Abstract
Background:
Artificial capnothorax during surgery potentially increases the risk of tumor cell dissemination and impacts survival. This trial aimed to investigate the effect of artificial capnothorax on the prognosis of patients with esophageal cancer who underwent minimally invasive esophagectomy.
Methods:
This prospective, randomized controlled trial was conducted in two high-volume hospitals in China. Between August 2019 and January 2020, 110 patients with resectable esophageal cancer were randomized to undergo single-lung ventilation (n = 55) or capnothorax procedures (n = 55). The analysis was based on the intention-to-treat principle. The final follow-up occurred in January 2023.
Results:
A total of 110 patients were included in the intention-to-treat analysis. After surgery, the incidence of patients exhibiting incremental changes in circulating tumor cell levels was 18.6% (8/43) in the capnothorax group and 2.7% (1/37) in the single-lung ventilation group (P = 0.033) (mean changes, −3.9 ± 3.4 [FU/3 mL] vs. −2.4 ± 2.9 [FU/3 mL], respectively; P = 0.039). Compared with the capnothorax group, the single-lung ventilation group had better 3-year overall survival rates (81.6%, 95% confidence interval [CI]: 72.4–92.0% vs. 65.2%, 95% CI: 59.3–78.8%; P = 0.049) and disease-free survival rates (81.6%, 95% CI: 72.4–93.0% vs. 61.6%, 95% CI: 50.1–75.7%; P = 0.019). Multivariate analysis indicated that artificial pneumothorax potentially impaired overall survival (hazard ratio [HR]: 2.35, 95% CI: 1.05–5.24; P = 0.037) and disease-free survival (HR: 2.70, 95% CI: 1.23–5.94; P = 0.014).
Conclusions:
Artificial capnothorax appears to be associated with poor oncological outcomes in patients with esophageal cancer. Single-lung ventilation in minimally invasive esophagectomy is safer and more favorable than capnothorax.
Trial Registration:
Chinese Clinical Trial Registry (http://chictr.org.cn), ChiCTR1900025262.
Keywords: Esophageal cancer, Artificial capnothorax, Minimally invasive esophagectomy, Circulating tumor cells, Survival
Introduction
Esophageal cancer is the seventh most common malignant tumor and the sixth leading cause of cancer-related death worldwide.[1,2] Comprehensive treatment based on surgical resection remains the main treatment for locally advanced esophageal cancer. In recent years, minimally invasive esophagectomy (MIE) has been increasingly adopted because of its lower morbidity and equivalent survival outcomes.[3,4] Both two-lung ventilation with carbon dioxide (CO2) insufflation pneumothorax (capnothorax) and single-lung ventilation are the main methods used to ensure a good surgical field of view and facilitate operations within the thoracic cavity.[5] Compared with capnothorax, single-lung ventilation is associated with better lung collapse, reduced occurrence of hypotension, and diminished PaCO2 accumulation during video-assisted thoracoscopic surgery (VATS), while increasing the complexity of placement and the risk of airway complications.[6] Capnothorax was first reported by Palanivelu et al[7] in 2006 and gained popularity. The short-term safety and feasibility of the capnothorax procedure in esophagectomy have been proven by several studies.[7,8]
However, the effect of capnothorax on long-term survival remains unclear. Potential problems, including detrimental survival and oncologic outcomes, have received much attention. Ramirez et al[9] emphasized that the effect of CO2 pneumoperitoneum, which is similar to an artificial pneumothorax and was initially applied in abdominal surgery, may be a potential risk factor for the inferior oncologic outcomes of minimally invasive surgery for cervical cancer. Furthermore, Jiang et al[10] reported that artificial capnothorax may facilitate the invasion and metastasis of esophageal cancer at the cellular level.
Currently, few comprehensive studies have considered the effects of artificial capnothorax on oncological and survival outcomes in patients with esophageal cancer undergoing thoracoscopic surgery. Based on prior studies,[9–11] we conducted the Thoracoscopic Esophagectomy under Non-Capnothorax (TENCAP) trial to validate the hypothesis that artificial capnothorax would result in poorer survival and oncologic outcomes for patients with esophageal cancer than single-lung ventilation procedures.
