Oesophageal cancer (OC) is frequently diagnosed at an advanced stage and needs a multidisciplinary treatment strategy to achieve cure.[
] Neoadjuvant chemoradiotherapy (nCRT) is a standard pre-operative therapy for oesophageal squamous cell carcinoma (OSCC), in most countries.[ 1 2 3 ] Although oesophagectomy forms the cornerstone of multimodality treatment, it is still a challenging procedure, associated with significant morbidity and mortality.[ 4 5 ] Since the 1990s, minimally invasive approaches showed better post-operative outcomes, when compared to open approaches, without compromising the oncological results.[ 6 5 7 8 ] 9
The technical difficulties encountered during minimally invasive oesophagectomy (MIO) following nCRT include difficult tumour bed dissection and lymphadenectomy, resulting from radiation-induced inflammation.[
10 ] This is particularly relevant in OSCC, which is often located in the thoracic oesophagus, in close relation to vital mediastinal structures.[ 11 10 11 ] Although majority of the initial publications which have looked at nCRT for OC have employed open oesophagectomy approaches, there is emerging evidence showing the feasibility and 12 safety of minimally invasive approaches following nCRT.[ 4 5 10 11 12 13 14 15 16 17 18 ] However, there is heterogeneity in the tumour characteristics, types of operations performed, approaches and the extent of lymphadenectomy in the reported literature. Moreover, studies incorporating MIO following nCRT have been predominantly reported from the West, where adenocarcinoma involving the distal oesophagus or gastro-oesophageal junction (GOJ) is the dominant histological type.[ 19 13 ] To date, there is only a single randomised trial that compared the 14 safety and early oncological outcomes of MIO following nCRT versus neoadjuvant chemotherapy (nCT), for OSCC.[ ] Moreover, long-term oncological data are scarce for the combination of MIO and nCRT, in the treatment of OSCC. Hence, in this study, we have attempted to look at the real-world experience in relation to the feasibility, 4 safety and oncological outcomes of MIO, for OSCC, following nCRT. MATERIALS AND METHODS
After obtaining the institutional ethics committee approval, a retrospective review of OSCC patients undergoing MIO following nCRT, between January 2013 and December 2019, was performed. All data relevant for the study were obtained from a prospective database and the electronic medical records of the hospital.
The diagnosis of OSCC was confirmed by pre-treatment oesophago-gastroduodenoscopy and biopsy. The location and longitudinal extent of the tumour were determined using endoscopy and/or a contrast-enhanced computed tomography (CECT). A CECT of the thorax/abdomen was used as the staging investigation, in all patients.
18F-fluorodeoxyglucose-positron emission tomography and/or an endoscopic ultrasound were selectively performed. The clinical staging was done according to the American Joint Committee on Cancer (AJCC) 8 th Edition.[ ] The patients in the earlier part of the study, who were staged according to AJCC 7 20 th Edition, were re-categorised to assess the stage-wise survival and conformity of data for analysis. Medically fit patients with locally advanced, resectable cancer (cT1-2N1-2/cT3-4aN0-2) received nCRT. Patients with tumours primarily located within 5 cm of the upper oesophageal sphincter received definitive chemoradiotherapy and did not form part of this study.
