1 Introduction
Lung cancer is the primary cause of incidence and mortality in China [
1]. In China, most patients with lung cancer are diagnosed at the middle or late stages when they seek medical treatment, and the 5-year survival rate of lung cancer patients is only 19.7% [
2]. Among patients with non-small cell lung cancer, the 5-year survival rate of stage IA1 is 90%, whereas the 5-year survival rate of stage IV is less than 10% [
3]. Therefore, early detection of lung cancer is crucial for improving its poor prognosis. Persistent pure ground-glass nodules (pGGNs) refer to focal nodular lesions with increased density that contain no internal solid components and they either stay unchanged or grow larger during a follow-up period of at least 3 months [
4]. Different pathological types of lung adenocarcinoma, such as atypical adenomatous hyperplasias (AAHs), adenocarcinomas
in situ (AIS), minimally invasive adenocarcinomas (MIAs), and invasive adenocarcinomas (IAs), may present as pGGNs [
5]. With the popularization of health check-ups and the extensive application of low-dose computed tomography in lung cancer screening, the detection rate of pulmonary nodules has been significantly improved. Early diagnosis and treatment of pulmonary nodules are crucial for improving the prognosis of lung cancer. For pulmonary nodules with unclear malignancy, current guidelines generally recommend periodic follow-up with computed tomography (CT) [
6–
8]. Before reaching the surgical intervention indications, patients often fall into a cycle of “re-examination-evaluation-waiting.” This long-term follow-up model not only exposes patients to risks [
9], but also aggravates the economic burden and causes a series of psychological stress issues. Follow-up is essentially a passive waiting process, which cannot prevent some benign nodules from transforming into malignancy. Once nodules are found to have enlarged or solid components during follow-up, the best treatment window is often missed. For patients with early-stage asymptomatic pGGNs, surgical resection is associated with significant surgical trauma and a high risk of postoperative pulmonary function impairment. Moreover, its use remains controversial due to the possibility of overtreatment.
Traditional Chinese medicine (TCM) has a therapeutic advantage in the treatment of pulmonary nodules. A meta-analysis showed that TCM effectively reduces the diameter and number of pulmonary nodules [
10]. Unlike passive waiting for follow-up, TCM can actively intervene in stages where the malignancy of nodules is unclear and does not meet surgical intervention indications. TCM provides a new option of “active treatment” for pGGN patients who require long-term management. YiFei SanJie Formula (YFSJF), as an empirical formula of Professor Jiansheng Li, takes “regulating pulmonary qi and resolving accumulations” as the basic principle of treatment, and shows positive effects in alleviating progression of pulmonary nodules. At present, most studies on the treatment of pGGNs with Chinese medicine are randomized controlled trials. These studies generally have small sample sizes, lack reasonable clinical research designs, have short observation periods, and are mostly single-center studies, which seriously restricts the reliability of research results and their promotion and application. Based on this, the researchers of this study conducted a 2-year multicenter, prospective cohort study. The aim was to understand the efficacy of YFSJF in treating pGGNs and its impact on prognosis through long-term observation, thereby providing evidence for the treatment of pGGNs with Chinese medicine in the real world.
2 Methods
2.1 Study design
This study was a multicenter, prospective cohort study. Patients with pGGNs were enrolled from the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, the First Affiliated Hospital of Henan University of Chinese Medicine, Hopeshine Minsheng Hospital of Xinzheng, Shangcheng County Traditional Chinese Medicine Hospital between January 2021 and December 2022, and the follow-up was completed in December 2024. This study was approved by the Ethics Committee (No. 2021HL-001) and registered with the Chinese Clinical Trial Registry (ChiCTR2100054679).
2.2 Study participants
Eligible patients from four hospitals in China were included if they met all the following criteria: (1) patients diagnosed with pGGNs in the lungs through thin-layer (with a slice thickness of 1 mm) spiral CT scanning of the chest; (2) pGGNs persisting for at least 3 months; (3) age between 18 and 80 years old; (4) good communication and comprehension abilities; (5) voluntary participation and provision of written informed consent. Patients were excluded if they met any of the following criteria: (1) Patients with pGGNs in the lungs who meet the surgical indications; (2) those considered to have metastatic pulmonary nodules; (3) diffuse pulmonary interstitial diseases, such as interstitial pneumonia, pulmonary interstitial fibrosis; (4) organ failure caused by diseases of various systems; (5) pregnant or lactating women.
