One-stage versus two-stage video-assisted thoracic surgery for synchronous bilateral pulmonary nodules: protocol for a prospective, multicentre, randomised controlled clinical trial in China (OTVATS-2)

Abstract

Introduction

With the increasing detection of synchronous bilateral pulmonary nodules in clinical practice, both one-stage and two-stage video-assisted thoracic surgery (VATS) have been widely applied. This study protocol describes the OTVATS-2 trial, which aims to compare perioperative complications and long-term outcomes between these two surgical strategies.

Methods and analysis

A prospective, multicentre, randomised controlled clinical trial will be conducted to compare the surgical outcomes of one-stage versus two-stage VATS in patients with synchronous bilateral pulmonary nodules. A total of 256 patients will be enrolled from three academic institutions in China. This trial is expected to last for 2 years, with patient recruitment starting in July 2025. The primary outcome is perioperative complication rate within 30 days. Secondary outcomes including 5-year overall survival, 5-year disease-free survival, surgical time, blood loss, duration of chest tube, length of stay, postoperative pain scores, quality of life scores as well as anxiety and depression scores.

Ethics and dissemination

This study has been approved by the Ethics Committee of China-Japan Friendship Hospital (No. 2025-KY-150) and the institutional review boards of all participating centres, including the Ethics Committees of Peking University Third Hospital and Beijing Hospital. Written informed consent will be obtained from all enrolled participants. Results of the research will be published in a peer-reviewed journal.

Trial registration number

ChiCTR 2500106215.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Both perioperative and long-term outcomes between one-stage and two-stage procedures will be compared in this study.

• Considering the patients’ individual differences and recovery status, the interval between the two operations in the staged group was not strictly restricted, which may introduce potential bias.

• This study will be conducted at only three tertiary hospitals in China, which limits the generalisability of its findings to other healthcare systems; additionally, the sample size may be insufficient to detect potential differences in 5-year survival outcomes

• The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire used for QoL assessment is a generic scale and is not specifically tailored for thoracic surgery or video-assisted thoracic surgery.

• Since blinding of patients, surgeons, and outcome assessors will not be feasible in this surgical trial, we will mitigate potential bias by adopting standardised outcome assessments and independent statistical analysis.

Introduction

The increasing clinical use of high-resolution CT (HRCT) for lung cancer screening has significantly increased the detection of synchronous multiple pulmonary nodules (SMPNs).¹ According to previous reports, the incidence of SMPNs ranges widely from 0.2% to 20%.² Surgical resection with curative intent for patients with SMPNs has been proved to be associated with survival benefits.^{3 4}

For bilateral synchronous pulmonary nodules, the surgical strategies include one-stage and two-stage procedures. Theoretically, simultaneous bilateral resection is more ideal than the staged strategy for preventing tumour progression.⁵ However, it should not be ignored that the one-stage procedure for bilateral pulmonary lesions is more invasive than the two-stage strategy and may cause severe complications.^{6 7} Therefore, one-stage bilateral resections have rarely been performed by thoracic surgeons for a long time.

In recent years, video-assisted thoracoscopic surgery (VATS) has increasingly become the preferred technique for thoracic surgery and has extremely reduced the surgical trauma, which makes one-stage resection for bilateral SMPNs feasible.⁸ Several retrospective studies have suggested that one-stage bilateral resection for SMPNs may be associated with higher complication rates relative to the two-stage procedure.^9–11 Lin et al¹² reported a case series of 35 patients who underwent simultaneous bilateral pulmonary resection with uniportal VATS and the postoperative complications were 28.6%. Zheng et al¹³ analysed 107 patients who received bilateral VATS lobectomy, 41 in the one-stage group and 66 in the two-stage group. The overall complication rates were comparable between one-stage and two-stage groups (26.8% vs 24.2%, p=0.85). Several other retrospective studies^14–16 have also reported no increase in morbidity associated with the one-stage procedure relative to the two-stage procedure. However, high-quality evidence comparing perioperative complications between the two kinds of procedures remains lacking.

On the other hand, staged surgery may carry the risk of contralateral tumour progression.⁵ Our previous study observed more favourable 3-year RFS outcomes in patients receiving one-stage resection compared with those undergoing two-stage surgery (90.7% vs 75.3%, p=0.039).⁵ The interval between the two operations is usually 4–8 weeks even if postoperative recovery proceeds smoothly. Otherwise, the second operation may be delayed due to complications from the first operation, psychological stress, as well as social and economic factors.

