Early outcomes of radical surgery in non-small-cell lung cancer patients with and without COVID-19 history: a multi-center real-world study

Abstract

Background:

Coronavirus disease (COVID)-19 can lead to chronic lung damage and respiratory issues, potentially increasing surgical difficulty and risk for patients with non-small-cell lung cancer (NSCLC). However, the impacts of a COVID-19 history on early outcomes in NSCLC patients remain controversial.

Objectives:

To evaluate the effect of COVID-19 history on early outcomes in NSCLC patients and identify high-risk groups undergoing radical resection based on the largest Chinese multi-center real-world data to date.

Design:

Multi-center retrospective cohort study.

Methods:

NSCLC patients with (POCVD group) or without (NCVD group) a history of COVID-19 who underwent radical surgery at six institutions from January 2022 to January 2024 were retrospectively reviewed from a prospectively maintained database. Propensity-score matching (PSM) was utilized to minimize patient selection bias.

Results:

Out of 7932 cases included, PSM resulted in 3021 cases per group. The two groups were comparable regarding the proportion of male patients (52.0% vs 51.6%) and those aged ⩾70 years (13.3% vs 13.8%). Although the two groups had comparable incidences of complications with Clavien-Dindo grades ⩾II (13.0% vs 14.4%, p = 0.117), the POCVD group had longer surgical durations (120.87 ± 40.23 min vs 110.74 ± 38.76 min, mean difference (95% confidence interval (CI) = 10.13 (8.138–12.122)) and higher rates of respiratory complications than the NCVD group. Subgroup logistic regression analysis indicated that patients aged ⩾70 years (odds ratio (OR) (95% CI) = 1.322 (1.022–1.876)) and those with a smoking history (OR (95% CI) = 1.235 (1.008–1.543)) had an increased risk of developing complications with Clavien-Dindo grades ⩾II. Further analysis confirmed that these high-risk patients experienced extended surgical durations, longer chest tube drainage, and prolonged postoperative hospital stay, along with increased postoperative respiratory complications following COVID-19.

Conclusion:

Generally, radical resection is safe for NSCLC patients with a COVID-19 history. However, these patients experienced prolonged surgical durations and a higher incidence of postoperative respiratory complications compared to those without a COVID-19 history. In addition, individuals aged ⩾70 years or with a smoking history faced elevated surgical risks following COVID-19.

Plain language summary

Analyzing the impact of COVID-19 history on early outcomes and identifying high-risk groups among non-small cell lung cancer patients undergoing radical resection

Aim and Purpose Research Question: Does a COVID-19 history affect the early outcomes of radical surgery (lobectomy/bi-lobectomy/pneumectomy) in patients with non-small cell lung cancer (NSCLC)? Hypothesis: Patients with a COVID-19 history face elevated surgical risks compared to those without. Objective: To understand how past COVID-19 infection impacts early outcomes in NSCLC patients undergoing surgery and to identify high-risk groups. Background Why This Study: COVID-19 can cause long-term lung damage, making surgery riskier for NSCLC. However, it’s unclear how past COVID-19 infection affects NSCLC patients receiving surgery. Importance: The research helps to understand the additional risks for NSCLC patients with a COVID-19 history based on the largest cohort to date, aiming to improve their surgical outcomes. Method and Design Research Design: Multi-center retrospective cohort study. Methods and Participants: 7932 NSCLC patients undergoing radical surgery between January 2022 and January 2024 were included and divided into two groups: those with a COVID-19 history (POCVD group) and those without (NCVD group). Result and Importance Findings: 1. The POCVD group had longer surgical durations and higher rates of respiratory complications compared to the NCVD group. 2. The POCVD and NCVD groups were associated with a comparable incidence of postoperative complications with Clavien-Dindo grades ⩾II. 3. The elderly (aged ⩾70 years) and smokers were at higher risk for complications post-COVID-19. Implications: While surgery is generally safe for NSCLC patients with a COVID-19 history, they do face increased risks and complications. This highlights the need for special care and monitoring for older patients and those with smoking histories. Key Message: NSCLC patients with a COVID-19 history can safely undergo radical surgery, but they may experience longer surgical durations and more postoperative respiratory complications, especially the elderly and smokers.

Keywords

Chinese population coronavirus disease-19 early outcomes non-small-cell lung cancer radical surgery

Introduction

Since its first appearance in 2019, the coronavirus disease (COVID)-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has profoundly disrupted healthcare systems globally.¹ Its ongoing societal and economic impacts are anticipated to continue, placing substantial burdens on morbidity and mortality.² Lockdown measures have reduced non-COVID-19 healthcare services, raising concerns about their effects on various patient populations, especially those with cancer, the group for whom timely diagnosis and treatment initiation are crucial for achieving optimal outcomes.^3,4 Under such circumstances, the effects of a history of SARS-CoV-2 infection on surgical outcomes have become a central research focus, as patients recovering from COVID-19 may face prolonged psychological and physiological challenges that could complicate their surgery and recovery.^5
–8

