What is the optimal lymph node dissection strategy for patients undergoing sublobar resection for early-stage peripheral non-small cell lung cancer?

Anatomical lobectomy has long been the established standard of care for curative resection of early-stage lung cancer (1,2). However, clinical experience has accumulated over decades (3), and recent pivotal trials, including the Japan Clinical Oncology Group (JCOG)0802/West Japan Oncology Group (WJOG)4607L trial and the Cancer and Leukemia Group B (CALGB)140503 trial (4,5), have identified sublobar resection as an alternative, or even possibly preferable treatment strategy to lobectomy for early-stage peripheral non-small cell lung cancer (NSCLC) measuring 2 cm or less.

For patients undergoing surgical resection, appropriate evaluation of lymph node metastasis using preoperative staging and surgical lymph node dissection is crucial, given that lymph node metastasis significantly affects recurrence and survival outcomes. In particular, considering previous reports of relatively higher locoregional recurrence rates in patients who underwent sublobar resection than in those who underwent complete lobectomy (1,4-7), relevant evaluation of nodal status would be important when performing sublobar resection. In this context, the lymph node dissection strategy is an important aspect in which the surgical process can affect treatment outcomes. Previous observational studies have consistently shown that for stage I NSCLC, survival outcomes were significantly better in patients who underwent sublobar resection with lymph node dissection (8,9). In a study comparing the overall and recurrence-free survival outcomes between sublobar resection (with or without lymph node dissection) and lobectomy for NSCLC measuring 2 cm or less, the outcomes did not differ significantly between patients who underwent sublobar resection with lymph node dissection and those who underwent lobectomy but were significantly worse for those who underwent sublobar resection without lymph node dissection (10). In contrast, systematic lymph node dissection is reported to be associated with higher postoperative complications and a longer length of hospital stay than no or selective lymph node dissection (11). To determine the optimal lymph node dissection strategy for sublobar resection, the associated risk factors, distribution, and recurrence pattern of lymph node metastasis after the resection of small peripheral NSCLC need to be considered. Recently, a supplemental analysis of the JCOG0802/WJOG4607L trial was published, providing insights to address these questions (12).

Before the publication of the JCOG0802/WJOG4607L trial, several studies attempted to clarify the reasonable extent of lymph node dissection during intentional sublobar resection for stage I NSCLC. In a study conducted by Matsumura et al. involving 307 patients who fulfilled the eligibility criteria for the JCOG0802/WJOG4607L trial (13), 34 patients (11%) had lymph node metastasis. All 34 patients had a solid-dominant component on computed tomography (CT). Larger tumor size and a more solid-dominant tumor pattern were significantly associated with lymph node metastasis. Of these 34 patients, nine showed involvement of an isolated lobar-segmental lymph node (defined as a lobar-segmental lymph node located in the segment without tumors). These nine patients had additional metastasis to station 12 or mediastinal lymph nodes, indicating no solitary isolated lobar-segmental lymph node metastasis. Therefore, the authors concluded that a reasonable extent of lymph node dissection for small peripheral NSCLC tumors includes lobar-segmental lymph nodes in the segment with tumors and hilar and mediastinal lymph nodes, and routine isolated lobar-segmental lymph node examinations may not be necessary. Additionally, the authors insisted that systematic lymph node dissection could be omitted in patients with ground-glass opacity (GGO)-dominant tumors.

A retrospective study by Maniwa et al. involved 350 patients with the same conditions as those in the target population of the JCOG0802/WJOG4607L trial (14), of whom 35 patients (10%) had lymph node metastasis. Notably, no cases with a consolidation-to-tumor (C/T) ratio <0.75 had lymph node metastasis or nodal recurrence. None of the 35 patients with lymph node metastases had solitary lymph node metastases beyond the extent of lobe-specific mediastinal lymph node dissection. Of the six patients who reported nodal recurrence, none had mediastinal lymph node recurrence beyond the extent of lobe-specific mediastinal lymph node dissection, except for two patients with primary tumors in S6. The authors argued that small peripheral NSCLC tumors with a C/T ratio <0.75 may not require mediastinal lymph node dissection when segmentectomy is performed, and that lobe-specific mediastinal lymph node dissection might be the optimal strategy for patients with a C/T ratio ≥0.75, except for those with S6 primary tumors.

Another study by Maniwa et al. investigated the need for dissection of the nonadjacent interlobar lymph nodes during segmentectomy, which is technically challenging (15). Among 310 patients with small-sized (≤2 cm) peripheral NSCLC (except those with pure GGO-dominant tumors), 33 (10.6%) had lymph node metastases. For the upper-lobe tumors, no non-adjacent interlobar lymph node metastasis was observed. However, three patients with tumors of diameter ≥15 mm in the lower lobes showed non-adjacent interlobar lymph node metastasis, and the authors concluded that the dissection of non-adjacent interlobar lymph nodes during segmentectomy may be omitted only in patients with tumors in upper lobes.

