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This study aimed to compare the recurrence-free survival (RFS) and overall survival (OS) among wedge resection (non-anatomical resection), segmentectomy and lobectomy for pathological stage IA non-small cell lung cancer (NSCLC) with spread through air spaces (STAS). Patients underwent surgical treatment for pathological stage IA NSCLC between January 1, 2005, and March 31, 2016, at our hospital. Surgical procedures were classified as lobectomy, segmentectomy, and wedge resection. Among the 555 analyzed cases, STAS was observed in 148 patients (26.7%). STAS was correlated with worse RFS (P < 0.001) and OS (P < 0.001) and was an independent poor prognostic factor for RFS (hazard ratio: 2.37, P < 0.001) and OS (hazard ratio: 2.02, P < 0.001) in the multivariate analysis. In patients with STAS, the RFS and OS in the segmentectomy group were comparable to those in the lobectomy group. However, the RFS and OS in the wedge resection group were significantly lower than those in the lobectomy group (RFS, P < 0.001; OS, P = 0.001). Wedge resection was an independent prognostic factor for poor RFS (hazard ratio [HR] = 3.87; 95% confidence interval [CI] = 1.84 – 8.12, P < 0.001), and poor OS (hazard ratio [HR] = 3.39; 95% confidence interval [CI] = 1.33 – 8.76, P = 0.011) in the multivariate analysis. Segmentectomy is an adequate operation for patients with stage IA NSCLC with or without STAS. However, wedge resection is associated with a higher risk of recurrence in this patient population.
Segmentectomy is an adequate operation for patients with stage IA non-small cell lung cancer that has spread through air spaces.
Perspective Statement
Segmentectomy is an adequate operation for patients with stage IA non-small cell lung cancer (NSCLC) with or without spread through air spaces (STAS). Despite the postoperative pathological diagnosis of STAS, the prognosis of patients who have undergone segmentectomy for stage IA NSCLC may provide comparable outcomes to lobectomy.
INTRODUCTION
Spread through air spaces (STAS) is a newly recognized invasion pattern that was described by the World Health Organization (WHO) in 2015.
Several studies have shown that STAS is recognized in approximately 15-60% of patients with lung cancer and is an independent poor prognostic factor for recurrence-free survival (RFS) and overall survival(OS) of lung cancer.
Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
Limited resection is associated with a higher risk of locoregional recurrence than lobectomy in stage I lung adenocarcinoma with tumor spread through air spaces.
Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
Limited resection is associated with a higher risk of locoregional recurrence than lobectomy in stage I lung adenocarcinoma with tumor spread through air spaces.
The most important point, supported by multiple publications on STAS, is that the surgical procedure greatly influences the prognosis of lung cancer with STAS.
Lobectomy is associated with better outcomes than sublobar resection in spread through air spaces (STAS)-positive T1 lung adenocarcinoma: A propensity score-matched analysis.
Due to the advances in imaging technology, lung cancer is being detected earlier. As a result, surgeons have more opportunities to choose sublobar resection for lung cancer. However, several reports have demonstrated that sublobar resection shows low RFS and OS in patients with STAS-positive tumors.
Lobectomy is associated with better outcomes than sublobar resection in spread through air spaces (STAS)-positive T1 lung adenocarcinoma: A propensity score-matched analysis.
Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
Limited resection is associated with a higher risk of locoregional recurrence than lobectomy in stage I lung adenocarcinoma with tumor spread through air spaces.
reported that STAS was significantly correlated to distant and locoregional recurrence in the limited resection group, while there was no association with recurrence in the lobectomy group. These studies compared lobectomy with reduction surgery but did not divide reduction surgery into segmentectomy and wedge resection.
In the present study, we aimed to analyze Japanese patients with therapy-naïve pathological stage IA non-small cell lung cancer (NSCLC) in the presence of STAS to compare RFS and OS among wedge resection, segmentectomy and lobectomy.
