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Single center consecutive series cohort study of minimally invasive versus open resection for cancer in the esophagus or gastroesophageal junction

Single center consecutive series cohort study of minimally invasive versus open resection for... Summary Minimally invasive esophagectomy (MIE) has been introduced at many centers worldwide as evidence is accumulating that it reduces the risk of postoperative morbidity and mortality and decreases the length of hospital stay compared to conventional open esophagectomy. The study is a single institution cohort study of 366 consecutive patients treated with curative intent for cancer in the esophagus or gastroesophageal junction, comparing MIE to open surgery. The outcomes studied were peroperative bleeding, operation time, lymph node yield, complications, length of stay and overall survival. The results showed that MIE was associated with reduced peroperative bleeding and operation time. The patients in the MIE group had a statistically significant reduced risk of postoperative complications, 60.2% compared to 78.8% in the open group. In the MIE group 28.4% of the patients had postoperative complications classified according to the Clavien–Dindo classification system as grade IIIb-V compared to 38.2% in the open group, P = 0.046. Median hospital stay was reduced with 10 days comparing MIE to open surgery, P < 0.001. Mean number of resected lymph nodes was 31 in the MIE group and 22 in the open group (P < 0.001), while the R0 resections were 91.5% versus 85% (P = 0.057). Overall long-term survival was higher in the MIE group, a difference that however did not reach statistical significance (adjusted hazard ratio for three-year survival 0.76, 95% CI 0.54–1.08). In conclusion, MIE at a high volume center with a devoted specialist team reduces the risk of peroperative bleeding, operation time, and severe postoperative complications compared to open surgery for esophageal or junctional cancer. The number of resected lymph nodes was increased and the R0 resections were similar between the groups indicating a good oncological quality of the surgery. INTRODUCTION Surgical resection of the primary tumor and regional lymph nodes remains the most important part of the curative intended treatment of cancer in the esophagus or gastroesophageal junction.1–3 Minimally invasive esophagectomy (MIE) can be performed with laparoscopy and thoracoscopy or a combination of the above with open dissection, so called hybrid-MIE (HMIE). These techniques have been introduced in many centers across the world over recent years and have been shown to reduce the risk of postoperative pulmonary complications compared to open surgery.4–7 Additionally, the quality of life was also improved one year after treatment in the MIE group.8 A recent randomized controlled trial (RCT) demonstrated a reduced risk of major postoperative morbidity from 64.4% after open surgery to 35.9% after HMIE with a combination of laparoscopic mobilization of the stomach and open thoracotomy.9 A retrospective single institution series of 222 patients treated with MIE showed a 30-day mortality of 1.4% and reduced length of hospital stay compared to previous series of open surgery.10 The scientific evidence for MIE is however limited with very few and relatively small RCTs combined with retrospective single institution studies. In a large population based cohort study in England, 7502 esophagectomies were evaluated. The results showed increased risk of reintervention in the MIE group and no differences concerning complications.11 A recent meta-analysis included 15,790 patients from 57 studies but only one of which was an RCT; the results showed reduced risk of postoperative morbidity and mortality, and no difference in the number of harvested lymph nodes after MIE compared to open surgery.12 Nevertheless, most studies have focused on the short-term outcomes after surgery. On the other hand, the long-term oncological results and possible effects on survival are poorly studied. The aim of this study is therefore to compare the short-term and long-term results of all MIEs and open resections performed in our institution over the period 2007–2017. METHOD Data source and data collection This study is a cohort study of all patients diagnosed with cancer of the esophagus or gastro-esophageal junction over the period 2007–2017, and was treated with esophagectomy with curative intent. The implementation of MIE, which has been described in detail elsewhere,13 was introduced in our unit in 2012 after fellowship and visit to high volume centers abroad as well as extensive collaboration and exchange program with colleagues from Tokyo, Japan. The technique was initially indicated in selected patients without large, bulky tumors, or advanced lymph node metastases. After 2015, all patients were operated with MIE except from cases requiring colonic interposition. All esophagectomies were extracted from the hospital surgical planning system (ORBIT) and cross-matched for validation with the electronic patient chart system (TakeCare). The data were retrieved and checked by 3 of the co-authors (FK, CMS, SK). Detailed clinical information regarding patient baseline characteristics (age, gender, American Society of Anesthesiologists (ASA)-score), tumor type, clinical tumor stage (TNM), neoadjuvant therapy, type of surgical procedure, and outcomes (postoperative complications, Clavien–Dindo score (C–D), length of hospital stay) were manually extracted from patient charts in TakeCare. The clinical TNM for all included patients was assessed by the use of endoscopy, and positron emission tomography computed tomography (PET-CT) and in selected cases endoscopic ultrasonography. The histopathology reports of the specimens were reviewed in order to confirm the pathologic tumor stage, the number of harvested lymph nodes and the radicality of the resection. Patients with macroscopic residual disease were excluded. Hypothesis Minimally invasive esophagectomy decreases the risk of postoperative complications without impairing the oncological quality of the resection or long-term survival compared to open surgery for cancer in the esophagus or gastroesophageal junction. Exposure data Patients were divided into subcohorts by the use of