Protocol of a single-arm, multicenter, phase III trial for selective lymph node dissection in cT1N0M0 invasive non-small cell lung cancer with consolidation-tumor ratio >0.5 located in the apical segment: Eastern Cooperative Thoracic Oncology Projects ECTOP-1018 (SELLAS study)

Introduction

Background

Lung cancer is the leading cause of cancer-related mortality in the world. Radical surgery is the most important treatment method for localized non-small cell lung cancer (NSCLC). Since 1960s, systemic mediastinal lymph node dissection (LND) has become an indispensable part of radical resection of NSCLC, with a purpose of confirming lymph node (LN) staging, evaluating prognosis and guiding postoperative therapy (1). However, although systemic LND is still the gold standard for NSCLC surgery, its necessity in early-stage patients without LN metastasis remains controversial. Liang et al. found a significant survival benefit for those subjects with more than 16 LNs removed in the pathologic nodal-negative cohort (2). In a randomized controlled clinical study (n=169) comparing systematic LND with LN sampling, Izbicki et al. found that LND only prolonged the recurrence-free survival (RFS) (P=0.037) of patients with LN metastasis (pN1 and pN2), but it could not reduce the local recurrence rate of patients without LN metastasis (pN0) and had no significant impact on survival (3). Therefore, preventive LND in pN0 patients does not improve prognosis. Recent research found that LND may suppress immunotherapy efficacy and accelerate tumor growth, which in turn poses a potential threat to patient survival (4). In addition, unnecessary LND prolongs the operation time and may cause surgical complications, such as bleeding, air leakage, nerve damage, and lymphatic damage. Therefore, how to avoid mediastinal LND in pN0 early-stage lung cancer patients to reduce surgical trauma and reduce the incidence of postoperative complications while ensuring oncological prognosis is a challenge faced by lung cancer surgery (5).

Rationale and knowledge gap

Selective LND, in which systemic mediastinal LND is waivered in some patients with a low probability of LN metastasis, is an important way to reduce surgical trauma in early-stage NSCLC patients. The key of this maneuver is to find accurate predictors of pN0. Previously, we conducted a series of studies around this key scientific issue and revealed that age, tumor size, location (central or peripheral), and histologic subtype were closely related to LN metastasis (6,7), and proposed valuable methods of prediction for mediastinal LN metastasis in clinical T1N0 NSCLC (8,9). Recently, we published the results of our prospective trial validating the specific mediastinal LN metastasis pattern in cT1N0 invasive NSCLC, which reveals that the tumor located in the apical segments will not have LN metastases in the lower mediastinum (10). Here, we initiated this multi-center, prospective, phase III clinical trial to explore the role of selective LND which waivers the inferior mediastinal LND, in terms of overall RFS, on cT1N0M0 invasive NSCLC located in the apical segment of the lung with a consolidation-tumor ratio (CTR) greater than 0.5.

Objective

The main aim of this prospective phase III study is to explore the prognosis of the patients with a cT1N0M0 invasive NSCLC (CTR >0.5) located in the apical segment of the lung, who receive radical lung cancer surgery but waiver lower mediastinal LND. The primary endpoint is RFS. The secondary purposes are to reveal overall survival (OS) rate of these patients, metastatic distribution of LNs in different histological subtypes of NSCLC, and consistency between frozen and paraffin pathology reports in determining the tumor invasiveness. The study protocol is illustrated as Figure 1.

Figure 1 Protocol flowchart. NSCLC, non-small cell lung cancer; CTR, consolidation-tumor ratio; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; DFS, disease-free survival.

Methods

This trial is a multi-center, single-arm, prospective confirmatory phase III clinical study. It mainly evaluates the 5-year RFS after curative surgery of selective LND on patients with cT1N0M0 NSCLC in the apical segment of the upper lobe of the lung with CTR >0.5 at computed tomography (CT) scan.

Eligibility criteria

All enrolled patients must meet the following criteria: (I) voluntarily participate in clinical research, be willing to follow and have the ability to complete all trial procedures; (II) aged 18–80 years old (including the critical value) when signing the informed consent form; (III) the Eastern Cooperative Oncology Group (ECOG) score 0 or 1 (11); (IV) have not received lung cancer surgery in the past; (V) patients with surgically resectable peripheral cT1N0M0 located in the apical segment of the upper lobe of the lung and with CTR >0.5; (VI) invasive NSCLC with predominantly non-lepidic subtype confirmed by intraoperative frozen pathology; and (VII) new to treatment and have not received radiotherapy or chemotherapy.

