ESO-Shanghai 13: another milestone in the treatment of oligometastatic disease?

Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of cancer death worldwide (1). Esophageal carcinomas can be subdivided into two histological subtypes, adenocarcinoma, and squamous cell carcinoma. The less common adenocarcinoma is mainly associated with the risk factor of Barrett’s esophagus, whereas squamous cell carcinoma is mainly associated with smoking and the consumption of hard alcohol (2).

Depending on the stage, the current treatment of early-stage squamous esophageal carcinoma consists of surgical resection alone. Treatment for locally advanced disease consists of neoadjuvant chemoradiotherapy followed by resection or definitive radiochemotherapy. Adjuvant immunotherapy is applied if after (salvage) resection residual vital tumor is present in the resection specimen (3,4). The standard-of-care for metastatic cancer is palliative systemic therapy. However, patients with limited metastatic disease (so-called oligometastatic disease) might benefit from metastasis-directed therapy in addition to standard-of-care systemic therapy (5,6).

The aim of local therapy for oligometastatic disease is to eradicate metastatic lesions and to render the patient disease-free, if patients are free from microscopic disease or if microscopic disease is controlled by systemic therapy (7). Accordingly, this treatment approach was assessed in the ESO-Shanghai 13 study.

In the ESO-Shanghai 13 study (8), 116 patients, aged at least 18 years old with an Eastern Cooperative Oncology Group (ECOG) 0–1, and a histological confirmation of oligometastatic squamous cell carcinoma of the esophagus were included between March 2019 and September 2021. Further inclusion criteria were a controlled primary tumor by surgery or radiotherapy with no progression ≤3 months. Oligometastatic disease was defined ≤4 metastatic lesions in ≤3 different organs and a diameter of ≤5 cm. All metastatic lesions were required to be amenable to local therapeutic intervention without having undergone prior treatment. Important exclusion criteria were the receipt of antitumor medication within 3 months or history of widespread metastases.

In total, 104 patients were randomized 1:1 to standard-of-care systemic therapy alone or systemic and local therapy. Randomization was balanced on the three prognostic covariates number of disease sites (one vs. two to four), the lines of systemic therapy (first-line vs. second-line) and the location of the metastases (non-regional nodes alone vs. visceral metastases).

The systemic therapy in both groups consisted of four cycles of standard-of-care chemotherapy and after an amendment in July 2020 optional immunotherapy with anti-PD-1 antibody. Immunotherapy in first- and second-line treatment was administered to 20 of 53 patients in the systemic and local therapy group, whereas 23 of 51 patients in the systemic therapy alone group received immunotherapy. The preferred local therapy with 89% was radiotherapy with stereotactic ablative body radiotherapy (SABR) being used in 38% of the patients, conventional fractionated intensity-modulated radiotherapy in 47% patients and hypofractionated radiotherapy in 4% of the patients. SABR was commonly applied with ≤5 fractions of ≥7 Gy, whereas conventional radiotherapy was performed using involved-field irradiation and a prescribed dose of at least 45–66 Gy with 1.8–2.0 Gy per fraction. For all lesions not amenable to SABR, local treatment options were conventional radiotherapy, surgery, or thermal ablation. Local lesions in the systemic therapy only group could only be treated in the event of progression, for symptom relief or as palliative radiotherapy otherwise the patient would be censored at the time of crossover.

The primary endpoint of the study was progression-free survival (PFS), while prespecified secondary endpoints were overall survival (OS), proportion of patients with local control, toxicity, and the quality of life.

The study demonstrated that the systemic and local therapy cohort had superior outcomes compared to the systemic therapy-only cohort. This was shown by improved PFS of 15.3 months in the systemic and local therapy group versus 6.4 months in the systemic therapy only group [stratified hzard ratio (HR) 0.26, 95% confidence interval (CI): 0.16–0.42; P<0.0001] and no significant differences in severe adverse events or quality of life. The substantial improvement in PFS translated into an OS benefit for the total patient population with the median OS not being reached in the systemic and local therapy group and 18.6 months in the systemic therapy only group (HR 0.42, 95% CI: 0.24–0.74; P=0.0020). The benefit of additional local therapy appeared diminished in patients receiving immunotherapy, while both study groups benefited from treatment with immunotherapy. However, it should be emphasized that the study was not powered to perform such subgroup analyses (HR 0.49, 95% CI: 0.24–0.99; P=0.044). As anticipated, the treatment failure pattern differed, with a higher incidence of new lesions in the systemic and local therapy group, whereas local control was significantly better with a HR of 0.11 (95% CI: 0.05–0.24; P<0.0001). The group receiving both systemic and local therapy showed a longer median time to new lesion appearance (16.8 months) compared to the group with only systemic therapy (12.3 months; P=0.0075).

The ESO-Shanghai 13 trial demonstrated robust adaptability to dynamic treatment paradigms during its enrollment period, characterized by its comprehensive inclusion criteria and diverse intervention strategies. Nonetheless, the interpretation of outcomes within the study cohorts is beset by notable methodological challenges. Principally, the variability in staging techniques employed prior to enrollment poses a potential source of selection bias, as it may result in the inadvertent inclusion of patients with occult metastases. Specifically, 38% of individuals in the systemic and local therapy group and 49% in the systemic therapy-only group underwent pre-enrollment positron emission tomograph computed tomography (PET-CT) examinations, introducing a potential confounding factor in the evaluation of trial outcomes.

