Colorectal cancer is one of the most common cancers in the world, and the incidence is increasing.1 With novel technical advances, better understanding of the physiology, and improved surgical technical skills, surgeons offer patients better outcomes after colorectal resections, albeit with complications.2 However, among postoperative complications, anastomotic leakage (AL) is the most serious complication that has a negative impact on both short- and long-term outcomes.3 The reported incidence rate of AL after colorectal surgery ranges from 3% to 20%.4,5 Some studies have suggested that AL is associated with reduced overall survival and increased rate of local recurrence after resection for colorectal cancer.3,6
Some investigators have found that poor blood supply and tension at the anastomotic site are the main risk factors for AL.7 It has been reported that blood supply is related to the location of the tumor, preoperative bowel obstruction, and perioperative transfusion.8 Moreover, absence of Riolan arterial arcade and sacrifice of left colic artery during resection may also be linked with poor blood supply.9,10
A variety of methods have been used to assess the anastomotic integrity intraoperatively, including mechanical patency (air leak and dye tests) and endoscopic assessment.11 Meanwhile, several clinical signs, including bowel serosal color and palpable mesenteric arterial pulsations, have been used to check the vascularity of the cut end of the bowel. However, these signs are subjective and may well lead to misinterpretations even by experienced surgeons. Moreover, some of these signs may not be feasible while performing laparoscopic colon resection.1
Recently, many studies have found that intraoperative indocyanine green (ICG) fluorescence angiography (ICGFA) might be useful in preventing AL in colorectal surgery by visualizing the bowel perfusion of the anastomotic region.12,13 Fluorescence imaging for tissue perfusion assessment has repeatedly been found to be beneficial in decision-making and improving surgical outcomes in plastic, cardiothoracic, hepatobiliary, and foregut surgeries.14–18 Also in colorectal surgery, ICG fluorescence imaging is useful for assessing anastomotic perfusion.19 ICG is a sterile, water-soluble tricarbocyanine compound that absorbs near infrared light with a peak spectral absorption at 800 nm. ICG is injected intravenously, which rapidly and extensively binds to plasma protein. It can be cleared by the liver in 3 to 5 minutes into the bile. It is a nontoxic and nonionizing agent with a maximal daily dose of 2 mg/kg, with few reported cases of adverse effect.20 There are few systematic reviews and meta-analyses conducted on the effect of ICGFA in colorectal cancer surgeries. Therefore, we aimed to analyze the current evidence for the impact of intraoperative ICGFA on AL after resection for colorectal cancer.
MATERIALS AND METHODS
This meta-analysis was carried out in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement.21
Potential relevant studies were identified by a comprehensive literature search, which covered the following electronic platforms: PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure. The search was performed independently by 2 researchers, and no language or date restrictions were applied. The last search was performed in August 2017. The following terms were used during literature search: anastomotic leakage, colorectal cancer, fluorescence angiography, fluorescence imaging, and indocyanine green. The reference lists of all retrieved articles were screened to identify other relevant studies.
Studies satisfying the following criteria were included in the meta-analysis: 1) comparative studies investigated the association between ICGFA and AL in patients undergoing surgery for colorectal cancer, 2) the diagnosis of AL was confirmed via CT, and 3) the outcomes of the study cohort undergoing ICGFA were compared with a control group in which ICGFA was not performed. Exclusion criteria were publication types such as case reports, letters reviews, meeting abstracts, meta-analyses, and proceedings, as well as studies lacking necessary data for calculation.
Data Extraction and Study Quality
Data were extracted by 1 investigator with complete and independent verification by another investigator. Each of the 2 reviewers assessed the studies independently based on the selection criteria to collect the following descriptive information from eligible studies: surname and initials of the first author, year of publication, journal, country where study was conducted, study design, number of subjects, type of operation, cancer type, demographic variables of the patients, ICG dose, and postoperative complications. Discrepancies between the 2 investigators were settled by discussion. Because of the mix of randomized controlled trials (RCTs) and cohort studies, risk of bias and qualities of included studies were assessed using the Newcastle–Ottawa Scale.22 Studies with a score of ≥7 were considered high quality.
All of the statistical analyses were performed with Review Manager 5.1 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). The ORs and 95% CIs were used as the statistical measures for dichotomous outcomes to calculate the relevance of ICGAF and the incidence of AL after colorectal cancer. ORs were calculated from the original data and combined with the Mantel–Haenszel method. OR > 1.0 indicated greater risk of an adverse event in the experimental group. A p < 0.05 was considered significant for all of the analyses. Heterogeneity among studies was tested using χ2 and I2 statistics and the funnel plot. A p < 0.05 and I2 > 50% indicate significant heterogeneity. In these cases, a random-effects model was used; otherwise a fixed-effect meta-analysis was performed.
Description of Included Studies
A total of 148 records were identified on initial searching. After the exclusion of 81 duplicated studies, the remaining studies (n = 67) were screened by title and abstract for relevance. Twenty-three studies were excluded because these were case reports, reviews, or conference abstracts (n = 14) or not related to research topics (n = 9). Full texts of the remaining 44 records were retrieved and evaluated. Among these 44 studies, 39 studies were unsuitable because of a lack of control group (n = 36) or necessary data (n = 3). In addition, among the included 5 studies, 1 study was excluded because the same patients were included in another recent study by the same authors.23,24 Finally, 4 retrospective case–control studies published from 2010 to 2017 were incorporated into the current meta-analysis.24–27 A flow diagram of study selection is displayed in Figure 1.
