Second primary lung cancer and treatment strategy after lobectomy vs. segmentectomy for first primary lung cancer

Introduction

Over the last few years, two large randomized controlled trials (RCTs) from Japan and the United States have shown the non-inferiority of segmentectomy compared to lobectomy for early-stage non-small cell lung cancer (NSCLC) (1,2). Segmentectomy has become the new standard for peripherally located small (≤2 cm) NSCLC, and its use is expected to expand. One proposed advantage is better preservation of pulmonary function; however, its clinical relevance remains uncertain. The difference in forced expiratory volume in 1 second (FEV₁)% change at 6 months between lobectomy and segmentectomy was modest in both of the trials; 2.0% in CALGB 140503 and 2.7% in JCOG 0802 (1,2).

Differences in pulmonary function may influence future treatment strategies for second primary lung cancer (SPLC). SPLC is a common issue after lung resection for NSCLC, and its incidence was reported as high as 2.71 per 100 patient-years in active smokers (3). The challenges in surveillance, diagnosis, and management of SPLC have been previously described (4), underscoring the need for tailored strategies. Due to the recent adoption of segmentectomy, the benefits of lung preservation in this setting are not yet fully understood. This study analyzes the incidence of SPLC and compares subsequent management following lobectomy versus segmentectomy for first primary lung cancer (FPLC), using data from a single center with long-term experience in segmentectomy. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1360/rc).

Methods

Patients

We conducted a single-institution, retrospective study comparing patients who underwent lobectomy vs. segmentectomy for clinical T1N0M0 NSCLC between 2013 and 2022. Among those with FPLC, patients diagnosed with SPLC were included. The distinction between SPLC and recurrence was based on comprehensive clinical judgment of the treating oncologists. SPLC was defined as tumors that exhibited a clear distinction in pathology or molecular profile by tissue sampling or, in the absence of these, were viewed and treated clinically as SPLC by the treating oncologists, distinct from recurrence. Classification was primarily based on the Martini and Melamed system (5), which is widely used in both clinical practice and research. According to this framework, tumors were considered SPLC if they were of a different histological type than the index tumor, of the same histological type but diagnosed at least 2 years later, or of the same histological type diagnosed within two years but located in a different lobe or lung without shared lymphatic spread or evidence of extrapulmonary metastasis. In addition, molecular profiling (including TP53, KRAS, and EGFR analysis) was also incorporated to support clinical judgment, as discordant driver mutations provide strong evidence for independent primaries, while concordant alterations require more cautious interpretation (4). For patients lacking histological confirmation, the distinction between SPLC and recurrence was made in a multidisciplinary conference, with careful consideration of clinical, radiographic, and temporal factors. For FPLC, patients undergoing wedge resection, bi-lobectomy, or pneumonectomy were excluded. Patients who received neoadjuvant treatment, exhibited carcinoid or small cell carcinoma histology, had benign disease, or synchronous tumors were also excluded (see Figure S1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Approval for this study was obtained from the Institutional Review Board of the University of Pittsburgh (No. STUDY20050076), which waived the requirement for individual patient consent due to the study’s retrospective nature.

All patients underwent preoperative imaging [computed tomography (CT) scan and/or positron emission tomography (PET)/CT]. Clinical stage was obtained with a combination of preoperative imaging and staging procedures. All patients with suspected nodal disease underwent preoperative nodal staging in the form of endobronchial ultrasound fine-needle aspiration or mediastinoscopy before resection. Anatomic segmentectomy was accomplished by the removal of one or more pulmonary segments with the goal of an R0 resection. This was accomplished by the individual isolation and division of at least two segmental bronchial and vascular structures. After resection, patients were followed according to the National Comprehensive Cancer Network (NCCN) guideline recommendations, with some modifications based on the treating surgeon’s discretion especially beyond 5 years after the operation.

Outcomes

Primary outcomes included the treatment modality for SPLC and overall survival following the initial surgery for FPLC and the diagnosis of SPLC, stratified by lobectomy and segmentectomy groups. The cumulative incidence of SPLC in the entire FPLC cohort was compared by smoking status at the time of FPLC surgery (non-smoker, past smoker, current smoker). Changes in pulmonary function [FEV₁% and diffusing capacity of the lung for carbon monoxide (DLCO)%] between FPLC and SPLC preoperative evaluations were also assessed and compared between the lobectomy and segmentectomy groups.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics version 29 (SPSS, Inc., Chicago, IL, USA), and R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria) was used for data visualization. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate. Continuous variables were compared using the Wilcoxon rank-sum test. Kaplan-Meier method was used to estimate overall survival and the incidence of SPLC, with the log-rank test used for group comparisons.

