Protocol for a single-arm, multicenter, prospective, confirmatory phase III trial of wedge resection for invasive ground glass opacity-featured lung cancer with a size ≤2 cm and a consolidation tumor ratio between 0.25 and 0.5 (ECTOP-1020 study)

Introduction

Lung cancer is the leading cause of cancer-associated mortality in both men and women (1). The wide implementation of cross-sectional imaging for lung cancer facilitates the detection of incidental ground glass opacities (GGOs). Among these methods, computed tomography (CT) is most commonly used. High-resolution CT (HRCT) scans enable the visualization of vague GGO and increase the number of GGOs detected, which are plausible indicators for lung cancer (2-6). GGOs that persist over time and increase in either the size of the ground glass or the solid component are highly suspicious for early-stage lung adenocarcinoma (LUAD) (7,8), which comprises the most common histological subtype of lung cancer. Pathologically, most LUADs follow a trajectory from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and ultimately invasive adenocarcinoma (IAC) from stages I to IV. Radiologically, they may manifest as pure GGOs at first, then as part-solid nodules, and eventually as solid nodules. For subsolid nodules, the consolidation tumor ratio (CTR) has been used to measure the solid proportion of GGOs (9-12). GGO-featured LUAD is a special stage of its natural progression and is a unique clinical subtype with distinctive features and a better prognosis. GGO-featured LUAD generally displays more indolent biological behavior than solid nodule-like LUAD; therefore, aggressive surgical resection may result in overtreatment. Lobectomy with systemic lymph node dissection has long been the standard treatment for early-stage non-small cell lung cancer (NSCLC) (13,14). However, with the shift in the disease spectrum and a deeper understanding of the disease, researchers and surgeons have found that sublobectomy (segmentectomy and wedge resection) can achieve comparable results and preserve more lung parenchyma at the same time, while wedge resection can preserve more pulmonary function and hilar structure intact when further compared with segmentectomy.

In recent decades, a series of randomized prospective clinical trials have been designed and launched to investigate the efficacy and safety of segmentectomy or wedge resection in treating small peripheral lung cancer. The Japan Clinical Oncology Group (JCOG) Lung Cancer Surgical Study Group launched the JCOG0804, JCOG0802, and JCOG1211 trials to investigate the value of radiological criteria in deciding the surgical strategy ahead of surgery. The JCOG0804 study concluded that wedge resection was recommended for patients with a tumor size ≤2 cm and a CTR ≤0.25 (15). The JCOG0802 study concluded that segmentectomy was appropriate for nodules ≤2 cm with a CTR >0.5 (16). The multicenter single-arm study JCOG1211 was launched in 2013 and evaluated the surgical efficacy and safety of segmentectomy for “radiologically invasive” tumors (those with tumors ≤2 cm and a CTR between 0.25 and 0.5; those with tumors between 2 and 3 cm and a CTR ≤0.5). The 5-year relapse-free survival (RFS) rate was 98.0% for the whole group. The JCOG1211 study concluded that segmentectomy was noninferior to lobectomy in treating this group of patients (17). Moreover, except for 42% of patients who were confirmed to be invasive by pathology, the remaining 58% of patients were pathologically confirmed to have AIS/MIA, for whom wedge resection has been shown to be a safe and effective surgical option, with a 100% 5-year recurrence-free survival (RFS) rate (18). In contrast, segmentectomy can cause overtreatment if it is not performed for improper locations. Therefore, subgroup analysis comparing segmentectomy and wedge resection is needed since neither of these studies could conclude whether segmentectomy or wedge resection is suitable for patients with invasive LUAD tumors ≤2 cm and a CTR between 0.25 and 0.5. To date, there are also no evidence-based guidelines for a definitive conclusion.

Some retrospective studies have conducted preliminary analyses on the surgical strategy for this group of patients. Chiang et al. (19) reported no significant differences in the survival of patients with cT1N0 LUAD who underwent segmentectomy or wedge resection. According to the subgroup analysis, wedge resection was sufficient for patients with invasive LUAD tumors ≤2 cm and a CTR ≤0.5. However, to decisively elucidate the surgical strategy, a specific comparison of survival outcomes following wedge resection or segmentectomy is necessary. Zhang et al. (20) reviewed the survival data of 1,503 patients with invasive LUAD that manifested as peripheral cT1N0 subsolid nodules who underwent segmentectomy or wedge resection for more than 12 years. They reported that for patients with tumor sizes ≤2 cm and CTRs between 0.25 and 0.5, wedge resection achieved comparable 5-year RFS and lung cancer-specific overall survival (LCS-OS) rates as segmentectomy, which were not worse than those of patients with invasive LUAD tumors ≤2 cm and CTRs ≤0.25. However, due to the lack of prospective research results, it is necessary to explore the optimal surgical approach for invasive LUAD patients with tumor sizes ≤2 cm and 0.25< CTR ≤0.5.

