Feasibility Is Not Benefit: Resectable, Irradiable, or Biologically Selected? A Critical Review of the Unresolved Local-Platform Question in Stage III/N2 NSCLC
8 affiliations
- 1Department of Radiation Oncology, University Hospital of Larissa, Medical School, University of Thessaly, 41110 Larissa, Greece
- 2Radiation Oncology Department, ARETAIEION University Hospital, Medical School, Kapodistrian University of Athens, 11528 Athens, Greece
- 3Department of Clinical Radiation Oncology, University Hospital ATTIKON, Medical School, Kapodistrian University of Athens, 12462 Athens, Greece
- 4Department of Medical Physics, University Hospital of Larissa, Medical School, University of Thessaly, 41110 Larissa, Greece
- 5Department of Minimally Invasive Thoracic Surgery, Metropolitan Hospital, 18547 Piraeus, Greece
- 6Department of Thoracic Surgery, Metropolitan General, 15562 Athens, Greece
- 7Department of Basic and Clinical Sciences, Medical School, University of Nicosia (UNIC), Athens Campus, 16777 Athens, Greece
- 82nd Department of Radiation Oncology, Metropolitan Hospital, Neo Faliro, 18547 Piraeus, Greece
Abstract
Stage III/N2 non-small-cell lung cancer (NSCLC) can often be treated with either surgery-based multimodality therapy or definitive chemoradiotherapy. Historical randomized trials showed that surgery improved local control without demonstrating an overall-survival benefit; neither platform demonstrated superiority, although none was designed to establish equivalence. In the immunotherapy era, both pathways have improved through separate evidence streams: perioperative trials compared immunotherapy with chemotherapy-based surgical controls, and PACIFIC compared durvalumab with placebo after chemoradiotherapy. Neither stream determines which complete modern pathway is better for a patient eligible for both, and cross-trial comparisons are confounded by differences in populations, randomization points, and endpoint definitions. This review distinguishes three questions that are often conflated: whether direct comparative evidence exists, how large any relative treatment effect may be, and whether sufficient clinical equipoise exists to justify randomization. Technical resectability, physiological operability, and irradiability define eligibility for a platform, not comparative benefit, and no current biomarker has been shown to modify the relative effect of the two platforms. Comparative uncertainty is most visible in multistation, bulky, or anatomically complex N2 disease, the most practicable starting point for randomization; superiority of either platform, however, has not been demonstrated at either end of the N2 spectrum. A staged randomized comparison of the complete modern pathways, with prespecified analyses of candidate treatment-effect modifiers, is proposed as a reasoned research strategy.
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BibTeX
@article{skarlos2026feasibility,
title = {{Feasibility Is Not Benefit: Resectable, Irradiable, or Biologically Selected? A Critical Review of the Unresolved Local-Platform Question in Stage III/N2 NSCLC}},
author = {Panteleimonas Skarlos and Ioannis Georgakopoulos and Andromachi Kougioumtzopoulou and Zoi Liakouli and Kiki Theodorou and Anna Zygogianni and Emmanouil Georgiannakis and Vasileios Kouloulias and George Maravelis},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203348},
url = {https://www.mdpi.com/2072-6694/18/20/3348},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Feasibility Is Not Benefit: Resectable, Irradiable, or Biologically Selected? A Critical Review of the Unresolved Local-Platform Question in Stage III/N2 NSCLC
AU - Panteleimonas Skarlos
AU - Ioannis Georgakopoulos
AU - Andromachi Kougioumtzopoulou
AU - Zoi Liakouli
AU - Kiki Theodorou
AU - Anna Zygogianni
AU - Emmanouil Georgiannakis
AU - Vasileios Kouloulias
AU - George Maravelis
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203348
UR - https://www.mdpi.com/2072-6694/18/20/3348
AB - Stage III/N2 non-small-cell lung cancer (NSCLC) can often be treated with either surgery-based multimodality therapy or definitive chemoradiotherapy. Historical randomized trials showed that surgery improved local control without demonstrating an overall-survival benefit; neither platform demonstrated superiority, although none was designed to establish equivalence. In the immunotherapy era, both pathways have improved through separate evidence streams: perioperative trials compared immunotherapy with chemotherapy-based surgical controls, and PACIFIC compared durvalumab with placebo after chemoradiotherapy. Neither stream determines which complete modern pathway is better for a patient eligible for both, and cross-trial comparisons are confounded by differences in populations, randomization points, and endpoint definitions. This review distinguishes three questions that are often conflated: whether direct comparative evidence exists, how large any relative treatment effect may be, and whether sufficient clinical equipoise exists to justify randomization. Technical resectability, physiological operability, and irradiability define eligibility for a platform, not comparative benefit, and no current biomarker has been shown to modify the relative effect of the two platforms. Comparative uncertainty is most visible in multistation, bulky, or anatomically complex N2 disease, the most practicable starting point for randomization; superiority of either platform, however, has not been demonstrated at either end of the N2 spectrum. A staged randomized comparison of the complete modern pathways, with prespecified analyses of candidate treatment-effect modifiers, is proposed as a reasoned research strategy.
SN - 2072-6694
ER -