The question of the most appropriate type of local therapy for oligometastatic disease cannot be answered after the ESO-Shanghai 13 study. A variety of different radiotherapy regimes [stereotactic body radiotherapy (SBRT) vs. conventional radiation therapy (RT) vs. hypofractionated RT], as well as surgery or thermal ablation were used for treatment of oligometastatic disease. A comparison of these does not appear to be expedient, especially given the relatively small number of patients in these subgroups and requires further studies that explicitly investigate this. A comparison of conventional RT and SBRT was not part of the study. Considering that almost 90% of patients in the experimental arm received some form of radiotherapy, we assume that the PFS and OS benefit is attributable to this. Nevertheless, these different treatment modalities may have an impact on the applicability to future patients. The applicability of the study is potentially limited in Western countries, where adenocarcinomas are the predominant histopathological entity in esophageal cancer. In China and worldwide, however, squamous cell carcinoma is the most common entity and should be investigated further, especially in high-risk regions like Eastern Asia (3,9). Furthermore, it is important to note that, due to change in the general treatment regime, not all patients received immunotherapy as part of their treatment. Additionally, the data on programmed death-ligand 1 (PD-L1) expression was not available for any of the study population. These factors should be considered when interpreting the results. Particularly in the context that both PFS and OS are less significant in the subgroups that received immunotherapy than in the overall population.

Lastly, the ESO-Shanghai 13 showed improved progressive-free survival compared to KEYNOTE-590 (10) and CheckMate 648 (11). The median PFS in the subgroup of the ESO-study, who received immunotherapy, is 18.0 months in the systemic and local therapy group and 9.6 months in the systemic therapy only group, while KEYNOTE-590 found a median PFS of 6.3 months in the pembrolizumab and chemotherapy group and 5.8 months in the placebo and chemotherapy group. CheckMate 648 did see a PFS of 5.8 and 5.6 months in the nivolumab plus chemotherapy and only chemotherapy group, respectively. This improved PFS might be explained by a controlled primary tumor with metachronous oligometastatic disease, a lower tumor burden and the benefit of local therapy.

The concept that ablative treatments prevent progression in treated metastatic sites is not new, but the study with its homogeneous patient collective of oligometastatic ESCC represents the first randomized controlled trial in the landscape of oligometastatic esophagogastric cancer. Prior to this study, only two prospective trials addressing this subject had been completed: a non-randomized prospective trial by the same researchers focusing on patients with oligometastatic ESCC, and the German FLOT-3 trial concentrating on patients with oligometastatic gastric or gastroesophageal junction cancer (12,13). Liu et al. conducted a phase 2 trial involving 34 oligometastatic ESCC patients, demonstrating that a combination therapy comprising SBRT for all metastatic lesions with or without chemotherapy (50% received chemotherapy) yielded a favorable OS rate, with a one- and two-year OS rates of 76.2% and 58.0% (12). The FLOT-3 trial, encompassing 252 patients, employed a three-arm study design to investigate the efficacy of neoadjuvant chemotherapy followed by definitive resection in patients with locally advanced disease (Arm A), chemotherapy and restaging followed by surgery with potential for R0 resection rate in patients with oligometastatic disease and consolidating chemotherapy (Arm B), or chemotherapy and palliative resection in patients with polymetastatic disease (Arm C). The response rate for Arm B was 60% (complete, 10%; partial, 50%) and 36 of 60 patients (60%) proceeded to surgery. The median OS was 31.3 months (95% CI: 18.9–upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI: 7.1–22.9) for the other patients (13).

The ESO-Shanghai 13 study builds on a growing body of evidence demonstrating the effect of local treatment for oligometastatic disease. Other important studies conducted in the field of oligometastatic diseaes are summarized in Table 1. In most studies, SBRT was the primary treatment modality to improve PFS, and in selected cases OS as well. The only exception is the study by Chmura et al. who were unable to show a PFS advantage in breast cancer (23).

In summary, Liu et al. (8) found an encouraging clinical benefit of local treatment in combination with systemic therapy in oligometastatic esophageal cancer. The magnitude of benefit for the interventional strategy was not only statistically significant but clinically relevant with a HR of 0.26 for PFS, which translated into a relevant OS advantage. Further investigation is needed to determine if a universally applicable definition exists for oligometastatic disease or if disease-specific adjustments, incorporating clinical and molecular factors, are necessary. Key elements for risk stratification include treatment of the primary tumor, number and location of metastatic foci, pattern of occurrence, PD-L1 expression, and recognition of molecular features. Integrative insights from translational analyses and collaborative efforts, like the oligometastasis in Esophago-gastric Cancer project (25), are eagerly anticipated to provide a comprehensive understanding of oligometastatic disease in esophagogastric tumors, paving the way for future prospective evidence.

Despite the benefit observed in this trial, it is crucial to continue enrolling oligometastatic esophageal cancer patients in phase 2 and 3 clinical trials to advance the science of medical treatments and determine the best approaches for patient care.

Acknowledgments

Funding: None.

Footnote

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

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