In the first 2 years of the study, the nCRT regimen consisted of total external radiation of 45 Gy in 25 fractions with concurrent chemotherapy using either two cycles of cisplatin and 5-fluorouracil or five cycles of paclitaxel and carboplatin. Subsequently, nCRT was given according to the CROSS protocol: total external radiation of 41.4 Gy in weekly fractions of 1.8 Gy with concurrent chemotherapy using five cycles of paclitaxel and carboplatin.[
] The clinical re-assessment using a CECT scan was performed at about the 6-week mark following nCRT and this was followed by surgery. 2
A minimally invasive McKeown's oesophagectomy (MIMcKO) in the left semi-prone position with two-field lymph nodal dissection (2F-LND) followed by a trans-mediastinal gastric pull-up and a cervical anastomosis was performed for all patients. The operative approach was either a hybrid oesophagectomy (HO), i.e., thoracoscopy and laparotomy, or a thoraco-laparoscopic oesophagectomy (TLO). The extent of mediastinal LND achieved was classified as standard type: infracarinal, extended type: standard + right paratracheal/recurrent laryngeal nerve (RLN) chain and total: standard + bilateral paratracheal/RLN chains.[
] A thoracic-epidural catheter was placed in all patients, for post-operative analgesia. 21
The operating surgeon had prospectively recorded the difficulty encountered during the tumour dissection or the mediastinal lymphadenectomy. The technical difficulties during the operation following nCRT may be the result of either 'mediastinal fibrosis' or 'tumour desmoplasia', leading to obscured tissue planes. The surgery was labelled as 'difficult' if one or more of the above factors were documented to have limited the easiness of operative dissection. The difference in surgical difficulty was assessed based on the techniques of radiation delivery, location of the primary tumour and pathological response in the primary tumour.
The post-operative complications were classified using Esophagectomy Complications Consensus Group (ECCG) guidelines[
] and the severity of complications was graded with Clavien–Dindo grading (CDG).[ 22 ] Respiratory complications included pneumonia, pleural effusion, empyema, pneumothorax, pulmonary embolism or respiratory failure. Pneumonia was defined as fever or leucocytosis with infiltrates on chest X-ray or positive sputum or endotracheal aspirate culture. The duration of post-operative ventilation, intensive care unit (ICU) stay, post-operative length of stay (LOS), 30-day re-interventions and 30-day and 90-day mortality were recorded. 23
The completeness of the resection (R0–2) and the grade of tumour regression were recorded as per the College of American Pathologists (CAP) system.[
] The pathological staging (ypTNM) was performed using AJCC 8 20 th Edition.[ ] The overall survival (OS) was defined as the interval from surgery to death due to any cause, censored at last follow-up. The recurrence-free survival (RFS) was defined as the interval from surgery to either first recurrence or death due to any cause, censored at last follow-up. The recurrences were classified as local (anastomosis or conduit), regional (regional lymphatic basins) or distant (non-regional nodes and non-contiguous organs). Follow-up was terminated on 11 April 2020. 20
The categorical variables were expressed as frequencies with percentages, while continuous variables were expressed as mean ± standard deviation or median with interquartile range or range, as appropriate. The proportion test was used to compare the difference in surgical difficulty between groups. Time to event outcome was analysed by the Kaplan–Meier method and comparisons were made with log-rank test. Univariate Cox proportional hazard model was used. The differences were considered significant if
P < 0.05. Statistical analysis was performed using SPSS Version 21, Chicago, IL, USA. RESULTS
Seventy-five patients were included in the study, as detailed in
Figure 1. Demographics and tumour profile details are elaborated in Table 1. Figure 1:
Flow diagram showing the selection of study population
Demography, tumour profile and neoadjuvant chemoradiotherapy details
Neoadjuvant chemoradiotherapy details are summarized in
Table 1. Although all patients completed the radiotherapy component of nCRT, the concurrent chemotherapy course was completed only by 19 (25.3%) patients. In the CROSS regimen group ( n = 47), only 55.3% of patients could complete a minimum of four chemotherapy cycles. Overall, the most common reasons for not completing the concurrent chemotherapy were neutropenia (66.0%) and fatigue (10.7%). Surgical difficulty factors
Surgical difficulty factors are summarized in
Table 2. At least one surgical difficulty factor was encountered in 41 (54.7%) patients, and a combination of more than one factor was seen in 27 (36.0%) patients. The most common factor influencing the difficulty of surgical dissection was mediastinal fibrosis ( n = 38; 50.7%). The surgical difficulty was significantly increased in tumours located in the mid-thoracic oesophagus or those exhibiting incomplete pathological response. There was a trend towards reduced surgical difficulty following the application of newer radiation delivery techniques. Table 2:
