Minimally invasive vs. hybrid esophagectomy: 10-year outcomes from a UK tertiary center

Introduction

Minimally invasive approaches to esophageal cancer surgery are accepted to be a safe and effective means of performing an esophagectomy (1). However, the uptake of two-stage Ivor-Lewis totally minimally invasive esophagectomy (MIE) worldwide remains limited. Within the United Kingdom (UK), open and hybrid esophagectomy (HE) approaches remain the most popular techniques accounting for 77.4% of esophagectomies performed between 2018 and 2020 for esophageal cancer as per the National Oesophagogastric Cancer Audit (NOGCA) database (2,3). A lack of global uptake of MIE may be due to several factors, most notably the difficulty in performing a safe and reliable esophagogastric anastomosis (3).

Concerns regarding the generalizability and feasibility of the MIE technique were ameliorated with the results of the prospective multicenter Eastern Cooperative Oncology Group (E2202) study (4). The study confirmed shorter intensive care unit (ICU) and hospital stay, along with low rates of anastomotic leak and pneumonitis. Similar short-term effectiveness of the MIE was reported in the TIME-trial (Traditional Invasive vs. MIE) study, which showed significantly fewer cardiopulmonary complications alongside superior overall 3-year survival at 50.5% (5). Furthermore, the MIRO trial demonstrated positive and substantial beneficial effects on health-related quality of life (HRQOL) with the use of MIE compared to HE (6).

Although there is enormous interest and focus on robotic-assisted MIE (RAMIE), there remain multiple barriers which need to be overcome for this technique to be widely and safely practiced. These include availability and access to technology as well as establishing a safe learning curve (7,8). Until such barriers are overcome, MIE and HE approaches will continue to be prevalent in practice. A recently published systematic review comparing the two techniques showed slightly better outcomes with MIE technique with short-term follow-up (9). However, the long-term results comparing these two techniques are still awaited. Our study aims to provide answers by evaluating postoperative outcomes and long-term survival associated with both techniques.

Aim

The primary outcome of the study was to analyze the 3- and 5-year survival outcomes following MIE and HE. The secondary outcome measures were postoperative complications, anastomotic leak rates, and 30/90-day survival following surgery. We present this article in accordance with the STROBE reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-22/rc).

Methods

A retrospective analysis was conducted using a prospectively maintained database of patients who underwent either MIE or HE at a medium-volume tertiary referral center in the UK. The study period spanned from 1^st January 2013 to 31^st December 2023.

Inclusion criteria encompassed adult patients who underwent MIE or a hybrid Ivor-Lewis two-stage esophagectomy for esophageal cancer, with a minimum follow-up of 1 year. Patients were excluded if they underwent esophagectomy using other techniques (open or robotic), had surgery for benign esophageal conditions, underwent trans hiatal or McKeown three-stage esophagectomy, or had surgery for gastric cancer (extended total gastrectomy).

All procedures were performed by experienced esophagogastric surgeons who had completed structured UK training in upper gastrointestinal (UGI) surgery, including formal fellowships in MIE. These surgeons met the Association of Upper Gastrointestinal Surgeons (AUGIS) recommendations of performing a minimum of 20 esophageal resections per surgeon per year, ensuring a high level of procedural expertise and consistency in surgical technique.

Prior to surgery, all cases were reviewed in a multidisciplinary upper GI cancer team meeting, and patients underwent comprehensive pre-operative evaluation by specialist oncologists. Neoadjuvant therapy was administered according to the prevailing standard at the time: epirubicin, cisplatin, and capecitabine (ECX) prior to February 2019, and 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT-4) thereafter.

Surgery—either MIE or HE—was typically scheduled approximately 6 weeks following completion of neoadjuvant therapy, after pre-operative assessment by an esophagogastric cancer anesthesiologist. The choice of surgical technique was non-randomized and primarily based on individual surgeon preference. While some surgeons continued to perform HE, others transitioned to MIE during the study period, reflecting evolving practice patterns and expertise.