Methods
Trial design
The TENCAP trial is a prospective, open-label, randomized controlled trial conducted between August 2019 and January 2020 in two tertiary hospitals in Southwest China (West China Hospital of Sichuan University and Chengdu Shangjin Nanfu Hospital). We compared single-lung ventilation with artificial capnothorax during MIE in patients with esophageal cancer. The inclusion criteria included (1) patients aged between 18 and 75 years; (2) patients who were diagnosed with squamous cell carcinoma or adenocarcinoma of the thoracic esophagus; and (3) patients with resectable disease. The exclusion criteria included (1) other histologic types; (2) patients with other gastroesophageal diseases; and (3) patients who refused to participate in this trial.
This trial complied with the guidelines for Consolidated Standards of Reporting Trials (CONSORT) and the principles of the Declaration of Helsinki. Ethics approval for this study was granted by the Ethics Committee of West China Hospital, Sichuan University (No. 2019548) and all participating centers. Written informed consent was obtained from all participants. The last author vouches for the accuracy and completeness of the data and the fidelity of the trial to the protocol. This study has been registered in the Chinese Clinical Trial Registry (ChiCTR1900025262).
Randomization and masking
We used computer-generated randomized numbers to assign patients to the single-lung ventilation group or capnothorax group at a 1:1 ratio, and both the investigators and patients were blinded to the allocation schedule prior to surgery. Every surgery started with a sealed, numbered envelope containing the assigned group for each patient. After the surgery, the trial was open-label, with both the investigators and patients aware of the assigned treatment.
Sample size
The sample size calculation was based on the overall survival rate at 3 years for patients with esophageal cancer receiving standard therapy of 58% in a previous study.[12] We expected that the overall survival rate at 3 years would increase to 80% in the single-lung ventilation group. Considering potential loss to follow-up, a total sample size of 110 (55 per group) was required to achieve 80% statistical power at a significance level of 0.05.
Preoperative neoadjuvant therapy
Preoperative tumor staging was based on esophagogastroduodenoscopy, contrast-enhanced computed tomography (CT) of the neck, chest, and abdomen, endoscopic ultrasonography, bone scan, and magnetic resonance imaging of the brain. Patients with highly suspicious metastatic lymph nodes are optionally subjected to positron emission tomography-CT (PET-CT). Preoperative chemoradiotherapy or chemotherapy was recommended for patients with cT1b-cT2, N+ or cT3-cT4a, any N disease. Preoperative chemotherapy regimens included paclitaxel plus cisplatin or 5-fluorouracil plus cisplatin. Concomitant radiotherapy was performed with a total dose of 40–50 Gy. Surgery was performed 6–8 weeks after preoperative therapy in accordance with the National Comprehensive Cancer Network guidelines (version 2. 2019).
Surgical procedures
In the capnothorax group, patients underwent single-lumen tube intubation and double-lung ventilation. Four ports (fourth and seventh intercostal spaces at the posterior axillary line, the ninth intercostal space at the subscapular line, and an incision below the subscapular angle) with artificial capnothorax at 8–10 mmHg positive pressure were placed during surgery. In the single-lung ventilation group, patients were intubated with a double-lumen tube for single-lung ventilation. We used three-port thoracoscopy without positive pressure capnothorax. Details on the port design and operative technique of this novel procedure were given in our previously published work.[13] All patients underwent a McKeown MIE approach. McKeown esophagectomy consisted of a thoracic phase (tumor resection and mediastinal lymph node dissection), an abdominal phase (mobilization of the stomach and abdominal lymph node dissection), and a cervical phase (esophagogastrostomy). The standard extent of radical complete two-field lymph node dissection was performed. Three-field lymph node dissection was performed only in patients with highly suspicious cervical nodal metastasis. Esophagogastrostomy was performed with double-layer sutures that were stitched by hand. All procedures were conducted by experienced surgeons with over 200 cases of expertise in performing MIE for esophageal cancer. Postoperative management was identical in both groups. The intervention was strictly conducted according to a unified standard operating procedure (SOP). Comprehensive training was provided to all the investigators to minimize operational variations between centers.
