A tale of two lung-sparing surgeries: the rise of segmentectomy and wedge resection in stage IA non-small-cell lung cancer

Since the inception of surgery as treatment for early-stage non-small-cell lung cancer (NSCLC), the optimal extent of resection has undergone major revisions. In the early 20^th century, pneumonectomy was initially regarded as the sole viable option for NSCLC resection (1). However, as pneumonectomy was associated with substantial morbidity and mortality, the 1960s witnessed a paradigm shift towards lobectomy as the preferred surgical procedure for early-stage NSCLC (2). Over the ensuing decades, numerous studies consistently demonstrated oncologic advantages with lobectomy compared to sublobar resection, including segmentectomy and wedge resection. These investigations revealed improved survival outcomes and reduced recurrence rates associated with lobectomy, solidifying its position as the prevailing surgical intervention for the management of early-stage NSCLC (3-5). The most pivotal of those was LCSG821, a multicenter, randomized trial reporting a three-fold increase in local recurrence and 50% higher cancer-related mortality with sublobar resection versus lobectomy for peripheral NSCLC measuring 3 cm or less in its greatest dimension and without lymph node metastasis (4). Consequently, sublobar resection became an option primarily reserved for patients with compromised cardiopulmonary function or comorbidities that contraindicated lobectomy (6-8).

While sporadic evidence hinting at oncologic equivalence between lobectomy and sublobar resection had surfaced as early as the 1990s (9,10), only recent years have witnessed a resurgence of interest in sublobar resection for early-stage NSCLC. This resurgence can be attributed to the confluence of lung cancer screening programs and advancements in diagnostic technologies, which have greatly increased the identification of early cases (11). Expanding on this foundation, several nonrandomized studies broadened the indications for sublobar resection to encompass small, peripheral, node-negative tumors even in patients who would otherwise qualify for lobectomy (12-14). These studies laid the groundwork for JCOG0802/WJOG4607L, which represents the second seminal study comparing lobectomy with sublobar resection, particularly segmentectomy (15). Reported in 2022, this Japanese randomized trial showed superiority of segmentectomy over lobectomy in terms of 5-year overall survival [94.3% vs. 91.1%; hazard ratio (HR), 0.663; 95% confidence interval (CI): 0.474–0.927; P=0.0082], while maintaining equivalent relapse-free survival in patients with peripheral, node-negative NSCLC measuring 2 cm or less.

The recently reported CALGB140503 provides the highest quality evidence to date when comparing sublobar resection (segmentectomy or wedge resection) with lobectomy for early-stage NSCLC (16). This randomized trial enrolled 697 patients from 83 institutions spanning the United States, Canada, and Australia. Patients with peripheral, clinical stage T1aN0 NSCLC (tumor size ≤2 cm) were randomized in a 1:1 ratio to undergo either sublobar resection or lobectomy following pathologic confirmation of node-negative disease. Among the 340 patients allocated to sublobar resection, 59.1% underwent wedge resection, while 37.9% underwent segmentectomy. After a median follow-up period of 7 years, the study established that sublobar resection was non-inferior to lobectomy for the primary endpoint of disease-free survival (HR, 1.01; 90% CI: 0.83–1.24). Additionally, overall survival rates were comparable between the treatment arms. Interestingly, an exploratory subgroup analysis of disease-free survival failed to reveal any significant differences between lobectomy and sublobar resection across a wide range of demographic, clinical, and pathologic characteristics. Nonetheless, it is important to recognize that the small sample sizes within certain subgroups may limit the ability to draw definitive conclusions. Overall, this large-scale, randomized trial, featuring an extensive follow-up duration, provides robust and compelling data supporting the contention that sublobar resection can yield oncologic outcomes on par with lobectomy for patients presenting with peripheral, node-negative NSCLC measuring 2 cm or less.

