Summary of the ROMIO randomized-control trial comparing clinical, economic and patient-reported outcomes between open versus hybrid esophagectomy in the United Kingdom

Surgical resection with associated lymphadenectomy, usually after neoadjuvant chemotherapy or chemoradiotherapy, is the mainstay of curative therapy for resectable esophageal cancer (1,2). Esophagectomy, however, is associated with significant morbidity and mortality, with the overall incidence of postoperative complications varying between 20% and 60% (3,4). Currently, Ivor Lewis esophagectomy can be performed by a variety of approaches, including open esophagectomy (OE) via combined thoracotomy and laparotomy, minimally invasive esophagectomy (MIE) via combined thoracoscopic and laparoscopic approach, and hybrid esophagectomy (HE) via a combined open thoracotomy with laparoscopic abdominal phase or vice versa.

In recent years, minimally invasive and hybrid approaches to esophagectomy have been increasingly utilized and their successful application has become commensurately represented in the literature (5). MIE/HE approaches aim to reduce damage to healthy tissues and allow more rapid recovery, while maintaining the clinical benefits of time-tested operations. The results of two multicenter randomized controlled trials (RCTs) have suggested that minimally invasive surgery may reduce postoperative complications, including the 2019 French Minimally Invasive Esophagectomy for Cancer (MIRO) trial (6) which compared HE and OE, and the 2012 European (The Netherlands, Spain, and Italy) Traditional Invasive vs. Minimally Invasive Esophagectomy (TIME) trial (7) that compared MIE and OE. However, the sample sizes of these two RCTs were too limited to confirm that MIE/HE achieve the same survival benefit as OE. As such, the ‘Randomised Oesophagectomy: Minimally Invasive or Open’ (ROMIO) study group out of the United Kingdom formed with the aim of addressing this evidence gap via a pragmatic RCT of more than 500 participants comparing OE and HE (8). In early 2024, short-term outcomes of the ROMIO trial up to 3-month post-randomization were reported in British Journal of Surgery (9).

The ROMIO trial

The ROMIO trial recruited from 8 hospitals in the United Kingdom from October 2016 to August 2019, with follow-up completed by August 2021. Eligible adult patients with localized adenocarcinoma or squamous cell cancer of the esophagus or esophagogastric junction were included. Participants were randomly assigned to either hybrid or open approach. The study included an expectation for Ivor Lewis esophagectomy with open right thoracotomy, and either an open abdominal approach in the OE group, or laparoscopic-assisted abdominal approach in the HE group. The primary objective of the trial was to evaluate the impact of laparoscopic vs. open abdominal approach on recovery of physical function. Secondary outcomes included pulmonary function, patient-reported pain scores, and 90-day clinical outcomes including the incidence of anastomotic leak, conduit necrosis/failure, recurrent laryngeal nerve injury and chyle leak severity (10). The final cohorts included 267 OEs and 266 HEs. The groups were well balanced in sociodemographic and clinical characteristics at the time of allocation.

Primarily, the ROMIO trial found no significant difference in patient-reported physical function in the first 3-month following surgery, in positive resection margins, lymph node harvest or final pathologic stage, and no difference in the incidence or severity of postoperative complications, pulmonary function or pain-scores between OE and HE. Hospital length-of-stays were similar between the two approaches and mortality at 30 and 90 days were similarly low in each group. Cost-effective analysis demonstrated no strong evidence for cost difference between HE and OE.

As such, the ROMIO trial concluded that no difference exists between HE and OE in patient-reported outcomes, clinical outcomes or cost-effectiveness. This suggests that surgeons who have a preference for, or find necessity for, an open abdominal approach may do so without compromising post-operative outcomes. Of course, the ROMIO study is subject to several limitations. These include potential surgeon bias due to the inability to blind the surgeon to treatment allocation and potential patient bias in that participants were aware of the surgical approach they had undergone when completing the patient-reported primary outcome measure. Another notable limitation is the potential variability in surgical technique across participating centers. Specifically, the ROMIO methodology highlights several surgeon-directed decisions that were not incorporated into the randomization process. For example, adjunct procedures including pyloroplasty or pyloromyotomy were optional and at surgeon discretion, and these intraoperative variables were not accounted for in the final analysis and may have influenced outcomes.

Other comparative studies

The MIRO trial (6) was published in 2019 and was a French prospective, open-label, multicenter (13 sites) RCT comparing HE (laparoscopic abdominal phase with open thoracotomy) and OE, both using the Ivor Lewis technique for patients with clinical stage I–III adenocarcinoma or squamous cell carcinoma of the middle or lower thoracic esophagus, regardless of if they received neoadjuvant therapy. The primary endpoint was major complications within 30-day of surgery defined as Clavien-Dindo Grade II or above, with secondary endpoints including 30-day mortality, all complications, disease free survival and overall survival. The final sample included 102 hybrid esophagectomies and 103 open esophagectomies, with the majority of patients in each group having undergone neoadjuvant therapy (75% and 72%, respectively).