Detection of circulating tumor cells
Circulating tumor cell (CTC) testing was conducted based on the voluntary principle. 3 mL of whole blood, anticoagulated with ethylene diamine tetraacetic acid (EDTA), were collected from patients both before and after surgery. A preoperative blood sample was collected prior to the incision, whereas a postoperative blood sample was obtained immediately after the closure of the chest cavity. Blood samples were stored at 4°C and processed within 24 h after collection. CTCs were detected and quantified using the FR+CTCs Detection Kit (Geno Biotech Co., Ltd., Shanghai, China). Initially, CTCs were enriched by lysing erythrocytes, followed by immune magnetic depletion of leukocytes in whole blood. A ligand-targeted polymerase chain reaction was subsequently used to quantify CTCs in each sample. We used self-referenced CTC units (FU) to determine the abundance of CTCs in 3 mL of peripheral blood. In addition, patients were stratified into high-risk and low-risk groups based on the optimal cutoff for CTC changes, which was determined using the minimum P-value approach. Survival differences between the groups were then analyzed.
Outcomes assessment
Tumor stage was identified according to the 8th edition of the American Joint Committee on Cancer TNM staging system.[14] The primary endpoints were survival outcomes, including 3-year overall survival (OS) rates and 3-year disease-free survival (DFS) rates. The secondary endpoints included changes in CTC levels before and after surgery, operative time, number of lymph nodes examined, number of stations examined, postoperative complications, length of postoperative hospital stay, and 90-day morbidity rate. The complications were defined according to the Esophagectomy Complications Consensus Group system[15] and were graded via the Clavien–Dindo classification.[16] Tumor recurrence, death cases, and survival status were recorded. All participants in the TENCAP trial were followed up through outpatient visits when feasible, and telephone interviews were conducted as an alternative if outpatient visits were not available. Routine follow-up included physical examination, contrast-enhanced CT of the chest and abdomen, and barium esophagram. Esophagogastroduodenoscopy was performed every two years, and PET-CT was also conducted if necessary. Patients who were alive or lost to follow-up were right-censored at the date of the last follow-up. The patients were followed up every three months for the first two years and every six months thereafter. Follow-up information was available over three years postoperatively or at the date of death. A case report form was used for every participant in this trial. All the data were centrally managed to ensure consistency and accuracy across the study centers.
Statistical analyses
Continuous variables following a normal distribution were presented as the mean ± standard deviations (SDs); if not, medians with the first quartile (Q1) and the third quartile (Q3) were used. And categorical variables were presented as frequencies and percentages. Categorical variables were compared via the chi-squared test, Yate’s correction, or Fisher’s exact test, whereas continuous variables were analyzed via the t test, Welch’s t-test, or Mann–Whitney U test. Univariate and multivariate analyses were performed with the Cox proportional hazards regression model to identify prognostic risk factors. Variables with a P value less than 0.05 in the univariate analysis were entered into the multivariate analysis. Survival analyses were analyzed using the survival package, and Kaplan–Meier survival curves were plotted using the survminer package in R programming language (version 3.6.3, R Foundation for Statistical Computing, Vienna, Austria). The log-rank test was used to compare the differences between survival curves. Statistical analyses were performed using GraphPad Prism (version 9, GraphPad Software Inc., San Diego, California, USA) and the R programming language (version 3.6.3, R Foundation for Statistical Computing). Statistical significance was set at a two-sided P value less than 0.05.
Results
Patient characteristics
Between August 2019 and January 2020, 115 patients were assessed for eligibility. Five patients were excluded; of these, 2 patients had distant metastases, 2 patients had other malignancies, and 1 patient refused surgery. Finally, 110 patients were included in the intention-to-treat (ITT) principle. Fifty-five patients were randomly assigned to undergo single-lung ventilation thoracoscopic esophagectomy, while other 55 were randomized to undergo an artificial capnothorax thoracoscopic esophagectomy [Figure 1]. Three patients were converted to open surgery because of severe pleural adhesions. There were no significant differences in age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, Eastern Cooperative Oncology Group (ECOG) status, comorbidities, tumor location, or clinical TNM stage. Patients with cT1b-cT2, N+ or cT3-cT4a, any N disease in either group received preoperative chemoradiotherapy [Table 1].
Figure 1.
Flow chart of enrollment and randomization of patients with esophageal cancer.
Table 1.