The included 4 studies were from 4 different countries with a total sample size of 1177 patients, and all of the studies divided samples into ICGFA group and control group. All 4 studies were retrospective case-matched and single-institutional studies with the primary end points being the incidence of AL requiring surgical reintervention and change in the surgical strategy. Three studies investigated patients with rectal cancer,24,26,27 and 1 study investigated patients with colorectal cancer.25 Moreover, the operation method differed among the studies: in 2 studies surgeries were performed by robot-assisted laparoscopic method,24,26 whereas in the other studies surgeries were conducted by laparoscopic/conventional method.25,27Table 1 shows the baseline characteristics of included studies. Two studies mentioned the use of diversion: in the study by Jafari et al,26 the rate of diversion was 75% in the ICG group and 77% in the control group, where the decision to use diversion was left to the discretion of the attending surgeon; in another study,24 concurrent ileal diversion was performed in patients with preoperative chemoradiotherapy or a complicated operation, including coloanal anastomosis or inadequate perfusion.
ICGFA and AL After Operation of Colorectal Cancer
This meta-analysis found that the use of intraoperative ICGFA was associated with lower incidence of AL after surgery for colorectal cancer (Fig. 2). Among the 4 studies, the main outcomes were 4.0% overall reduction in leak rate and 16.4% change in surgical plan,25 12.0% overall reduction in leak rate and 19.0% change in resection margins,26 5.0% overall reduction in leak rate and 4.7% change in surgical plan,27 and 4.9% overall reduction in leak rate.24 The corresponding OR values were 0.45 (95% CI, 0.18–1.12), 0.30 (95% CI, 0.03–2.98), 0.17 (95% CI, 0.01–3.69), and 0.12 (95% CI, 0.03–0.52). The combined OR value was 0.27 (95% CI, 0.13–0.53). The result revealed that ICGFA was associated with a lower AL rate after colorectal resection. The difference was statistically significant (p < 0.001), and there was no significant heterogeneity (χ2 = 2.48; degrees of freedom = 3; p = 0.48; I2 = 0).
From the funnel plot (Fig. 3), the included studies were of symmetrical distribution, and the p value for the Egger test was 0.373. Both demonstrated that there was no evidence of significant bias in this meta-analysis; therefore, our results were statistically reliable.
This meta-analysis found that use of ICGFA was associated with a lower AL rate after colorectal resection. Thus, we conclude that intraoperative ICGFA has a link with a lower AL rate of colorectal cancer surgery. The lower AL rate is probably attributed to better assessment of bowel perfusion and vascularity with the help of ICG. Moreover, ICGFA changed the surgical plan by guiding the appropriate line of bowel transection in 4.7% to 19.0% of cases.25–27
Recently, fluorescence angiography using ICG has become the most promising technology that allows for real-time intraoperative objective evaluation of bowel perfusion.13,26,28 A review by Mizrahi and Wexner29 pointed out that every surgeon needs to become familiar with methods of using ICG and its numerous clinically important applications.29 A systematic review about near-infrared fluorescence (NIRF) angiography in anastomotic colorectal surgery for cancers, diverticulitis, and Crohn's disease concluded that 3.5% (31 of 894) of all NIRF patients and 7.4% (32 of 434) of all control patients developed an anastomotic leakage (p=0.002).30 Another meta-analysis including 5 studies concluded the similar result,31 but the surgical indication of one included study was not only cancer but also IBD and diverticular disease.32 The results of non-colorectal cancer surgery may affect the final statistics. In addition, it included a study that may be outdated that we mention in the "Description of Included Studies" section.23,24 Therefore, we performed the current meta-analysis to investigate the correlation between intraoperative ICGFA and the AL rate after colorectal resection for colorectal cancer. All 4 of the studies showed that ICGFA reduced the AL rate after colorectal resection. Because the difference in AL rate was statistically significant with no significant heterogeneity or bias, it is clear that ICGFA was related to a lower AL rate after colorectal resection. We have also tried to perform some similar operations with the use of ICG. However, because of several technological limitations and insufficient sample size, our results were not as robust as the results of recent studies. Despite this we estimated that the reduction rate of AL in our clinical trials was ≈4% to 6%. However, there were differences in the included studies. Table 2 shows the detailed characteristics of these studies.
With the development of surgical techniques, many surgeries for colorectal cancer are being increasingly performed by laparoscopic and robot-assisted methods. Studies have found good long-term results with laparoscopic colorectal resection for colorectal cancer.33,34 On the other hand, robotic-assisted laparoscopic surgery also has shown some advantages over open surgery.35,36 However, there was no difference between laparoscopic and robot-assisted resection in terms of postoperative AL rate.37,38 Therefore, we believe that the type of operation is unlikely to affect the results of this meta-analysis. Similarly, other factors like patient demographic and preoperative characteristics were considered to have no significant differences.
Several limitations in this meta-analysis should be mentioned. First, we did not take unpublished articles and abstracts into account because the necessary data were lacking. A second potential limitation was that, among the 4 studies, the administered dose of intraoperative ICG and camera systems were different, and whether the different doses would influence the results needs to be confirmed. Also, this limitation may introduce a little heterogeneity. Last but not least, this meta-analysis did not include RCTs, and the pooled data were not randomized. Accordingly, larger, multicenter, high-quality RCTs are needed to verify the findings of this meta-analysis.
This meta-analysis showed significant benefit of ICGFA in reducing the incidence of AL, thereby improving patient outcomes. In the long term, it may offer the possibility to lower the rate of mortality, as well as more promising advantages, such as lymph node evaluation.
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