Sublobar resection for adenocarcinoma in situ and minimally invasive adenocarcinoma diagnosed by intraoperative frozen section (ECTOP-1019): a study protocol of prospective, single-arm, multicenter, phase III study

Introduction

Lung cancer is the second most commonly diagnosed cancer as well as the leading cause of cancer related death worldwide (1). Nevertheless, the prognosis of early-stage lung cancer is still favorable. According to the classification of lung adenocarcinoma (LUAD) proposed by the World Health Organization (WHO), adenocarcinoma in situ (AIS) is defined as small (≤3 cm) adenocarcinomas with a pure lepidic growth, and minimally invasive adenocarcinoma (MIA) as adenocarcinoma with less than 5 mm invasion. Both AIS and MIA are the pre- and minimally invasive stages of LUAD (2).

According to our previous study, the 5-year recurrence-free survival (RFS) rate of AIS/MIA after surgical treatment was 100%, and the 5-year overall survival (OS) rate was 98.8% (3). Moreover, AIS and MIA do not cause lymph node metastasis. Sublobar resection without lymph node dissection may be the preferred surgical procedure for patients with AIS or MIA. Intraoperative frozen section (FS) is key for indeterminate nodule diagnosis and guiding surgical practice (4). Our previous study retrospectively explored the concordance between intraoperative FS diagnosis and final pathology (FP) in early-stage LUAD, and evaluated its efficacy and safety for sublobar resection (5). The total concordance rate between FS and FP was 84.4%. If atypical adenomatous hyperplasia (AAH), AIS, and MIA were grouped together, the concordance rate was 95.9%. In another study, invasive LUAD patients undergoing sublobar resection due to misdiagnosis of AAH, AIS, or MIA by intraoperative FS were analyzed, with an incidence of underdiagnose 6.3% (6). Among these patients, no lymph node metastasis was found and the 5-year RFS was still 100%. The above studies indicated that sublobar resection guided by FS diagnosis might be adequate for AIS, MIA, and even underestimated invasive LUAD. However, high-level evidence-based medical data confirming this surgical management is still lacking.

Based on this background, we initiated a prospective, single-arm, multicenter, confirmatory phase III trial to confirm the effect and safety of sublobar resection for cT1N0M0 non-small cell lung cancers (NSCLC) which are diagnosed as AIS or MIA by FS in China. We present this article in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-623/rc).

Methods

Objectives

This study aims to confirm the efficacy and safety of sublobar resection for AIS and MIA diagnosed by FS.

Study setting

This study is a prospective, single-arm, multicenter, confirmatory phase III study.

Endpoints

The primary endpoint is 5-year RFS. RFS is defined as the time from surgery to recurrence or death from any cause, and it would be censored on the last day when it was confirmed that the patient was alive without any evidence of recurrence. The secondary endpoints are 5-year OS, the concordance rate between FS and FP, adverse events, proportion of local recurrence and metastasis, the completion rate of sublobar resection and R0 resection. OS is defined as the period from surgery to death from any cause. Patients who are lost to follow-up are censored for OS. Adverse events are assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Local recurrence is defined as tumor recurrence at the location of the primary tumor, resection margins of the lung and bronchus, hilar lymph nodes, mediastinal lymph nodes, ipsilateral lung, pleura, and malignant pleural effusion. Metastasis is defined as tumor recurrence in the location other than local recurrence.

Eligibility criteria

We use a two-step registration because intraoperative histological confirmation of AIS or MIA by intraoperative FS is mandatory. Patient recruitment began in October 2023. It is expected to continue for the next two years.

All patients need to undergo preoperative contrast-enhanced thin-section computed tomography (CT) scan (slice thickness 1 to 1.5 mm) to evaluate the entire lung for preoperative staging, and the inclusion criteria for primary registration are as follows: (I) Suspected with cT1N0M0 NSCLC with peripheral lung nodule mainly composed of ground glass components, or pure ground glass nodule. Patients with multiple nodules are eligible, but the primary nodule should fulfill the above criteria and the other nodules should be smaller than the primary nodule. (II) Age 18–79 years old. (III) Eastern Cooperative Oncology Group performance status of 0–1. (IV) No prior thoracic surgery. (V) No prior chemotherapy, radiation therapy, molecular target therapy or immune checkpoint inhibitors for any malignant diseases. (VI) Sufficient pulmonary function for sublobar resection, fulfilling both of the following conditions: (i) forced expiratory volume in one second (FEV1) ≥50%, (ii) diffusing capacity of the lungs for carbon monoxide (DLCO) ≥50%. (VII) Sufficient organ function: (i) white blood cell count ≥3.5×10⁹/L, (ii) hemoglobin ≥90 g/L, (iii) platelet count ≥100×10⁹/L, (iv) total bilirubin ≤21 µmol/L, (v) aspartate aminotransferase ≤100 U/L, (vi) alanine aminotransferase ≤100 U/L, (vii) creatinine ≤150 µmol/L. (VIII) Written informed consent.

