Segmentectomy versus lobectomy for ground-glass opacity dominant cT1N0 invasive lung adenocarcinoma

Introduction

With the increasing using of computed tomography (CT) screening, ground glass opacity (GGO) lung adenocarcinoma has been more frequently detected (1,2). GGO has been recognized as a different subtype lung cancer from pure solid nodule for less invasiveness and excellent postoperative survival (3). Research has purposed that sublobar resection might be an acceptable procedure for early-stage GGOs, but there is still no consistent standard (4-6).

A recent study demonstrated that pure GGO lung adenocarcinoma had no recurrence in 10 years after surgery and could be cured by limited pulmonary resection (7). The Japan Clinical Oncology Group (JCOG) conducted a series of clinical trials to investigate the optimal mode of surgery for GGO dominant lung cancer. JCOG0804 research revealed that sublobar resection with enough surgical margin should be the first choice for GGO ≤2 cm or less in size with consolidation tumor ratio (CTR) ≤0.25 (8). The results of JCOG0802 trial recommended segmentectomy as the standard surgical procedure for lung tumor ≤2 cm with CTR >0.5 (9). JCOG1211 focused on the rest of population, patients with GGO between 2–3 cm with CTR ≤0.5 or ≤2 cm with CTR between 0.25–0.5, and the newly published results suggested that segmentectomy should be considered as standard treatment for these patients. However, JCOG1211 involved totally 346 patients including 88 adenocarcinoma in situ (AIS) patients and 117 minimally invasive adenocarcinoma (MIA) patients (10). Previous studies have demonstrated that AIS/MIA has excellent postoperative survival without recurrence and wedge resection is curative (11-15). In our clinic practice, there are some invasive adenocarcinomas featured as the radiological criteria of JCOG1211. It still remains an issue for whether segmentectomy is the optional surgical choice these patients.

This study excluded patients with AIS/MIA and reported the long-term follow-up for these patients with GGO featured cT1N0 invasive adenocarcinoma (2 cm < tumor diameter ≤3 cm, CTR ≤0.5 or tumor diameter ≤2 cm, 0.25< CTR ≤0.5) undergoing segmentectomy or lobectomy, aiming to clarify the precise procedure for this population of patients. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-191/rc).

Methods

Patients and clinicopathological characteristics

This study reviewed patients with completely resected primary cT1N0 (according to the eighth edition Tumor Node Metastasis classification) lung adenocarcinoma undergoing segmentectomy or lobectomy at the Department of Thoracic Surgery, Fudan University Shanghai Cancer Center from January 2010 to December 2020. Patients were involved only when the tumor radiologically featured as GGO in size between 2–3 cm with CTR ≤0.5 or ≤2 cm with CTR between 0.25–0.5. Pathologically diagnosed AIS/MIA were excluded. Patients who received neoadjuvant therapy, who had previous cancer history and who had multiple synchronous lung nodules were excluded. This study paid close attention to compare the survival outcomes of segmentectomy and lobectomy performing on GGO featured cT1N0 invasive adenocarcinoma.

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Institutional Review Board of the Fudan University Shanghai Cancer Center (No. IRB2008223-9). The requirement for informed consent was waived as it was a retrospective research. Age at diagnosis, gender, smoking status, pathological stages and histological subtypes according to the 2021 World Health Organization classification (16) were collected.

Procedure

For patients with cT1N0 GGO featured adenocarcinoma (tumor diameter≤3cm and CTR ≤0.5), segmentectomy was performed for nodules in the proper location, where sufficient margin distance and R0 resection were ensured. For both lobectomy and segmentectomy approaches, either systematic mediastinal lymph nodes dissection or selective dissection was accepted. Systematic mediastinal lymph node dissection was defined as complete removal of at least 3 mediastinal nodal stations. Selective mediastinal lymph node dissection was defined as no more than 2 mediastinal stations were performed. In general, stations 2R, 4R, 7, and 8 for right-located tumors and stations 5, 6, 7, and 8 for left-located tumors were removed as the standard resection (17-19). Selective dissection was generally preferred for the nodules with low CTR or intraoperative frozen section diagnosis of lepidic predominant adenocarcinoma. In this study, the surgical approach and the mode of lymph node dissection for each patient was documented by reviewing the surgery records and postoperative pathological reports.