The revelation from CALGB140503 that sublobar resection attains comparable oncologic outcomes to lobectomy marks a substantial departure from the earlier LCSG821. Several factors contribute to this shift in evidence. Firstly, a noteworthy proportion of the T1N0 tumors in LCSG821 fell within the 2 to 3 cm range, while CALGB140503 stipulated a maximum tumor size of 2 cm. Presently, there is insufficient evidence to advocate for sublobar resection in cases of tumors larger than 2 cm. Furthermore, LCSG821 data precede the era of routine computed tomography and positron emission tomography staging, which now enables the detection of less extensive, and likely more indolent, tumors that may be suitable for sublobar resection. Moreover, the relatively shorter median follow-up period in LCSG821 may not have afforded sufficient time for a comprehensive final evaluation of survival rates within each treatment group. In addition, surgical techniques have seen significant advancement since the time of LCSG821. The widespread adoption of mechanical staplers and energy devices has greatly facilitated parenchymal division, leading to improved margin clearance with sublobar resection. Lastly, progress in histopathologic analysis enables more precise staging, thereby discouraging sublobar resection in cases with potentially more advanced disease. In sum, the strides made in patient selection, imaging modalities, surgical instrumentation, and pathologic assessment over the past decades serve to elucidate the emerging oncologic equivalence observed in sublobar resection for small, node-negative NSCLC.

The primary distinction between CALGB140503 and JCOG0802 was the type of sublobar resection employed. Segmentectomy represents an anatomical resection of the involved bronchopulmonary segment, while wedge resection is a non-anatomical excision of the tumor. While CALGB140503 permitted both techniques, JCOG0802 mandated the use of segmentectomy. Despite yielding congruent results, segmentectomy is generally considered oncologically superior due to its capacity to provide a more thorough assessment of margins and lymph nodes through the division of parenchyma along intersegmental planes. Conversely, wedge resection is recognized for its expediency, simplicity, and preservation of greater pulmonary parenchyma.

Considering the equivalency in outcomes observed thus far, both segmentectomy and wedge resection are likely to have a role contingent upon patient and tumor factors. For instance, larger tumors may necessitate segmentectomy to ensure negative resection margins. In contrast, small nodules in older, frail patients may benefit from wedge resection to mitigate postoperative morbidity. Patients presenting with multifocal ground glass opacities may also be candidates for wedge resection to circumvent the need for repeated segmentectomies. Furthermore, certain tumors situated in challenging locations, such as the basal segments, may be more technically feasible to remove via wedge resection, particularly when employing minimally invasive approaches. Until more detailed data become available, the choice between segmentectomy and wedge resection will hinge on certain patient and tumor characteristics, as well as the surgeon’s expertise.

As sublobar resection gains increasing favor as an alternative to lobectomy for early-stage NSCLC, several nuanced aspects of surgical technique warrant careful consideration. Foremost among these is the imperative for meticulous lymph node assessment, as the presence of nodal involvement requires a shift to lobectomy for achieving complete resection. In CALGB140503, the negative status of hilar and mediastinal lymph nodes was rigorously confirmed through intraoperative frozen section analysis when invasive mediastinal staging had not been performed preoperatively. However, it is important to acknowledge that the availability of frozen section examination may be limited in certain settings, especially those with resource constraints. In such contexts, particularly when the pretest probability of nodal metastasis is high, an upfront lobectomy could be considered the preferred strategy over sublobar resection to avoid the need for reoperation. Additionally, meticulous attention must be directed towards ensuring adequate resection margins, a criterion not explicitly mandated in CALGB140503. By comparison, JCOG0802 required frozen section or cytologic confirmation of negative margins if they measured less than 2 cm or the maximal tumor diameter, with provisions for additional resection or conversion to lobectomy in case of positive margins. In routine practice, it is crucial to ensure adequate resection margins to minimize the risk of local recurrence. Furthermore, sublobar resections should preferably be performed through minimally invasive approaches to maximize their functional benefits over lobectomy (17). Nevertheless, video-assisted thoracoscopic segmentectomy presents certain technical challenges (18,19). Irrespective of the chosen surgical approach, strict quality control and standardization of methods are of paramount importance to achieve outcomes that can be extrapolated beyond clinical trial settings. Overall, adequate lymph node analysis, thorough resection margin evaluation, and the utilization of minimally invasive surgery whenever feasible emerge as critical contributors to favorable outcomes in the context of sublobar resection.

