Towards better outcomes: segmentectomy for ground-glass opacity-dominant non-small cell lung cancer 3 cm or less—insights from JCOG1211

Introduction

Since the Lung Cancer Study Group performed a prospective and randomized study of sublobar resection vs. lobectomy for non-small cell lung cancer (NSCLC) ≤3 cm in the 1980s and reported that sublobar resection was associated with a higher risk of local recurrence than lobectomy (1), lobectomy has become the gold standard surgical procedure for NSCLC, even for small tumors. However, because of the increasing number of small-sized NSCLCs with a large ground-glass opacity (GGO) component and the advent and widespread use of high-resolution thin-slice computed tomography (CT), many previous studies of sublobar resection for NSCLC have addressed such GGO-dominant tumors (2-6). A GGO component on CT reflects a component of noninvasive carcinoma on histopathological examination (7), and pure GGO lesions and mostly GGO lesions ≤2 cm on CT indicate noninvasive lung cancer, represented by lung adenocarcinoma without nodal involvement, vascular invasion, or lymphatic invasion (8). Thus, small-sized GGO-dominant NSCLCs are considered a potential indication for intentional sublobar resection for patients who can tolerate lobectomies.

JCOG1211

JCOG1211 was a multi-institutional, single-arm, phase 3 trial designed to confirm the efficacy and safety of segmentectomies for GGO-dominant NSCLC with a diameter ≤3 cm (9). A single-arm study was conducted because a large number of participants would be required for a randomized controlled trial because of the good postoperative prognosis of the target population. When the consolidation-to-tumor ratio (CTR) was defined as the largest diameter of the solid part of the tumor divided by the total diameter (including the GGO), GGO-dominant tumors had a CTR ≤0.5. The eligibility criteria for the study were as follows: (I) patients with a tumor >2–3 cm and a CTR ≤0.5; (II) those with a tumor ≤2 cm and a CTR >0.25–0.5; and (III) those with a non-peripheral tumor ≤2 cm and a CTR ≤0.25.

Segmentectomies with hilar, interlobar, and intrapulmonary lymph node dissections were performed, and a resection surgical margin greater than the maximum tumor diameter or >2 cm was mandatory (9). The histopathological diagnosis of adenocarcinoma was confirmed preoperatively or intraoperatively by a frozen section examination. The surgical procedure was converted to lobectomy when lymph node metastases were identified intraoperatively or when a sufficient surgical margin could not be secured. The primary endpoint was 5-year relapse-free survival (RFS) for all patients who underwent segmentectomy. The secondary endpoints were the annual overall survival (OS) rate, proportion of local relapse, postoperative pulmonary functions, and adverse events. All patients were followed up for at least 5 and 10 years after they were registered.

A total of 396 patients were enrolled; of these patients, 357 who underwent segmentectomies were the target population for the primary analysis (9). The surgical procedure was converted to lobectomy for 19 of the 396 patients. Among the 357 patients who underwent segmentectomies, 154 (43%) had a tumor >2–3 cm and a CTR ≤0.5 (group 1), 163 (46%) had a tumor ≤2 cm and a CTR >0.25–0.5 (group 2), and 40 (11%) had a non-peripheral tumor ≤2 cm and a CTR ≤0.25 (group 3; Table 1). Of these patients, 352 (99%) underwent complete resections (R0). The final histopathological diagnoses were minimally invasive adenocarcinoma for 117 (33%) patients, adenocarcinoma in situ (AIS) for 88 (25%) patients, lepidic predominant invasive adenocarcinoma for 82 (23%) patients, squamous cell carcinoma for 3 (1%) patients, and noncancerous lesions (including atypical adenomatous hyperplasia) for 5 (1%) patients. Only one patient had pathological hilar lymph node metastases (N1).

Based on the Common Terminology Criteria for Adverse Events version 4.0 (11), no grade 5 treatment-related deaths occurred; however, grade 3 or grade 4 early postoperative complications occurred in 7 patients (2%) (9).

