Perfusion outcomes with near-infrared indocyanine green imaging system in laparoscopic total mesorectal excision for mid-rectal or low-rectal cancer (POSTER): a study protocol

Abstract

Introduction

Anastomotic leakage (AL) is defined as the failure of complete healing or disruption of the anastomosis subsequent to rectal cancer surgery, resulting in the extravasation of intestinal contents into the intra-abdominal or pelvic cavity. It is a serious complication of rectal cancer surgery, accounting for a considerable increase in morbidity and mortality. The use of fluorescence imaging technology in surgery allows surgeons to better evaluate blood perfusion. However, the conclusions of some existing studies are not consistent, so a consensus on whether the near-infrared indocyanine green (NIR–ICG) imaging system can reduce the incidence of AL is needed.

Methods

This POSTER trial is designed as a multicentre, prospective, randomised controlled clinical study adhering to the “population, interventions, comparisons, outcomes (PICO)” principles. It is scheduled to take place from August 2019 to December 2024 across eight esteemed hospitals in China. The target population consists of patients diagnosed with rectal cancer through pathological confirmation, with tumours located≤10 cm from the anal verge, eligible for laparoscopic surgery. Enrolled patients will be randomly assigned to either the intervention group or the control group. The intervention group will receive intravenous injections of ICG twice, with intraoperative assessment of anastomotic blood flow using the near-infrared NIR–ICG system during total mesorectal excision (TME) surgery. Conversely, the control group will undergo conventional TME surgery without the use of the NIR-ICG system. A 30-day follow-up period postoperation will be conducted to monitor and evaluate occurrences of AL. The primary endpoint of this study is the incidence of AL within 30 days postsurgery in both groups. The primary outcome investigators will be blinded to the application of ICG angiography. Based on prior literature, we hypothesise an AL rate of 10.3% in the control group and 3% in the experimental group for this study. With a planned ratio of 2:1 between the number of cases in the experimental and control groups, and an expected 20% lost-to-follow-up rate, the initial estimated sample size for this study is 712, comprising 474 in the experimental group and 238 in the control group.

Ethics and dissemination

This study has been approved by Ethics committee of Beijing Friendship Hospital, Capital Medical University (approval number: 2019-P2-055-02). The results will be disseminated in major international conferences and peer-reviewed journals.

Trial registration number

NCT04012645.

Correspondence to Zhongtao Zhang; [email protected]

Strengths and limitations of this study

• This is a national multicentre prospective randomised controlled study.

• All participating centres are high-quality medical centres.

• Our study focuses on patients with mid-to-low rectal cancer (tumour edge≤10 cm from the anal margin).

• The occurrence of anastomotic leakage, the primary endpoint, may be influenced by a variety of factors other than anastomotic haemodynamics.

Introduction

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies in China.^{1 2} According to the latest data, there were approximately 408 000 new cases in China, accounting for 18.05% of all cases worldwide.² Despite improvements in lifestyle and living standards, the incidence of rectal cancer continues to increase.³ Surgery is still the main treatment for rectal cancer.⁴

Anastomotic leakage (AL) is a serious complication of rectal cancer surgery, with the incidence of varying between 2% and 20%.^{5 6} The mortality rate after AL can be as high as 16%. Several studies have shown that males, smoking, obesity, large tumours, diabetes, gut microbiota and many other factors are high-risk factors for the occurrence of AL.^{5 6} However, several studies have suggested that inadequate intestinal blood supply around the anastomosis may be an important factor contributing to the development of AL.

Routinely, surgeons use their own experience and naked eye to assess the blood supply near the anastomosis. Near-infrared (NIR) fluorescence imaging is a tool that allows real-time fluorescence visualisation of blood vessels during laparoscopic surgery. NIR-ICG imaging technology refers to the use of ICG to receive the signal generated after the excitation of NIR light to achieve the targeted marking or tracing of blood flow in specific tissues during the operation. The surgeon can therefore use this tool to assess the haemodynamic situation more objectively. Surgeons can assess tissue perfusion in real-time, endoscopically and in high resolution.

