Patient-reported outcomes of radiofrequency ablation-video-assisted thoracoscopic surgery (VATS) hybrid surgery vs. uniportal VATS for multiple primary lung nodules: a longitudinal cohort study

Introduction

Background

Lung cancer persists as the predominant cause of cancer-related mortality globally, exhibiting the highest incidence among solid malignancies (1). The widespread implementation of low-dose computed tomography (LDCT) screening has substantially increased the detection of early-stage lung adenocarcinoma manifesting as ground-glass nodules (GGNs). Notably, 41% of GGN-positive patients present with multifocal lesions, and 32% exhibit radiologic progression within 36 months (2), underscoring the clinical complexity of multiple primary lung nodules (MPLNs) characterized by distinct histopathological heterogeneity and therapeutic dilemmas. While video-assisted thoracoscopic surgery (VATS) remains the gold standard for managing high-risk GGNs (3,4), extensive resection of all suspicious nodules in MPLN may cause unnecessary pulmonary functional compromise and escalate healthcare expenditures. This gives rise to a significant clinical dilemma: how to manage these synchronous nodules, balancing the oncological imperative to treat all potential malignancies against the risk of overtreatment, the desire to preserve pulmonary function and patients’ preference.

Previous study utilized a hybrid surgical approach combining electromagnetic navigation bronchoscopy-guided microwave ablation for MPLNs (5-7). Our team has developed a hybrid surgical approach combining image-guided thermal ablation (IGTA) [including radiofrequency ablation (RFA)] for low-risk secondary lesions with uniportal VATS resection of dominant primary lesions.

Nevertheless, conventional clinician-reported outcomes inadequately capture patient-centered recovery metrics. Over the past decade, patient-reported outcomes (PROs) have emerged as critical endpoints in therapeutic evaluation, providing granular insights into symptom trajectories and functional rehabilitation (8-12). Regulatory agencies, including the US Food and Drug Administration, now endorse PRO integration in labeling claims for medical interventions (13). In thoracic surgical research, PROs have been systematically utilized across multiport VATS, uniportal VATS, and conventional thoracotomy approaches (14-16). However, in patients undergoing HBD, no studies to date have incorporated systematical PROs into their analytical frameworks.

Objective

This longitudinal cohort study aims to illustrate PRO profiles following these two minimally invasive surgical modalities, providing evidence of their impacts on post-surgery recovery trajectories. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-996/rc).

Methods

Study design and patients

This cohort study consecutively enrolled patients with a clinically confirmed primary early-stage lung cancer and at least one synchronous, ipsilateral, non-dominant pulmonary nodule who presented at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between April 1, 2024 and December 31, 2024. All enrolled patients then underwent standardized multidisciplinary team (MDT) evaluation, with surgical strategies determined through structured shared decision-making (SDM) protocols. Following predetermined clinical pathways, patients underwent either uniportal VATS or HBD. All procedures were performed by a designated surgical team in the Department of Thoracic Surgery at our institution. After surgical procedures, patients were entered into an established standardized follow-up registry, with planned prospective prognostic surveillance spanning at least 3 years, in accordance with our institutional guidelines for early-stage lung cancer. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (IRB 24/124-4404). All participants provided written informed consent.

Inclusion criteria were as follows: (I) age ≥18 years; (II) pathologically confirmed stage 0 or IA non-small cell lung cancer (NSCLC) of the primary resected lesion, classified by the American Joint Committee on Cancer (AJCC) 9th edition tumor-node-metastasis (TNM) system (pT1a-cN0M0); (III) chest computed tomography (CT) showing at least one pulmonary nodule in the ipsilateral lung, with the lesions classified as category 2 [pure GGNs (pGGNs)] or ≥3 [mixed GGNs (mGGNs) and solid nodules] according to the Lung Imaging Reporting and Data System (Lung-RADS) classification system (17); (IV) initial diagnosis of GGNs and underwent more than 1 year of regular follow-up and anti-infection treatment; (V) co-assessment by MDT indicating the need for VATS or simultaneous RFA-VATS hybrid surgery (HBD) for GGNs. Exclusion criteria were as follows: (I) history of myocardial infarction or stroke within 6 months prior to surgery; (II) preoperative pulmonary function tests (PFTs) showing forced expiratory volume in 1 second (FEV1)% <40%; (III) severe bleeding tendency, platelets <50×10⁹/L, or prothrombin time >18 s or prothrombin time activity <40% or deep vein thrombosis (DVT); (IV) other conditions unsuitable for surgical intervention.