Comparison of baseline demographics and characteristics in patients with esophageal cancer undergoing capnothorax versus single-lung ventilation (intention-to-treat population).
| Characteristics | Capnothorax group (N = 55) | Single-lung ventilation group (N = 55) | Statistic values | P values |
|---|---|---|---|---|
| Age (years) | 63 ± 7 | 62 ± 8 | 0.259 | 0.796* |
| BMI (kg/m2) | 21.85 ± 3.47 | 22.55 ± 2.79 | –1.166 | 0.246† |
| Sex | 0.978 | 0.323‡ | ||
| Female | 12 (21.8) | 8 (14.6) | ||
| Male | 43 (78.2) | 47 (85.4) | ||
| ASA score | 3.514 | 0.173‡ | ||
| I | 11 (20.0) | 19 (34.5) | ||
| II | 35 (63.6) | 26 (47.3) | ||
| III | 9 (16.4) | 10 (18.2) | ||
| ECOG status | 0.216 | 0.897§ | ||
| 0 | 30 (54.5) | 31 (56.4) | ||
| 1 | 22 (40.0) | 22 (40.0) | ||
| 2 | 3 (5.5) | 2 (3.6) | ||
| Comorbidity | 1.533 | 0.216‡ | ||
| No | 41 (74.5) | 35 (63.6) | ||
| Yes | 14 (25.5) | 20 (36.4) | ||
| Location | 1.745 | 0.418‡ | ||
| Lower | 24 (43.6) | 27 (49.1) | ||
| Middle | 27 (49.1) | 21 (38.2) | ||
| Upper | 4 (7.3) | 7 (12.7) | ||
| Histology | <0.001 | >0.999§ | ||
| AC | 1 (1.8) | 1 (1.8) | ||
| ESCC | 54 (98.2) | 54 (98.2) | ||
| cT | 2.720 | 0.257‡ | ||
| cT1 | 7 (12.7) | 13 (23.6) | ||
| cT2 | 17 (30.9) | 18 (32.7) | ||
| cT3 | 31 (56.4) | 24 (43.6) | ||
| cN | 2.314 | 0.314§ | ||
| cN0 | 37 (67.3) | 36 (65.5) | ||
| cN1 | 14 (25.5) | 18 (32.7) | ||
| cN2 | 4 (7.3) | 1 (1.8) | ||
| Neoadjuvant therapy | 2.516 | 0.284‡ | ||
| Neoadjuvant chemoradiation | 17 (30.9) | 10 (18.2) | ||
| Neoadjuvant chemotherapy | 14 (25.5) | 15 (27.3) | ||
| None | 24 (43.6) | 30 (54.5) |
Data are presented as number with percentage or mean with standard deviation. AC: Adenocarcinoma; ASA: American Society of Anesthesiologists; BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; ESCC: Esophageal squamous cell carcinoma; t-test*; Welch’s t-test†; Chi-squared test‡; Yate’s correction§.
Surgical outcomes and postoperative complications
There were no significant between-group differences in total operative time (295 [Q1, Q3: 240, 325] min vs. 280 [Q1, Q3: 240, 313] min, P = 0.595), conversion to open (3.6% [2/55] vs. 1.8% [1/55], P >0.999), positive margin (5.5% [3/55] vs. 1.8% [1/55], P = 0.618), number of regional nodes examined (21 [Q1, Q3: 17, 26] vs. 22 [Q1, Q3: 18, 26], P = 0.537), or number of regional stations examined (10 [Q1, Q3: 9, 11] vs. 11 [Q1, Q3: 9, 12], P = 0.409) [Table 2].
Table 2.
Comparison of surgical details and postoperative complications in patients with esophageal cancer undergoing capnothorax versus single-lung ventilation (intention-to-treat population).
