Impact of segmentectomy on treatment for secondary malignancies and other causes of death after lung cancer surgery.

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Central Message

Segmentectomy was associated with a lower rate of other deaths compared with lobectomy and may be considered when weighing the risks of such deaths against potential curative outcomes.

Perspective

The JCOG0802 trial showed segmentectomy was superior to lobectomy in terms of OS, despite a higher recurrence rate. Our study revealed that other deaths impacted long-term survival, and segmentectomy was associated with a lower rate of such deaths. This underscores the importance of balancing the risk of other deaths with the potential for curative outcomes when considering segmentectomy.

Two randomized controlled trials, the JCOG0802 trial and the CALGB 140503 trial, demonstrated that limited resection for small-sized non–small cell lung cancer in the periphery was noninferior to lobectomy. 1 , 2 Furthermore, the JCOG0802 trial demonstrated that segmentectomy was superior to lobectomy in overall survival (OS), despite a higher local recurrence rate. Notably, deaths not associated with primary lung cancer accounted for 56.0% of all deaths in the JCOG0802 trial, with a similar rate of 58.5% reported in a retrospective study. 3 These findings highlight the significant impact of deaths not associated with primary lung cancer on survival and underscore the importance of addressing these factors to improve prognosis after curative lung cancer resection. Chronic obstructive pulmonary disease, heart failure, and advanced age have been identified as risk factors for deaths not associated with primary lung cancer. 3 , 4 The JCOG0802 trial suggests that the choice of surgical procedure may influence the incidence of such deaths.

The incidence of secondary malignancies in the JCOG0802 trial was 15.6%, and the incidence of second primary lung cancer in the CALGB140503 trial was 15.9%. 1 , 5 Furthermore, the JCOG0802 trial found that segmentectomy was associated with a lower mortality rate from secondary malignancies compared with lobectomy, despite both groups having similar incidences of secondary malignancies. Per these findings, differences in management of secondary malignancies may influence long-term survival. Provision of guideline-concordant treatment for malignancies is strongly recommended to improve OS. 6 Further investigation into the rate of guideline-concordant treatment for secondary malignancies after lung cancer surgery could help clarify the reasons behind the differences in mortality between surgical procedures, which remain unexplained in the JCOG0802 trial.

We hypothesized that segmentectomy would be associated with a higher rate of guideline-concordant treatment for secondary malignancies, resulting in reduced deaths not associated with primary lung cancer. This study aims to examine the impact of segmentectomy on these outcomes after lung cancer surgery by comparing the incidence of deaths not associated with primary lung cancer, the incidence of secondary malignancies, and the rate of guideline-concordant treatment for secondary malignancies between segmentectomy and lobectomy groups.

Material and Methods

Study Design and Population

This was a retrospective, single-center study. We reviewed medical records and the department's database to analyze patients' backgrounds, surgical details, radiological diagnosis, and pathology. This study was conducted following the Declaration of Helsinki and Japan's Ethical Guidelines for Epidemiological Research. It was approved by the Ethical Review Board of the National Cancer Center Japan (Approval No. 2018-045, approval date: May 25, 2018). Because the study was retrospective and did not involve interventions or invasive procedures, written consent was waived.

The study included patients who had tumors measuring 3 cm or less on preoperative computed tomography images and staged cN0M0 who underwent lobectomy or segmentectomy between January 2013 and December 2016. Patients with (1) histological types of carcinoid or large cell neuroendocrine carcinoma, (2) a history of lung cancer, (3) incomplete resection, (4) simultaneous bilateral thoracic surgery, and (5) no preoperative pulmonary function test results were excluded ( Figure 1 ).

Patients were divided into 2 groups: lobectomy and segmentectomy groups. Treatment plans were determined in a multidisciplinary conference. During the study period, segmentectomy was indicated when the tumor size was 3 cm or less in diameter and the consolidation/tumor ratio was 50% or less, based on the JCOG1211 criteria 7 or if the patient had limited cardiovascular function and could not tolerate lobectomy ( Video 1 ).