SARS-CoV-2 primarily transmits through aerosols, infecting the respiratory system and causing symptoms that can progress to severe pneumonia or respiratory failure.⁹ Although the virus can affect multiple organs, the respiratory system is generally the most impacted.^10,11 Recent studies reveal that SARS-CoV-2 can cause highly variable lung damage and respiratory problems, which may lead to long-term complications such as pulmonary fibrosis, chronic inflammation, and diminished immune function.^12,13 Unfortunately, many patients may experience permanent lung damage.¹⁴ This is especially concerning for those requiring surgery for non-small-cell lung cancer (NSCLC), a leading cause of cancer-related mortality worldwide and a major public health issue.^15
–18 These effects are particularly problematic for patients undergoing radical resections, the definitive curative treatment when complete resection is feasible, with lobectomy as the standard approach, as these patients are more vulnerable to adverse outcomes compared to those undergoing lung-sparing procedures like wedge resection and segmentectomy.^{9,11,15,19,20} Therefore, it is crucial to understand whether a history of SARS-CoV-2 infection could influence perioperative outcomes and to identify the population at increased surgical risk following SARS-CoV-2 infection for NSCLC surgery.

The impact of a history of COVID-19 on the perioperative outcomes of NSCLC patients has been extensively studied, yet the results remain inconsistent. Some studies suggest that a history of COVID-19 does not significantly affect perioperative outcomes, while others report an association with increased postoperative complications and delayed recovery.^{6,9,11,15,21,22} This controversy may stem from differences in epidemiological characteristics of SARS-CoV-2 infection, genetic backgrounds, vaccination status of patients, and varying medical and surgical standards across different countries and regions. Importantly, these previous results are derived from a limited number of cases or single-center practices, significantly restricting their representativeness and persuasiveness. Consequently, controversy persists on whether a COVID-19 history elevates the surgical risk for NSCLC.

Herein, based on real-world data from six medical centers and the largest cohort of NSCLC patients to date, this study systematically examines the impact of COVID-19 history on early outcomes and identifies the population at heightened surgical risk due to prior COVID-19 infection. The findings are expected to provide valuable insights into the understanding of perioperative management following radical resection in the COVID-19 era for NSCLC patients, ultimately guiding the development of more robust and patient-specific therapeutic strategies.

Methods

Study design and patients

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology statement (Supplemental File).²³ In this multi-center retrospective cohort study, eligible NSCLC patients aged ⩾18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and with or without a history of COVID-19, who underwent radical surgery at six Chinese medical centers from January 2022 to January 2024 were reviewed from a prospectively maintained database. The original database was established and maintained by dedicated employees who retrieved specific patient information from the electronic medical records using their developed algorithms. After passing the ethical review and gaining application approval, our research team accessed this database. Subsequently, some of our researchers verified and supplemented essential information by reviewing electronic medical records. In addition, the accuracy of this database was further validated through selective examinations conducted by other members of our research team.

The institutions are as follows: Shanghai Chest Hospital, The Affiliated Lihuili Hospital of Ningbo University, The First Affiliated Hospital of Ningbo University, Zhoushan Putuo District People’s Hospital, The First Affiliated Hospital of Shaoyang University, and Shaoyang Central Hospital. The exclusion criteria were as follows: (1) with missing essential information (defined as all variables included and analyzed, encompassing patient baseline characteristics and early outcomes); (2) undergoing bilateral operations or concurrent additional esophageal, mediastinal, or cardiac surgery; (3) with a history of malignancy; (4) with clinical stage T4, N3, or M1 disease; and (5) with perioperative COVID-19 (defined as an in-hospital COVID-19 infection confirmed by real-time quantitative polymerase chain reaction (RT-qPCR)).

Preoperative evaluation

Before the operation, patients were informed of the potential risk of surgery during the COVID-19 pandemic and possible perioperative complications caused by the history of COVID-19, and the surgical approach was finally decided by patients and surgeons together. RT-qPCR was applied every day until discharge to assess perioperative COVID-19. Patients’ tolerability for surgery was evaluated through comprehensive preoperative tests, including electrocardiograms, echocardiography, and pulmonary function tests. Additional tests like coronary computed tomography (CT) angiography and pulmonary ventilation/perfusion scans were conducted as required. Assessment of lymph node (LN) status primarily utilized positron emission tomography/CT (PET/CT), with invasive methods such as endobronchial ultrasound-guided trans-bronchial needle aspiration and mediastinoscopy employed when necessary. Distant metastases were evaluated using PET/CT, cranial-enhanced magnetic resonance imaging (MRI), ultrasound, and whole-body bone scintigraphy. Staging for all patients was performed according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition.²⁴

Preoperative laboratory tests, including RT-PCR and immunoglobulin (Ig) G/M antibody tests for SARS-CoV-2, were conducted on all patients to identify both current and past COVID-19 infections. Patient self-reports were also considered a crucial reference for determining COVID-19 history, given that the widespread use of SARS-CoV-2 vaccines may compromise the reliability of the IgG/M antibody test. Patients considered to have a prior COVID-19 infection should meet any of the following standards: (1) documented evidence of a past positive laboratory test (RT-qPCR or rapid antigen test); (2) a formal diagnosis certificate of COVID-19 infection; and (3) the presence of IgG/M antibodies without prior SARS-CoV-2 vaccination. Patients considered to have no prior COVID-19 infection needed to meet both of the following criteria: (1) absence of typical clinical and radiological COVID-19 symptoms and (2) negative results for all laboratory tests expect positive IgG/M antibody tests with documented SARS-CoV-2 vaccination. Patients whose COVID-19 history could not be definitively determined were classified as having an uncertain/unknown COVID-19 history and were not initially included in this study. The timing of a prior COVID-19 infection was determined based on the most recent date of diagnosis or positive laboratory test. For patients with multiple prior infections, the time interval to surgery is calculated from the date of the most recent confirmed SARS-CoV-2 infection to the date of surgery.