Results

During the study period, 1,363 patients underwent either lobectomy (954 patients) or segmentectomy (409 patients) for their first stage IA NSCLC. There was no difference in the overall survival between the lobectomy and segmentectomy groups (median 106.6 vs. 104.7 months; P=0.47; Figure S2). Over a median follow-up of 90.5 months with reverse Kaplan-Meier method, SPLC was diagnosed in 99 lobectomy patients and 51 segmentectomy patients (150 patients overall, 11.0%). The median interval between the surgery for FPLC and the diagnosis of SPLC was 37.0 months. The 5-year cumulative SPLC incidence varied by smoking status (3.9% non-smokers, 11.1% past smokers, 17.9% current smokers, P=0.003; Figure 1). In addition, univariable analysis identified squamous cell carcinoma histology as a risk factor for SPLC (P<0.001), while age, sex, tumor size, node (N) stage, and segmentectomy vs. lobectomy were not. Multivariable analysis showed that squamous cell carcinoma histology [hazard ratio (HR) =1.77, P=0.002] and current smoking (HR =2.57, P=0.02) were associated with increased risk of SPLC, while past smoking showed a non-significant trend (HR =1.82, P=0.11).

Figure 1 Cumulative incidence of SPLC after surgery for FPLC, stratified by smoking status at the time of FPLC surgery. The 5-year cumulative incidence was highest in current smokers (red), followed by past smokers (yellow) and non-smokers (blue) (P=0.003). Shaded areas represent 95% confidence intervals. FPLC, first primary lung cancer; SPLC, second primary lung cancer.

Among the 150 patients who developed SPLC, the median age at FPLC was 69 years, and 87 (58.0%) were female. Table 1 summarizes the clinical backgrounds of FPLC for those who developed SPLC. The patients in the segmentectomy group tended to be older than the lobectomy group, but the difference was not statistically significant (71 vs. 67 years old; P=0.056). There was no significant difference in smoking status or pulmonary function test results, including FEV₁% and DLCO%. Tumor sizes were smaller in the segmentectomy group both clinically and pathologically (both 1.8 vs. 2.0 cm; P=0.009 and 0.02 respectively), which resulted in a higher clinical and pathological T stage (P=0.043 and 0.003 respectively). On the other hand, there was no difference in pathological N stage (P=0.70), which resulted in a similar distribution of pathological stage between the groups (P=0.55). Details of the anatomic resection are summarized in Table 2. All procedures were started in a minimally invasive approach, while 7 patients (7.1%) in the lobectomy group experienced a conversion to open.

The characteristics of SPLC are summarized in Table 3. There were no significant differences in age or pulmonary function test results at the time of SPLC diagnosis. SPLC developed on the same side as FPLC in 33% of patients in both groups. The histologic subtype was similar (P=0.85), with NSCLC comprising 74 cases (74.7%) in the lobectomy group and 40 cases (78.4%) in the segmentectomy group. Twenty-five patients (16.7%) did not have tissue diagnosis, and most of them were treated with ablative therapy (20 patients; 80%). Of note, the median interval from FPLC to SPLC was longer in this population (44.7 months). Clinical stage distribution was also comparable (P=0.79), with stage I disease in 74 patients (74.7%) and 40 patients (78.4%) in the lobectomy and segmentectomy groups, respectively. Heterogeneity in histologic subtype and staging contributed to differences in treatment selection; however, the distribution of treatment modalities remained similar between the lobectomy and segmentectomy groups. Surgical resection for SPLC was performed in 41 patients in the lobectomy group and 25 in the segmentectomy group (41.4% vs. 49.0%, P=0.39). Among those resected, anatomic resection was performed less frequently in the lobectomy group compared to the segmentectomy group (53.7% vs. 88.0%, P=0.006).

Pulmonary function test for SPLC was performed in 109 patients (72.7%), while DLCO was available in 98 patients (65.3%). As shown in Figure 2, the changes in pulmonary function between the FPLC and SPLC workups did not differ statistically between the lobectomy and segmentectomy groups (median; FEV₁%: −4.5% vs. −5.0%, P=0.56; DLCO%: −7.0% vs. −5.5%, P=0.29). A limited number of the patients underwent pulmonary function tests after treatment for SPLC. There was no statistically significant difference in median FEV₁% (n=30; −7.0% vs. +4.0% P=0.19) and DLCO% (n=25; −13.0% vs. 0%, P=0.07) between surgical resection and SBRT/ablation for SPLC.

Figure 2 Violin plots showing the distribution of changes in pulmonary function between the workup for FPLC and SPLC, stratified by initial surgical procedure (lobectomy: red, segmentectomy: blue). (A) Change in percent predicted FEV₁ (n=109). (B) Change in percent predicted DLCO (n=98). Each plot displays the median (dot), interquartile range (box), and data distribution (violin shape). Whiskers represent the range within 1.5 times the interquartile range from the first and third quartiles. DLCO, diffusing capacity of the lung for carbon monoxide; FEV₁, forced expiratory volume in 1 second; FPLC, first primary lung cancer; SPLC, second primary lung cancer.