Patients who had never smoked cigarettes were designated as “never smokers,” whereas those who had ceased smoking at least 1 year before surgery were classified as “former smokers.” The clinical stage was determined in accordance with the Union for International Cancer Control 8th edition, 8 whereas the pathological stage was determined in accordance with the 4th edition of the World Health Organization classification. 9 The presence of comorbidities before surgery was evaluated using the Charlson Comorbidity Index (CCI), which was classified as CCI = 0, CCI = 1-2, CCI = 3-4, and CCI 5 or greater, in accordance with previous reports. 10

Definition of Cause of Death

Death not associated with primary lung cancer was defined as those due to causes unrelated to the original lung cancer and categorized into other malignancy or nonmalignancy deaths. Other malignancy deaths included deaths from cancers other than the original lung cancer, including secondary primary lung cancer. Nonmalignancy deaths included causes unrelated to malignancy, including unexpected sudden deaths in patients with no evidence of recurrence.

Definitions of Secondary Malignancy and Guideline-Concordant Treatment

Secondary malignancy was defined as any malignancy diagnosed after lung cancer surgery. Only the first malignancy after surgery was included in the study for patients with more than 1 malignancy. Second primary lung cancer and lung cancer recurrences were identified based on the American College of Chest Physicians guidelines ( Appendix E1 ). 11 We determined the frequency of guideline-concordant treatment for patients who developed secondary malignancies after lung cancer surgery. Guideline-concordant treatment was defined as standard treatments recommended by the National Comprehensive Cancer Network Guidelines ( Appendix E1 ). 12 Patients with insufficient information regarding their treatment for secondary malignancy were excluded from the analysis related to secondary malignancies.

End Points

The primary end point of this study is deaths not associated with primary lung cancer, and secondary end points are other malignancy deaths, nonmalignancy deaths, incidence of secondary malignancies, and guideline-concordant treatment for secondary malignancies. These items were compared between the lobectomy group and the segmentectomy group.

Statistical Analysis

Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as medians and interquartile ranges. OS was defined as the time from the surgery date to the time of death. Patients who were alive at the last visit were censored. The differences in survival between the lobectomy and segmentectomy groups were compared using the log-rank test. Because lung cancer deaths and deaths not associated with primary lung cancer were competing events, a competing risk analysis was conducted, and annual incidence rates were estimated using the cumulative incidence function. Gray's test was used to compare the cumulative incidence of deaths between the lobectomy and the segmentectomy groups. To adjust for selection bias and confounding factors between the lobectomy and the segmentectomy groups, a 2:1 propensity score matching (PSM) was conducted using the greedy nearest-neighbor matching method, with a caliper value set to 0.2 times the SD of the propensity score logit. The covariates for PSM were age, sex, smoking history, body mass index, predicted forced vital capacity, predicted forced expiratory volume in 1 second, CCI, and history of malignancy. Standard mean differences were calculated before and after PSM to evaluate group balance.

The Fine-Gray regression model was used for multivariable analysis, with age, sex, smoking history, body mass index, CCI, and previous malignancies as independent variables and deaths not associated with primary lung cancer as the dependent variable. Statistical analyses were performed using EZR version 1.66 (Saitama Medical Center, Jichi Medical University, Saitama, Japan).

Results

Baseline Characteristics

A total of 999 patients (758 in the lobectomy group and 241 in the segmentectomy group) were included in the analysis. Patient characteristics are summarized in Table 1 . Compared with the lobectomy group, the segmentectomy group had a higher proportion of patients with early-stage disease, adenocarcinoma, and a history of malignancy. Other baseline characteristics were similar between the 2 groups.

Cause of Death According to Surgical Procedure

The median postoperative follow-up period was 5.6 years, ranging from 0.1 to 8.7 years. The 5-year OS for all cases was 90.7% (95% CI, 88.7-92.4), and those for the lobectomy and segmentectomy groups were 89.0% (95% CI, 86.4-91.1) and 96.2% (95% CI, 92.7-98.0), respectively ( Figure E1 , A and B ). A total of 127 patients experienced lung cancer recurrence.

Details of the causes of death are presented in Table 2 . Of the 122 deaths, 51 (41.8%, 51/122) were deaths not associated with primary lung cancer, including 28 deaths from nonmalignancy causes and 23 from other malignancies. The incidence of deaths not associated with primary lung cancer was higher in the lobectomy group compared with the segmentectomy group (5.9%, 45/758 vs 2.5%, 6/241). The 5-year cumulative incidence rates of deaths not associated with primary lung cancer were 4.2% (95% CI, 2.9-5.9) and 1.7% (95% CI, 0.6-4.1) in the lobectomy and segmentectomy groups, respectively ( Figure 2 , A ).

