The initial search resulted in 22 studies. Finally, 13 full articles including 7 RCTs and 6 retrospective studies were included for review (Figure 1). The sample sizes were mainly small (range from 11 to 210 patients); therefore, the evidence level of these researches was mainly downgraded.
The effect of vein-first ligation on the survival of the patients
To date, 7 articles (2 RCTs and 5 observational studies) involving 1688 patients had been published, which investigated the role of vein-first procedure in the prognosis of the lung cancer patients (Table 1) [4, 5, 10-14].Vein-first ligation was performed on 869 patients, while the other 819 patients underwent artery-first surgery. Among them, 4 studies indicated that the interruption sequence of the vessels did not significantly affect the survival; whereas the other 3 studies demonstrated an obvious survival benefit for the patients in vein-first group.
The RCT by Kozak et al. randomized 385 NSCLC patients in the vein-first (n = 170) and artery-first group (n = 215) respectively [10], which demonstrated similar 5-year OS. Refaely et al. retrospectively reviewed 279 NSCLC patients, and both groups (133 cases in vein-first and 146 cases in artery-first) reported similar tumor recurrence [12]. Li et al. also reported similar OS; whereas artery-first procedure could reduce bleeding and postoperative complications [13]. Bai et al. found that vein-first vs. artery-first procedure did not affect the outcomes of early stage NSCLC patients in terms of local recurrence (6.7% vs 4.4%; p > 0.05) and distant metastasis (17.8% vs 13.3%; p > 0.05) [15].
On the contrary, a propensity-matched analysis showed that the vein-first patients demonstrated significantly better 5-year OS (73.6% vs 57.6%; p < 0.01), DFS (63.6% vs 48.4%; p < 0.01) and lung cancer-specific survival (76.4% vs 59.9%; p < 0.01) than the control [4]. In addition, a retrospective study showed that the DFS in vein-first and non-vein-first groups was 6.7% (7/104) vs 18.1% (15/83) respectively (p < 0.05) [5]. Moreover, a retrospective study of 60 NSCLC patients (33 in vein-first and 27 in artery-first group) reported similar OS (p > 0.05); however, vein-first procedure delivered better survival in squamous cell carcinoma patients [14].
Furthermore, Wei et al. reported that vein-first procedure was correlated with better survival in stage I/Ⅱ patients but not stage Ⅲ cases [4]. Sumitomo et al. also indicated that vein-first ligation provided better survival for the patients in stage I but not stage Ⅱ or ⅢA diseases [5].
Quantitative data synthesis
Seven reports in Table 2 were possible for meta-analyses. The forest plots for the comparisons of local recurrence, distant metastasis, DFS and OS between the groups were generated respectively (Figure 2).
For the 4 reports with a local recurrence rate, the heterogeneity was as follows: I² = 0%. No significant difference in terms of local recurrence was noted (RR 0.96 in favour of vein-first ligation; 95% confidence interval [CI] 0.77-1.19, p = 0.68). Moreover, for the 3 reports with distant metastasis data, the heterogeneity was as follows: I² = 67%. No significant difference regarding distant metastasis was observed (RR 0.93 in favour of vein-first ligation; 95% CI 0.34-2.54, p = 0.89).
Three reports presented DFS data, and the heterogeneity was as follows: I² = 40%. Vein-first group demonstrated lower risk of mortality compared to the control (RR 0.58 in favour of vein-first ligation; 95% CI 0.42-0.81, p = 0.001). Similarly, for the 4 reports with OS rate, the heterogeneity was as follows: I² = 63%. Vein-first group demonstrated better 5-year overall survival compared to the counterpart (RR 0.72; 95% CI 0.52-0.99, p = 0.04).
Sensitivity analysis
We combined different study types in the above meta-analyses. Thus, a sensitivity analysis was conducted. When the 2 RCTs were excluded from the meta-analysis (Kozak, 2013; Bai, 2016) [10, 11], the results were not changed. In detail, both groups showed similar local recurrence and distant metastasis rate (p > 0.05, respectively); whereas the vein-first patients demonstrated better 5-year OS compared to artery-first group (RR 0.61; 95% CI 0.48-0.77, p < 0.001). Furthermore, the funnel plot in the meta-analysis suggested somewhat publication bias (Figure 3).
The effect of vein-first ligation on CTCs
Seven studies presented the change of tumor cells in the effluent PV after lung cancer surgery (Table 2), including 5 RCTs and 2 observational studies [1, 4, 15-19]. Three of them indicated that vein-first ligation was associated with a lower risk of intraoperative tumor dissemination; whereas the others recorded similar outcomes. However, a quantitative meta-analysis regarding CTCs was not possible because these studies used different tumor biomarkers and detection methods.
A multicenter RCT (NCT03436329) showed an incremental change of CTCs in 26 of 40 patients (65.0%) in the artery-first group and 12 of 38 (31.6%) in the vein-first group (p < 0.01) after surgery for NSCLC [4]. Kurusu et al. examined the presence of CTCs as reflected by carcinoembryonic antigen (CEA) mRNA in 30 NSCLC patients [15]. Of the 14 initially negative samples (7 in each group), 9 samples became positive during the operation, and such conversion was more common with artery-first (6 patients, 85.7%) than vein-first procedure (3 patients, 42.9%). In addition, exploiting cytokeratin 19 and CEA mRNA as markers of malignant cells, Ge et al. collected 23 NSCLC patients [16], which showed that vein-first procedure may partly prevent release of tumor cells into bloodstream. Moreover, Song et al. randomized NSCLC patients into artery-first and vein-first group (15 cases in each) [18]. The expression of cytokeratin 19 and adhesion molecule CD44v6 mRNA as biomarkers of lung cancer micrometastasis in the late period of surgery were higher than those in the early period in artery-first group (p < 0.05); whereas neither the cytokeratin 19 nor CD44v6 after surgery in the vein-first group exhibited significant change versus those before surgery (p > 0.05). The authors therefore concluded that vein-first ligation help lower the risk of manipulation-related micrometastasis. Similarly, a prospective study of 33 patients showed that the number of CTCs was 3.36 before PV interruption which increased to be 14.88 after lobectomy for lung cancer [1]; therefore, surgical manipulation may dislodge tumor cells into the PV whereas vein-first procedure may decrease the CTCs entry into the circulation.
On the other hand, Hashimoto et al. reported that the increase of CTCs in the PV was not significantly associated the sequence of vessel interruption [19].