Benefit from addition of local therapy in oligometastatic oesophageal squamous cell carcinoma

Systemic therapy is the standard treatment in management of metastatic oesophageal squamous cell carcinoma (SCC), with a 5-year overall survival (OS) rate of only 5%; underscoring the need for innovative therapeutic approaches to improve patient outcomes (1). The concept of the oligometastatic state offers a compelling rationale for investigating tailored treatment strategies (2). This transitional phase between early locoregional disease and widespread metastasis has garnered substantial interest, driven by advancements in imaging modalities facilitating improved detection of limited disease, the efficacy of systemic therapies in controlling micrometastatic lesions, and the evolution of local therapies such as stereotactic body radiotherapy (SBRT) with reduced toxicities (3,4). Prospective studies have shown survival gain for local therapy in oligometastatic disease in other malignancies (5,6). Despite promising retrospective data, a significant gap in evidence exists regarding the role of local therapy in oligometastatic oesophageal SCC. The ESO-Shanghai 13 study represents the first prospective randomised trial evaluating the role of local therapy in oligometastatic oesophageal SCC (7).

ESO-Shanghai 13 was a multicentre open label randomised phase 2 study conducted in patients with oligo-recurrent oesophageal SCC (7). Patients with control of their previously treated primary tumour and ≤4 new metastatic lesions were randomised to standard-of-care chemotherapy with or without local therapy. The protocol was amended during the trial period to allow concurrent and maintenance anti-PD1 antibodies in both treatment arms due to a change in the standard of care. Local therapy in the experimental arm was administered prior to chemotherapy using SBRT, conventional radiotherapy, surgery or thermal ablation. The study was powered to detect a doubling of the primary end-point of progression-free survival (PFS).

A total of 104 patients were included in the analysis. The majority of patients in the experimental arm were treated with SBRT (83%). The trial was closed early at a pre-specified interim analysis based on significant benefit of the experimental arm. At a median follow-up of 30.5 months, the primary endpoint of the study was met [median PFS, 15.3 vs. 6.4 months, hazard ratio (HR) =0.26]. The improvement in local control (83% vs. 26%, HR =0.11) from local therapy also translated to an OS benefit (HR =0.42). Grade 3 or higher toxicities were similar between the two arms (47% vs. 51%, P=0.54), most commonly related to systemic therapy (leukocytopenia and neutropenia). Similar to other studies, the addition of SBRT to chemoimmunotherapy was deemed safe and feasible (8,9).

The results of the ESO-Shanghai 13 trial were consistent with the landmark SABR COMET trial which included a variety of malignancies, in demonstrating an improvement in both OS (HR =0.47) and PFS (HR =0.48) with the addition of SBRT to standard-of-care systemic therapy (5). Furthermore, large retrospective comparative series focusing on oligometastatic oesophageal SCC have also consistently shown the benefit of local therapy (10-14). Predominant local therapy in these series was conventionally fractionated chemoradiotherapy utilising relatively lower biologically effective radiotherapy doses (BED) (10,11). Li et al. highlighted the importance of achieving greater tumour local control, showing that higher radiotherapy doses (>60 Gy BED) were associated with higher OS (11). The evolution of radiotherapy, particularly with the advent of SBRT, has revolutionized the oligometastatic treatment landscape. It has become feasible to achieve higher ablative biologically effective radiotherapy doses (>100 Gy BED) with minimal toxicities (4). A study by Liu et al. represents the only prospective single arm study utilizing SBRT followed by chemotherapy in oesophageal SCC, demonstrating impressive local control rates of 92% (15). The majority of patients in the ESO-Shanghai 13 trial were treated with SBRT (83%), but it also allowed a range of other local therapies which represents a limitation of the study. Therefore, the optimal local treatment modality remains a subject of debate, with pragmatic considerations allowing for a range of approaches reflective of contemporary clinical practice. Given that the majority of failures in the experimental arm of the ESO-Shanghai 13 trial were new distant metastases (75%), selecting the local treatment modality with the least toxicity and minimal interruption of systemic therapy is paramount.