Inclusion criteria at the second registration include: (I) Histologically confirmed AIS or MIA by intraoperative FS. (II) Technically possible to perform wedge resection or anatomical segmentectomy. (III) No signs of direct invasion into surrounding organs except for adjacent lung regions, regional lymph node metastasis, dissemination or malignant effusion.

Exclusion criteria

Patients who meet any of the following criteria are excluded from the registration: (I) History of other malignancy. (II) Active infection requiring systemic therapy. (III) Women during pregnancy or breast-feeding. (IV) Systemic treatment with steroids or immunosuppressive agents. (V) Unstable angina or history of myocardial infarction within 6 months prior to registration. (VI) Severe heart valve disease, dilated cardiomyopathy or hypertrophic cardiomyopathy. (VII) Uncontrolled hypertension. (VIII) Uncontrolled diabetes mellitus. (IX) Interstitial pneumonitis, pulmonary fibrosis, or severe pulmonary emphysema.

Treatment methods

Sublobar resection (wedge resection or anatomical segmentectomy) without hilar and mediastinal lymph node dissection or sampling is performed. However, necessary segmental or lobar lymph node dissection is allowed during anatomical segmentectomy. The type of sublobar resection (wedge resection or segmentectomy) and the choice of surgical procedure (thoracotomy or video- or robotic-assisted thoracoscopic surgery) was at the surgeon’s discretion. In order to identify the small pulmonary nodules, CT-guided hook-wire localization of pulmonary nodules can be performed prior to surgery. Wedge resection and dissection of the intersegmental plane of segmentectomy are performed by stapling. A resection margin greater than the maximum tumor diameter or greater than 2 cm is mandatory. Histologically or cytologically confirmation during surgery for suspected resection margin is needed. Additional resection will be performed for positive resection margin. The surgical procedure will be converted to anatomical segmentectomy (for wedge resection) or lobectomy until a negative resection margin is achieved.

After the tumor is removed by sublobar resection, intraoperative FS diagnosis of the specimen will be performed by experienced pathologists immediately. The specimen is sliced at the largest diameter of tumor. Usually, one section is used for FS diagnosis. Remaining tissues will be fixed in 10% formaldehyde, paraffin-embedded (FFPE), continuously sectioned at 5 µm, and subject to hematoxylin and eosin (H&E) staining for postoperative pathological analysis. FP diagnosis is based on both the corresponding FS block and FFPE block of the entire tumor through extensive sampling to capture as many panoramas of the tumor as possible. The 2021 version of the WHO classification for LUAD is applied in both FS and FP analysis. The histological types include AIS, MIA, and invasive adenocarcinoma. If the lesion is diagnosed as AIS or MIA by intraoperative FS, the patient will be included at the second registration.

Follow-up

The follow-up of all patients will continue until at least five years after surgery in the outpatient department. And the primary and second endpoints will be evaluated. Thoracic CT scan will be performed annually after surgery.

Statistical analysis

JCOG0201 was an important study conducted by the Japan Clinical Oncology Group (JCOG) which predicted less invasive LUAD by thin-section chest CT scan (7).

The study showed that LUAD with a maximum of tumor diameter ≤2.0 cm and a ratio of consolidation component diameter to the maximum tumor diameter ≤0.25 on thin section CT was consistent with a less invasive tumor. Furthermore, the JCOG0804 study showed that the 5-year OS and RFS rates for less invasive LUAD patients who underwent sublobar resection were 99.4% and 99.7%, respectively, and 98.6% and 98.5%, respectively, for 10-year OS and RFS rates (8). Therefore, we assumed the expected 5-year RFS for AIS/MIA patients diagnosed by intraoperative frozen diagnosis as 98%, with a lower limit as 95%. If we set 3% as the non-inferiority boundary, the bilateral alpha of 5%, and a power of more than 90%, the required sample size was calculated as 390 patients in total.

