Interpreting JCOG1409 (MONET): what does non-inferiority really mean for minimally invasive oesophagectomy?

The JCOG1409 (MONET) trial is an important contribution to the evidence base for minimally invasive esophagectomy (1). It is the first large, multicenter, randomized phase III trial to use overall survival as the primary endpoint when comparing thoracoscopic and open transthoracic esophagectomy. This alone represents a major methodological advance over earlier trials, which focused primarily on perioperative morbidity (2-4).

However, careful interpretation of the results requires attention to both the study methodology and the clinical context in which it was conducted.

The trial was designed as a non-inferiority study, with a 9% margin for 3-year overall survival, corresponding to a hazard ratio of 1.44. This margin implies that thoracoscopic esophagectomy could be associated with a substantial reduction in survival and still be considered clinically acceptable. In surgical oncology, where long-term survival remains the dominant outcome, this is a relatively wide margin. Non-inferiority margins in contemporary oncological trials are often considerably narrower, commonly in the range of hazard ratios of 1.20–1.30 (5). While the authors justify this choice based on potential advantages in postoperative recovery, pain, cosmesis, and quality of life, these benefits were not clearly demonstrated in the trial. Quality-of-life outcomes were similar between groups, and major postoperative morbidity did not differ meaningfully. When the anticipated trade-offs do not materialize, the rationale for allowing a large potential reduction in survival becomes less compelling (4).

The statistical methods of the trial further affect interpretation. The study was powered at 75%, rather than the more conventional 80–90%. In non-inferiority trials, this is particularly relevant because protocol deviations, crossovers, and intention-to-treat analyses tend to bias results toward non-inferiority. A lower power increases the probability of falsely concluding non-inferiority when a clinically important difference exists (6).

This concern is reinforced by the trial’s early termination. MONET was stopped at the second interim analysis, when just over half of the planned number of events had occurred. At that time, thoracoscopic esophagectomy appeared to have a favorable hazard ratio for overall survival. However, in the subsequent updated analysis with longer follow-up, the hazard ratio approached unity, and the confidence intervals were wide, encompassing both a clinically relevant benefit and a potentially important disadvantage. This pattern is consistent with the well-recognized tendency of early-stopped trials to overestimate treatment effects (7). These considerations do not invalidate the findings of MONET, but rather support a more cautious interpretation of the strength and applicability of the conclusions.

Beyond these statistical issues lies a fundamental question of generalizability. MONET was conducted in a highly selected Japanese population dominated by squamous cell carcinoma and treated almost exclusively with McKeown-type esophagectomy and cervical anastomosis. In contrast, Western practice is largely centered on adenocarcinoma of the distal esophagus and gastro-esophageal junction, treated with Ivor Lewis esophagectomy and an intrathoracic anastomosis. These are not merely technical differences. Squamous cell carcinoma and adenocarcinoma differ in biological behavior, response to neoadjuvant therapy, and patterns of recurrence (8). Similarly, cervical and intrathoracic anastomoses have very different clinical consequences when complications occur due to the anatomical placement of the anastomosis and potential treatment options related to this. Furthermore, treatment paradigms differ substantially between East and West, including the use of neoadjuvant chemotherapy in Japan versus chemoradiotherapy-based approaches such as the CROSS regimen in many Western centers.

In MONET, thoracoscopic esophagectomy was associated with a numerically higher rate of clinically significant anastomotic leakage (11% vs. 5%), although this did not reach conventional statistical significance. The authors argue that, because all anastomoses were cervical, these leaks were relatively contained and unlikely to affect long-term survival. That may be true in this specific setting, but it also highlights a key limitation for extrapolation. In Western Ivor Lewis surgery, an intrathoracic leak carries a much higher risk of mediastinitis, sepsis, and mortality, and therefore a different balance between minimal invasiveness and anastomotic risk may apply. In addition, the chosen neoadjuvant regimen may limit the study’s generalizability, especially in a Western perspective, where most patients with squamous cell carcinoma will receive preoperative chemoradiation in the CROSS regimen (9,10).

The authors state that anastomotic leakage likely did not significantly affect survival. One could argue that the potentially deleterious effect of (borderline significant) increased anastomotic leakage was offset by lower postoperative inflammation, a lower incidence of pneumonia, reduced blood loss, and less pronounced deterioration in respiratory function in the thoracoscopic arm. This is an important point as it is another reason for preferring minimally invasive surgery and is consistent with prior randomized evidence demonstrating reduced pulmonary morbidity after minimally invasive esophagectomy (2-4).

As the authors point out themselves; the inclusion of patients in the study has been skewed since thoracoscopic procedures are preferred by patients. The inclusion was also unbalanced, with one center enrolling more than a third of all patients. Although these are not flaws in the design of the study, but rather a result of the realities of conducting a study like this, one could argue that the low numbers of patients willing to undergo open surgery could contribute to the higher rate of R1 resections and increased blood loss in the open surgery arm. Importantly, the study reported a numerically higher rate of R1 resections in the open arm (10%), a finding not further addressed in the discussion despite its potential impact on both overall and recurrence-free survival. However, this interpretation remains speculative and should be considered hypothesis-generating rather than conclusive.

As MONET was designed as a non-inferiority rather than a superiority trial, the study does not permit definitive conclusions regarding the superiority of thoracoscopic esophagectomy, despite hazard ratios that numerically favor the minimally invasive approach in interim analyses. However, taken together, MONET provides strong evidence that thoracoscopic McKeown esophagectomy for squamous cell carcinoma, performed at high-volume Japanese centers with rigorous quality control, does not appear to be inferior to open surgery with respect to short-term overall survival. What it does not establish is oncological equivalence for minimally invasive Ivor Lewis esophagectomy in predominantly adenocarcinoma populations.

For European and North American practice, the study should therefore be interpreted as supportive but not definitive. It reassures us that a thoracoscopic approach can be delivered safely and without an obvious early survival penalty in an optimal setting. It does not remove the need for disease-specific, procedure-specific, and region-specific evidence before minimally invasive esophagectomy can be considered fully interchangeable with open surgery in all contexts.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0009/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0009/coif). M.P.A. reports payments made to his institution from Arthrex and Olympus; serves as the Chair of the Upper GI Surgery Section under the Danish Surgical Society and UEMS MJC Upper GI Surgery; and holds warrants in Ampa Medical. The other author has 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.

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