Surgical difficulty factors in minimally invasive oesophagectomy following neoadjuvant chemoradiotherapy and surgical difficulty based on the radiation delivery technique, tumour location and pathological complete response of the primary tumour (
n=75) Surgery and peri-operative outcomes
Surgical and peri-operative outcomes are summarized in
Table 3. TLO was performed in 60 (80%) patients and HO in 15 (20%) patients. A total 2F-LND was attempted in all patients but could be completed only in eight (10.7%) patients. There were two conversions to open operation in the TLO group (laparotomy for colonic conduit, 1; thoracotomy due to dense adhesive fibrosis, 1) and one conversion in the HO group (thoracotomy due to dense adhesive fibrosis), with an overall conversion rate of 4.0%. The average duration of surgery (DuS) was 434.07 ± 43.97 min and the mean estimated blood loss (EBL) was 200.67 ± 123.43 mL. The DuS was significantly longer in the 'difficult' surgery group, compared to the 'not difficult' surgery group (447.32 ± 45.28 min vs. 418.09 ± 37.01 min; P = 003). However, there was no statistically significant difference in the EBL between these groups. Only one patient required post-operative elective ventilation and the median ICU stay was 1 day (range: 0–7 days). Table 3:
Peri-operative details and post-operative outcomes
Post-operative outcomes are summarized in
Table 3. The 30-day overall and major (CDG ≥3) post-operative complication rates were 48% and 20.0%, respectively. Respiratory complications (20.0%) including pneumonia (8.0%) were the most common complication. A detailed description of the classification and grading of complications is given in Table 3. The median post-operative LOS was 9 days (range: 6–33 days), the overall 30-day re-intervention rate was 10.7%, and there was no 30-day mortality. One patient who was stented for an anastomotic leak developed erosion of the stent into the left subclavian artery and died on the 50 th post-operative day. Oncological outcomes
The rate of complete resection (R0), the median lymph node yield (LNY) and the pathological complete response (pCR) achieved were 93.3%, 8 (range: 1–25) and 48%, respectively. The overall recurrence rate was 32.4%, and the majority of these involved a distant site (58.3%) [
Table 4]. The mean OS time was 62.2 months (95% confidence interval [CI]: 52.6–71.8) and the mean RFS time was 53.5 months (95% CI: 43.5–63.5). The 1-, 2- and 3-year OS was 89.5%, 78.8% and 64.4% and corresponding RFS was 71.1%, 61.3% and 56.6% [Figure 2a and b]. The risk of dying was high for pathological stage II (Hazard ratio [HR]: 3.43, 95% CI: 0.69–17.16, P = 0.133) and stage III (HR: 5.46, 95% CI: 1.84–16.21, P = 0.002), as compared to stage I. Those who had pathological stage II (HR: 4.51, 95% CI: 1.34–15.15, P = 0.015) and stage III (HR: 6.51, 95% CI: 2.63–16.11, P < 0.001) had a high chance of recurrence, as compared to those with stage I [Figure 2c and d]. Table 4:
Kaplan–Meier survival curves for (a) overall survival, (b) recurrence-free survival, (c) overall survival by pathological (ypTNM) stage, (d) recurrence-free survival by pathological (ypTNM) stage
Although chemoradiotherapy has gained acceptance as the standard neoadjuvant therapy for OSCC, it may increase the incidence of early treatment-related mortality, unrelated to the disease progression.[
] However, many of the earlier studies utilising nCRT for OSCC employed predominantly the open operative approach, with a resultant increase in post-operative morbidity and mortality. Minimally invasive approaches were shown to have better peri-operative outcomes, especially in pulmonary morbidity, when compared to open surgery without compromising the oncological outcomes.[ 6 24 ] Further, in patients with OSCC receiving nCRT, MIO is an independent predictor of OS, compared to open surgery.[ 25 ] In this study, we have analysed the operative and oncological 17 safety of MIO following nCRT for thoracic OSCC.
In our experience, the tolerance of patients to the chemotherapy component of the nCRT was poor. In patients receiving nCRT using the CROSS regimen, only 55.3% of the patients could complete a minimum of four cycles of chemotherapy and the most common reason to stop chemotherapy was the persistence of neutropaenia. Although >90% of the patients could complete all five cycles of chemotherapy in the CROSS trial,[
] the real-world experiences with this regimen in OSCC have shown reduced chemotherapy tolerance.[ 2 ] Further detailed analysis of factors (patient, tumour and therapy-related) leading to this poor chemotherapy tolerance is out of the scope of this manuscript. 12 Does neoadjuvant chemoradiotherapy for oesophageal squamous cell carcinoma make minimally invasive oesophagectomy technically more challenging?