Identification of primary and secondary lesions

The characteristics of primary lesions are as follows: (I) predominantly solid components, as mGGN with a solid component diameter >6 mm or solid nodules with a diameter >8 mm; (II) larger size, pGGN with a diameter >8 mm that persist without regression after at least 1 year of regular follow-up and standardized anti-inflammatory treatment; (III) close to trachea or blood vessels; (IV) abnormal lymph node enlargement in the drainage area; (V) signs of pleural indentation. While the features of secondary lesions are as follows: (I) predominantly ground‐glass components, usually ≥50%, and persist without regression after at least 1 year of regular follow-up and standardized anti-inflammatory treatment; (II) smaller size; (III) distant from large blood vessels and high‐grade bronchi; (IV) no local lymph node enlargement in the drainage area; (V) tumor was not amenable to wedge resection due to its central location of the chest.

Decision-making process for hybrid surgery or uniportal VATS

Surgical strategy is mainly determined by spatial distribution of lesions: primary and secondary lesions within the same lobe warrant synchronous resection. For multiple lesions located in anatomically non-adjacent pulmonary lobes, resection of the primary lesion with ablation of secondary lesions is indicated. For lesions located in ipsilateral adjacent lobes despite lobar discontinuity, the hybrid or VATS approach is recommended following SDM.

In our clinical approach, we used a hexagon conceptual model to illustrate the tendency of hybrid surgery or uniportal VATS. Each axis of the hexagon represents a specific dimension, including nodule size, distance to the pulmonary hilum, consolidation‐to‐tumor ratio, nodule dimensions, proximity to major bronchi/vessels, and lymph node status. Detailed illustration can be seen in our previous work (18,19).

Surgical techniques

HBD

Patients were positioned in the lateral decubitus position on a CT-integrated operating table. Percutaneous trajectory planning was initiated with CT-guided cutaneous demarcation using a radiopaque grid template to triangulate GGN coordinates and optimize electrode access pathways. Under local infiltration anesthesia (1% ropivacaine hydrochloride + 2% lidocaine) and mask airway ventilation, multiplanar CT scanning (1-mm slice thickness, lung kernel) were iteratively acquired during controlled inspiratory breath-holds to validate the puncture trajectory.

Senior thoracic surgeons (>50 RFA cases experience) modulated ablation parameters according to maximum axial diameter, consolidation-to-tumor ratio, proximity to segmental vasculature and distance from the pleura to the nodule. Radiofrequency ablation was performed using the STARmed^TM VIVA^TM System (Gyeonggi-do, Korea) with 17-gauge internally cooled electrodes, employing standardized protocols (generator frequency: 480 kHz, impedance-controlled power delivery: 60 W median while range 50–80 W, time of RFA: 5 min median while range 3–6 min. Immediate technical success required circumferential ground-glass opacity (GGO) margins ≥5 mm beyond gross tumor volume (GTV) on intraoperative CT, with supplemental ablation cycles administered for inadequate treatment zones (20). Longitudinal efficacy assessment involved volumetric analysis of the post-ablation target zone (PTZ) using 6-month CT demonstrating characteristic PTZ contraction (>30% volume reduction) indicative of successful fibrosis evolution.

Following RFA completion, anesthesia was transitioned to general endotracheal intubation (double-lumen tube) for subsequent uniportal VATS within the hybrid operating suite.

Uniportal-VATS

Following the induction of general anesthesia with double-lumen endotracheal intubation for selective lung ventilation, all patients were placed in the lateral decubitus position. A single 3–5 cm utility incision was created at the 4th or 5th intercostal space along the anterior axillary line, using a wound protector without rib spreading (the resected lung specimen was retrieved through the mentioned wound protector. The primary lesion(s) resected during surgery serves as the basis for pathological staging assessment in HBD group. In VATS group, all lesions with high suspicion of malignancy underwent surgical resection. A chest drainage tube (14-F chest tube). Patient-controlled analgesia (PCA) was applied postoperatively, while oral pain medications (paracetamol 500 mg-codeine phosphate 30 mg or ketorolac tromethamine capsules 10 mg) were prescribed as needed (21).