Patients have any of the following conditions will be excluded from this study: (I) intraoperative staging is not T1N0M0; (II) the nodule is not located in the apical segment of the upper lobe of the lung or CTR ≤0.5; (III) cytologically or histologically confirmed pre-invasive NSCLC, lepidic-predominant NSCLC, or other lung malignant tumors other than NSCLC; (IV) have had lung cancer surgery in the past; and (V) non-treatment-naïve patients who have received radiotherapy or chemotherapy.

Patient withdrawal or termination criteria

All data in this study are obtained based on existing examinations and operations and do not cause any additional harm to the patients. The patients can withdraw anytime from this study if: (I) the patient requests that his/her data not be used in this clinical study; (II) patient enrollment errors (e.g., patients do not meet the inclusion/exclusion criteria); and (III) the patient voluntarily requests to withdraw from the clinical study.

Preoperative CT imaging evaluation and clinical staging

All patients must complete a thin-section (1 mm) contrast-enhanced CT scan of the chest before enrollment. According to the CT scan results, the long diameter of the tumor is the maximum diameter of the tumor (solid component + ground glass component) on the CT transverse section. The size of the solid component is the maximum diameter of the solid component on the CT transverse section. The CTR is defined as the ratio of the size of the solid component to the long diameter of the tumor. For pure ground-glass nodules with no solid component, the CTR is 0. cN0 means the shortest diameter of intrapulmonary, interlobar, hilar, and mediastinal LNs on enhanced CT is ≤1 cm, or there is no increased uptake of LNs on positron emission tomography (PET)/CT (12). If PET is positive in LNs, the patient would be excluded from the study. Peripheral type is defined as tumors located in the subsegment and the small bronchi below. The 8^th edition of the tumor-node-metastasis (TNM) lung cancer staging system is applied in this study.

Treatment

The eligible patients receive lung surgery and selective LND which waives the lower mediastinal LNs. There are 15 experienced thoracic surgeons doing this procedure. The type of the incisions is up to the surgeon’s preference. Most surgeons prefer single-port VATS, and the incision is made in the 4^th intercostal space between the anterior axillary line and the mid-axillary line. Some surgeons prefer two holes adding an observational port in the 7^th intercostal on the mid-axillary. Others choose three ports VATS. For some difficult cases, open muscle-sparing incision in the 4^th intercostal space is also applied. Lobar or sublobar resection (segmentectomy or wedge resection) is performed on patients who meet the inclusion criteria, and frozen pathology diagnosis is routinely performed during the operation. The definition of LN stations is according to the 8^th edition of TNM staging LN chart. All samples will be labeled and sent for paraffin pathologic assessment. All operative records or videotapes will be reviewed and evaluated by the principal investigator. Based on previous research results, lung cancer with CTR ≤0.5 indicates no LN metastasis (9). Therefore, this study only prospectively explores the efficacy of sparing LND of the lower mediastinum in NSCLCs with CTR >0.5 and located at the apical segment. The upper mediastinal, hilar, and intersegmental LNs exposed during the operation need to be removed and sent for pathologic examination using ultrasound scalpel and electric hook (13). Specifically, for tumors located in the right apical segment, removal of nodal stations #2R, #4R, and #10R was required. For tumors located in the left apical segment, removal of nodal stations #4L, #5, #6, and #10L was required.

Intraoperative and paraffin pathologic evaluation

All primary tumors will be sent to the pathology room for frozen pathologic diagnosis immediately after resection. Frozen samples are taken from the largest diameter of the tumor, and usually two slices are taken for intraoperative pathological diagnosis. Diagnosis is based on the 2015 version of World Health Organization (WHO) classification criteria. All frozen sections will be evaluated by two experienced pathologists. The paraffin pathological diagnosis of postoperative tumors is still based on the 2015 version of WHO classification criteria. This study included patients whose final postoperative pathology is NSCLC. All pathology reports will be evaluated by the principal investigator. The postoperative management will be based on the final pathologic reports and the patient’s specific conditions and follow the latest guidelines.

Documentation of patient compliance

The principal investigator or researcher instructs the subjects to comply with the requirements and plan of this study, and records the subjects’ actual performance and treatment effects in the case report form (CRF).