The primary end-point analysis of MIRO showed that HE was associated with significantly lower rates of 30-day major morbidity compared to OE (36% vs. 64%; P<0.001) and this finding persisted following risk-adjustment for confounders. Specifically, HE was associated with a lower incidence of major pulmonary complications within 30 days than open surgery (18% vs. 30%). Moreover, the risk of major pulmonary complications within 30 days was 50% lower in the hybrid-procedure group than in the open group. Other end points, including operative time, median length of hospital stay, overall survival and disease-free survival were similar between the two groups.

Overall, MIRO demonstrated that HE resulted in fewer perioperative complications, particularly respiratory complications, compared to OE, indicating a laparoscopic approach may be beneficial compared to laparotomy for esophagectomy. However, like any clinical trial, the MIRO trial had several limitations. The MIRO trial focused on early-stage cancer and therefore was limited by selection bias, limiting the generalizability of the results. Furthermore, this trial focused on perioperative complications and short-term recovery. While these are important, the trial did not provide long-term survival data or long-term quality of life outcomes. Thus, it remains unclear whether the benefits of HE extend beyond the immediate postoperative period.

The TIME trial (7) was another pivotal study comparing MIE to OE for patients with esophageal cancer where MIE was performed via laparoscopy and right thoracoscopy, whereas MIRO and ROMIO trial patients underwent a thoracotomy during esophagectomy. The TIME trial recruited from 5 sites in Europe across The Netherlands, Spain, and Italy, enrolling patients who had undergone neoadjuvant therapy. The primary outcome was postoperative pulmonary infection, defined as clinical manifestation of pneumonia within the first 2 weeks of surgery and during the entire hospital stay. Secondary outcomes included hospital length of stay, quality of life 6 weeks after surgery, pathologic parameters of the specimen, postoperative morbidity and 30-day postoperative mortality. The final analysis included 53 MIE and 50 OE.

The TIME trial found that patients who underwent MIE had significantly fewer pulmonary infections in the first 2 weeks after surgery than those who underwent OE. Additionally, the study found that hospital length of stay was significantly shorter and the physical components of quality of life at 6 weeks were significantly better for patients in the MIE group compared to the OE group. There were no differences in anastomotic leak or reoperations, pathologic parameters or 30-day mortality.

Overall, the TIME trial was the first randomized trial to compare OE with MIE, demonstrating patients undergoing the MIE have an improved short-term outcome for pulmonary infections, hospital length of stay, and quality of life than do those undergoing OE, with no compromise of the quality of the resected specimen, arguing that these findings provide evidence for the short-term benefits of MIE. As always, several limitations should be considered—primarily, the TIME trial had a relatively small sample size, with only 115 patients. While this size was sufficient to demonstrate a difference in short-term outcomes like pulmonary complications, it may have been underpowered to detect differences in long-term survival or other less common complications. Long-term data on overall survival, recurrence rates, and long-term quality of life including postoperative pain and gastrointestinal function were not addressed, leaving uncertainty about the impact of MIE on long-term patient experience, cancer control and survival.

Outside of the RCTs mentioned (MIRO and TIME) which were limited by sample size, several retrospective papers have emerged with supporting results from larger datasets (5). In particular, an 11-year retrospective review of 13,457 esophagectomies from American College of Surgeons National Surgical Quality Improvement Program Database [2007–2018] including 83.2% OE and 16.8% MIE showed that patients undergoing minimally invasive esophagectomy had lower rates of postoperative complications regardless of esophagectomy techniques (Ivor Lewis, McKeown esophagectomy or transhiatal approach). Specifically, patients who underwent MIE had lower rates of morbidity, respiratory complications, urinary tract infection, renal complications, bleeding complications, and non-home discharge, and had shorter length of stay (11).

While ROMIO and MIRO focus on evaluating the impact of the abdominal approach, several studies have also compared MIE and HE, focusing on the impact of thoracotomy vs. thoracoscopy which many believe has a greater influence on the overall morbidity following esophagectomy. Patel et al. conducted two studies comparing outcomes after HE and complete MIE, the first evaluating all types of two-stage esophagectomies, and the latter evaluating Ivor Lewis esophagectomies. Both identified lower incidence of pulmonary infections in patients who underwent complete MIE with a thoracoscopic approach compared to patients who received HE via thoracotomy (12,13).