MATERIALS AND METHODS
Patients
This retrospective cohort study was approved by the Institutional Review Board of Kagawa University (approval number: 2020-090, approval date: September 1, 2020). Written informed consent for the publication of study data was obtained from all the participants. We reviewed patients with therapy-naïve NSCLC who underwent lobectomy, segmentectomy or wedge resection at Kagawa University between January 1, 2005 and March 31, 2016. Cases with multifocal invasive carcinomas, pneumonectomy, induction therapy, positive surgical margin, and inappropriate tissue which hindered STAS evaluation were excluded from the study. The patient selection scheme is shown in Figure 1.
Figure 1CONSORT diagram. NSCLC, non-small cell lung cancer; STAS, spread through air spaces.
Clinical data were collected from our prospectively maintained lung carcinoma database. Disease recurrences were confirmed according to clinical, radiological, or pathological assessments. The disease TNM stage was assigned based on the 8th edition of the American Joint Committee on Cancer TNM Staging Manual.
Hematoxylin and eosin-stained slides were reviewed by 2 pathologists without the knowledge of the patient's clinical outcomes using the Olympus BX53 upright microscope (Olympus Corporation, Japan) with a standard 22 mm diameter eyepiece. Tumors were classified in accordance with the 2015 WHO classification of lung carcinomas.
Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
The edge of the main tumor was defined as the outer border of the tumor, which is typically determined by low-power histologic examination.
Surgical Procedure
In all the cases, the surgical margins were negative. The surgical margin was equivalent to the lesion diameter or at least 20 mm from the primary lesion. Segmentectomy or wedge resection was considered for patients with small peripheral tumors (invasive tumor size < 10 mm) or for patients whose tumors’ ground glass opacity diameter was more than half of the tumor diameter.
Wedge resection was performed especially on peripheral tumors with sufficient surgical margin from the tumor. In some cases, segmentectomy or wedge resection was performed for patients who could not tolerate lobectomy due to poor pulmonary function. Mediastinal lymph node dissection was performed when preoperative computed tomography showed lymph nodes with a minor axis of 10 mm or more or when accumulation was observed in positron emission tomography. For tumors with no evidence of lymph node metastasis on preoperative images, we resected the hilar lymph nodes and made frozen sections from the resected nodes. We omitted mediastinal lymph node dissection when no hilar lymph node metastasis was observed in the frozen sections. We used infrared thoracoscopy with indocyanine green to visualize the adjacent lung segments for segmentectomy.
Follow-Up Evaluation and Definition of Recurrence Location
All recurrences were confirmed by clinical, radiological, or pathological assessments. A total of 11 lesions suspected of recurrence could be biopsied, a biopsy was performed and evaluated. A total of 58 lesions that were difficult to biopsy were evaluated clinical and radiological findings. Recurrences were classified into locoregional (pooling local + regional) and distant recurrences.
American College of Chest Physicians and Society of Thoracic Surgeons consensus statement for evaluation and management for high-risk patients with stage I non-small cell lung cancer.
Local recurrence was defined as evidence of a tumor in the same lobe or at the surgical margin of the original tumor, whereas regional recurrence was defined as evidence of a tumor in a second ipsilateral lobe, in the ipsilateral hilar lymph nodes, or in the ipsilateral mediastinal lymph nodes. Distant recurrence was defined by the presence of a tumor in the contralateral lung, in the contralateral mediastinal lymph nodes, in the ipsilateral supraclavicular lymph nodes, or outside the hemithorax.
Statistical Analysis
Associations between variables were analyzed using Fisher's exact test for categorical variables. RFS was defined as the time from the surgical resection to the date of disease recurrence, death, or last follow-up. OS was defined as the time from the surgical resection to the date of death or last follow-up. RFS and OS were compared between study groups using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards regression model. Multivariate models included factors that were significant in the univariate analysis. All associations between pathologic factors were checked, and if any strong associations were discovered, only one factor was included in the model. All statistical tests were two-sided and used a 5% significance level. Statistical analyses were conducted using IBM SPSS Statistics for Windows (version 23.0; IBM Corporation, Armonk, NY).
