Definition and treatment strategies for oligometastatic esophageal squamous cell carcinoma (OMESQ): a study protocol for global multidisciplinary consensus using the modified Delphi method

Introduction

Background

Esophageal cancer is the eleventh most common cancer worldwide and the seventh leading cause of cancer-related deaths (1). Esophageal squamous cell carcinoma (ESCC) is the predominant histological type globally, particularly in Asian countries or regions, whereas the incidence of esophageal adenocarcinoma has markedly increased in developed countries (2). Systemic therapy, including immune checkpoint inhibitors, has transformed the treatment landscape for recurrent or metastatic esophageal cancer (3-5). These regimens have achieved higher response rates than conventional cytotoxic chemotherapy.

The concept of oligometastatic disease (OMD), first introduced in 1995, describes an intermediate state between localized and widespread metastatic cancers, in which long-term disease control or even a cure may be achievable with local treatment (6). In recent years, OMD has been increasingly recognized in various malignancies, and the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) have proposed a classification system for OMD (7).

Rationale and knowledge gap

The definition and classification of OMD for esophagogastric adenocarcinoma have been established by the oligometastatic esophagogastric cancer (OMEC) consortium, consisting of adenocarcinoma experts. However, ESCC is the predominant subtype worldwide, particularly in East Asia, and exhibits distinct metastatic patterns compared with adenocarcinomas (8,9). These biological differences suggest that the definitions and treatment strategies for OMD in ESCC should not be extrapolated from those for adenocarcinoma. Consequently, definitions and treatment strategies derived for adenocarcinoma cannot be directly extrapolated to ESCC.

Currently, there is no globally standardized definition or treatment algorithm for oligometastatic esophageal squamous cell carcinoma (OMESQ), leading to inconsistent clinical management and impeding the design of high-quality prospective trials. To address this critical gap, we initiated the OMESQ project.

Objective

The OMESQ project aims to develop a global multidisciplinary consensus on the definition, diagnosis, and treatment of OMESQ, using the modified Delphi method. Furthermore, this consensus is intended to serve as the foundation for the development of future clinical trials. We present this article in accordance with the ACCORD reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-42/rc).

Methods

The project will be conducted in accordance with the World Medical Association’s Ethical Principles for Medical Research Involving Human Subjects (Declaration of Helsinki). The retrospective study (OMESQ-3) was approved by the Institutional Review Board of Kyoto University (No. R4674) and the participating institutions. Ethical approval was waived for the systematic review (OMESQ-1) and the expert consensus studies (OMESQ-2 and OMESQ-4) as they do not involve direct patient intervention. Ethical approval for the prospective trial (OMESQ-5) will be obtained prior to its initiation. The methodology of the OMESQ project is comparable to the multidisciplinary consensus efforts for the OMEC project (10-13).

OMESQ project

The OMESQ project is led by the Japan Esophageal Oncology Group (JEOG). The OMESQ consortium consists of esophageal cancer experts located in 58 centers across 14 countries or regions, including Belgium, China, Czech Republic, Denmark, Germany, Italy, Japan, the Netherlands, Norway, Poland, South Korea, Spain, Switzerland, and Taiwan. Table 1 shows the characteristics of the participating centers in the OMESQ consortium.

Study design

The OMESQ project consists of four sub-studies. Figure 1 shows a schematic overview of the OMESQ project.

Figure 1 Schematic overview of the OMESQ project. OMESQ, oligometastatic esophageal squamous cell carcinoma.

OMESQ-1

The first study (OMESQ-1) was a systematic review. The review protocol is prospectively registered in the online International Prospective Register of Systematic Reviews (PROSPERO) database for systematic reviews with the registration number CRD42024617344. Reporting is performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement (PRISMA) (14). This study aims to identify the definitions of OMESQ in the current literature. Therefore, PubMed, Embase, CENTRAL, and ClinicalTrials.gov will be systematically searched by two independent authors for studies or study protocols reporting a definition of OMESQ histology. Studies or study protocols reporting fewer than seven patients, repeat OMD or induced OMD, or regional lymph node metastasis (including supraclavicular nodes) without distant metastases will not be included. Studies performing local treatment for esophageal cancer reporting on a definition of OMD (i.e., the maximum number of organs and metastases) will be excluded. The Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool will be used for quality assessment (15). Finally, the references of the included articles will be screened for other potentially relevant articles using cross-referencing methods. Furthermore, a meta-analysis will be performed of pooled hazard ratios for overall survival after local treatment for OMD with or without systemic therapy versus systemic therapy alone.

