MIE, without compromised quality of resection. There are, however, several limitations to this trial. The first and perhaps most striking is the very high rate of pulmonary infection (34%) in the open esophagectomy arm. This is exceptionally high, compared with other reported rates, which are typically in the range of 15% to 25%. Moreover, no multivariate analysis was performed to assess the effect of a minimally invasive resection on the postoperative outcomes evaluated.

As the initial TIME study was not conducted with an emphasis on long-term oncologic out-comes, a study focusing on 3-year follow-up was pursued by the TIME investigators.¹⁶ The primary outcome evaluated in this follow-up study was 3-year disease-free survival, with secondary outcomes of overall survival and rates of local recurrence and distant metastases. At 3 years, there were no statistically significant differences in overall (41% vs 43%) or disease-free (37% vs 43%) survival between the open and MIE groups, respectively. “Full responders,” or patients with no residual tumor on final pathologic analysis after induction treatment, had markedly better oncologic outcomes, as had previously been demonstrated. Multivariable analysis (adjusted for age, sex, disease stage) did not reveal a significant difference in overall or disease-free survival. Similarly, there were no differences in rates of local recurrence or distant metastases. This intermediate-term follow-up study, albeit somewhat underpowered for secondary endpoints, provided further data that MIE is a safe, oncologically sound approach for esophageal cancer.

As implied by the above data, there is a paucity of high-quality randomized clinical trials investigating the outcomes of MIE; however, several large database studies and meta-analyses have been published comparing open versus MIE techniques. A National Cancer Database study published by Duke University retrospectively reviewed 4266 patients, 1308 (31%) of whom underwent MIE.¹⁷ Following appropriate propensity matching and stratification by histologic type, 3-year overall survival was not statistically significantly different between the 2 techniques. More specifically, 3-year overall survival for patients with esophageal adenocarcinoma was 49% for open esophagectomy versus 57% for MIE. Similar 3-year survival outcomes were found for squamous cell carcinoma: 56% for open esophagectomy versus 55% for MIE. Additional factors evaluated in these propensity mass groups were 30-day mortality, rate of R0 resection, rate of unplanned readmission, number of lymph nodes harvested, and hospital length of stay. There were no differences detected between groups for 30-day mortality, unplanned readmission, or rates of R0 resection. The number of lymph nodes resected was subtly but statistically significantly higher in the MIE group (15 vs 13). A significant decrease in hospital length of stay of 1 day was also associated with MIE. Although it was not the primary goal of the study, this study offered a look at the temporal trends and utilization of MIE at different locations. Between 2010 and 2012, use of MIE increased approximately 10%, from 27% to just over 37%. Interestingly, however, the median number of esophagectomies performed per center was only 2 per year. Despite a reasonable number of studies demonstrating better outcomes when MIE is performed at a high-volume center, this study implied that, even with a median number of esophagectomies per center of only 2 per year, perioperative outcomes were not significantly different between open and minimally invasive techniques. This is confounded, however, by the lack of granularity in the National Cancer Database for identifying and classifying specific perioperative complications, and one must interpret the study conclusions within that context.

A similar recent study using the Society of Thoracic Surgeons National Database evaluated early surgical outcomes between open esophagectomy and MIE.¹⁸ Thirty-day postoperative morbidity and mortality were not statistically significantly different between the 2 modalities. Although 30-day mortality was fairly low (3.9% for open esophagectomy and 3.3% for MIE), rates of perioperative complications in the initial 30 days were still fairly high in both groups (approximately 60%). Furthermore, rates of anastomotic complications were similar between the groups. MIE was associated with a shorter median length of stay by approximately 1 day (10 vs 9 days). Open esophagectomy, however, was associated with increased need for postoperative transfusion as well as ileus. Similar to the Duke study mentioned above, this study showed that outcomes were comparable between high- and low-volume centers, which held true following propensity matching.