There was no significant difference in the 5-year overall survival between groups, either from the surgery for FPLC (83.2% vs. 84.3%; P=0.87; Figure 3A) or diagnosis of SPLC (48.0% vs. 56.1%; P=0.47; Figure 3B). Among the 82 patients with stage IA NSCLC as SPLC, overall survival from the diagnosis of SPLC did not differ between those treated with surgical resection and those treated with SBRT/ablation (P=0.99; Figure S3).

Figure 3 Kaplan-Meier overall survival curves for patients who developed SPLC, stratified by the initial surgical approach for FPLC. (A) Overall survival from the time of FPLC surgery comparing lobectomy and segmentectomy groups. (B) Overall survival from the time of SPLC diagnosis, again stratified by initial surgical approach for FPLC. Shaded areas indicate 95% confidence intervals. No statistically significant survival differences were observed between groups in either analysis. FPLC, first primary lung cancer; SPLC, second primary lung cancer.

Discussion

In this retrospective study of patients who developed SPLC after surgery for stage IA NSCLC, the incidence of SPLC was non-negligible, particularly among smokers. Changes in pulmonary function between FPLC and SPLC were small and comparable between lobectomy and segmentectomy groups; however, the initial surgical approach influenced subsequent management- patients who had segmentectomy for FPLC were more likely to undergo anatomic resection for SPLC. Although no clear survival benefit with surgery for SPLC was observed, the segmentectomy group showed a trend toward longer overall survival, suggesting potential long-term advantages of parenchyma-sparing surgery for FPLC. Reflecting our early adoption of intentional segmentectomy for early-stage NSCLC (6), there was no significant difference in patient background or pulmonary function between lobectomy and segmentectomy groups.

The high incidence of SPLC has long been recognized. A study from Memorial Sloan Kettering, evaluating patients with stage I NSCLC between 1973 and 1985, reported an SPLC rate of over 10% (70/598) (5). In 2003, a sub-analysis of a prospective multicenter trial confirmed similar findings and highlighted the influence of smoking: the incidence of SPLC was 1.77 per 100 patient-years in former smokers and 2.71 in current smokers, with no cases observed in never smokers (3). Most recently, an analysis of a large population-based cohort, including 7059 patients with FPLC, demonstrated that both cumulative tobacco exposure (HR =1.18 per 10 pack-years, P<0.001) and smoking intensity (HR =1.30 per 10 cigarettes/day, P<0.001) were associated with increased SPLC risk (7). Notably, smoking cessation after FPLC was linked to a significant reduction in risk (HR =0.17; P<0.001).

The median interval from FPLC to SPLC was 51 and 46 months in the latter two studies, respectively (3,7). Also, updated data from Memorial Sloan Kettering showed that the risk of SPLC remains 3–6% per person-year without decline over time (8). Our cohort showed a comparable median interval of 37 months, reinforcing the observation that SPLC commonly arises more than 3 years after initial resection and not rarely beyond 5 years. Taken together, these findings underscore the need for prolonged surveillance, possibly beyond 5 years, particularly among smokers. Clinicians should counsel patients on the long-term risk of SPLC and the importance of ongoing follow-up and smoking cessation, even after curative resection of FPLC.

Our cohort showed only modest changes in pulmonary function following initial resection, regardless of the extent of surgery. Moreover, the difference between lobectomy and segmentectomy was minimal (FEV₁%: −0.5%; DLCO%: −1.5%), even smaller than the differences reported in the two RCTs (1,2). One potential explanation is high proportion of left upper division segmentectomies (37.3%), which is technically equivalent to right upper lobe resection. Prior studies have shown greater declines in pulmonary function following segmentectomy involving two or more segments (9), particularly with left upper division resections (10). That said, upper division resection remains a reasonable strategy to preserve the lingula and continues to be one of the most commonly performed segmentectomies (11). Of note, pulmonary function data for SPLC were missing in approximately 30% of patients; this missingness may reflect underlying functional status and could have introduced bias in comparisons between lobectomy and segmentectomy groups.