Until now, the safety and reliability of the NIR-ICG imaging system for anastomotic blood flow assessment in CRC surgery have been discussed worldwide.⁷ Several studies have discussed the application of the NIR-ICG imaging system for intraoperative blood flow assessment of CRC patients.^8–10 In the PILLAR II study, of the 139 patients who underwent left-sided colectomy and anterior resection with the fluorescence angiography (FA), 11 had their original surgical decision changed by the surgeon during the operation as a result of the evaluation.⁸ However, there were still some studies showing opposite results. In PILLAR III study, 347 patients from multiple institutions were randomised 1:1 to standard surgery and NIR-ICG. The final results of this study, however, showed that perfusion assessment via ICG fluoroscopy does not change the rate of AL.¹⁰ There a meta-analysis result showed that FA was significantly protective against AL (p=0.04). But there was a non-significant decrease in RD of AL by 4 percentage points (p=0.06) with FA.¹¹ Therefore, further studies are needed to confirm the effectiveness of blood transport assessment for reducing the incidence of AL. And whether intraoperative assessment of intestinal blood flow using NIR-ICG imaging system can reduce the incidence of AL or not deserves to be explored and validated by more high-quality studies.

The probability of anastomotic fistula after surgery is higher in patients with low and intermediate rectal cancer than in those with CRC in other locations. However, this specific group of patients is not targeted in the available studies. In addition, neoadjuvant therapy is also recommended as treatment option for low and intermediate rectal cancer. And whether this technique can help to better assess intraoperative bowel haemodynamic in patients who have received neoadjuvant therapy is one of the main points we ultimately want to explore. Last, studies investigating the use of this technique in bowel cancer surgery patients have been initiated mainly in Europe and the USA, and the type of bowel cancer/tumour distribution and anatomical structure in Asian populations may be different from those in Western countries. There is a more noticeable lack of quality guidelines related to this in China, and we very much hope that our study will yield some better results and provide more scientific references for more doctors in China. To further address these issues, we believe that multicentre, large-sample, high-level evidence-based medical studies are still needed in China.

Therefore, we hypothesised that accurate intraoperative evaluation of anastomotic blood perfusion for low- and medium-rectal cancer patients undergoing TME surgery and timely changes in intraoperative decision-making and surgical methods for patients with poor blood supply may reduce the risk or even prevent the occurrence of AL. Now, we propose a prospective, randomised, controlled study of a population at high risk for AL. The subjects of this study are patients with low-rectal cancer undergoing laparoscopic TME surgery, and the aim of the study is to explore the application of the NIR-ICG imaging system to optimise the surgical mode and reduce the incidence of postoperative AL in such high-risk patients.

Methods

Study design

This POSTER trial is a multicentre, prospective and randomised controlled clinical study of patients with mid-rectal or low-rectal cancer who undergo laparoscopic TME surgery that aims at to explore whether the application of NIR-ICG imaging system can reduce the incidence rates of postoperative AL in mid-rectal or low-rectal cancer patients.

Five hundred and forty-seven patients with pathologically diagnosed locally advanced rectal cancer (LARC) at eight centres in China will be enrolled, and detailed participation centres are shown in online supplemental table 2. The study will be performed in accordance with the principles of the Declaration of Helsinki. The Ethics Committee of Beijing Friendship Hospital, Capital Medical University approved the study protocol on 25 April 2019 (approval number: 2019-P2-055-02). All the enrolled patients or their designated agents will sign the informed consent. Moreover, all the enrolled patients will be provided information describing the significance and methods of the study as well the importance of their cooperation with the follow-up. All clinical data for each patient will be collected during visits.

Patient population

Consecutive patients aged≥18 years who were diagnosed with rectal carcinoma (cT_1-4N_0-2M₀) with a tumour distal location≤10 cm from the anal verge (determined by MRI scan) are eligible for inclusion in this study. The major exclusion criteria are patients allergic to ICG or iodine and patients with intestinal obstruction, intestinal perforation and intestinal bleeding who need emergency operation. Detailed inclusion and exclusion criteria are shown in box 1.

Box 1

Inclusion and exclusion criteria.

Inclusion criteria:

• The age was over 18 years at the time of diagnosis.

• Diagnosis of rectal carcinoma and was confirmed by preoperative pathology.