Do these radiation-induced changes make the surgery technically more difficult? In our experience, an overall increased level of difficulty in surgical dissection was seen in nearly 55% of patients, with more than one factor accounting for the technical difficulty in 36% of patients. The most common factor that affected the operative difficulty was radiation-induced adhesive fibrosis. However, in nearly 45% of patients, the operating surgeon did not feel that the dissection was more difficult. This was particularly true when the peri-oesophageal tissues were found to be more 'oedematous' than fibrotic following the radiation.
The operative difficulty following radiation may be influenced by tumour location, dose and technique of radiotherapy, time interval to surgery and the treatment response. Since the delivered radiation dose was uniform at 41–45 Gy, and the median time interval to surgery following nCRT was within 6–8 weeks in the majority of the patients, these factors probably did not impact the degree of operative difficulty in a significant manner. We found that the difficulty of tumour dissection was maximally encountered when the tumour was epi-centred around the mid-thoracic oesophagus. The mid-thoracic tumours are located in close vicinity to the major airways, descending thoracic aorta/arch of the aorta and the recurrent laryngeal nerves and often necessitate wider mediastinal irradiation, including the draining nodal basins. Even in a non-irradiated patient, the mid-thoracic location is technically more challenging to resect, compared to tumours located in the distal oesophagus/GOJ. This technical difficulty is further accentuated due to the radiation-induced inflammation which results in unclear tissue planes, particularly around the vital mediastinal structures.[
10 ] An interesting thing to note was that the surgical difficulty was significantly lower in patients exhibiting a pCR in the primary tumour, as compared to those with residual tumour [ 11 Table 2]. This probably suggests that a good tumour response translates to downstaging and downsizing of the primary tumour and the nodes which may ease the surgical dissection, following nCRT, compared to the tumours which exhibit poor response and remain bulky. The advancements in radiation delivery techniques help in better tumour volume targeting and thus reduce the extent of peri-tumoural radiation-induced inflammation. Although relatively reduced surgical difficulty was seen in the conformal radiation delivery techniques using a linear accelerator, compared to the conventional technique, the differences were statistically not significant.
The operative surgeon should keep in mind certain technical points while performing the thoracic phase of MIO following nCRT. The dissection should start from areas with well-defined tissue planes and gradually move to areas with fibrosis and adhesions. Slow, precise intra-thoracic dissection is crucial, avoiding excessive traction or shearing forces that may potentially damage the adjacent structures (major airway or aorta). The operating surgeon must also learn to recognise the tactile feel from the laparoscopic instrument to assess tumour mobility and to safely dissect the difficult tissue planes.[
] 11 Can a complete mediastinal lymphadenectomy be safely performed following neoadjuvant chemoradiotherapy?
