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Publications

Journal Article Ahead of print

PubMed: 42747081 DOI: 10.1093/jjco/hyag153

Metastasis-directed local therapy and strategic de-escalation of systemic therapy for oligometastatic esophageal squamous cell carcinoma.

Jpn J Clin Oncol

Authors: Motoo Nomura, Ken Kato, Takashi Ogata, Mitsuro Kanda, Yoichi Hamai, Yasuhiro Tsubosa, Takako Yoshii, Mitsuhiro Furuta, Katsuyuki Sakanaka, Kazuaki Matsui, Satoru Matsuda, Takahiro Tsushima, Hiroya Takeuchi

Affiliations

  • Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan.
  • Department of Head and Neck Oncology and Innovative Treatment, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center, Tokyo, Japan.
  • Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan.
  • Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
  • Division of Esophageal Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
  • Department of Gastroenterology, Saitama Prefectural Cancer Center, Ina, Japan.
  • Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan.
  • Department of Radiation Oncology, Kindai University Faculty of Medicine, Sakai, Japan.
  • Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
  • Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
  • Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Abstract

The introduction of immune checkpoint inhibitors (ICIs) has transformed the treatment of advanced esophageal squamous cell carcinoma (ESCC), yet the optimal duration of systemic therapy remains unsolved. Pivotal phase III trials capped ICI administration at 24 months, a design choice supported only indirectly by evidence from other tumor types suggesting a biological plateau in the antitumor immune response, since direct ESCC-specific evidence is lacking. In practice, however, 'oncological inertia,' the indefinite continuation of ICI therapy without a predefined stopping rule or objective marker of safety, contributes to cumulative toxicity and financial burden. This review proposes a 'strategic de-escalation' framework as an exit strategy. This framework uses metastasis-directed local consolidation therapy (LCT), surgical metastasectomy or ablative/precision radiotherapy to oligometastatic foci. This approach achieves definitive control of residual disease and thereby recasts subsequent ICI as a finite-duration adjuvant course. This course is analogous to postoperative nivolumab after chemoradiotherapy. It is an alternative to open-ended maintenance. Immediate, circulating tumor DNA (ctDNA)-driven discontinuation without an adjuvant course is a plausible but currently unproven alternative. Direct ESCC evidence for this exit strategy remains limited, and randomized trials in esophagogastric adenocarcinoma (REGATTA, RENAISSANCE) caution that aggressive local intervention can worsen outcomes without rigorous patient selection. The oligometastatic esophageal squamous cell carcinoma project uses a modified Delphi method to standardize the definition of oligometastatic ESCC and identify appropriate candidates. CtDNA may eventually guide the timing of treatment interruption and rechallenge. We discuss the rationale, current limitations, and prospective validation needs for this strategy in the multidisciplinary management of ESCC.

MeSH

Radiotherapy, Cells, Carcinoma, Squamous Cell, Neoplasms, Drug Therapy, Immunotherapy, Neoplasm Metastasis, Esophageal Squamous Cell Carcinoma, Therapeutics, Esophageal Neoplasms, Chemotherapy