• MRI was performed before operation, and the distance between the lower margin of tumour and the anal margin was no more than 10 cm.

• The colon-rectum or colon-anus anastomosis was performed by laparoscopic TME operation.

• Baseline clinical tumour stage TNM I–III phase: cT1-4N0-2M0 (AJCC-8 version).

Exclusion criteria:

• Allergic to ICG or iodine.

• Patients with intestinal obstruction, intestinal perforation, intestinal bleeding who need emergency operation.

• Patients requiring combined organ resection that the tumour involves adjacent organs.

• Patients with recurrence of tumour or distant metastasis.

• Patients with multiple colorectal cancer.

• Patients with history of inflammatory bowel disease or familial adenomatous polyposis.

• Patients who have participated in or are participating in other clinical trials in the past 4 weeks.

• Patients whose ASA level is larger than III.

• Physical condition: patients with KPS less than or equal to 60 points or ECOG larger than or equal to two points.

• Patients with hepatic dysfunction and MELD larger than 12 points.

• Patients with a history of serious mental illness.

• Pregnant or lactating women.

• Patients who are improper to participate in the study in the opinion of the researchers.

ASA, American Society of Anaesthesiologists; ECOG, Eastern Cooperative Oncology Group; ICG, indocyanine green; KPS, Karnofsky performance status; MELD, model for end-stage liver disease; TME, total mesorectal excision.

Randomisation and blinding

This study is a multicentre, prospective, open, randomised controlled clinical study. The primary outcome investigators are blinded to the use of ICG angiography. Patients eligible based on inclusion/exclusion criteria will be randomised at the preoperative visit to either the intervention group or the control group.

Patient information will be collected and written informed consent will be received from all participants before randomisation. The number of patients who refuse to participate in the study will also be collected.

Intervention

The experimental design involves an intervention group and a control group.

Intervention group

Patients in this group will undergo laparoscopic TME and colon-rectum or colon-anal anastomosis. A NIR-ICG imaging system will be used to evaluate anastomotic flood perfusion during the operation. The operator can decide whether to change the surgical programme based on the outcome of the evaluation.

In the 1970s, it was first observed that on injection into the human body, ICG immediately binds tightly to plasma proteins in the blood without facile decomposition or alteration of protein molecular structure. It exhibits high selectivity for uptake by hepatocytes and rapid excretion into bile without involvement in other metabolic processes within the body. Under NIR light irradiation at wavelengths ranging from 750 to 810 nm, it emits light at approximately 840 nm, enabling fluorescence penetration through tissues/organs of 8–10 mm thickness. Following capture by a fluorescence camera, it undergoes photoelectric conversion to form a visible green image to the naked eye.^{7 8} The half-life period of ICG in blood is 3–5 min (180–300 s). When the NIR camera system is used to observe vascular perfusion, the median development time of ICG is 35 s (range 29–44 s) and the duration is approximately 3 min. If the ICG vascular perfusion is well visualised within 60 s, the case is judged to be well perfused. If the perfusion evaluation is insufficient (longer than 60 s), the incision position will be changed, and the details will be recorded (the boundary between perfused and nonperfused tissue will be recorded and compared with the planned incision). The intestinal wall will be dissected along the ischaemic line, and the direction and distance of change will be recorded in detail.

The criteria for using the NIR system to determine the imaging effect and vascular perfusion are described in table 1, as well as the criteria for visual assessment (clinical assessment) by the surgeon.

Table 1

Criteria for determining blood perfusion

Grade	1	2	3	4	5
Clinical assessment (the intestinal tube was visualised with the naked eye)	The tissue was dull in colour.	The tissue was bloody and patchy.	The bowel was pink, but there was no arterial bleeding or anastomotic oozing.	The bowel was pink, the mesenteric blood vessels were pulsating and the anastomotic oozes blood, but clinical survival remained a concern.	The bowel was pink, the mesenteric blood vessels are pulsatile and the anastomotic oozes was bleeding.
Fluorescent rendering	No obvious fluorescence was observed.	The fluorescence was patchy.	Marked and uniform hypo fluorescence.	Contrast of high and low fluorescence intensity can be discernible by naked eye.	All regions showed strong fluorescence.

