The high-risk features and effect of postoperative radiotherapy on survival for patients with surgically treated stage IIIA-N2 non-small cell lung cancer

Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related lethality globally [1]. Non-small cell lung cancer (NSCLC) accounts for about 85% of patients with lung cancer, and one-third have been diagnosed with locally advanced NSCLC [2]. Surgery-based multimodality therapies are one of the available curative treatments for operable advanced NSCLC, especially pathological N2 IIIA NSCLC [3‐5]. Notably, the role of PORT in the survival of patients with stage IIIA-N2 NSCLC has caused considerable controversy [3, 4]. It is widely revealed that PORT contributes to a significant benefit in local–regional control in patients with surgically treated stage IIIA-N2 NSCLC [3, 4, 6, 7]. However, the benefit of local–regional control did not stand for an OS advantage. Additionally, PORT naturally increases adverse events, such as cardiopulmonary toxicity [3, 8, 9]. In general, the role of PORT in patients with surgically treated stage IIIA-N2 NSCLC remains controversial [3, 4]. Therefore we aimed to assess the role of PORT on the survival of patients with stage IIIA-N2 NSCLC by a Surveillance, Epidemiology, and End Results Program (SEER) population-based study.

Data were extracted from the SEER database, a national registry funded by the National Cancer Institute since 1971. This study population was chosen from the SEER Research Plus Database (17 Regs, Nov 2021Sub [2000–2019]) using SEER*stat Version 8.4.0.1 software. Patients who were 18 years old or more diagnosed with primary IIIA-N2 NSCLC were included according to the International Classification of Diseases for Oncology, 3rd edition morphological code including adenocarcinoma (SEER code 8140–8143, 8211, 8230 8250–8255 8323 8480 8481 8490 8550 8570,8572,8574), squamous cell carcinoma (SEER code 8050, 8052, 8070–8078, 8083, 8084, 8123), and others (SEER code 8012–8014, 8046, 8003, 8004, 8022, 8030–8032, 8200, 8240, 8249, 8560). Furthermore, we checked and reclassified the stage IIIA-N2 NSCLC according to the latest 8th Edition of American Joint Committee on Cancer (AJCC) TNM staging system instead of the TNM staging system by SEER [10].

Although a previous study reported that the use of PORT has declined for surgically treated stage IIIA-N2 NSCLC [11], we found that the number of surgically treated stage IIIA-N2 NSCLC following PORT was still large. However the role of PORT in patients with surgically treated stage IIIA-N2 NSCLC remains controversial [3, 4]. Consequently, there is a compelling need to explore the use of PORT on the survival of patients with stage IIIA-N2 NSCLC.

In previous studies, 20–60% patients with pathological N2 NSCLC had a locoregional recurrence [6, 12]. It is widely accepted that PORT contributes significantly to local–regional control in patients with surgically treated stage IIIA-N2 NSCLC [3, 4, 6, 7]. Therefore, PORT has been considered a strategy to improve outcomes by reducing the risk of local recurrence in patients with surgically treated stage III-N2 NSCLCT [6]. But PORT does not seem to improve OS in patients with surgically treated stage III-N2 NSCLCT [7, 13]. There are some possible reasons for the contradiction. Firstly, the benefit of PORT might be outweighed by itself as PORT naturally increases adverse events, such as cardiopulmonary toxicity [3, 8, 9]. However, several recent studies found that PORT might not contribute to an increase in the hazard for cardiac-related mortality [9, 14, 15]. A SEER population-based study reported no statistically significant difference in cardiac-related mortality between the PORT and non-PORT groups in stage IIIA-N2 NSCLC patients in all periods [9]. In the PORT-C trial, due to modern radiation techniques, such as IMRT, there were no radiotherapy-related grade 4 or 5 adverse events, and only 0.7% of patients had grade 3 radiation pneumonitis. With such low toxic effects, PORT still did not improve OS and DFS for patients with surgically treated stage IIIA-N2 NSCLC compared with the non-PORT group [5]. Secondly, because stage IIIA-N2 NSCLC is a systemic disease, it may be meaningless of local–regional control from PORT for patients with surgically treated stage IIIA-N2 NSCLC. The benefit of local–regional control is not equal to a survival benefit.

Patients with stage IIIA-N2 NSCLC in previous studies mostly were based on the former edition of TNM staging, but the edition of TNM staging have been re-defined. In this study patients were accurately diagnosed with primary IIIA-N2 NSCLC according to the latest 8th edition of TNM staging system, so the results in this study are more consistent with current clinical practice. Besides OS, CSS that only NSCLC-related death other than other causes was censored considered as endpoint was also taken into consideration to minimize the impact of other factors, such as cardiac-related mortality. Furthermore, PSM was performed to reduce the bias caused by selection, meanwhile both Cox multivariate analysis and PSM confirmed that PORT did not significantly improve OS or CSS in patients with IIIA-N2 NSCLC.

This study did not completely deny the application of PORT in surgically treated stage IIIA-N2 NSCLC. Although we do believe that PORT should have a survival benefit in selected patients with unique features, such as multiple N2 stations, a larger number of lymph nodes involvement, a bulky disease and high lymph node ratio (LNR) [16‐22], the details or cut-off value of particular features have not yet come to a unified definition. Constructing a risk model, such as patient prognostic scores, might be a more potential candidate to select the proper patients with surgically treated stage IIIA-N2 NSCLC for PORT [12, 20]. Therefore, further studies exploring which patients with surgically treated stage IIIA-N2 NSCLC might optimally have a survival benefit from PORT are required.

There were several limitations in our study. First, potential selection bias cannot be excluded due to its retrospective nature. Second, due to the lack of the related details in SEER database, several important issues were still suspended, such as the PORT timing (concomitant, sequential, or alone) analysis, the N2 surgical resection (clinical N0, limited disease, single station disease, salvage surgery) and the metastatic station number: N2a1 (a single metastatic station with no hilar involvement), N2a2 (a single metastatic station with hilar involvement), and N2b (multiple metastatic stations) [23, 24]. Third, recent treatments, like molecular targeted therapy and cancer immunotherapy, play a vital role in treating patients with surgically treated stage IIIA-N2 NSCLC. Therefore, the impact of molecular targeted therapy and cancer immunotherapy cannot be excluded from this study due to the lack of data in the SEER database.

Generally, we found that PORT did not contribute to a survival benefit in unselected patients with surgically treated stage IIIA-N2 NSCLC. Further prospective randomized controlled trials are needed to confirm the findings.