| Characteristics | Capnothorax group (N = 55) | Single-lung ventilation group (N = 55) | Statistic values | P values |
|---|---|---|---|---|
| Thoracic operative time (min) | 120 (62, 178) | 120 (65, 175) | –0.168 | 0.776* |
| Total operative time (min) | 295 (240, 325) | 280 (240, 313) | –0.535 | 0.595* |
| Conversion to open | 2 (3.6) | 1 (1.8) | >0.999† | |
| Positive margin | 3 (5.5) | 1 (1.8) | 0.618† | |
| Regional stations examined | 10 (9, 11) | 11 (9, 12) | 0.829 | 0.409* |
| Regional nodes examined | 21 (17, 26) | 22 (18, 26) | 0.620 | 0.537* |
| 30-day morbidity | 0 | 0 | >0.999† | |
| 90-day morbidity | 1 (1.8) | 0 | >0.999† | |
| Clavien–Dindo classification | ||||
| I–II | 7 (12.7) | 7 (12.7) | <0.001 | >0.999‡ |
| III–IV | 7 (12.7) | 11 (20.0) | 1.063 | 0.303‡ |
| Type of postoperative complications | ||||
| Pneumonia | 8 (14.5) | 15 (27.3) | 2.694 | 0.101‡ |
| Respiratory failure | 4 (7.3) | 4 (7.3) | >0.999† | |
| Chylothorax | 0 | 1 (1.8) | >0.999† | |
| Anastomotic leak | 5 (9.1) | 3 (5.5) | 0.135 | 0.716‡ |
| Deep venous thrombosis | 0 | 1 (1.8) | >0.999† | |
| Recurrent laryngeal nerve injury | 3 (5.5) | 0 | 0.243† | |
| Chest tube drainage | 0.293 | 0.589‡ | ||
| ≤10 days | 46 (83.6) | 48 (87.3) | ||
| >10 days | 9 (16.4) | 7 (12.7) | ||
| ICU readmission | 6 (10.9) | 3 (5.5) | 0.484 | 0.489‡ |
| Length of postoperative stay, days | 11 (10, 13) | 10 (10, 11) | –1.928 | 0.054* |
Data are presented as number with percentage or median with the first quartile and the third quartile. Mann–Whitney U test*; Fisher’s exact test†; Chi-squared test‡. ICU: Intensive care unit.
Postoperative overall complications occurred in 18 patients (32.7%) in the single-lung ventilation group and 14 patients (25.5%) in the capnothorax group (P = 0.529). The rate of severe complications was comparable between the two groups (12.7% [7/55] vs. 20.0% [11/55], P = 0.303). There were no significant between-group differences in ICU readmission (10.9% [6/55] vs. 5.5% [3/55], P = 0.489), length of postoperative stay (11 [Q1, Q3: 10, 13] days vs. 10 [Q1, Q3: 10, 11] days, P = 0.054), or 90-day morbidity (1.8% [1/55] vs. 0, P >0.999) [Table 2].
CTC analysis
The preoperative baseline CTCs were 12.3 ± 3.5 (FU/3 mL) in the single-lung ventilation group and 11.8 ± 2.7 (FU/3 mL) in the capnothorax group. There were no significant between-group differences in preoperative CTC levels (P = 0.505). After surgery, the incidence of patients with incremental changes in CTC levels was 18.6% (8/43) in the capnothorax group and 2.7% (1/37) in the single-lung ventilation group (P = 0.033). The mean changes in CTC levels after surgery were −3.9 ± 3.4 (FU/3 mL) in the single-lung ventilation group and −2.4 ± 2.9 (FU/3 mL) in the capnothorax group (P = 0.039) [Figure 2]. The high-risk group tended to have a worse prognosis than the low-risk group, but the difference was not statistically significant [Supplementary Figure 1, http://links.lww.com/CM9/C445].
Figure 2.
Folate receptor-positive circulating tumor cells (FR+CTCs) before and after surgery in the single-lung ventilation group (A) and the capnothorax group (B). CTC: Circulating tumor cell; FR: Folate receptor-positive.
Survival analysis and recurrence patterns
The median follow-up for the entire cohort was 38.4 (95% CI: 36.8–40.4) months using the reverse Kaplan–Meier method. The 3-year OS rate was 81.6% (95% CI: 72.4–92.0%) among 55 patients with single-lung ventilation and 65.2% (95% CI: 59.3–78.8%) among 55 patients with capnothorax. There was a significant difference in overall survival between these two groups (HR: 2.21, 95% CI: 1.01–4.93, P = 0.049) [Figure 3A] based on the log-rank test. The 3-year DFS rate was 81.6% (95% CI: 72.4–93.0%) among 55 patients without capnothorax and 61.6% (95% CI: 50.1–75.7%) among 55 patients with capnothorax. There was a significant difference in disease-free survival between these two groups (HR: 2.56, 95% CI: 1.16–5.62, P = 0.019) [Figure 3B] based on the log-rank test.