Surgical technique

MIE in this study refers to a totally minimally invasive Ivor-Lewis two-stage procedure, comprising:

• Laparoscopic gastric mobilization in the supine position;
• Thoracoscopic esophageal mobilization and intrathoracic anastomosis in the left lateral position;
• A five-port thoracoscopic approach with a circular stapled anastomosis;
• Lymphadenectomy included a D2 abdominal lymphadenectomy, along with thoracic lymph node dissection involving the paraoesophageal, subcarinal, and paratracheal lymph nodes.

HE was defined as a laparoscopic-assisted Ivor-Lewis procedure, involving:

• Laparoscopic gastric mobilization in the supine position;
• Open right posterolateral thoracotomy for esophageal mobilization and intrathoracic anastomosis.

Data collection and statistical analysis

Data collected included explanatory variables such as patient demographics, clinical presentation, operative details, histopathological findings, and treatment regimens.

Primary outcomes assessed were perioperative outcomes and complications, including anastomotic leaks, conduit necrosis, chyle leaks, and Clavien-Dindo grade III or higher complications. Secondary outcomes included 30- and 90-day mortality, as well as 5-year overall survival.

Statistical analysis was performed using SPSS version 29 (IBM Corp., Chicago, IL, USA). Discrete variables were presented as frequencies and percentages, while continuous variables were expressed as means or medians, as appropriate. Categorical variables were compared using the Chi-squared or Fisher’s exact test, and continuous variables were analyzed using the Student’s t-test or Mann-Whitney U test. Multivariate analysis was conducted using logistic regression, and 5-year survival was assessed using Cox proportional hazards modelling and the log-rank test.

Ethics

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval for the use of routinely collected patient data related to UGI disorders was obtained through the NorSTRA research database, approved by the Nottingham Research Ethics Committee (REC reference: 20/EM/0193). As this was a retrospective analysis of fully anonymized data, the requirement for individual informed consent was waived by the ethics committee.

Results

Patient demographics

A total of 456 patients underwent esophagectomy during the inclusion period of which 271 patients underwent MIE. Compared with the MIE cohort, patients in the HE group were older (median 71 vs. 68 years, P<0.001) and had a higher body mass index (BMI) (27.5 vs. 25.4 kg/m², P<0.001), while American Society of Anesthesiologists (ASA) grade III was more frequent in the MIE group (50.2% vs. 35.1%, P=0.01). Other baseline characteristics, including sex, mode of presentation, tumor histology, and clinical stage, were comparable between the two groups (Table 1).

Tumor histology, stage, and pre-operative treatment

Adenocarcinoma was the predominant histology in the MIE group, present in 228 patients (84.1%), followed by squamous cell carcinoma in 40 patients (14.8%). The majority of patients were staged clinically as T3N1–3M0 (42%), followed by T3N0M0 (25%), with stage III esophageal cancers being the most common stage of disease presentation (Table 1). Overall, 205 patients (75.6%) in the MIE cohort received neoadjuvant therapy (chemotherapy or chemoradiotherapy): 129 (47.6%) received ECX- or cisplatin and capecitabine (CX)-based chemotherapy, 53 (19.6%) received FLOT-4, and 23 (8.5%) received neoadjuvant chemoradiotherapy. A further 46 patients (17.0%) proceeded directly to surgery without neoadjuvant treatment; in the remaining 20 patients (7.4%), neoadjuvant therapy status was incompletely recorded, but these patients were retained in the overall analysis.

Within the HE cohort, adenocarcinoma was the predominant histology in 174 patients (94.1%), inpatient followed by squamous cell carcinoma (n=7, 3.8%). Similar to the MIE group, the majority of patients presented with stage III disease with T3N1–3M0 (37.8%), followed by T3N0M0 (31.9%) being the most common. In the HE cohort, 150 patients (81.1%) received neoadjuvant therapy. Overall, 109 patients (58.9%) received ECX chemotherapy, 35 (18.9%) received FLOT-4, and 6 (3.2%) underwent neoadjuvant chemoradiotherapy. Twenty-one patients in each group (7.7% in the MIE group and 11.4% in the HE group) required urgent hospital admission due to complications such as progressive dysphagia, UGI bleeding, or significant nutritional compromise. These admissions, although not necessitating emergency surgery, underscore the aggressive nature of esophageal malignancies and their potential to disrupt planned oncological treatment pathways (Table 1).