2.3 Sample size
The primary outcome measure of this study was the growth rate of pulmonary nodules. Previous literature reports that the 2-year natural growth rate of pGGNs is 13.5% [
11], which was used as the growth rate of the non-exposed group. Based on previous clinical observations, it is expected that the 2-year growth rate of pGGNs after the intervention of TCM was 6.75%. The significance level was set as α = 0.05 (two-sided), and the power was 1-β = 0.80. With the ratio of the exposed group to the non-exposed group being 1:1, the data were input into the PASS software for calculation. After correcting the sample size according to a 20% loss to follow-up rate, the result showed that there were 390 cases in both the exposed group and the non-exposed group, making a total of 780 cases.
2.4 Procedures
During the follow-up process of the included patients, detailed demographic, clinical, and other study data were collected through electronic and paper-based case report forms. Follow-up included systematic visits every 3 months and collection of pulmonary CT data, all of which were recorded in a dedicated data form. Information regarding the use of treatments among pGGN patients was recorded during follow-up. The measurement of imaging-related indicator data mainly adopts the pulmonary nodule medical image processing system. In this study, the Myrian pulmonary nodule medical imaging processing system was used, and core indicators such as diameter, volume, and density of the nodules were measured by trained diagnostic physicians. Finally, all measurement results were reviewed by a senior professional physician. At the same time, we developed a standardized operating procedure for measuring pulmonary nodules for multicenter studies, in order to ensure consistency in evaluation between different centers and different measurers.
Exposure factor was defined as the continuous medication for more than 3 months, or intermittent medication for a patient with a total duration of more than 6 months. Patients were divided into YFSJF group and non-YFSJF group based on exposure to YFSJF treatment. The YFSJF group was stratified into three subgroups based on treatment duration: low exposure (3–6 months), medium exposure (6–12 months), and high exposure (≥ 12 months).
YFSJF is composed of such medicinal herbs as Ginseng, Gynostemma pentaphyllum, Pinellia ternata (processed), and Fritillaria thunbergii. The YFSJF used in this study was administered as standardized granules, with the administration regimen of one sachet per dose, three times daily. Meanwhile, we conducted standardized follow-up visits every 3 months to record the patients’ actual medication status in detail, so as to ensure and evaluate their medication compliance.
The clinical efficacy difference between the YFSJF group and non-YFSJF group was compared during the 2-year follow-up. The primary outcome was pGGN growth rate at the 2-year follow-up. The definition of pGGN growth was as follows: volume increase of at least 25%, occurrence of solid components, mean CT attenuation increase of at least 30%, or occurrence of malignant signs [
8,
12,
13]. The secondary outcomes included volume of pGGN, maximum diameter of pGGN in axial plane, mean CT attenuation of pGGN in axial plane, and nodule regression rate at the 2-year follow-up. Nodule regression was defined as a volume reduction of at least 25%, including complete regression (100% volume reduction) and partial regression (≥ 25% to < 100% volume reduction).
Safety outcomes included adverse events and abnormal laboratory indicators during the follow-up.
2.5 Statistical analysis
Statistical analyses were performed using SPSS 26.0. Normally distributed continuous variables were described as mean and standard deviation (SD), and compared between two groups using independent samples t-test. Non-normally distributed continuous variables were presented as median and interquartile range (IQR), and analyzed using the Mann–Whitney U test. Categorical variables were described as numbers and percentages, and compared using chi-square test or Fisher’s exact test. Linear regression analysis was used for continuous variable outcome data, while logistic regression analysis was used for binary variable outcome data to correct for confounding factors affecting YFSJF’s effect on pGGN growth. A two-sided P < 0.05 was considered statistically significant.