Radiological evaluation

All patients received at least one CT scan at our hospital before surgery by a 64-slice multidetector scanner (Siemens Somatom Sensation, Germany). The parameters were as follows: pitch, 1.2; reconstruction section thickness and interval, 1.0 mm and 1.0 mm, respectively; field of view, 375 mm; voltage, 120 kV; and electric charge, 270 mAs. CTR was defined as the ratio of the maximum diameter of consolidation to the maximum radiological tumor diameter. Each CT scan was independently reviewed by two thoracic surgeons and two radiologists. Any discrepancies were reviewed by another experienced radiologist and were resolved by consensus. CTR was documented by the last CT scan before surgery. The allowed longest interval between the last CT scan and surgery was 1 month.

Follow-up strategy and outcomes

Patients were followed every 6 months for the first 3 years after the operation, every 8 months for the next 2 years, and every 12 months thereafter. Postoperative outcome information was recorded from the follow-up visits and supplemented by telephone. The last telephone follow-up for this cohort was finished at December 2022. Overall survival (OS) was defined as the time from the date of surgery to the date of death or last negative follow-up. Relapse-free survival (RFS) was defined as the time from the date of surgery to the date of first relapse or death or last negative follow-up. Local relapse was defined as cancer recurrence in the ipsilateral thorax, including the resection margin of the lung or bronchus, hilar lymph nodes, mediastinal lymph nodes, and malignant pleural effusion. Complications were evaluated following the Common Terminology Criteria for Adverse Events, version 5.0. Early postoperative complication was defined as complications occurring within 30 days after surgery.

Statistical analysis

R Statistical Language (version 3.6.1) were used to analyze the data. Clinicopathological characteristics were compared between groups by Pearson’s Chi-squared test or the Fisher exact test. Propensity score matching (PSM) with a 1:1 ratio was performed between patients of lobectomy group and segmentectomy group, and clinicopathological variables were matched using the nearest matching method with a caliper width of 0.1. OS and RFS were estimated by Kaplan-Meier method with log-rank test. All the tests were two-tailed with statistical significance set at P<0.05.

Results

Baseline and clinicopathological characteristics

In total, 617 patients were enrolled in this study, 159 received segmentectomy and 458 received lobectomy. The average age was 60.5±8.6 years in lobectomy group and 60.4±9.1 years in segmentectomy group (P=0.92). There were 152 (33.2%) male patients in lobectomy group and 56 (35.2%) in segmentectomy group (P=0.64). 98 (21.4%) lobectomy patients and 39 (24.5%) segmentectomy patients had ever smoked (P=0.41). The distributions of histological subtypes and locations showed no significant differences between two groups (histological subtype: P=0.95, location: P=0.57). There were 300 (65.5%) patients of target subgroup A (2 cm < tumor size ≤3 cm, CTR ≤0.5) and 158 (34.5%) of target subgroup B (tumor size ≤2 cm, 0.25< CTR ≤0.5) in lobectomy subgroup; 96 (60.4%) patients of target subgroup A and 63 (39.6%) of target subgroup B in segmentectomy group (P=0.29). The frequencies of systematic mediastinal lymph node dissection and selective dissection for lobectomy group and segmentectomy group were comparable (P=0.11). In lobectomy group, pathological stage of 37 (8.1%) were IB and of 6 (1.3%) were IIB. In segmentectomy group, pathological stage of 10 (6.3%) were IB and no patient was N1 stage (P=0.26) (Table 1).