In a small subset of patients (n=25; 22 MIE and 3 HE), the clinical T category was not documented in the MDT record despite confirmation of nodal status and absence of distant metastasis; these cases are presented in Table 1 as “T stage not recorded, N0–2M0”.

Surgical and post-operative care

The median operating time for MIE was 613 minutes (range, 425–938 minutes). The vast majority of patients (95.6%) were admitted to the high dependency unit (HDU) in the immediate postoperative period as a planned admission. The median duration of stay in HDU was 2.6 days (range, 0.6–45.0 days). The median inpatient length of stay (LOS) for patients undergoing MIE was 7.0 days (range, 4.23–78.86 days). Fifty-one patients (18.8%) required return to theatre within 14 days with 42 patients (15.5%) needing readmission to HDU. Nine patients (3.3%) required endoscopy only, while others required surgical intervention. Two patients (0.7%) died within a 30-day period, and 9 patients had a 90-day mortality (3.3%), with 36 patients (13.3%) being readmitted within a 30-day period (Table 2).

In comparison, the median operating time for HE was significantly less at 470 minutes (range, 263–859 minutes, P<0.001). The median duration of stay in HDU was 2.2 days (range, 0.6–51.8 days, P=0.23). The median inpatient LOS for patients undergoing HE was significantly higher at 8.55 days (range, 5.35–202.22 days, P=0.004). Forty-six patients (24.9%) required return to theatre within 14 days (P=0.15), and 25 patients (13.5%) had readmission to HDU. Endoscopy only was carried out 14 (7.5%) patients, while others required surgical intervention. The 30- and 90-day mortality was seen in 1 (0.5%) and 6 (3.2%) patients, respectively (P=0.96), with a 30-day readmission rate of 15.1% (P=0.76) (Table 2).

The role of endoscopy was primarily to assess the viability of the gastric conduit and exclude ischemia. It was also employed therapeutically to manage complications such as anastomotic leaks, often through the placement of fenestrated tube drains (EndoVAC therapy). In the earlier years of the study, these endoscopic interventions were typically performed in the operating theatre and therefore coded as returns to theatre. However, as clinical practice evolved, such procedures have increasingly been performed in the HDU under sedation, reflecting a shift towards less invasive and more efficient management strategies.

Post-operative complications

Serious complications were defined as Clavien-Dindo III grades and higher and were seen in 22.1% (n=60) of patients within the MIE cohort with pulmonary complications seen in 79 patients (29.1%) (Table 3). Anastomotic leak and gastric conduit necrosis were defined according to the Esophageal Complications Consensus Group (ECCG) definitions (10). Anastomotic leak was seen in 42 patients (15.5%) with major anastomotic leak defined as need for radiological/endoscopic/surgical intervention was seen in 9 (3.3%, type II) and 23 (8.5%, type III) patients. Necrosis of the gastric conduit requiring disconnection was seen in 3 patients (1.1%). Chyle leak was seen in 7 patients (2.6%) with one patient requiring surgical intervention (Figure 1).

Figure 1 Kaplan-Meir curve showing stage wise 5-year survival between MIE and HE. Five-year survival between groups for (A) stage IB, (B) stage IIA, (C) stage IIB, (D) stage IIIA, (E) stage IIIB, and (F) stage IVA. CI, confidence interval; HE, hybrid esophagectomy; MIE, minimally invasive esophagectomy; mo, months; NA, not available.

In contrast, the overall complication Clavien-Dindo III and above in the HE cohort was seen in 45 patients (24.3%, P=0.59) with pulmonary complication being the most common at a marginally higher rate in 66 patients (35.7%, P=0.14). There was no significant difference between the anastomotic leak rates between the two techniques (n=31, 16.8%, P=0.72) with 5 (2.7%) type II and 23 (12.4%) type III leaks, respectively. Two patients (1%) needed disconnection of the gastric conduit for necrosis, and 2 patients (1%) with Chyle leak were managed conservatively (Figure 1).