Surgical approaches and postoperative management

Generally, lung surgery was recommended to be delayed for at least 4 weeks after SARS-CoV-2 infection, following the established methodologies as previously documented.^19,25
–28 All patients underwent intravenous (i.v.) anesthesia with double-lumen intubation and selective single-lung ventilation managed by specialized thoracic anesthesiologists. Typically, minimally invasive surgery (MIS) was accomplished through three or four minimal incisions without spreading the rib. The camera port was established at the 6th or 7th intercostal space (ICS) along the anterior axillary line. Then, two incisions were made at the 3rd or 4th ICS and the 8th ICS on the anterior and posterior axillary lines, respectively. A fourth port was introduced at the 9th ICS along the posterior axillary line to assist. By contrast, thoracotomy was conducted through a rib-spreading posterolateral incision, approximately 15 cm long, at the 5th ICS. A comprehensive procedure, including systemic mediastinal LN dissection, was performed, involving the dissection of at least three mediastinal LN stations. An intraoperative frozen section assessment was conducted for the primary tumor lesion and resection margin in all patients. Following confirmation of no active bleeding in the thoracic cavity and no air leakage from the bronchial stump, the chest wall was closed, and two 24F chest tubes were placed in the pleural cavity.

All patients received the enhanced recovery protocol as follows: (1) Smoking cessation: patients are required to cease smoking for at least 2 weeks before surgery. (2) Nebulized inhalation therapy: patients receive nebulized inhalation therapy preoperatively and postoperatively, administered twice daily. Typically, the inhaled medication is budesonide, which may be combined with additional long-acting β2-agonists, long-acting muscarinic antagonists, or expectorants, especially for those with high airway resistance and a history of smoking. The duration of this treatment is determined by the physician based on the patient’s specific condition. (3) Encouraged postoperative activities: Patients are encouraged to engage in appropriate extended off-bed exercises under analgesia and to perform breathing exercises using a handheld respiratory training device starting 24 h after surgery. (4) Measures to prevent lower limb venous thrombosis and promote expectoration. Postoperative pain management involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and self-controlled analgesia for patients after surgery, supplemented as necessary with additional i.v. NSAIDs, meperidine, and tramadol. Upon confirmation of the resolution of evident air leakage and subcutaneous emphysema, alongside a drainage volume below 200 mL/day and the absence of densely bloody, cloudy, or purulent pleural effusion, and with chest X-ray images indicating satisfactory lung re-expansion, the chest tube was subsequently removed.²⁶ Patients were discharged from the hospital within 1–2 days following drainage tube removal unless they exhibited persistent morbidities necessitating further intervention.

Outcome measurement

The surgical duration commenced at the onset of the incision and concluded upon the closure of the wound. Conversion was defined as commencing the procedure using an MIS but concluding it with a rib-spreading thoracotomy. Postoperative complications occurring within the initial 30 days were classified according to the Clavien-Dindo system as follows: Grade I pertains to minor deviations not mandating specific intervention; Grade II encompasses complications necessitating pharmacological measures, blood transfusions, or total parenteral nutrition; Grade III involves comorbidities necessitating either operative or endoscopic intervention; Grade IV denotes conditions requiring intensive care unit management; and Grade V indicates patient mortality.²⁹ The respiratory complications were defined as follows: (1) An air leak is observed as bubbling in the closed chest drainage device bottle when patients breathe, take deep breaths, or cough. A prolonged air leak is defined as an air leak that persists for more than 5 days postoperatively.³⁰ (2) Pleural effusion is identified on a chest radiograph by blunting of the costophrenic angle, loss of the sharp silhouette of the ipsilateral hemidiaphragm in the upright position, evidence of displacement of adjacent anatomical structures, or a hazy opacity in one hemithorax with preserved vascular shadows in the supine position.³¹ (3) Atelectasis is characterized by lung opacification accompanied by a shift of the mediastinum, hilum, or hemidiaphragm toward the affected area and compensatory over-inflation of the adjacent non-atelectatic lung.³¹

Planned postoperative follow-up

Although the long-term survival data were not collected in this study, a lifelong follow-up assessment protocol has been established for all NSCLC patients: an initial evaluation 1 month post-operation, followed by varying schedules. Patients with a histology of minimally invasive adenocarcinoma are evaluated annually, whereas other patients are assessed every 6 months for the first 5 years and annually thereafter. For postoperative follow-up, thoracic CT scans, serum tumor marker tests, and ultrasound are routinely employed, with additional PET-CT, cranial MRI, bone scintigraphy, or invasive methods used for those with suspected recurrence or metastasis. For patients unable to regularly visit the outpatient clinic, telephone or internet follow-ups are conducted annually until death or loss of follow-up.