The 5-year RFS for all 357 patients who underwent segmentectomies was 98.0% (Table 1) (9). For the 154 patients in group 1 (tumor >2–3 cm and a CTR ≤0.5), the 5-year RFS was 98.0% and the 5-year OS was 98.0%. For patients with pathologically invasive cancers (invasive size ≥0.5 cm), the 5-year RFS rate was 97.0%. During follow-up, only two patients developed postoperative recurrence (ipsilateral intrathoracic lymph nodes in one patient and the bone in one patient). Nine patients died as a result of lung cancer (one patient), other cancers (five patients), non-malignant disease (two patients), and unknown causes (one patient).

Regarding the postoperative pulmonary function, data of patients in the lobectomy group of JCOG0802/WJOG4607L (10) were used for comparative analyses. The differences in the median forced expiratory volume in 1 s changes were 5.2% at 6 months and 4.7% at 12 months for the patients who underwent segmentectomy in JCOG1211 and those in the lobectomy group in JCOG0802/WJOG4607L (9). The differences in the median forced vital capacity changes were 5.0% at 6 months and 4.1% at 12 months for the two groups.

Intentional sublobar resection for GGO-dominant NSCLC >2–3 cm and CTR >0.25–0.5

AIS was formerly referred to as bronchioloalveolar carcinoma (12,13). AIS is a subtype of lung adenocarcinoma that does not develop lymph node metastases and can be cured by surgical resection. Thus, the initial strategy of sublobar resection for NSCLC in patients who could tolerate lobectomies targeted these tumors, which were represented by GGO-dominant small lesions on CT (2,3,5). In these studies, pure GGO lesions and mostly GGO lesions ≤2 cm were addressed, by adding the intraoperative pathological diagnosis of AIS using a frozen section examination. According to another recently reported JCOG trial (JCOG0804/WJOG4507L) of sublobar resection, which addressed the radiological noninvasive peripheral lung adenocarcinoma (≤2 cm with CTR ≤0.25) (6), the majority of patients underwent wedge resections (82.1%) as sublobar resections, and the 10-year RFS and OS for patients who underwent sublobar resections were 98.6% and 98.5%, respectively, during the median follow-up of 10.1 years (Table 1). It is noteworthy that JCOG1211 investigated GGO-dominant tumors >2–3 cm as well as those with CTRs >0.25, suggesting not only AIS but also pathologically invasive NSCLCs (9). Few prospective studies of sublobar resection for NSCLC have investigated these subgroups. In fact, in JCOG1211, among the 357 patients who underwent segmentectomy, 264 (74%) patients had pathological invasive carcinoma (minimally invasive adenocarcinoma in 117, invasive mucinous adenocarcinoma in 2, lepidic predominant invasive adenocarcinoma in 82, acinar predominant invasive adenocarcinoma in 12, papillary predominant invasive adenocarcinoma in 44, micropapillary predominant invasive adenocarcinoma in 2, solid predominant invasive adenocarcinoma in 1, other cancers in 1, and squamous cell carcinoma in 3), whereas 88 (25%) patients had AIS. Moreover, on pathological examination, 4 (1.1%) patients had pleural invasion, 3 (0.8%) had vascular invasion, 8 (2.3%) had lymphatic permeation, and one had lymph node metastases (Table 1). Although many patients with pathologically invasive carcinoma and a considerable number of patients with pathological metastases or invasions were included in the JCOG1211 trial, the postoperative outcomes after segmentectomies were excellent (5-year RFS, 98.0%). Even for patients with pathologically invasive carcinomas, the 5-year RFS was 97.0%, and only two patients developed postoperative recurrence during the follow-up of more than 5 years. Although a recent study of uniportal anatomical segmentectomy for stage IA NSCLC showed relatively worse postoperative survival for patients with pathological stage IA3 disease compared to those with pathological stage IA1 and IA2 diseases (14), only 12 (3%) patients had pathological stage ≥ IA3 disease in the JCOG1211 trial. The JCOG1211 trial indicated a curative effect of segmentectomy for patients with NSCLC with a GGO-dominant tumor ≤3 cm, especially in tumors that exceed 2 cm in size and 0.25 in CTR (9). A multi-institutional, single-arm confirmatory trial to evaluate the efficacy and safety of watchful waiting for patients with tumors ≤2 cm and CTRs ≤0.25 is ongoing (15); however, GGO-dominant tumors >2–3 cm or CTRs >0.25 should be considered for surgical resection. In North America, for solitary part-solid nodules with a solid component >0.6 cm, short-term CT follow-up is recommended; while ¹⁸F-fluoro-2-deoxy-D-glucose positron emission tomography/CT (¹⁸F-FDG-PET/CT), biopsy, or surgical resection are recommended for those with a solid component >0.8 cm (16). However, JCOG1211 suggested that a CTR >0.25 is associated with a high probability of carcinoma including invasive adenocarcinoma among lung nodules >2–3 cm, and that GGO dominant tumors with a solid component ≤0.8 cm may be an indication for surgical resection if the CTR exceeds 0.25.

