Background
Curative treatment of gastric cancer (GC) depends on operation-centered comprehensive treatment. Effectively achieving systematic lymphadenectomy without increasing surgical complications is the goal of surgeons. Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy, a recently developed technique with upgraded minimally invasive visual display systems, is believed that could be used to achieve this goal [
1].
The key to effective intraoperative lymph node (LN) visualization depends on ICG injection. The existing injection methods include the submucosal approach (SMA) and subserosal approach (SSA). The results of previous retrospective studies [
2,
3] and randomized controlled trial (RCT) [
4] showed that submucosal injection of ICG around tumors 1 day before surgery could achieve good tracing of perigastric LNs, thus significantly increasing the overall number of retrieved LNs without increasing surgery-related complications in patients undergoing laparoscopic surgery.
Traditional preoperative submucosal injections seem to be the preferred method. However, preoperative submucosal ICG injection is generally performed 1 day before surgery when patients have extremely high physical and mental burden [
5]. This method may increases patient discomfort and the endoscopist’s workload while performing tracer injection in cases of unresectable GC, such as GC with unpredictable peritoneal metastases, which is prone to medical waste. Moreover, according to the refined modern medical division of labor, in many centers, intraoperative submucosal injection usually requires an extra endoscopic team in addition to the surgeon, which dramatically reduces the convenience and coordination during surgery, which limits the application this technique. Herrera-Almario et al. [
6] found that subserosal injection of ICG helps surgeons visualize LNs effectively in robotic gastrectomy, thus improving the quality of lymphadenectomy. A retrospective study by Baiocchi et al. [
7] suggested that ICG tracer-guided LN dissection can be achieved either by submucosal or subserosal injection. Compared with submucosal injection 1 day before surgery, intraoperative subserosal injection before lymphadenectomy is theoretically more convenient for surgeons and can reduce the workload of endoscopists; however, it is associated with a possible risk of poor imaging.
Currently, the optimal ICG injection method for laparoscopic fluorescence imaging-guided lymphadenectomy in radical GC surgery, considering the effectiveness of LN tracing, economic benefits, and patient burden, is controversial. Hence, the Fujian Medical University Union Hospital Gastric Surgery Study (FUGES) Group conducted a RCT (FUGES-019) to compare the efficacy, safety, and cost-effectiveness of the SMA and SSA for ICG injection for LN tracing during laparoscopic gastrectomy in patients with GC.
Discussion
To the best of our knowledge, this study is the first RCT comparing the efficacy of different ICG injection modalities for LN tracing during laparoscopic radical GC resection. Preoperative submucosal and intraoperative subserosal ICG injection were comparable in terms of the total number of retrieved LNs, LN noncompliance rates, operative time, and surgical burden. However, intraoperative subserosal ICG injection was associated with better patient satisfaction and lower fluorescence costs compared with preoperative submucosal ICG injection.
Within the specified dissection range, increasing the number of LN dissections and avoiding missed dissection of positive LNs retrieved are significantly associated with accurate staging, subsequent treatment options, and prognosis improvement of GC [
19‐
21]. Therefore, it is important to thoroughly dissect perigastric LNs in resectable GC. Consistent with a previous study [
4], we found that ICG fluorescence imaging-guided lymphadenectomy significantly improved the quality of LN dissection in GC. The number of LNs dissected was ≥ 30 in > 95% patients in both groups, and the LN dissection noncompliance rate in both groups was significantly lower than that reported in previous studies [
22,
23]. Further analysis showed that the average number of fluorescent LNs detected was significantly higher than that of nonfluorescent LNs in both groups. Compared with the average number of LN dissection in the non-ICG group (42) in the previous study [
4], we found that SMA (49.8) or SSA (49.2) in this study (Additional file
3: Fig. S8) can effectively increase the average number of LN dissection (
P both < 0.001). This indicates that both injection methods are equally effective for LN tracing in D2 lymphadenectomy.
Several studies have suggested that the injection site of the LN tracer should not be limited to the submucosa [
24,
25]. Jamieson and Dobson found that the lymphatic fluid flows from the submucosa into the subserosal plexus [
26]. In our study, the injected tracer in the submucosa immediately stained the subserosa in postoperative specimens. The submucosa was also stained with a tracer injected into the subserosa in resected specimens. Further, consistent with the previous report [
26,
27], our results inferred that submucosal lymphatic vessels are connected with subserosal lymphatic vessels through the intermuscular lymphatic network (Fig.
1C, Additional file
3: Fig. S9). It is postulated that the ICG injected into the submucosa around the tumor would likely disperse through the same route as that injected into the subserosal layer. Therefore, it is assumed that there is no difference in LN dissection results using the SMA or SSA. Moreover, the accuracy of fluorescent lymphography for detecting metastatic stations was comparable between the two methods.
