Prognostic factors of resectable anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients: a retrospective analysis based on a single center

Introduction

Lung cancer remains a leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases, and the 5-year survival rate of NSCLC has stagnated at around 22% (1,2). Anaplastic lymphoma kinase (ALK) rearrangement represents a distinct subtype of genetic mutation, accounting for approximately 5% of all NSCLC cases (3,4). ALK rearrangement is more frequently observed in never-smokers, adenocarcinomas, and younger patients, and those with advanced stage (5-7).

ALK rearrangement presents an aggressive tumor phenotype and a higher propensity to have lymph node metastasis (LNM) compared to wild-type in lung adenocarcinoma (8-10). Moreover, the majority of patients with LNM are occult. The survival rate was reported to be significantly worse in patients with occult lymph node metastasis (OLNM) than those without OLNM in clinically nodal negative NSCLC patients (11). Understanding the risk factors associated with OLNM is essential to improve the prognosis of patients (12).

Five-year risk of progression is higher for advanced stage lung adenocarcinoma patients with ALK mutation compared to those without ALK mutation (13). In addition, the 5-year recurrence-free survival (RFS) of ALK-rearranged patients is significantly worse compared to ALK-negative patients (55.9% vs. 78.8%) in stage I lung adenocarcinoma (14). ALK rearrangement is identified as an independent risk factor for recurrence (15). Advanced T stage and echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 are linked to worse disease-free survival (DFS) among ALK-rearranged NSCLC patients (16). However, the risk factors of recurrence and adjuvant treatment in resectable ALK-rearranged NSCLC have not been extensively studied.

Therefore, this study aimed to analyze the rate and risk factors of OLNM in ALK-rearranged NSCLC patients. Furthermore, we conducted a comprehensive analysis to identify independent risk factors for postoperative recurrence subgrouped by lymph node (LN) status. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-606/rc).

Methods

Patient selection

This retrospective study included patients with ALK-rearranged NSCLC who underwent lung resections at Shanghai Pulmonary Hospital from June 2016 to August 2021. The exclusion criteria consisted of the following: (I) a history of cancer; (II) received neoadjuvant therapy; (III) incomplete information available. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and was approved by the institutional board of Shanghai Pulmonary Hospital (No. K23-250). Individual consent for this retrospective analysis was waived.

ALK rearrangement confirmed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Tumor staging was assessed according to the 8th edition lung cancer staging system of the American Joint Committee on Cancer (AJCC), which evaluated the primary tumor (T), lymph node (N), and metastasis (M) (17). OLNM was defined as the presence of LNM confirmed through postoperative pathology in patients initially presenting with clinically negative nodes. LNs with less than or equal to 10 mm short-axis diameters on chest computed tomography (CT) images and no indication of LNM on positron emission tomography-CT (PET-CT) were characterized as clinically negative LNs. Tumor differentiation was determined according to the 2015 World Health Organization Classification of lung tumors (18).

Follow-up and postoperative recurrence

Follow-up was conducted via regular outpatient clinic visits or telephone interviews. Patients underwent physical examinations and chest CT scans every 3 months during the first 3 years, followed by examinations every 6 months for the subsequent 3–5 years, and then annually thereafter. Brain magnetic resonance imaging (MRI), abdominal ultrasonography, and bone emission computed tomography (ECT) were performed annually or at the doctor’s discretion. The last follow-up date was October 30, 2022. RFS was defined as the time interval from the date of diagnosis to recurrence or the last date known to be alive without recurrence, while overall survival (OS) was defined as the time interval from the date of diagnosis to death or the last follow-up.

Statistical analysis

Categorical variables were analyzed using the Chi-squared test or Fisher’s exact test. Normally distributed continuous variables were analyzed utilizing Student’s t-test, and non-normally distributed continuous variables were analyzed using the Mann-Whitney U test. Logistic regression analyses were performed to evaluate risk factors of OLNM, and Cox regression analyses were used to analyze risk factors of recurrence. Variables with P<0.05 in univariate analysis were included in multivariate analysis. RFS and OS were analyzed by the Kaplan-Meier method and compared by the log-rank test. Two-sided P<0.05 was considered statistically significant. The statistical analysis was performed using R software (version 4.2.1).

Results

Characteristics of pathologically nodal negative and positive patients

A total of 603 resectable ALK-rearranged NSCLC patients were included (Figure 1). The mean age was 55 years old, and the mean pathological tumor size was 20.7 mm. The majority of patients were female (n=347, 57.5%) and non-smokers (n=494, 81.9%), with nearly all cases diagnosed as adenocarcinoma (n=591, 98.0%). There were 171 patients confirmed to have LNM according to postoperative pathology. Significant differences were observed in gender (P=0.023), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (P=0.047), tumor location (P=0.007), spread through air space (STAS) (P=0.001), clinical N stage (P<0.001), and pathology (P=0.001) between pathologically nodal negative and positive patients (Table 1).