Statistical analysis

The categorical variables were expressed using frequencies and percentages, while the continuous variables were expressed using the mean ± standard deviation (SD). Pearson’s chi-square tests or Fisher’s exact tests were applied to compare categorical variables. If the Kolmogorov–Smirnov test indicated normal distribution and homogeneous variance of the variables, the Student’s t-test was carried out to compare continuous variables. Otherwise, the Mann–Whitney U test was performed.

A two-step logistic regression analysis was conducted to identify independent risk factors for postoperative complications with Clavien-Dindo grades ⩾II.³² Initially, univariable logistic regression was used to screen potential risk factors among all patient baseline variables. Variables with a p value <0.05 were then included in a multivariable logistic regression analysis using a backward stepwise method. Specifically, all included variables were introduced into the model, and the decision to retain or exclude variables was based on the Wald test, which retained statistically significant variables (p < 0.05) and excluded those that were not (p ⩾ 0.05).

Propensity-score matching (PSM) was applied based on 14 key baseline characteristics as follows: gender, age, smoking history, body mass index, ECOG performance status, % of predicted forced expiratory volume in 1 s, % of predicted diffusing capacity for carbon monoxide, surgical approaches, tumor histology, resection extent, tumor diameter, clinical T stage, clinical LN metastasis, and neoadjuvant therapy history. The caliper matching strategy with a caliper value of 0.02 was utilized for achieving a 1:1 NCVD versus POCVD group. Specifically, for each patient in the POCVD group, only those in the NCVD group with propensity scores within a 0.02 range were considered potential matches, aiming to achieve a high level of covariate balance between the two groups after matching, thereby minimizing the impact of confounding bias. In cases where multiple POCVD patients were equally suitable matches for a single NCVD patient within the caliper range, the algorithm selected the first suitable match based on a predetermined order (e.g., nearest neighbor in the dataset). Any instances of multiple matches were corrected to ensure strict adherence to the 1:1 matching protocol. Statistical analysis, multivariable logistic regression, and PSM were carried out using SPSS for Windows version 26.0 (IBM Corporation, Armonk, NY, USA). A prespecified two-sided p value less than 0.05 was considered to be statistically significant.

To calculate the needed sample size for the study, we first retrospectively reviewed NSCLC patients receiving radical surgery between January 2023 and April 2023 from our database, finding that patients with a COVID-19 history were potentially associated with increased postoperative respiratory complications compared with those without (19.8% vs 14.6%). However, whether this conclusion was valid in a larger patient cohort over a more extended period remained unrevealed. Therefore, we further performed the present study with the calculation of the required sample size based on the following assumptions and inputs: (1) the two-sided significance to be 0.05; (2) the power to be 0.80; (3) the proportions of respiratory complications in two groups; and (4) the ratio of case number at 1:1 NCVD versus POCVD after PSM. As a result, the minimum required sample size was 1652 (826 cases per group). The sample size estimation was conducted using MedCalc version 22.032 (https://www.medcalc.org).

Results

Baseline clinical characteristics

The study flow chart is shown in Figure 1. As expressed in Table 1, 7932 patients were included in the study, with 4255 having no history of COVID-19 (NCVD group) and 3677 having a preoperative history of COVID-19 (POCVD group). The two groups differed significantly in terms of age, smoking history, pulmonary function, and neoadjuvant therapy history (all P < 0.001). To balance the baseline characteristics between the groups, PSM was applied, resulting in 3021 cases with well-balanced baseline characteristics and a similar distribution of propensity scores (Supplemental Figure S1) in both groups (all P > 0.050). These findings illustrated that PSM effectively balanced potential confounding factors across groups.

Figure 1.

Flow chart of the study.

Table 1.

Patient baseline characteristics.