Although we have conducted a prospective, single-centre, non-randomised clinical trial (OTVATS-1)¹⁷ to compare the perioperative and long-term outcomes between one-stage and two-stage procedures, significant limitations exist including selection bias of the patients and the formulation of surgical strategy by the surgeons. For elderly patients with a high burden of comorbidities, the surgeon tended to prefer a two-stage surgical approach in clinical practice. To eliminate these biases, we conduct this randomised clinical trial.

Our preliminary study identified that a Charlson Comorbidity Index (CCI) score >3 is an independent risk factor for higher complication rates in patients undergoing simultaneous surgery. Furthermore, our clinical observations indicated that elderly patients aged over 75 years who received simultaneous surgery were also at elevated risk of postoperative complications. To guarantee patient safety and adhere to ethical standards, we set strict inclusion criteria for this multicentre randomised controlled trial (OTVATS-2), including an age cut-off of 75 years and a CCI score of <3. In addition, perioperative quality of life and postoperative pain scores will be assessed and compared between the two groups.

This multicentre, prospective randomised clinical trial (OTVATS-2) aims to compare the short and long-term outcomes of one-stage and two-stage VATS for patients with synchronous bilateral pulmonary nodules.

Methods and analysis

Study design

OTVATS-2 is a multi-institutional, randomised clinical trial, with a 1:1 allocation ratio (figure 1). This study is sponsored by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2024-I2M-C&T-B-091) and was registered with the China Clinical Trial Registry (ChiCTR2500106215), led by China-Japan Friendship Hospital. Patients will be recruited from three academic clinical centres in China, including China-Japan Friendship Hospital, Peking University Third Hospital and Beijing Hospital. All three participating centres are high-volume, academic tertiary hospitals located in urban areas of China, with standardised thoracic surgery systems and rigorous clinical quality control. These centres have rich experience in the diagnosis and surgical management of synchronous bilateral pulmonary nodules, and routinely perform both one-stage and two-stage VATS procedures with stable and standardised surgical protocols. In addition, the three centres have sufficient annual case volumes of lung cancer surgery (each centre performs more than 2000 cases annually). The enrolment period is planned to last 2 years, followed by a 5-year follow-up. This report follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist (online supplemental material 1).¹⁸

Figure 1. Study flowchart.

Objectives

This study aims to compare the perioperative and long-term outcomes between one-stage and two-stage VATS for patients with synchronous bilateral pulmonary nodules (figure 2).

Figure 2. Diagram of one-stage or two-stage surgery for BMPNss.

Study participants and recruitment

Participants are currently being recruited from among lung cancer outpatients at China-Japan Friendship Hospital, Peking University Third Hospital and Beijing Hospital.

Participant eligibility

The following participants are eligible for inclusion:

1. 18 to 75 years old.

2. Pathologically or clinically diagnosed with synchronous bilateral non-small cell lung cancer, with at least one lesion meeting surgical indication on each side with clinical stage cT1-2N0-1M0 (9th edition of the National Comprehensive Cancer Network).

3. American Society of Anesthesiologists classification stage: I-II.

4. CCI score <=3.

5. Both bilateral lesions are amenable to minimally invasive surgical resection.

6. Preoperative haematological and cardiopulmonary function assessments within normal ranges, indicating tolerance for bilateral surgical procedures.

7. Signed the informed consent (online supplemental material).

Exclusion criteria

Patients are excluded if they meet any of the following criteria:

1. Underwent neoadjuvant therapy previously.

2. History of other malignant tumours.

3. Bilateral lobectomy is planned for the patient.

4. Combined with other pulmonary diseases such as pulmonary fibrosis, interstitial pneumonia or emphysema.

Withdrawal criteria

1. Pathologically confirmed benign, metastatic tumour or small cell lung cancer.

2. Changed the surgical plan.

Randomisation and data management

Patients who meet the study inclusion criteria will be identified through the hospital’s electronic medical record system. Eligible patients will then be approached in person by the research team, who will clearly explain the study’s purpose, procedures, potential benefits and risks to obtain their voluntary informed consent before enrolment. After confirming eligibility and obtaining informed consent, patients are enrolled in the study and undergo a baseline assessment. Table 1 describes the detailed schedule of enrolment and assessments, including the HADS and QoL questionnaires. After completing the baseline assessment, patients will be randomly assigned at a 1:1 ratio to the one-stage or two-stage groups. Case Record Forms and electronic data capture (EDC) will be used for data collection and management. A stratified block randomisation method will be used in this trial. The stratification variable is hospital site. The random sequence is generated by SPSS V.26.0 software (IBM, New York, USA); and the concealment mechanism adopts EDC embedded allocation.