Figure 3.
Three-year overall survival (A) and disease-free survival (B) for patients with esophageal cancer who underwent single-lung ventilation versus capnothorax procedures. CI: Confidence interval; HR: Harzard ratio.
Univariate Cox regression analysis indicated that capnothorax (OS: HR: 2.22, 95% CI: 1.00–4.94; P = 0.049; DFS: HR: 2.56, 95% CI: 1.17–5.63; P = 0.019) and stage III disease (OS: HR: 10.58, 95% CI: 1.43–78.42; P = 0.021; DFS: HR: 11.29, 95% CI: 1.53–83.49; P = 0.018) were associated with worse survival [Table 3]. Multivariate Cox regression models finally determined that artificial pneumothorax (HR: 2.35, 95% CI: 1.05–5.24; P = 0.037 for OS; HR: 2.70, 95% CI: 1.23–5.94; P = 0.014 for DFS) and the III stage (HR: 8.33, 95% CI: 1.07–64.78; P = 0.043 for OS; HR: 9.02, 95% CI: 1.17–69.64; P = 0.035 for DFS) were independent predictors of OS and DFS [Table 4].
Table 3.
Univariate Cox proportional hazards model for survival analysis after patients with esophageal cancer undergoing capnothorax versus single-lung ventilation.
| Characteristics | Overall survival | Disease-free survival | ||
|---|---|---|---|---|
| Hazard ratio (95% CI) | P values | Hazard ratio (95% CI) | P values | |
| Age | ||||
| <60 years | Reference | Reference | ||
| ≥60 years | 1.50 (0.63–3.55) | 0.355 | 1.20 (0.55–2.63) | 0.655 |
| Sex | ||||
| Male | Reference | Reference | ||
| Female | 2.09 (0.91–4.77) | 0.463 | 1.80 (0.80–4.08) | 0.156 |
| BMI | ||||
| <18.5 kg/m2 | Reference | Reference | ||
| 18.5–24.9 kg/m2 | 0.90 (0.80–1.03) | 0.119 | 0.90 (0.80–1.02) | 0.090 |
| 25–29.9 kg/m2 | 0.46 (0.15–1.41) | 0.176 | 0.43 (0.14–1.28) | 0.130 |
| ≥30 kg/m2 | 0 (0–Inf) | 0.997 | 0 (0–Inf) | 0.997 |
| ASA score | ||||
| I | Reference | Reference | ||
| II | 1.68 (0.61–4.58) | 0.313 | 1.24 (0.51–3.02) | 0.634 |
| III | 2.16 (0.66–7.07) | 0.204 | 1.53 (0.51–4.55) | 0.445 |
| ECOG status | ||||
| 0 | Reference | Reference | ||
| 1 | 1.50 (0.70–3.24) | 0.299 | 1.36 (0.64–2.89) | 0.425 |
| 2 | 1.03 (0.14–7.89) | 0.976 | 1.86 (0.42–8.20) | 0.410 |
| Neoadjuvant therapy | ||||
| None | Reference | Reference | ||
| Neoadjuvant chemoradiotherapy | 1.50 (0.64–3.50) | 0.354 | 1.40 (0.61–3.25) | 0.427 |
| Neoadjuvant chemotherapy | 0.71 (0.25–1.98) | 0.535 | 0.82 (0.32–2.13) | 0.684 |
| Comorbidity | ||||
| No | Reference | Reference | ||
| Yes | 0.76 (0.32–1.80) | 0.535 | 0.79 (0.35–1.78) | 0.570 |
| Margin | ||||
| R0 | Reference | Reference | ||
| R1 | 2.22 (0.53–9.39) | 0.278 | 2.25 (0.54–9.49) | 0.268 |
| Location | ||||
| Upper | Reference | Reference | ||
| Middle | 1.31 (0.29–5.85) | 0.725 | 1.46 (0.33–6.48) | 0.617 |
| Lower | 1.38 (0.31–6.13) | 0.670 | 1.54 (0.35–6.77) | 0.568 |
| Procedure | ||||
| Single-lung ventilation | Reference | Reference | ||
| Capnothorax | 2.22 (1.00–4.94) | 0.049 | 2.56 (1.17–5.63) | 0.019 |
| pTNM | ||||
| I | Reference | Reference | ||
| II | 1.44 (0.15–13.85) | 0.752 | 1.97 (0.22–17.64) | 0.544 |
| III | 10.58 (1.43–78.42) | 0.021 | 11.29 (1.53–83.49) | 0.018 |
| Major complication | ||||
| No | Reference | Reference | ||
| Yes | 1.28 (0.44–3.71) | 0.645 | 1.17 (0.41–3.37) | 0.769 |
AC: Adenocarcinoma; ASA: American Society of Anesthesiologists; BMI: Body mass index; CI: Confidence interval; ECOG: Eastern Cooperative Oncology Group; ESCC: esophageal squamous cell carcinoma; pTNM: Pathological TNM.