RESULTS
Patient Clinicopathologic Characteristics
The median age of the 555 enrolled patients was 69.4 (range, 21 – 92) years. Half of the patients were men (n = 295), and most patients had pathological stage IA1 disease (n = 269). Most patients had undergone lobectomy (n = 417). A total of 68 patients had undergone segmentectomy, and 70 patients had undergone wedge resection. A total of 73 patients had not undergone lobectomy because of small size peripheral tumors, and 65 patients had not undergone lobectomy due to poor lung function. The consolidation diameter of tumors in patients who underwent segmentectomy or wedge resection tended to be smaller than in those who underwent lobectomy (median ± SD, lobectomy 12.7 mm ± 8.34 vs. segmentectomy 12.0 mm ± 7.60 vs. wedge resection 9.6 mm ± 8.24, P = 0.018) (Supplementary Table 1).
A total of 25 patients received adjuvant chemotherapy with tegafur-uracil.
Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a meta-analysis of six randomized controlled trials.
During the study period, 69 patients experienced recurrence and 76 patients died. Of the patients with STAS, 45 patients had recurrence and 32 patients died in the study. The median follow-up period for patients who were alive at the time of the last follow-up was 60.5 (median ± SD, 64.7 ± 33.3) months.
Association of STAS with Clinicopathological Features
STAS was observed in 148 patients (26.7%) and was more frequent in male (P < 0.001), as well as in patients with high pathological stage (P < 0.001), lymphatic invasion (P < 0.001), and vascular invasion (P < 0.001) (Table 1). The presence of STAS did not tend to be correlated with surgical procedure (P = 0.078) and histology (P = 0.214). Recurrence was observed in 45 patients with STAS (30.4%), and the recurrence rate was significantly higher than that in patients without STAS (P < 0.001).
Table 1Association of STAS With Clinicopathologic Features
In this cohort, we confirmed that STAS was associated with a higher risk of recurrence and worse survival (P < 0.001 and P = 0.002, respectively) (Supplementary figure. 1A and 1B). The univariate and multivariate associations of RFS and OS with clinicopathological factors are presented in supplementary tables 2 and 3. The multivariate analysis of all the patients revealed that STAS was an independent prognostic factor for poor RFS (hazard ratio [HR] = 1.48; 95% confidence interval [CI] = 1.00 – 2.46, P = 0.048). The presence of STAS tended to correlate with poor OS, although this association was not statistically significant (HR = 1.48; 95% CI = 0.78 – 2.27, P = 0.29).
STAS and Patient Outcome According to the Types of Surgery
In patients without STAS, the RFS and OS in the segmentectomy group were not significantly different from those in the wedge resection group (5 year RFS: segmentectomy 80.0% vs wedge resection 72.6%, P = 0.12; 5-year OS: segmentectomy 89.2% vs wedge resection 78.8%, P = 0.091) (Supplementary Figure. 2A and 2B).
Among patients with STAS as in patients without STAS, the RFS and OS in the segmentectomy group were comparable to those in the lobectomy group (5 year RFS: lobectomy 72.6% vs segmentectomy 70.6%, P = 0.550; 5 year OS: lobectomy 83.6% vs segmentectomy 92.9%, P = 0.213). However, the RFS and OS in the wedge resection group were significantly lower than those in the lobectomy group (5 year RFS: lobectomy 72.6% vs wedge resection 19.3%, P < 0.001; 5 year OS: lobectomy 83.6% vs wedge resection 41.3%, P = 0.001) (Fig. 2A and 2B). The univariate and multivariate associations of RFS and OS with clinicopathological factors are presented in Tables 2 and 3. The multivariate analysis of patients with STAS revealed that wedge resection was an independent prognostic factor for poor RFS (hazard ratio [HR] = 3.87; 95% confidence interval [CI] = 1.84 – 8.12, P < 0.001), and poor OS (hazard ratio [HR] = 3.39; 95% confidence interval [CI] = 1.33 – 8.76, P = 0.011). Regarding local recurrence, lobectomy and segmentectomy were at a similar risk of recurrence, whereas wedge resection showed a higher recurrence rate (lobectomy 5.5% vs segmentectomy 5.9% vs wedge resection 26.3%). Similarly, regarding regional recurrence, wedge resection showed a higher recurrence rate than lobectomy and segmentectomy (lobectomy 10.7% vs segmentectomy 0% vs wedge resection 26.3%).