Incidence of Deaths Not Associated With Primary Lung Cancer After Propensity Score Matching

After PSM, 466 and 233 patients remained in the lobectomy and segmentectomy groups, respectively. The standard mean differences for all variables included in the PSM were less than 0.1, indicating a satisfactory balance between the 2 groups ( Table 1 ). The 5-year cumulative incidence rates of deaths not associated with primary lung cancer were 4.8% (95% CI, 3.0-7.1) and 1.3% (95% CI, 0.4-3.6) in the lobectomy and segmentectomy groups, respectively ( Figure 2 , B ).

Subgroup Analysis in Patients With Tumors Measuring 2 cm or Less

In the subgroup analysis conducted in patients with tumors measuring 2 cm or less, 307 and 107 patients were included in the lobectomy and segmentectomy groups, respectively. The 5-year cumulative incidence of deaths not associated with primary lung cancer was 3.8% (95% CI, 2.0-6.5) in the lobectomy group and 1.2% (95% CI, 0.2-3.9) in the segmentectomy group, as shown in Figure 2 , C .

Multivariable Analysis of the Cause of Deaths Not Associated With Primary Lung Cancer

Table 3 demonstrates the results of multivariable analysis regarding the cumulative incidence of deaths not associated with primary lung cancer in all cases. Segmentectomy was associated with a lower risk of deaths not associated with primary lung cancer than lobectomy (hazard ratio [HR], 0.32, 95% CI, 0.13-0.79). Conversely, increasing age (HR, 1.07, 95% CI, 1.04-1.11), male sex (HR, 2.51, 95% CI, 1.11-5.67), and CCI of 5 or higher (HR, 7.31, 95% CI, 1.01-53.0) were associated with a higher risk of deaths not associated with primary lung cancer.

Secondary Malignancy After Lung Cancer Surgery

A total of 141 patients (14.1%, 141/999) developed secondary malignancies, including 71 cases of second primary lung cancer ( Table E1 ). Fifteen patients in the lobectomy group and 4 patients in the segmentectomy group had 2 or more secondary malignancies. In the lobectomy group, 112 patients (14.8%) developed secondary malignancies, and 20 patients (2.6%) died because of these malignancies. In the segmentectomy group, 29 patients (12.0%) developed secondary malignancies, and 3 patients (1.2%) died as the result of them. The incidence of secondary malignancies was similar between the 2 groups.

Rate of Guideline-Concordant Treatment for Secondary Malignancies

Table 4 presents treatment details for secondary malignancies. Seven patients in the lobectomy group and 1 patient in the segmentectomy group were excluded from the analysis because of treatment received at outside institutions with unknown details. Of the remaining 133 patients with known treatment plans for their secondary malignancies, 87 patients (65.4%) received guideline-concordant treatment. The rates of patients who received guideline-concordant treatment for secondary malignancies were 63.8% in the lobectomy group and 71.4% in the segmentectomy group. For second primary lung cancer, the rates were 47.3% in the lobectomy group and 57.1% in the segmentectomy group. For secondary malignancies other than lung cancer, the rates were 82.0% in the lobectomy group and 85.7% in the segmentectomy group. These findings indicate that second primary lung cancer was treated with guideline-concordant treatment less frequently than other secondary malignancies.

Discussion

This study demonstrates that segmentectomy was associated with a lower incidence of deaths not associated with primary lung cancer compared with lobectomy. When categorized further, both nonmalignancy- and malignancy-related deaths were lower in the segmentectomy group than in the lobectomy group. The incidence of secondary malignancies was similar between the 2 groups. However, the rate of patients who received guideline-concordant treatment for secondary malignancies was higher in the segmentectomy group.

In our study, the 5-year OS for all cases was 90.7%, and lung cancer-specific deaths accounted for 7% (71/999). These findings suggest that curative resection was achieved in a substantial proportion of patients after surgery for early-stage lung cancer. In contrast, our study found that deaths not associated with primary lung cancer accounted for 41.8% of all postoperative deaths, highlighting their substantial impact on survival after curative resection of early-stage non–small cell lung cancer, as previously reported. 1 , 3 , 4 Therefore, as curative outcomes are achieved in many cases of early-stage lung cancer, treatment decisions should factor in not only the risk of primary lung cancer recurrence but also deaths not associated with primary lung cancer.