However, data from several other meta-analyses comparing open esophagectomy with MIE have been somewhat conflicting. Some meta-analyses have demonstrated reduced length of stay, respiratory complications, and postoperative morbidity, along with improved postoperative quality of life, for patients undergoing MIE.^2,19–21 Conversely, other meta-analyses have demonstrated no difference in postoperative complication rates, in particular pulmonary complications. In fact, a more recent meta-analysis examining approximately 1700 patients in the Netherlands detected higher rates of anastomotic leak and more postesophagectomy interventions required after MIE.²² Given the lack of granularity in these large database studies and meta-analyses, one must be careful when drawing conclusions from such data.

Postoperative quality of life

With improvements in operative techniques and postoperative patient care, intermediate and long-term survivors of esophageal cancer are becoming more common, and therefore there is increased emphasis on postoperative quality of life. While it may be expected that minimally invasive approaches to esophagectomy are associated with better quality of life, analogous to the experience with other minimally invasive surgical procedures, there are insufficient data at present to support this view. Furthermore, a recently published systematic review assessing quality of life between open esophagectomy and MIE found similar declines in physical function, choking, dysphagia, and general eating problems between approaches.²³ MIE was associated with improved social and emotional function, compared with open esophagectomy; however, with the possibility of publication and selection bias, this finding must be interpreted cautiously, as the authors of the study note.

Some data, however, do suggest that MIE is associated with improved quality of life, at least in the first postoperative year. Previous studies of open esophagectomy have demonstrated that quality of life approaches the patient’s initial baseline at approximately 1 year postoperatively.²⁴ The 3-year follow-up to the TIME trial, discussed previously, identified improved quality of life in patients who had undergone MIE, rather than open esophagectomy, starting 6 weeks post-operatively and persisting for up to 1 year.¹⁶ Similarly, 2 additional studies demonstrated that patients who underwent MIE returned to baseline quality of life by 6 months, which was potentially attributable to the avoidance of thoracotomy and/or laparotomy.^25,26

The uncertain role of pyloric drainage

At present, there is no clear consensus on the role that pyloric drainage procedures should play in patients undergoing esophagectomy with gastric conduit creation. In theory, all esophagectomies (with the exception of vagal-sparing procedures) entail bilateral vagotomy, rendering the stomach denervated and causing reduced gastric tone and motility, along with disruption of pyloric motility. Pyloric drainage procedures are used to reduce the risk of gastric outlet obstruction and thereby reduce the incidence of postoperative aspiration pneumonia from stasis within the gastric conduit. Proponents of this approach state that pyloric drainage decreases the rate of postoperative delayed gastric emptying and, consequently, anastomotic leak and aspiration pneumonia. Unfortunately, pyloric drainage procedures are not without their own set of risks and may place patients at an increased risk of dumping and symptomatic bile reflux. The addition of pyloric drainage procedures as an adjunct to esophagectomy remains hotly debated in the context of conflicting data and support.

An early study, from 1984, demonstrated poor gastric emptying and increased perioperative pulmonary complications in patients with a vagotomized, intrathoracic stomach who did not undergo a pyloric drainage procedure.²⁷ Multiple subsequent investigations attempted to evaluate the role of pyloric drainage procedures after esophagectomy. One of the earliest to rigorously examine the effect of pyloric drainage on patient outcomes was a 2002 meta-analysis that collectively analyzed 553 patients from 9 previously completed randomized controlled trials.²⁸ Data from this meta-analysis demonstrated that, whereas pyloric drainage decreased the incidence of early postoperative gastric outlet obstruction after esophagectomy, it did not alter either early (anastomotic leak, pulmonary morbidity, fatal pulmonary aspiration) or late (gastric emptying, obstructive foregut symptoms, nutrition status) postoperative outcomes.

Subsequent single-institution studies have yielded seemingly conflicting results. A retrospective study from Massachusetts General Hospital published in 2007, predominantly comprising traditional open esophagectomies (Ivor Lewis, transhiatal, left thoracoabdominal), examined the incidence of gastric outlet obstruction after esophagectomy.²⁹ No differences in postoperative gastric outlet obstruction were identified between those who underwent pyloromyotomy and those who did not. Similarly, no differences in short-term outcomes of pneumonia, respiratory failure, or length of stay were seen. Interestingly, this study also observed that, when it occurred, postoperative gastric outlet obstruction could be successfully managed endoscopically with pyloric dilation.

