Chasing shadows in the dark: a comment on the Thoracic Surgical Oncology Group 102 study of ground glass opacities

The members of the Thoracic Surgical Oncology Group (TSOG) should be commended for the recent publication in the journal of thoracic and cardiovascular surgery (1). The TSOG study is a multi-center prospective registry of patients with ground glass opacities (GGOs). This is the largest cohort of patients in North America in such a study. The objective of this registry is to assess the safety of active surveillance for patients with two or more ground-glass predominant lung nodules that are 3 cm or less in total size. In the published report, the authors indicate they were able to meet their target accrual, indicating that the registry trial was feasible.

The pragmatic study design and patient selection criteria of this present trial will yield results that can be generalized to the United States patient population. It will also provide significant insight into the treatment of GGOs as well as their natural history. The optimal management of GGOs remains controversial in thoracic oncology, weighing the risk for progression to malignancy versus the cost and potential harm of unnecessary interventions. There are currently no widely accepted guidelines to dictate the optimal timing for intervention on these lesions, and active surveillance has been increasingly used in other solid cancers with good results (2,3). The current literature is largely based on small, retrospective cohort studies with limited applicability to the patient population of the United States, and they fail to address the variable characteristics of GGOs that make their management so challenging (4-6). One retrospective study from Japan looked at over 7,000 patients undergoing lung cancer screening, tracking 439 solitary pure GGOs overtime for growth and development of malignancy, but they excluded patients with GGOs larger than 5 mm or those with solid components (6). Meanwhile, previous studies based in Japan and South Korea have suggested that larger initial lesion size and the presence of solid components are risk factors for GGO growth, making inclusion of larger lesions and solid components key to better understanding optimal clinical management (7,8). Another study from South Korea followed 122 pure GGOs over 5 years, and the authors found that approximately 90% of pure GGOs did not grow during follow-up, but the authors excluded patients with previous malignancy, resection of any GGO in the last 2 years, and any GGOs with solid components (5). This patient cohort contrasts with the TSOG 102 cohort where solid components up to 50% of the lesion are allowed and 51% of patients have a history of lung cancer. Additionally, in the TSOG 102 cohort 70% of patients are former smokers and 9% are current smokers while the South Korean study’s cohort consists of 34% non-smokers, 27% former smokers, and 39% current smokers (5). With the limitations of previously published studies, the TSOG 102 multicenter prospective registry trial provides the unique opportunity to obtain pragmatic data that providers can apply to everyday practice.

The current guidelines on lung cancer screening from the National Comprehensive Cancer Network (NCCN) recommend interval computed tomography scans at 12 months for non-solid pulmonary nodules less than 2 cm and at 6 months for those greater than 2 cm with further evaluation by biopsy or excision based on GGO growth and the development of solid components (9). For part-solid nodules, size of the solid component and growth overtime are also used to determine when further investigation with either a positron emission tomography scan or biopsy is warranted (9). In addition to the NCCN, the Fleischner society, the British Thoracic Society, and the Japan Clinical Oncology Group (JCOG) have published recommendations for the surveillance and treatment of GGOs and part-solid nodules, agreeing that lesion growth and the development of solid components confer a higher risk of malignancy, but much is left up to center-specific guidelines based on individual patient risk factors (10). Predictive models such as the Brock Model have been designed to help clinical decision making, which incorporates lesion size and location, presence of a solid component, and past medical history to predict the risk of malignancy, but it does not account for lesion growth overtime (11). In short, if you ask ten different thoracic surgeons across North America, what to do about a specific ground glass lesion, you may get ten different answers.

The management of GGOs is complicated by the variable risk profile they carry based on nodule characteristics, growth overtime, and individual patient risk factors. Some studies report that up to 63% of GGOs harbor malignancy, but in cases of solitary pure GGOs with no solid component, as little as 1% of lesions develop into malignancy in select patient populations (2,6). In contrast, in a study published in Japan, 104 GGOs with solid components (comprising less than 50% of the lesion) were resected, and the majority were found to be low-stage adenocarcinoma (12). However, it is not known how aggressive these adenocarcinomas would be, some of which are stage zero, if left for observation. The literature suggests that risk factors for GGO growth include larger initial lesion size, smoking history, old age, and the presence of a solid component, but again these are based on small, retrospective studies with low generalizability (4,7,8). To better inform clinical practice in the United States and guide future guidelines, pragmatic information that can be applied to a broad array of clinical scenarios is needed.