Based on these results, we hypothesize that wedge resection is a sufficient and safe option or a new standard treatment for LUAD patients with a tumor size ≤2 cm and a CT scan of 0.25< CTR ≤0.5. This single-arm multi-institutional prospective confirmatory trial (ECTOP-1020) was therefore initiated to evaluate the efficacy and safety of wedge resection for patients with tumors ≤2 cm and a CTR between 0.25 and 0.5. We present this article following the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-440/rc).

Methods

Study design and setting

The ECTOP-1020 study is designed as a single-arm, multicenter, prospective, confirmatory phase III trial to confirm the noninferiority of wedge resection in GGO-featured lung cancer patients with a size ≤2 cm and a CTR between 0.25 and 0.5. The study procedure is shown in Figure 1.

Figure 1 Study procedure. GGO, ground glass opacity; CTR, consolidation tumor ratio; ECOG, Eastern Cooperative Oncology Group; CT, computed tomography; IAC, invasive adenocarcinoma.

The primary endpoint is the 5-year overall survival (OS) of all patients enrolled. The secondary endpoints are 5-year RFS, the R0 resection rate, pulmonary function, recurrence and metastasis sites, and adverse events after wedge resection.

Subgroup analysis will be performed by clinicopathological features, such as age, tumor stage, subtype of malignancy, and comorbidities. Secondary analysis will be performed per protocol for the explanatory purpose of assessing the impact of adherence to the intervention on outcomes.

In this trial, OS is defined as the period from surgery to death from any cause, censored at the last day on which the patient is confirmed to be alive. RFS is defined as the period between surgery and tumor recurrence, censored at the last day of follow-up of the survivors without recurrence. R0 resection is defined as microscopic margin-negative resection, in which no macroscopic or microscopic evidence of residual tumor remains in the primary tumor bed. The R0 resection rate is defined as the proportion of patients with no residual tumor after radical wedge resection compared to all patients who underwent wedge resection according to the final pathology report. Pulmonary function is re-examined 6 months and one year after surgery, and the average proportion of reduced forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) will be calculated compared with the preoperative pulmonary function result. The recurrence/metastasis sites and relapse time are evaluated during outpatient follow-up every 6 months after surgery. Surgical adverse events, such as air leakage, atrial fibrillation, postoperative hemorrhage, postoperative infection, and bronchopleural fistula, are surgery-related complications after wedge resection and will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 1.

Treatment

For all registered patients, physical examinations, including enhanced CT of the chest; pulmonary function tests; and ultrasound of the neck, clavicle, liver, gallbladder, spleen, pancreas, kidney, adrenal gland, lower limb veins, and carotid artery, are performed before surgery. All eligible patients underwent wedge resection, and intraoperative frozen-section (FS) analysis is routinely performed to confirm the pathological diagnosis of LUAD. Subsequently, all the samples are labeled and sent for final paraffin pathological evaluation. All surgical records or videotapes were reviewed and evaluated by the principal investigator. Based on the results of previous studies, no lymph node metastasis was found in lung cancer patients with a CTR less than 0.5 (12). Therefore, mediastinal lymph node dissection is not further performed in this study, and surgeons could perform it according to individual experience. The hilar, interlobar, and intersegmental lymph nodes exposed during the operation are removed together for examination. To ensure the thoroughness of the surgery, the distance between the tumor and the closest incision margin and the tumor should be at least 2 cm.

Follow-up

For all registered patients, survival information is obtained until the longest possible follow-up period of up to 10 years. Physical examinations, including enhanced CT of the chest, contrast-enhanced brain magnetic resonance imaging (MRI), and ultrasound of the neck, clavicle, liver, gallbladder, spleen, pancreas, kidney, adrenal gland, lower limb veins, and carotid artery, are performed every 6 months for the first 3 years after the termination of protocol treatment and yearly thereafter for the next 7 years. Pulmonary function tests are performed 6 months and one year after the termination of protocol treatment.

