Active surveillance for patients with multifocal ground-glass nodules: protocol of a prospective, multi-center, single-arm trial (ECTOP-1021)

Introduction

Lung cancer remains the leading cause of cancer-related death worldwide. With the clinical adoption of low-dose computed tomography for lung cancer screening, there is an increased detection of early-stage lung cancers, often presenting as ground-glass opacity (GGO) in radiology. These lung cancers exhibit a favorable prognosis following surgical resection, with a 5-year recurrence-free survival (RFS) of 99.4% for pure ground-glass nodules (GGNs) and 91.7% for part-solid nodules (1). For pure GGNs with tumor diameter <3 cm, the 5-year RFS is 100%, and surgical resection is offered as a curative treatment (2). Nevertheless, concerns are rising about the potential overtreatment at a population level associated with the resection of specific GGNs, given their indolent biological behavior (3). In a surveillance study of GGO predominant nodules with a tumor diameter less than 3 cm and a median follow-up period of 4.3 years, 14% of pure GGNs and 48% of part-solid showed an increase of over 2 mm in size. Only 5.4% of the pure GGNs developed a solid component, while 22% of the part-solid nodules demonstrated an increase in solid component size of over 2 mm (4). Conversely, surgical resection is associated with the loss of lung parenchyma and the inherent risk of adverse events. Consequently, there is a perspective advocating for a surveillance approach, rather than immediate resection, as a viable option for certain GGNs.

The surgical curative time window for treating lung cancer is subsequently proposed, defined as clinical and pathological disease stages during which 5-year RFS reaches 100% after complete resection. The time window includes pure GGNs in radiology with size <3 cm, as well as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) stages in pathology (5). Surgical intervention is deemed appropriate at any point within this time window, eliminating the necessity for immediate surgery upon initial detection. However, uncertainties persist regarding the impact of delayed surgery on survival and the optimal timing of surgery within a surveillance context. Thus, urgent prospective studies are warranted to address these critical aspects.

In our previous study, patients with invasive adenocarcinoma tumors measuring diameter ≤2 cm and consolidation-to-tumor ratio (CTR) ≤0.25 demonstrated a 5-year lung cancer-specific overall survival (OS) of 100% and a 5-year RFS of 100% (6). Based on these findings, this clinical trial aims to enroll patients characterized by GGNs with a tumor diameter ≤2 cm, CTR ≤0.25, and the presence of three or more nodules. Radiological surveillance will be performed until their diseases progress to a point surgical intervention be necessary. Subsequently, a comprehensive evaluation will be conducted to assess the prognosis of patients with or without surgery. We present the protocol in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1956/rc).

Methods

This clinical trial is one in a series of clinical trials collectively known as the Eastern Cooperative Thoracic Oncology Projects (ECTOP), specifically numbered as 1021. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center in November 2023 (No. 2310284-13) and informed consent will be taken from all the patients. The protocol is slated for review by the respective review boards of upcoming participating centers prior to patient registration. Patient accrual commenced in November 2023. This trial is officially registered on ClinicalTrials.gov (NCT06097910).

Objectives

The aim of the trial is to confirm the safety of active surveillance for patients with early-stage multifocal GGNs. This study is a prospective, multi-center and single-arm trial (Figure 1).

Figure 1 Flow chart of the trial. CTR, consolidation-to-tumor ratio.

Endpoints

The primary endpoint is the 5-year OS of all enrolled patients. OS is defined as the period from the initial detection of the lung lesions to death from any causes, with censoring at the last confirmed survival date.

The secondary endpoints are listed below.

• 10-year OS.
• 5- and 10-year operation-free survival.
• 5- and 10-year proportion of extensive lung resection.
• 5- and 10-year proportion of unresectable progression.
• 5- and 10-year lung cancer-specific survival.
• 5- and 10-year of proportion of lesion progression.
• 5- and 10-year of proportion of non-per-protocol surgery.

Operation-free survival is defined as the period from the initial detection of the lung lesions to the time point of surgical resection, unresectable progression, or death from any cause, whichever observed first, with censoring at the last confirmed survival date without evidence of these events. Proportion of extensive lung resection is defined as the proportion of resected cases in which a more extensive resection of lung tissue occurs (e.g., sublobar resection instead of wedge resection, or lobectomy instead of sublobar resection) compared to the surgery plan initially specified at enrollment, compared to all cases. Proportion of unresectable progression is defined as the proportion of cases in which tumor metastasis occurs to contralateral mediastinal lymph nodes, pleural effusion, or distant organs, in relation to all enrolled cases. Lung cancer-specific survival is defined as the period from the initial detection of the lung lesions to death specifically from lung cancer, with censoring at the last confirmed survival date. Proportion of lesion progression is defined as the proportion of cases in which the tumor diameter increases >2 mm in any lesion, the solid component diameter increases >2 mm in any lesion, or the detection of any new lesion, compared to all cases. Proportion of non-per-protocol surgery is defined as the proportion of resected cases prompted solely by patient subjective preferences, despite the researchers’ assessment of its lack of necessity at that point, compared to all cases.

Eligibility criteria

Inclusion criteria

Patients eligible for enrollment in the study are required to meet all the following criteria.

• Demonstrates the following on thin-section computed tomography (TSCT) scan:
  • Presence of three or more GGNs (bilateral lesions are permitted).
  • All lesions have remained stable without regression or enlargement for at least 3 months.
  • The dominant lesion (the lesion with the largest maximum tumor diameter) has a maximum tumor diameter ≥0.6 and ≤2 cm.
  • CTR ≤0.25 in all lesions.
  • No lymph node with a diameter >1 cm in the mediastinal view.
  • Not adjacent to the pleura in dominant lesion and no sign of pleural retraction in any lesions.
• Aged 18–75 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Has not previously undergo any anti-tumor drug or radiation therapy.
• Written informed consent.