Control groups

Patients in this group will undergo laparoscopic TME operation, and the operator will judge the anastomotic blood supply with the naked eye and perform surgical intervention based on experience.

Study process

After admission, patients will undergo a baseline assessment. According to the judgement of clinicians, patients who receive neoadjuvant therapy for rectal cancer should first receive the standard regimen of neoadjuvant radiotherapy. These patients will be evaluated again 6 weeks after the end of radiotherapy, and those eligible for TME surgery will be selected for inclusion.

The enrolled patients will first be randomised into two groups, and different surgical procedures will be performed according to the corresponding groups (as mentioned above). Patients will be followed up 30 days after the operation, and plain CT scans of the abdomen and pelvis will be reviewed to monitor and judge the occurrence of AL. The flow chart of this trial is illustrated in online supplemental figure 1.

Therapeutic schedule

• Drug and configuration: prepare the injection before use, and dilute ICG for injection into 2.5 mg/mL with sterilised water. The injection dose of ICG is 0.1 mg/kg, and the upper limit is 5 mg/kg/day after injection.¹²

• Surgical methods: both groups need to undergo routine preoperative preparation before surgery, and the TME operation will be performed by the same surgical treatment group. During the operation, the intervention group will be injected with ICG twice (before and after the completion of intestinal anastomosis). The surgeon should judge the blood flow of the patient through the fluoroscopy system and decide whether to change the planned incision.

Trail quality assurance

In this study, the anastomotic blood supply will be evaluated by fluorescence imaging in the intervention group, and that of the control group will be judged according to the surgeon’s experience.

To ensure both surgical quality and the centre’s capability to adhere to the study protocol, we formulated the study protocol and standardised the operation of the trial in the early stage. These criteria were used to measure adherence to surgical quality standards among participating teams and to screen surgical teams for entry into the trial. Before entering the trial, interested teams were invited to participate in a pilot trial, and each surgeon needed to submit two unedited videos of ICG injection during laparoscopic TME surgery. The videos will be sent anonymously to three surgeons experienced in TME surgery, who will jointly assess whether the centre meets the study criteria and to ultimately select those eligible to participate in the formal trial. Eventually, we screened 8 of the 19 eligible subcentres from around the country to participate in the formal trial.

At the same time, to ensure that the quality of the study was up to standard at all stages of the trial, we established an audit team consisting of three senior surgeons with extensive surgical experience. We needed each centre to reserve videos of patients receiving two intraoperative ICG injections in the trial group and regularly submit them to the data review team, who would anonymously examine the details of the secondary video. After synthesising the results, we will give regular feedback to each subcentre.

Outcome

Primary outcome measures

The primary endpoint of this study was the occurrence of AL within 30 days after surgery. In this study, the diagnosis of AL and its grading should be made in conjunction with the patient’s imaging findings, laboratory test results and clinical symptoms. When assessing for rectal AL, physicians primarily consider three aspects:

• Patient symptoms: if the patient exhibits abdominal pain, fever or discharge resembling pus or faeces from the anus, drainage tube or vagina, further examination and treatment may be warranted.

• Imaging studies: utilising techniques such as X-ray, CT scan, or MRI, physicians can visually inspect the condition of the anastomosis, detecting any perforations or anomalies.

• Laboratory tests: analysing the patient’s blood for white blood cell count and C-reactive protein levels helps identify signs of infection or inflammation.

Based on this information, AL is classified into three grades: grade A, characterised by asymptomatic leakage visible only on imaging, requiring no specific intervention; grade B, exhibiting symptoms such as abdominal pain and fever, necessitating conservative treatment with medication and grade C, presenting more severe symptoms like peritonitis and sepsis, requiring secondary surgical intervention.

Secondary outcome measures

The secondary endpoints of this study are changes in intraoperative decision-making, including the location of intestinal dissection and anastomotic reconstruction. The change in intraoperative decisions included (1) the change in the position of intestinal dissection; (2) the removal of the anastomotic stoma and rebuilding or reperforming the Hartmann operation and (3) the decision to perform unplanned, diverting ileostomy due to ICG test results.

Follow-up

Follow-up data were collected by professional researchers through telephone and regular outpatient visits. Follow-up was performed during postoperative hospitalisation and 30 days after surgery.