Histopathological analysis and resection margins

The Mandard tumor regression score, which indicates response to neoadjuvant therapy, showed a favorable distribution, with 119 patients (43.9%) of the MIE group achieving significant tumor regression (Mandard grades 1–3) (Table 4) (11). Mandard tumor regression grade was not recorded for 46 MIE patients (17.0%) and 22 HE patients (11.9%), mainly from the earlier years of the cohort before routine reporting of regression grade. These cases are listed as “Data unavailable” in Table 4 but were retained in the overall survival analysis. With respect to circumferential resection margin (CRM), 198 (73.1%) patients achieved R0 resections, while 68 patients (25.1%) had circumferential R1 positive margins (microscopic residual tumor), and two patients had R2 margins (macroscopic residual tumor). Circumferential margin involvement was defined as per the British Society of Pathology criteria, whereby if microscopic tumor was within 0.1 mm of the inked margin, this would be considered positive (12). The median number of lymph nodes harvested in the MIE cohort was 38 (range, 9–75), and a lymph node yield ≥15 nodes was achieved in 258 patients (95.2%). Node-negative disease (pN0) was documented in 144 MIE patients (53.1%). Reliable pN0 data were not available for the HE cohort because nodal status was incompletely recorded in the early years of the study; we therefore chose not to present HE pN0 rates to avoid biased comparison.

Good response to neoadjuvant therapy was also seen in patients undergoing HE, with 91 (49.2%) achieving significant tumor regression. A negative CRM was achieved in 145 patients (78.4%; P=0.20), with 39 patients (21%) having an R1 positive margin and one patient having a macroscopic residual tumor (R2). The median number of lymph nodes harvested in the HE cohort was 27 (range, 3–60), significantly lower than in MIE (P<0.001), with ≥15 nodes retrieved in 173 patients (93.5%) (Table 4).

Completion of adjuvant therapy and long-term survival

Eligibility for adjuvant chemotherapy was defined as having an R0 or R1 resection, no radiological evidence of metastatic disease at discharge, survival beyond 90 days after surgery, and being considered fit for systemic therapy at the postoperative MDT. On this basis, 203 of 271 patients (74.9%) in the MIE cohort were eligible for adjuvant chemotherapy, of whom 116 (57.1%) completed all planned cycles (Table 4). In the HE cohort, 144 of 185 patients (77.8%) met these eligibility criteria, of whom 76 (52.8%) completed adjuvant chemotherapy. Long-term survival analysis was available for 456 patients with complete survival data, comprising 271 MIE and 185 HE cases. Median follow-up was 39 months [interquartile range (IQR), 17–86 months] for the MIE group and 34 months (IQR, 15–74 months) for the HE group. During follow-up, there were 145 deaths in the MIE cohort and 102 deaths in the HE cohort. Three- and 5-year overall survival for the MIE cohort were 61.3% (n=166) and 52.0% (n=141), respectively, compared with 58.9% (n=109) and 49.2% (n=91) for the HE cohort (log-rank P=0.62 and P=0.55, respectively) (Figure 2).

Figure 2 Kaplan-Meier curve comparing the 10-year survival between MIE and HE. CI, confidence interval; HE, hybrid esophagectomy; MIE, minimally invasive esophagectomy; mo, months.

A multivariable Cox proportional hazards model including surgical approach, age, sex, ASA grade, pathological stage, and histology was performed in 429 patients with complete data (MIE n=247; HE n=182; 237 deaths). Surgical approach was not independently associated with overall survival [adjusted hazard ratio (aHR) for MIE vs. HE =0.87, 95% confidence interval (CI): 0.68–1.10, P=0.24]. In contrast, increasing age and higher tumor stage were associated with worse survival (age per year: aHR =1.02, 95% CI: 1.01–1.03, P<0.001; stage III vs. stage I–II: aHR =1.68, 95% CI: 1.28–2.20, P<0.001; stage IV vs. stage I–II: aHR =1.85, 95% CI: 1.08–3.16, P=0.03), and male sex was also associated with an increased risk of death (aHR =1.57, 95% CI: 1.08–2.27, P=0.02). ASA grade and histological subtype (adenocarcinoma vs. squamous/other) were not independently associated with survival (both P>0.35). Stage-stratified Kaplan-Meier curves (Figure 1) demonstrate the expected stepwise reduction in survival with advancing pathological stage; within each stage, there was no statistically significant difference in survival between MIE and HE.