Patient selection

Inclusion criteria

The inclusion criteria for this study are as follows:

• Patients who voluntarily participate in clinical research, are willing to follow, and can complete all trial procedures.
• The participants are aged 18–80 years old (including the threshold) when signing the informed consent form.
• An Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 is given.
• Patients have not previously undergone lung cancer surgery.
• The nodules on CT appear as GGOs or multiple pulmonary nodules, with the main lesion being the following nodules: small (diameter ≤2 cm) and peripheral (located on the outer third of the lung field) with a CTR larger than 0.25 but no more than 0.5.
• All the patients are initially treated and have not previously received radiotherapy or chemotherapy in the past.
• The preoperative lymph node stage is cN0, and there is no distant metastasis.
• Wedge resection can completely remove the tumor according to the evaluation of the surgeon.

Exclusion criteria

Patients meeting any of the following criteria are excluded:

• When the nodule is more than 2 cm, the CTR is not between 0.25 and 0.5.
• The nodule could not be completely resected by wedge resection.
• The nodule is postoperatively confirmed as pre- and minimally invasive LUAD by final pathology, namely, AIS/MIA, for which wedge resection is already widely accepted.
• The nodule is cytologically or histopathologically confirmed to be a lung malignancy other than LUAD.
• Patients have previously undergone lung cancer surgery.
• The patient is not initially treated and has received radiotherapy or chemotherapy in the past.

Patient and public involvement

A patient advisory board will be established to review the study progress, provide feedback on materials, and offer insights into patient-centered outcomes. From the protocol concept to the writing of the informed consent document, all patients participated in our discussion.

Sample size calculation and statistical analysis

This single-arm, multicenter, prospective, confirmatory phase III trial was designed to confirm the noninferiority of wedge resection in GGO-featured lung cancer patients with a size ≤2 cm and a CTR between 0.25 and 0.5 by assessing the primary outcome of 5-year OS. Based on our previous study (20), the 5-year OS after segmentectomy for LUAD patients with a size ≤2 cm and a CTR between 0.25 and 0.5 was 97.6%. Therefore, we limit the expected 5-year OS of this cohort who underwent wedge resection to 95.6%, and the lower limit was defined as 90.6%. With 5% as the noninferiority margin, a total of 286 patients needed to be included in this study. The statistical analysis is performed after the postoperative pathologic results are obtained for the last patient. The accrual period is 2 years, and the maximum follow-up period is 10 years.

Five years after the accrual completion, a primary analysis will be conducted. The Kaplan-Meier method will be used to estimate the 5-year OS, and the confidence interval (CI) will be calculated by Greenwood’s formula. If the lower limit of the 90% CI exceeds the threshold value of 90.6%, noninferiority to standard surgery results is confirmed and wedge resection will be an option for the standard of care. At 10 years after accrual completion, if the 10-year RFS is no lower than 90.6%, the standard of care will be replaced by wedge resection. Primary analysis will be performed for all registered patients.

Exploratory analysis

For ancillary research, tumor and paracancerous tissue samples will be collected from all study participants during surgery to investigate potential biomarkers, genomic profiles, and other molecular characteristics that may be associated with treatment outcomes or prognosis. Because sufficient statistical power is not ensured for the subgroup analysis and no adjustment for multiplicity is made, the results of subgroup analyses will therefore be treated as exploratory results.

Interim analysis and monitoring

All the statistical analyses will be conducted by the leading center (Fudan University Shanghai Cancer Center). Interim analysis is not planned because few events occur until the 3-year follow-up due to the excellent prognosis of this study population. If the number of treatment-related deaths reaches three, registration will be suspended unless the Fudan University Shanghai Cancer Center Medical Ethics Committee approves the continuation of the trial.

The leading center and the study coordinator will conduct central monitoring and will issue an in-house monitoring report every 6 months to evaluate study progress and improve data integrity and patient safety.

Ethics and dissemination

The participating institutions are as follows: Fudan University Shanghai Cancer Center, Fujian Cancer Hospital, Taizhou First People’s Hospital, Yangzhou Jiangdu People’s Hospital, Liaocheng Cancer Prevention and Treatment Hospital, and Suzhou Wujiang District Second People’s Hospital.

The Fudan University Shanghai Cancer Center Medical Ethics Committee approved this study protocol in January 2024 (No. 2401289-10). The study follows the precepts established in the Declaration of Helsinki (as revised in 2013) and the Clinical Trials Act.