In this series, a total mediastinal LND was attempted in all patients. Although a standard-type mediastinal LND was completed in all patients, a total mediastinal LND could be safely completed only in eight (10.7%) patients. The radiation-induced inflammation limited the extent of supracarinal LND, and often with the tissue planes being obscured, the supracarinal lymphadenectomy was technically challenging, especially along the left RLN chain. The feasibility and outcomes of a total 2F- or 3F-LND following nCRT for OSCC have been reported from a few Asian centres.[
4 12 ] In their randomised trial by Wang 26 et al.,[ ] all the patients with OSCC in the nCRT and nCT arms received TLO with at least a total 2F-LND. However, the proportion of patients where total 2F-LND could be safely completed in either arm was not reported. A minimally invasive total 2F-LND, though feasible following nCRT, is technically more challenging, often prolongs the surgical duration and may carry higher morbidity, when compared to standard LND.[ 4 12 ] Due to these reasons, in Japan and the East, nCT, rather than nCRT, is still the standard pre-operative therapy for OSCC, which allows the performance of a total mediastinal LND. 17
Can nCRT make extended nodal dissections less essential? There is an on-going debate about the optimal extent of LND following the application of nCRT.[
17 27 ] Although the survival effects of an extended lymphadenectomy following nCRT is debated, it does increase the LNY, resulting in the accurate staging of the disease.[ 28 26 29 30 31 ] In addition, thoracic OSCC frequently metastasises to supracarinal nodes, especially along the RLN chains, and the persistence of occult disease in these regions is not uncommon despite pre-operative nodal irradiation.[ 32 ] Hence, the lymphadenectomy should aim at dissecting these high-risk nodal areas, taking adequate care that this does not lead to increased RLN palsy rates. Individualised selective nodal station dissection, tailored according to the patient and tumour characteristics may help in this regard.[ 33 ] However, reliable pre-operative predictors of superior mediastinal nodal involvement, which may help with the performance of selective superior mediastinal LND, are yet to be defined.[ 27 12 26 27 ] Therefore, in the authors' opinion, a complete intra-thoracic lymphadenectomy should at least be attempted in all OSCC patients, regardless of the administration of neoadjuvant therapy or the surgical approach. 28 Peri- and post-operative outcomes of minimally invasive oesophagectomy following neoadjuvant chemoradiotherapy
In their cohort of OSCC patients receiving nCRT and MIO, Tang
et al.[ ] reported overall morbidity of 43.4% and CDG ≥3 morbidity of 14.5%, and Liu 10 et al.[ ] reported overall morbidity of 34.1%. In the current study, the overall complication and the major complication (CDG ≥3) rates were 48% and 20.0%, respectively. The rate of cervical anastomotic leak (9.3%), respiratory complications (20.0%) including pneumonia (10.7%), RLN palsy (6.7%), chylothorax (1.3%) and arrhythmias (4.0%) in our series were comparable to studies that employed MIMcKO following nCRT where patients with OSCC formed the dominant/entire cohort 11 Table 5. The application of nCRT did not lead to an increased leak rate, and the majority of the leaks (71.4%) were ECCG type II. The placement of a routine-thoracic epidural catheter and a low conversion rate (4%) to an open operation probably also contributed to lesser respiratory complications, particularly pneumonia in our series. One patient developed a high-output chyle leak which was managed with thoracoscopic ligation of the duct. All the cases of RLN palsy were ECCG type IA and recovered within 3 months. Despite the operative difficulty in the thoracic phase, there was no major airway or vascular injuries. Table 5:
Comparison of the current study with recent studies on minimally invasive oesophagectomy following chemoradiotherapy for oesophageal squamous cell carcinoma
Although the overall DuS was longer, particularly in the 'difficult' surgery group, owing to the technical difficulty following nCRT and the learning curve, the EBL was acceptable and the rate of elective ventilation (1.3%), duration of ICU stay (median, 1 day) and the LOS (median, 9 days) were comparable or better than similar studies
Table 5. A recent network meta-analysis compared various surgical approaches for OC and showed that TLO and HO resulted in longer DuS but a reduced EBL and LOS, compared to open surgery.[ ] In the Japanese National Data Base analysis, studying the outcomes of various surgical approaches following nCRT for OC, better peri-operative outcomes were seen following minimally invasive approaches, compared to open approaches.[ 24 ] We feel that similar favourable peri-operative outcomes were obtained in our study with application of minimally invasive surgery. 5
The successful management of post-operative morbidities requiring a re-intervention was achieved safely. Among those who required a re-operation (
n = 5), all except one was managed with a minimally invasive approach. This was feasible since the index operations were performed by minimal access approach. Two patients developed a late anastomotic stricture and required endoscopic dilatations. There was no 30-day mortality in this series, and there was only one surgery-related 90-day mortality.