Long-term survival of lobectomy and segmentectomy patients

The median follow-up time was 61.1 months (IQR: 42.3–71.7 months). Although clinicopathological characteristics were well balanced, a PSM was performed to analyze the survival because of the numerical difference between the lobectomy and segmentectomy groups. According to the characteristics after PSM listed in Table S1, all segmentectomy patients were involved. The 5-year overall survival rate was 98.6% (96.8–99.5%) for lobectomy and 99.3% (98.2–99.8%) for segmentectomy (P=0.99) (Figure 1A), after PSM, the 5-year overall survival rate was 98.8% (97.9–99.6%) for lobectomy (P=0.42) (Figure 1B). The 5-year relapse-free survival rate was 95.5% (94.1–97.2%) for lobectomy and 95.2% (92.3–98.7%) for segmentectomy (P=0.74) (Figure 2A), after PSM, the 5-year relapse-free survival rate was 95.3% (92.2–97.6%) for lobectomy (P=0.81) (Figure 2B). Either with or without PSM, the overall survival and relapse-free survival between two groups were comparable.

Figure 1 Overall survival of lobectomy and segmentectomy groups (A) and of lobectomy and segmentectomy groups after propensity score matching (B).

Figure 2 Relapse-free survival of lobectomy and segmentectomy groups (A) and of lobectomy and segmentectomy groups after propensity score matching (B).

Besides, we compared the survival of subgroup A and subgroup B patients undergoing segmentectomy and lobectomy, there was no significant difference of RFS (P=0.12) and OS (P=0.29) among segmentectomy subgroup A, segmentectomy subgroup B, lobectomy subgroup A and lobectomy subgroup B patients (Figure S1).

Postoperative outcomes of lobectomy and segmentectomy groups

The proportion of patients with recurrence was 4.1% for lobectomy and 4.4% for segmentectomy (P=0.89). Five of 458 (1.1%) lobectomy patients and 3 of 159 (1.8%) segmentectomy patients had local relapse (Table 2). Until the last follow-up date, 13 (2.8%) lobectomy patients and 4 (2.5%) segmentectomy patients have died (P=0.83). In lobectomy group, 4 patients died due to lung cancer, 6 died due to other cancer and 1 die due to other diseases. In segmentectomy group, 1 patient died due to lung cancer, 2 died due to other cancer and 1 die due to other diseases (Table S2). The proportion of patients with grade 2 and above early postoperative complications was 9.6% for lobectomy and 8.8% for segmentectomy (P=0.86), and the proportion of patients with grade 2 late postoperative complications was 1.4% for lobectomy and 0.6% for segmentectomy (P=0.48) (Table 3). Details of early and late postoperative complications are listed in Table S3.

Discussion

For decades, lobectomy has been the standard surgical procedure for invasive lung cancer (20,21). Nearly ten years ago, AIS and MIA were newly defined as two non-invasive subtypes of lung adenocarcinoma (22). In recent years, research demonstrated that the 5-year RFS of AIS and MIA was 100% regardless of the surgical modes (11,13). Shortly afterward, long-term follow-up of patients with resected AIS/MIA has been reported by studies and the results indicated that sublobar resection is curative (14,15).

GGO has been increasing in prevalence rapidly. In 2011, JCOG0201 study proposed the concept of “radiological non-invasive lung cancer” and reported that the criteria for non-invasiveness were CTR 0.25 or less with tumor size of 2 cm or less (23). Then a single-arm study, JCOG0804 demonstrated that radiological non-invasive lung cancer could be curable with sublobar resection instead of lobectomy (8).

