Short- and Long-term Outcomes of Robotic-assisted Versus Video-assisted Thoracoscopic Lobectomy in Non-small Cell Lung Cancer Patients Aged 35 Years or Younger: A Real- world Study with Propensity-score Matched Analysis

doi:10.21203/rs.3.rs-2721743/v1

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Research Article

Short- and Long-term Outcomes of Robotic-assisted Versus Video-assisted Thoracoscopic Lobectomy in Non-small Cell Lung Cancer Patients Aged 35 Years or Younger: A Real- world Study with Propensity-score Matched Analysis

https://doi.org/10.21203/rs.3.rs-2721743/v1

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Journal Publication

published 30 May, 2023

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Purpose

This study compared short- and long-term outcomes of robotic-assisted thoracoscopic surgery (RATS) versus video-assisted thoracoscopic surgery (VATS) for lobectomy in young adults aged ≤ 35 years with non-small cell lung cancer (NSCLC), aiming to assess the superiority of RATS over VATS for this special group of patients.

Methods

A total of 1355 consecutive NSCLC cases aged 18–35 years undergoing RATS (n = 105) or VATS (n = 1250) between 2014 and 2021 were retrospectively identified from a prospectively maintained database. Propensity-score matching (PSM) was applied to establish a 1:3 RATS versus VATS ratio. Baseline clinicopathological characteristics, perioperative outcomes, lymph node (LN) assessment, and long-term survival were investigated.

Results

Following PSM, 105 and 315 cases were in the RATS and VATS groups, respectively. RATS led to a shorter postoperative hospital stay than VATS (4 [3–4] vs 4 [3–5] days, p = 0.02). The two groups were comparable in other perioperative outcomes and postoperative complications (all p > 0.05). Moreover, RATS assessed more LNs (9.4 ± 4.4 vs 8.3 ± 3.6, p = 0.03), especially N1 LNs (4.2 ± 3.1 vs 3.5 ± 2.2, p = 0.02), than VATS. By comparison, no difference in 5-year recurrence-free survival (RFS) or overall survival (OS) was found between the two groups (all p > 0.05). Further subgroup analyses also observed similar long-term outcomes between the two groups in terms of age, gender, and smoking history. Finally, Cox’s analyses found that the surgical approach was not independently correlated with RFS or OS.

Conclusion

RATS shortened postoperative hospital stay, assessed more N1 and total LNs, and achieved comparable long-term outcomes to VATS for very young NSCLC patients.

Non-small cell lung cancer

Robotic-assisted thoracoscopic surgery

Video-assisted thoracoscopic surgery

Perioperative outcomes

Lymph node assessment

Long-term survival

Non-small cell lung cancer (NSCLC) is one of the most common malignancies and has become a major public health problem in the world (Siegel et al. 2023). NSCLC typically affects elderly individuals with a median age at the first diagnosis of approximately 70 years, and younger adults are uncommon to suffer from primary NSCLC (Garrana et al. 2021). Nevertheless, with the increased implementation of thin-section thoracic computed tomography (CT) and advances in diagnostic modalities which effectively contribute to assessing early-stage disease, a growing number of young adults are diagnosed with NSCLC in recent years with the most prevalent histology being adenocarcinoma and the preponderance of female (Thai et al. 2021; Galvez-Nino et al. 2020; Sacher et al. 2016). Therefore, the optimal surgical approach is of critical importance for young patients, especially very young adults aged ≤ 35 years who may be associated with high reproduction and financial concerns, to achieve better oncological outcomes, emotional and psychological conditions, and quality of life (Galvez-Nino et al. 2020; Subramanian et al. 2010; Landwehr et al. 2016).