Although the post-operative morbidity outcomes in our study could not be compared to that following nCT, there have been few retrospective studies that have made such comparisons [
Table 5]. Wang et al.[ ] compared the post-operative morbidity of MIO for OSCC, based on the type of neoadjuvant therapy, in their randomised study. The rate of total post-operative complications (47.4% vs. 42.6%, 4 P = 0.48) and major (CDG ≥3b) complications (11.4% vs. 10.2%, P = 0.77) did not differ between treatment arms. The authors were able to show that MIO could be safely applied for thoracic OSCC following nCRT. Oncological outcomes of minimally invasive oesophagectomy following neoadjuvant chemoradiotherapy
The completeness of the oncological resection (R0-93.3%) was not compromised by the application of MIO and the pCR rates were high (48.0%), in concurrence with reported literature [
Table 5]. The median LNY was 8 (range: 1–25), which perhaps is the reflection of the difficulty in completion of a total mediastinal LND in majority of the patients. Further, the induction therapy with nCRT may have negatively affected the LNY, due to involution of nodes, as also reported in the literature.[ 10 34 35 ] 36
The OS in our study (1/2/3-year OS- 89.2%, 78.8%, 64.4%) [
Figure 2] was comparable with the OSCC cohort in the CROSS trial (1/2/3-year OS - 85.4%, 73.1%, 68%) which employed predominantly an open surgical technique.[ ] It was also comparable to the OS in the NEOCRTEC5010 trial (1/2/3-year OS - 90%, 75.1%, 69%) which recruited only OSCC.[ 37 ] Among their patients with OSCC undergoing MIO following nCRT, Tang 3 et al.[ ] reported a 3-year OS of 76.9% and Wang 10 et al.[ ] reported a 1-year OS of 87.1%. In our series, the best OS and RFS were seen in patients with no residual disease in the primary tumour and nodes, i.e., ypT0N0 [Figure 4 2b and c], similar to that reported previously.[ 3 ] 37
Despite the high pCR rates and a low proportion of patients with residual nodal disease, the overall recurrence rate (32.4%) was high, especially those involving a distant site. The rate of isolated mediastinal nodal recurrence (RLN chain) was 6.7% and there was no isolated cervical nodal recurrence. However, further long-term follow-up is required to fully evaluate the pattern of recurrence and the factors influencing the same in our patients. The majority (78.7%) of our patients could not complete the entire course of the concurrent chemotherapy, due to tolerance issues, which may account for a higher incidence of distant recurrences. Following nCRT and surgical resection, patients with significant pathological residual disease are currently not offered adjuvant therapy. However, patients with poor response to neoadjuvant therapy, particularly in the lymph nodes, may be ideal candidates for targeted and immunotherapy. The recent results of the CheckMate trial are indeed very promising in this regard.[
The strengths of our study include the inclusion of only OSCC patients receiving 41–45 Gy radiation, uniformity of surgical procedure performed (MIMcKO with 2F-LND), appropriate definition of outcome parameters and inclusion of survival analysis. Although our study represents the real-world scenario, it was limited by the inherent bias of a retrospective study, including the lack of a comparator group (nCT). The documented surgical difficulty factor by an individual surgeon may have been subjective. The other drawbacks include the poor tolerability to the chemotherapy component of nCRT, the low LNY and the lack of adequate long-term follow-up.