In contrast, JCOG0802/WJOG4607L (10) in Japan and CALGB140503 (15) in North America, which were multicenter, phase 3, randomized trials of sublobar resection vs. lobectomy, investigated patients with NSCLC with peripheral tumors ≤2 cm and CTRs >0.5 (JCOG0802/WJOG4607L), and with peripheral tumors ≤2 cm and CTRs >0 (excluding pure GGOs; CALGB140503). Although the JCOG1211 trial included a considerable number of patients (264 patients; 74%) with pathological invasive adenocarcinomas, there were few patients with lymph node metastasis as well as postoperative recurrence. In contrast, in JCOG0802/WJOG4607L, 31 of 554 (5.6%) patients in the lobectomy group and 34 of 552 (6.2%) patients in the segmentectomy group had pathological lymph node metastasis (Table 1) (10).

Extent of pulmonary resection during intentional sublobar resection for GGO dominant NSCLC: segmentectomy or wedge resection?

In JCOG1211, segmentectomies with hilar, interlobar, and intrapulmonary lymph node dissections were performed, and a resection surgical margin ≥2 cm or greater than the maximum tumor size was secured (9). Theoretically, segmentectomy is a superior oncological approach to wedge resections and has the advantages of more radical resection (17). Although segmentectomies and wedge resections are collectively included in sublobar resections, segmentectomy can provide a sufficient surgical margin with evaluating the hilar lymph nodes (18). In previous studies of sublobar resection for peripheral pure GGO lesions and mostly GGO lesions ≤2 cm suggesting pathologically noninvasive carcinomas, wedge resection was performed for the majority of enrolled patients (2,3,5,6). In these studies, wedge resection was performed as the first choice of treatment, and segmentectomy was performed only when the surgical margin was insufficient. Although wedge resection may be a curative treatment option for noninvasive carcinoma ≤2 cm, segmentectomy has the advantage of securing an appropriate surgical margin compared to wedge resection, especially for tumors >2–3 cm. In JCOG1211, 164 (46%) patients underwent simple segmentectomy and 191 (54%) patients underwent multiple segmentectomies. This suggests that it was difficult to achieve a resection surgical margin greater than the maximum tumor diameter or >2 cm even with simple segmentectomy or, needless to say, with wedge resection. Moreover, in the previous study (19), wedge resection was associated with a higher risk (hazard ratio, 5.787) of locoregional recurrence than segmentectomy for NSCLCs ≤3 cm on preoperative CT among patients who underwent sublobar resection. Thus, segmentectomy may have contributed to excellent postoperative outcomes with an extremely low incidence of locoregional recurrence by securing appropriate surgical margins in JCOG1211, which included a high proportion of patients with pathologically invasive carcinoma.