Although traditional thoracotomy is still the standard approach in treating NSCLC, minimally invasive surgery (MIS) technics have been widely applied in recent years. Video-assisted thoracoscopic surgery (VATS) is the most prevalent adopted MIS approach which reduces operation-related complications, accelerates postoperative recoveries, and leads to better life qualities compared with thoracotomy for early-stage NSCLC patients (Bendixen et al. 2016). Since its first performance in 2002, robotic-assisted thoracoscopic surgery (RATS) has attracted the growing interest of thoracic surgeons and is becoming increasingly prevalent in treating NSCLC as an alternative to thoracotomy and VATS (Huang et al. 2021). The robotic-assisted surgical system provides a high-definition, three-dimensional (3D), and 10–15 times magnified operation field and highly flexible robotic arms with an increased degree of motion and rotational freedom, allowing operators to perform the surgery more conveniently and accurately (Jin et al. 2022). Previous studies have compared the feasibility and oncological efficacy of RATS versus VATS for NSCLC, suggesting that RATS assessed more lymph nodes (LNs), reduced operation-related pain, led to a higher postoperative quality of life, and achieved similar long-term outcomes (Veronesi et al. 2016; Kneuertz et al. 2019). Therefore, RATS might be especially suitable for very young patients pursuing a quick postoperative recovery and high quality of life. However, RATS usually increased expenditures with its superiority over VATS concerning short- and long-term outcomes remaining unrevealed specified for young adults with NSCLC (Jin et al. 2022). Consequently, debate persists on the application of this novel modality for this special group of patients.

In the present study, we retrospectively identified a large cohort of NSCLC patients aged ≤ 35 years undergoing RATS or VATS lobectomy from a prospectively maintained database and compared the perioperative outcomes, LN dissection, and long-term survival between the two surgical approaches, aiming to assess the advantages of RATS over VATS.

Patient selection and data collection

We retrospectively identified NSCLC patients aged 35 years or younger who underwent RATS or VATS lobectomy in Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine during the period of November 2014 and March 2021 (Fig. 1). The inclusion criteria were as follows: (1) receiving RATS or VATS lobectomy; (2) aged 18–35 years; (3) pathology-confirmed NSCLC. The exclusion criteria were as follows: (1) surgery not for lung malignancy or cases with incomplete information; (2) History of lung surgery; (3) History of malignancy; (4) Undergoing segmentectomy, wedge resection, pneumonectomy, bi-lobectomies, bronchial sleeve resection, or bilateral operation; (5) pathology-proven adenocarcinoma in situ (AIS) or malignancy other than NSCLC; (6) clinical/pathological T4 or N3 disease; (7) R2 resection (residual macroscopic tumor) or without mediastinal LN assessment; (8) preoperative intrapulmonary or distant metastasis. A total of 1355 patients were finally enrolled and further divided into the RATS (n = 105) and VATS (n = 1250) groups. The following data were collected: (1) baseline clinicopathological characteristics such as gender, age, history of smoke, body mass index (BMI), preoperative comorbidities, pulmonary functions [% of forced expiratory volume in 1 s (FEV1%), and % of diffusing capacity for carbon monoxide (DLCO%)], surgical location, tumor size, pathological T, N, and TNM stage of the disease, induction therapy, and adjuvant therapy; (2) perioperative outcomes including surgical duration, conversion, reoperation, intraoperative bleeding, postoperative blood transfusion, postoperative ICU admission, duration and volume of chest tube drainage, length of postoperative hospital\ stays, and postoperative complications; (3) LN assessment including the N1, N2, and the total number of dissected LNs and LN stations; (4) long-term outcomes including 1-, 3-, and 5-year recurrence-free survival (RFS) and overall survival (OS). All cases were staged following the 8th edition of the TNM staging system of the International Association for the Study of Lung Cancer.