Figure 2Spread through air spaces (STAS) and patient outcome, determined as recurrence-free survival (RFS) and overall survival (OS), according to surgical procedure. (A) In patients with STAS, the 5 year RFS of patients who underwent wedge resection (5 year RFS; 19.3%, 95% CI; 1.5% – 52.4%) was significantly lower than that of patients who underwent lobectomy (5 year RFS; 72.6%, 95% CI; 62.8 – 80.4, P < 0.001) and that of patients who underwent segmentectomy (5-year RFS; 70.6%, 95% CI; 43.1% – 86.6%, P < 0.001). (B) Among patients with STAS, the 5 year OS of patients who underwent wedge resection (5 year OS; 41.3%, 95% CI; 12.5% – 68.7%) was significantly lower than both that of patients who underwent lobectomy (5 year OS; 83.6%, 95% CI; 74.9 – 89.5, P = 0.001) and that of patients who underwent segmentectomy (5-year OS; 92.9%, 95% CI; 59.1% – 99.0%, P < 0.001).
In this study, we examined a uniform, large cohort of patients with therapy-naïve pathological stage IA NSCLC who had undergone lobectomy, segmentectomy, or wedge resection at a single institution. We demonstrated that the RFS and OS of patients who underwent segmentectomy for STAS-positive pathological stage IA NSCLC were favorable and comparable to those of patients who underwent lobectomy. Notably, wedge resection led to higher local and regional recurrence rates than lobectomy and segmentectomy (Fig. 3).
Figure 3In patients with STAS, the 5 year RFS of patients who underwent wedge resection (5 year RFS; 19.3%, 95% CI; 1.5% – 52.4%) was significantly lower than that of patients who underwent lobectomy (5 year RFS; 72.6%, 95% CI; 62.8 – 80.4, P < 0.001) and that of patients who underwent segmentectomy (5 year RFS; 70.6%, 95% CI; 43.1% – 86.6%, P < 0.001). Similarly, the 5 year OS of patients who underwent wedge resection (5 year OS; 41.3%, 95% CI; 12.5% – 68.7%) was significantly lower than both that of patients who underwent lobectomy (5 year OS; 83.6%, 95% CI; 74.9 – 89.5, P = 0.001) and that of patients who underwent segmentectomy (5 year OS; 92.9%, 95% CI; 59.1% – 99.0%, P < 0.001). (A) A decreased 5 year RFS tended to be correlated with patients who underwent wedge resection (5 year RFS; 72.6%, 95% CI; 55.2% – 84.1%) rather than patients who underwent segmentectomy (5 year RFS; 80.0%, 95% CI; 64.9% – 89.1%), although this association was not statistically significant (P = 0.12). (B) A decreased 5 year OS tended to be correlated with patients who underwent wedge resection (5 year OS; 78.8%, 95% CI; 61.1% – 89.1%) rather than patients who underwent segmentectomy (5 year OS; 89.2%, 95% CI; 75.9% – 95.4%), although this association was not statistically significant (P = 0.091). NSCLC, non-small cell lung cancer; STAS, spread through air spaces.
Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
Limited resection is associated with a higher risk of locoregional recurrence than lobectomy in stage I lung adenocarcinoma with tumor spread through air spaces.
Lobectomy is associated with better outcomes than sublobar resection in spread through air spaces (STAS)-positive T1 lung adenocarcinoma: A propensity score-matched analysis.
identified STAS as an unfavorable prognostic factor for recurrence (HR = 1.79 – 1.98) and survival (HR = 1.49 – 1.78) in patients with non-small cell lung carcinoma. Liu et al.
reported that in the subgroup analysis of a meta-analysis that included 14 studies, the presence of STAS was associated with shorter RFS in those undergoing limited resection (HR = 4.05; 95% CI = 2.31 – 7.09). Therefore, it is desirable to accurately determine the presence or absence of STAS pre or intra-operatively. However, preoperative or intra-operative evaluation of STAS is difficult. Walts et al.
reported that the sensitivity of frozen sections in detecting STAS is only 50% and concluded that it is difficult to use intra-operative STAS detection as a useful predictive feature for stratifying patients for either lobectomy or sublobar resections. Morimoto et al.
indicated that the evaluation of STAS in frozen sections is difficult because resected lungs are not sufficiently inflated. Several studies aimed to indirectly predict STAS preoperatively based on the imaging findings of lung cancer, and reported that STAS is associated with computed tomography features such as a tumor diameter >20 mm, a high consolidation to tumor ratio, or fluorodeoxyglucose-positron emission tomography and/or computed tomography features such as a high maximum standardized uptake value.