Following these series of studies, it is worthy to figure out whether lobectomy is still the optimal choice for small sized GGO featured invasive lung cancer. Retrospective studies have indicated that lobectomy and segmentectomy show comparable survival outcomes in clinical stage IA lung cancer (24-26). In 2022, JCOG0802, a multicenter randomized controlled trial, focusing on “radiological invasive lung cancer” (tumor ≤2 cm with CTR >0.5) published the final results and clarified the non-inferiority of segmentectomy to lobectomy (9). However, for GGO featured invasive lung cancer (2 cm < tumor diameter ≤3 cm, CTR ≤0.5 or tumor diameter ≤2 cm, 0.25< CTR ≤0.5) patients, the proper surgical approach remains controversial. A non-randomized confirmatory trial, JCOG1211 has been conducted to evaluate the feasibility of segmentectomy for GGO featured invasive lung cancer (2 cm < tumor diameter ≤3 cm, CTR ≤0.5 or tumor diameter ≤2 cm, 0.25< CTR ≤0.5). The results of JCOG 1211 revealed that the 5-year RFS was 98.0% for patients receiving segmentectomy (10).

Of note, over 50% patients of JCOG1211 had AIS/MIA. On one hand, the excellent survival with no recurrence impacted the RFS of the whole cohort. On the other hand, wedge resection is curative for AIS/MIA. Here, we referred to the inclusion radiological criteria of JCOG1211 and retrospectively reviewed patients with GGO featured cT1N0 invasive adenocarcinoma (2 cm < tumor diameter ≤3 cm, CTR≤0.5 or tumor diameter ≤2 cm, 0.25< CTR ≤0.5) undergoing segmentectomy or lobectomy. To be clear, we excluded patients AIS/MIA. We collected long-term survival data of the study cohort with median follow-up of 61.1 months. Baseline clinicopathological characteristics of patients between segmentectomy and lobectomy groups were well distributed. The 5-year OS rate, 5-year RFS rate, the proportions of recurrence and the frequencies of grade 2 and above early postoperative complications between two groups showed no significant difference. After PSM, the OS and RFS between two groups were also comparable. Our results indicated that for cT1N0 GGO featured invasive adenocarcinoma (2 cm < tumor diameter ≤3 cm, CTR ≤0.5 or tumor diameter ≤2 cm, 0.25< CTR ≤0.5), segmentectomy could be the standard surgical approach. We believed that this study could provide complementary information for JCOG1211.

Frankly, some limitations existed in our work. Although we checked the data carefully to avoid selection bias, it is still a single-center retrospective study based on Chinese population. In addition, our study spanned from 2010 to 2020, systematic mediastinal lymph node dissection or selective dissection was performed with segmentectomy during this long period of time. The lymph node dissection strategy for lung cancer has been revolutionized in the last decade. Recently, limited lymphadenectomy is more frequently performed as our knowledge about predictor of node-negative status is constantly updated following continuous research (19,27). Our recent study proposed that mediastinal lymph node dissection was unnecessary for lung cancer patients with GGO dominant and CTR ≤0.5 (28). To note, JCOG1211 performed a segmentectomy with only hilar, interlobar and intrapulmonary lymph node dissection for each patient. Moreover, the data of postoperative pulmonary function were not routinely recorded in our department. It is a limitation that we could not present a comparison of preoperative and postoperative pulmonary functions. JCOG1211 found that reduction proportions of pulmonary function parameters at 6 months and at 12 months for segmentectomy were less than those for lobectomy (10).

Conclusions

For patients with cT1N0 GGO featured invasive adenocarcinoma (2 cm < tumor diameter ≤3 cm, CTR ≤0.5 or tumor diameter ≤2 cm, 0.25< CTR ≤0.5), if the nodule is in a proper location with ensured sufficient margin distance, segmentectomy is confirmed to be the standard surgical approach.

Acknowledgments

The abstract of this study has been published in 2023 AATS International Thoracic Surgical Oncology Summit.

Funding: This work was supported by the National Natural Science Foundation of People’s Republic of China (81930073), the Shanghai Technology Innovation Action Project (20JC1417200), Shanghai Municipal Key Clinical Specialty Project (SHSLCZDZK02104), and the Cooperation Project of Conquering Major Diseases in Xuhui District (XHLHGG202101) (to H.C.).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-191/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-191/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-191/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-191/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 approved by the Institutional Review Board of the Fudan University Shanghai Cancer Center (No. IRB2008223-9). The requirement for informed consent was waived as it was a retrospective research.

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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