Discussion

The study compares the two most commonly performed techniques for esophagectomy in Europe and North America and aims to determine their long-term outcomes. The significantly higher proportion of male patients in both groups reflects the characteristic demographic distribution of esophageal adenocarcinoma. Additionally, the higher number of patients within the MIE group corresponds to the gradual adoption of the MIE technique by surgeons during the study period.

The significantly longer operative time associated with MIE can be attributed to the technical demands of the procedure, particularly the reconstruction phase (13,14). However, this increased duration is offset by the advantages of MIE, such as reduced thoracotomy pain and a significantly shorter length of hospital stay, findings that have been demonstrated consistently across various studies (6). Concerns about the generalisability and potentially higher anastomotic leak rates due to its technical complexity with MIE were not supported by the findings of this study, as the study revealed equivocal leak rates between the two techniques. This suggests that MIE is a safe technique in experienced hands (15). A higher leak rate has been shown in some earlier studies; however, this may be reflective of morbidity associated with the learning curve required to gain proficiency—a challenge inherent to learning new complex surgical techniques (15).

Despite its technical challenges, MIE offers several significant advantages. The absence of a large thoracotomy incision reduces the need for postoperative analgesia and alleviates the work of breathing (16). Moreover, the lower incidence of pulmonary complications observed in the study aligns with findings from other studies researching the short-term outcomes after MIE (17). Some studies have also demonstrated a lower rate of Surgical site infection with MIE when compared with an open thoracotomy incision, particularly with respect to deep-seated infection leading to osteomyelitis (18).

Second, the advantage of using a laparoscope within the thoracic cavity provides for high-quality images, which may guide improved oncologic clearance. Historically, concerns that MIE might compromise oncologic outcomes have been dispelled by recent studies showing comparable or superior lymph node retrieval compared to open or hybrid techniques (19). The total number of nodes retrieved are a good surrogate marker for a radicality of surgical resection as well as not compromising the oncological safety (20). By employing a fully minimally invasive approach (MIE), a significantly high median lymph node yield of 38 nodes was achieved compared to 27 nodes with HE, both which was higher than the reported NOGCA registry data (21). This enhanced lymphadenectomy not only improves staging accuracy but also has prognostic significance. Evidence consistently shows that increased lymph node harvest is associated with improved survival, particularly in patients who have undergone neoadjuvant therapy (22). Although no statistically significant differences in 3- or 5-year overall survival were observed between the groups, the clinical implications remain noteworthy. Stage IIIB, which represented the largest subgroup of patients, demonstrated better survival outcomes with MIE. In contrast, other stages may have been underpowered, limiting the ability to detect meaningful differences. Larger studies are needed to confirm these findings and explore potential stage-specific benefits. Taken together, the superior lymph node retrieval and oncological adequacy demonstrated by MIE reinforce its role as a safe and effective surgical approach in the management of esophageal cancer.

Another important aspect highlighted in the study was that nearly a quarter of the patients who underwent esophagectomy in both groups were elderly (>75 years). Elderly patients are known to face an increased risk of postoperative complications, longer hospital stays, and cognitive decline (21). Pulmonary complications account for nearly half of perioperative deaths in this population (23). While randomized studies have yet to examine this population specifically, a retrospective analysis has demonstrated significantly lower rates of postoperative complications with MIE, particularly concerning pulmonary issues, alongside a shorter inpatient stay compared to a thoracotomy incision—a finding corroborated in our study as well (21). Given the challenges we face in dealing with a growing elderly population, this point is of particular significance for modern-day surgical practice.