However, these features are indicative of invasive carcinoma, and we chose lobectomy for tumors with these features. Thus, these findings are not useful in determining the surgical procedure for small lung cancer. Surgery is the only method for evaluating STAS, and the presence of STAS is only definitely known after surgery and cannot influence the decision regarding the surgical procedure.
Lobectomy is associated with better outcomes than sublobar resection in spread through air spaces (STAS)-positive T1 lung adenocarcinoma: A propensity score-matched analysis.
reported that in patients with STAS-positive T1N0M0 lung adenocarcinoma, the lobectomy group had a better prognosis than the sublobar resection group. Interestingly, the authors also reported that in STAS-negative tumors, the sublobar resection group in which the surgical margin was sufficiently wide (surgical margin to tumor diameter ratio ≥1) had lower locoregional recurrence than the group, in which the surgical margin was insufficiently wide (surgical margin to tumor diameter ratio <1). However, in case of STAS-positive tumors with sublobar resection, there was no significant difference between the groups with sufficiently and insufficiently wide surgical margins. Thus, when dealing with STAS-positive tumors, it may be inappropriate that the surgical margin of the sublobar resection in early-stage lung cancer to be equal to the tumor diameter. In our study, the sublobar resection group was further divided into a wedge resection group and a segmentectomy group for comparison. Our results showed that the surgical margin provided control of local recurrence in segmentectomy similar to that in lobectomy. However, our data also demonstrated that wedge resection was associated with inadequate surgical margins and a high risk of recurrence for lung cancer in patients with STAS. The wedge resection should be chosen more carefully due to the high recurrence rate, although wedge resection was performed on relatively small lesions in our study. Further, additional treatment options such as radical lobectomy and postoperative chemotherapy should be considered in patients who undergo wedge resection for stage IA NSCLC and was diagnosed STAS presence after surgery.
There are a few limitations to this study. First, this was a retrospective study and involved data from a single institution. Therefore, the number of cases is small and there may be a bias. Second, the majority lesions suspected of recurrence are difficult to diagnose by biopsy and are evaluated based on clinical and radiological findings. Third, we did not evaluate the distance from the tumor edge to the detection of STAS. We also did not investigate the distance between the tumor and the nearest resection margin from the tumor. Therefore, we have not been able to determine the optimal surgical margin to prevent local recurrence of lung cancer in patients with STAS. However, it is known that segmentectomy can provide a wider margin than wedge resection,
and our results also showed that segmentectomy can provide sufficient distance to prevent local recurrence of lung cancer with STAS.
CONCLUSION
In conclusion, segmentectomy could be a completion operation for patients with stage IA NSCLC with STAS. Even if the postoperative pathological diagnosis involves STAS, patients who have undergone segmentectomy for stage IA NSCLC may be comparable outcomes to lobectomy.
Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
Limited resection is associated with a higher risk of locoregional recurrence than lobectomy in stage I lung adenocarcinoma with tumor spread through air spaces.
Lobectomy is associated with better outcomes than sublobar resection in spread through air spaces (STAS)-positive T1 lung adenocarcinoma: A propensity score-matched analysis.
American College of Chest Physicians and Society of Thoracic Surgeons consensus statement for evaluation and management for high-risk patients with stage I non-small cell lung cancer.
Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a meta-analysis of six randomized controlled trials.
Read at the AATS 101st Annual Meeting: A Virtual Learning Experience, April 30-May 2, 2021.
Funding: This study did not receive any specific funding.
Institutional Review Board Approval: This retrospective study was approved by the Institutional Review Board of Kagawa University (approval number: 2020-090, approval date: September 1, 2020).
Informed Consent Statement: Written informed consent was obtained from all participants.
Conflicts of Interest: The authors report no conflicts of interest.
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