Tajima et al. [
28] found that intraoperative subserosal injection was less accurate than preoperative submucosal injection of ICG for detecting sentinel LNs. Moreover, some retrospective studies [
29,
30] support the use of submucosal injection of ICG for fluorescence-guided lymphadenectomy the day before surgery. These inconsistent results may be explained by the selection bias inherent in retrospective investigations and varying injection sites, time, and concentrations of ICG used across studies. Therefore, we proposed Huang’s subserosal hexa-points maneuver according to the drainage characteristics of perigastric LNs and the criteria for D2 lymphadenectomy [
8,
31]. It overcomes the shortcomings of the traditional four-point peritumor subserosal injection, in which it is challenging to identify the tumor location from the outside of the stomach without intraoperative localization of the tumor, especially in early GC cases [
6,
32]. We found that stable and good LN visualization can be achieved at the D2 station after 20 min of subserosal injection. Because the surgeon can perform the essential omental separation and perigastric adhesion separation during this waiting period, our results showed that intraoperative subserosal injection conducted in this way does not significantly increase the total operative time. Therefore, ICG injection followed by sequential lymphadenectomy is easy for the surgeon to control. It will not interfere with the routine operation procedure while ensuring clear fluorescence images.
Patients often experience nausea, vomiting, and coughing during routine gastroscopy. In our study, patients in the SSA group had a better hospital experience than those in the SMA group. Intraoperative subserosal injection is effective in reducing patient anxiety and discomfort compared to preoperative endoscopic submucosal injection. Efficient use of medical resources to provide patients with cost-effective medical solutions has been the new quest in the era of patient-centered precision surgery [
33]. Cost-effectiveness analysis has shown that intraoperative subserosal injection as part of a complete procedure can significantly reduce the fluorescence-related cost and workload of endoscopists while achieving comparable LN tracing compared to preoperative submucosal injection. In addition, subserosal injection is a convenient method in surgical centers that do not routinely perform therapeutic gastroscopy, which suits the operation of the surgeon and facilitates the promotion of fluorescence imaging technology. Moreover, for patients with early GC (cT1) who need preoperative endoscopic localization, ICG submucosal injection can go together with preoperative endoscopic localization to efficiently save time in practical application.
We found that among the 259 patients included in the primary analysis of this study, 123 patients underwent ICG fluorescence imaging-guided laparoscopic TG, with an average of 50.9 LNs retrieved, while 136 patients underwent ICG fluorescence imaging-guided laparoscopic DG, with an average of 48.2 LNs retrieved. The number of LNs retrieved in the patients who underwent TG was 2.7 more than those who underwent DG. This is similar to the results of previous studies [
4,
34‐
36]. We also found that, whether DG or TG, the most retrieved LNs were mainly in the infrapyloric area and the suprapancreatic area. In addition, the total number of LNs dissection in patients with gastric cancer has been significantly increased by the use of ICG fluorescence imaging. Compared with the total LNs retrieved (approximately 50), the average difference of 2.7 may not appear that significant. This may be the reason why the number of LNs retrieved in patients who underwent ICG fluorescence imaging-guided laparoscopic TG is not much higher than that in patients who underwent ICG fluorescence imaging-guided laparoscopic DG.
This study has several limitations. First, although the study results showed that both the injection methods were effective in guiding LN dissection, the effect of different injection methods on long-term survival needs to be confirmed. Second, this study was conducted at high-volume referral centers with extensive experience in the surgical treatment of GC, and more future research are needed to solidly establish the sound generalizability of the findings to other centers with different levels of experience. Third, this RCT did not include patients who received neoadjuvant therapy, and patients often have tumor and LN regression and fibrotic response after neoadjuvant therapy. The role of ICG fluorescence imaging-guided surgery in patients who have undergone neoadjuvant therapy need to be further explored. Fourth, ICG is a dye that appears green under natural light [
37], which can be clearly distinguished from almost colorless normal saline, a crystalloid solution. At present, there is no well-recognized safe and effective placebo with the same color as ICG approved by FDA for intragastric injection, so it is difficult for endoscopists and surgeons to make blind allocation during operation. This study was not only conducted to compare the efficacy, safety of the SMA, and intraoperative SSA for ICG injection for LN tracing during laparoscopic gastrectomy in patients with GC, but also aimed to evaluate the cost-effectiveness of the two approaches. Therefore, if both groups of patients underwent endoscopy the day before surgery, it cannot truly reflect the impact of the two injection approaches on the treatment experience and the economic burden of patients. Finally, similar to a previous study [
28], ICG fluorescence imaging could not accurately indicate metastatic LNs with either subserosal or submucosal injections.
Acknowledgements
We thank those who have devoted a lot to this study, including nurses, pathologists, further-study doctors, statisticians, reviewers, and editors, especially Ms. Fang-Jing Wang, Dr. Lv-Ping Zhuang, Dr. Fang-Fang Liu, Mr. Lei Lin, and Prof. Bin Lin. They were not financially compensated for their contributions.
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