Endpoints

The primary endpoint of this study is RFS which is defined as recurrence and death from any cause, and the duration is defined as the time from surgery to tumor recurrence or the last follow-up visit. The secondary purposes are (I) OS, the duration is defined as the time from surgery to the patient’s death or last follow-up. (II) LN metastasis of pure-solid and subsolid tumors and among different histologic subtypes of NSCLC. The main pathological subtypes of NSCLC based on postoperative pathology results will be determined, and LN metastasis of different types of nodes will be counted. (III) Consistency between intraoperative frozen pathology and postoperative paraffin pathology in determining the invasiveness of NSCLC.

We plan the 10-year following strategy to evaluate survival endpoints. For the first 2 years after surgery, outpatient follow-up procedures include physical examination, chest CT, neck and abdominal ultrasonography every 6 months, and then annually. Brain imaging and radionuclide bone scan will be performed as appropriate based on patient conditions. For those who miss the outpatient visit over time, we will make phone calls to the patients or their relatives in order to confirm the survival status.

Data management and quality control

Plan revision

Any modifications or additions to the plan should be stated in a written plan amendment, and the plan amendment can only be implemented after approval by the Independent Ethics Committee (IEC)/Institutional Review Board (IRB). During the course of the study, deviations from the protocol are inevitable. In an emergency, immediate measures must be taken to ensure the safety of the subjects, even if such measures lead to deviations from the protocol. Any deviations from the plan should be recorded in the CRF, and the deviations and reasons for the deviations should be described in the documents.

CRF

All CRFs recording, corrections, and modifications must be completed by the investigator or other authorized research personnel, as described in detail in our previous study which demonstrated their validity and reliability (10). All original documents (e.g., informed consent forms, laboratory reports, treatment history, procedure notes, results of physical examination and treatment, diagnoses, follow-up results) must be maintained on file. The above documents will be saved and will be kept for at least 5 years after the research has been suspended or completed.

Data management

The researchers must maintain adequate and accurate records so that research can be fully documented and research data can be subsequently verified. These documents will be divided into two different, independent categories: (I) investigator study documents; and (II) patient clinical documents. The investigator documents will include the research protocol/revised protocol, case report and inquiry form, IEC approval document, sample informed consent form, surgical records, staff resumes, and other relevant documents. In addition to the leading unit, patients from at least two other medical centers were enrolled, and each center enrolled at least 20 cases. Participating units must keep accurate clinical data archives and research documents, including CRFs, informed consent forms, IEC approval documents, informed consent sample forms, surgical records, staff resumes and other relevant documents. All documents are summarized and analyzed by the leading unit.

Statistical analysis

Statistical plan

The statisticians and principal investigators will formulate a statistical analysis plan based on the research protocol, and conduct statistical analysis according to the statistical plan after the data is locked.

Data selection for statistical analysis

Two data sets are established when doing statistical analysis, including full analysis set (FAS) and per-protocol set (PPS). FAS is a data set determined according to the ITT principle and includes all enrolled cases that underwent segmental resection. PPS is a subset of the FAS population, including all cases that comply with the trial protocol and complete CRF. In this trial, FAS is used for baseline and effectiveness analysis, and PPS is analyzed to determine the main efficacy indicators. However, the FAS outcomes are mainly used. When the results obtained by FAS and PPS are consistent, the credibility of the conclusion can be increased. The missing data after dropout are estimated using the LOCF method for the FAS. Laboratory examination data, adverse events, and adverse reaction data were analyzed using SPSS and STATA software.

Calculation of sample size

Based on our previous studies (10,14), the 5-year RFS after systemic mediastinal LND for cT1N0M0 apical non-lepidic-predominant invasive NSCLC with CTR >0.5 was 84.3%. Therefore, we limit the expected 5-year RFS of patients with apical CTR >0.5 cT1N0M0 nodules who undergo selective LND to 85%, and the lower limit is defined as 80%. Taking 5% as the non-inferiority margin, a total of 634 cases need to be included in this study. According to the results of the Z0030 study, 4% of patients with cT1N0M0 NSCLC may develop N2 LN metastasis, and systemic LND in these patients still cannot improve the prognosis. Therefore, in order to prevent patients from having mediastinal LN metastasis that affects their long-term prognosis, this study is set to terminate if >4% of the patients develop mediastinal LN metastasis during follow-up when enrolling 211 patients in the first third stage of the program. The statistical analysis will be performed after the postoperative pathologic results are obtained for the last case.