Outcome measures

PROs

The PRO measurement in this study includes the MD Anderson Symptom Inventory-Lung Cancer module (MDASI-LC). The MDASI-LC is disease-specific, valid, reliable, and sensitive module that includes 13 core symptoms and 3 lung cancer-specific symptoms (coughing, constipation, sore throat) in Part I, along with 6 functional impairment items in Part II. It can be used to assess symptoms in lung cancer patients and is also applicable in epidemiological studies investigating the prevalence and severity of symptoms (22-24). Patients can assess the severity of symptoms and functional impairment using a 0–10 point scale, which was anchored as follows: 0 indicated “symptom absent”, and 10 indicated “the worst imaginable severity”. Any item with a score of 4 or above was deemed to represent a moderate-to-severe condition.

The MDASI-LC scale was completed through electronic questionnaires (ePRO assessments) or structured telephone question-and-answer format if patients cannot read or use mobile phone. ePRO assessments were scheduled preoperatively (as baseline), postoperatively daily (up to 7 days), days 10, 14, 17, 21, 30, 42, 56, 70 and 90 after surgical treatment (25).

Complications

Postoperative complications ≥ grade II according to the Clavien-Dindo classification were recorded for up to 3 months after discharge (26). The postoperative complications profiles mainly included respiratory failure, pneumothorax, subcutaneous emphysema, hemoptysis, hemothorax, chylothorax, DVT, pulmonary embolism, atelectasis, pneumonia and fever. A prospective complication registry was established in the research center following the STROBE guideline (27). All ≥ grade II events were adjudicated by an independent clinical endpoint group using source-verified data from: (I) institutional electronic hospital record with real-time adverse event tracking; (II) surgeon’s daily rounding documentation using standardized case report forms; (III) postoperative 1mm intervals-CT evaluations during follow-up at postoperative days (PODs) 1, 30, and 90; (IV) structured telephone interviews following the World Health Organization Adverse Event Terminology (WHO-ART) were conducted weekly for 3 consecutive months, paralleled with patient-initiated reporting through a validated electronic PRO (ePRO) platform. Data consistency was ensured through quarterly Good Clinical Practice (GCP) audits.

Statistical analysis

The patients were divided into two groups (VATS and HBD groups) according to the surgical treatment confirmed through the shared-decision making process.

Descriptive statistics were used to summarize the data: normally distributed continuous variables as mean ± standard deviation, non-normally distributed variables as median (interquartile range, IQR), and categorical variables as numbers (percentages). Comparisons of baseline and clinical characteristics between the VATS and RFA groups were performed using the t-test or Mann-Whitney U test for continuous variables, and the Chi-squared test (with Yates’ correction) or Fisher’s exact test for categorical variables.

Longitudinal PROs were analyzed at baseline (thus, POD 0), PODs 1 to 7, 10, 14, 17, 21, 24, 30, 42, 56, 70 and 90 follow-ups. The prevalence of moderate-to-severe symptoms (defined as scoring ≥4 at a time point) was quantified and demonstrated every time point (PODs 0–7, 10, 14, 17, 21, 24, 30, 42, 56, 70, 90) and reported as proportions of patients with 95% confidence intervals (CIs) (28,29). Linear mixed-effects models were used to assess differences in symptom and function scores over time (PODs 0–7, 10, 14, 17, 21, 24, 30, 42, 56, 60, 70, 90) between the two surgical groups (HBD vs. VATS). For each MDASI-LC item, the score was treated as the continuous dependent variable. The models included patient-specific random intercepts to account for the correlation of repeated measurements within individuals. Fixed effects included time (treated as a continuous variable), treatment group (HBD vs. VATS), the time-by-group interaction, and baseline covariates that differed significantly between groups (sex, solid component). An unstructured covariance matrix was used to model the within-patient error covariance structure. Additionally, the relative risks for moderate-to-severe symptoms and functional outcome on PODs 3, 7, 30 and 90 were calculated using a mixed-effects model. Variables with statistical differences between the two groups mentioned above were included in the mixed-effects model for adjustment. Meanwhile, data were assumed to be missing at random, and mixed-effects models inherently handle such missing data by utilizing all available observations. Given the exploratory nature of this study and the multiple PRO endpoints assessed across numerous time points, no formal statistical correction for multiplicity [Bonferroni or false discovery rate (FDR) correction] was applied. Therefore, all reported P values should be interpreted as exploratory and hypothesis-generating, and statistical significance should be viewed with caution.