MIMcKO is feasible and safe in patients with locally advanced OSCC receiving nCRT. Although the radiation component increases the degree of operative difficulty, especially during the supracarinal lymphadenectomy, this does not adversely affect the short-term surgical and long-term oncological outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Samarasam I. Esophageal cancer in India: Current status and future perspectives Int J Adv Med Health Res. 2017;4:5
2. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al Preoperative chemoradiotherapy for esophageal or junctional cancer N Engl J Med. 2012;366:2074–84
3. Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, et al Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial J Clin Oncol. 2018;36:2796–803
4. Wang H, Tang H, Fang Y, Tan L, Yin J, Shen Y, et al Morbidity and mortality of patients who underwent minimally invasive esophagectomy after neoadjuvant chemoradiotherapy vs.neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma: A Randomized Clinical Trial JAMA Surg. 2021;156:444–51
5. Yoshida N, Yamamoto H, Baba H, Miyata H, Watanabe M, Toh Y, et al Can minimally invasive esophagectomy replace open esophagectomy for esophageal cancer.Latest analysis of 24,233 esophagectomies from the Japanese National Clinical Database? Ann Surg. 2020;272:118–24
6. Kumagai K, Rouvelas I, Tsai JA, Mariosa D, Klevebro F, Lindblad M, et al Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers Br J Surg. 2014;101:321–38
7. Straatman J, van der Wielen N, Cuesta MA, Daams F, Roig Garcia J, Bonavina L, et al Minimally invasive versus open esophageal resection: Three-year follow-up of the previously reported randomized controlled trial: The TIME Trial Ann Surg. 2017;266:232–6
8. Luketich JD, Pennathur A, Awais O, Levy RM, Keeley S, Shende M, et al Outcomes after minimally invasive esophagectomy: Review of over 1000 patients Ann Surg. 2012;256:95–103
9. Gottlieb-Vedi E, Kauppila JH, Malietzis G, Nilsson M, Markar SR, Lagergren J. Long-term survival in esophageal cancer after minimally invasive compared to open esophagectomy: A systematic review and meta-analysis Ann Surg. 2019;270:1005–17
10. Tang H, Zheng H, Tan L, Shen Y, Wang H, Lin M, et al Neoadjuvant chemoradiotherapy followed by minimally invasive esophagectomy: Is it a superior approach for locally advanced resectable esophageal squamous cell carcinoma? J Thorac Dis. 2018;10:963–72
11. Liu G, Han Y, Peng L, Wang K, Fan Y. Reliability and
of minimally invasive esophagectomy after neoadjuvant chemoradiation: A retrospective study J Cardiothorac Surg. 2019;14:97
12. Sasikumar K, Kalayarasan R, Gnanasekaran S, Chandrasekar S, Pottakkat B. Minimally invasive oesophagectomy with a total two-field lymphadenectomy after neoadjuvant chemoradiotherapy for locally advanced squamous cell carcinoma of the oesophagus: A prospective study J Minim Access Surg. 2021;17:49–55
13. Lubbers M, van Det MJ, Kreuger MJ, Hoekstra R, Hendriksen EM, Vermeer M, et al Totally minimally invasive esophagectomy after neoadjuvant chemoradiotherapy: Long-term oncologic outcomes J Surg Oncol. 2018;117:651–8
14. Spector R, Zheng Y, Yeap BY, Wee JO, Lebenthal A, Swanson SJ, et al The 3-hole minimally invasive esophagectomy: A safe procedure following neoadjuvant chemotherapy and radiation Semin Thorac Cardiovasc Surg. 2015;27:205–15
15. Khan M, Ashraf MI, Syed AA, Khattak S, Urooj N, Muzaffar A. Morbidity analysis in minimally invasive esophagectomy for oesophageal cancer versus conventional over the last 10 years, a single institution experience J Minim Access Surg. 2017;13:192–9
16. Chang T, Hsiao PN, Tsai MY, Huang PM, Cheng YJ. Perioperative management and outcomes of minimally invasive esophagectomy: Case study of a high-volume tertiary center in Taiwan J Thorac Dis. 2018;10:1670–6
17. Chen D, Wang W, Mo J, Ren Q, Miao H, Chen Y, et al Minimal invasive versus open esophagectomy for patients with esophageal squamous cell carcinoma after neoadjuvant treatments BMC Cancer. 2021;21:145
18. Subramanyeshwar RT, Raju KV, Patnaik SC, Saksena AR, Pratap RR, Rayani BK, et al Minimally invasive esophagectomy the standard of care: Experience from a tertiary care cancer center from India Indian J Surg Oncol. 2021;12:335–49
19. Jakhmola CK, Trehan V, Kumar SS. Minimally invasive esophagectomy for carcinoma esophagus-outcome of surgical management: A single centre experience Int Surg J. 2018;5:1469
20. Rice TW, Patil DT, Blackstone EH. 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: Application to clinical practice Ann Cardiothorac Surg. 2017;6:119–30
21. Hagens ER, van Berge Henegouwen MI, Cuesta MA, Gisbertz SS. The extent of lymphadenectomy in esophageal resection for cancer should be standardized J Thorac Dis. 2017;9:S713–23
22. Low DE, Alderson D, Cecconello I, Chang AC, Darling GE, D'Journo XB, et al International consensus on standardization of data collection for complications associated with esophagectomy: Esophagectomy Complications Consensus Group (ECCG) Ann Surg. 2015;262:286–94
23. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, et al The Clavien-Dindo classification of surgical complications: Five-year experience Ann Surg. 2009;250:187–96
24. Siaw-Acheampong K, Kamarajah SK, Gujjuri R, Bundred JR, Singh P, Griffiths EA. Minimally invasive techniques for transthoracic oesophagectomy for oesophageal cancer: Systematic review and network meta-analysis BJS Open. 2020;4:787–803
25. Xiong WL, Li R, Lei HK, Jiang ZY. Comparison of outcomes between minimally invasive oesophagectomy and open oesophagectomy for oesophageal cancer ANZ J Surg. 2017;87:165–70
