Locoregional relapse after segmentectomy: interpreting JCOG0802 in the context of modern practice

The JCOG0802/WJOG4607L trial (1) has redefined the role of anatomic segmentectomy in the management of small, peripheral non-small cell lung cancer (NSCLC), establishing it as an effective oncologic option for tumors ≤2 cm. At the same time, the trial identified an increase in locoregional relapse following segmentectomy compared with lobectomy (8.9% vs. 6.9%), a finding that has generated considerable discussion regarding the limits of parenchyma-sparing surgery. While this relapse signal is clinically relevant, its interpretation is inherently context-dependent and should not be viewed as a fixed procedural limitation of segmentectomy. The supplementary analysis of the JCOG0802/WJOG4607L trial by Nakagawa et al. (2) was undertaken to better characterize patterns and risk factors for locoregional relapse following segmentectomy in patients with small, peripheral NSCLC. They identified pure-solid appearance, pathologic margin distance smaller than tumor size, and male sex as factors associated with an increased risk of locoregional relapse after segmentectomy. These findings provide important insight into technical and radiologic correlates of relapse in the context of parenchyma-sparing surgery. The observed increase in locoregional relapse in JCOG0802 must be understood in light of three key considerations: first, the heterogeneity of relapse definitions used in the trial; second, the absence of critical biological variables [such as spread through air space (STAS), histologic grade, and metabolic activity] that are now known to strongly influence local control; and third, the technical context of the trial, which reflects an earlier era of segmentectomy prior to widespread adoption of advanced imaging, three-dimensional planning, and refined intersegmental techniques.

With the increasing adoption of segmentectomy, accurate interpretation of locoregional relapse has become more critical. Even when relapse is amenable to salvage therapy, it imposes significant clinical, psychological, and functional burdens, often necessitating additional interventions such as reoperation or radiation therapy. However, the definition of “locoregional relapse” varies considerably across studies. Some definitions are restricted to parenchymal staple-line recurrence, while others encompass nodal or pleural involvement (3). Importantly, the supplementary data indicate that the absolute number of margin-related recurrences was small, with only 11 surgical-margin events among 529 segmentectomies (2.1%), while the majority of locoregional relapses occurred at nodal or pleural sites rather than at the parenchymal resection margin. This inconsistency raises a key question regarding the higher locoregional relapse rate observed in JCOG0802: does it reflect inherent limitations of segmentectomy, or are differences in classification, biological characterization, or technical context responsible?

The observed association between pure-solid morphology and increased relapse risk is consistent with previous evidence. Multiple studies have demonstrated that pure-solid tumors exhibit more aggressive behavior and a higher likelihood of local relapse compared to part-solid lesions. Post-hoc analyses of the JCOG0802 dataset indicated favorable overall survival (OS) following segmentectomy, but lower relapse-free survival in certain pure-solid subgroups (4). These findings support the concept that radiologic appearance reflects underlying biological aggressiveness. Earlier work by Hattori et al. reported locoregional relapse rates approaching 20% after segmentectomy for pure-solid clinical T1a tumors, reinforcing concerns regarding this radiologic phenotype; however, more recent contemporary series have not demonstrated a significant difference in local relapse between segmentectomy and lobectomy (5-7).

It remains unclear whether solid radiologic morphology serves as a surrogate for unmeasured pathological or molecular factors. Important biological determinants of local recurrence, such as STAS, predominant histologic patterns, and genomic alterations, were not assessed in the Japan Clinical Oncology Group (JCOG) supplementary analysis, despite being recognized contributors to recurrence following sublobar resection. For instance, pure-solid nodules correlate with a higher incidence of STAS, a known independent risk factor for recurrence after segmentectomy. This provides a biological mechanism linking morphology to relapse risk (8). Therefore, the observed association between pure-solid morphology and locoregional relapse may reflect a combination of imaging characteristics and unmeasured biological risk. The central role of tumor biology in driving relapse after sublobar resection has been demonstrated recently by Caso et al., who identified solid computed tomography (CT) morphology [hazard ratio (HR) 1.80], increasing positron emission tomography (PET) maximum standardized uptake value (SUVmax) (HR 1.05 per unit), and micropapillary/solid histology as independent predictors of worse disease-free survival (DFS) in stage IA NSCLC ≤2 cm, with lobectomy providing a DFS benefit only in patients with two or more high-risk biological features (9). Similarly, Bongiolatti et al. reported significantly worse 5-year DFS after segmentectomy in patients with high-grade adenocarcinoma patterns (>20% solid or micropapillary: 53% vs. 75%, P<0.01; HR 2.43), reinforcing that aggressive biological features rather than resection extent itself are the primary determinants of relapse (10). While the radiologic solid component is valuable for predicting clinical outcomes, its impact in JCOG0802 should be interpreted with these limitations in mind. Although specific genomic alterations are not yet established as determinants of surgical strategy, certain molecular subtypes may correlate with aggressive tumor behavior and could eventually contribute to more refined risk stratification when integrated with imaging and histopathologic features.