Postoperative recovery was defined as the first day when symptoms scores decreasing to none/mild level (0–3 on a 10-point scale) after reaching ≥4. A subgroup analysis was performed to compare recovery trajectories based on surgical groups using Kaplan-Meier analysis and the log-rank test. This analysis included only patients with moderate-to-severe symptoms or functional impairment at baseline, as the prevalence of these conditions differed between the two groups.

Statistical significance was defined as a two-sided P value <0.05, with all analyses conducted using SAS 9.4 and GraphPad Prism 10.

Results

Baseline and pathological characteristics

Ultimately, 118 patients undergoing VATS and 65 patients receiving hybrid thermal ablation (HBD). Sex distribution differed significantly between groups (VATS: 64.4% female; HBD: 83.1% female; P=0.01), while age (VATS: median, 59 years, IQR, 50–66 years; HBD: median, 56 years, IQR, 48–64 years; P=0.13) and body mass index (VATS: 24.0±3.0 kg/m²; HBD: 23.6±2.7 kg/m²; P=0.34) were comparable (Table 1).

Tradition clinical outcomes

Tumor staging (99.2% stage I in VATS vs. 96.9% in HBD; P=0.29) and lymph node resection rates (systematic lymph node resection: 50.0% VATS vs. 47.7% HBD; P=0.35) showed no significant differences. Postoperative outcomes, including median hospital stay (5.0, IQR, 3.0–7.0 vs. 5.0, IQR, 4.0–7.0 days; P=0.56), median chest tube duration day (3.0, IQR, 3.0–4.0 vs. 3.0, IQR, 3.0–4.0 days; P=0.68), and drainage volume (330.0, IQR, 150.0–620.0 vs. 270.0, IQR, 180.0–500.0 mL; P=0.74), were similar (Table 1).

Pathologically, HBD had similar proportion of invasive adenocarcinoma (54.5% vs. 52.5%), adenocarcinoma in situ (33.6% vs. 36.8%) and minimally invasive adenocarcinoma cases (11.9% vs. 10.7% in VATS; P=0.81). The 6 non-adenocarcinoma in the VATS group included 4 squamous cell carcinoma and 2 atypical adenomatous hyperplasia (AAH). The 2 non-adenocarcinoma in the HBD group was AAH (Table 2).

The HBD cohort (n=65) experienced complications including pneumothorax (1.54%), pleural effusion (1.54%), fever >38 ℃ (4.62%), pneumonia (4.62%), and atelectasis (1.54%). No cases of subcutaneous emphysema, thromboembolism, or respiratory failure were observed. The VATS group (n=118) reported pneumothorax (1.69%), fever >38 ℃ (3.39%), pneumonia (4.24%), atelectasis (1.69%), subcutaneous emphysema (2.54%), and coagulated hemothorax (0.85%), with no pleural effusion, thromboembolism, or respiratory failure. Overall complication rates were comparable (HBD: 12.31% vs. VATS, 10.17%; P=0.82, Fisher’s exact test), with no significant differences between groups (Table S1).

Both cohorts demonstrated 100% recurrence-free survival throughout the 12-month follow-up period (Figure S1).

Ablation parameters

In 69 RFA-treated (HBD group) lesions, pGGOs (81.2%) were most common, with a median lesion diameter of 6.0 mm (IQR, 4.2–7.9 mm). Median ablation power was 60 W (IQR, 50–60 W), achieving a maximum ablation zone diameter of 22.00 mm (IQR, 17.25–30.05 mm) and a lesion-to-margin distance of 9.04 mm (IQR, 7.16–10.67 mm) (Table 3).

The longitudinal follow-up of PRO data

All the 183 patients provided MDASI-LC at the baseline. The completion rates of the MDASI-LC questionnaire were 97.81% to 96.72% during the 1–7 PODs, and from 97.81% to 70.49% in the follow-up (Table S1).