An important consideration when interpreting the benefit of local therapy for metastatic malignancy is the efficacy of the concurrent systemic therapy. Chemoimmunotherapy represents the new standard of care in metastatic oesophageal SCC based on the OS benefit of the KEYNOTE-590 (HR =0.72, median OS: 12.6 vs. 8.8 months) and RATIONALE-306 (HR =0.66, median OS: 17.2 vs. 10.6 months) studies (16,17). In the ESO-Shanghai 13 trial, 58 patients were treated with chemotherapy alone and 43 patients with chemoimmunotherapy. An underpowered ad-hoc analysis showed a PFS benefit of local therapy in both the chemotherapy only (HR =0.23) and the chemoimmunotherapy group (HR =0.49). In the chemoimmunotherapy group, the benefit of local therapy in improving OS (30.7 vs. 20.6 months) did not reach statistical significance due to the insufficient patient numbers and limited follow-up. However, an impressive OS of 30.7 months in the ESO-Shanghai 13 study would represent the new standard in oligometastatic oesophageal SCC with additional confirmatory studies.

Given the heterogeneity in outcomes of metastatic oesophageal SCC, patient selection for local therapy is key. Patients with a limited disease burden are likely to benefit the most from the addition of local therapy. Studies by Yamashita et al. and Li et al. showed that the number of metastases, disease-free interval (DFI) >12 months, concurrent chemotherapy and smaller tumour size were associated with the greatest survival benefit from local therapy (14). Patients enrolled to the ESO-Shanghai 13 study had favourable prognostic features with the majority having metachronous oligometastatic disease (72%), a median DFI of 12 months and ≤2 sites of metastasis (81%). However, a limitation of the study was that only 49% of patients underwent fludeoxyglucose-18 positron emission tomography (FDG-PET) staging, potentially diluting the benefit of local therapy by inclusion of polymetastatic patients. Therefore, it is possible that with better patient selection the benefit of local therapy in the experimental arm might have been greater. The results also raise an interesting question for a future clinical trial investigating the role of consolidative radiotherapy in limited burden polymetastatic disease. This treatment paradigm has been tested in other tumour types with the biological rationale of removing tumour clonogens to prevent further metastatic seeding and delay systemic treatment resistance (6,18).

Conducting large phase 3 randomised clinical studies in oligometastatic disease is desirable but highly challenging given the rarity of disease, the heterogeneous patient population and continuously evolving systemic therapies. Given the effectiveness of local therapies such as SBRT with minimal additional toxicities (<5% grade 3), there will be a continued role for randomised phase 2 studies in subgroups of patients with oligometastatic disease (4). Authors of the ESO-Shanghai13 study should be congratulated for a well-conducted phase 2 randomised study showing a large benefit of local therapy in oligometastatic oesophageal SCC. The results of the study, along with other emerging evidence, suggests that local therapy can alter disease trajectory and improve survival outcomes.

In oligometastatic disease management, the role of local therapy continues to evolve with several avenues for future research. The ESO-Shanghai13 trial raises important clinical questions regarding optimal duration of induction therapy and selection criteria for appropriate local therapy. Currently, patient selection for local therapy primarily relies on clinical factors such as the number of metastases and FDI. However, there is potential for biological and radiological biomarkers to refine patient selection criteria, highlighting the need for sub-studies within oligometastatic clinical trials (19). Additionally, an emerging area of interest lies in exploring the role of radiotherapy in oligoprogressive disease, where targeted radiation may offer opportunities to alter disease course. Moreover, as the contemporary era of chemo-immunotherapy transforms the treatment landscape, there are pending trials investigating the efficacy of local therapy in oligometastatic esophageal adenocarcinoma (20,21).

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.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-41/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-41/coif). F.D. reports a contract for the provision of nivolumab to the institution for clinical trial conduct from Bristol Myers Squibb and a research grant for clinical trial conduct from Varian Medical Systems. J.M. reports a research grant for clinical trial conduct from Varian Medical Systems. 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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