OMESQ-2

The second study (OMESQ-2) will consist of a discussion of real-life clinical cases by multidisciplinary tumor boards of esophageal cancer expert centers. The methodology of this study is comparable to that of a simulated multidisciplinary expert opinion study on OMEC-2 (11). In total, 58 esophageal cancer expert centers agreed to discuss 15 real-life anonymized clinical cases in their multidisciplinary tumor board meetings. Each center will host a multidisciplinary tumor board meeting with at least a surgical oncologist, medical oncologist, and radiation oncologist present to ask for the multidisciplinary team’s responses on whether the case is considered OMD and what the proposed treatment should be. These 15 real-life anonymized clinical cases will vary in terms of (I) location of metastatic lesion; (II) number of metastatic lesions; (III) timing of detection (synchronous or metachronous); (IV) sum of diameters of distant metastases; (V) primary tumor and regional lymph node metastases status; and (VI) response to systemic therapy at restaging. The clinical case information of OMESQ-2 will consist of (I) the patient history (including primary tumor stage and previous treatment); (II) the current problem (including location and size of metastases); (III) pathology of the primary tumor and metastases; and (IV) imaging of the primary tumor and metastases (computed tomography, magnetic resonance imaging, or ¹⁸F-fluorodeoxyglocose positron emission tomography). The experts will be unaware of the actual diagnosis or treatment of the real-life clinical cases.

The primary outcome will be agreement with the definition of OMESQ at diagnosis. The secondary outcomes will be the minimum duration of systemic therapy and agreement on treatment strategies for OMESQ. Treatment strategies for OMD will be categorized as upfront local treatment with curative intent (metastasectomy, stereotactic body radiation therapy, or other local treatment for OMD) or systemic therapy followed by restaging to consider local treatment or systemic therapy alone.

OMESQ-3

The third study (OMESQ-3) will be a multicenter retrospective study of ESCC with five or fewer distant metastatic lesions. This multicenter retrospective study aims to evaluate the clinical outcomes of patients with ESCC with five or fewer distant metastases (excluding primary tumors and regional lymph node metastases). Data will be collected from patients treated between 2017 and 2023 at the participating centers of the JEOG. Primary tumors and regional lymph node metastases, including those in the supraclavicular nodes, are not counted as distant metastases. The primary endpoint is overall survival, which will be compared between systemic plus local therapy, upfront local treatment, and systemic therapy alone using propensity score-adjusted models to minimize selection bias.

OMESQ-4

The fourth study (OMESQ-4) serves as the pre-final phase of the project, aiming to establish a global multidisciplinary consensus. This study integrates the findings from the preceding steps: systematic review (OMESQ-1), discussion of cases (OMESQ-2), and retrospective analysis (OMESQ-3). Based on these synthesized data, which cover both systematic evidence and real-world clinical patterns, a modified Delphi method will be employed to reach consensus. The expert panel will consist of international specialists from multiple disciplines, including esophageal surgeons, medical oncologists, and radiation oncologists.

Prior to the initial Delphi round, all participating experts will be provided with detailed results from OMESQ-1, OMESQ-2, and OMESQ-3. The consensus process will utilize an online questionnaire. Experts will be asked to evaluate statements regarding the definition, diagnosis, and treatment of OMESQ using a 7-point Likert scale (ranging from 1, “strongly disagree” to 7 “strongly agree”). Additionally, a comment field will be provided for each statement to collect qualitative feedback and suggestions for modification. This process will be iterative, with questionnaires administered in multiple rounds. In each subsequent round, participants will be provided with feedback, including the distribution of scores and anonymous comments from the previous round. This cycle continues until a consensus is reached or the topics have been sufficiently debated to clarify points of disagreement.

After the completion of the Delphi rounds, a consensus meeting will be convened. This meeting aims to facilitate final discussions and resolutions on items where consensus remains pending or where further deliberation is required to formulate the final consensus statement.

OMESQ-5

The final study (OMESQ-5) will be a prospective international multicenter clinical trial for patients with OMESQ. This study will be a collaborative effort by the OMESQ consortium. Only patients with OMESQ according to the OMESQ consensus are included. The treatment arms will be determined in a later stage, depending on the OMESQ consensus findings and on what will become the most promising and urgent comparison of treatment strategies at the time of designing the study. The trial aims to improve overall survival or progression-free survival.