Figure 1 Study flow diagram. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer.

Video-assisted thoracoscopic surgery (VATS) was the primary surgical approach (n=569, 94.4%), with lobectomy being the most frequently performed type of resection (n=512, 84.9%). All patients underwent R0 resections. Pleural effusion was the most common postoperative complication (n=6, 1.0%), and remarkably, there were no perioperative deaths within the 90-day window (Table 2).

Nearly half of the patients received adjuvant chemotherapy (n=266, 44.1%), while a small number of patients received adjuvant radiotherapy (n=40, 6.6%) or ALK-tyrosine kinase inhibitors (TKI) alone (n=13, 2.2%). Alectinib and Crizotinib were commonly used ALK-TKI. None of the patients discontinued medication due to severe drug-related side effects. Pathologically nodal positive patients were more likely to experience surgical complications and receive adjuvant treatment (Table 2).

OLNM analysis

Among 514 clinically nodal negative ALK-rearranged NSCLC patients, 88 patients (17.1%) were confirmed to occur OLNM based on postoperative pathology, and 426 patients (82.9%) were confirmed not to occur OLNM. Patients with OLNM were observed to have a higher ratio of ECOG PS 1–2, STAS and vascular invasion than patients with no OLNM (NOLNM). In addition, patients with pathological N2 stage exhibited a higher ratio of OLNM than patients with pathological N1 stage (Figure 1; Table 3). Univariate logistic regression analysis revealed that clinical tumor size, CT density and ECOG PS were associated with OLNM. Multivariate analysis confirmed that clinical tumor size [odds ratio (OR), 1.032; 95% confidence interval (CI): 1.011–1.054] and CT density (OR, 1.007; 95% CI: 1.004-1.010) remained as independent risk factors (Table 4).

RFS and OS analysis

The median follow-up time was 33 months [interquartile range (IQR), 22–52 months]. The 3-year RFS were 92.5% and 59.7% in patients with pathologically nodal negative and nodal positive patients, respectively. Pathologically nodal positive patients had a worse RFS (median: 48 months) and OS compared to those with pathologically negative LNs, and pathologically nodal positive patients did not reach the median OS (Figure 2A,2B).

Figure 2 Survival curves of ALK-rearranged NSCLC patients. (A) Comparison of RFS between nodal negative (N−) and positive (N+) patients. (B) Comparison of OS between nodal negative (N−) and positive (N+) patients. (C) Comparison of RFS in nodal positive patients with adjuvant chemotherapy versus ALK-TKI. (D) Comparison of OS in nodal positive patients with adjuvant chemotherapy versus ALK-TKI. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; RFS, recurrence-free survival; OS, overall survival; TKI, tyrosine kinase inhibitor.

In pathologically nodal negative patients, univariate Cox regression analysis showed that vascular invasion, histological differentiation, pathological tumor size, and pleural invasion were associated with postoperative recurrence. Multivariate Cox regression analysis demonstrated that pathological tumor size [hazard ratio (HR), 1.061; 95% CI: 1.036–1.086] and pleural infiltration (HR, 4.009; 95% CI: 1.759–9.135) remained independent risk factors of postoperative recurrence (Table 5).

Adjuvant chemotherapy and ALK-TKI in pathologically nodal positive patients were further analyzed. Patients receiving ALK-TKI therapy were typically older than those undergoing chemotherapy. There were no significant differences between the two treatment groups in terms of gender, smoking history, tumor location, pathology, operative procedure, and histological differentiation. In addition, adjuvant chemotherapy and ALK-TKI had comparable side effects, with digestive symptoms being the most common adverse effect for both treatments (Table 6). The Kaplan-Meier analysis found that patients with adjuvant chemotherapy obtained a similar RFS (median: 46 months) and OS compared to those with adjuvant ALK-TKI, and patients with adjuvant chemotherapy did not reach the median OS (Figure 2C,2D).

Risk factors for recurrence in pathologically nodal positive patients were further analyzed. Univariate Cox regression analysis revealed that pathological N stage, pathological tumor size, vascular invasion, OLNM and metastatic LN station were associated with postoperative recurrence. Subsequent multivariate Cox regression analysis showed that only pathological N stage (N2 vs. N1, HR, 2.734; 95% CI: 1.409–5.307) remained an independent predictor, while OLNM exhibited a comparable RFS to clinically evident LNM (HR, 0.625; 95% CI: 0.378–1.034) (Table 7).

Discussion

Our study comprised the largest cohort of resectable ALK-rearranged NSCLC patients. Clinical tumor size and CT density resected were predictors of OLNM. Additionally, pathological tumor size and pleural infiltration emerged as risk factors for recurrence in pathologically nodal negative patients. Furthermore, among pathologically nodal positive patients, OLNM exhibited a comparable RFS to clinically evident LNM, and adjuvant ALK-TKI demonstrated a comparable RFS to chemotherapy.

