Is metastasis-directed local therapy the new standard of care for patients with oligometastasic esophageal squamous cell carcinoma?—a perspective on the ESO-Shanghai 13 Trial

The current standard of care therapy for patients with metastatic or recurrent esophageal squamous cell carcinoma (ESCC) is nivolumab plus 5-fluorouracil and platinum-based chemotherapy or ipilimumab plus nivolumab as determined by the CHECKMATE 648 trial (1). Compared with chemotherapy alone, utilizing immunotherapy with or without chemotherapy demonstrated an overall survival (OS) benefit of 13.2 vs. 10.7 months with an even larger benefit seen in the subgroup of patients with programmed death ligand 1 (PD-L1) expression greater than 1%. However, 2-year OS was approximately 20–30% and 3-year was approximately 10%, suggesting this is an area of significant need (2).

There is a developing interest in the use of metastasis-directed locally consolidative therapy (LCT) in select patients with oligometastatic malignancy. The randomized phase II SABR-COMET trial generated substantial enthusiasm as it demonstrated an improvement in progression-free survival (PFS) and OS (5-year: 42% vs. 17%) for the use of metastasis-directed stereotactic body radiation (SBRT), compared with systemic therapy alone, for patients with oligometastatic malignancy across several histologic subtypes (3).

For metastatic ESCC, prior retrospective studies have provided hypothesis generating data suggesting LCT is associated with improved survival compared with systemic therapy alone (4). Shi et al. (5) evaluated 314 patients with up to 1–5 synchronous metastatic lesions from ESCC and were treated with either total consolidation (metastases and primary) vs. chemotherapy alone. There was a survival benefit to LCT of 18.5 vs. 15.6 months. Patients with 1–3 metastatic lesions had better survival than patients with 4–5 lesions. Furthermore, Yamamoto performed a study evaluating 131 metachronous pulmonary oligometastases that were treated with SBRT following prior definitive therapy to the primary disease. LCT was associated with a 3-year OS of 37.5%, 3-year freedom from further metastases of 25%, and 3-year local control (LC) of 70% (6).

Building upon this work, the ESO-Shanghai 13 trial by Liu et al. (7) prospectively evaluated the benefit of adding LCT (with either radiotherapy, thermal ablation, or surgery) to standard systemic therapy for patients with oligometastatic ESCC. The authors did recommend attempting radiation as the primary consolidative modality in the protocol. This trial was a phase II randomized trial for patients who had oligometastatic disease following definitive primary therapy, including patients with synchronous oligometastasis (18%) or oligorecurrence (82%). A total of 104 patients were randomized to either standard of care systemic therapy with or without LCT to all disease sites. Most patients had metachronous cancer (72%), defined as greater than 6 months to recurrence from prior definitive therapy. Importantly, patients had limited metastatic burden with most having up to two foci of disease (85% within the LCT group vs. 76% in the systemic only). The locations of metastases included a large proportion of non-regional nodal only metastases (43% and 45% in the LCT and systemic arm respectively). Further if an organ was involved it was in most instances a single organ involved (79% and 73% in the LCT and systemic arm respectively). The modality for LCT was radiotherapy in 83% of patients consisting of SBRT in 38% of the cases. When SBRT was administered the goal was to administer over 80 Gy₁₀ biologically effective dose (BED), assuming an α/β=10 Gy with planning dose-volume parameters for organs at risk following national guidelines discussed in the appendix. The study was powered to detect an improvement of PFS from 5 to 10 months with the addition of LCT. Due to a change in systemic therapy during enrollment (Checkmate 648), there were 20 (38%) patients in the LCT and 23 (45%) patients in the systemic therapy only group who received anti-PD-1 therapy.

OS was also improved with LCT, with median OS not reached in the LCT group vs. 18.6 months in the systemic therapy arm, hazard ratio (HR) 0.42 (95% CI: 0.24–0.74; P=0.0020).

Median PFS was 15.3 months in the LCT arm and 6.4 months in the systemic therapy only group (stratified HR 0.26; P<0.0001). This effect was consistent regardless of receipt of immunotherapy or not, as patients who received immunotherapy had a median PFS of 18 vs. 9.6 months. Impressively, 2-year PFS was 60.4% in the LCT arm vs. 9% in the systemic arm. On subgroup analysis, the PFS effect size was stronger for patients who had one site of metastatic disease. When more than one organ was involved, there was no significant benefit to LCT. Furthermore, LCT was associated with greater benefit in the subset with metastatic disease limited to non-regional lymph nodes (HR 0.259) compared with visceral metastases (HR 0.468). Altogether these subset analyses are hypothesis generating and can potentially inform future trial design in terms of separating out which patients receive maximal benefit of therapy.

Disease progression occurred in 90% in the systemic therapy alone group and 62% in the LCT group. The pattern of disease progression differed in each of the treatment groups with the primary site of progression being distant metastases in the LCT arm (75% vs. 22%) compared with fewer progression events at the initial local sites of metastatic disease (18% vs. 65%). Upon progression 52% of patients in the systemic therapy only arm received salvage LCT. There was no significant difference in grade 3 or greater adverse side effects which were 47% in the LCT arm vs. 45% in the systemic alone arm, thus supporting the relatively limited added morbidity of LCT. There were 2 treatment related deaths in LCT arm from esophageal fistula and one death in the systemic arm from pneumonitis. While there was more censoring present in the LCT arm over the systemic arm (17 vs. 4 patients) there was little censoring within the first two years and by 12 months there was an appreciable difference in PFS event rate (8).

Overall, ESO-Shanghai 13 demonstrated that LCT for a population of oligometastatic ESCC (limited primarily up to 2 lesions) improves PFS and OS in a statistically and clinically meaningful way. ESO-Shanghai 13 demonstrates an even greater relative benefit than that seen with the addition of immunotherapy in the practice changing CHECKMATE 648 trial. Such results would benefit from confirmation within a prospective phase 3 randomized trial with an OS primary endpoint. However, the wide therapeutic ratio with significant clinical benefit and limited morbidity does support LCT as a new option for clinicians to treat patients with limited oligometastatic ESCC. Questions remain regarding generalizability and future work is needed to better identify optimal candidates for LCT. Future larger confirmatory trial trials with more nuanced secondary correlates (biomarkers, circulating tumor DNA, immune correlates) will certainly expand upon this important study by informing patient selection, guiding prognosis (9,10). Understanding of the unique biology of metastases (11) and the likelihood of further metastatic spread could elucidate which patients may derive best benefit (12). We await the results of ECOG 2183 which is exploring a similar question for patients with esophageal adenocarcinoma.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-57/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-57/coif). K.R.J. has received within the past 3 years honoraria from Radonc Questions LLC. The other author has no 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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