Variables	NCVD (n = 4255)	POCVD (n = 3677)	p value	NCVD (n = 3021)	POCVD (n = 3021)	p value
Gender, n (%)			0.280			0.757
Male	2233 (52.5)	1885 (51.3)		1570 (52.0)	1558 (51.6)
Female	2022 (47.5)	1792 (48.7)		1451 (48.0)	1463 (48.4)
Age (years), n (%)			<0.001			0.848
18–59	1723 (40.5)	1401 (38.1)		1229 (40.7)	1218 (40.3)
60–69	2004 (47.1)	1675 (45.6)		1390 (46.0)	1386 (45.9)
⩾70	528 (12.4)	601 (16.3)		402 (13.3)	417 (13.8)
Smoking history, n (%)			<0.001			0.825
Presence	1478 (34.7)	1105 (30.1)		970 (32.1)	962 (31.8)
Absence	2777 (65.3)	2572 (69.9)		2051 (67.9)	2059 (68.2)
BMI (kg/m²), mean ± SD	24.0 ± 3.0	23.9 ± 3.0	0.139	23.9 ± 2.9	23.9 ± 3.0	0.735
ECOG performance status, n (%)			0.068			0.820
0	3472 (81.6)	2941 (80.0)		2433 (80.5)	2440 (80.8)
1	783 (18.4)	736 (20.0)		588 (19.5)	581 (19.2)
Pulmonary function, mean ± SD
FEV1 (% of predicted)	97.2 ± 9.3	96.1 ± 9.5	<0.001	96.7 ± 9.2	96.6 ± 9.5	0.678
DLCO (% of predicted)	99.3 ± 10.8	98.4 ± 11.0	<0.001	99.0 ± 10.9	98.8 ± 10.9	0.558
Surgical approaches, n (%)			0.204			0.660
MIS	3840 (90.2)	3349 (91.1)		2730 (90.4)	2740 (90.7)
Open	415 (9.8)	328 (8.9)		291 (9.6)	281 (9.3)
Tumor histology, n (%)			0.621			0.879
Adenocarcinoma	3687 (86.7)	3200 (87.0)		2620 (86.7)	2624 (86.9)
Non-adenocarcinoma	568 (13.3)	477 (13.0)		401 (13.3)	397 (13.1)
Resection extent, n (%)			0.433			0.857
Lobectomy	4131 (97.1)	3567 (97.0)		2935 (97.2)	2934 (97.1)
Bi-lobectomy	106 (2.5)	100 (2.7)		77 (2.5)	80 (2.6)
Pneumectomy	18 (0.4)	10 (0.3)		9 (0.3)	7 (0.2)
Tumor diameter, cm, mean ± SD	2.1 ± 1.1	2.1 ± 1.1	0.832	2.1 ± 1.1	2.1 ± 1.1	0.901
Clinical T stage, n (%)			0.930			1.000
T1a	298 (7.0)	250 (6.8)		210 (7.0)	208 (6.9)
T1b	1307 (30.7)	1149 (31.2)		934 (30.9)	937 (31.0)
T1c	1484 (34.9)	1283 (34.9)		1059 (35.1)	1063 (35.2)
T2a	584 (13.7)	518 (14.1)		419 (13.9)	423 (14.0)
T2b	377 (8.9)	314 (8.5)		264 (8.7)	259 (8.6)
T3	205 (4.8)	163 (4.4)		135 (4.5)	131 (4.3)
Clinical LN metastasis, n (%)	268 (6.3)	246 (6.7)	0.480	196 (6.5)	200 (6.6)	0.835
Neoadjuvant therapy			<0.001			0.721
Presence	440 (13.5)	377 (10.3)		366 (12.1)	357 (11.8)
Absence	2915 (86.5)	3300 (89.7)		2655 (87.9)	2664 (88.2)

Continuous data are expressed as mean ± SD, and categorical data are shown as number (percentage). Bold values indicate statistical significance (p < 0.050).

BMI, body mass index; DLCO, diffusing capacity for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 s; LN, lymph node; MIS, minimally invasive surgery; SD, standard deviation.

Perioperative outcomes

Then, the perioperative outcomes of the two groups were compared, revealing that the POCVD group had a significantly longer surgical duration (120.87 ± 40.23 min vs 110.74 ± 38.76 min, mean difference (95% confidence interval (CI) = 10.13 (8.138–12.122), p < 0.001) and a tendency toward a higher volume of postoperative tube drainage (1202.68 ± 559.13 mL vs 1180.39 ± 469.87 mL, p = 0.094) compared to the NCVD group (Table 2). The groups were comparable regarding conversion rate, intraoperative bleeding, LN dissection, chest tube drainage duration, and postoperative hospitalization (all p > 0.050). Furthermore, although the two groups had a similar distribution of conversion reasons (p = 0.075), the POCVD group exhibited an approximately 1.5-fold higher incidence of dense adhesions than the NCVD group (Supplemental Table S1). Moreover, patients in the two groups were associated with comparable proportions and frequencies of additional i.v. analgesic applications in the postoperative day (POD) 1 and POD 2 (all p > 0.050; Supplemental Figure S2).

Table 2.

Perioperative outcomes of the matched cohort.

Variables	NCVD (n = 3021)	POCVD (n = 3021)	p value
Surgical duration (min), mean ± SD	110.74 ± 38.76	120.87 ± 40.23	<0.001
Conversion of MIS, n (%)	312 (10.3)	330 (10.9)	0.452
Intraoperative bleeding (mL), n (%)			0.104
⩽100	2489 (82.4)	2440 (80.8)
>100	532 (17.6)	581 (19.2)
LN dissection count, mean ± SD	12.88 ± 6.74	12.82 ± 6.79	0.730
LN station dissection count, mean ± SD	6.02 ± 1.00	6.00 ± 0.99	0.435
Chest tube drainage, mean ± SD
Length (days)	4.22 ± 2.38	4.32 ± 2.44	0.107
Volume (mL)	1180.39 ± 469.87	1202.68 ± 559.13	0.094
Postoperative hospitalization (days), mean ± SD	5.14 ± 2.99	5.26 ± 3.04	0.122

Continuous data are expressed as mean ± SD, and categorical data are shown as numbers (percentage). Bold values indicate statistical significance (p < 0.050).

LN, lymph node; MIS, minimally invasive surgery; SD, standard deviation.

Postoperative complications

In addition, postoperative complications were compared, indicating that the POCVD group had slightly increased incidences of postoperative complications (16.7% vs 18.2%, p = 0.119) and those with Clavien-Dindo grades ⩾II (13.0% vs 14.4%, p = 0.117) than the NCVD group, though these differences were not statistically significant (Table 3). The two groups were comparable in the distribution of Clavien-Dindo grades (p = 0.465). Further analysis revealed that patients in the POCVD group had an increased incidence of respiratory complications, particularly atelectasis (4.8% vs 6.1%, p = 0.027), prolonged air leak (4.5% vs 5.6%, p = 0.046), and pleural effusion (3.4% vs 4.5%, p = 0.041).