3 Results
3.1 Characteristics of the study participants
A total of 780 patients were judged eligible for this study. During the 2-year follow-up period, 63 patients dropped out (19 due to surgical resection, 29 lost to follow-up, and 15 with poor compliance). Ultimately, 717 patients (91.9%) were included in the final analysis, comprising 374 in the YFSJF group and 343 in the non-YFSJF group (Fig. 1). In this study, there were 271 males and 446 females. The average age at which most patients started YFSJF treatment was 51.39 years, with 139 patients (37.2%) being male and 235 patients (62.8%) being female. Among patients with pGGNs treated with YFSJF and those not treated with YFSJF, 57 cases (15.2%) and 59 cases (17.2%) had a history of smoking, 8 cases (2.1%) and 14 cases (4.1%) had a history of occupational exposure, 33 cases (8.8%) and 26 cases (7.6%) had a family history of lung cancer, and 58 cases (15.5%) and 63 cases (18.4%) had high-risk factors for lung cancer, respectively. The other basic characteristics of the two groups are shown in Table 1.
3.2 pGGN growth rate and growth risk: 2-year follow-up
After a 2-year follow-up, we compared the growth status of pGGNs between the YFSJF group and the non-YFSJF group. Specifically, pGGN growth was observed in 27 patients (7.2%) in the YFSJF group, while in the non-YFSJF group, pGGN growth was observed in 48 patients (14.0%). Further statistical analysis showed that the growth risk of pGGNs in the YFSJF group was significantly lower than that in the non-YFSJF group (OR, 0.48; 95% CI, 0.29–0.79; P = 0.004) (Table 2).
3.3 Logistic regression analysis of the risk of pGGN growth
As reported in Table 2, after adjustment for confounding factors including YFSJF therapy, male sex, age, smoking, chronic respiratory diseases, family history of lung cancer, high-risk population for lung cancer, solitary nodule number, location, round nodule shape, microvascular sign, bubble-like lucencies, air bronchogram, pleural retraction, previous history of malignant tumors, maximum diameter, volume, and mean CT attenuation, multivariable logistic regression analysis demonstrated that YFSJF therapy remained an independent factor that was associated with a 58% risk reduction of pGGN growth risk (OR, 0.42; 95% CI, 0.25–0.71; P = 0.001). Older age (OR, 1.03; 95% CI, 1.01–1.05; P = 0.015), microvascular sign (OR, 2.41; 95% CI, 1.40–4.16; P < 0.002), and previous history of malignant tumor (OR, 4.91; 95% CI, 1.90–12.70; P < 0.001) were still associated with a higher pGGN growth risk.
In the YFSJF group, compared with low exposure level, medium exposure level was associated with a 74% reduction in pGGN growth risk (OR, 0.26; 95% CI, 0.08–0.89; P = 0.032), while high-exposure level showed an inhibitory trend, but the difference was not statistically significant (OR, 0.22; 95% CI, 0.03–1.70; P > 0.05) (Table 3).
3.4 pGGN volume
During the 2-year follow-up, there was no significant decrease in volume in the YFSJF group compared with the baseline (P > 0.05), whereas the non-YFSJF demonstrated a significant increase (P < 0.001). There was no statistically significant difference in volume between the two groups (P > 0.05). Compared with the non-YFSJF group, the YFSJF group exhibited greater improvement in the volume from baseline (P < 0.001) (Table 4).
In the linear regression analysis, the YFSJF group had a significant reduction in volume of pGGNs compared with the non-YFSJF group (P < 0.001); microvascular sign, bubble-like lucencies sign, maximum diameter, and volume at baseline were still significantly associated with the volume change of pGGNs to some extent (P < 0.05), but some variables (such as high-risk population for lung cancer, Solitary nodules, and round nodule shape) were significant in the univariate under the condition of variable, but were no longer significant after multivariable adjustment (P > 0.05) (Table 5).
3.5 pGGN maximum diameter
During the 2-year follow-up, the maximum diameter in the YFSJF group showed no significant decrease compared with the baseline (P > 0.05), while the non-YFSJF group demonstrated a significant increase (P = 0.005). However, the difference from baseline in maximum diameter did not significantly differ between the two groups (P > 0.05) (Table 4).