Sample size and statistical analysis

Determination of sample size

According to the literature,^{5 6 13} it was assumed that the immediate AL rate in the control group was 10.3%, the corresponding rate in the experimental group was 3%. The number of experimental group cases: the number of control group cases=2:1. A total of 379 cases were needed in the experimental group, and 190 cases were needed in the control group, with a total of 569 cases in the two groups. Considering a loss to follow-up rate of 20%, the total number of samples in this study was preliminarily estimated to be 712, with 474 cases in the experimental group and 238 cases in the control group.

Analysis method

Primary outcome

The difference in AL incidence between the control group and the intervention group will be compared between the groups using the χ² test or Fisher’s exact test of categorical variables. All p values are double-sided, and the statistical significance is set at the 5% level. Proportion and 95% CI will be calculated. SPSS (IBM) will be used for statistical analysis of all data.

Secondary outcome

Secondary outcomes will be summarised and analysed using descriptive language.

Patient and public involvement

Neither the patients nor the public were involved in the design, conduct, reporting or dissemination plans of this research.

Discussion

AL is a severe postoperative complication of CRC. Due to its high incidence and mortality, AL has always been a topic of discussion in colorectal surgery.¹⁴ In the past, the assessment of anastomotic blood supply mainly depended on the experience of the surgeon and was not objective nor accurate. Therefore, it is difficult to use a unified and quantifiable standard to evaluate intestinal blood flow.

In 1956, ICG-NIR technology was approved for clinical use.¹⁵ For decades, ICG has been clinically applied to determine cardiac output, liver function and hepatic blood flow and for ocular angiography.^{16 17} In 2006, Koichi Nagata et al applied ICG to colorectal surgery, and since then, it has emerged in this field.¹⁸ Henceforth, a growing number of high-quality studies have been conducted worldwide to address these issues.

Several study results suggest that ICG NIR imaging can reduce the incidence of AL in patients undergoing laparoscopic CRC surgery. In a single-centre study in Japan, the incidence of AL was 2.8% (4/141) in the ICG-FA group and 12.4% (87/703) in the control group (p=0.001).¹⁹ The Jafari’s team and Kudszus’ team also reached the same conclusion in their research.^{20 21} De Nardi and colleagues reported outcomes for 252 patients who underwent laparoscopic left-sided colon and rectal resection with FA.²² However, there was no statistically significant reduction in the AL rate in the ICG arm.

It has been mentioned in some studies that factors affecting the occurrence of AL may include the level of tumour location.^{23 24} The results of a single-centre randomised controlled study in Russia showed that ICG FA did not decrease the AL rate of high (at 9–15 cm from anal verge) anastomoses: 1.3% versus 4.6% in the non-ICG FA group (p=0.37).²⁵ In contrast, a decrease in the AL rate was found for low (4–8 cm) colorectal anastomoses (14.4% in ICG FA vs 25.7% non-ICG FA in the non-ICG FA group (p=0.04)).²⁵ This further suggests that the incidence of AL may be negatively correlated with the distance at which the tumour is located away from the anal verge. Therefore, the subjects of our study were medium-low (≤10 cm from anal verge) rectal cancer patients.

Therefore, to further understand whether intraoperative use of the ICG system in patients with middle and low rectal cancer can reduce the incidence of AL after surgery, we designed such a large multicentre prospective randomised controlled study. The results of this study will also help to establish norms and guidelines for the prevention of AL after rectal surgery in China, as well as guide and standardise the use of ICG in gastrointestinal surgery.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors (1) Conception and design: ZZ, H-WY, GW, LS and JG; (2) administrative support: ZZ and H-WY; (3) provision of study materials or patients: H-WY, LS, JG and ZY; (4) collection and assembly of data: LS, JG, CM and PW; (5) data analysis and interpretation: LS, JG (6) manuscript writing: all authors; (7) final approval of manuscript: all authors.

Funding This work was supported by grants from the National Key Technologies R&D Programme (no. 2015BAI13B09), National Key Technologies R&D Programme of China (no. 2017YFC0110904), Clinical Center for Colorectal Cancer, Capital Medical University (no. 1192070313).

Competing interests None declared.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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