PROs

Proportion of moderate-to-severe symptoms and functional impairment

The completion rate of the ePRO questionnaire at each assessment point were calculated to ensure the validity of the ePRO results (Table S2). Among the top six symptoms with the highest proportions of moderate-to-severe cases reported during the PODs 1–7 were pain (45.93%), fatigue (40.65%), shortness of breath (40.00%), disturbed sleep (40.00%), coughing (31.46%) and constipation (30.81%) based on 1,230 symptom assessments conducted throughout the postoperative period (Table S3). The prevalence of moderate-to-severe symptoms for the six most burdensome PROs is illustrated in Figure 1A-1F. The symptom escalation patterns revealed three distinct subgroups: first, parallel progression group: pain, fatigue and disturbed sleep exhibited same recovery patterns between VATS and HBD groups, with all intergroup comparisons remaining non-significant (all P>0.05). Second, divergent progression group: short-of-breath demonstrated increasing between-group differences over time (POD 7 HBD-VATS difference +12.83%, P=0.63; but POD 90 difference −3.67%, P=0.35). Constipation showed divergent recovery in two groups (POD 3 difference +6.67%, P=0.87; POD 7 difference −2.20%, P=0.60). Third, cohort-specific group: while coughing recovery pattern paralleled between groups, HBD maintained higher moderate-to-severe prevalence throughout follow-up (difference range: POD 3 +29.78%, P=0.06 to POD 90 +7.92%, P=0.33). Notably, despite these between-group variations in symptom recovery patterns, mixed-effects model analysis revealed no statistically significant protective advantage for VATS over HBD in mitigating most symptom severity at postoperative evaluation interval (PODs 3, 7, 30, 90; all between-group P values >0.05) (Tables S4-S7). Similarly, within daily functional interference, mood disturbances (mood) exhibited cohort-specific burden trajectories (difference range: POD 3 +3.0%, P=0.27 to POD 30 +6.43%, P=0.68), whereas general activity, work, relations, enjoyment, and walking demonstrated divergent progression patterns between surgical cohorts (Figure 1G-1L). However, certain symptoms or functional impairment exhibited significant difference at specific time points were shown in Table S8. All the trajectories of 22 items were demonstrated in Figure S2.

Figure 1 Temporal changes in moderate-to-severe proportions of the top six most prevalent symptoms and six functional impairment domains between HBD and VATS cohorts. (A) Pain. (B) Fatigue. (C) Shortness of breath. (D) Disturbed sleep. (E) Coughing. (F) Constipation. (G) Work. (H) General activity. (I) Walking. (J) Enjoyment. (K) Mood. (L) Relations. Comparisons of moderate-to-severe symptom proportions between groups at PODs 3, 7, 30, and 90 were performed using mixed-effects models, with adjustments for baseline covariates including sex, solid component diameter, CTR, maximum nodule diameter, and pathological subtype. Detailed calculations are shown in Tables S4-S7. CTR, consolidation-to-tumor ratio; HBD, radiofrequency ablation combined with VATS hybrid surgery; POD, postoperative day; VATS, video-assisted thoracoscopic surgery.

Mixed-effects modeling of MDASI-LC score trajectories demonstrated differential protective effects between surgical approaches: the VATS cohort showed a clinically meaningful reduction in coughing severity (group estimate: −0.8829, P=0.041). (Figure S3). Significant time-by-group interactions emerged for work (interaction estimate: 0.0096, P=0.040) and walking (interaction estimate: 0.0115, P=0.006), indicating a gradual slowing of function recovery in the VATS group compared with the HBD cohort (Figure S4). The time and group effects are calculated in Table 4.

Symptom or functional interfered recovery

The recovery trajectories of patients with moderate-to-severe symptoms or functional impairment were compared between the two groups. Although the symptom recovery survival curves demonstrated no statistically significant differences in recovery patterns for most symptoms (P>0.05), the VATS group exhibited more rapid early improvement in pain, fatigue, and sleep-related symptoms compared to the HBD group. Conversely, the HBD group showed faster initial recovery in distress, short-of-breath, memory, appetite loss, cough, and sore throat. Notably, a statistically significant advantage in early numbness recovery (P=0.01) was observed in the HBD group compared to the VATS group (Figure 2). Regarding functional impairment recovery, both groups exhibited comparable recovery trajectories with no statistically significant differences on survival analysis (Figure 3).

Figure 2 Symptom recovery trajectories through Kaplan-Meier analysis. The figure illustrates the symptom recovery trajectories through Kaplan-Meier analysis for patients experiencing moderate-to-severe symptoms, where the y-axis represents proportion of non-recovery and the x-axis represents postoperative time intervals. Comparative survival analysis between HBD and VATS cohorts demonstrated statistically distinct recovery patterns (log-rank test P<0.05) in numbness, while other symptoms have no significant difference. HBD, radiofrequency ablation combined with VATS hybrid surgery; VATS, video-assisted thoracoscopic surgery.