Robotic-assisted minimally invasive esophagectomy (RAMIE) is a newer modality for esophagectomy developed to benefit from improved surgical robotic instrumentation compared to standard MIE, with several recent clinical trials evaluating its effectiveness compared to other modalities. The ROBOT trial out of The Netherlands identified comparable oncologic outcomes between RAMIE and OE, but reduced cardiopulmonary complications after RAMIE (14). The RAMIE trial out of China, also compared MIE and RAMIE outcomes, and identified similar post-operative complications between the two approaches, with observed shorter operative time and higher efficiency in lymph node dissection for some patients in the RAMIE arm (15). Finally, a recent meta-analysis investigating how outcomes after RAMIE compare to OE and MIE identified similar rates of major post-esophagectomy complications after RAMIE and MIE, but reduced rates compared to OE (16).

Comparison of ROMIO and MIRO/TIME

Before comparing the results of the three major randomized clinical trials evaluating MIE/HE vs. OE (ROMIO, MIRO and TIME), it is important to first recognize several important differences in methodology that likely affected post-esophagectomy outcomes. Table 1 summarizes the characteristics of the three trials, most importantly it should be noted that in both ROMIO and MIRO, patients underwent thoracotomy, with the difference between study arms being the abdominal approach (i.e., laparotomy vs. laparoscopy), while patients in the TIME trial either received a laparotomy with thoracotomy or a completely minimally invasive esophagectomy.

Table 2 summarizes the rates of in-hospital complications and 30-day mortality rates for both open and minimally invasive comparator groups in the three trials. The most prominent difference was that the ROMIO trial did not identify a difference in the rate of pulmonary infections between OE and HE, which had previously been observed in the MIRO trial. While many variables contribute to the incidence of pulmonary complications after esophagectomy, whether the chest was accessed via thoracotomy or minimally invasive methods has been consistently described as a contributing factor as discussed earlier, including in the TIME trial (12-14). However, since both ROMIO and MIRO trials implemented thoracotomy in all study arms, this factor cannot explain the variability between their results. Other major differences in outcomes include a higher rate of anastomotic leak after HE and MIE compared to OE in the MIRO and TIME trials, while anastomotic leak rates were similar between surgical approaches in ROMIO, which may reflect surgeons’ increasing comfort and capability with minimally invasive surgery over time.

One should consider that the ROMIO trial was conducted much more recently than TIME and MIRO trials and as such outcomes may reflect changes and improvements in peri-operative esophagectomy care that may not have been implemented at the time of the MIRO and TIME trials, including enhanced recovery after surgery (ERAS) protocols. Additionally, ROMIO had a higher requirement for institutional esophagectomy volume compared to the MIRO and TIME trials, and institutional volume has been associated with improved post-esophagectomy outcomes (17-20). There were also differences in functional status between the trials and study arms. In the MIRO study, a greater proportion of participants allocated to open surgery were disabled [World Health Organization (WHO) performance status score 1+, 49%] compared to those allocated to the hybrid surgery group (35%). This may have influenced the occurrence of and response to complications, as functional status has consistently been linked with outcomes. The ROMIO study improved upon this limitation with equivalent distribution of patient functional status between the two study arms (see Table 1).

Another important topic that deserves continued investigation is factors affecting post-operative quality of life (QOL), particularly for esophagectomy which has a frequently complicated postoperative course and has a demonstrated negative impact on health-related QOL (21,22). The findings of ROMIO are consistent with those of MIRO regarding no differences in short-term physical function metrics, which may indicate there is little difference in speed of recovery between OE and HE. However, ROMIO did not explore effects on other aspects of QOL included in the QLQ surveys. On the contrary, the TIME trial and other non-randomized studies have concluded that patients undergoing MIE have better short-term QOL scores including physical function compared to open surgery (4). van der Sluis et al. also reported improved QOL outcomes after RAMIE compared to OE during their clinical trial (14). As such, additional investigation into understanding the differential effects of surgical approach on post-esophagectomy QOL is necessary.

ROMIO provided particularly novel information in the form of cost-benefit analysis comparing OE and HE, as no other clinical trials have investigated the costs associated with esophagectomy. Several non-trial studies have observed improved cost-effectiveness of MIE most likely associated with shorter length of stay (LOS), fewer post-operative complications, and slightly higher QOL and functional status post-esophagectomy seen with MIE (23). However, other studies have reported that the elevated cost associated with minimally invasive surgery compared to open surgery is not always offset by the post-operative benefits, and may be influenced by institutional experience and volume (24). Studies investigating cost effectiveness will be critical in esophagectomy as most studies continue to identify minimally invasive techniques to generally be clinically advantageous.

In summary, the ROMIO trial provides a contemporary picture of post-esophagectomy outcomes with higher statistical power compared to prior studies. The similarities of the ROMIO trial and its predecessors indicate similar survival and pathologic results between open and minimally invasive techniques, indicating surgeons may choose an approach based on preference or other factors without sacrificing oncologic principals or treatment efficacy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1862/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1862/coif). The authors have no conflicts of interest to declare.

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