Table 4.
Multivariate Cox proportional hazards model for survival analysis after patients with esophageal cancer undergoing capnothorax versus single-lung ventilation.
| Characteristics | Overall survival | Disease-free survival | ||
|---|---|---|---|---|
| Hazard ratio (95% CI) | P values | Hazard ratio (95% CI) | P values | |
| Procedure | ||||
| Single-lung ventilation | Reference | Reference | ||
| Capnothorax | 2.35 (1.05–5.24) | 0.037 | 2.70 (1.23–5.94) | 0.014 |
| pTNM | ||||
| I | Reference | Reference | ||
| II | 1.61 (0.16–16.03) | 0.684 | 2.24 (0.24–20.88) | 0.478 |
| III | 8.33 (1.07–64.78) | 0.043 | 9.02 (1.17–69.64) | 0.035 |
CI: Confidence interval; pTNM: Pathological TNM.
Nine patients in the single-lung ventilation group and 20 patients in the capnothorax group experienced recurrence, which indicated that single-lung ventilation was associated with a lower risk of recurrence compared with capnothorax group (P = 0.017). However, no significant differences were observed between the two groups when considering recurrence pattern, including locoregional, distant recurrence, or both [Table 5].
Table 5.
Recurrence pattern between patients with esophageal cancer undergoing capnothorax or single-lung ventilation.
| Items | Capnothorax group (N = 55) | Single-lung ventilation group (N = 55) | Statistic values | P values |
|---|---|---|---|---|
| Recurrence | 20 (36.4) | 9 (16.4) | 5.666 | 0.017* |
| Recurrence patterns | ||||
| Locoregional | 11 (20.0) | 6 (10.9) | 1.739 | 0.187* |
| Distant | 7 (12.7) | 3 (5.5) | 1.760 | 0.185* |
| Both | 2 (3.6) | 0 | 0.509 | 0.475† |
Data are presented as number with percentage. *Chi-squared test; †Yate’s correction.
Discussion
Artificial capnothorax appears to be a common practice in the use of numerous VATS and robotic surgery for lung and esophageal cancer. However, the long-term effect of capnothorax on the prognosis of patients with malignancies remains unclear. In this prospective, randomized, controlled trial, we found that capnothorax in MIE had less reduction in CTC levels than single-lung ventilation procedure after surgery, but with a comparable intraoperative index and postoperative complications. It’s worth noting that patients who underwent MIE with capnothorax were associated with worse OS and DFS than those with single-lung ventilation.