Perioperative Evaluation And Surgical Techniques

Pulmonary and cardiac function tests were routinely performed before the operation to ensure the surgical tolerance of patients. High-resolution thoracic CT and/or positron emission tomography/CT (PET/CT) were conducted to assess mediastinal and pulmonary LN status. PET/CT, bone scintigraphy, abdominal ultrasound, and enhanced cranial magnetic resonance imaging were carried out to determine distant metastasis. RATS and VATS were performed through 4 minimal invasions without spreading ribs, and a radical lobectomy combined with systemic LN dissection or LN sampling was conducted. After ensuring the absence of active bleeding in the thoracic cavity and air leakage from the bronchial stump, the incisions were closed with 1–2 chest tubes left.

Postoperative Management And Follow-up

All patients received the enhanced recovery protocol including smoking cessation 2 weeks before surgery, breathing exercises, and early postoperative exercises. Conventionally, patients were discharged 1 day after removing drainage tubes, unless there were comorbidities that still required intervention. Standard adjuvant therapy including chemotherapy, immunotherapy, and/or radiotherapy was recommended for patients, if necessary. Thoracic CT and brain MRI scans were performed every 3–6 months after the operation during the first 2-year period, followed by an annual follow-up assessment of patients. Telephone and/or Internet follow-ups were conducted every year for patients who did not regularly come to the outpatient clinic until death or March 2023. The latest electronic medical data were recorded for patients lost to follow-up. The radiological recurrence tumors were defined as multiple new pulmonary lesions with the consolidation-to-tumor ratio (the ratio of the size of the solid component to the overall tumor diameter) of > 0.5 for all nodules, following the guidelines of radiologists (Yotsukura et al. 2021). RFS was defined as the duration from operation to any local or distant tumor recurrence. OS was defined as the duration from operation to death.

Statistical analysis

Categorical variables were expressed using frequencies and percentages, while continuous variables were expressed using mean ± standard deviation (SD) or median and interquartile range (IQR). To compare categorical variables, Pearson’s chi-square tests or Fisher’s exact tests were adopted. The homogeneity of variance and normality of distribution for continuous variables were determined using the Kolmogorov-Smirnov test. The student’s t-test was conducted for continuous variables with normal distribution and homogeneous variance, and the Mann-Whitney U test was performed otherwise. Kaplan-Meier curves log-rank (Mantel-Cox) test was carried out to analyze survival profiles. Cox hazard regression model analysis was further conducted to identify factors relevant to RFS, OS, and CSS. To mitigate potential patient selection bias, propensity score matching (PSM) was carried out based on 14 critical baseline characteristics, including gender, age, history of smoke, BMI, FEV1%, DLCO%, surgical location, tumor size, tumor histology, pathological T stage, pathological N stage, pathological TNM stage, neoadjuvant therapy, and adjuvant therapy to establish a 1:3 RATS versus VATS ratio. SPSS version 26.0 (IBM Corporation, Armonk, NY, USA) was applied for statistical analysis and PSM, while GraphPad Prism-9 (GraphPad Software Inc., San Diego, CA, USA) was used for analyzing survival profiles. A two-tailed p-value less than 0.10 was considered statistically significant for the Cox hazards regression model analysis, while less than 0.05 was considered statistically significant in all other tests.

Baseline clinicopathological characteristics

The baseline clinicopathological characteristics of the included patients before PSM were shown in Table 1. Patients who received RATS or VATS were associated with a similar distribution of gender (p = 0.90), age (32.2 ± 3.0 vs 32.0 ± 2.8 years, p = 0.34), history of smoke (p = 0.76), BMI (22.0 ± 2.8 vs 21.8 ± 4.4 kg/m², p = 0.62), preoperative comorbidities (p = 0.59), FEV1% (96.8 ± 11.5 vs 96.3 ± 12.2, p = 0.47), DLCO% (97.5 ± 13.5 vs 97.8 ± 16.9, p = 0.72), surgical location (p = 0.34), tumor histology (p = 0.68), tumor size (16.7 ± 9.9 vs 17.4 ± 10.1 mm, p = 0.69), pathological T (p = 0.78), N (p = 1.00), and TNM (p = 0.99) stage of the disease, neoadjuvant therapy (p = 1.00), and adjuvant therapy (p = 0.75). PSM was then applied to establish a 1:3 RATS versus VATS ratio and all baseline cofounding features of included cases were well balanced between the two groups following PSM (all p > 0.05).