open or minimally invasive surgical technique. Transthoracic esophagectomy according to the Ivor–Lewis technique was the standard approach in the open surgery group for middle and lower third esophageal as well as junctional tumors whereas a three-field McKeown approach was used for upper third esophageal tumors. In the MIE group, a total minimally invasive approach was applied with either an intrathoracic or neck anastomosis depending on the tumor location. A dedicated team of experienced esophageal cancer surgeons performed all procedures. The MIE included the laparoscopic mobilization of the stomach and en-bloc resection of lymph nodes with the patient in supine position. The gastric tube was constructed with the use of linear Endo-GIA triple staplers with a bridge of tissue left in the proximal part anchored to the specimen enabling the pull up in the thorax for the reconstruction. The patient was then put in the prone position for the following thoracoscopy. The intrathoracic anastomosis was performed with linear stapler and the remaining defect was closed with V-loc sutures. The specimen was removed through a mini thoracotomy. Patients requiring three-field dissection esophagectomy received a hand-sutured anastomosis in the neck.14 Outcome data All postoperative complications including anastomotic leakage or conduit necrosis, verified with endoscopy or radiological examination were recorded, and classified according to the Clavien–Dindo scoring system.15 Length of hospital stay and number of resected lymph nodes were compiled. Overall all-cause 30 and 90-day mortality, and long-term survival was recorded. Statistical analyses Differences between the groups concerning binary variables have been analyzed with the Chi2 test. For postoperative 30 and 90-day mortality, and one-year survival logistic regression models were used to calculate univariate and multivariate adjusted odds ratios (OR) with 95% confidence intervals (CI). Cox proportional hazard regression models expressed in hazard ratios (HR) were used to assess the association between exposure and 3-year survival after surgery. The following confounders with categorizations were predefined and adjusted for in all above-mentioned models in the analyses: ASA-score (ordinal I-IV), neoadjuvant therapy (yes or no), and clinical T-stage (categorical according to TNM 7th ed.). Minimally invasive procedures that were converted to open were analyzed in the MIE group. The regional ethics committee at Karolinska University Hospital, Stockholm, Sweden approved the study. RESULTS During the study period 2007–2017, 366 consecutive patients underwent esophagectomy with curative intent for esophageal or gastroesophageal junction cancer (Table 1). All patients were operated electively and the majority of patients were male. Open esophagectomy was the only used technique in the beginning of the study period. In total, 165 (45.1%) were operated with open technique and 201 (54.9%) with MIE. The groups were comparable regarding base line characteristics. The clinical tumor stage was slightly higher in the minimally invasive group while more patients were clinically node positive in those undergoing an open operation. The majority of patients in the minimally invasive group (62.2%) received neoadjuvant chemoradiotherapy, while the patients in the open surgery group were more evenly divided between neoadjuvant chemotherapy, chemoradiotherapy, and surgery alone (Table 1). Table 1 Characteristics of patients with esophageal cancer stratified by surgical technique n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) †Tumor stage was assessed by endoscopy and PET computed tomography with optional use of endoscopic ultrasonography. ASA, American Society of Anesthesiologists; PET, positron emission tomography. View Large Table 1 Characteristics of patients with esophageal cancer stratified by surgical technique n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) †Tumor stage was assessed by endoscopy and PET computed tomography with optional use of endoscopic ultrasonography. ASA, American Society of Anesthesiologists; PET, positron emission tomography. View Large The mean operation time was 39 minutes shorter in the MIE group (P < 0.001). Mean peroperative blood loss was 226 mL in the MIE group and 759 mL in the open group (P < 0.001). Total postoperative complication rate was 60.2% in the MIE group compared to 78.8% in the open group, P < 0.001 (Table 2). The intrathoracic anastomotic leak rate was 16.9% in the MIE group versus 16.8% in the open group (ns). The leak rate for neck anastomoses was 29.6% in MIE versus 26.5% in open (ns). Postoperative complications classified according to the Clavien–Dindo classification system as grade IIIb-V occurred more frequently after open surgery compared to MIE (38.2% vs. 28.4%, P = 0.046). Table 2 Outcome of treatment according to surgical technique n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 View Large Table 2 Outcome of treatment according to surgical technique n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 View Large MIE patients had a significantly shorter median hospital stay compared to patients who underwent open surgery (14 days vs. 24 days). Mean number of resected lymph nodes was 31 in the MIE group, and 22 in the open group, P < 0.001, whereas the R0 resection rate did not differ between the two groups (91.5% in the MIE group, and 85.0% in the open group and, P = 0.057, Table 2). Interestingly, the number of resected lymph nodes in the open group after the introduction of MIE remained 22. The 90-day postoperative mortality was 6.7% in the MIE group compared to 10.3% in the open group (P = 0.230). Similarly, the adjusted OR for 90-day mortality in patients in the MIE group was 0.53 (95% CI 0.23–1.19), P = 0.124, (Table 3). One-year and 3-year survival was improved in the MIE group but those differences did not reach statistical significance (Table 3, Fig. 1). Fig. 1 View largeDownload slide Kaplan–Meier survival curve according to surgical technique for patients operated due to esophageal cancer. Fig. 1 View largeDownload slide Kaplan–Meier survival curve according to surgical technique for patients operated due to esophageal cancer. Table 3 Survival analyses in univariate and multivariate regression models according to surgical