OLNM is a potential risk factor for recurrence and metastasis, being of great clinical significance for prognosis (19,20). In comparison to a large cohort of 2,623 NSCLC patients who underwent surgery, wherein 29.7% had LNM (21), our study revealed a similar rate (28.4%) of LNM in ALK-rearranged NSCLC patients, with 51.5% of which being occult. In addition, ALK rearrangement was reported to be associated with a higher rate of OLNM compared to ALK-negative adenocarcinomas (22,23). We further identified clinical tumor size and CT density as independent predictors. Patients with tumors (>30 mm) exhibited a significantly higher rate of OLNM. Gallina et al. also reported similar results, showing that tumor diameter significantly predicted OLNM (23). These risk factors could be further utilized to construct a model for predicting OLNM, thereby offering enhanced guidance for surgery.

The status of LN could influence the recurrence, and thus, we analyzed recurrence factors subgrouped by LN status. Pathological tumor size and pleural infiltration were identified as independent predictors in pathologically nodal negative patients. These findings were consistent with the research by Schuchert et al., who also found that large tumors had a significantly higher risk of recurrence (24). Additionally, Wang et al. ever demonstrated that visceral pleural invasion was remarkably associated with a higher rate of recurrence in patients with stage I NSCLC (25). These findings contributed to a better assessment of recurrence risks in pathologically nodal negative patients and provided guidance for monitoring strategies.

LNM can potentially change the risk factors of postoperative recurrence. Our study reported a lower 3-year RFS in pathologically nodal positive patients compared to those with pathologically negative LNs (59.7% vs. 92.5%). Further analysis of the risk factors for recurrence demonstrated that N2 stage patients obtained a worse RFS than N1 stage patients. Isaka et al. also showed that N2 with N1 stage was the primary risk factor for local recurrence compared to N1 stage (26). These emphasized the need to tailor more specific treatments for patients with different N stages. In addition, Cho et al. showed that multiple metastatic N2 stations exhibited a higher RFS than single N2 station in N2 stage NSCLC (27). However, multiple metastatic LN stations presented a comparable RFS to single metastatic LN station in pathologically nodal positive patients in our study. The difference may be because single and multiple LN stations could be classified as similar N stages and not restricted to specific N2 stage, as in the study of Cho et al. In addition, OLNM exhibited a comparable RFS to clinically evident LNM, suggesting that the hidden nature of the LNM was not the primary factor for monitoring recurrence.

Adjuvant treatment is usually necessary for nodal positive ALK-rearranged patients; however, the most effective treatment type remains to be determined. ALK rearrangement was reported to be associated with a low response rate to immunotherapy (28). Advanced stage ALK-rearranged NSCLC patients treated with ALK-TKI reported superior progression-free survival (PFS) and objective response rates (ORRs) compared to those undergoing chemotherapy (29,30). A recent study analyzed the efficacy of adjuvant therapy in a cohort of 59 ALK-rearranged lung cancer patients and found that patients with adjuvant ALK-TKI demonstrated a better DFS and OS compared to those with chemotherapy (31). However, our study did not find a significant difference in postoperative RFS between ALK-TKI and chemotherapy in pathologically nodal positive patients, but adjuvant ALK-TKI showed a trend toward a lower risk of recurrence. The limited number of patients (n=11, 6.4%) who received ALK-TKI may reduce this statistical power. The ALINA trial was an ongoing phase III randomized trial targeting patients with resectable ALK-rearranged NSCLC to compare the efficacy of 2 years of adjuvant alectinib treatment with chemotherapy (5,32).

There are several limitations that should be acknowledged. First, as a retrospective study, there may be potential selection bias such as the administration of adjuvant treatment. Second, the small number of ALK-rearranged NSCLC patients who received adjuvant ALK-TKI could affect statistical power. Third, the follow-up regarding drug side effects should have been more thoroughly investigated. Fourth, the study lacks a detailed analysis of ALK variants. Fifth, only 180 patients (29.9%) underwent PET-CT scans, and for the remaining patients, clinically negative LNs could not be defined using PET-CT. Sixth, this study is single-center, and its applicability to a broader population awaits further analysis.

Conclusions

ALK-rearranged NSCLC patients with large tumors characterized by high CT densities require assessing the potential risk of OLNM when crafting surgery strategies. Even with pathologically negative LNs, patients with large tumors or pleural infiltration should undergo vigilant postoperative monitoring. Moreover, adjuvant ALK-TKI may offer comparable RFS outcomes to chemotherapy among pathologically nodal positive patients, pending further validation with substantial sample data.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (Grant No. 82172848), and Shanghai Pulmonary Hospital Fund (fkzr2105 and fkyq1908).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-606/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-606/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-606/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-606/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and was approved by the institutional board of Shanghai Pulmonary Hospital (No. K23-250). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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