Study design
This multi-centre, open-label, parallel, superiority, randomised trial will compare the effectiveness of non-muscle cutting periumbilical transverse incision versus midline incision on the incidence of incisional hernia in patients undergoing laparoscopic colon cancer surgery in the following four tertiary hospitals in the Republic of Korea: Chonnam National University Hwasun Hospital, Kyungpook National University Chilgok Hospital, Jeonbuk National University Hospital, and Pusan National University Yangsan Hospital. The study flow of the assessment, intervention, and follow-up is summarised in Fig. 1.
Participants
Eligible individuals are identified by the usual clinical team on a list of planned elective surgeries by reviewing patient information in the hospital’s electronic medical records at each institution. When eligibility is confirmed, surgeons will contact patients to provide details of the study background and process will request their participation in the study. Written informed consent will be obtained from each patient before the initiation of the study protocol. We began recruitment on 20 April 2021 and anticipate its conclusion in February 2024.
Inclusion and exclusion criteria
Patients scheduled for elective laparoscopic surgery for colon cancer at participating institutions are eligible if they meet the following inclusion criteria: (i) age ≥ 20 years; (ii) pathologically confirmed colon cancer (adenocarcinoma, mucinous carcinoma, or signet ring cell carcinoma); and (iii) ability to understand verbal explanations, read instruction documents, and sign informed consent forms.
Patients meeting at least one of the following exclusion criteria are ineligible for this trial: planned open surgery; expected incision length of < 1 or ≥ 10 cm; rectal cancer (lower border of tumour located within ≥ 15 cm from the anal verge); planned small incision outside of the umbilical area ; (palliative) surgery for stage IV tumours; planned protective or permanent diversion; emergent surgery; current unhealed wound, fracture, peptic ulcer, or intraabdominal abscess; history of incisional hernia; and participation in any other interventional clinical trial within 6 months.
Randomization and blinding
Patients will be allocated in a 1:1 ratio, either the midline incision or non-muscle cutting periumbilical transverse incision group, after stratifying by the location of the tumour (right-sided: caecum-transverse colon; left-sided: descending-rectosigmoid colon), according to the random sequence generated by a web-based randomisation system. A unique study identification number will be assigned to the patients during data collection and analysis to ensure anonymity. The surgery team will not be blinded because the small incisions made during the operation will be different in each case. Patients will also not be blinded, as the incisions will be visible during postoperative wound care. To reduce the bias associated with data collection, the outcome assessor will be separate from the surgery team and blinded to the allocation. The allocation information will also be blinded to the data analyser. The allocation will not be made public until a final comparison is performed.
Perioperative management
Patients in both groups receive treatment for colon cancer using the same strategy, according to the National Comprehensive Cancer Network Guidelines. Perioperative management is standardised at all institutions.(7) One day before surgery, patients complete mechanical bowel preparation, except for those with right-sided colon cancer, for which mechanical bowel preparation is selectively administered according to the surgeon’s discretion. On the day of surgery, prophylactic broad-spectrum antibiotics are administered before the incision. Surgery is performed using a laparoscopic approach, for which, one 11-mm camera port is placed at the periumbilical area, and three or four 5-mm trocars are used. Modified complete mesocolic excision with central vascular ligation is performed according to tumour location.(8) A small incision for specimen extraction is made according to group allocation. Stapled anastomosis is performed extracorporeally through a small incision, except for cases of anterior resection, for which intracorporeal colorectal anastomosis is performed.
Intervention
A small incision is made by extending the periumbilical port for the camera scope in both groups. The size of the small incision is determined based on the tumour size and physical habitus of the patients. The fascial closure methods are standardised as continuous closure using Stratafix (SF Symmetric PDS Plus®) with a 4:1 ratio (4-to-1 suture to wound length ratio) and bites of < 1-cm. The methods for closure of the subcutaneous fat and skin (skin stapler or 3 − 0 nylon vertical mattress) depend on the surgeon’s discretion. Patients randomised to the midline group will undergo an incision along the midline skin, subcutaneous fat, and linea alba.