The TSOG 102 trial has been excellently designed to provide pragmatic data that can be generalized to a large patient population and many different clinical scenarios (1). The idea of pragmaticism in the context of clinical trials was first discussed in the literature in the 1960s, and it was contrasted with explanatory features found in many clinical trials (13). In general terms, a pragmatic trial is meant to provide information to help inform clinical decision-making in the everyday setting, and their cohorts will commonly include patients with more comorbid conditions, worse performance statuses, and more significant past medical history (14,15). Explanatory trials are well resourced with a highly selected patient population where strict adherence is typically enforced, and their results are usually less generalizable to the patient population in question (14,15). The TSOG 102 prospective registry trial differs from previous literature and other prospective registry trials being undertaken internationally. It does not limit the number of GGOs in a single patient, and it includes patients with poor performance status, advanced age, and previously treated stage IA lung cancer. In their publication of patient characteristics, the authors revealed that the cohort is composed of 70% former smokers with a mean of 30 tobacco pack years. Additionally, 51% of patients have previous lung cancer, and 86% of patients were already undergoing active surveillance at the time of enrollment. Furthermore, even patients who undergo intervention, such as biopsy or surgical excision, continue to undergo active surveillance of their GGOs so long as they continue to meet eligibility criteria (1). Although the pragmatic study design is a strength of the TSOG 102 trial, the authors must also proceed with caution to avoid common pitfalls of this design, such as inter-center variability in data collection. In particular, adherence monitoring will be key to ensure each individual center provides high fidelity data and follows the standardized protocol of the trial. A considerable effort will also be required to prevent patient attrition during the long-term surveillance stage of the trial.

In comparison to the TSOG trial, the JCOG study 1906 is limited to those with only 1–3 GGOs, patients no older than 79 years of age with performance status 0–1, and no prior treatment for any neoplasm or prior radiation to the lungs or mediastinum (16). Additionally, the Eastern Cooperative Thoracic Oncology Project 2021 trial, another prospective registry trial for the active surveillance of GGOs, excludes patients with previous anti-tumor or radiation therapy, any prior malignancy in the past 5 years, performance status greater than 1, history of any lung surgery, and any severe disease that reduces life expectancy to 10 years or less (17). These exclusion criteria represent a more selective patient population, and as a result, the findings will be less applicable to all patients undergoing surveillance of GGOs. Furthermore, it is well established that multifocal GGOs in the Asian population is likely a different entity than multifocal GGOs in the North American population, especially when comparing non-smokers to smokers. For example, a prior study of patients undergoing resection for sub-solid lung adenocarcinoma found that Asian patients were more likely to be non-smokers and have an EGFR mutation when compared to Caucasian patients who were more likely to have a KRAS mutation (18). With recent data predicting a 90% increase in the number of people in the United States with multiple comorbid conditions by 2050, pragmatic study designs, such as the one utilized in the TSOG 102 trial, are becoming increasingly important (19). Although necessary in many contexts, the use of highly selective patient criteria can restrict the findings of prospective trials, making it more difficult to create guidelines that can be applied to actual clinical practice. By removing patients with poor performance status, previous malignancy, or high-risk comorbid conditions, studies can miss a key demographic, and the data may be skewed to underestimate the actual risk in these patient groups.

The true contribution of this trial will hinge upon the long-term outcomes and authors’ ability to maintain standardization throughout the follow-up phase. Additionally, the results of this study will need to be validated in diverse populations, and the findings should be used with caution in patients without a smoking history or previous lung cancer. Again, congratulations to the authors of the TSOG 102 prospective registry trial for the publication of their patient characteristics and completion of the accrual phase (1). Given the composition of the patient cohort, thanks to well thought out patient selection, the outcomes of the follow-up phase will provide excellent insight into the treatment of GGOs in a large portion of patients in the United States.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-5/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-5/coif). The authors have no conflicts of interest to declare.

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