Table 1

Baseline clinicopathological characteristics of patients before and after PSM
Variables	Before PSM			After PSM
Variables	RATS (n=105)	VATS (n=1250)	p-value	RATS (n=105)	VATS (n=315)	p-value
Gender, n (%) Male Female	38 (36.2) 67 (63.8)	445 (35.6) 805 (64.4)	0.90	38 (36.2) 67 (63.8)	116 (36.8) 199 (63.2)	0.91
Age (years), mean ± SD	32.2±3.0	32.0±2.8	0.34	32.2±3.0	32.2±2.9	0.99
History of smoke, n (%) Ever Never	8 (7.6) 97 (92.4)	106 (8.5) 1144 (91.5)	0.76	8 (7.6) 97 (92.4)	22 (7.0) 293 (93.0)	0.83
BMI (kg/m²), mean ± SD	22.0±2.8	21.8±4.4	0.62	22.0±2.8	22.0±3.1	0.86
Comorbidities, n (%) Yes No	6 (5.7) 99 (94.3)	89 (7.1) 1161 (92.9)	0.59	6 (5.7) 99 (94.3)	21 (6.7) 294 (93.3)	0.73
Pulmonary function, mean ± SD FEV1% (of predicted) DLCO% (of predicted)	96.8±11.5 97.5±13.5	96.3±12.2 97.8±16.9	0.47 0.72	96.8±11.5 97.5±13.5	96.7±10.5 97.6±13.9	0.61 1.00
Surgical location, n (%) Left upper lobe Left lower lobe Right upper lobe Right middle lobe Right lower lobe	10 (9.5) 26 (24.8) 29 (27.6) 17 (16.2) 23 (21.9)	207 (16.6) 245 (19.6) 335 (26.8) 182 (14.6) 281 (22.5)	0.34	10 (9.5) 26 (24.8) 29 (27.6) 17 (16.2) 23 (21.9)	34 (10.8) 81 (25.7) 82 (26.0) 50 (15.9) 68 (21.6)	0.99
Tumor histology, n (%) MIA Adenocarcinoma Others ^a	29 (27.6) 71 (67.6) 5 (4.8)	300 (24.0) 879 (70.3) 71 (5.7)	0.68	29 (27.6) 71 (67.6) 5 (4.8)	87 (27.6) 215 (68.3) 13 (4.1)	1.00
Tumor size (mm), mean ± SD	16.7±9.9	17.4±10.1	0.69	16.7±9.9	16.4±10.8	0.48
Pathological T stage, n (%) T1a(mi) T1a T1b T1c T2a T2b T3	29 (27.6) 19 (18.1) 37 (35.2) 8 (7.6) 8 (7.6) 3 (2.9) 1 (1.0)	300 (24.0) 215 (17.2) 429 (34.3) 97 (7.8) 104 (8.3) 69 (5.5) 36 (2.9)	0.78	29 (27.6) 19 (18.1) 37 (35.2) 8 (7.6) 8 (7.6) 3 (2.9) 1 (1.0)	87 (27.6) 58 (18.4) 112 (35.6) 22 (7.0) 24 (7.6) 9 (2.9) 3 (1.0)	1.00
Pathological N stage, n (%) N0 N1 N2	98 (93.3) 3 (2.9) 4 (3.8)	1154 (92.3) 40 (3.2) 56 (4.5)	1.00	98 (93.3) 3 (2.9) 4 (3.8)	294 (93.3) 9 (2.9) 12 (3.8)	1.00
Pathological TNM stage, n (%) IA1 IA2 IA3 IB IIA IIB IIIA IIIB	48 (45.7) 35 (33.3) 6 (5.7) 5 (4.8) 3 (2.9) 4 (3.8) 4 (3.8) 0 (0.0)	515 (41.2) 407 (32.6) 79 (6.3) 82 (6.6) 48 (3.8) 56 (4.5) 57 (4.6) 6 (0.5)	0.99	48 (45.7) 35 (33.3) 6 (5.7) 5 (4.8) 3 (2.9) 4 (3.8) 4 (3.8) 0 (0.0)	145 (46.0) 105 (33.3) 18 (5.7) 19 (6.0) 6 (1.9) 9 (2.9) 12 (3.8) 1 (0.3)	1.00
Neoadjuvant therapy, n (%)	4 (3.8)	53 (4.2)	1.00	4 (3.8)	13 (4.1)	1.00
Adjuvant therapy, n (%)	9 (8.6)	119 (9.5)	0.75	9 (8.6)	29 (9.2)	0.84