Figure 3 Functional impairment recovery trajectories through Kaplan-Meier analysis. The figure illustrates the functional impairment recovery trajectories through Kaplan-Meier analysis for patients experiencing moderate-to-severe functional impairment, where the y-axis represents proportion of non-recovery and the x-axis represents postoperative time intervals. Comparative survival analysis between HBD and VATS cohorts revealed statistically comparable recovery trajectories (log-rank test P>0.05) across all functional impairment domains, indicating non-significant differences in the temporal dynamics of functional restoration between the two surgical treatments. HBD, radiofrequency ablation combined with VATS hybrid surgery; VATS, video-assisted thoracoscopic surgery.

Discussion

Findings and explanations

This longitudinal cohort study provides analysis of patient-centered recovery trajectories between HBD and conventional uniportal VATS for early-stage lung cancer. Our analyses mainly detected negative results in PRO profiles between the HBD and conventional uniportal VATS, albeit with distinct symptom trade-offs, like coughing. These results advance our understanding of PROs in lesion-specific multimodal therapy and offer insights for refining perioperative care.

The absence of significant differences in PRO trajectories between HBD and VATS challenge historical assumptions that radiofrequency ablation might exacerbate postoperative symptom burden due to combined procedural trauma. Interestingly, HBD patients exhibited accelerated recovery of numbness (P=0.01), likely attributable to reduced intercostal nerve injury during limited thoracoscopic access compared to extended anatomic resection. This aligns with emerging evidence that similar hybrid approaches mitigate surgical invasiveness while maintaining oncologic rigor, notwithstanding rigorous longitudinal studies remain imperative to verify oncological outcomes of ablation therapy (30). Preliminary evidence from our single-arm retrospective study demonstrated acceptable short-term safety and oncologic efficacy of this strategy (19). Definitions of the relevant complications are provided in Table S9. Conversely, the persistent coughing burden in HBD (POD 3 difference +29.8%, P=0.06) may reflect ablation induced bronchial irritation or sub-clinical inflammation—a phenomenon previously documented in thermal ablation research (31-33). The persistent coughing burden in HBD may also be associated with the relatively higher complication rate observed in the HBD group, although the difference in complication rates between the two groups was not statistically significant. The underlying pathophysiological mechanism may involve a local inflammatory cascade triggered by RFA thermal injury, which could lead to systemic febrile reactions and increased susceptibility to pneumonia. In future practice, consideration might be given to the prophylactic use of anti-inflammatory agents (primarily non-steroidal anti-inflammatory drugs) and antibiotics, or to refining the ablation protocol (reducing redundant ablation time and energy while ensuring complete tumor ablation). This underscores the need for targeted antitussive protocols in hybrid surgery pathways.

The divergent functional recovery patterns carry significant implications for personalized rehabilitation planning. VATS patients demonstrated gradual slowing of work and walking recovery, potentially attributable to prolonged visceral pain modulation or diaphragmatic dysfunction post-lobectomy. In contrast, HBD’s accelerated return to baseline ambulation aligns with its parenchymal preservation benefits, corroborating spirometric advantages reported in prior studies (5-7). These functional trade-offs highlight the importance of PRO-guided SDM, particularly for occupationally active patients.

Patients in the HBD group showed a numerically faster, though not statistically significant, resolution of early psychological distress (POD 30 difference: −3.17%, P=0.45). While the underlying reasons for this observation are not elucidated by our data, we can hypothesize that it may be related to patients’ perceptions of receiving comprehensive treatment for all visible nodules in a single session while maximally preserving lung tissue. This could potentially alleviate the anxiety associated with untreated nodules. However, this interpretation remains speculative. This finding should be interpreted with caution as it was a secondary endpoint, and dedicated psycho-oncological studies are required to confirm this potential benefit and explore its mechanisms (34-36). However, this psychological advantage must be balanced against HBD’s marginally higher complication rate (HBD: 12.31% vs. VATS: 10.17%, P=0.82), predominantly low-grade febrile events manageable in outpatient settings.

The predominance of pain (45.9%), fatigue (40.7%), and short-of-breath (40.0%) as universal early recovery challenges—irrespective of surgical approach—mandates standardized PRO-driven enhanced recovery protocols. The temporal discordance between clinician-reported complications and patient-reported symptom burden (such as delayed coughing resolution despite “successful” ablation radiomics) further validates PROs as indispensable complements to traditional endpoints.