Similar with a previous study conducted by Ramirez et al[9] regarding radical hysterectomy, a minimally invasive approach was associated with lower rates of 3-year OS than open surgery (93.8% vs. 99.0%, respectively; HR: 6.00, 95% CI: 1.77–20.30) among patients with cervical cancer. This outcome presumably resulted from the effect of insufflation gas (CO2) on promoting tumor invasion and dissemination. Moreover, Volz et al[11] reported that CO2 pneumoperitoneum could induce intraperitoneal melanoma tumor growth by damaging the peritoneum. In addition, several studies using cellular or animal models have elucidated the possible molecular mechanisms of tumor proliferation, invasion, and metastasis that may enable this process.[17–20]
The dissemination of CTCs is one of the critical events in tumor progression, and several studies have indicated that CTC status was an independent prognostic indicator and clinical staging parameter in patients with nonmetastatic esophageal cancer.[21,22] In the present trial, we also found that the reduction in CTC levels after surgery was less significant in the capnothorax group than in the single-lung ventilation group. Additionally, the incidence of increased CTC levels after surgery was observed more frequently in the capnothorax group than in the single-lung ventilation group. These findings suggest that capnothorax may influence postoperative CTC dynamics. The potential explanation may be that a high-pressure environment or changed pH could cause tumor dissemination.[10,23–25] Although a low intrathoracic pressure (<8 mmHg) can help limit the extent of pathophysiological changes in circulation and respiration,[26,27] Ren et al[28] reported that intrathoracic pressure overshoot frequently occurs during thoracoscopic surgery with artificial capnothorax pneumothorax. These events may lead to adverse effects on oncological outcomes. Although we proposed some possible mechanisms, further studies investigating the underlying molecular mechanisms are warranted. The CTC high-risk group in this trial tended to have a worse prognosis; however, this difference did not reach statistical significance. This may potentially be attributed to factors such as limited sample size, the specific study design, or the influence of confounding variables.
Notably, we found no significantly statistical differences in the intraoperative indices or postoperative complications between the capnothorax group and the single-lung ventilation group. These findings parallel the results obtained in previous studies.[8,29] A randomized controlled trial by Knoll et al[30] indicated that the incidence of vocal cord lesions was increased in the single-lung ventilation group compared to the capnothorax group (44% vs. 17%, respectively; P = 0.046); however, no major complications were observed in either group. Regrettably, the potential harm of capnothorax to the long-term prognosis was not investigated in their study.
This trial is a prospective randomized clinical study that investigates the effects of capnothorax on CTCs and survival outcomes in patients with esophageal cancer undergoing MIE. Notably, Chen et al[31] reported similar oncological outcomes between capnothorax and single-lung ventilation in MIE patients based on a retrospective study without a standard operating procedure. The strengths of our study include its robust trial design and rigorous statistical methods. As reported in our preliminary work, the single-lung ventilation procedure was safe and feasible.[13] Patients who underwent this procedure avoided the potential harm caused by CO2 insufflation and had noninferior short-term outcomes. Furthermore, such a procedure may have survival benefits by reducing the dissemination of CTCs during operation. Hence, MIE under single-lung ventilation should be recommended for the treatment of esophageal cancer.
The current study also has some limitations. First, nearly half of the patients with local advanced disease in this trial received neoadjuvant therapy according to the National Comprehensive Cancer Network (NCCN) guidelines. The effect of neoadjuvant therapy on CTCs may introduce bias. However, no significant between-group differences in preoperative CTC levels were found. Second, squamous cell carcinoma remained the most common histological type in this trial. The generalizability of these findings to a wider population remains unclear. Finally, only 3-year survival rates in this trial were available because of the length of follow-up. Longer-term survival outcomes will be assessed in future.
In this randomized clinical trial, single-lung ventilation was associated with decreased CTC levels and improved survival outcomes compared to capnothorax in patients with esophageal cancer. Thus, single-lung ventilation in MIE is safer and more favorable than capnothorax. Long-term follow-up and further investigations are warranted to confirm these findings.
Funding
This work was supported by the Science and Technology Plan Project of Sichuan Province (No. 2023YFS0304), the Postdoctoral Fellowship Program of CPSF (No. GZB20230474), and the Sichuan Science and Technology Program (No. 2025ZNSFSC1864).
Data availability
The data that support the findings of this study are available on request from Yi-Min Gu (yimin_gu@aliyun.com) and Wen-Ping Wang (drwangwp@163.com).
Conflicts of interest
None.
Supplementary Material
Footnotes
How to cite this article: Gu YM, Yang YS, Shang QX, Zhang HL, Yan CY, Liu BW, Liu YX, Lin HH, Liu SX, Yang L, Cui RC, Lin HN, Hu WP, Tian D, Zhu YK, Hu Y, Yuan Y, Chen LQ, Wang WP. Artificial capnothorax versus single-lung ventilation in minimally invasive esophagectomy for esophageal cancer: A randomized controlled trial. Chin Med J 2026;139:3066–3075. doi: 10.1097/CM9.0000000000003628
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from Yi-Min Gu (yimin_gu@aliyun.com) and Wen-Ping Wang (drwangwp@163.com).