Table 1. Study calendar of the OTVATS-2 study.

Study period	Enrolment	Allocation	Post-allocation
Time point			Baseline (preoperative)	POD 1, 7	POD 30	6 month	1 year	Per 1 year up to 5 years
Enrolment
Eligibility screen	X
Informed consent	X
Interventions
One-stage group		X
Two-stage group		X
Perioperative outcomes				X	X
Pain score			X	X	X
Anxiety and depression scores			X		X
Quality of life			X		X	X	X
Survival								X

QoL surveys will be administered by trained research coordinators who have received professional training on questionnaire guidance to ensure consistent and standardised administration. For data collection, QoL surveys will be conducted at specified time points (preoperatively, 1 month, 3 months, 6 months, 1 year postoperatively) through face-to-face interviews or standardised online questionnaires, depending on the patient’s condition and willingness. All collected QoL data will be entered into a secure EDC system by designated data entry personnel. To ensure data accuracy, a double-entry verification process will be implemented, and any data discrepancies will be reviewed and corrected by the study statistician and principal investigator. Additionally, all data will be encrypted and stored in a password-protected database, with access restricted to authorised study personnel only, to ensure data confidentiality and compliance with relevant data protection regulations.

Study outcomes

Primary outcome

The primary outcome of this trial is complication rate within 30 days postoperatively. The complications include: postoperative bleeding, air leakage, pleural effusion, pulmonary infection, pulmonary embolism, chylothorax, atrial fibrillation and wound infection. The complication will be assessed according to the Clavien-Dindo classifications.

Secondary outcomes

The secondary outcomes are categorised as follows:

1. Surgical time: from the moment of the initial incision until closure of the surgical wound (minutes).

2. Blood loss during the operation (ml).

3. Duration of chest tube (days).

4. Length of stay (days).

5. Postoperative Pain Score: Visual Analogue Scale (VAS) will be used to evaluate the postoperative pain at following times: postoperative day 1, 7 and 1 month. Baseline (preoperative) pain score will be recorded. The VAS pain score ranges from 0 to 10.

6. Anxiety and depression scores: (Hospital Anxiety and Depression Scale, HADS) will be used to evaluate the emotional status at following times: preoperative <5 days and 1 month after operation.

7. Quality of life score: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) V.3.0 will be used to evaluate QoL at the pre-operative <5 days, and at 1 month, 6 month, 1 year postoperatively.

8. 5-year overall survival (Exploratory outcome): OS events are defined as the time between the date at diagnosis and the date of death from any cause.

9. 5-year disease-free survival (Exploratory outcome). DFS events are defined as the time from surgery to recurrence of tumour or death from any cause.

For the two-stage group, the complication rate, surgical time, blood loss, duration of chest tube placement and length of hospital stay are calculated as the cumulative totals from two-stage operations. The definitions of primary and secondary outcomes, together with measurement approaches, data sources and variable types are summarised (online supplemental table 1). Rates of unplanned reoperation, emergency department visits and hospital readmission will also be recorded as supplementary outcomes.

Intervention

Preoperative assessment

The preoperative staging workup including HRCT of the chest, abdominal and adrenal ultrasonography, electrocardiography, pulmonary function tests and routine blood tests. For patients with solid nodules, MRI of the brain and whole-body bone scintigraphy (or PET-CT) will be performed for staging.