Multiple segmentectomies were selected to achieve sufficient surgical margins in 191 patients in JCOG1211; however, the excision of four segments did not show superiority in terms of postoperative pulmonary function compared with lobectomy (9). Although multiple segmentectomies are often required to achieve sufficient surgical margins, the resection of multiple segments may not result in the advantage of preserving postoperative pulmonary function.

Future directions for intentional sublobar resections for NSCLC after JCOG1211

JCOG1211 investigated the effect of segmentectomy on patients with NSCLC with a GGO-dominant tumor ≤3 cm and indicated the efficacy of segmentectomy even for tumors >2–3 cm and those with CTRs >0.25–0.5 (9). Among patients with radiological solid-dominant (CTR >0.5) NSCLCs ≤3 cm, NSCLC patients with a tumor with GGO components had better postoperative survival rates than patients with a radiologically pure solid tumor (without GGO components; CTR =1.0) (20), therefore, the next potential target for sublobar resection may be a radiological solid dominant (non-pure-solid) tumor >2–3 cm, such as a tumor with a CTR >0.5–0.75. Moreover, because a high maximum standardized uptake value on FDG-PET/CT correlates with more advanced disease and high-risk features of lung adenocarcinoma (21), such parameters may provide valuable information regarding radiologically solid-predominant tumors and may contribute to the selection of appropriate patients and surgical modes of sublobar resection for these NSCLCs.

Systematic hilar, interlobar, and intrapulmonary lymph node dissections were mandatory in JCOG1211, and only 11 (3%) patients underwent systematic mediastinal lymph node dissection (9). It is well known that GGO-dominant tumors in NSCLCs have a low risk of lymph node metastases (22). In fact, among the 357 patients who underwent segmentectomies in JCOG1211, only one patient had pathological hilar lymph node metastases and one patient developed locoregional recurrence. The necessity and extent of systematic lymph node dissection should be considered for intentional sublobar resections of GGO-dominant tumors. Selective lymph node dissection and sampling should be considered for GGO-dominant tumors such as those investigated in JCOG1211, and systematic mediastinal lymph node dissection may not be necessary for those tumors.

Limitations of JCOG1211

The limitations of JCOG1211 include the quality and reproducibility of radiological examinations because the patients were enrolled only in Japan (9). The uniformity of the segmentectomy method also may have varied depending on the country and the institution. Another limitation of JCOG1211 may have been the follow-up period. Indolent tumors were examined; therefore, the follow-up period of 5 years may have been too short for these tumors with a low risk of postoperative cancer recurrence and death. Moreover, an additional limitation may have been the study design (single-arm, phase 3 trial). It would be interesting to conduct a randomized, controlled, and comparative trial involving segmentectomy vs. lobectomy/wedge resection of GGO-dominant tumors that were examined in JCOG1211.

Conclusions

JCOG1211 revealed that even for GGO-dominant NSCLCs >2–3 cm with CTRs >0.25–0.5, segmentectomy is standard and curative surgical treatment for patients with such tumors according to a multi-institutional, single-arm, phase 3 trial in Japan (9). Although a considerable number of patients with invasive adenocarcinoma and pathological metastases or invasions were included, excellent postoperative disease control and survival were demonstrated. In the future, the necessity and extent of systematic lymph node dissection should be considered for patients in the subgroup with GGO-dominant NSCLCs that were investigated in JCOG1211.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-10/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-10/coif). The authors’ affiliated institution (Thoracic and Cardiovascular Surgery, Niigata University) is a member of the Japan Clinical Oncology Group. The authors have no other 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.