The JCOG0802/WJOG4607L trial was a randomized controlled non-inferiority study to compare segmentectomy and lobectomy in patients with clinical stage IA small-sized (≤2 cm) peripheral NSCLC with a C/T ratio >0.5 (4). In a supplemental analysis by Maniwa et al. (12), 63 (6.0%) of 1,056 eligible patients had lymph node metastasis. In multivariable logistic regression analyses, the only statistically significant risk factor for lymph node metastasis was the radiologic finding of pure-solid nodules (adjusted odds ratio, 8.834; 95% confidence interval: 3.891–20.058; P<0.0001). Among the 533 patients with part-solid nodules, 8 (1.5%) had lymph node metastasis and 3 (0.6%) had pathologic N2 disease. None of the patients with part-solid tumors <1.5 cm in diameter had lymph node metastasis, and none with part-solid tumors had non-adjacent interlobar lymph node metastasis. Of the 523 patients with pure-solid nodules, 55 (10.5%) had lymph node metastasis, 28 (5.4%) had pathologic N2 disease, and five had non-adjacent interlobar lymph node metastasis. Notably, none of the patients with pure-solid tumors in the upper lobes showed subcarinal lymph node metastasis, and none of the patients with pure-solid tumors in the lower lobes had solitary upper mediastinal lymph node metastases, except for patients with S6 tumors. Similar rates of ipsilateral lymph node recurrence were observed between patients who underwent systematic lymph node dissection and those who underwent selective lymph node dissection for upper lobe and basal lung cancers. Specifically, patients with S6 tumors who underwent systematic lymph node dissection had no lymph node recurrence, whereas those who underwent selective lymph node dissection had a recurrence rate of 4%. The authors proposed the following optimal lymph node dissection strategies for segmentectomy in patients with clinical stage IA small-sized (≤2 cm) peripheral NSCLC with a C/T ratio >0.5: (I) non-adjacent interlobar lymph node dissection and mediastinal lymph node dissection could be omitted for patients with part-solid tumors, and for patients with upper lobe nodules, intraoperative sampling of the superior mediastinal lymph nodes can be considered; (II) patients with pure-solid tumors located in the upper lobe or basal segment could undergo selective (lobe-specific) lymph node dissection when combined with sufficient intraoperative hilar and mediastinal lymph node sampling; (III) patients with pure-solid S6 tumors could be managed with systematic lymph node dissection, considering the possibility of solitary lymph node metastasis to the upper mediastinum as well as ipsilateral mediastinal lymph node recurrence after selective lymph node dissection; and (IV) for patients with pure-solid tumors, sampling non-adjacent interlobar lymph nodes during segmentectomy should be considered, given the reported occurrence of isolated non-adjacent interlobar lymph node metastasis.

In previous studies, S6 tumors have repeatedly been reported to show a higher prevalence of lymph node metastasis (16). Possible explanations include the anatomical proximity of the superior segment to the hilar and upper mediastinal structures, enhanced lymphatic streams in the superior segment, and a higher possibility of insufficient hilar lymph node dissection owing to technical difficulties during S6 segmentectomy (16-18). It should be noted that lymph node metastasis from S6 part-solid tumors has been reported, surpassing the innately low risk of lymph node metastasis in part-solid tumors.

The increased worldwide implementation of low-dose chest CT screening and advances in preoperative staging techniques, such as endobronchial ultrasonography, have led to more prompt detection and diagnosis of early-stage peripheral NSCLC (19). In the era of precision medicine and personalized treatment, including sublobar resection for early-stage NSCLC, determining the optimal strategy and adequate extent of lymph node dissection is of utmost importance. Compared with the aforementioned studies, the supplemental analysis of the JCOG0802/WJOG4607L trial has several strengths. First, it evaluated a subgroup of a large prospectively enrolled population through a multicenter randomized controlled trial, thus strengthening the generalizability of the study results. Second, the study conducted stratified analyses based on the tumor type (i.e., part-solid or pure-solid). This stratification provides clinically valuable information regarding the differences in pathologic, genetic, and molecular perspectives between part-solid and pure-solid tumors (20). This is also in line with the observation that the radiological finding of a pure-solid tumor is the sole statistically significant risk factor for lymph node metastasis. By dividing the two heterogeneous features, more clinically relevant proposals for optimal lymph node dissection were suggested.

Despite the valuable insights provided by Maniwa et al., the high proportion (62.7%) of the study population who underwent selective lymph node dissection hampers the relevant evaluation of lymph node status not included in the extent of selective lymph node dissection. The JCOG1413 study was conducted to compare selective and systematic lymph node dissection in early-stage NSCLC (21). However, clinically relevant conclusions were difficult to draw because this study also included patients with stage II NSCLC and did not classify part-solid and pure-solid tumors. Therefore, confirmatory randomized trials that fulfill certain criteria are needed, including classification of part-solid and pure-solid nodules, inclusion of multinational institutions, and comparison of interventional lymph node staging with systematic lymph node dissection (6). Meanwhile, an individualized approach to lymph node dissection (at least selective lymph node dissection) should be used in patients undergoing sublobar resection for solid-dominant early-stage lung cancer. Moreover, considering data from previous studies showing that a relatively low proportion of patients undergoing surgery for early-stage lung cancer (including lobectomy and sublobar resection) undergo complete lymph node dissection (22), optimization of accurate preoperative clinical staging with minimally invasive methods, including advanced imaging and endobronchial ultrasonography-guided sampling of lymph nodes, must be emphasized to comprehensively evaluate the lymph node metastasis status before planning surgical lymph node dissection.

Acknowledgments

Funding: None.

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