3.6 pGGN mean CT attenuation
During the 2-year follow-up, the YFSJF group had a decrease in the mean CT attenuation compared with baseline (P = 0.016), while the non-YFSJF group showed an increase (P < 0.001). However, there was no statistical difference in mean CT attenuation from baseline between the two groups (P > 0.05) (Table 4).
3.7 pGGN regression
After 2-year follow-up, pGGN regression was observed in 27 patients (7.2%) in the YFSJF group, compared to 13 patients (3.8%) in the non-YFSJF group (Table 4). The YFSJF group had a higher probability of regression than the non-YFSJF group (OR, 1.98; 95% CI, 1.00–3.89; P = 0.049) (Table 6).
3.8 Logistic regression analysis of the risk of pGGN regression
As reported in Table 6, in the regression analysis that was adjusted for YFSJF therapy, male sex, age, occupational exposure history, smoking, chronic respiratory diseases, family history of lung cancer, high-risk population for lung cancer, solitary nodule number, location, round nodule shape, spiculation, microvascular sign, bubble-like lucencies, previous history of malignant tumors, maximum diameter, volume, and mean CT attenuation, bubble-like lucencies remained an independent factor that was associated with a 87% risk reduction of pGGN regression risk (OR, 0.13; 95% CI, 0.03–0.54; P = 0.005). YFSJF therapy (OR, 2.31; 95% CI, 1.15–4.65; P = 0.019) and sex (male) (OR, 2.26; 95% CI, 1.15–4.48; P = 0.019) were still associated with a higher pGGN regression risk.
Additionally, no adverse events were observed in either group during the follow-up period.
4 Discussion
PGGNs usually grow inertly and previous studies on TCM intervention for pulmonary nodules have mainly focused on randomized controlled trials (RCTs), and there is a common limitation of short observation periods (often < 1 year), which makes it difficult to fully demonstrate the long-term intervention effects of pGGNs and other inert lesions. In this 2-year prospective cohort study, the impact of the YFSJF on pGGNs was evaluated for the first time in the real world. The results showed that the pGGN growth rate was 7.2% in YFSJF group, significantly lower than that in the non-YFSJF group. The 2-year growth rate of the non-exposed group was 14%, which was basically consistent with the 2-year growth rate of pGGN in the study of Takahashi
et al. [
14]. The study of Chang
et al. showed that the proportion of pGGN growing nodules in two years was 13.5% [
11]. This result showed that YFSJF could delay the growth of GGNs to a certain extent. Moreover, after adjusting for confounding factors such as male sex, age, smoking, chronic respiratory diseases, family history of lung cancer, high-risk population for lung cancer, solitary nodule number, location, round nodule shape, YFSJF remained an independent protective factor—reducing the risk of pGGNs growth by 58% (OR, 0.42; 95% CI, 0.25–0.71;
P = 0.001). This result confirms the delaying effect of YFSJF on the growth of pGGNs, and provides evidence for the application of TCM in the long-term management of pGGNs. At present, there is no direct research on the growth assessment of pGGNs treated with TCM. Although there are many studies on the natural course growth of pGGNs, there are relatively few reports on its effective intervention. This study has preliminarily revealed the impact of YFSJF on the patients with pGGNs, and further studies are still needed to further explore the role of YFSJF in the treatment of pGGNs.
This study further investigated the effects of different exposure levels of YFSJF on the growth of pGGNs. The results showed that moderate exposure of YFSJF for 6–12 months significantly reduced the growth risk of pGGNs compared with low exposure level (OR, 0.26; 95% CI, 0.08–0.89; P = 0.032). As an important imaging manifestation of early lung lesions, the growth rate of pGGNs is closely related to the progression of the disease, and the follow-up management of pGGNs in clinical practice often takes 6–12 months as the key period. However, although the research results of high exposure for more than 12 months showed an inhibitory trend, they may not have reached statistical significance due to insufficient sample size and long-term confounding factors. Their true effects and safety need further verification. In the future, it is necessary to clarify the optimal exposure time interval for YFSJF by refining subgroups and controlling confounding factors, to provide more reliable evidence for its promotion and application in the stage-based management of pGGNs.