technique (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 †Adjusted for age, ASA score, neoadjuvant treatment, and clinical tumor stage. ASA, American Society of Anesthesiologists. View Large Table 3 Survival analyses in univariate and multivariate regression models according to surgical technique (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 †Adjusted for age, ASA score, neoadjuvant treatment, and clinical tumor stage. ASA, American Society of Anesthesiologists. View Large DISCUSSION This single institution consecutive case cohort study aimed to evaluate the effects of MIE compared to open esophagectomy concerning peroperative bleeding, operation time, lymph node yield, complications, length of stay, and overall survival. The results showed a decreased number of postoperative complications, and reduced risk of severe postoperative complications with a Clavien–Dindo score of IIIb or higher in the MIE group. The number of resected lymph nodes was statistically significant increased indicating that MIE is a technique with high oncological quality, which the high number of R0 resections supports. Limitations of the study include the observational design with risk of selection bias potentially leading to some base line differences between the groups. Patient selection could possibly influence the results, however our resection rate during the last years has increased, which makes it unlikely that the improvement would be due to selection bias. A multivariable regression model including these variables (age, ASA score, neoadjuvant treatment, and clinical tumor stage) has been performed to adjust for these differences. Another disadvantage is the fact the type of surgery is not evenly distributed over the years of the study period with an inherent risk of residual confounding by possible incremental improvements in perioperative care during the study period. Strengths of the study include that the same team of surgeons performed all operations, and that the introduction of the new technique eventually included all patients, which consequently reduced the risk of selection bias. All data were prospectively recorded. It has been previously shown that there is a significant learning curve in the introduction of minimally invasive surgical technique.16 This study includes the first 201 MIEs performed at our unit, thus including the entire learning curve, indicating that the introduction of the new technique was performed in a safe way, at least not worse than the old open surgery standard.13 A recent study of the learning curve in MIE showed that the average center caseload to reach plateau level, with regard to postoperative complications and length of stay took as much as 119 operations.17 Our results are consistent with previous studies showing a decreased risk of postoperative morbidity and mortality4–5,7,9,10,18 among patients who underwent MIE compared to those who had an open surgery. In this study, the improved postoperative outcomes in the MIE group may have been influenced by an enhanced recovery program (ERP), which was introduced for esophageal cancer patients in our unit in 2014. It has previously been demonstrated that ERP following esophagectomy is associated with a reduction in the incidence of anastomotic leakage; nonsurgical complications and length of hospital stay.19–22 After launching ERP, all patients who underwent an esophagectomy were included in this program regardless of the type of surgery. However, the majority of the patients after 2014 had an MIE and consequently this group of patients had a greater benefit of the program compared to the open surgery group. On the other hand, MIE can be considered a component of ERP with an independent synergistic effect.23 The results after MIE, which in this study included the entire learning curve, were better than after open surgery despite the well-documented long learning curve of MIE.17 In accordance with previous studies, we could also demonstrate a significantly reduced peroperative bleeding in the MIE group.4,6 We could also, somewhat surprisingly, demonstrate a shorter operation time for MIE, which contrasts with previously published series.4,6 A possible explanation could be the superior vision for all surgeons’, and the fact that the same dedicated team with long experience in laparoscopic surgery prior to the implementation of MIE performed all operations. The finding that MIE may yield a significantly larger number of resected lymph nodes than open esophagectomy has been described previously.7 The excellent view of the operation field and the wide bimanual operation field access, as well as the favorable surgeon’ ergonomic position during the thoracoscopic dissection in the prone position could explain the improved lymph node harvesting. At the same time, the numbers of resected lymph nodes in the open group did not increase after the introduction of MIE. The trend toward increased number of R0 resections in the MIE group in our analysis might be attributed to the fact that more patients within this cohort received neoadjuvant chemoradiotherapy compared to the open group. It is well known that chemoradiotherapy is effective in clinical down staging and thus offers an improved locoregional control and subsequently increases the chance for R0 resection.24–26 Nevertheless, advanced tumors, T4, were overrepresented among the MIE, which should mitigate, to some extent, this imbalance in preoperative oncological treatment. In addition, neoadjuvant chemoradiotherapy is well known for reducing the total lymph node yield,24–28 which makes the higher yield after MIE even more noteworthy. Finally, our results demonstrate a trend toward improved 3-year survival after MIE compared to open surgery, though not statistically significant. It has to be pointed out that the patients in the MIE group in this study have a shorter average follow-up time than in the open group, which decreases the power of the overall survival analyses. Furthermore, a part of this trend could be linked to a higher proportion of MIE patients who received neoadjuvant chemoradiotherapy compared to open surgery group. However, it seems unlikely that this was the sole explanation as the open esophagectomy patients received more neoadjuvant chemotherapy and the optimal type of neoadjuvant therapy