Aim: To investigative the efficacy of carbon nanoparticles (CNs) to identify the lymph nodes during radical surgery in colorectal cancer. Method: The MEDLINE, EMBASE and Cochrane Library databases were searched electronically to identify the studies that compared the use of CNs (CN group) with control group in patients undergoing colorectal cancer radical surgery (from January 2009 to November 2018). The primary outcome was the number of retrieved central lymph nodes. Results: This meta-analysis identified 2 randomized controlled trials and 5 non-randomized controlled trials. Compared with the control group, the CN group resulted in an average of 7.16 more lymph nodes removed per patient (WMD = 7.16, 95% CI = 3.76 to 10.57, p < 0.01), 7.26 minutes less required for retrieving lymph nodes (WMD = -7.26, 95% CI = -13.43 to -1.09, p = 0.02), and 15.1 ml less blood loss during operation (WMD = -15.11, 95% CI = -23.15 to -7.06, p < 0.01). Although there was no significant difference in the metastatic lymph nodes between the two groups (OR = 1.02, 95% CI = 0.79 to 1.31, p = 0.87), there was 1.45 times more metastatic lymph of the stained nodes in CN group than in the control group (OR = 1.45, 95% CI = 1.13 to 1.85, p < 0.01). In addition, lymph nodes less than 5 mm were detected significantly more in the CN group than in the control group (OR = 2.15, 95% CI = 1.77 to 2.63, p < 0.01). Conclusions: The technique of CNs labeled lymph node staining in curative colorectal carcinoma is easy and effective, which can improve the retrieved number of lymph nodes, especially for nodes < 5 mm. The black stained lymph node indicate s higher risk of metastasis. Further high quality RCT is needed to verify the se conclusions.
Radical colorectal surgery is the main treatment for colorectal cancer [
The carbon nanoparticles (CNs) can be injected as a suspension that can enter the lymphatic capillaries rather than the capillary vessels [
Therefore, this meta-analysis was designed to evaluate the efficacy of CNs during radical colorectal surgery. This study included all comparative researches using CNs as a tracer for lymph node dissection or not during radical surgery for colorectal cancer. By summarizing initial recommendations on the injection site and total dose, and waiting time for the use of CNs in these studies, we can investigate the relationship between the number of nodes retrieved and the rate of node positivity, and evaluate the effect of submucosal CNs staining on improvements in lymph node detection and staging accuracy.
MEDLINE, EMBASE, PubMed, the Web of Science, and the Cochrane Library databases were systematically searched for all comparative studies from January 2009 to November 2018, using the keywords carbon nanoparticles, lymph node, colorectal cancer. The reference lists of relevant articles were manually searched to identify other relevant trials. Only trials published in English or Chinese were included. Studies in animals and review articles were excluded. Studies identified through the search were independently screened by two authors (Miao Liu and Ai Shen) for inclusion. Any disagreements were arbitrated by a third author (Hao Sun).
Inclusion Criteria
Studies met the following criteria characteristics can included in this study. Included articles must compare the use of CNs with at least 1 control group which did not use a tracer during colorectal cancer under radical surgery. Only randomized controlled study (RCT) and non-randomized comparative study (NRCT) were included.
Subjects
Patients underwent a radical surgery for colorectal cancer with a diagnosis confirmed by pathology results.
Interventions
Patients in the experimental group were injected with CNs before surgery, and patients in the control group did not receive an injection of tracer.
Observation Indexes
The primary outcome was the number of retrieved central lymph nodes per patient. Other outcomes included the staining rates of lymph nodes, the rates of metastatic nodes in all retrieved central lymph nodes, operation time, time for dissection lymph nodes, blood loss, total number of lymph nodes and small ones (<5 mm). At least 1 index was described separately for each study group.
Exclusion Criteria
Non-independent clinical controlled trials, studies with a patient number < 15, or studies with incomplete data were excluded.
The quality of RCT studies was assessed according to the Jadad scoring system. The scale consists of 3 items: randomization (0 - 2 points), blinding (0 - 2 points), and descriptions of the withdrawals and dropouts (0 or 1 point). The total possible score was 5 points. Trials with a score of 0 to 2 were considered to be of low quality, and those with a score of 3 to 5 were considered to be of high quality (
All analysis was performed with Rev Man 5.2. Based on the results of heterogeneity tests and study designs, a random effects model was used for all analyses. Weighted mean differences (WMDs) were calculated for the continuous outcome variables, and odd ratios (ORs) and risk differences (RDs) were calculated for the dichotomous outcome variables. In addition, 95% confidence intervals (CIs) were calculated for the WMDs, ORs, and RDs. Differences were considered to be statically significant at p < 0.05. A sensitivity analysis was performed to exclusively examine the pooled results of these studies. If result of the comparison had changed, the result was presented.
