Minimally Invasive Esophagectomy: A New Era of Surgical Resection

Background

Esophageal cancer is the sixth most common cause of cancer-related death and eighth most common cancer overall, with adenocarcinoma or squamous cell carcinoma representing the main subtypes. ¹ Less developed regions have the majority of the cases, with squamous cell carcinoma of the esophagus being the predominant subtype in Asia, Africa, South America, and thus globally. ² In the United States, the incidence of squamous cell carcinoma of the esophagus has decreased and incidence of adenocarcinoma has increased. ³ This is in contrast with the black population in North America, which represents a subset of patients with increased incidence of esophageal squamous cell carcinoma. ² These geographic and racial differences may be reflective of the risk factors associated with each esophageal cancer subtype, which includes smoking and alcohol use for squamous cell carcinoma, and obesity, smoking, and symptoms of gastroesophageal reflux disease for adenocarcinoma. ³ Furthermore, irrespective of other factors, men are more likely to be affected than women, and prognosis remains poor in both genders with 5-year survival rates, although increasing in more recent years, still remaining less than 20%. ⁴ More concerning is that adenocarcinoma of the esophagus continues to increase in incidence and has become a significant health problem in Western countries. About 16,980 new esophageal cancer cases will be diagnosed (13,570 in men and 3410 in women) in 2015, resulting in 15,590 deaths (12,600 in men and 2990 in women). ³

Options are limited for advanced esophageal cancer, with chemoradiation and palliation being appropriate for metastatic disease. The mainstay of therapy for curative intent in early stage (localized) esophageal cancer is surgical resection with or without neoadjuvant therapy. ⁵ Despite modern advancements in operative methods, mortality and morbidity after esophagectomy remain high. ⁶ The lowest rates of adverse events are reported in high-volume single-institution studies. ⁷ As such, efforts have been made to find ways to decrease morbidity and mortality. Hence, there has been increased utilization of minimally invasive esophagectomy in an effort to reduce high rates of morbidity, mortality, and lengthy hospital stays often associated with the morbidity of open esophagectomy.

The early 1990s marked the beginning of applying minimally invasive approaches to esophagectomies. Cuschieri et al., ⁸ followed by Azagra et al. ⁹ and Collard et al., ¹⁰ described esophagectomies using thoracoscopic techniques on small subsets of patients. Shortly after, in 1995, DePaula et al. described laparoscopic transhiatal esophagectomy. ¹¹ Since then, multiple techniques and approaches have been described. These include laparoscopic transhiatal or a transthoracic approach with either a cervical or thoracic anastomosis and robot-assisted minimally invasive approaches.

Neoadjuvant Therapy

Patients with esophageal cancer tend to present with locally advanced disease and have poor overall survival. Local–regionally advanced disease is defined as a T stage of T2–T4 and nodal status of N1–N2 and no distant metastases. ¹² Poor outcomes are thought to be attributable to unseen dissemination occurring beyond the area of surgical intervention and high rates of local–regional occurrence. ¹³ Consequently, neoadjuvant therapy has become a topic of therapeutic interest as well as debate for preoperative standard of care. The ultimate goal of this approach is to enhance overall survival and increase the potential for curative resection by aiding with local tumor control, decreasing rates of recurrence, and treating undetectable metastasis. With respect to esophageal cancer, the neoadjuvant therapy is chemoradiotherapy (CRT).

Controversies still exist on the merits of surgery in conjunction with CRT. This is due to conflicting data regarding the added benefit of surgery after CRT, specifically a study by Stahl et al. In this study, patients were randomized to neoadjuvant CRT (40 Gy), followed by surgery versus CRT alone, using at least 65 Gy, and in all cases, patients had locally advanced squamous cell carcinoma. No significant survival advantage was detected with the addition of surgery, even though there was a higher rate of recurrence in the nonsurgical arm. ¹⁴ Similar results were also presented by Bedenne et al. ¹⁵ However, it should be noted that the majority of the patients in these studies had squamous cell carcinoma, and with higher prevalence of adenocarcinoma in the Western Hemisphere, these results cannot be generalized. In addition, a randomized controlled trial comparing surgery alone with neoadjuvant CRT, followed by surgery, did not show a survival benefit with neoadjuvant therapy. However, this trial was stopped early and enrolled patients had very high postoperative mortality rate and underwent a more toxic neoadjuvant therapy. ¹⁶

Despite the previously identified discrepancies, meta-analyses that reviewed surgery alone versus neoadjuvant therapy, followed by surgery, have presented some evidence of a survival advantage for patients who received CRT ¹⁷ as well as no difference in postoperative complications in patients who received neoadjuvant treatment. ¹⁸ The best overall survival figures have been produced in the Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS), in which weekly low-dose carboplatin, weekly low-dose paclitaxel, and external beam radiation were used neoadjuvantly. Preoperative CRT versus surgery alone for T1N1 or T2-3N0-1 showed statistically improved overall and disease-free survival with neoadjuvant treatment. ¹⁹ Thus, to date, the best evidence for neoadjuvant therapy in esophageal cancer remains the CROSS trial. However, more data collection is necessary and more targeted therapy should be studied to aid in treatment of adenocarcinoma and squamous cell carcinoma alike.

