The significance of local intervention for oligometastatic esophageal squamous cell carcinoma

In 1995, Hellman and Weichselbaum introduced the concept of oligometastases (1). They defined oligometastases as an intermediate clinical state between localized disease and widespread systemic metastasis. According to the consensus document of the European Society for Radiotherapy and Oncology and American Society for Radiation Oncology, oligometastases are characterized as the presence of 1 to 5 metastatic lesions that can be managed safely, either in the presence or absence of a controlled primary tumor (2). Oligometastases are classified into two statuses: oligo-recurrence (OR) and sync-oligometastases (SO) (3). OR is a status with 1 to 5 recurrences and a controlled primary lesion, while SO is a status with 1 to 5 recurrences and an uncontrolled primary lesion. For esophagogastric cancer, the latest European guidelines defined as patients with esophagogastric cancer with 1 organ affected by ≤3 metastases or 1 involved extra-regional lymph node station (4). Oligometastatic cancer is an intermediate stage before widespread metastatic disease; therefore, there is some possibility of cure by multimodal treatment [e.g., combining surgery with induction chemoradiotherapy (CRT) or induction chemotherapy (CT)]. Niibe et al. (5) reported superior overall survival (OS) for pulmonary OR compared with pulmonary SO after treatment with stereotactic radiosurgery or stereotactic body radiation therapy.

Several studies on therapies for oligometastases of esophageal squamous cell carcinoma (SCC) have been reported, mostly targeting OR. Yamashita et al. (6) reported that the 3-year OS rate of patients who received CRT was 39.7%, compared with 20.8% for patients who received radiotherapy (RT) (P=0.000055). Chen et al. (7) reported that the disease control rate after CRT was 81.6%, compared with 64.5% after RT (P<0.001). Both of these studies compared CRT with RT, and found that CRT was superior to RT. Shi et al. (8) compared the therapeutic outcomes after CRT and CT for patients with SO. The median OS after CRT and CT was 18.5 and 15.2 months respectively (P<0.001), while the median progression-free survival (PFS) was 9.7 and 7.6 months, respectively (P<0.001). Therefore, CRT appears to have superiority over CT. This presumably arises through the local therapeutic power of CRT. Surgical resection for oligometastases has been undertaken, and the outcomes of these procedures have been reported. Ohkura et al. (9) reported the 3- and 5-year OS rates of patients who did and did not undergo surgical resection for OR. They observed that patients who underwent resection had notably higher 3- and 5-year OS rates of 64.3% and 55.6%, respectively. Tsai et al. (10) reported a similar tendency; the 3-year OS rates in patients who did and did not undergo surgical resection were 42.9% and 23.5%, respectively. Although it is difficult to determine the best practice to cure oligometastases, these studies are precious and provide valuable information because they suggest the importance of local therapy for this disease status.

In the article of interest, Liu and colleagues conducted ESO-Shanghai 13, the first randomized phase 2 trial worldwide for oligometastatic (OR-only) esophageal SCC (11). Eligible patients were randomly allocated in a 1:1 ratio to receive either systemic therapy alone (i.e., systemic therapy-only group) or a combination of systemic and local therapy (i.e., systemic and local therapy group). The systemic therapy regimens in both groups, including CT alone, anti-PD-1 antibodies alone, or a combination of both, were determined by the investigator. In the systemic and local therapy group, local treatments (such as RT, surgery, or thermal ablation) were applied to all metastatic lesions. In the trial, a total of 104 patients were analyzed for 2.5 years. The systemic and local therapy group had a median PFS of 15.3 months, which was significantly superior to the median PFS of 6.4 months in the systemic therapy only group; the stratified hazard ratio (HR) was 0.26 [95% confidence interval (CI): 0.16–0.42] with stratified log-rank P<0.0001. Although grade 1–2 acute esophagitis was increased by addition of local therapy, there were no differences in severe treatment-related adverse events. Treatment-related death occurred in two patients in the group combined systemic and local therapy and one patient in the group undergoing systemic therapy alone.