with regard to long-term survival remains debatable.24,25,28 A trend toward better survival after MIE has also been described in preliminary data from a recently completed French RCT suggesting improved survival among patients submitted to HMIE compared to those who underwent open surgery.9 A possible survival advantage after MIE could perhaps be attributed to a reduced risk of postoperative morbidity, quicker postoperative recovery, and theoretically perhaps less immune system impairment than open esophagectomy, contributing to a positive long-term oncological outcome.5 In conclusion, this study suggests that MIE at a high volume center with a devoted specialist team decreases the operation time, peroperative bleeding, length of hospital stay, and decreases the risk of postoperative morbidity compared to open esophagectomy. It also shows that the lymph node yield was better in MIE than in open surgery in this cohort. Notes Specific author contribution: Study design: Fredrik Klevebro, Magnus Nilsson, Lars Lundell, Ioannis Rouvelas; Data gathering: Fredrik Klevebro, Satoshi Kamiya, Chiara Maria Scandavini; Analyses: Fredrik Klevebro, Ioannis Rouvelas; Manuscript writing and review: Fredrik Klevebro, Chiara Maria Scandavini, Satoshi Kamiya, Magnus Nilsson, Lars Lundell, Ioannis Rouvelas. The authors have no conflicts of interest. References 1 Napier K J , Scheerer M , Misra S . Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities . World J Gastrointest Oncol 2014 ; 6 : 112 – 20 . Google Scholar Crossref Search ADS PubMed 2 Lagergren J . Oesophageal cancer in 2014: advances in curatively intended treatment . Nat Rev Gastroenterol Hepatol 2015 ; 12 : 74 – 75 . Google Scholar Crossref Search ADS PubMed 3 Rouvelas I , Zeng W , Lindblad M , Viklund P , Ye W , Lagergren J . Survival after surgery for oesophageal cancer: a population-based study . Lancet Oncol 2005 ; 6 : 864 – 70 . Google Scholar Crossref Search ADS PubMed 4 Biere S S , van Berge Henegouwen M I , Maas K W et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial . Lancet North Am Ed 2012 ; 379 : 1887 – 92 . Google Scholar Crossref Search ADS 5 Briez N , Piessen G , Torres F , Lebuffe G , Triboulet J P , Mariette C . Effects of hybrid minimally invasive oesophagectomy on major postoperative pulmonary complications . Br J Surg 2012 ; 99 : 1547 – 53 . Google Scholar Crossref Search ADS PubMed 6 Smithers B M , Gotley D C , Martin I , Thomas J M . Comparison of the outcomes between open and minimally invasive esophagectomy . Ann Surg 2007 ; 245 : 232 – 40 . Google Scholar Crossref Search ADS PubMed 7 Yerokun B A , Sun Z , Yang C F J et al. Minimally invasive versus open esophagectomy for esophageal cancer: a population-based analysis . Ann Thorac Surg 2016 ; 102 : 416 – 23 . Google Scholar Crossref Search ADS PubMed 8 Maas K W , Cuesta M A , van Berge Henegouwen M I et al. Quality of life and late complications after minimally invasive compared to open esophagectomy: results of a randomized trial . World J Surg 2015 ; 39 : 1986 – 93 . Google Scholar Crossref Search ADS PubMed 9 Christophe Mariette B M D P , Cecile Dalban, Denis Collet, Pascal-Alexandre Thomas, Cecile Brigand, Thierry Perniceni, Nicolas Carrere, Franck Bonnetain, Guillaume Piessen; Department of Digestive and Oncologic Surgery, Claude Huriez University Hospital, Lille, France; Department of Digestive Surgery, Pontchaillou University Hospital, Rennes, France; CHU Estaing, Clermond Ferrand, France; Centre Georges-François Leclerc, Dijon, France; Haut-Levêque University Hospital, Bordeaux, France; Department of Thoracic Surgery, Hôpital Nord, Marseille, France; Department of Digestive Surgery, Hautepierre University Hospital, Strasbourg, France; Institut Mutualiste Montsouris, Paris, France; Department of Digestive Surgery, Purpan University Hospital, Toulouse, France; Centre Hospitalier Régional et Universitaire de Besançon, Besançon, France; University Hospital of Lille, Lille, France. ESMO 2017: MIRO Trial: 3-Year Outcomes Favor Laparoscopic Surgery for Esophageal Cancer. [Abstract] . In press 2017 (forthcoming) . 10 Luketich J D , Alvelo-Rivera M , Buenaventura P O et al. Minimally invasive esophagectomy: outcomes in 222 patients . Ann Surg 2003 ; 238 : 486 – 94 ; discussion 94–5 . Google Scholar PubMed 11 Mamidanna R , Bottle A , Aylin P , Faiz O , Hanna G B . Short-term outcomes following open versus minimally invasive esophagectomy for cancer in England: a population-based national study . Ann Surg 2012 ; 255 : 197 – 203 . Google Scholar Crossref Search ADS PubMed 12 Yibulayin W , Abulizi S , Lv H , Sun W . Minimally invasive oesophagectomy versus open esophagectomy for resectable esophageal cancer: a meta-analysis . World J Surg Oncol 2016 ; 14 : 304 . Google Scholar Crossref Search ADS PubMed 13 Nilsson M , Kamiya S , Lindblad M , Rouvelas I . Implementation of minimally invasive esophagectomy in a tertiary referral center for esophageal cancer . J Thorac Dis 2017 ; 9 : S817 – 25 . Google Scholar Crossref Search ADS PubMed 14 Irino T , Tsai J A , Ericson J , Nilsson M , Lundell L , Rouvelas I . Thoracoscopic side-to-side esophagogastrostomy by use of linear stapler-a simplified technique facilitating a minimally invasive Ivor-Lewis operation . Langenbecks Arch Surg 2016 ; 401 : 315 – 22 . Google Scholar Crossref Search ADS PubMed 15 Clavien P A , Sanabria J R , Strasberg S M . Proposed classification of complications of surgery with examples of utility in cholecystectomy . Surgery 1992 ; 111 : 518 – 26 . Google Scholar PubMed 16 Schmidt H M , Gisbertz S S , Moons J et al. Defining benchmarks for transthoracic esophagectomy: A multicenter analysis of total minimally invasive esophagectomy in low risk patients . Ann Surg 2017 ; 266 : 814 – 21 . Google Scholar Crossref Search ADS PubMed 17 van Workum F , Stenstra M , Berkelmans G H K et al. Learning curve and associated morbidity of minimally invasive esophagectomy: a retrospective multicenter study . Ann Surg 2017 . 