The supplementary analysis also identified an association between limited surgical margins and increased relapse, warranting careful consideration. JCOG data indicated that a pathologic margin smaller than the tumor size independently predicted locoregional relapse. However, the broader literature suggests a more nuanced relationship between margin distance and clinical outcomes. Several retrospective studies, including those by Mohiuddin et al. (11) and Nagano et al. (12), have found that larger margins or a margin-to-tumor (M/T) ratio of at least 1 are associated with reduced relapse risk, supporting the principle that greater parenchymal clearance is beneficial. Additionally, Huang et al. (13) proposed that an absolute margin of approximately 20 mm may provide protective effects. Recently, Hurley et al. reported a 9.1% locoregional recurrence rate after segmentectomy for stage IA1–2 NSCLC, with margins <5 mm associated with a three-fold higher risk of locoregional relapse (20.3% vs. 5.8%), while pure-solid morphology and PET hypermetabolism independently predicted poorer event-free survival (14). These results all seem to affirm the ‘one-size-fits-all’ margin rule. However, can we further consider that the ‘minimum effective margin’ may vary by histology (e.g., lepidic vs. solid/micropapillary), thereby questioning the universal applicability of the ‘margin > tumor size’ standard?

Recent data suggest that short margins do not consistently result in higher relapse rates. Donlagic et al. (15) found that margins less than 10 mm or an M/T ratio below 1 did not negatively impact mid-term outcomes for cT1N0 tumors when anatomical completeness was achieved. This variability indicates that margin adequacy is influenced not only by numerical thresholds but also by anatomical context, tumor biology, and the precision of the surgical resection. Furthermore, the effect of margin length observed in JCOG0802 may have been accentuated by technical limitations of the trial period, such as the lack of advanced imaging and intersegmental mapping technologies that now enable more precise dissections. Additionally, the trial was conducted during the early adoption of video-assisted thoracic surgery (VATS) segmentectomy. Surgeons’ limited experience and technique variability at that time, compounded by simpler technology, may have increased margin-related risks and relapse rates. In conclusion, studies evaluating M/T ratio and absolute margin distance have demonstrated variable cutoffs associated with local control, indicating that margin length interacts with tumor biology, anatomical constraints, and the precision of the resection rather than acting as an isolated determinant of outcome. Therefore, margin planning should be individualized rather than rule based. When generous margins are anatomically achievable, segmentectomy can provide excellent local control. Conversely, in situations where adequate margins are unlikely, such as deep lesions, anatomically constrained segments, or tumors with high-risk biological features, surgeons should anticipate this limitation preoperatively and consider alternative strategies, including extended segmentectomy, conversion to lobectomy, or intensified intraoperative margin assessment. In our opinion, the margin findings from JCOG0802 are best interpreted not as a prescriptive cutoff, but as support for a tailored, biology- and anatomy-informed approach to operative decision-making.