The outcome of this trial is important because it represents the first randomized non-case-control study for oligometastatic esophageal SCC. Moreover, the better median PFS compared with that in previous studies is worthy of special mention. The median PFS of 15.3 months in the systemic plus local therapy group was favorable, and the median OS was not reached. Even the systemic therapy only group had favorable survival compared with that in previous studies. These findings must be affected by immunotherapy developments in recent years. Sun et al. (12) published the results of the KEYNOTE-590 study in 2021, an international, placebo-controlled, double-blind, randomized, phase III trial testing the superiority of pembrolizumab plus 5-fluorouracil and cisplatin (CF) therapy over standard CF therapy in the primary treatment of unresectable advanced or recurrent esophageal cancer. At the first interim analysis (median follow-up of 22.6 months), pembrolizumab plus CF was superior to placebo plus CF for OS in patients with esophageal SCC [12.6 vs. 9.8 months; HR 0.72 (95% CI: 0.60–0.88); P=0.0006], and in all randomized patients [12.4 vs. 9.8 months; HR 0.73 (95% CI: 0.62–0.86); P<0.0001]. Similar results were obtained for PFS. Also in 2021, Luo et al. (13) reported the results of the ESCORT-1st trial, a randomized, blinded, phase III trial comparing camrelizumab plus CT (paclitaxel and cisplatin) to CT in untreated advanced or metastatic esophageal SCC in China. The median OS was 15.3 months (95% CI: 12.8–17.3; 135 deaths) in the camrelizumab plus CT group, compared to 12.0 months (95% CI: 11.0–13.3; 174 deaths) in the placebo plus CT group [HR for death, 0.70 (95% CI: 0.56–0.88); P=0.001]. The median PFS for the camrelizumab plus CT group was 6.9 months (95% CI: 5.8–7.4; 199 progressions or deaths), whereas it was 5.6 months (95% CI: 5.5–5.7; 229 progressions or deaths) for the placebo plus CT group [HR for progression or death, 0.56 (95% CI: 0.46–0.68); P<0.001]. In 2022, Doki et al. (14) published the results of CheckMate 648, an international phase III trial evaluating the efficacy and safety of nivolumab plus CF, and nivolumab plus ipilimumab versus standard CF therapy in the first-line treatment of advanced esophageal SCC. Median OS in the overall population was 13.2 months (95% CI: 11.1–15.7 months) in the nivolumab + CF group and 10.7 months (95% CI: 9.4–11.9 months) in the CF group, significantly higher in the nivolumab + CF group (HR =0.74, 99.1% CI: 0.58–0.96, P=0.002). All of the above trials showed the superiority of immune checkpoint inhibitors over conventional CT, and pembrolizumab and camrelizumab were used in the current study. Not only immunotherapies but also another molecular targeted drugs and combination therapies should be developed from now on.

Although the latest European guidelines (4) recommend systemic therapy first for oligometastatic patients, followed by re-staging and then local therapy if staging with ⁸F-fluorodeoxyglucose positron emission tomography/computed tomography shows no progression, the result of ESO-Shanghai 13 suggest that systemic plus local therapy as first-line treatment may be an appropriate option.

There are also some issues in the trial that require consideration. First, three modalities, namely RT, surgery, and thermal ablation, were used as local therapies. Ideally, subanalyses in the individual local therapy groups should be conducted because each therapy has its characteristic merits and demerits. In the trial, the local therapy modalities were not regulated thoroughly. Thus, it remains unclear which modality was effective for which state of oligometastases. Studies with larger numbers of patients undergoing surgical resection and thermal ablation are required. Second, the regimen for systemic therapy needs to be unified. For the time being, systemic therapy for esophageal SCC patients will remain in the immunotherapy era. The efficacy of immunotherapy and immunotherapy plus local therapy for oligometastatic esophageal SCC needs to be examined under strict regulation. Finally, a randomized study using immunotherapy and immunotherapy plus local therapy for SO is desired.

In conclusion, the effectiveness of adding local therapy to systemic therapy for oligometastatic esophageal SCC was clarified by the ESO-Shanghai 13 study. In the near future, in clinical practice, combined systemic and local therapy for oligometastatic esophageal SCC may become one of the first-line treatments.

Acknowledgments

The authors thank Alison Sherwin from Edanz for editing a draft of this manuscript.

Funding: 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.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-38/coif). The authors have no conflicts of interest to declare.

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