Outcome measures

The aim of the OMESQ project is to develop a multidisciplinary global consensus statement for the definition, diagnosis, and treatment of OMESQ. The prespecified outcomes are categorized as follows:

• Definition: this section focuses on defining the maximum number of distant metastatic organs and lesions, the maximum size or volume of these lesions, specific metastatic organ sites, laterality of lesions, and the status of primary tumor and regional lymph node metastases.
• Diagnosis: this section determines the preferred imaging modality for the baseline staging and restaging of OMESQ.
• Treatment: this section focuses on establishing the treatment of OMESQ for the indications for either upfront local treatment, systemic therapy alone, or systemic therapy followed by restaging to consider local treatment. Regarding systemic therapy, consensus will be sought on the preferred regimens, duration of treatment, and required tumor response to consider subsequent local interventions. Furthermore, for local therapy, the appropriate treatment modalities and precise extent of treatment required to improve outcomes will be defined.

Statistical analysis

The agreement across definitions in the literature or statements in the Delphi process will be either scored as absent/poor (<50% agreement), fair (≥50% and <75% agreement), or consensus (≥75% agreement), comparable with recent studies on the definition of OMD for other tumors (7,13,16,17). Moreover, this choice was also in accordance with a recent systematic review, which reported that the most common definition for consensus in Delphi studies was percent agreement.

Discussion

To the best of our knowledge, the OMESQ project is the first global multidisciplinary initiative aimed at establishing a standardized consensus for the definition, diagnosis, and treatment of OMESQ. While the concept of OMD offers a potential window for curative intent in metastatic cancer, the lack of standardized criteria for ESCC has historically led to heterogeneous clinical management and hampered the generation of high-quality evidence. This project aims to resolve these inconsistencies and provide a robust framework for future clinical practices and research.

A critical premise of this project is that ESCC requires a distinct approach compared with esophageal adenocarcinoma. The OMEC project has successfully established consensus criteria for oligometastatic esophagogastric adenocarcinoma (10-13). However, ESCC is characterized by different biological behaviors, including a higher propensity for lymphatic spread and distinct sensitivity to radiotherapy and chemotherapy, compared to adenocarcinoma (8,9). Therefore, simply extrapolating the OMEC criteria to ESCC may misclassify patients and lead to suboptimal treatment strategies. The OMESQ project addresses this gap by specifically focusing on the unique clinical entity of ESCC, particularly involving experts from Asian countries or regions, where the disease burden is highest, alongside European experts.

The timing of this consensus is particularly relevant, given the transforming treatment landscape. The advent of immune checkpoint inhibitors has significantly improved the survival outcomes of advanced ESCC (3-5). As systemic control improves, the role of local consolidative therapy for residual or oligometastatic lesions becomes increasingly important. Indeed, a recent multicenter study reported that conversion therapy after systemic chemotherapy is feasible and may offer long-term survival for selected patients with metastatic esophageal cancer (18). The OMESQ project will specifically address how to integrate local therapies, whether as an upfront treatment or as conversion therapy following systemic treatment, into the modern therapeutic algorithm. By defining the criteria for “conversion therapy”, which showed promising survival benefits in our preliminary analysis (OMESQ-3), this consensus aims to standardize aggressive multimodal strategies that are currently applied inconsistently.

A major strength of the OMESQ project is its comprehensive and stepwise methodology. Rather than relying solely on expert opinion, the Delphi process (OMESQ-4) will be informed by triangulation of data sources: a systematic review of existing definitions (OMESQ-1), an assessment of real-world decision-making variability (OMESQ-2), and a large-scale retrospective analysis of survival outcomes (OMESQ-3). This ensures that the final consensus statements are grounded in the best available evidence and reflect actual clinical challenges. Furthermore, the inclusion of a diverse panel of surgeons, medical oncologists, and radiation oncologists from 14 countries or regions ensures that the consensus is multidisciplinary and globally generalizable.

This study protocol has some limitations. The evidence feeding into the consensus (OMESQ-1 and OMESQ-3) is primarily based on retrospective data, which carry inherent selection biases. Additionally, the rapid evolution of systemic therapies may outpace the publication of consensus guidelines for their use. However, the modified Delphi method allows for the synthesis of expert wisdom to bridge gaps where high-level evidence is currently lacking.

In conclusion, the OMESQ project aims to harmonize the definitions, diagnosis, and treatment of OMESQ. The resulting consensus will not only standardize current clinical practice but also serve as the essential foundation for the OMESQ-5, a future prospective multicenter trial designed to validate these strategies and ultimately improve patient survival.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus for the series “Multimodal Approach and Clinical Application for Esophageal Cancer”. The article did not undergo external peer review.