Our study showed that 14.1% of patients developed secondary malignancies, highlighting the importance of addressing secondary malignancies in clinical practice after lung cancer surgery. The rate of patients who received guideline-concordant treatment for secondary malignancies was higher in the segmentectomy group than in the lobectomy group. This may have contributed to the lower rate of other malignancy deaths in the segmentectomy group, because offering guideline-concordant treatment is highly recommended to improve survival in cancer patients. 6 The difference in the rate of guideline-concordant treatment between the groups was larger (9.8%) for second primary lung cancer. Patients who had undergone lobectomy more frequently chose lesser resection or radiotherapy as alternative treatments for second primary lung cancer. However, other factors might affect the prognosis of secondary malignancy in addition to guideline-concordant treatment examined in this study. Further investigation is necessary to explain the lower rate of secondary malignancy death in the segmentectomy group.

Nonmalignancy deaths were more frequent in the lobectomy group than in the segmentectomy group, with respiratory disease being the most common cause of nonmalignancy death in the lobectomy group. Our findings suggest that lobectomy is associated with a higher incidence of respiratory disease-related deaths compared with segmentectomy, consistent with previous reports. 13 Although the difference in the median reduction of forced expiratory volume in 1 second between the lobectomy and segmentectomy groups after 1 year was modest (3.5%) in the JCOG0802 trial, the smaller loss of lung parenchyma in the segmentectomy group may have contributed to the beneficial effect on respiratory disease–related death. Further investigation is warranted to elucidate the long-term changes in respiratory and cardiopulmonary function, including cardiac function and pulmonary vascular resistance, that may explain the differences in survival between the groups.

Limitations

This study has several limitations that should be acknowledged. First, it was a retrospective, single-center analysis, and although we used PSM to minimize selection bias, residual confounding factors could not be entirely excluded. In particular, tumor location was not included as a matching variable because of the limited number of patients, which may have affected the comparability between groups. Second, postoperative pulmonary function tests were not routinely performed, and such data were unavailable for most patients; consequently, the relationship between postoperative respiratory function and nonmalignancy deaths could not be evaluated. Third, the number of events in the segmentectomy group, including deaths not associated with primary lung cancer and secondary malignancies, was relatively small. Therefore, caution is warranted when interpreting the findings regarding nonmalignancy deaths and guideline-concordant treatment of secondary malignancies. In addition, although only 2.2% of the patients were censored within 1 year postoperatively, the inclusion of patients with extremely short follow-up periods may limit the robustness of the long-term outcome assessment. Furthermore, the NCCN guidelines used to evaluate the standard treatment for secondary malignancies in this study may differ from the guidelines at the time of treatment. Moreover, the analysis regarding secondary malignancy treatment in this study included only the first malignancies that occurred after lung cancer surgery. Because patients with lung cancer may experience multiple malignancies, other malignancies that were not included in the analysis may have influenced survival outcomes. More prospective studies with larger cohorts should be conducted in the future to validate and expand on our findings.

Conclusions

Segmentectomy was associated with a lower incidence of deaths not associated with primary lung cancer than lobectomy. The higher rate of guideline-concordant treatment for secondary malignancies in the segmentectomy group may partially explain its lower mortality from secondary malignancies. Our study suggests that careful patient selection for segmentectomy is essential, balancing the reduction in other deaths not associated with primary lung cancer with the potential for curative outcomes.

Conflict of Interest Statement

The authors reported no conflicts of interest.

The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Footnotes

Date and number of Institutional Review Board approval: May 25, 2018; No. 2018-045.

Informed Consent Statement: The requirement for informed consent was waived because of the retrospective nature of the study.

Appendix. E1Supplementary Text

Definition of Second Primary Lung Cancer

This study defined second primary lung cancer and pulmonary metastasis based on modified criteria from the American College of Chest Physicians guidelines, supplemented by a multidisciplinary conference discussion. Specifically, second primary lung cancer was defined as a lesion whose histology differed from that of the initial primary lung cancer or a lesion with the same histology that developed at least 4 years after the initial treatment. Pulmonary metastasis was defined as a lesion with the same histology that developed within 2 years. Lesions appearing between 2 and 4 years post-treatment were evaluated based on imaging findings and pathological analyses, including morphological and immunohistochemical evaluation.