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References

1. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22; discussion 622-3. [Crossref] [PubMed]
2. Yamato Y, Tsuchida M, Watanabe T, et al. Early results of a prospective study of limited resection for bronchioloalveolar adenocarcinoma of the lung. Ann Thorac Surg 2001;71:971-4. [Crossref] [PubMed]
3. Yoshida J, Nagai K, Yokose T, et al. Limited resection trial for pulmonary ground-glass opacity nodules: fifty-case experience. J Thorac Cardiovasc Surg 2005;129:991-6. [Crossref] [PubMed]
4. Koike T, Togashi K, Shirato T, et al. Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg 2009;88:1106-11. [Crossref] [PubMed]
5. Sagawa M, Oizumi H, Suzuki H, et al. A prospective 5-year follow-up study after limited resection for lung cancer with ground-glass opacity. Eur J Cardiothorac Surg 2018;53:849-56. [Crossref] [PubMed]
6. Yoshino I, Moriya Y, Suzuki K, et al. Long-term outcome of patients with peripheral ground-glass opacity-dominant lung cancer after sublobar resections. J Thorac Cardiovasc Surg 2023;166:1222-1231.e1. [Crossref] [PubMed]
7. Yang ZG, Sone S, Takashima S, et al. High-resolution CT analysis of small peripheral lung adenocarcinomas revealed on screening helical CT. AJR Am J Roentgenol 2001;176:1399-407. [Crossref] [PubMed]
8. Suzuki K, Koike T, Asakawa T, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6. [Crossref] [PubMed]
9. 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;11:540-9. [Crossref] [PubMed]
10. 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;399:1607-17. [Crossref] [PubMed]
11. National Cancer Institute (U.S.). Common terminology criteria for adverse events (CTCAE). Rev. ed. Bethesda, MD.: U.S. Dept. of Health and Human Services, National Institutes of Health, National Cancer Institute; 2009. Available online: https://view.officeapps.live.com/op/view.aspx?src=https%3A%2F%2Fctep.cancer.gov%2FprotocolDevelopment%2Felectronic_applications%2Fdocs%2FCTCAE_4.03.xlsx&wdOrigin=BROWSELINK
12. Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 1995;75:2844-52. [Crossref] [PubMed]
13. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85. [Crossref] [PubMed]
14. Gioutsos K, Hayoz YJ, Dorn P. Clinical and Oncological Outcomes after Uniportal Anatomical Segmentectomy for Stage IA Non-Small Cell Lung Cancer. Medicina (Kaunas) 2023;59:1064. [Crossref] [PubMed]
15. 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;388:489-98. [Crossref] [PubMed]
16. MacMahon H, Naidich DP, Goo JM, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017;284:228-43. [Crossref] [PubMed]
17. Koike T, Goto T, Sato S, et al. Radical segmentectomy as a potential alternative surgical treatment with curative intent in early-stage non-small cell lung cancer. J Thorac Dis 2020;12:6115-9. [Crossref] [PubMed]
18. Okada M. Invited commentary. Ann Thorac Surg 2009;88:1111. [Crossref] [PubMed]
19. Koike T, Koike T, Yoshiya K, et al. Risk factor analysis of locoregional recurrence after sublobar resection in patients with clinical stage IA non-small cell lung cancer. J Thorac Cardiovasc Surg 2013;146:372-8. [Crossref] [PubMed]
20. Hattori A, Matsunaga T, Fukui M, et al. Prognostic Impact of Very Small Ground-Glass Opacity Component in Stage IA Solid Predominant Non-small Cell Lung Cancer. Semin Thorac Cardiovasc Surg 2022; Epub ahead of print. [Crossref] [PubMed]
21. Koike T, Sato N, Hosoda Y, et al. Maximum Standardized Uptake Value on Positron Emission Tomography is Associated With More Advanced Disease and High-risk Features in Lung Adenocarcinoma. Semin Thorac Cardiovasc Surg 2022;34:1051-60. [Crossref] [PubMed]
22. Koike T, Koike T, Yamato Y, et al. Predictive risk factors for mediastinal lymph node metastasis in clinical stage IA non-small-cell lung cancer patients. J Thorac Oncol 2012;7:1246-51. [Crossref] [PubMed]