Splitting hairs or not: importance of N2 subclassification after neoadjuvant treatment and surgery

Neoadjuvant treatment of locally advanced non-small-cell lung cancer (NSCLC) is crucial in reducing tumour size and increasing the potential for complete resection while also ‘eliminating’ micro-metastatic disease. The role of neoadjuvant chemotherapy has been clearly shown by meta-analyses, where 5-year overall survival (OS) is increased from 40% to 45% when compared to surgery alone [1]. Furthermore, the addition of radiotherapy to neoadjuvant chemotherapy has been shown to improve pathological complete response rates and mediastinal downstaging rates, with tolerable additional morbidity [2]. While the landmark North American Intergroup randomized controlled trial comparing neoadjuvant chemoradiation plus surgery versus full-dose chemoradiation demonstrated only significant progression-free survival but not OS in favour of the surgery group [3], it is worth noting that this study, similar to many other similar trials, did not differentiate different N2 subgroups. Numerous previous studies have reiterated one of the most significant prognostic factors after neoadjuvant treatment being mediastinal down-staging, and those with persistent N2 after induction are known to have poorer survival. Therefore, it has been a decade-long debate whether patients with persistent N2 after neoadjuvant treatment should be offered curative surgery.

However, with recent knowledge, N2 status is in fact a vastly heterogenous group, and different subgroups have significantly different prognosis. This is reflected in the latest 8th edition of TNM staging, where N2 is subdivided into N2a1 (skip metastasis to a single N2), N2a2 (single N2 plus N1 metastasis), and N2b (multiple N2), in decreasing order of survival [4]. Moreover, numerous authors have reported that middle or lower lobe cancers with single skip N2 are probably at higher stage than upper lobe tumours [5], one of the possible explanations being upper lobe tumours have more direct lymph channels draining into mediastinal lymph nodes as reflected in cadaveric studies. In the same line of thought, post-neoadjuvant cancers with persistent N2 should also be examined in different N2 subgroups to search for potential benefits in the addition of surgery.

We read with interest Stamatis et al.’s retrospective mono-institutional study analysing the outcomes of different N2 subgroups in NSCLC with persistent mediastinal disease after neoadjuvant chemotherapy or chemoradiotherapy [6]. A total of 145 patients between 1998 and 2015 underwent anatomical surgical resection after induction therapy, with low operative mortality of 2.6%. Overall survival and disease-free survival at 5 years are significantly better in single N2 group (47.3%, 30.6%), compared to single N2 + N1 group (30.2%, 23.4%) and multiple N2 group (<5%, <5%, respectively). There is an OS advantage in the lobectomy/bilobectomy group compared to the pneumonectomy group in the multivariable analysis, echoing with other prior studies. The authors conclude that lobectomy/bilobectomy should be considered a potentially curative option with satisfactory long-term results in those with persistent N2a1 or N2a2 disease after neoadjuvant treatment.

The authors should be applauded for their rigorous scientific method, as reflected in the large number of lymph nodes taken during surgery (median of 15), and their effort in histological confirmation of persistent N2 disease before surgery. The data accrual rate is high at 89%, while the mortality and morbidity of surgeries are comparable to international standards. While there is little surprise in the presence of survival distinction between different N2 subgroups, the true astonishment lies in the fact that 5-year survival of N2a1 subgroup (47%) in this study is far more superior than those in historical trials (∼27%) with mixed N2 groups [3]. However, this may be attributable to the higher proportion of pre-treatment multiple/bulky N2 disease included in prior studies.

The study is limited by its retrospective nature and its long timespan between 1998 and 2015, where older neoadjuvant regimes were employed. The types of induction therapy and the extent of surgery performed were heterogenous, encompassing chemotherapy alone or chemoirradiation, and different forms of anatomical lung resection ranging from segmentectomy to pneumonectomy. There is also a mixture of stage IIIA and IIIB patients at initial diagnosis, although the former consists of the majority. More importantly, post-induction N2 status is analysed in bulk without taking into consideration of whether mediastinal downstaging occurred. Obviously, a patient who progressed from N2a1 to N2a2 despite neoadjuvant treatment may have a different prognosis compared to another who is downstaged from N2b to N2a2 after induction therapy. The current guidelines recommend staging MRI brain for locally advanced cancers, as the rate of occult brain metastasis is up to 28%. However, such was not available in this study, and up to 19.6% of those who later relapsed were brain metastases, yet we could not be sure they were not already present at the time of surgery.

To answer whether the addition of surgery to neoadjuvant treatment in stage IIIA (N2) NSCLC with persistent N2 would improve survival, randomized controlled trials with a comparison arm are necessary. More excitingly, future studies involving neoadjuvant targeted therapies or immunotherapies are upcoming. The current standard for stage III non-resectable NSCLC is concurrent chemoradiation plus consolidation durvalumab, with encouraging OS of 49.6% after 4 years in the PACIFIC trial [7]. Preclinical data have suggested that neoadjuvant immune checkpoint inhibitors (ICI) are more effective than adjuvant ICI, possibly due to the more immunogenic tumour microenvironment versus that of post-surgical micro-metastases. Multiple phase II trials on neoadjuvant ICI have proven its safety and feasibility, with few side effects and high major pathological response rates [8]. Numerous phase III trials on neoadjuvant ICI are underway, one of which has already released its early favourable results in May 2021. The CheckMate 816 trial compared nivolumab plus platinum-doublet chemotherapy versus chemotherapy alone as neoadjuvant treatment for stage IB to IIIA resectable NSCLC and found that the former significantly improved pathological complete response rates [9], although long-term data on survival are still pending. While the ADAURA trial showed that Osimertinib significantly improved progression-free survival in completely resected stage IB to IIIA disease [10], EGFR tyrosine kinase inhibitors have at times conflicting results in the neoadjuvant setting in terms of response rate and survival [8]. With the efficacy of the latest ICI and tyrosine kinase inhibitors, it will be interesting to explore whether surgery in addition to these agents would benefit those with persistent N2 after induction therapy.

Conflict of interest: Calvin S.H. Ng is a consultant for Johnson and Johnson, Medtronic, USA, and Siemens Healthineers. Rainbow W.H. Lau is a consultant for Medtronic, USA, and Siemens Healthineers. All remaining authors declare no potential conflicts of interest that exist with any companies/organizations whose products or services are discussed in this article.

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