The changes in maximum diameter and volume of nodules are important indicators for evaluating the growth status of pGGNs, and dynamic monitoring of both is crucial for evaluating the efficacy of intervention measures. Current positive standard for the growth of pulmonary nodules has not yet been unified. The growth of pulmonary nodules mainly refers to an increase in diameter or volume as shown in CT scan images at different time points [
15,
16]. The study by Chen
et al. found that the maximum diameter of pGGNs decreased after TCM treatment [
17]. The research of Chu
et al. also showed that TCM treatment could reduce the maximum diameter of the target nodule [
18]. The results of this study suggest that YFSJF did not significantly reduce the diameter of pulmonary nodules, and further research is needed to confirm the results. In terms of the volume of pGGNs, the exposed group showed a decrease of risk in volume enlargement of pGGNs compared with baseline after a 2-year follow-up (
P < 0.001). The absolute difference in nodule volume between the two groups at 2-year follow-up did not reach statistical significance (
P > 0.05). After adjusting for confounding factors, the results indicate that the effect of YFSJF may be to delay the volume increase of pGGNs rather than directly reduce the existing volume of nodules. This provides evidence from the aspect of volume change that YFSJF has a delaying effect on the growth of pGGNs. Studies have shown that compared with the two-dimensional diameter measurement, the three-dimensional volume measurement can more accurately reflect the true growth status of subsolid nodules [
19]. Compared with semi-automatic volume measurement, the use of average or maximum axial diameter to evaluate nodule volume will result in the nodule volume being overestimated by an average of 47.2% and 85.1%, which makes it difficult to accurately express the size of uncertain nodules only by diameter [
20], the size of pulmonary nodules based on manual diameter measurement is prone to be affected by the edge of the nodule, while the semi-automatic volume measurement almost ignore this effect, which has obvious advantages in the determination of pulmonary nodule size and growth assessment [
21]. This study found that YFSJF can reduce the risk of pGGN volume enlargement. At present, there is a lack of direct research on the effect of TCM in the treatment of pGGN on its volume. Subsequent studies need to be carried out to further explore the effect of TCM on the volume of pGGN.
CT features play a significant role in distinguishing the invasiveness of pGGNs. The maximum diameter of invasive adenocarcinoma (IAC) lesions is larger than that of preinvasive lesions (PIL), and their mean CT value is also higher than that of PIL [
22]. During the growth of nodules, the increase in density accounts for a higher proportion in the early stage of growth than the change in size, and the rate of density increase is faster. Clinicians need to pay close attention to nodules with newly appearing solid components and formulate corresponding management decisions in a timely manner [
23]. The change in mean CT value can intuitively reflect the density of pulmonary nodules. Different density ranges and thresholds can distinguish different pathological types, and CT can more accurately reflect the tumor density with pathological invasiveness. GGNs with low invasiveness exhibit an indolent growth pattern. Compared with AAH and AIS, invasive GGNs have a greater increase in density/CT value in subsequent follow-ups, so higher CT values usually indicate stronger invasiveness [
24,
25]. After analyzing and comparing the CT features of 172 patients with pGGNs, Chu
et al. found that the CT values of MIA and IAC were significantly higher than those of AAH and AIS, and the optimal cutoff value of the average CT value for differentiating non-invasive lesions from lesions was −632 HU [
26]. In this study, there was no statistical difference in the mean CT attenuation from baseline between the two groups (
P > 0.05). This may be related to the limitations of sample size and follow-up duration in this study, as changes in pGGN density often require longer periods of dynamic monitoring to show significant inter-group differences. Currently, there is a lack of large sample studies on the effect of TCM on pGGN mean CT attenuation, and the impact of YFSJF on pGGN mean CT attenuation still needs to be further studied.