18 Palanivelu C , Prakash A , Senthilkumar R et al. Minimally invasive esophagectomy: thoracoscopic mobilization of the esophagus and mediastinal lymphadenectomy in prone position–experience of 130 patients . J Am Coll Surg 2006 ; 203 : 7 – 16 . Google Scholar Crossref Search ADS PubMed 19 Markar S R , Karthikesalingam A , Low D E . Enhanced recovery pathways lead to an improvement in postoperative outcomes following esophagectomy: systematic review and pooled analysis . Dis Esophagus 2015 ; 28 : 468 – 75 . Google Scholar Crossref Search ADS PubMed 20 Rotter T , Kinsman L , James E et al. Clinical pathways: effects on professional practice, patient outcomes, length of stay and hospital costs . Cochrane Database Syst Rev 2010 : CD006632 . 21 Munitiz V , Martinez-de-Haro L F , Ortiz A , Ruiz-de-Angulo D , Pastor P , Parrilla P . Effectiveness of a written clinical pathway for enhanced recovery after transthoracic (Ivor Lewis) oesophagectomy . Br J Surg 2010 ; 97 : 714 – 8 . Google Scholar Crossref Search ADS PubMed 22 Lee L , Li C , Robert N et al. Economic impact of an enhanced recovery pathway for oesophagectomy . Br J Surg 2013 ; 100 : 1326 – 34 . Google Scholar Crossref Search ADS PubMed 23 Findlay J M , Gillies R S , Millo J , Sgromo B , Marshall R E , Maynard N D . Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines . Ann Surg 2014 ; 259 : 413 – 31 . Google Scholar Crossref Search ADS PubMed 24 Burmeister B H , Thomas J M , Burmeister E A et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial . Eur J Cancer 2011 ; 47 : 354 – 60 . Google Scholar Crossref Search ADS PubMed 25 Klevebro F , Alexandersson von Dobeln G , Wang N et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction . Ann Oncol 2016 ; 27 : 660 – 7 . Google Scholar Crossref Search ADS PubMed 26 van Hagen P , Hulshof M C , van Lanschot J J et al. Preoperative chemoradiotherapy for esophageal or junctional cancer . N Engl J Med 2012 ; 366 : 2074 – 84 . Google Scholar Crossref Search ADS PubMed 27 Klevebro F , Lindblad M , Johansson J , Lundell L , Nilsson M . Outcome of neoadjuvant therapies for cancer of the oesophagus or gastro-oesophageal junction based on a national data registry . Br J Surg 2016 ; 103 : 1864 – 73 . Google Scholar Crossref Search ADS PubMed 28 Stahl M , Walz M K , Stuschke M et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction . J Clin Oncol 2009 ; 27 : 851 – 6 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Single center consecutive series cohort study of minimally invasive versus open resection for cancer in the esophagus or gastroesophageal junction

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
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1120-8694
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1442-2050
DOI
10.1093/dote/doy027
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Abstract

Summary Minimally invasive esophagectomy (MIE) has been introduced at many centers worldwide as evidence is accumulating that it reduces the risk of postoperative morbidity and mortality and decreases the length of hospital stay compared to conventional open esophagectomy. The study is a single institution cohort study of 366 consecutive patients treated with curative intent for cancer in the esophagus or gastroesophageal junction, comparing MIE to open surgery. The outcomes studied were peroperative bleeding, operation time, lymph node yield, complications, length of stay and overall survival. The results showed that MIE was associated with reduced peroperative bleeding and operation time. The patients in the MIE group had a statistically significant reduced risk of postoperative complications, 60.2% compared to 78.8% in the open group. In the MIE group 28.4% of the patients had postoperative complications classified according to the Clavien–Dindo classification system as grade IIIb-V compared to 38.2% in the open group, P = 0.046. Median hospital stay was reduced with 10 days comparing MIE to open surgery, P < 0.001. Mean number of resected lymph nodes was 31 in the MIE group and 22 in the open group (P < 0.001), while the R0 resections were 91.5% versus 85% (P = 0.057). Overall long-term survival was higher in the MIE group, a difference that however did not reach statistical significance (adjusted hazard ratio for three-year survival 0.76, 95% CI 0.54–1.08). In conclusion, MIE at a high volume center with a devoted specialist team reduces the risk of peroperative bleeding, operation time, and severe postoperative complications compared to open surgery for esophageal or junctional cancer. The number of resected lymph nodes was increased and the R0 resections were similar between the groups indicating a good oncological quality of the surgery. INTRODUCTION Surgical resection of the primary tumor and regional lymph nodes remains the most important part of the curative intended treatment of cancer in the esophagus or gastroesophageal junction.1–3 Minimally invasive esophagectomy (MIE) can be performed with laparoscopy and thoracoscopy or a combination of the above with open dissection, so called hybrid-MIE (HMIE). These techniques have been introduced in many centers across the world over recent years and have been shown to reduce the risk of postoperative pulmonary complications compared to open surgery.4–7 Additionally, the quality of life was also improved one year after treatment in the MIE group.8 A recent randomized controlled trial (RCT) demonstrated a reduced risk of major postoperative morbidity from 64.4% after open surgery to 35.9% after HMIE with a combination of laparoscopic mobilization of the stomach and open thoracotomy.9 A retrospective single institution series of 222 patients treated with MIE showed a 30-day mortality of 1.4% and reduced length of hospital stay compared to previous series of open surgery.10 The scientific evidence for MIE is however limited with very few and relatively small RCTs combined with retrospective single institution studies. In a large population based cohort study in England, 7502 esophagectomies were evaluated. The results showed increased risk of reintervention in the MIE group and no differences concerning complications.11 A recent meta-analysis included 15,790 patients from 57 studies but only one of which was an RCT; the results showed reduced risk of postoperative morbidity and mortality, and no difference in the number of harvested lymph nodes after MIE compared to open surgery.12 Nevertheless, most studies have focused on the short-term outcomes after surgery. On the other hand, the long-term oncological results and possible effects on survival are poorly studied. The aim of this study is therefore