Despite minimal differences in pulmonary function in our cohort, we observed a small difference in SPLC management between groups. A notable finding in the segmentectomy group was the high rate of lobectomy or bi-lobectomy (52%) among resections for SPLC. Surgical decision-making often extends beyond pulmonary function alone and incorporates factors such as overall functional status, tumor location, laterality, and stage. In our cohort, the laterality of SPLC relative to the initial FPLC was similar between groups (contralateral in 66.7%), as was the clinical stage. Despite minimal differences in pulmonary function, there may be hesitation to perform a second lobectomy in patients with prior lobectomy, as it could effectively result in a “functional pneumonectomy” unless the middle lobe is involved. Redo surgery for lung cancer is an emerging issue due to overall improvements in survival after initial treatment. Several reports have demonstrated the feasibility of such approaches (12,13), including middle lobe-preserving serial right upper and lower lobectomies (14,15). In this context, incorporation of segmentectomy represents a reasonable strategy to maximize lung preservation. Although our series does not provide objective data to identify the precise reasons, segmentectomy for FPLC may help preserve options for subsequent SPLC management.

There is a recent report with a similar concept with our study using Surveillance Epidemiology End Results (SEER) database in 2024, which analyzed SPLC treatment patterns after segmentectomy (n=127) or lobectomy (n=1,530) for stage IA NSCLC (16). In this study, no significant difference in treatment approach was observed in the propensity-matched analysis, although the segmentectomy group tended to undergo surgery more frequently (54.7% vs. 46.2%; P=0.22). Among those resected, lobectomy for SPLC was more common after initial lobectomy (42.0% vs. 31.8%), while anatomic resection overall was more frequent after segmentectomy (65.1% vs. 57.7%). Importantly, this study included patients treated between 2004 and 2017, prior to the segmentectomy RCTs, and likely reflects selective use in higher-risk patients. The absence of pulmonary function data also limits interpretation. While the SEER study captured national trends in a large cohort, our data add physiologic and operative detail, enabling more meaningful comparisons. However, our survival analyses may have been underpowered due to the limited number of events. A post hoc exploratory analysis using Schoenfeld’s method showed that with 55 deaths, the study had 80% power to detect HRs of ≥2.22, suggesting smaller survival differences may have been missed.

There are limited survival data specific to the SPLC population. The SEER analysis demonstrated no significant differences in overall survival between patients who developed SPLC after undergoing lobectomy versus segmentectomy for FPLC, both in unmatched (5-year survival 42.7% vs. 51.1%; P=0.31) and matched analysis (38.6% vs. 36.6%), with a slight trend favoring the lobectomy group (16). However, as the study cohort primarily reflected an era when segmentectomy was reserved for patients with limited pulmonary reserve. With the lack of pulmonary function data, propensity matching could not adjust for this critical factor. In contrast, our cohort had balanced baseline characteristics between groups. While there was no significant survival difference, we observed a modest trend favoring segmentectomy for FPLC. Although SBRT offers promising outcomes for early-stage NSCLC, surgery remains the standard of care, and segmentectomy may help preserve future treatment options. Taken together, segmentectomy may be a preferable approach in smokers, given the high prevalence of SPLC and the importance of preserving surgical reserve.

One of the main limitations of this study is the relatively small sample size. Although SPLC is not rare, it typically develops over time, with a median of 38 months in our cohort, which requires long-term consistent follow-up. Loss to follow up is not uncommon, and collecting high-quality data is a challenge, especially for segmentectomy, which has only recently become standard practice. Our institution has adopted segmentectomy for NSCLC since the early 2000s, and the presented data represents our detailed data with uniquely long follow-up in this population. It should be noted that the generalizability of our findings may be limited, as outcomes can be influenced by surgical volume and the learning curve. With the recent broader adoption of segmentectomy in the United States, additional time may be needed for many centers to mature in patient selection and technical expertise. The non-uniform criteria used to distinguish SPLC from recurrence is another limitation, although this mirrors the diagnostic uncertainty encountered in clinical practice (4). In our study, clinical classification was primarily based on the Martini and Melamed system (5), which has been utilized and validated in prior SPLC studies (3,17). While most SPLC diagnoses in our cohort were supported by differing histologic subtypes or molecular profiles, some relied on clinical judgment. Additionally, 16.7% of patients did not have tissue confirmation, which is not uncommon in practice, especially when SBRT is used for local control. This diagnostic uncertainty may introduce misclassification bias in cases without tissue or genetic confirmation, though the effect is unclear in this small population of the cohort.

Conclusions

The present study demonstrates a substantial incidence of SPLC following resection of stage IA NSCLC, particularly among smokers. Segmentectomy for FPLC was associated with a higher likelihood of subsequent anatomic resection for SPLC, reflecting preserved surgical options. Given the high rate of SPLC, segmentectomy may offer long-term advantages for smokers by maintaining treatment flexibility.

Acknowledgments

This paper was presented at the 105th Annual Meeting of the American Association for Thoracic Surgery, 2025.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1360/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1360/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1360/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1360/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 and its subsequent amendments. Approval for this study was obtained from the Institutional Review Board of the University of Pittsburgh (No. STUDY20050076), which waived the requirement for individual patient consent due to the study’s retrospective nature.

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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