More recently, Antonoff and colleagues retrospectively reviewed their institution’s postesophagectomy outcomes, with a focus on the effect of pyloric drainage on short- and long-term postoperative outcomes and a particular emphasis on postoperative “aspiration events”.³⁰ “Aspiration events” were defined as witnessed events of vomiting that occurred before coughing or acute respiratory decompensation. Visible aspiration occurring on contrast esophagrams was also included. Several operative pyloric drainage procedures were performed, leading to a some- what heterogeneous data set. The included operative techniques were pyloromyotomy, pyloroplasty, and manual/digital pyloric dilation. Some patients (approximately 15%) who underwent pyloric Botox injection combined with digital or endoscopic balloon dilation, intraoperatively at the time of index operation, were also included. The study’s data demonstrated an association between lack of a pyloric procedure during esophagectomy and increased rates of postoperative aspiration events. Interestingly, the use of Botox plus dilation was fairly equivalent to operative pyloric drainage, minus the risk of leak from the associated surgical site.

The role of pyloric drainage, specifically in the context of MIE, was retrospectively reviewed at Memorial Sloan Kettering Cancer Center recently.³¹ Two hundred eighty-three patients undergoing MIE between 2011 and 2017 were identified. Patients were stratified into 3 groups by procedure: surgical pyloric drainage (pyloromyotomy, pyloroplasty), pyloric Botox, and no drainage procedure. No differences in the rates of postoperative complications were observed between groups. Interestingly, at early and intermediate postoperative time points, patients who underwent pyloric interventions at the time of the index operation paradoxically had more symptoms than patients in whom no pyloric drainage was performed. Similarly, patients who underwent pyloric interventions also had higher rates of pyloric dilation than those in whom no drainage was performed. The results of this study imply that pyloric drainage after MIE can be omitted.

The studies mentioned above, along with others, demonstrate a lack of consensus and clear guidelines regarding the role of pyloric drainage.^28–34 Furthermore, the surgical characteristics of the patients composing many of these studies are highly heterogeneous. Consequently, it is nearly impossible to account for variation in surgical technique among different surgeons (both type of esophagectomy and pyloric drainage), anastomotic level, level of pylorus, conduit choice, and location of conduit in the chest, leading to significant difficulty interpreting these data and applying them to clinical practice. On the basis of our experience, our preference is to avoid the routine use of pyloric drainage procedures. It appears that only a minority of patients go on to develop postoperative symptoms attributable to pyloric dysfunction, which may be dealt with via endoscopic dilation. It is our opinion that avoiding post-MIE bile reflux and dumping syndrome by omitting pyloric drainage procedures is appealing.

Aging populations

With advances in general medical care, the improved health of patients worldwide, and the increasing incidence of esophageal cancer, older patients with esophageal cancer are being referred with increasing frequency for consideration of esophagectomy. Owing to the advantages of minimally invasive resections, which may reduce the morbidity of a large surgery, surgical resection may be expanded to older patients.

Although no randomized studies have examined this population, a retrospective study evaluated 407 patients, older than 70 years, who underwent esophagectomy for malignancy.³⁵ From this cohort, matched pairs of 58 patients who underwent MIE were compared with 58 patients who underwent open esophagectomy. Matching by age, sex, medical comorbidities, stage, tumor histologic subtype, and technique of esophagectomy was used. The rate of postoperative complications was significantly lower among older patients who underwent MIE than among those who underwent open esophagectomy (38% vs 60%; P = 0.016). More specifically, the rates of pulmonary complications were markedly lower, by almost 20%, in the MIE arm. Similarly, the length of stay was shorter by 2 days in the MIE arm. However, there were no differences in overall survival between groups.

Although the investigation mentioned above must be considered with all the caveats inherent to retrospective studies, it is encouraging that we may be able to offer a less morbid approach to older patients, who may be more medically complex at baseline and potentially more susceptible to perioperative complications.