Continuous data are expressed as mean ± SD and categorical data are shown as number (percentage). Bold indicates the statistically significant p value (p < 0.05). Others ^a: squamous cell carcinoma, carcinoid tumor, mixed tumor, and mucosa-associated lymphoid tissue lymphoma. RATS, robotic-assisted thoracoscopic surgery; VATS, video-assisted thoracoscopic surgery; SD, standard deviation; BMI, body mass index; FEV1, forced expiratory volume in 1 s; DLCO, diffusing capacity for carbon monoxide; MIA, minimally invasive adenocarcinoma.

Perioperative Outcomes And LN Dissection

The perioperative outcomes of matched patients were expressed in Table 2. By comparison, RATS and VATS were associated with a similar surgical duration (91.4 ± 23.4 vs 94.3 ± 34.6 mins, p = 0.95), the incidence of conversion (p = 1.00) and reoperation (p = 1.00), intraoperative bleeding (p = 0.81), and postoperative blood transfusion (p = 1.00). Moreover, the RATS group had a shorter length of postoperative hospital stay (4 [3–4] vs 4 [3–5] days, p = 0.02) than the VATS group. Additionally, no difference was found between the two groups in postoperative ICU admission (6.7% vs 9.2%, p = 0.42), chest tube drainage volume (640 [430–820] vs 670 [490–810] mL, p = 0.41) and duration (3 [3–4] vs 3 [3–4] days, p = 0.51), and postoperative complications (all p > 0.05). Meanwhile, no operation-related mortality was found in the RATS or VATS groups. Finally, patients receiving RATS or VATS were associated with comparable Clavien-Dindo postoperative complication scores (Fig. 2).

Table 2

Perioperative outcomes and LN dissection of matched patient
Variables	RATS (n = 105)	VATS (n = 315)	p-value
Surgical duration (mins), mean ± SD	91.4 ± 23.4	94.3 ± 34.6	0.95
Conversion to thoracotomy, n (%)	1 (1.0)	5 (1.6)	1.00
Reoperation, n (%)	0 (0.0)	2 (0.6)	1.00
Intraoperative bleeding (mL), n (%) <100 ≥100	72 (68.6) 33 (31.4)	212 (67.3) 103 (32.7)	0.81
Postoperative blood transfusion, n (%)	1 (1.0)	3 (1.0)	1.00
ICU admission, n (%)	7 (6.7)	29 (9.2)	0.42
Chest tube drainage, median [IQR] Length (days) Volume (mL)	3 [3–4] 640 [430–820]	3 [3–4] 670 [490–810]	0.51 0.41
Postoperative hospital stays (days), median [IQR]	4 [3–4]	4 [3–5]	0.02
Postoperative complications, n (%) Any comorbidities Prolonged air leak > 5 days Pneumonia requiring antibiotics Hemorrhage requiring intervention Chylothorax Arrhythmia Vocal cord paralysis Chest tube reinsertion Readmission within 30 days	6 (5.7) 3 (2.9) 1 (1.0) 1 (1.0) 1 (1.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)	22 (7.0) 11 (3.5) 5 (1.6) 2 (0.6) 4 (1.3) 2 (0.6) 1 (0.3) 1 (0.3) 2 (0.6)	0.65 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Number of dissected LNs, mean ± SD N1 LNs count N2 LNs count Total N1 + N2 LNs count	4.2 ± 3.1 5.2 ± 2.7 9.4 ± 4.4	3.5 ± 2.2 4.8 ± 2.5 8.3 ± 3.6	0.02 0.08 0.03
Number of dissected LN stations, mean ± SD N1 station count N2 station count Total N1 + N2 stations count	2.5 ± 0.8 3.2 ± 1.1 5.6 ± 1.4	2.4 ± 0.9 3.1 ± 0.9 5.4 ± 1.4	0.07 0.45 0.35