All patients will receive information for decision-making to participate in this trial. Consent to publication will include the use of a general consent form, and each participant’s data will be handled anonymously. All participants’ information will be stored in the leading center.

Discussion

Lung cancer is the foremost contributor to cancer-related mortality worldwide, affecting individuals of all genders. Recent strides in medical imaging technology, particularly the widespread adoption of low-dose CT (LDCT) scans, have markedly enhanced the early detection of pulmonary abnormalities, among which GGOs hold significant diagnostic relevance. Radiologically, pure GGOs could remain the same or even vanish, gradually evolve to part-solid GGOs and solid GGOs, or simply increase in size and persist over time. Pathology revealed AAH to AIS, MIA, and eventually invasive LUAD from stage I to IV. The evaluation of GGOs necessitates an assessment of the CTR. Subsolid nodules, characterized by a combination of ground glass and solid elements, have garnered considerable attention in shaping optimal therapeutic strategies. LUAD with a predominant GGO appearance represents a distinct clinical entity and is often associated with a more favorable prognosis than its solid nodule counterpart. This study involves nodules that appear as GGOs with a size of no more than 2 cm on CT scan and a CTR between 0.25 and 0.5, indicating invasive LUAD according to pathology.

The surgical strategies used for IAC include pneumonectomy, lobectomy, and sublobectomy, which include segmentectomy and wedge resection. On the one hand, as long-term follow-up studies have confirmed the good prognosis of certain types of LUAD, surgeons are obligated to perform limited resections to preserve the normal lung parenchyma as much as possible for patients. Obviously, among all the surgical strategies mentioned above, wedge resection is the surgical approach that causes the least damage to patients. On the other hand, Yotsukura et al. (21) reported the estimated incidence rates of metachronous second primary lung cancer (SPLC) at 10 years after resection for AIS (5.6%) and MIA (7.7%), with median intervals between the initial surgery and the occurrence of SPLC of 87 and 97 months, respectively. Another study by Li et al. (22) reported similar results for the 10-year postoperative incidence of developing SPLC for patients with AIS and MIA. Therefore, a large population that may need a second operation may experience further deterioration of the parenchyma and pulmonary function. If the first surgery is a mere wedge resection, the intact hilar structure would enable the possibility of a successful second operation.

No evidence-based guidelines are available for a definitive conclusion for the surgical strategy of this population of patients until now. The existing clinical trials have sought to delineate radiological criteria guiding surgical decision-making. The most relevant factor to our target population, JCOG1211, contains other confounding factors. Subgroup analysis comparing segmentectomy and wedge resection is urgently needed. Therefore, this is the first prospective trial to investigate the noninferiority of wedge resection for invasive GGO-featured lung cancer patients with a size ≤2 cm and a CTR between 0.25 and 0.5. This trial could support less invasive treatment as a new standard of care for this group of patients. Although this trial is not a randomized controlled study, it compares ECTOP-1020 data with robust historical control data and, therefore could be considered a confirmatory trial.

This is the first multi-institutional confirmatory clinical trial for the surgical treatment of specifically invasive GGO-featured lung cancer patients with tumor sizes no more than 2 cm and a CTR between 0.25 and 0.5.

There are several limitations. First, this is a single-arm study design, and the potential for inherent biases, such as lack of a control group and selection bias, does exist. Randomized controlled trials or other rigorous study designs need to be employed to provide more robust evidence. Additional limitations, including potential challenges in patient recruitment, loss to follow-up, or other logistical or operational barriers, could impact the study’s implementation and interpretation of the results. To minimize the impact, in the inclusion of patients, we will attempt to include as many standardized patients as possible. For loss to follow-up, the following measures will be taken to carry out additional outreach initiatives to re-engage individuals who have ceased responding or dropped out, impute missing data using statistical techniques, and carry out sensitivity analysis to determine the effect of loss to follow-up on research outcomes.