Centralization

As with other disease sites in the context of complex oncologic resections, the centralization of patients with esophageal cancer who underwent esophagectomy to specialized centers has been associated with favorable short- and long-term outcomes.^36,37 The presence of an experienced multidisciplinary team with significant experience in pre-, intra-, and postoperative care of patients with esophageal cancer is ideal and likely facilitates beneficial outcomes at higher-volume centers. For patients with esophageal cancer, 5-year overall survival was approximately 17% lower at low-volume centers than at high-volume centers.³⁶ Similarly, a study from the UK examined the reorganization of esophagogastric cancer care between 2003 and 2014; the number of centers performing the associated surgeries decreased from 113 to 43, with a corresponding decrease in 30-day postoperative mortality from 7.4% to 2.5%.³⁸

Low-volume centers may never perform enough cases to become truly proficient at MIE. Several studies have attempted to determine the MIE learning curve. A study from 2016 examined the learning curve for MIE with the patient in prone positioning for the chest portion of the procedure.³⁹ By the use of CUSUM analysis, a learning curve of 44 procedures was identified. This is approximately the number identified in a study from Massachusetts General Hospital, which detailed their experience with their first 80 consecutive MIEs.⁴⁰ Compared with the initial 40 patients, the second group of 40 patients had “improved operative and postoperative parameters.” More specifically, CUSUM analysis identified decreased chest tube duration after 38 patients, decreased length of stay after 33 patients, earlier start of oral diet after 35 patients, and decreasing total surgical time after 54 patients. On the basis of these findings, the authors stated that a potential learning curve for MIE is approximately 35 to 40 patients.

Robotic-assisted minimally invasive esophagectomy

Robotic-assisted MIE (RAMIE), first introduced in 2003, has been increasingly used during the last 15 years, with a particular increase in interest during the last 5 years. Multiple institutional series of RAMIE have been reported. Several larger series of RAMIE have recently been reported, with the observation that the procedure is not only technically feasible but is also safe and likely equivalent to standard MIE in terms of both surgical and short-term oncologic outcomes.^41–53 As this technique is still in its infancy, without wide adoption just yet, there is a paucity of data on long-term outcomes after RAMIE. Studies have demonstrated that there is no obvious significant difference between RAMIE and MIE in terms of intraoperative and postoperative complications. Furthermore, quality parameters, such as extent of lymphadenectomy, have been found to be satisfied by RAMIE, with some vocal proponents remarking that a robotic approach may facilitate a greater lymphadenectomy.

A recently published randomized clinical trial (ROBOT trial) attempted to compare safety and efficacy between RAMIE and open esophagectomy.⁵⁴ In this single-center experience, 112 patients with potentially resectable esophageal cancer were randomized to undergo either open esophagectomy or RAMIE. It is important to note that, in this study, the investigators had already passed the learning curve for RAMIE, possessing 10 years of experience with robotic esophagectomy before initiation of the trial. The primary endpoint investigated was percentage of surgery-related postoperative complications. Compared with open esophagectomy, RAMIE was associated with lower rates of surgery-related postoperative complications, including operative blood loss, cardiopulmonary complications, and mean postoperative pain scores. This investigation also explored short-term quality of life; postoperative quality of life scores were higher at both discharge and 6 weeks for those who underwent RAMIE. Although they were not the primary endpoints of the study, disease-free and overall survival were not statistically significantly different between the 2 study groups at a median follow-up of 40 months.

A comparison of conventional MIE and RAMIE is a logical next step. This will, however, likely require a multi-institution randomized controlled trial to enroll a sufficient number of subjects to accurately detect what will likely be small differences in outcomes. The cost-effectiveness of robotic approaches to the esophagus also remains to be determined.

Conclusion

During the last 15 years, interest in and utilization of MIE have significantly increased to the point that many would term it the preferred approach for esophageal cancer resection. There is an abundance of data supporting the safety of this approach. Furthermore, multiple studies have demonstrated that MIE achieves comparable oncologic outcomes as open approaches, perhaps with less postoperative morbidity and improved quality of life. The operation, however, is technically demanding, and there is a steep learning curve required to demonstrate proficiency and safety.