Exclusion criteria

Patients will be excluded if they meet any of the following criteria.

• History of any prior malignancies within the past 5 years.
• History of lung surgery.
• History of interstitial pneumonia, pulmonary fibrosis or other severe pulmonary diseases.
• Presence of severe or uncontrolled diseases that may possibly reduce the 10-year life expectancy.

Treatment and follow-up

For the recruitment period, if a patient has previously undergone lung TSCT with a slice thickness of ≤1 mm, the eligibility evaluation will be based on the first TSCT that reveals the presence of lung lesions. A confirmatory TSCT performed at least 3 months later is mandatory to ensure all detected lesions are persistent. If no prior TSCT is available, the eligibility evaluation will be based on the TSCT conducted at the time of enrollment, and a confirmatory TSCT will be performed at the 3 months later. Radiologic information from participating centers will be centrally reviewed by two experienced radiologists at Fudan University Shanghai Cancer Center. For irregular lesions or solid components, multiple plane reconstruction will be employed, with the largest dimension analyzed. Any discrepancies between the two radiologists will be resolved through discussion to reach a consensus.

For the active surveillance period, radiologic follow-up will be conducted every 12 months over a period of 10 years, all using TSCT. The surgery plan is specified at the time of enrollment. The decision regarding surgery is based on the surgeon’s evaluation of radiologic follow-up. The reference resection criteria encompass: (I) any lesion that progresses to a tumor diameter larger than 2 cm or has CTR greater than 0.25. (II) clinical tumor, node, metastasis (TNM) stage upstaging. The study employs the ninth edition of the International Association for the Study of Lung Cancer (IASLC) TNM classification for lung cancer. For patients undergoing surgical resection, survival information is obtained throughout the maximum follow-up period, extending up to 10 years after the initial detection of the lung lesions.

Sample size

The study hypothesizes that, for patients with early-stage multifocal GGNs (tumor diameter ≤2 cm and CTR ≤0.25), delaying surgery until lung lesions progress offers a prognosis equivalent to those undergoing immediate surgical resection, potentially allowing many to avoid surgery altogether. According to our previous study, patients meeting the inclusion criteria for this study are expected to have a favorable prognosis, with lung cancer-related mortality anticipated to be zero (6). Thus, OS is primarily determined by patient age. The mean age of the cohort in our previous study was 56.3 years. Based on the 2019 life table of China published by the World Health Organization, the predicted 5-year OS for this population is 96.46% (7). To account for a clinically acceptable decrease in survival, the threshold is set at 93.46%. The estimated sample size is 370, with a two-side alpha level of 5%, a power of 0.8, an expected 5% loss to follow-up rate, an accrual period of 3 years, and a follow-up period of 5 years. If the lower limit of the 95% confidence interval of 5-year OS is greater or equal to 93.46% at the analysis, coupled with a notable reduction in the necessity for surgical resection, it will be inferred that the active surveillance strategy can be clinically applied for patients with early-stage multifocal GGNs.

Discussion

Currently, there is a lack of high-quality evidence supporting the active surveillance strategy for patients with GGNs. The ongoing prospective study, Japan Clinical Oncology Group study 1906 (JCOG1906), is actively recruiting patients with GGO nodules characterized by tumors with a diameter ≤2 cm, CTR ≤0.25, and involving two or fewer lung lesions (8). Additionally, a multi-center study in North America, the Thoracic Surgery Oncology Group 102, has completed enrolling patients with two or more GGO predominant nodules, where tumor diameter ranges between 0.6–3 cm and involves two or more nodules (9).

Different from the JCOG1906 study, we aim to enroll patients characterized by three or more GGOs in this trial. Given that surgery for multifocal nodules often necessitates more extensive loss of lung parenchyma and involves a more intricate surgical plan compared to isolated nodules, the potential of avoiding surgery holds greater significance for these patients. Therefore, the study’s focus on patients with three or more nodules carries substantial clinical value.

Furthermore, we include the proportion of non-per-protocol surgery as one of the secondary endpoints, to evaluate the extent of patient’s adherence to the active surveillance strategy. It is common for patients reconsidering their options during active surveillance, influenced by their own concerns or advice from relatives and friends. The measurement reflects the proportion of resected cases prompted solely by patients’ subjective preferences, despite the researchers’ assessment of its current lack of necessity.

In essence, this study is a prospective, multi-center and single-arm trial aimed at verifying the safety of an active surveillance strategy for patients with early-stage multifocal GGNs. The primary endpoint is the 5-year OS. A positive confirmation of the primary endpoint will establish the observation strategy, involving the avoidance or delay of surgery within the surgical curative time window, as a standard treatment for patients with multifocal GGNs. This will also help confirm the timing of surgery to prevent immediate procedures that often result in overtreatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1956/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1956/prf

Funding: This research is supported by the National Natural Science Foundation of China (Nos. 82430099 and 81930073), the Cooperation Project of Conquering Major Diseases in Xuhui District (No. XHLHGG202101), and the National Key R&D Program of China (No. 2022YFA1103900).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1956/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 The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center in November 2023 (No. 2310284-13) and informed consent will be taken from all the patients. The protocol is slated for review by the respective review boards of upcoming participating centers prior to patient registration.

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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