Reporting Checklist: The authors have completed the ACCORD reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-42/rc

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-2025-1-42/coif). The series “Multimodal Approach and Clinical Application for Esophageal Cancer” was commissioned by the editorial office without any funding or sponsorship. K.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. M.N. has received honoraria from Bristol Myers Squibb, Ono Pharmaceutical, MSD and BeOne Medicines. K.K. has received consulting fees from Bristol Myers Squibb, Merk Sharp & Dohme, BeiGene, Roche, AstraZeneca, and Bayer; honoraria from Ono Pharmaceutical, Bristol Myers Squibb, and Taiho pharmaceutical; and research funding outside the submitted work from Ono Pharmaceuticals, Bristol Myers Squibb, Merk Sharp & Dohme, BeiGene, Chugai, Shionogi, AstraZeneca, and Bayer. M.K. has received honoraria Eli Lilly Japan and MSD. Y.H. has received honoraria from Bristol Myers Squibb, Ono Pharmaceutical, BeOne Medicines, and MSD. T.Y. has received honoraria from Bristol Myers Squibb, Ono Pharmaceutical, and MSD. K.S. has received Speakers’ Bureau from MSD, Ono Pharmaceutical; and Travel, Accommodations, Expenses from MSD, Ono Pharmaceutical. S.M. has received honoraria from Bristol Myers Squibb, Ono Pharmaceutical, BeOne Medicines, and MSD. T.T. has received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, MSD and BeOne Medicines. H.T. has received honoraria from Bristol Myers Squibb, Ono Pharmaceutical, MSD, BeiGene, Taiho Pharmaceutical, Johnson&Johnson, Medtronic, Daiichi Sankyo, and Otsuka Pharmaceutical Factory. 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 project will be conducted in accordance with the World Medical Association's Ethical Principles for Medical Research Involving Human Subjects (Declaration of Helsinki). The retrospective study (OMESQ-3) was approved by the Institutional Review Board of Kyoto University (No. R4674) and the participating institutions. Ethical approval was waived for the systematic review (OMESQ-1) and the expert consensus studies (OMESQ-2 and OMESQ-4) as they do not involve direct patient intervention. Ethical approval for the prospective trial (OMESQ-5) will be obtained prior to its initiation.

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/.

References

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
2. Kimura Y, Okamura A, Takeuchi M, et al. Comprehensive registry of esophageal cancer in Japan, 2016. Esophagus 2025;22:475-505. [Crossref] [PubMed]
3. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021;398:759-71. [Crossref] [PubMed]
4. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022;386:449-62. [Crossref] [PubMed]
5. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol 2023;24:483-95. [Crossref] [PubMed]
6. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8-10. [Crossref] [PubMed]
7. Guckenberger M, Lievens Y, Bouma AB, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol 2020;21:e18-28. [Crossref] [PubMed]
8. Ohkura Y, Shindoh J, Ueno M, et al. Clinicopathologic Characteristics of Oligometastases from Esophageal Cancer and Long-Term Outcomes of Resection. Ann Surg Oncol 2020;27:651-9. [Crossref] [PubMed]
9. Yoshida K, Yasufuku I, Terashima M, et al. International Retrospective Cohort Study of Conversion Therapy for Stage IV Gastric Cancer 1 (CONVO-GC-1). Ann Gastroenterol Surg 2022;6:227-40. [Crossref] [PubMed]
10. Kroese TE, van Laarhoven HWM, Nilsson M, et al. Definition of oligometastatic esophagogastric cancer and impact of local oligometastasis-directed treatment: A systematic review and meta-analysis. Eur J Cancer 2022;166:254-69. [Crossref] [PubMed]
11. Kroese TE, van Hillegersberg R, Schoppmann S, et al. Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe. Eur J Cancer 2022;164:18-29. [Crossref] [PubMed]
12. Kroese TE, van Laarhoven HWM, Schoppman SF, et al. Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe. Eur J Cancer 2023;185:28-39. [Crossref] [PubMed]
13. Kroese TE, Bronzwaer S, van Rossum PSN, et al. European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4). Eur J Cancer 2024;204:114062. [Crossref] [PubMed]
14. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372: [Crossref] [PubMed]
15. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919. [Crossref] [PubMed]
16. Dingemans AMC, Hendriks LEL, Berghmans T, et al. Definition of synchronous oligometastatic nonesmall cell lung cancerda consensus report. J Thorac Oncol. 2019;14:2109-2119. [Crossref] [PubMed]
17. Aluwini SS, Mehra N, Lolkema MP, et al. Oligometastatic Prostate Cancer: Results of a Dutch Multidisciplinary Consensus Meeting. Eur Urol Oncol 2020;3:231-8. [Crossref] [PubMed]
18. Tsuji T, Matsuda S, Sato Y, et al. Safety and Efficacy of Conversion Therapy After Systemic Chemotherapy in Advanced Esophageal Cancer with Distant Metastases: A Multicenter Retrospective Observational Study. Ann Surg Oncol 2025;32:274-83. [Crossref] [PubMed]