Continuous data are expressed as mean ± SD or median [IQR] and categorical data are shown as number (percentage). Bold indicates the statistically significant p value (p < 0.05). RATS, robotic-assisted thoracoscopic surgery; VATS, video-assisted thoracoscopic surgery; SD, standard deviation; IQR, interquartile range; LNs, lymph nodes.

In terms of the LN dissection, RATS harvested significantly increased number of N1 (4.2 ± 3.1 vs 3.5 ± 2.2, p = 0.02) and total (9.4 ± 4.4 vs 8.3 ± 3.6, p = 0.03) LNs compared with VATS. Meanwhile, the two groups had a comparable number of harvested N2 LNs (5.2 ± 2.7 vs 4.8 ± 2.5, p = 0.08). Moreover, no difference was found in assessing N1 (2.5 ± 0.8 vs 2.4 ± 0.9, p = 0.07), N2 (3.2 ± 1.1 vs 3.1 ± 0.9, p = 0.45), and total (5.6 ± 1.4 vs 5.4 ± 1.4, p = 0.35) LN stations between two surgical approaches.

Long-term Survival

The median follow-up of RATS and VATS groups was 62 months [range 24–99 months] and 65 months [range 24–98 months], respectively. In the RATS group, the 5-year RFS and OS of patients were 87.0% and 95.9%, respectively. In the VATS group, the 5-year RFS and OS were 86.2% and 95.7%, respectively (Fig. 3A-B). The two surgical approaches achieved comparable RFS (p = 0.86) and OS (p = 0.96) profiles. Furthermore, patients who underwent RATS or VATS were associated with comparable recurrence and mortality patterns (Fig. 3C-D). Additionally, patients were divided into subgroups concerning the histology type (MIA and the others), age (18–30 and 31–35 years), and gender (male and female), and the analysis within the subgroups also suggested that RATS and VATS led to similar long-term outcomes (Fig. 4A-D, Supplementary Fig. 1A-D, Supplementary Fig. 2A-D). Finally, multivariable Cox hazard regression analysis revealed that the surgical method (RATS vs VATS) was not independently correlated with RFS [hazard ratio (HR) = 0.96, p = 0.90, Supplementary Table 1) or OS (HR = 0.86, p = 0.80, Supplementary Table 2). Meanwhile, gender, age, and history of smoke were also not independent predictors of prognosis (all p > 0.05). Nevertheless, the advanced disease and LN metastasis were independently associated with the shortened DFS and OS.

The feasibility and efficacy of VATS have been well established, making VATS to be the most prevalent MIS technic in treating NSCLC. Nowadays, RATS is also increasingly applied for NSCLC and has been accepted to be safe and oncological effective (Jin et al. 2022; Huang et al. 2021). However, the epidemiological characteristics of NSCLC determine that the vast majority of cases occur in elderly individuals aged over 60 years. Consequently, the perioperative outcomes and long-term survival data of RATS for young NSCLC cases remain unrevealed. In this study, we retrospectively compared the short- and long-term outcomes of RATS and VATS lobectomy in NSCLC patients aged 35 years or younger based on real-world practice, suggesting that RATS accelerated postoperative recoveries, assessed increased LNs, and achieved comparable intraoperative outcomes and long-term survival when compared with VATS.