to compare the short-term and long-term results of all MIEs and open resections performed in our institution over the period 2007–2017. METHOD Data source and data collection This study is a cohort study of all patients diagnosed with cancer of the esophagus or gastro-esophageal junction over the period 2007–2017, and was treated with esophagectomy with curative intent. The implementation of MIE, which has been described in detail elsewhere,13 was introduced in our unit in 2012 after fellowship and visit to high volume centers abroad as well as extensive collaboration and exchange program with colleagues from Tokyo, Japan. The technique was initially indicated in selected patients without large, bulky tumors, or advanced lymph node metastases. After 2015, all patients were operated with MIE except from cases requiring colonic interposition. All esophagectomies were extracted from the hospital surgical planning system (ORBIT) and cross-matched for validation with the electronic patient chart system (TakeCare). The data were retrieved and checked by 3 of the co-authors (FK, CMS, SK). Detailed clinical information regarding patient baseline characteristics (age, gender, American Society of Anesthesiologists (ASA)-score), tumor type, clinical tumor stage (TNM), neoadjuvant therapy, type of surgical procedure, and outcomes (postoperative complications, Clavien–Dindo score (C–D), length of hospital stay) were manually extracted from patient charts in TakeCare. The clinical TNM for all included patients was assessed by the use of endoscopy, and positron emission tomography computed tomography (PET-CT) and in selected cases endoscopic ultrasonography. The histopathology reports of the specimens were reviewed in order to confirm the pathologic tumor stage, the number of harvested lymph nodes and the radicality of the resection. Patients with macroscopic residual disease were excluded. Hypothesis Minimally invasive esophagectomy decreases the risk of postoperative complications without impairing the oncological quality of the resection or long-term survival compared to open surgery for cancer in the esophagus or gastroesophageal junction. Exposure data Patients were divided into subcohorts by the use of open or minimally invasive surgical technique. Transthoracic esophagectomy according to the Ivor–Lewis technique was the standard approach in the open surgery group for middle and lower third esophageal as well as junctional tumors whereas a three-field McKeown approach was used for upper third esophageal tumors. In the MIE group, a total minimally invasive approach was applied with either an intrathoracic or neck anastomosis depending on the tumor location. A dedicated team of experienced esophageal cancer surgeons performed all procedures. The MIE included the laparoscopic mobilization of the stomach and en-bloc resection of lymph nodes with the patient in supine position. The gastric tube was constructed with the use of linear Endo-GIA triple staplers with a bridge of tissue left in the proximal part anchored to the specimen enabling the pull up in the thorax for the reconstruction. The patient was then put in the prone position for the following thoracoscopy. The intrathoracic anastomosis was performed with linear stapler and the remaining defect was closed with V-loc sutures. The specimen was removed through a mini thoracotomy. Patients requiring three-field dissection esophagectomy received a hand-sutured anastomosis in the neck.14 Outcome data All postoperative complications including anastomotic leakage or conduit necrosis, verified with endoscopy or radiological examination were recorded, and classified according to the Clavien–Dindo scoring system.15 Length of hospital stay and number of resected lymph nodes were compiled. Overall all-cause 30 and 90-day mortality, and long-term survival was recorded. Statistical analyses Differences between the groups concerning binary variables have been analyzed with the Chi2 test. For postoperative 30 and 90-day mortality, and one-year survival logistic regression models were used to calculate univariate and multivariate adjusted odds ratios (OR) with 95% confidence intervals (CI). Cox proportional hazard regression models expressed in hazard ratios (HR) were used to assess the association between exposure and 3-year survival after surgery. The following confounders with categorizations were predefined and adjusted for in all above-mentioned models in the analyses: ASA-score (ordinal I-IV), neoadjuvant therapy (yes or no), and clinical T-stage (categorical according to TNM 7th ed.). Minimally invasive procedures that were converted to open were analyzed in the MIE group. The regional ethics committee at Karolinska University Hospital, Stockholm, Sweden approved the study. RESULTS During the study period 2007–2017, 366 consecutive patients underwent esophagectomy with curative intent for esophageal or gastroesophageal junction cancer (Table 1). All patients were operated electively and the majority of patients were male. Open esophagectomy was the only used technique in the beginning of the study period. In total, 165 (45.1%) were operated with open technique and 201 (54.9%) with MIE. The groups were comparable regarding base line characteristics. The clinical tumor stage was slightly higher in the minimally invasive group while more patients were clinically node positive in those undergoing an open operation. The majority of patients in the minimally invasive group (62.2%) received neoadjuvant chemoradiotherapy, while the patients in the open surgery group were more evenly divided between neoadjuvant chemotherapy, chemoradiotherapy, and surgery alone (Table 1). Table 1 Characteristics of patients with esophageal cancer stratified by surgical technique n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) †Tumor stage was assessed by endoscopy and PET computed tomography with optional use of endoscopic ultrasonography. ASA, American Society of Anesthesiologists; PET, positron emission tomography. View Large Table 1 Characteristics of patients with esophageal cancer stratified by surgical technique n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) n (%) Open surgery Minimal invasive P-value Total 165 (45.1) 201 (54.9) Age, median (range) 65 (36–82) 67 (33–83) 0.146 Gender 0.886 Female 33 (20.0) 39 (19.4) Male 132 (80.0) 162 (80.6) Treatment year, median (range) 2010 (2007–2017) 2015 (2012–2017) Histological tumor type 0.353 Adenocarcinoma 120 (72.7) 153 (76.1) Squamous cell carcinoma 42 (25.5) 41 (20.4) Other 3 (1.8) 7 (3.5) Clinical T-stage† <0.001 T1 28 (17.5) 19 (9.5) T2 34 (21.3) 31 (15.4) T3 93 (58.1) 119 (59.2) T4 5 (3.1) 32 (15.9) Missing data 5 – Clinical N-stage† 0.007 N-negative 60 (37.5) 104 (51.7) N-positive 100 (62.5) 97 (48.3) Missing data 5 – ASA-score 0.459 I 42 (25.5) 66 (32.8) II 87 (52.7) 99 (49.3) III 35 (21.2) 35 (17.4) IV 1 (0.6) 1 (0.5) Location of anastomosis 0.002 Intrathoracic 131 (79.4) 130 (64.7) Cervical 34 (20.6) 71 (35.3) Neoadjuvant therapy < 0.001 Surgery alone 51 (30.9) 56 (27.9) Neoadjuvant chemotherapy 59 (35.8) 20 (10.0) Neoadjuvant chemoradiotherapy 55 (33.3) 125 (62.2) †Tumor stage was assessed by endoscopy and PET computed tomography with optional use of endoscopic ultrasonography. ASA, American Society of Anesthesiologists; PET, positron emission tomography. View Large The mean operation time was 39 minutes shorter in the MIE group (P < 0.001). Mean peroperative blood loss was 226 mL in the MIE group and 759 mL in the open group (P < 0.001). Total postoperative complication rate was 60.2% in the MIE group compared to 78.8% in the open group, P < 0.001 (Table 2). The intrathoracic anastomotic leak rate was 16.9% in the MIE group versus 16.8% in the open group (ns). The leak rate for neck anastomoses was 29.6% in MIE versus 26.5% in open (ns). Postoperative complications classified according to the Clavien–Dindo classification system as grade IIIb-V occurred more frequently after open surgery compared to MIE (38.2% vs. 28.4%, P = 0.046). Table 2 Outcome of treatment according to surgical technique n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 View Large Table 2 Outcome of treatment according to surgical technique n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 n (%) Open surgery Minimal invasive P-value Operation time (mean min) 432 393 <0.001 Peroperative bleeding (mean mL) 759 226 <0.001 Postoperative complication 130 (78.8) 123 (60.2) <0.001 Conversion to open technique – 10 (5.0) – Intrathoracic anastomotic leak 22 (16.8) 22 (16.9) 1.0 Cervical anastomotic leak 9 (26.5) 21 (29.6) 0.820 Clavien–Dindo Score 0.518 II 39 (30.0) 42 (34.2) IIIa 28 (21.5) 24 (19.5) IIIb 17 (13.1) 21 (17.1) Iva 22 (16.9) 22 (17.9) IVb 19 (14.6) 9 (7.3) V 5 (3.9) 5 (4.1) Clavien–Dindo score ≥ IIIb 63 (38.2) 57 (28.4) 0.046 Length of stay (median days) 24 14 <0.001 Mean number of resected lymph nodes 22 31 <0.001 Mean number of metastatic lymph nodes 3 3 0.214 R0 resection margins 130 (85.0) 173 (91.5) 0.057 30-day mortality 5 (3.0) 5 (2.7) 0.834 90-day mortality 17 (10.3) 12 (6.7) 0.230 View Large MIE patients had a significantly shorter median hospital stay compared to patients who underwent open surgery (14 days vs. 24 days). Mean number of resected lymph nodes was 31 in the MIE group, and 22 in the open group, P < 0.001, whereas the R0 resection rate did not differ between the two groups (91.5% in the MIE group, and 85.0% in the open group and, P = 0.057, Table 2). Interestingly, the number of resected lymph nodes in the open group after the introduction of MIE remained 22. The 90-day postoperative mortality was 6.7% in the MIE group compared to 10.3% in the open group (P = 0.230). Similarly, the adjusted OR for 90-day mortality in patients in the MIE group was 0.53 (95% CI 0.23–1.19), P = 0.124, (Table 3). One-year and 3-year survival was improved in the MIE group but those differences did not reach statistical significance (Table 3, Fig. 1). Fig. 1 View largeDownload slide Kaplan–Meier survival curve according to surgical technique for patients operated due to esophageal cancer. Fig. 1 View largeDownload slide Kaplan–Meier survival curve according to surgical technique for patients operated due to esophageal cancer. Table 3 Survival analyses in univariate and multivariate regression models according to surgical technique (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 †Adjusted for age, ASA score, neoadjuvant treatment, and clinical tumor stage. ASA, American Society of Anesthesiologists. View Large Table 3 Survival analyses in univariate and multivariate regression models according to surgical technique (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 (95% confidence interval) Odds ratio 90-day mortality 1.0 0.63 (0.29–1-35) 0.233 Adjusted odds ratio 90-day mortality† 1.0 0.53 (0.23–1.19) 0.124 Odds ratio 1-year mortality 1.0 1.09 (0.65–1.82) 0.738 Adjusted odds ratio 1-year mortality† 1.0 0.92 (0.53–1.57) 0.751 Hazard ratio 3-year mortality 1.0 0.82 (0.58–1.14) 0.233 Adjusted hazard ratio 3-year mortality† 1.0 0.76 (0.54–1.08) 0.127 †Adjusted for age, ASA score, neoadjuvant treatment, and clinical tumor stage. ASA, American Society of Anesthesiologists. View Large DISCUSSION This single institution consecutive case cohort study aimed to evaluate the effects of MIE compared to open esophagectomy concerning peroperative bleeding, operation time, lymph node yield, complications, length of stay, and overall survival. The results showed a decreased number of postoperative complications, and reduced risk of severe postoperative complications with a Clavien–Dindo score of IIIb or higher in the MIE group. The number of resected lymph nodes was statistically significant increased indicating that MIE is a technique with high oncological quality, which the high number of R0 resections supports. Limitations of the study include the observational design with risk of selection bias potentially leading to some base line differences between the groups. Patient selection could possibly influence the results, however our resection rate during the last years has increased, which makes it unlikely that the improvement would be due to selection bias. A multivariable regression model including these variables (age, ASA score, neoadjuvant treatment, and clinical tumor stage) has been performed to adjust for these differences. Another disadvantage is the fact the type of surgery is not evenly distributed over the years of the study period with an inherent risk of residual confounding by possible incremental improvements in perioperative care during the study period. Strengths of the study