The volume regression rate also reflects the therapeutic effect of YFSJF. The volume regression rate of pGGN in the YFSJF group reached 7.2%, which was higher than in the non-YFSJF group (3.8%;
P = 0.046). More importantly, after logistic regression analysis (adjusting for confounding factors such as YFSJF intervention, gender, age, occupational exposure history, smoking history, chronic respiratory disease, family history of lung cancer, and high-risk population for lung cancer), YFSJF remained an independent promoting factor for pGGN regression, (OR, 2.31; 95% CI, 1.15–4.65;
P = 0.019). This result confirms the positive effect of YFSJF on pGGN regression, providing evidence for the efficacy of TCM intervention in pGGNs. This may be related to the improvement of the microenvironment of the lung by YFSJF, which promoted the absorption and regression of nodules. In the existing related studies, the follow-up CT scan results showed that 42.7% of the localized ground-glass opacities (GGOs) disappeared [
27]. Oh JY’s study also showed that the disappearance or regression probability of pGGO was 37.6% [
28]. However, compared with these studies, the regression rates in both the exposed group and the non-YFSJF in this study were relatively low. This difference may be related to the selection of research objects. The subjects of this study had pGGNs that persisted for more than 3 months, and these nodules usually have higher stability, and it is more difficult for them to regress naturally or after treatment, resulting in a relatively low regression rate. The observation objects of other studies may include a considerable proportion of transient pGGNs. These transient nodules are often more likely to regress naturally or after treatment, resulting in a relatively high overall regression rate. Although there are differences in regression rates between this study and other studies, this further illustrates the significant impact of the selection of research objects on the results of the study.
This study evaluates the impact of YFSJF on pGGNs from multiple perspectives. YFSJF consists of medicinal substances including
Panax ginseng,
Fritillaria thunbergii,
Prunella vulgaris, vinegar-processed
Curcuma zedoaria rhizome, among others. It is speculated that the active ingredients in this formula may inhibit the growth of pGGNs by modulating the host immune response. Specifically, they may enhance immune surveillance to eliminate abnormal cells, restore immune homeostasis, and simultaneously interfere with proliferative signaling pathways to block aberrant cell growth. For example, in the formula, ginseng has various biological activities, including anti-inflammatory, antioxidant, and anticancer effects [
29]. Its active ingredient, ginsenoside, can regulate immunity, enhance immune surveillance, prompt immune cells to identify and eliminate abnormal cells, and may also affect the proliferation and differentiation of lung cells by intervening in cell signaling pathways [
30,
31]. Studies have shown that the active ingredients of
Curcuma zedoaria rhizome have clear cytotoxic effects on non-small cell lung cancer cells and can induce apoptosis in cancer cells. In addition, these ingredients can also effectively inhibit the invasion and migration ability of cancer cells by regulating related signaling pathways, thereby playing a role in curbing the development of pGGNs [
32]. Regarding the mechanism of action of YFSJF in the treatment of pGGNs, our team is conducting experimental research, and we will publish our research results in the future.
5 Limitations
Due to the extremely slow growth of pGGNs, according to the Fleischner guidelines for pulmonary nodules, the recommended follow-up duration for pure or mixed-glass nodules with a diameter > 6 mm is 5 years. In addition, several studies have shown that even after 5 years of follow-up, there is still a certain risk of growth for GGNs [
33,
34]. Therefore, the long-term natural course of GGNs is still unclear. Our team has only completed a 2-year follow-up at present, during which the efficacy of YFSJF on pGGNs was preliminarily evaluated. Subsequently, we will further follow up the long-term efficacy of YFSJF on pGGNs and its impact on the malignant transformation rate. At present, our research on the treatment of pGGN with YFSJF is only carried out in the real world. To more accurately confirm its efficacy, deeply explore the mechanism of action, and provide stronger evidence-based medical evidence for clinical treatment, we plan to further carry out RCTs subsequently.
6 Conclusions
During the 2-year follow-up period, YFSJF may have a certain effect on pGGNs, which can delay the growth of pGGNs and improve the regression.
The Author(s). This article is published with open access at link.springer.com and journal.hep.com.cn
PDF
(751KB)