Surgical Technique

Described elsewhere, two main operative techniques are used at our institution, namely a two-incision minimally invasive esophagectomy with intrathoracic anastomosis and a three-incision minimally invasive McKeown esophagectomy with cervical anastomosis.^20,21 In short, laparoscopic and thoracoscopic dissection is performed for both techniques, followed by a side-to-side stapled thoracic anastomosis for the Ivor Lewis esophagectomy, or stapled side-to-side cervical esophagogastric anastomosis for the minimally invasive McKeown approach. An extended lymphadenectomy is performed with both techniques. Other groups prefer circular anastomoses.^22–24 In a review of transoral versus transthoracic stapled anastomoses for Ivor Lewis esophagectomy, no differences were found between circular or linear side-to-side approaches. ²⁵ In addition, multiple groups perform laparoscopic transhiatal esophagectomies. Additionally, a group from China described a series of 194 patients who underwent mediastinoscopic esophagectomies with low rates of perioperative morbidities, ²⁶ while another group published similar results of video-assisted mediastinoscopic transhiatal esophagecomies. ²⁷

As with other technically complex operations, robot assistance has also been adopted in minimally invasive esophagectomies, with mainly case series being reported in literature. In a systematic review by Ruurda et al., ∼300 cases of robot-assisted minimally invasive esophagectomies were reported in the articles combined. All reviewed articles involved small series of patients making any generalization difficult. Regardless, the reported complication rates were high, ranging from 6% to 45% for pneumonia, 10%–68% for anastomotic strictures, and 4%–38% anastomotic leaks. As expected, lymph node yield was adequate (range of 18–38). ²⁸ Indeed, given high rates of complications and high costs of the operations, it is hard to justify these techniques at this time.

Transhiatal and transthoracic esophagectomies have been reported as having varying mortality rates, with a lower perioperative mortality rate of 6.7% for the transhiatal approach versus 13.1% in the transthoracic approach. However, the 5-year survival between the approaches is not significant when adjusting for stage as well as patient and provider factors. ²⁹ In a landmark article by Hulscher et al., the choice of operative approach was further explored regarding extended lymphadenectomy in the transthoracic approach compared with the transhiatal esophagectomy. As expected, the transthoracic approach yielded more lymph nodes, with nearly 90% of the cases having >15 lymph nodes. In addition, while the disease-free and overall survival was similar in the initial perioperative time period, there was a trend toward improved survival in the extended transthoracic approach. ³⁰ Indeed, lymph node status has great prognostic value, with staging based on number of nodes involved and removal of more lymph nodes increasing the overall survival. ³¹ This is why our group favors a minimally invasive McKeown approach, which allows us to perform an extensive thoracic lymphadenectomy and lower the perioperative mortality by utilizing a cervical anastomosis. Furthermore, a recent study based on the CROSS trial demonstrated that in the surgery alone arm, the amount of resected lymph nodes was significantly associated with improved survival. This was not seen in the neoadjuvant CRT group, drawing to question the need for extended lymphadenectomy after neoadjuvant therapy. ³²

In a systematic review of patient positioning in minimally invasive esophagectomy, prone versus lateral decubitus was evaluated in a pooled analysis. Ten publications were evaluated with primary end points of early morbidity and in-hospital mortality. No significant differences were seen in either of those values, nor the secondary outcomes of anastomotic leaks, chylothorax, laryngeal nerve palsy, length of stay, or pulmonary complications, although the latter showed a trend toward increased incidence in the lateral decubitus positioning. ³³ In addition, prone positioning increased mediastinal lymph node harvest. A prior review had shown similar results with no significant differences seen in prone compared with lateral decubitus positioning. ³⁴

Postoperative Outcomes

Since esophagectomy procedures are inherently high-risk procedures with high morbidities and mortalities, postoperative outcomes after open versus minimally invasive approaches are important to address. There have been several single-institution studies and meta-analyses on minimally invasive esophagectomy, which have shown comparable oncological and postoperative outcomes when compared with open esophagectomy.^35–39 However, only one randomized controlled trial (TIME) has been published to date, comparing minimally invasive to open esophagectomy in esophageal cancer. ⁴⁰ This multicenter study showed a statistically significant decrease in incidence of postoperative pulmonary infection in addition to improved secondary outcomes of length of stay and quality of life in minimally invasive esophagectomies. Minimally invasive esophagectomy had a rate of pulmonary infections of 12% versus 34% for open procedures and decreased length of stay (11 days versus 14 days). Other secondary outcomes such as anastomotic leakage were not statistically significant, although vocal cord paralysis showed statistically significant difference with 14% of patients in the open group and 2% of patients in the minimally invasive group having this complication. ⁴⁰ In a follow-up study 1 year postoperatively, vocal cord paralysis was 7% for the open group and 2% for the minimally invasive group, no longer statistically significant. Differences between the groups in other late complications such as anastomotic stenosis and intrathoracic herniation were also not statistically significant. ⁴¹