Our results showed that RATS led to a shorter postoperative hospital stay than VATS, which potentially be attributed to the flexibility of the robot arms and high-quality surgical view which enables a more precise resection and minimizes unnecessary damage and thus expedites postoperative recoveries of patients. Given current clinical practice trends, there are increasing publications comparing perioperative recoveries between RATS and VATS, but conflicting results have been reported. Recently, three studies analyzing the Premiere database observed that RATS was associated with a shorter length of postoperative hospitalization (Reddy et al. 2018; Oh et al. 2017; Kent et al. 2023). This superiority of RATS, however, was not found in the other two publications based on public databases (Louie et al. 2016; Veluswamy et al. 2020). Furthermore, our results showed that RATS and VATS led to similar duration and volume of chest tube drainage, which were concordant with most previous studies. Nevertheless, Jin et al. found an increased chest tube volume with RATS, possibly due to the advantages of RATS in accessing LNs which might damage the bronchial and lymphatic vessels connected with LNs (Jin et al. 2022). Finally, no surgical-related mortality and low incidence of blood transfusion was found in the RATS and VATS groups, suggesting that both surgical approaches are safe for lobectomy in treating very young NSCLC patients.

LN retrieval is a vital part of MIS lobectomy in treating NSCLC and an important measurement of surgical quality. Numerous previous studies have determined the capacity of the robotic-assisted surgical system in LN assessment, but have produced conflicting conclusions. Three studies suggested that RATS harvested higher numbers of LNs and LN stations than VATS (Jin et al. 2022; Nelson et al. 2019; Ma et al. 2021). Nevertheless, Kneuertz et al. and Guo et al. independently found that the two procedures exhibited comparable capacity in LN exanimation (Kneuertz et al. 2019; Guo, Ma, and Li 2019). Our results indicated that RATS assessed more LNs, especially N1 LNs, while examining similar N2 LNs and LN stations when compared with VATS. This superiority of RATS might be attributed to the higher quality of the surgical field and the enhanced maneuverability provided by the robotic-assisted surgical system, which enables operators to harvest LNs around vessels and bronchi more conveniently. Nevertheless, the increased LN dissection could damage the normal mediastinal lymphatic, vascular, and neurogenic tissues and may thus result in comorbidities including recurrent laryngeal nerve injury and chylothorax (Allen et al. 2006). In our study, RATS did not increase postoperative complications when harvesting more LNs compared with VATS. Given this, RATS might be especially suitable for patients with a high risk of LN metastasis who demand a more complete mediastinal and pulmonary LN assessment.

In terms of long-term outcomes, our results suggested that RATS and VATS achieved comparable 5-year RFS and OS in the young. These findings are consistent with and could be a complement to several previous studies which enrolled older cases, suggesting that RATS might be oncological effective for all-age resectable NSCLC patients (Montagne et al. 2022; Pan et al. 2022; Merritt et al. 2022). The very young NSCLC patients usually have distinctive clinic-demographic and genomic features, and are associated with a higher risk to suffer from the multiple pulmonary lesions than older individuals (Viñal et al. 2021). Hence, identifying the optimal extent of resection to preserve more normal lung tissue for the potential multiple lung surgeries is of critical importance for this special group of patients. Recently, two multicenter, noninferiority, phase 3 trials, namely JCOG0802/WJOG4607L and CALGB 140503 trials, showed that sub-lobectomy was not inferior to lobectomy, and thus might be considered one of the standard treatments for patients with a peripheral stage IA NSCLC with a tumor size ≤ 2cm (Altorki et al. 2023; Saji et al. 2022). Moreover, two independent studies also found that patients with AIS/MIA were associated with 100% RFS during the follow-up for at least 5 years, regardless of the surgical method (lobectomy, segmentectomy, or wedge resection) (Yotsukura et al. 2021; Zhang et al. 2022). These important discoveries are expected to promote the prevalence of sub-lobectomy in treating early-stage NSCLC. In our study, most young patients had early-stage disease and meet the criteria for sub-lobar resection proposed by the aforementioned trials. Therefore, further comparison of surgical-related outcomes and oncological efficacies of RATS versus VATS for sub-lobectomy in young NSCLC cases is important to expand the scope of the application of RATS.