26. Chao YK, Chiu CH, Liu YH.
and oncological efficacy of bilateral recurrent laryngeal nerve lymph-node dissection after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma: A propensity-matched analysis Esophagus. 2020;17:33–40
27. Hagens ER, van Berge Henegouwen MI, van Sandick JW, Cuesta MA, van der Peet DL, Heisterkamp J, et al Distribution of lymph node metastases in esophageal carcinoma [TIGER study]: Study protocol of a multinational observational study BMC Cancer. 2019;19:662
28. Borggreve AS, Kingma BF, Domrachev SA, Koshkin MA, Ruurda JP, van Hillegersberg R, et al Surgical treatment of esophageal cancer in the era of multimodality management Ann N Y Acad Sci. 2018;1434:192–209
29. Noordman BJ, Wijnhoven BP, van Lanschot JJ. Optimal surgical approach for esophageal cancer in the era of minimally invasive esophagectomy and neoadjuvant therapy Dis Esophagus. 2016;29:773–9
30. Koen Talsma A, Shapiro J, Looman CW, van Hagen P, Steyerberg EW, van der Gaast A, et al Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: Prognostic and therapeutic impact on survival Ann Surg. 2014;260:786–92
31. Brunner M, Merkel S, Krautz C, Kersting S, Grützmann R, Weber GF. The prognostic value of the number of harvested negative lymph nodes in patients treated by esophagectomy with or without neoadjuvant chemoradiation Anticancer Res. 2020;40:2833–40
32. Wang J, Yang Y, Shafiulla Shaik M, Hu J, Wang K, Gao C, et al Three-field versus two-field lymphadenectomy for esophageal squamous cell carcinoma: A meta-analysis J Surg Res. 2020;255:195–204
33. Li ZG, Zhang XB, Wen YW, Liu YH, Chao YK. Incidence and predictors of unsuspected recurrent laryngeal nerve lymph node metastases after neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma World J Surg. 2018;42:2485–92
34. Yeung JC, Bains MS, Barbetta A, Nobel T, DeMeester SR, Louie BE, et al How many nodes need to be removed to make esophagectomy an adequate cancer operation, and does the number change when a patient has chemoradiotherapy before surgery? Ann Surg Oncol. 2020;27:1227–32
35. Kauppila JH, Wahlin K, Lagergren P, Lagergren J. Neoadjuvant therapy in relation to lymphadenectomy and resection margins during surgery for oesophageal cancer Sci Rep. 2018;8:446
36. van der Werf LR, Dikken JL, van Berge Henegouwen MI, Lemmens VE, Nieuwenhuijzen GA, Wijnhoven BP. A population-based study on lymph node retrieval in patients with esophageal cancer: Results from the Dutch Upper Gastrointestinal Cancer Audit Ann Surg Oncol. 2018;25:1211–20
37. Shapiro J, van Lanschot JJ, Hulshof MC, van Hagen P, van Berge Henegouwen MI, Wijnhoven BP, et al Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): Long-term results of a randomised controlled trial Lancet Oncol. 2015;16:1090–8
38. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer N Engl J Med. 2021;384:1191–203