Definition of Guideline-Concordant Treatment for Secondary Malignancies

Guideline-concordant treatment was defined as treatment consistent with the standard recommendations of the National Comprehensive Cancer Network Guidelines, the most recent version available as of July 24, 2022.

For cases of second primary lung cancer, sublobar resection was considered guideline-concordant only when performed for peripheral nodules measuring 2 cm or less located in the outer third of the lung parenchyma, fulfilling at least 1 of the following criteria: (1) pure adenocarcinoma in situ; (2) a consolidation-to-tumor ratio of ≤0.5; or (3) a long tumor doubling time (≥400 days) observed on radiographic surveillance.

Radiation therapy for unresectable secondary lung cancer was considered guideline-concordant only when used as definitive treatment in patients who were considered medically unresectable.

Supplementary Data

Video 1

Representative right S 10 segmentectomy performed at our hospital. Video available at: https://www.jtcvs.org/article/S2666-2736(25)00229-3/fulltext .

References

1. Saji H., Okada M., Tsuboi M., et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet. 2022;399(10335):1607–1617. doi: 10.1016/S0140-6736(21)02333-3.

2. Altorki N., Wang X., Kozono D., et al. Lobar or sublobar resection for peripheral stage IA non-small-cell lung cancer. N Engl J Med. 2023;388(6):489–498. doi: 10.1056/NEJMoa2212083.

3. Eguchi T., Bains S., Lee M.C., et al. Impact of increasing age on cause-specific mortality and morbidity in patients with stage I non-small-cell lung cancer: a competing risks analysis. J Clin Oncol. 2017;35(3):281–290. doi: 10.1200/JCO.2016.69.0834.

4. Sekine Y., Behnia M., Fujisawa T. Impact of COPD on pulmonary complications and on long-term survival of patients undergoing surgery for NSCLC. Lung Cancer. 2002;37(1):95–101. doi: 10.1016/s0169-5002(02)00014-4.

5. Stinchcombe T.E., Wang X., Damman B., et al. Secondary analysis of the rate of second primary lung cancer from cancer and leukemia group B 140503 (alliance) trial of lobar versus sublobar resection for T1aN0 non-small-cell lung cancer. J Clin Oncol. 2024;42(10):1110–1113. doi: 10.1200/JCO.23.01306.

6. Farrow N.E., An S.J., Speicher P.J., et al. Disparities in guideline-concordant treatment for node-positive, non-small cell lung cancer following surgery. J Thorac Cardiovasc Surg. 2020;160(1):261–271. doi: 10.1016/j.jtcvs.2019.10.102.

7. Aokage K., Suzuki K., Saji H., et al. Segmentectomy for ground-glass-dominant lung cancer with a tumour diameter of 3 cm or less including ground-glass opacity (JCOG1211): a multicentre, single-arm, confirmatory, phase 3 trial. Lancet Respir Med. 2023;11(6):540–549. doi: 10.1016/S2213-2600(23)00041-3.

8. Brierley J.D., Gospodarowicz M.K., Wittekind C., editors. The TNM Classification of Malignant Tumours. Wiley-Blackwell; 2017.

9. Travis W.D., Brambilla E., Burke A.P., Marx A., Nicholson A.G. International Agency for Research on Cancer; 2015. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.

10. Birim O., Kappetein A.P., Waleboer M., et al. Long-term survival after non-small cell lung cancer surgery: development and validation of a prognostic model with a preoperative and postoperative mode. J Thorac Cardiovasc Surg. 2006;132(3):491–498. doi: 10.1016/j.jtcvs.2006.04.010.

11. Kozower B.D., Larner J.M., Detterbeck F.C., Jones D.R. Special treatment issues in non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e369S–e399S. doi: 10.1378/chest.12-2362.

12. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/category_1

13. Isaka T., Ito H., Yokose T., et al. Impact of segmentectomy and lobectomy on non-lung cancer death in early-stage lung cancer patients. Eur J Cardiothorac Surg. 2022;63(1):ezac458. doi: 10.1093/ejcts/ezac458.

Associated Data

Supplementary Materials

Video 1

Representative right S 10 segmentectomy performed at our hospital. Video available at: https://www.jtcvs.org/article/S2666-2736(25)00229-3/fulltext .