Commentary: is segmentectomy curative in patients with early-stage ground glass opacity predominant non-small cell lung cancer?

In the June issue of the Journal of The Lancet Respiratory Medicine, a multicenter, single arm trial (JCOG 1211) examining outcomes associated with segmentectomy in patients with ground-glass dominant non-small cell lung cancer (NSCLC) is reported (1). This study was published on the heels of the high-profile randomized trials comparing segmentectomy or sublobar resection to lobectomy, namely JCOG0802/WJOG4607L from Japan and the North American study, CALGB 140503 (2,3). These two randomized trials focused on patients with stage I NSCLC ≤2 cm, and both demonstrated that sublobar resection is not inferior (and possibly superior in the in JCOG 0802/WCOG4607L) to lobar resection, swinging the pendulum away from lobar resection as the standard of care for standard-risk operable patients. JCOG 1211 adds to our understanding of when to apply segmentectomy and importantly looks at a different patient group from the two major randomized trials. Eligible patients in JCOG 1211 included patients with pure ground glass or ground-glass dominant tumors [consolidation-to-tumor ratio (CTR) ≤0.5] 3 cm or less. Patients with peripheral tumors of 2 cm or less and a CTR of ≤0.25 that could be treated with wedge resection were excluded, whereas patients with central tumors ≤2 cm and CTR ≤0.25 not amenable to wedge, but amenable to segmentectomy were included. Other trial-specific factors to consider when applying the lessons of JCOG1211 to clinical practice, is that a resection margin of at least 2 cm or greater than the tumor diameter was required. Patients were also allowed to have up to two additional secondary tumors (the first tumor being ≤2 cm and a CTR ≤0.25, and the second tumor being a pure ground-glass lesion of 10 mm or more). These additional lesions had to be eligible for wedge resection only. The inclusion of patients with additional tumors does muddy the waters when interpreting the results of the study given that it might impact patterns of local and distant recurrence. A second lesion in the same lobe might represent an indication for lobectomy rather than two segmental resections, while a second lesion in a different lobe might be suitable for a segmental resection. On the other hand, this may have been necessary to allow the study to complete enrollment, and to provide a more real-world experience, since it is not unusual to see patients presenting with more than one ground glass lesion.

There were 357 patients who underwent segmentectomy out of 396 patients who were registered. Most patients underwent a thoracoscopic or hybrid approach (95%), with ≤2 segments resected (89%). Hilar, interlobar, and intrapulmonary lymph node dissections were performed. The authors reported a 5-year recurrence-free survival of 98.0% [95% confidence interval (CI): 95.9–99.1%] at a median follow-up of 5.4 [interquartile range (IQR), 5.0–6.0] years. Although not the primary aim of the study, the overall survival was 98.2% for the 396 registered patients, both excellent outcomes.

Pure ground-glass and ground-glass dominant tumors have been previously shown to carry a favorable prognosis following surgical resection (4). Previous studies suggest that they carry a very low likelihood of lymph node metastasis and that often, local control of the main tumor with adequate margins is sufficient (2). Hence, lobectomy might be considered too aggressive, particularly in patients with marginal pulmonary function tests. Studies have suggested that sublobar resection represents a valid treatment alternative in patients with ground glass opacity (GGO)-dominant clinical stage IA NSCLC (4-6). Nonetheless, to date, no randomized controlled trial has compared segmentectomy outcomes to lobectomy in patients with predominantly GGO tumors. Based on the results of previous studies showing favorable prognosis in patients with GGOs, it was estimated that a large number of patients would be required to power a randomized clinical trial to identify differences in survival, and hence, a single arm prospective study was conducted by the Japanese group (4). This is the first prospective trial examining the efficacy of segmentectomy in patients with predominant GGO tumors with CTR ≤0.5 and tumor size of >2 to 3 cm. The results of this study support the use of segmentectomy for appropriately selected patients, with tumors up to 3 cm in size. In addition, segmentectomy has been shown to be a rational surgical method that does not compromise oncological therapeutic efficacy. In the examined cohort, R1 margins, vascular invasion, lymphatic invasion, and lymph node metastasis were observed in <1%, 1%, 2%, and 1% respectively.

While the study offers valuable insights, several pertinent questions remain unanswered. It could be argued that the eligible patients in this study had indolent tumors and may have achieved as good outcomes with wedge resection with closer margins, or perhaps non-operative therapy such as stereotactic body radiation therapy (SBRT) or thermal ablation could have been applied. For example, a study by Jang et al., which examined 89 patients, showed a 5-year survival rate of 82.8% in patients with GGO and CTR ≤0.5 (7,8). Detterbeck et al. study examining the literature on the indication and outcome of surgery vs. ablation vs. SBRT suggested that SBRT/ablation results in short-term benefits and long-term downsides compared to surgery although increasing age/frailty accentuates short-term benefits and diminishes long-term downsides of SBRT/ablation when compared to surgery. In patients with limited pulmonary reserve, SBRT/ablation may carry lower short-term toxicity although an individualized approach based on patient’s priority can guide best treatment approach (7). In the absence of demonstratable growth on computed tomography (CT) scans, another question is whether continued observation could provide good results for ground-glass lesions between 2–3 cm? These questions will need to be investigated in future studies.

Nevertheless, we applaud the authors for this excellent study, which adds to the growing evidence supporting sublobar resection and segmentectomy for early-stage lung-cancer. Studies such as this are useful to inform surgeons on how to best tailor resection for patients with a particular tumor presentation.

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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