Regarding long-term survival, both the 3- and 5-year survival rates were better with MIE compared to HE, although the difference was not statistically significant. These survival rates, while marginally better than those reported in the UK NOGCA registry, are consistent with long-term survival outcomes observed in other international registries (24). On multivariate analysis, clinical stage of the disease emerged as the primary determinant of long-term survival. Anastomotic leak was not associated with decreased long-term survival, a finding that has been corroborated in previous studies (9). Since its adoption as the standard of care in the UK in the late 2019, the FLOT-4 chemotherapy regimen is anticipated to improve 5-year survival rates over time (25). One critical factor in influencing better long-term outcomes may be the completion of adjuvant chemotherapy (26). Notably, the study highlights that patients who underwent MIE demonstrated a slightly higher rate of completion of adjuvant chemotherapy compared to those who underwent HE.

Recently, there has been a growing global interest in RAMIE. Despite its increasing popularity, RAMIE has not yet been established as the preferred approach to esophagectomy. Its uptake may be limited by a lack of robotic access in some centers, particularly given the substantial financial investment required for this technique (7,8). Nevertheless, in a recently published study comparing RAMIE and MIE, similar long-term outcomes were observed between the two techniques (27).

Overall, this study offers several important contributions. While a recent study comparing the two techniques provided valuable insights into recurrence and survival following esophagectomy, our analysis adds further depth by evaluating both short- and long-term outcomes of MIE and HE within a UK-specific context (28,29). Drawing from a prospectively maintained clinical database, our study reflects real-world practice in a medium-volume center, enhancing the relevance and applicability of the findings. The use of internationally standardized ECCG definitions for postoperative complications—including anastomotic leak, conduit necrosis, and Clavien-Dindo grade III+ events—enables robust benchmarking and comparison. Additionally, the significantly higher lymph node yield observed with MIE (median 38 vs. 27) suggests potential oncological advantages of thoracoscopic dissection. The inclusion of a substantial proportion of elderly patients (≥75 years) and the demonstration of comparable outcomes in this subgroup further underscore the feasibility of MIE in an ageing surgical population. Moreover, by extending survival analysis to 10 years, our study provides a longer-term perspective beyond the 5-year outcomes typically reported in national audits such as NOGCA.

However, these strengths must be interpreted in light of certain limitations. As a retrospective study based on a non-transformed dataset, inherent differences existed between the MIE and HE groups. Although we considered propensity score matching (PSM) to adjust for baseline differences, we opted against its use due to the anticipated reduction in sample size, which could have compromised statistical power and limited the generalizability of our findings. This decision represents a methodological limitation, and future prospective studies with matched cohorts or randomized designs would be instrumental in validating our observations.

Additionally, while our dataset included a significant number of elderly patients, frailty scores were not consistently captured during the earlier years of data collection. Recognizing the growing importance of frailty assessment in surgical outcomes, we have since incorporated prospective frailty scoring into our data collection. Lastly, although overall survival data were reliably obtained through primary care network notifications, the lack of routine documentation regarding cause of death—unless occurring in hospital—limits our ability to distinguish between cancer-related mortality and deaths from other causes, particularly in a frail population.

Conclusions

In conclusion, the study provides a comprehensive comparison between MIE and HE, providing valuable insights into their long-term outcomes. While both MIE and HE demonstrated comparable 3- and 5-year survival rates, MIE offered significant short-term advantages, including reduced LOS. Additionally, the inclusion of elderly patients in both groups highlights the importance of tailored perioperative management and the growing recognition of frailty assessment in improving outcomes for this vulnerable cohort. Future prospective studies comparing HE, MIE, and RAMIE, along with quality-of-life assessments, will be critical to help make informed decisions for patients with esophageal cancer.

Acknowledgments

The authors wish to acknowledge the contributions made by Mr. Edward Cheong, a former consultant colleague, in establishing MIE in our unit.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus for the series “Expert Perspectives on Minimally Invasive Esophagectomy”.

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-22/rc

Data Sharing Statement: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-22/dss

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-22/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-22/coif). The series “Expert Perspectives on Minimally Invasive Esophagectomy” was commissioned by the editorial office without any funding or sponsorship. B.K. served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Esophagus from December 2025 to November 2027. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval for the use of routinely collected patient data related to UGI disorders was obtained through the NorSTRA research database, approved by the Nottingham Research Ethics Committee (REC reference: 20/EM/0193). As this was a retrospective analysis of fully anonymized data, the requirement for individual informed consent was waived by the ethics committee.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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