Table 3.

Postoperative complications of the matched cohort.

Variables	NCVD (n = 3021)	POCVD (n = 3021)	p value
Any complications, n (%)	505 (16.7)	551 (18.2)	0.119
Clavien-Dindo grades ⩾II, n (%)	394 (13.0)	436 (14.4)	0.117
Clavien-Dindo grades, n (%)	2516 (85.9)	2470 (84.2)	0.465
Grade 0 (absence of complications)
Grades I–II	357 (11.8)	393 (13.0)
Grades III–IV	129 (4.3)	136 (4.5)
Grade V	19 (0.6)	22 (0.7)
Respiratory, n (%)
Atelectasis	146 (4.8)	185 (6.1)	0.027
Prolonged air leak >5 days	136 (4.5)	170 (5.6)	0.046
Pleural effusion	104 (3.4)	135 (4.5)	0.041
Pneumonia	78 (2.6)	86 (2.8)	0.527
Respiration failure	65 (2.2)	75 (2.5)	0.392
Empyema	6 (0.2)	9 (0.3)	0.438
Cardiac, n (%)
Atrial fibrillation	142 (4.7)	156 (5.2)	0.406
Myocardial ischemia/infarction	8 (0.3)	11 (0.4)	0.491
Pulmonary embolism	3 (0.1)	4 (0.1)	1.000
Acute cerebral infarction	1 (0.0)	1 (0.0)	1.000
Others, n (%)
Hemorrhage	29 (1.0)	33 (1.1)	0.610
Chylothorax	21 (0.7)	24 (0.8)	0.654
Bronchopleural fistula	16 (0.5)	12 (0.4)	0.449
Hoarse voice	4 (0.1)	5 (0.2)	0.754

Data are shown as numbers (percentage). One patient could be associated with multiple complications. Bold values indicate statistical significance (p < 0.050).

PSM using a stringent caliper strategy was conducted to improve covariate balance, resulting in 76.2% (6042 out of 7932) of cases being successfully matched and 23.8% (1890 out of 7932) remaining unmatched. To assess the impact of these unmatched cases on results, a sensitivity analysis using multiple logistic regression for postoperative complications with Clavien-Dindo grades ⩾II was performed, considering age, smoking history, lung function, and neoadjuvant therapy history as control variables. As shown in Supplemental Table S2M, the logistic regression analysis yielded similar results for both unmatched and matched cohorts, suggesting that the robustness of results was satisfactory despite the presence of unmatched cases.

Identifying potential populations associated with an increased surgical risk following COVID-19

Given the aforementioned results indicating that patients with a history of COVID-19 may experience increased complications, a stratified analysis was conducted to identify populations with significantly higher surgical risks following COVID-19. Generally, patients aged ⩾70 years (21.4% vs 28.5%, p = 0.018) and those with a smoking history (15.1% vs 18.6%, p = 0.037) were at increased risk of developing complications with a Clavien-Dindo grade ⩾II (Supplemental Table S3). Further logistic regression analysis illustrated that the odds ratio (OR) (95% CI) of patients aged ⩾70 years and those with smoking history were 1.322 (1.022–1.876) and 1.235 (1.008–1.543), respectively (Figure 2).

Figure 2.

Subgroup logistic regression analysis of postoperative complications with Clavien-Dindo grades ⩾II for patients with versus without a COVID-19 history. Within each stratified group, univariable logistic regression was used to assess the potential influence of COVID-19 history and to screen for risk factors. This was followed by multivariable logistic regression to control for confounding factors with a p value <0.05, specifically in stratified groups where a COVID-19 history was identified as a potential risk factor.

Analysis of perioperative outcomes and detailed postoperative complications for populations with high surgical risks

Finally, the perioperative outcomes were analyzed for patients aged ⩾70 years and those with a smoking history. The results indicated that in both populations, patients with a COVID-19 history experienced prolonged surgical duration, chest tube duration, and postoperative hospitalization (Supplemental Tables S4 and S5).

Postoperative complications were then compared within these two high-risk cohorts. The findings showed that the POCVD group had a higher incidence of respiratory complications than the NCVD group in both populations, although the distribution of Clavien-Dindo grades was comparable between the groups (Figure 3a–d). Further analysis of detailed complications revealed that, compared to the NCVD group, the POCVD group had a higher incidence of atelectasis (5.7% vs 9.6%, p = 0.038) in patients aged ⩾70 years (Supplemental Table S6). Among patients with a smoking history, the POCVD group had higher incidences of atelectasis (5.3% vs 7.7%, p = 0.030), prolonged air leak (5.2% vs 7.7%, p = 0.023), and pleural effusion (3.3% vs 5.2%, p = 0.038; Supplemental Table S7).

Figure 3.

Subgroup analysis of postoperative complications. Distribution of Clavien-Dindo grades (a) and categories of postoperative complication (b) for patients with versus without a COVID-19 history aged ⩾70 years. Distribution of Clavien-Dindo grades (c) and categories of postoperative complication (d) for patients with versus without COVID-19 history with a smoking history.