A further consideration is the evolution of surgical techniques and technology since the JCOG enrollment period. Modern segmentectomy frequently incorporates three-dimensional planning, high-resolution imaging, and fluorescence-guided segmentation, which facilitate more accurate identification of intersegmental planes and may enhance margin acquisition. Recent studies, including those by Yano et al. (16) and Tsubokawa et al. (17), have reported excellent local control using these advanced techniques for deep or central tumors, even in complex cases. These findings indicate that certain technical limitations contributing to relapse in JCOG0802 may be less applicable in current practice. Similarly, in a modern uniportal minimally invasive cohort, Kostovski et al. observed no statistically significant difference in recurrence between segmentectomy and lobectomy for stage IA tumors ≤2 cm, suggesting that when contemporary techniques and appropriate selection are applied, local control after segmentectomy can be comparable to lobectomy, even beyond highly selected low-risk phenotypes (18). A recent multicenter analysis by Mimae et al. (19) evaluated 941 patients with peripheral radiologically solid-dominant NSCLC ≤2 cm treated between 2010 and 2020 and found no evidence that segmentectomy increased the risk of locoregional relapse. Locoregional relapse occurred in only 2% after segmentectomy versus 5% after lobectomy (P=0.037), and stump recurrence rates were nearly identical (1% vs. 0.8%). Importantly, in the pure-solid subgroup, there was no significant difference in LR between procedures (4% vs. 7%, P=0.11). These findings reinforce those of other modern cohorts demonstrating that, when guided by careful selection and contemporary operative techniques, segmentectomy provides oncologic control comparable to lobectomy even for solid-dominant tumors.

Interpretation of the JCOG results is further complicated by variations in the definition of locoregional relapse. The JCOG framework encompasses ipsilateral thoracic relapse, nodal failure (mediastinal and hilar), contralateral nodal relapse, pleural dissemination, and malignant pleural effusion. In contrast, many institutional series define “local relapse” solely as regrowth near the staple line, categorizing nodal or pleural relapse separately. This discrepancy hinders direct comparison between JCOG and other studies. Recent reports may demonstrate low relapse rates after segmentectomy, even with modest margins (15,20). These definitional differences underscore the necessity of contextualizing locoregional relapse outcomes in JCOG0802 within a broader spectrum of definitions.

Caution is warranted when interpreting segment-specific recurrence patterns in the JCOG supplementary analysis. Segments such as the lingula, left S6, and basal segments appeared to have higher crude relapse rates. However, these differences did not remain significant after adjusting for clinical and pathological factors. This likely reflects the limited number of events within individual segments. This observation is consistent with the findings of Jones et al., who reported significant heterogeneity in long-term outcomes according to segmentectomy location in a large single-institution series of intentional segmentectomies. Right S6 resection was independently associated with worse 5-year DFS (57.6% vs. 77.1%) and 5-year OS (66.3% vs. 79.5%) compared with basilar segmentectomy (21). Segmentectomy is a heterogeneous procedure. Its technical complexity and achievable margins vary considerably across segments. Contemporary practice now utilizes three-dimensional planning, fluorescence-guided delineation, and tailored intersegmental dissection. These advancements substantially mitigate anatomical constraints that were more pronounced during the JCOG enrollment period. Therefore, the segment-level observations reported in the trial should be viewed as descriptive signals rather than procedure-defining rules. They should not be generalized to current surgical environments, where advanced techniques can equalize technical difficulty across segments. For instance, techniques like indocyanine green fluorescence staining now enable precise real-time visualization of intersegmental planes, even in complex segments, ensuring reliable margins and effectively equalizing technical difficulty across segments.

In summary, the findings from the JCOG0802 supplementary analysis provide valuable prospective insights into relapse patterns following segmentectomy, but should be viewed as an informative foundation rather than a definitive guideline. These results need to be integrated with current biological knowledge, standardized definitions of relapse, and the technical advancements that define modern segmentectomy. As surgical practice becomes more individualized, clinical decisions should prioritize a comprehensive assessment of tumor biology, imaging features, anatomical feasibility, and operative precision over reliance on fixed margin thresholds or broad radiologic categories. The primary goal is to match segmentectomy to the appropriate patient and segment, employing the most precise technical approach to maintain functional benefits without compromising oncologic safety.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://shc.amegroups.com/article/view/10.21037/shc-2025-1-11/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2025-1-11/coif). M.G. serves as an unpaid editorial board member of Shanghai Chest from April 2024 to March 2026. The other author has no conflicts of interest to declare.

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