The combined results from CALGB140503 and JCOG0802 hold profound implications for lung cancer screening programs. The widespread implementation of lung cancer screening has led to an increase in the detection of stage IA NSCLC (20). However, until recently, lobectomy remained the standard of care for these tumors. Demonstrating the oncologic equivalence of sublobar resection now offers the prospect of surgical, curative treatment for patients with borderline pulmonary function or severe comorbidities who may have been previously considered unsuitable candidates for surgery. The growing acceptance of sublobar resection as a viable alternative to lobectomy for small peripheral tumors has the potential to expand the pool of individuals who can benefit from lung cancer screening in terms of survival. Additionally, sublobar resection has the potential to better preserve pulmonary function compared to lobectomy. Although the magnitude of this benefit may be modest (16), it carries particular significance for patients with chronic obstructive pulmonary disease, a prevalent comorbidity among heavy smokers undergoing screening. This comorbidity significantly elevates the risk of pulmonary complications associated with lobectomy (21). The adoption of sublobar resection may help mitigate surgical risks and improve the overall tolerability of the procedure for this patient population.

While CALGB140503 has underscored the effectiveness of sublobar resection for small peripheral NSCLC, it has simultaneously given rise to several questions requiring further investigation. One such question pertains to the optimal approach for managing positive resection margins. In JCOG0802, intraoperative frozen section analysis of margins prompted the decision to proceed with completion lobectomy in just three patients after final pathology results. However, in “real-world” clinical settings where such modalities may not be readily available, the rates of positive margins could be considerably higher. Depending on patient-specific comorbidities, functional status, and pulmonary reserve, completion segmentectomy or lobectomy may be contemplated in cases of positive margins. Nonetheless, it is worth acknowledging that resorting to lobectomy may run counter to the primary goal of lung preservation inherent in sublobar resection. Moreover, reoperations often pose technical challenges due to the presence of adhesions and fibrosis around hilar structures (22). We eagerly await the forthcoming granular data analysis on margin status from CALGB140503. Until then, decisions regarding the management of positive margins are best approached through the collaborative deliberation of a multidisciplinary tumor board. These decisions should be presented to the patient as part of a shared decision-making process.

Another outstanding issue revolves around the prognostic significance of spread through air spaces (STAS), defined as the presence of cancer cells in alveolar spaces adjacent to the main tumor. Emerging evidence underscores STAS as an independent risk factor of recurrence in small lung adenocarcinomas treated with limited resection (23). A comprehensive propensity-matched study revealed a notable increase in recurrence rates with sublobar resection as opposed to lobectomy for T1N0 adenocarcinomas exhibiting STAS (24). This finding lends weight to the consideration of completion lobectomy when STAS is identified on pathologic analysis. However, a smaller retrospective study has provided a somewhat different perspective (25). Among patients with stage IA NSCLC where STAS was present, recurrence-free and overall survival rates were comparable between segmentectomy and lobectomy. Nevertheless, this equivalence did not extend to wedge resection, which was associated with significantly inferior recurrence-free and overall survival when contrasted with lobectomy. Considering this ongoing uncertainty, there is a lack of consensus among experts regarding the necessity of completion lobectomy when STAS is identified on final pathology.

While CALGB140503 provides strong evidence for sublobar resection as an appropriate treatment for peripheral, node-negative NSCLC measuring 2 cm or less in its greatest dimension, further research is warranted to validate and expand upon these findings. Conducting additional randomized trials within diverse patient populations would bolster the evidentiary base and enhance its generalizability. Meta-analyses, pooling data from multiple randomized clinical trials, could offer a more robust framework for delineating the characteristics of suitable candidates and promoting the standardization of techniques across surgical practice. In addition, ongoing research efforts should strive to identify radiological and molecular factors that can reliably predict the likelihood of successful sublobar resection. Imaging features, such as consolidation-to-tumor ratio and maximum standardized uptake value, may emerge as valuable tools for selecting suitable candidates. Concurrently, molecular markers reflecting tumor biology could potentially serve as indicators of indolent disease amenable to sublobar resection. The development and validation of predictive models, incorporating a multitude of factors, could ultimately facilitate personalized decision-making regarding the choice between wedge resection, segmentectomy, or lobectomy. In the continuum of ongoing research, with a focus on refining patient selection criteria and surgical strategies, sublobar resection may well find its place as an established and standard alternative to lobectomy for an expanding cohort of patients diagnosed with early-stage NSCLC.

Acknowledgments

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: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-40/coif). S.L. serves as an unpaid editorial board member of AME Clinical Trials Review from August 2023 to July 2025. The author has no other conflicts of interest to declare.

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