Ethical aspects and dissemination

The study will follow the Declaration of Helsinki (as revised in 2013). The study protocol and its related documents were approved by the Institutional Review Board of the Fudan University Shanghai Cancer Center (SCCIRB) in June 2023 (No. 2306277-6, version identifier V2.0, 2023.07.01), and informed consent will be obtained from all individual participants.

Any alterations that could impact the execution of the trial, including revisions to the design, aims, sample size, or significant administrative aspects, will necessitate a formal protocol amendment to be submitted to the Institutional Review Board for approval.

Regarding matters of privacy and confidentiality, measures will be taken to ensure participant anonymity is maintained, and the collected data will be utilized solely for the intended research objectives. The study findings are intended for submission to a peer-reviewed scientific journal for publication, as well as for presentation at relevant conferences in the field.

Registration number

This trial has been registered at ClinicalTrials.gov (identification number: NCT06031181).

Discussion

Surgical strategy for stage I NSCLC is still a controversial issue. In particular, with the increasing number of ground glass opacity (GGO) types of lung cancer, more individualized surgical strategies are needed. Although many ongoing trials focus on the surgical treatment of these patients, current evidences of strategies including indications for sublobar resection and lymph node dissection are still limited. In this study, we intend to use intraoperative FS to accurately diagnose AIS and MIA, followed by sublobar resection, and aim to confirm the efficacy and safety of this surgical strategy.

Several studies have analyzed the accuracy of intraoperative FS for diagnosing early-stage LUAD according to the WHO classification system. Walts and Marchevsky recategorized and compared the diagnosis of intraoperative FS and the FP and found that the accuracy rates of intraoperative FS diagnoses for invasive LUAD, AIS and MIA were 97%, 59% and 46%, respectively (9). The most common error of intraoperative FS was overdiagnosis of MIA as invasive LUAD. Our previous studies retrospectively analyzed several cohorts of early-stage LUAD. The earliest study analyzed 803 cases with clinical stage I peripheral LUAD undergoing sublobar resection (5). The accuracy of the FS diagnoses for AIS and MIA were 88.0% and 89.4%. And the concordance rate was 95.9% for one low-risk group consisting of AAH, AIS and MIA. The next study analyzed 3,031 patients who underwent sublobar resection of AAH, AIS or MIA diagnosed intraoperatively by FS (6). The overall concordance rate between FS and FP was 93.7% for one low-risk group. Finally, another study reviewed 1,644 cases with a pathologic diagnosis of AIS or MIA by FP (3). The overall sensitivity of FS diagnosis for AIS or MIA lesions was 92.4%. However, all of these data were from retrospective studies. This prospective study will provide more convincing data on the consistency of FS and FP for the diagnosis of AIS and MIA.

Sublobar resection is an important surgical procedure for early-stage lung cancer. According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: NSCLC (Guidelines ver. 1 2024), anatomic pulmonary resection is preferred for the majority of patients with NSCLC. For peripheral T1abN0 tumors, segmentectomy and wedge resection should be strongly considered. Furthermore, sublobar resection should sample appropriate N1 and N2 lymph node stations as well unless not technically feasible without substantially increasing the surgical risk. However, the NCCN guidelines are not precise enough to recommend the indication for sublobar resection, especially because they do not distinguish between GGO type lung cancer and solid lung cancer. AIS and MIA generally appear as GGO on high resolution CT (HRCT). Our previous study revealed that the 5-year RFS rate of AIS and MIA was 100% (3). The 5-year OS rate of AIS and MIA was 98.8% in the wedge resection group and 98.2% in the segmentectomy group. Therefore, sublobar resection, especially wedge resection without lymph node dissection, might be suitable for AIS or MIA patients. These results were similar to those from other recent studies. The recent results from JCOG0804, JCOG0802, and CALGB 140503 trials provided potential evidence for the validity of sublobar resection in patients with small size (less than 2 cm) lung cancers (8,10,11). However, in these studies, the decision on the surgical plan was based on the CT imaging characteristics rather than pathological diagnosis. Usually, pathology is the gold standard for diagnosis of cancer. Therefore, in this study, it may be more accurate to use intraoperative FS to guide surgery than CT.

With the completion of this study, we hope to deliver new evidence on the efficacy and safety of sublobar resection without lymph node dissection for cT1N0M0 NSCLC which are diagnosed as AIS or MIA by FS.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-623/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-623/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-623/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 study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol was approved by the Institutional Ethics Board of Fudan University Shanghai Cancer Center (SCCIRB) in June 2023 (No. 2306277-6) and informed consent will be obtained from all individual participants.

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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