include that the same team of surgeons performed all operations, and that the introduction of the new technique eventually included all patients, which consequently reduced the risk of selection bias. All data were prospectively recorded. It has been previously shown that there is a significant learning curve in the introduction of minimally invasive surgical technique.16 This study includes the first 201 MIEs performed at our unit, thus including the entire learning curve, indicating that the introduction of the new technique was performed in a safe way, at least not worse than the old open surgery standard.13 A recent study of the learning curve in MIE showed that the average center caseload to reach plateau level, with regard to postoperative complications and length of stay took as much as 119 operations.17 Our results are consistent with previous studies showing a decreased risk of postoperative morbidity and mortality4–5,7,9,10,18 among patients who underwent MIE compared to those who had an open surgery. In this study, the improved postoperative outcomes in the MIE group may have been influenced by an enhanced recovery program (ERP), which was introduced for esophageal cancer patients in our unit in 2014. It has previously been demonstrated that ERP following esophagectomy is associated with a reduction in the incidence of anastomotic leakage; nonsurgical complications and length of hospital stay.19–22 After launching ERP, all patients who underwent an esophagectomy were included in this program regardless of the type of surgery. However, the majority of the patients after 2014 had an MIE and consequently this group of patients had a greater benefit of the program compared to the open surgery group. On the other hand, MIE can be considered a component of ERP with an independent synergistic effect.23 The results after MIE, which in this study included the entire learning curve, were better than after open surgery despite the well-documented long learning curve of MIE.17 In accordance with previous studies, we could also demonstrate a significantly reduced peroperative bleeding in the MIE group.4,6 We could also, somewhat surprisingly, demonstrate a shorter operation time for MIE, which contrasts with previously published series.4,6 A possible explanation could be the superior vision for all surgeons’, and the fact that the same dedicated team with long experience in laparoscopic surgery prior to the implementation of MIE performed all operations. The finding that MIE may yield a significantly larger number of resected lymph nodes than open esophagectomy has been described previously.7 The excellent view of the operation field and the wide bimanual operation field access, as well as the favorable surgeon’ ergonomic position during the thoracoscopic dissection in the prone position could explain the improved lymph node harvesting. At the same time, the numbers of resected lymph nodes in the open group did not increase after the introduction of MIE. The trend toward increased number of R0 resections in the MIE group in our analysis might be attributed to the fact that more patients within this cohort received neoadjuvant chemoradiotherapy compared to the open group. It is well known that chemoradiotherapy is effective in clinical down staging and thus offers an improved locoregional control and subsequently increases the chance for R0 resection.24–26 Nevertheless, advanced tumors, T4, were overrepresented among the MIE, which should mitigate, to some extent, this imbalance in preoperative oncological treatment. In addition, neoadjuvant chemoradiotherapy is well known for reducing the total lymph node yield,24–28 which makes the higher yield after MIE even more noteworthy. Finally, our results demonstrate a trend toward improved 3-year survival after MIE compared to open surgery, though not statistically significant. It has to be pointed out that the patients in the MIE group in this study have a shorter average follow-up time than in the open group, which decreases the power of the overall survival analyses. Furthermore, a part of this trend could be linked to a higher proportion of MIE patients who received neoadjuvant chemoradiotherapy compared to open surgery group. However, it seems unlikely that this was the sole explanation as the open esophagectomy patients received more neoadjuvant chemotherapy and the optimal type of neoadjuvant therapy with regard to long-term survival remains debatable.24,25,28 A trend toward better survival after MIE has also been described in preliminary data from a recently completed French RCT suggesting improved survival among patients submitted to HMIE compared to those who underwent open surgery.9 A possible survival advantage after MIE could perhaps be attributed to a reduced risk of postoperative morbidity, quicker postoperative recovery, and theoretically perhaps less immune system impairment than open esophagectomy, contributing to a positive long-term oncological outcome.5 In conclusion, this study suggests that MIE at a high volume center with a devoted specialist team decreases the operation time, peroperative bleeding, length of hospital stay, and decreases the risk of postoperative morbidity compared to open esophagectomy. It also shows that the lymph node yield was better in MIE than in open surgery in this cohort. Notes Specific author contribution: Study design: Fredrik Klevebro, Magnus Nilsson, Lars Lundell, Ioannis Rouvelas; Data gathering: Fredrik Klevebro, Satoshi Kamiya, Chiara Maria Scandavini; Analyses: Fredrik Klevebro, Ioannis Rouvelas; Manuscript writing and review: Fredrik Klevebro, Chiara Maria Scandavini, Satoshi Kamiya, Magnus Nilsson, Lars Lundell, Ioannis Rouvelas. The authors have no conflicts of interest. References 1 Napier K J , Scheerer M , Misra S . Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities . World J Gastrointest Oncol 2014 ; 6 : 112 – 20 . Google Scholar Crossref Search ADS PubMed 2 Lagergren J . Oesophageal cancer in 2014: advances in curatively intended treatment . Nat Rev Gastroenterol Hepatol 2015 ; 12 : 74 – 75 . 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Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Diseases of the Esophagus – Oxford University Press

Published: Oct 1, 2018

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