A total of 156 references were initially identified. After reading titles and abstracts, 35 references were eliminated for non-colorectal cancers’ study. Additional 28 references were excluded for non-clinical studies, duplicate publication and non-controlled trials (
Study | Tumor Type | Number | Study Design | Injection Site | Dose ml | Waiting Time | Laparoscopic | Indices |
---|---|---|---|---|---|---|---|---|
Cai et al. [ | Colorectal | 60 | RCT | 4-quadrant region around the mass | 1 | 10 min | No | ①④⑨ |
Zhang et al. [ | Rectal | 87 | NRCT | Around the submucosa of the rectum | 5 | 30 min | In 96% cases | ①④ |
Wang et al. [ | Rectal | 152 | NRCT | 3 points around the submucosal layer of mass | 0.5 | 1 day | in 97% cases | ①②⑧ |
Yang et al. [ | Colorectal | 65 | RCT | 4 - 6 points around the mass | 0.15 - 0.25 | 10 min | Yes | ①②③④ |
Zhang et al. [ | Colorectal | 53 | NRCT | 4 points around the submucosal layer of mass | 0.15 - 0.25 | 1 - 3 day | Yes | ①②③④⑧ |
Wang et al. [ | Colorectal | 54 | NRCT | 4 points around the submucosal layer of mass | 1 | 10 min | Yes | ①⑤⑦⑧ |
Wang et al. [ | Colorectal | 470 | NRCT | 4 - 6 points around the mass | 1 | 30 min | No | ①②⑤⑦ |
Observation indices: ① the number of retrieved lymph nodes in the CN and control groups, ② the total metastatic rate of the retrieved lymph nodes in the CN and control groups, ③ the metastatic rate of stained/non-stained lymph nodes in the CN and control groups, ④ the number of tiny lymph nodes (<5 mm) in the CN and control groups, ⑤ the surgical time in the CN and control groups, ⑥ the lymph node dissection time between the CN and control groups, ⑦ the surgical blood loss in the CN and control groups, ⑧ the number of patients who had dissected lymph nodes > 12 in the CN and control groups, and ⑨ the number of lymph nodes in the CN and MB groups. CN: carbon nanoparticles; MB: methylene blue.
Study | Randomization | Concealment of Allocation | Blinding | Loss to Follow-Up, % | Quality Assessment |
---|---|---|---|---|---|
Cai et al. [ | No detailed description | Only mentioned randomized | Unclear | 0 | 2 |
Yang et al. [ | Divided randomly into label group | Sealed envelopes | No blinding | 0 | 3 |
Study | Study Design | Selection | Comparability | Exposure | Quality Assessment |
---|---|---|---|---|---|
Zhang et al. [ | Prospective controlled study | 4 | 2 | 2 | 8 |
Wang et al. [ | Prospective controlled study | 4 | 2 | 2 | 8 |
Zhang et al. [ | Prospective controlled study | 3 | 2 | 2 | 7 |
Wang et al. [ | Retrospective study | 3 | 2 | 2 | 6 |
Wang et al. [ | Prospective controlled study | 4 | 2 | 2 | 8 |
Study characteristics and quality assessment. Two of the 5 studies were RCTs, involving 125 patients [
Intervention Effects
Number and metastatic rate of retrieved lymph nodes in the CN group and control group:
Compared with the control group, the use of CNs resulted in an average of 7.16 more lymph nodes removed per patient (WMD = 7.16, 95% CI = 3.76 to 10.57, p < 0.01,
There’s a small amount of studies reported the time of surgery, with respect to the general surgical time, the CN group is slightly less than the control group (WMD = −7.54, 95% CI = −13.81 to −1.28, p = 0.02,
Carbon nanosuspensions have highly lymphoid system tropism with an average diameter of 100 nm [
At present, the advantages of laparoscopic radical resection for colon cancer have been widely recognized and this micro-invasive method was written into the NCCN guidelines for colon cancer treatment. This method has become the standard surgical procedure for colon cancer. In addition, laparoscopic surgery for rectal cancer has also been widely carried out [
Laparoscopic surgery for colorectal cancer has a magnification effect of 2 - 3 times, with clear anatomical space and structure, which is easy to identification and conducive to nerve protection and lymph node dissection, as well as complete mesenteric resection (CME) and total mesenteric resection (TME) [
CNs can improve the detection rate of lymph nodes, guide pathological staging and postoperative adjuvant therapy. From the 2010 Edition of NCCN guidelines for the diagnosis and treatment of colorectal cancer, sufficient number of lymph nodes no less than 12 should be included in the postoperative pathological examination to ensure the accuracy and reliability of the pathological result evaluation and guide the postoperative adjuvant treatment [
This study has some limitations. First, the available articles were limited to English or Chinese publications. No publications written in other languages were included. The quality assessment scores of the 2 included randomized controlled trials were relatively low with the lack of blinding; the other 5 studies were nonrandomized controlled trial. Thus, further research is needed to verify the conclusions in the present study.
Carbon nanoparticles are helpful in curative colorectal surgery. CNs can improve the retrieved number of lymph nodes, especially for nodes < 5 mm. The black stained lymph node indicates higher risk of metastasis. A large scale high quality randomized controlled study is needed to verify these conclusions.
This study was supported by the project from Chongqing Science and Technology Bureau (cstc2018jscx-msybX0156).
The authors declare no conflicts of interest regarding the publication of this paper.
Liu, M., Shen, A., Li, W., Chen, L.H., Chen, X.F. and Sun, H. (2019) Carbon Nanoparticles for Identifying Lymph Nodes during Surgery in Colorectal Cancer: A Meta-Analysis. Journal of Cancer Therapy, 10, 134-145. https://doi.org/10.4236/jct.2018.102010