In summary, our study is a preliminary study exploring the surgical efficacy and safety of wedge resection for small (tumor size ≤2 cm with a CTR between 0.25 and 0.5) invasive GGO-featured lung cancer. We expect that these results will provide higher-level evidence for the efficacy and safety of wedge resection for surgical decision-making for this group of patients and motivate further investigation and validation in the field. Ultimately, we hope to contribute to the refinement of treatment strategies for IAC patients to improve patient outcomes and enhance quality of life.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of the People’s Republic of China (81930073 to H.C.), the Shanghai Technology Innovation Action Project (20JC1417200 to H.C.), the Cooperation Project of Conquering Major Diseases in Xuhui District (XHLHGG202101 to H.C.), and the National Key R&D Program of China (2022YFA1103900 to H.C.). The funders did not play a role in the manuscript design, data collection, data analysis, data interpretation, or manuscript writing.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-440/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-440/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-440/coif). H.C. serves as an unpaid editorial board member of Journal of Thoracic Disease from October 2022 to September 2024. The other 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 Fudan University Shanghai Cancer Center Medical Ethics Committee (No. 2401289-10) approved the study. The study follows the precepts established in the Declaration of Helsinki (as revised in 2013) and the Clinical Trials Act. All patients will receive information for decision-making to participate in this trial. Consent to publication will include the use of a general consent form, and each participant’s data will be handled anonymously. All participants’ information will be stored in the leading center.

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/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. [Crossref] [PubMed]
3. Kaneko M, Eguchi K, Ohmatsu H, et al. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996;201:798-802. [Crossref] [PubMed]
4. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242-5. [Crossref] [PubMed]
5. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99-105. [Crossref] [PubMed]
6. Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol 2000;73:1252-9. [Crossref] [PubMed]
7. Tang EK, Chen CS, Wu CC, et al. Natural History of Persistent Pulmonary Subsolid Nodules: Long-Term Observation of Different Interval Growth. Heart Lung Circ 2019;28:1747-54. [Crossref] [PubMed]
8. Kakinuma R, Noguchi M, Ashizawa K, et al. Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study. J Thorac Oncol 2016;11:1012-28. [Crossref] [PubMed]
9. Hattori A, Matsunaga T, Hayashi T, et al. Prognostic Impact of the Findings on Thin-Section Computed Tomography in Patients with Subcentimeter Non-Small Cell Lung Cancer. J Thorac Oncol 2017;12:954-62. [Crossref] [PubMed]
10. Hattori A, Matsunaga T, Takamochi K, et al. Neither Maximum Tumor Size nor Solid Component Size Is Prognostic in Part-Solid Lung Cancer: Impact of Tumor Size Should Be Applied Exclusively to Solid Lung Cancer. Ann Thorac Surg 2016;102:407-15. [Crossref] [PubMed]
11. Hattori A, Matsunaga T, Takamochi K, et al. Importance of Ground Glass Opacity Component in Clinical Stage IA Radiologic Invasive Lung Cancer. Ann Thorac Surg 2017;104:313-20. [Crossref] [PubMed]
12. Zhang Y, Fu F, Wen Z, et al. Segment Location and Ground Glass Opacity Ratio Reliably Predict Node-Negative Status in Lung Cancer. Ann Thorac Surg 2020;109:1061-8. [Crossref] [PubMed]
13. 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]
14. CAHAN WG. Radical lobectomy. J Thorac Cardiovasc Surg 1960;39:555-72. [Crossref] [PubMed]
15. Suzuki K, Watanabe SI, Wakabayashi M, et al. A single-arm study of sublobar resection for ground-glass opacity dominant peripheral lung cancer. J Thorac Cardiovasc Surg 2022;163:289-301.e2. [Crossref] [PubMed]
16. 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]
17. 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]
18. Zhang Y, Ma X, Shen X, et al. Surgery for pre- and minimally invasive lung adenocarcinoma. J Thorac Cardiovasc Surg 2022;163:456-64. [Crossref] [PubMed]
19. Chiang XH, Lu TP, Hsieh MS, et al. Thoracoscopic Wedge Resection Versus Segmentectomy for cT1N0 Lung Adenocarcinoma. Ann Surg Oncol 2021;28:8398-411. [Crossref] [PubMed]
20. Zhang C, Pan Y, Li H, et al. Extent of surgical resection for radiologically subsolid T1N0 invasive lung adenocarcinoma: When is a wedge resection acceptable? J Thorac Cardiovasc Surg 2024;167:797-809.e2. [Crossref] [PubMed]
21. Yotsukura M, Asamura H, Motoi N, et al. Long-Term Prognosis of Patients With Resected Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung. J Thorac Oncol 2021;16:1312-20. [Crossref] [PubMed]
22. Li D, Deng C, Wang S, et al. Ten-year follow-up of lung cancer patients with resected adenocarcinoma in situ or minimally invasive adenocarcinoma: Wedge resection is curative. J Thorac Cardiovasc Surg 2022;164:1614-1622.e1. [Crossref] [PubMed]