Discussion

The COVID-19 pandemic has significantly disrupted healthcare systems worldwide, potentially causing long-term highly variable respiratory, cardiac, immune, and coagulation issues.^{7,13,15,33,34} As a result, patients with a history of COVID-19 may face increased surgical difficulty and risk. Therefore, it is crucial to determine whether a prior SARS-CoV-2 infection could impact perioperative outcomes and identify populations at higher surgical risk for NSCLC surgery following the infection. However, it remains uncertain whether a history of COVID-19 elevates surgical risk for NSCLC. This study’s findings indicate that patients with a history of COVID-19 experienced longer surgical durations and a higher incidence of postoperative respiratory complications compared to those without such a history. In addition, individuals aged ⩾70 years or those with a smoking history faced greater surgical risks following COVID-19. To the best of our knowledge, this study, which spans six medical centers and includes 7932 cases, is the largest retrospective analysis to date.

This study found that patients recovering from COVID-19 infection had longer surgical durations, likely due to chest cavity adhesions and fibrosis resulting from SARS-CoV-2-induced pneumonia.^12,13 However, these conditions did not significantly increase surgical difficulty, as the conversion rate and intraoperative bleeding were similar between the NCVD and POCVD groups, and both groups also had low incidences of life-threatening complications and mortality. Therefore, we believe that radical surgery is generally safe for patients with a history of COVID-19. Further research is needed to explore the relationship between COVID-19 severity and the complexity of radical resection in NSCLC patients, which may help identify those who would benefit most from open thoracotomy.

Numerous studies have demonstrated that perioperative outcomes significantly impact the overall prognosis and quality of life for NSCLC patients, particularly those with high surgical risk.^7,35
–37 Research has shown that postoperative outcomes in SARS-CoV-2-infected patients undergoing emergency or major surgery are considerably worse than pre-pandemic baseline rates for mortality and pulmonary complications.^38,39 Importantly, it is widely recognized that NSCLC patients with perioperative COVID-19 face a significantly increased risk of severe postoperative comorbidities and mortality.^9,40 Many studies have investigated the effect of COVID-19 history on postoperative outcomes in NSCLC patients, but findings have been inconsistent. Gabryel et al. and Pages et al. have independently reported that patients with a history of COVID-19 are associated with increased postoperative complications or delayed recovery.^11,21 By contrast, other studies have found that a history of COVID-19 does not significantly affect perioperative outcomes.^6,22 Our study, focusing on Chinese populations, indicated that both groups of patients had comparable postoperative comorbidities and recovery times. These discrepancies may result from variations in the epidemiological characteristics of SARS-CoV-2 infection, genetic backgrounds, vaccination status, and differences in medical and surgical standards across countries and regions.

Previous studies have determined that men, elderly individuals, those with preoperative comorbidities, and patients undergoing cancer surgery are at particularly high risk for severe postoperative morbidity and mortality.^38,39 Consistent with these findings, our study revealed that patients aged ⩾70 years and those with a history of smoking had a significantly higher likelihood of experiencing complications with Clavien-Dindo grades ⩾II following COVID-19. This increased risk may be attributed to the detrimental effects of SARS-CoV-2 infection on pulmonary and cardiac function, as well as the chronic systemic inflammation it could cause.^13,33,41,42 These high-risk groups are more susceptible to these pathological conditions, making them more prone to adverse events during and after surgery. These findings underscore the necessity for thorough preoperative evaluation and enhanced postoperative care for these high-risk populations undergoing radical resection for NSCLC. We believe that a better protocol to enhance recovery may include (1) appropriately extending the smoking cessation period beyond the standard 2 weeks for the planned lung surgery after considering the risk of disease progression carefully; (2) appropriately extending preoperative and postoperative nebulized inhalation therapy based on the patient’s respiratory functions and smoking conditions; and (3) tailoring preoperative breathing exercises and postoperative analgesia and expectoration strategies for improved efficacy. These patient-specific strategies are expected to optimize their perioperative management.

Effective NSCLC management relies heavily on the successful execution of surgical interventions focused on tumor removal and staging, provided the surgery is feasible.^7,19 However, any delays in surgery or modifications to surgical plans can negatively impact long-term survival outcomes.⁴³ Analysis of data from the US National Cancer Database indicates that survival rates are lower for early-stage lung cancer patients when the interval between initial diagnosis and surgical treatment exceeds 6–12 weeks, compared to shorter intervals.⁴⁴ Thus, the optimal timing for surgery following a COVID-19 infection, which remains a topic of debate, is of paramount importance. Two international studies and accompanying guidelines advise deferring elective surgeries for at least 7 weeks post-COVID-19 diagnosis to lower perioperative complications and mortality.^39,45 The American Society of Anesthesiologists recommends postponing surgery for 4–12 weeks after SARS-CoV-2 infection, based on the infection’s severity and the patient’s vaccination status.⁷ However, the cohort studies that these guidelines are based on were conducted before widespread vaccination and did not account for the beneficial effects of vaccination on postoperative risks. In light of this, two recent studies from China suggest delaying pulmonary tumor resection for at least 2–4 weeks following a SARS-CoV-2 infection.^7,46 Nonetheless, for patients who have suffered from severe COVID-19, a group usually associated with prolonged and more severe pulmonary and systemic sequelae, a thorough multidisciplinary evaluation and appropriate postponement of surgery are recommended to avoid severe complications.⁴⁷

