Segmentectomy for partially solid non-small cell lung cancer: what counts—the resection or the patient?

Introduction

The impact of lung cancer is still not negligible, with an incidence of more than 200,000 cases per year in the United States and with a general poor prognosis (1,2). However, especially in the last decades, the development of screening programs including high-risk patients, led to an increased diagnosis at operable/early stages, with consequent survival improvement (3,4), and the implementation of knowledge about the tumor biology led to classification of pre-invasive and/or minimally invasive subtypes of adenocarcinomas, with an excellent prognosis when surgically treated.

Moreover, the correlation of computed tomography findings with pre- or minimally invasive tumors (5,6) opened a new scenario in the management and the survival of non-small cell lung cancer (NSCLC) patients. Indeed, neoplastic lesions such as atypical adenomatous hyperplasia, adenocarcinoma in situ or minimally invasive adenocarcinoma, present an excellent survival rate and a low risk of nodal involvement and recurrence, so, actually, the indicated treatment is surgical resection only. In consideration of this excellent prognosis with disease specific survival approaching the 100% at 5 years (7), the extent of parenchymal resection is now under consideration, with intra- and peri-operative technical improvements that permitted the execution of segmentectomy via minimally invasive techniques in a safe and effective manner, opening the possibility to increase this kind of resection that permits to save parenchyma with different potential advantages (7-9).

Indeed, despite the primary advantage being tied to the possibility to preserve the lung function compared to lobectomy in patients at risk to develop multiple tumors, it allows for iterative resections.

However, one of the most important points that remains to be addressed is in which patients segmentectomy should be the treatment of choice.

The good prognosis of patients with tumor size less than 2 centimeters permitted the design of two prospective trials, the JCOG0802/WJOG4607L and the CALGB140503 trial (10,11), that reported similar results in survival terms comparing segmentectomy and lobectomy.

Nevertheless, some issues remain to be defined, such as the prognosis related to the solid/subsolid ratio or the prognosis after segmentectomy in patients with tumors dimension >2 centimetres.

The JCOG1211 trial, entitled “Segmentectomy for ground-glass-dominant lung cancer with a tumour diameter of 3 cm or less including ground-glass opacity (JCOG1211): a multicentre, single-arm, confirmatory, phase 3 trial” (12), aimed to give an answer to these questions.

The JCOG1211 trial

The JCOG1211 trial is a multicenter, single-arm, confirmatory phase 3 trial conducted in 42 Japanese centers involving patients who underwent segmentectomy for NSCLC at stage IA and performance score 0–1, including pure ground glass opacity (GGO) and predominant GGO nodules. Patients were operated between September 2013 and November 2015 and then underwent active follow-up, which had a median of 5.4 years.

The primary endpoint was 5-year relapse-free survival (RFS), and the study was focused on 3 categories of patients:

• Those with a tumor diameter from more than 2 to 3 cm, and a consolidation to tumor ratio (CTR) of 0.50 or less;
• Those with a tumor diameter of 2 cm or less and a CTR from more than 0.25 to 0.50;
• Those with a tumor diameter of 2 cm or less and a CTR of 0.25 or less.

All patients underwent segmentectomy with hilar, interlobar, and intrapulmonary lymph node dissection, categorizing segmentectomy according to the number of segments involved, ranging from 1 to 4.

The study involved 357 patients, of those, the major part presented pT1a tumors (78%), while adenocarcinoma in situ and minimally invasive adenocarcinoma were revealed in the 25% and the 33% of cases, respectively.

The median number of resected lymph nodes was 6 [3–11] and the median number of resected nodal stations was 5 [4–7]. A single segmentectomy was performed in less than the half of patients (48%), nodal metastasis was detected in only 1 case and involved N1 lymph nodes and the median forced expiratory volume in 1 second (FEV₁) reduction at 6 and 12 months resulted of about the 7–8%.

A complete resection was achieved in all patients, and the authors stated that this was the most important point when considering segmentectomy for these kinds of tumors.

Regarding the survival outcome, the primary endpoint was reached, with the 5-year RFS of 98.0% (95% CI: 95.9–99.1%), exceeding the fixed threshold of 87%, so the authors concluded that segmentectomy should be considered the standard treatment in patients with pure and dominant GGO less than 3 centimeters.

Comment

In this study, the feasibility and the outcome of segmentectomy were investigated in healthy patients with stage IA tumors and with pure and dominant GGO, showing that in these patients this kind of resection ensures excellent results in terms of survival.