In the present study, most young NSCLC patients were associated with early-stage disease and achieved excellent 5-year survival outcomes. However, many previous publications have found distinct clinic-epidemiological features, indicating that NSCLC in the young may represent a more aggressive tumor and most young cases had the late-stage (III-IV) disease at the first diagnosis and were associated with a poor prognosis (Duan et al. 2013; Subramanian et al. 2010; Galvez-Nino et al. 2020). Nevertheless, most included cases in these studies were diagnosed before 2016 and early-stage NSCLC is increasing prevalent nowadays with the increased implementation of thin-section thoracic CT and development in diagnostic modalities. Meanwhile, more attention has been paid on physical health and the routine medical examination is becoming increasingly popular among young adults in recent years. Our study identified young NSCLC patients undergoing surgery after 2016 and thus included more early-stage cases. Moreover, the present study excluded patients with stage T4/N3 disease or intra-pulmonary or distant metastasis, and therefore the vast majority of patients with advanced disease were excluded.

To the best of our knowledge, the present study is the first retrospective analysis comparing perioperative outcomes and long-term survival of RATS versus VATS lobectomy specified for very young NSCLC patients aged ≤ 35 years based on real-world practice. However, we have also acknowledged some limitations of the present study. The retrospective analysis usually leads to undiscovered patient selection bias and unbalanced case distribution. The huge difference in the size of included patients resulted in the excluding of many patients in the VATS group, and the potential selection bias may still exist, despite PSM having been applied in the present study to balance the key confounding factors of patients. Moreover, the single-center analysis property of the present study limited the size of the case sample and weakened its representative, though the patient data were identified from one of the most famous and highest-volume medical centers in China. Therefore, further multi-center prospective research is necessary to validate the findings of our analysis.

In conclusion, RATS exhibited superiorities over VATS in shorter postoperative hospital stay and more assessed LNs than VATS, and the two surgical approaches achieved similar long-term outcomes, in treating NSCLC patients aged 35 years or younger

Funding

This work was supported by National Nature Science Foundation (Grant No. 81772482), the Joint Clinical Research Centre of Institute of Medical Robotics@SJTU-Shanghai Chest Hospital (IMR-XKH202104), and the Shanghai Hospital Development Center (Grant No. SHDC12016113).

Conflicts of Interest

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Pan HB, Zhang JQ, and Tian Y contributed equally to this work as the co-first authors. Conceptualization and design: Huang J, Luo QQ; Methodology: Pan HB, Zhang JQ, Tian Y, Jin WQ; Resources: Tian Y, Gu ZN, Ning JW, Zhu HD, Jiang L; Formal analysis and investigation: Pan HB, Zhang JQ, Tian Y, Zhu HD, Jin WQ; Writing-original draft preparation: Pan HB, Zhang JQ, Tian Y; Writing-review and editing: Jiang L, Huang J, Luo QQ; Funding acquisition: Luo QQ; Supervision: Huang J, Luo QQ.

Data availability

The data generated and analyzed during the present study are available from the corresponding authors Prof. Huang J and Luo QQ upon reasonable request.

Ethical Statement

This study was conducted following the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine (approval No. KS1735). The written informed consent was waived due to the retrospective nature of this study.

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Short- and Long-term Outcomes of Robotic-assisted Versus Video-assisted Thoracoscopic Lobectomy in Non-small Cell Lung Cancer Patients Aged 35 Years or Younger: A Real- world Study with Propensity-score Matched Analysis

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