In a retrospective propensity score-matched comparison of open versus minimally invasive esophagectomy for squamous cell carcinoma, 444 paired cases were analyzed. Statistically significant and improved outcomes with the minimally invasive approach included shorter hospital stay, fewer major complications (including respiratory), and lower readmission rate to the intensive care units. In this study, the anastomotic leak rate was high for the minimally invasive approach, which the authors accounted for with their learning curve and known higher rate of cervical anastomotic leak. ⁴²

In a population-based national study from England, a prospectively collected database was analyzed for minimally invasive and open esophagectomies, yielding 7502 patients, of which 15.4% underwent minimally invasive esophagectomy. Minimally invasive esophagectomies not only reduced the risk of postoperative respiratory complications but also were associated with a higher rate of surgical reintervention. ⁴³ In a prospective multicenter trial, 95 patients underwent minimally invasive esophagectomy, with acceptable perioperative mortality of 2.9%, anastomotic leak of 8.6%, and pneumonitis of 3.8%. ⁴⁴

Multiple groups have shown the feasibility and safety of minimally invasive esophagectomy. The highest single-institution series of minimally invasive esophagectomies is from the University of Pittsburgh, in which a retrospective series of 1011 patients was performed. Approximately half of the patients underwent minimally invasive esophagectomy with intrathoracic anastomosis (their current approach) and the other half underwent three-incision esophagectomy with cervical anastomosis. Their 30-day mortality was 1.68%, and there were no significant differences in their two approaches in other morbidities, including anastomotic leak (4%–5%), or pulmonary complications (2%–6%). However, there was significantly less vocal cord paresis in the Ivor Lewis group. ²³ Long-term data are lacking, and oncological outcomes are based on lymph node retrieval and R0 resection, as opposed to long-term survival.

Impact of Neoadjuvant CRT

Minimally invasive esophagectomies in conjunction with neoadjuvant therapy have few published data comparing patients receiving neoadjuvant therapy with surgery alone. We have previously published a series of 61 consecutive patients, 41 of which received neoadjuvant therapy. There were no significant differences seen between the two groups in terms of complications or oncological outcomes. ⁴⁵ Similarly, in a study by Spector et al., 119 patients underwent three-hole minimally invasive esophagectomy, with 78 patients receiving neoadjuvant therapy. No differences were seen between the two groups in terms of postoperative complications. ⁴⁶ Given the TIME trial, in which most patients received neoadjuvant therapy, and these two studies, although limited in number of patients and in their retrospective nature, minimally invasive approaches are safe in more locally advanced esophageal malignancies after CRT.

Other Considerations

In a follow-up study of the TIME trial, patients received quality of life questionnaires. Although scores were better for both groups compared with postoperative levels, the 1-year scores were significantly different for physical activity, global health, and pain in the minimally invasive group. ⁴¹ In a propensity score-matched study of patients with squamous cell carcinoma in either a minimally invasive or open approach, the minimally invasive group had better physical function scores, but lower scores for other categories such as fatigue and pain. As expected, neoadjuvant therapy had a negative impact on global scores, as did increased age. ⁴²

Improved nutrition through the enteral method has been shown to be an important factor in reducing life-threatening postoperative morbidities after open esophagectomy. ⁴⁷ In a randomized prospective trial comparing enteral and parenteral nutrition in minimally invasive (thoracoscopic) esophagectomy, the incidence of pneumonia was decreased in the enteral nutrition group; however, this was not statistically significant. ⁴⁸ Hence, all patients with >T2 or node-positive disease as determined by radiographic findings or endoscopic ultrasound with dysphagia received preneoadjuvant CRT enteral feeding tube to supplement their nutrition during this phase of their treatment.

Last, there continues to be significant discrepancy between blacks and whites for 5-year survival rates in esophageal cancer, with lower rates of black patients receiving surgery and lower rates of overall survival, and survival after cancer-directed surgery independent of stage. ⁴⁹ This may be, in part, due to black patients undergoing esophagectomy at lower volume hospitals. Indeed, operative mortality rates for esophagectomy are dependent on hospital volume, with observed rates from 8.7% in very high centers, performing more than 19 cases per year, to 23.1% in very low centers, performing less than 2 cases per year. ⁵⁰ Surgeon volume also seems to play a factor in mortality. However, there is no strong evidence for minimum recommended numbers since there is no reportable plateau to decrease in mortality with higher volume. ⁵¹ Interestingly, in a cost-effectiveness study, using a decision analysis model, minimally invasive esophagectomy was estimated to cost less than open esophagectomy, giving further evidence for advocating toward adoption of minimally invasive techniques. ⁵²

Conclusion

Minimally invasive esophagectomy is associated with appropriate tumor clearance, acceptable postoperative morbidity, and decreasing mortality compared with open esophagectomy. Many studies support the continued safe use of esophagectomy for malignant esophageal diseases and some have even suggested that it is more cost-effective. Given the current available literature, randomized control trials are still needed to assess the long-term oncological outcomes, complications, and survival benefits of minimally invasive esophagectomies.