However, there are some questions that should be discussed.

Firstly, these patients, in fact, did not present nodal involvement and perhaps will never present. In particular, these data seem evident considering that about 1 lymph node for resected nodal station was analysed and the RFS resulted 98%. In consideration of these results, the question should be: why choose segmentectomy over atypical resection?

Indeed, one advantage of segmentectomy is the resection of the afferent segmental bronchus, which clears the afferent lymph nodes.

Other studies have reported the same survival outcome performing sampling or radical lymph node dissection in stage IA tumors without nodal involvement (13,14), and considering the absence of positive lymph nodes in the JCOG1211 trial, the execution and the extension of lymphadenectomy may be questionable and need more investigation.

Lymph node assessment remains a fundamental part of surgery for NSCLC, but in recent years, its paradigm has been changing. Indeed, also considering the possible complications due to extended lymph node assessment and in the paradigm of minimally invasive surgery concept, other nodal assessment than mediastinal radical node dissection are now under evaluation (15). In particular, in determinate cases, it is possible to adopt different strategies, such as lobe specific nodal dissection, selective nodal dissection, and mediastinal lymph node sampling. However, one of the most important points regarding lymphadenectomy is the possibility to intercept unexpected nodal metastases with consequent upstage, fundamental for the prognosis definition but essential for the administration of adjuvant therapies. Indeed, despite in solid tumors the upstaging rate is always reported and may vary according to tumor characteristics but it is also function of the number of resected nodes/stations (16,17), in some histology of the adenocarcinoma spectrum, the possibility to detect nodal involvement is quite nil. For example, two large studies, which involved minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma, or invasive mucinous adenocarcinoma and adenocarcinoma in situ, reported no nodal metastases in the examined lymph nodes (18,19). The JCOG1211 trial substantially confirmed these studies, reporting the absence of nodal involvement in GGO and predominant GGO tumors and suggesting that in these cases lymphadenectomy may be limited, even if its execution will be probably questioned in the future.

Another point regards the technical aspects of segmentectomy and the comparison to lobectomy. Indeed, the concluded trials reported a better functional outcome in segmentectomy vs. lobectomy, even if the difference was about 5% of FEV₁ in favour of segmentectomy (11). In detail, in this trial, only 48% of patients received a single segmentectomy, but how can we think that there is a significant difference considering multiple segmentectomy? Indeed, in case of resection of 2–3 segments, the difference compared to right upper lobectomy (three segments) should be inexistent. The data from the JCOG802/WJOG4607L trial are not clear on this topic, reporting a significantly better FEV₁ in segmentectomy with one to three excision segments compared to lobectomy (one segment, P<0.0001; two segments, P<0.0001; three segments, P=0.0033), while no FEV₁ differences were present with the excision of four segments (P=0.6250) (11). However, the authors did not report the kind of lobectomy performed, and if there was a predominance of left upper lobe or lower lobes it is quite simple to explain this difference, while it would be interesting to compare two-three segmentectomies with right upper lobes or middle lobes that included the same segments number.

Remaining on this topic, considering 357 patients enrolled in 42 institutions, resulted a mean of less than 5 patients/institution per year. This data is very interesting, as it shows that patients eligible for this kind of treatment are very uncommon. Moreover, considering that the majority were non-smokers, the individuation of these cases is very hard, also because they do not meet any criteria for lung cancer screening program (20). Finally, it would be interesting to understand if this low number of enrolled patients is only due the strict inclusion/exclusion criteria or there is also a technical aspect regarding segmentectomy indication, with exclusion of some patients due to the difficulties to perform segmentectomy for the tumor location. In this case, the adoption of this strategy may result extremely hard to be transmitted to the daily clinical practice and risks to be opportune only for few extremely selected patients.

For these reasons, this trial covers quite an uncommon aspect of lung cancer, confirmed by the high number of pre or minimally invasive lesions (about 60%). On the other hand, this study gives encouraging information regarding the outcome of these patients, with an excellent prognosis when radically resected and with low risks of nodal metastases, suggesting this approach in this particular class of tumor characteristics.

However, the best treatment in this scenario still needs to be clarified, especially regarding the potential advantages of segmentectomy instead lobectomy or wedge resection.

In the future, ad hoc studies will analyse the survival in these cases, suggesting the best treatment in consideration of the favourable clinical outcome of this NSCLC spectrum.

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.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-14/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-14/coif). The authors have no conflicts of interest to declare.

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