The evolution and mutation of SARS-CoV-2 over time have led to the emergence of multiple variants with varying transmissibility, severity, and immune evasion capabilities.⁴⁸ However, there are no studies specifically addressing the impact of different SARS-CoV-2 variants on surgical risk for NSCLC patients to date. We hypothesize that patients infected with variants with a greater ability to cause irreversible changes in lung structure and function and lead to long-term complications may face higher surgical risks. Although SARS-CoV-2 vaccines are widely used and considered effective in preventing severe complications, mortality, and long-term effects from COVID-19, they may also have potential adverse effects, such as neurological, cardiac, and immunological disorders.^49
–51 Further research is needed to assess the impact of vaccines’ protection efficacies and side effects on surgical risks for NSCLC patients recovering from COVID-19. Our study, which includes a large cohort from multiple medical centers, provides insights into the potential effects of past COVID-19 infection on surgical risk and identifies high-risk populations. While it does not specifically evaluate the influence of SARS-CoV-2 variants and vaccination status, it may still serve as a valuable reference for future clinical practice and further investigations into their impacts on surgical risks for patients recovering from COVID-19.

We have recognized several limitations in this study. First, its retrospective design may introduce undisclosed biases in patient selection, despite using PSM to ensure comparability of baseline clinical features between the two groups. Consequently, further prospective observational studies are necessary to validate our findings. Second, this research focuses exclusively on the Chinese population, raising questions about the generalizability of our conclusions, thus necessitating additional validation through international studies. Third, our database lacks detailed information on the timing of surgery following SARS-CoV-2 infection, the severity of COVID-19, the type of SARS-CoV-2 variants, and detailed strategies of postoperative care for individual patients. Consequently, we could not evaluate their impacts on the early outcomes in NSCLC patients. Therefore, further investigation incorporates a more detailed COVID-19 infection history and patient postoperative care is required. Lastly, this study only addresses early outcomes and does not investigate long-term survival outcomes. Additional follow-up is necessary to determine whether COVID-19 affects the long-term survival of NSCLC patients.

Conclusion

Radical resection is generally safe for NSCLC patients with a COVID-19 history. However, these patients experienced longer surgical durations and a higher incidence of respiratory complications compared to those without a past COVID-19 infection. Furthermore, individuals aged ⩾70 years or those with a smoking history faced increased surgical risks after COVID-19. These findings provide significant real-world evidence that may aid in developing more robust and patient-specific therapeutic strategies for NSCLC patients undergoing radical resection in the COVID-19 era.

Supplemental Material

sj-docx-1-tar-10.1177_17534666241298794 – Supplemental material for Early outcomes of radical surgery in non-small-cell lung cancer patients with and without COVID-19 history: a multi-center real-world study

Supplemental material, sj-docx-1-tar-10.1177_17534666241298794 for Early outcomes of radical surgery in non-small-cell lung cancer patients with and without COVID-19 history: a multi-center real-world study by Hanbo Pan, Hang Chen, Wanyu Li, Yu Tian, Zhen Ge, Weicheng Kong, Zenan Gu, Ningyuan Zou, Hongda Zhu, Jiaqi Zhang, Yixing Tao, Junwei Ning, Jia Huang, Hui Yin, Ming Zhang, Chengwei Zhou, Hui Wang, Guodong Xu and Qingquan Luo in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

We would like to thank the following colleagues who contributed to this work: Dr. Weicheng Kong (Department of Thoracic Surgery, Zhoushan Putuo District People’s Hospital); Drs. Ningyuan Zou, Hongda Zhu, Jiaqi Zhang, Yixing Tao, and Jia Huang (Department of Thoracic Surgical Oncology, Shanghai Chest Hospital); Dr. Junwei Ning (Department of Thoracic Surgery, Shanghai Tongren Hospital); Dr. Chengwei Zhou (Department of Cardiothoracic Surgery, The First Affiliated Hospital of Ningbo University); and Dr. Hui Yin (Department of Thoracic Surgery, The First Affiliated Hospital of Shaoyang University and Department of Thoracic Surgery, Shaoyang Central Hospital).

Declarations

ORCID iDs

Jia Huang

Qingquan Luo

Supplemental material

Supplemental material for this article is available online.

Abbreviations

BMI body mass index

CI confidence interval

COVID coronavirus disease

CT computed tomography

DLCO diffusing capacity for carbon monoxide

EBUS-TBNA endobronchial ultrasound-guided trans-bronchial needle aspiration

ECOG Eastern Cooperative Oncology Group

FEV1 forced expiratory volume in 1 s

ICS intercostal space

IQR interquartile range

LN lymph node

MIS minimally invasive surgery

MRI magnetic resonance imaging

NSCLC non-small-cell lung cancer

NSAIDs nonsteroidal anti-inflammatory drugs

OR odds ratio

PET positron emission tomography

POD postoperative day

PSM propensity-score matching

RT-qPCR real-time quantitative polymerase chain reaction

SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

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