While HBD offers a promising parenchyma-sparing option, it is imperative to define its clinical boundaries. This approach is not universally applicable; however, there is currently no standardized protocol for the treatment of multiple pulmonary nodules. Limited application scenarios for RFA of secondary lesions include: (I) nodules located in close proximity (<5 mm) to major vessels, the heart, or central airways, where the risk of thermal injury to critical structures is high; (II) lesions for which a definitive pathological diagnosis is required to guide further treatment (e.g., nodules with atypical features suspicious for non-adenocarcinoma histology or metastases); (III) clustered nodules within a single lobe where an anatomical resection (segmentectomy or lobectomy) can achieve complete oncological clearance without compromising excessive lung function; and (IV) nodules larger than 2 cm, where the efficacy of RFA for achieving local control is less established (30). A thorough evaluation by a MDT is crucial to select appropriate candidates for the HBD procedure, balancing the benefits of lung preservation against the imperative of oncological safety.

This study illustrates HBD through three principal dimensions. First, it represents the documentation of PROs following HBD, systematically quantifying postoperative symptom trajectories. Second, through comparative analysis with VATS cohorts, we demonstrate that HBD exhibits similar short-term symptom burden progression patterns and further detect no significant differences between HBD and VATS in terms of short-term safety and symptomatic outcomes based on our previous research (19). Third, based on divergent postoperative trajectories between HBD and VATS, we propose a framework categorizing symptoms and functions into three distinct subgroups—a stratification that may inform personalized rehabilitation protocols for optimizing oncological outcomes and functional recovery in patients with multifocal pulmonary nodules.

Limitations

There are several limitations in this study. First, The single-center design and modest sample size limit statistical power and generalizability. The control group (uniportal VATS only) limits comparisons to multiportal VATS or thoracotomy. Group allocation based on nodule anatomy may introduce selection bias. Second, the 90-day follow-up is too short to assess long-term oncological efficacy and functional outcomes. The lack of correlation between PFTs and PROs limits direct evidence for the benefits of lung preservation. Our multicenter studies incorporating quantitative CT-based lung volume analysis, follow-up PFT and extended PRO surveillance (≥3 years) are needed to validate these findings. Third, despite implementing dual-tracking via automated digital reminders and dedicated telephone follow-up, longitudinal PRO surveillance was challenged by patient attrition, with the completion rate decreasing to approximately 70% by day 90, raising the potential for non-random attrition bias (such as if patients with worse outcomes dropped out), which cannot be fully addressed statistically. Although in similar observational studies, the compliance rate within POD 30 can be as low as 62.30% (15). Fourth, RFA-treated lesions lacked pathologic confirmation. Despite strict selection criteria, this introduces oncological uncertainty and a risk of overtreating benign nodules, mandating vigilant long-term surveillance. Finally, the technique’s resource demands (such as hybrid operating room) limit broad applicability. However, the procedure can be adapted: ablation and surgery may be performed sequentially in separate suites, facilitated by interventional radiologists. While not universally available, this flexibility may enhance feasibility across settings. The lack of a formal cost-effectiveness analysis leaves the value of the initial investment uncertain.

Conclusions

In this longitudinal cohort study, the HBD for treating primary lung cancer with synchronous ipsilateral nodules resulted in short-term PRO trajectories that were broadly similar to those of uniportal VATS. Our findings suggest potential symptom trade-offs, with a signal for faster resolution of numbness but a more persistent post-procedural cough in the HBD group. These results position HBD as a viable parenchyma-sparing alternative, and provide an evidence framework for patient-centric surgical decision-making in the era of precision thoracic oncology, but its long-term functional and oncological outcomes remain to be determined. Future research should focus on mitigating the post-ablation cough and validating the long-term safety and efficacy of this hybrid strategy in larger, randomized trials.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-996/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-996/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-996/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82203154), the Capital’s Funds for Health Improvement and Research (No. 2024-2-4027), National Key R&D Program of China (No. 2022YFC2407404), National High Level Hospital Clinical Research Funding and Cooperation Fund of CHCAMS Beijing & Langfang & SZCH (Nos. CFA202501002, CFA20252013 and CFA202503003), National High Level Hospital Clinical Research Funding (Nos. LC2024D01, LC2024C02, and 80102022501), CAMS Innovation Fund for Medical Sciences (CIFMS) (Nos. 2025-I2M-C&T-B-041 and 2025-I2M-C&T-B-058), and Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2021L01).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-996/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 was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (IRB 24/124-4404). All participants provided written informed consent.

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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