Ethical issues

Potential subjects will be fully informed of the risks and requirements of the study, and provided with any new information during the study that may affect their continued participation in the study. They will be informed that participation in the study is voluntary and there will video recording during the operation. They may withdraw at any time without giving any reason and without penalty or loss of any deserved benefits. Only the subjects who can fully understand the risks, benefits, and potential adverse events of this study and voluntarily sign an informed consent form will be enrolled. 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 (No. FUSCC2304), and informed consent will be obtained from all individual participants.

Researchers’ responsibilities

Before starting the trial, the investigator needs to sign the protocol signature page to confirm that he/she agrees to conduct the trial in accordance with these documents. Investigators are responsible for ensuring that clinical studies are conducted in compliance with the study protocol, Good Clinical Practice (GCP) guidelines, and applicable regulatory requirements.

IEC/IRB

The protocol and informed consent form must be reviewed and approved by a properly constituted IEC/IRB before the trial can be initiated. Before the trial is initiated, a document that the protocol and informed consent form have been approved by IEC/IRB must be submitted to the principal investigator, signed and dated.

Informed consent

Before being enrolled in a clinical trial, the subjects should be able to understand and sign a written informed consent form approved by IEC/IRB, and be able to date the consent form. If the patient is unable to do this, his/her legal representative may sign. Informed consent must be written in a language that the subject (or his or her legal representative) can read and understand. Informed consent forms should comply with the Declaration of Helsinki, current International Conference of Harmonization (ICH) and GCP guidelines, and corresponding regulations.

Before a subject joins the trial, the researcher or a person recognized by the research institution is responsible for explaining the purpose, methods, possible benefits, and potential risks of the study to the subject (or his or her legal representative). Subjects should be informed that participation in the trial is voluntary and that they can withdraw at any time. After signing the informed consent form, subjects should receive a copy of the informed consent form.

Confidentiality of personal data

Personal data collected and processed from the participants will be limited to that necessary to fulfill the purposes of this study. Adequate precautions will be taken when collecting and using this data to ensure confidentiality and to comply with privacy protection laws and regulations. Appropriate technical and organizational measures will be adopted to protect personal data against unauthorized disclosure or access, or accidental loss or alteration.

Discussion

This clinical trial is a multi-center, prospective, non-randomized confirmatory study aiming to explore the role of selective LND which waivers the inferior mediastinal LND, in terms of RFS, on cT1N0M0 invasive NSCLC located in the apical segment of the lung with a CTR greater than 0.5. The aim is to prospectively validate our prior retrospective findings that cT1N0M0 NSCLC in the apical segment do not need LND in lower mediastinum. The rationale for the study is well-supported by previous evidence questioning the necessity of complete mediastinal LND in early-stage lung cancer without LN metastasis.

Some potential biases and limitations associated with the study design have to be addressed before it can be fully conducted. Firstly, this trial is designed as a single-arm, cohort study, not as a randomized controlled trial (RCT). The reason for the designation is that RCT would have been stronger on the evidence level. However, considering the excellent survival of ground-glass opacity (GGO)-featured lung cancer, RCTs regarding LND strategies require excessive sample size and follow-up time. It may be very difficult or even impossible to conduct such RCTs. Therefore, in order to ensure the operability of the study, we decide to conduct it as a non-randomized manner. Secondly, although this trial is planned as multi-center study, the centers are all from mainland China and the enrolled patients are limited to East-Asians, thereby raising concerns about the generalizability of the results, as the histologic spectra of NSCLC may be different among different ethnicities. At last, the specific procedures for LND may vary as there will be multiple surgeons from different medical centers performing the procedure. We solve this problem through frequent academic exchanges and training to ensure the consistency of the surgical operation.

Acknowledgments

Funding: This work was supported by the Shanghai Pujiang Program (2020PJD014), the National Natural Science Foundation of People’s Republic of China (82430099 and 81930073), the Cooperation Project of Conquering Major Diseases in Xuhui District (XHLHGG202101), and the National Key R&D Program of China (2022YFA1103900).

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1114/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1114/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 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 (No. FUSCC2304), 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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