Surgical procedures

Double-lumen endotracheal intubation with single-lung ventilation will be performed in both groups, with the patient in a lateral decubitus position. A 1–2 cm incision is made at the seventh interspace for the endoscopic hole, and a 3–4 cm incision is made at the fourth interspace for the operative hole. For the one-stage group, the operation usually starts from the side requiring less invasive resection (wedge resection or segmentectomy). After resection of the first side is accomplished, a chest tube is indwelled and the patient is rotated to the opposite side for contralateral surgery. If single-lung ventilation could not be maintained following resection of the first side, the surgical plan will be revised to a two-stage procedure. For the two-stage group, anaesthesia and surgical procedures follow the same protocol as those for the one-stage group. The interval between the two operations in the two-stage group is generally 4–8 weeks.

The 4–8 week interval for re-operation is determined based on the clinical recovery characteristics of patients. Due to individual differences in physical condition, postoperative recovery speed and presence of potential complications, a fixed single date cannot fully adapt to all patients’ needs. Although this may introduce bias, the 4–8 week range is designed to flexibly match the actual recovery status of different patients.

For patients who do not undergo the second operation or whose re-operation is outside the 8-week window, we will record these cases in detail, including the specific reasons. These patients will be included in the intention-to-treat (ITT) analysis to ensure the comprehensiveness of the study data. For patients not undergoing the second operation, we will track their long-term prognosis and include this information in the supplementary analysis.

Postoperative management

The indications for chest tube removal are as follows: (1) Daily drainage volume <200 mL, (2) Without air leakage or bleeding in the drainage bottle and (3) No pneumothorax or localised pleural effusion is observed on chest X-ray.

Follow-ups

Post-discharge follow-ups will be performed via clinic visits or telephone. Follow-up evaluations will include routine physical examinations, blood examinations and chest CT scans. Further evaluations, including abdominal CT or ultrasound, head MRI, bone scintigraphy and positron emission tomography, will be performed when symptoms or signs of recurrence are detected. Follow-up visits will be conducted every 6 months for the first 2 years and at 1-year intervals thereafter.

Sample size calculation

According to the reports of previous studies and our experience, the perioperative complications rate of one-stage group is expected to be approximately 29%,^{9 10 12} while the complications rate of two-stage group is preset at 20%.^{11 13} This 9% difference is supported by previous clinical experience and literature,^9–13 which confirms that such a magnitude of reduction in complication rates is sufficient to distinguish the efficacy of different surgical strategies. It also provides actionable clinical evidence for guiding the selection of one-stage or two-stage VATS, ensuring that the study outcomes have practical clinical value for improving patient prognosis. Clinically, a 9% reduction in perioperative complications translates to fewer patients experiencing pain, prolonged hospitalisation or additional interventions, which significantly improves patients’ short-term recovery experience and reduces physical and psychological burdens.

Assuming a Type I error rate (α) of 0.05 and a Type II error rate (β) of 0.2, sample size calculations using power analysis and sample size 15 software indicated that 115 subjects would be needed in each group (N1=115 for the experimental group and N2=115 for the control group). Considering a possible dropout rate of 10%, a minimum of 128 subjects per group are required, for a total of 256 patients.

Statistical analysis plan

All statistical analyses will be performed using Stata/IC V.18.0 or SPSS V.26.0 software (IBM, New York, USA). Categorical data will be presented as numbers (percentages) and analysed using χ² tests or Fisher’s exact tests. Student t-test or the Wilcoxon rank sum test will be implemented to compare continuous variables. Overall survival and DFS curves will be plotted using the Kaplan-Meier method, and differences in variables will be determined using the log-rank test. For all statistical analyses, p<0.05 will be considered to be statistically significant.

We will conduct ITT analysis to analyse according to the initial randomisation group regardless of cross-over and per-protocol analysis, which exclude cross-over cases to evaluate the effect of the original treatment plan.

Missing data

Patients with substantial missing data will be excluded. For missing data in quality of life assessments, the last-observation-carried-forward method will be employed.

Patient and public involvement

None.

Ethics and dissemination

The study is being conducted in accordance with the World Medical Association Declaration of Helsinki. The protocol was approved by the Ethics Committee of China-Japan Friendship Hospital under No. 2025-KY-150. Informed consent will be obtained from all participants prior to enrolment to ensure they fully understand the study’s purpose, procedures, risks and benefits.

Throughout data collection, collected data will be processed, and only data essential to fulfilling the study objectives will be retained. The results of the trial will be updated and findings will be published in peer-reviewed journals and presented at international conferences.

Data availability statement

No data are available.