In the non-muscle cutting transverse group, the method of small incision is the same as in a previous report.(6) Briefly, the skin incision of the 11-mm periumbilical port is extended transversely. The anterior and posterior rectus sheaths are transversely incised using monopolar electrocautery with crossing linea alba. Lateral traction of the rectus abdominis muscle using an army retractor is helpful to expose the posterior rectus sheath (Supplemental Video 1). The transversalis fascia and parietal peritoneum are further incised transversely. Continuous fascia closure is separately performed for the anterior and posterior rectus sheath. Implementing Vertical or transverse incision will not require alteration to usual care pathways (including use of any medication) and these will continue for both trial arms.
Outcomes (schedule of outcome measurement)
Data will be collected at baseline (before surgery), during the hospital stay, and at 30 days, and at 6, 12, and 36 months after surgery (Table 1). The primary outcome of this study is the incidence of incisional hernias including both symptomatic and radiologic hernias at 12 months after surgery. Incisional hernia is assessed by interviewing patients regarding subjective symptoms, performing physical examination of the abdomen, and reviewing abdomino-pelvic computed tomography (CT) scans. Incisional hernia is defined as either symptomatic hernia during interview or radiologic hernia when it is diagnosed on both abdomino-pelvis CT scan and physical examination in cases without subjective symptoms. The secondary outcomes are length of hospital stay, estimated blood loss, pain numerical rating scale (0: no; 10: worst pain imaginable) score on postoperative days 1, 2, and 3; reoperation, open conversion, 30-day postoperative complications, (as grouped by the Clavien–Dindo classification)(9), surgical site infection (as grouped by the Center for Disease Control and Prevention criteria(10) and ASEPSIS score(11)), 30-day mortality, incidence of repair of incisional hernia, pathologic result of colon cancer (pathologic stage, histologic type, differentiation, number of harvested/metastatic regional lymph nodes, lymphovascular, venous, and perineural invasion, and distant metastasis), and patient-reported outcomes (Short-from-12 Health Survey Questionnaire [SF-12] before surgery and at 12 months after surgery and Body Image Questionnaire at 12 months after surgery).(12, 13) The incidence of incisional hernia at 36 months after surgery is another secondary outcome that will be separately analysed and reported after the last patient enrolled completes follow-up.
Table 1
Schedule for assessment, interventions, and follow-up
Time point
(visit number)
|
Baseline
V0
|
Operation
V1
|
1 month
V2
|
6 months
V3
|
12 months
V4
|
Assessment
|
|
|
|
|
|
Eligibility assessment
|
|
|
|
|
|
Consent
|
X
|
|
|
|
|
Demographics
|
|
|
|
|
|
Baseline data
|
X
|
|
|
|
|
Colonoscopy
|
*
|
|
|
|
|
Operative outcomes
|
|
X
|
|
|
|
30-day morbidity
|
|
X
|
X
|
|
|
30-day mortality
|
|
X
|
X
|
|
|
Symptomatic hernia
|
|
|
X
|
X
|
X
|
Radiologic hernia
|
|
|
|
X
|
X
|
Pathologic report
|
|
|
*
|
|
|
Adjuvant chemotherapy
|
|
|
|
*
|
|
Body image questionnaire
|
|
|
|
|
X
|
SF-12
|
X
|
|
|
|
X
|
Assessments undertaken as routine care for colon cancer are displayed with *. |
SF-12, ShortForm-12 Health Survey Questionnaire. |
Withdrawal of patients
The participants are free to discontinue their participation at any time for any reason, without any consequences. If a participant meets newly established or previously unrecognised exclusion criteria, or an urgent medical condition that disqualifies the patient from participating, the investigator may opt to remove them removed from the research. Patients who withdraw consent after randomisation but before surgery, will be replaced, whereas those who withdraw their consent after surgery will not be replaced. The data from these patients will not be included in the analysis.
Data management and control
Participants’ identities will be kept private by utilising a research identification number that cannot be linked to their individual identities. Each centre will keep all patient-identifiable information in the file, apart from the data needed for analysis. To ensure consistent assessment, researchers are uniformly trained. The result assessor at each centre will first input data into a registered paper-based case report form before entering it into the predesigned electronic version of the case report form. Both the paper and electronic versions of case report forms will be maintained in a safe location, with only the members of the research team having access to them. All records will be stored for inspection at any time during and at 3 years after the completion of the study report. The study will be monitored by a committee of the Chonnam National University Hwasun Hospital.
Day-to-day support will be provided by the principal investigator (supervision of the trial, recruitment and medical responsibility of the patients) and the research coordinator (data collection and follow-up of the patients) of each participating institution. The principal investigator and research coordinator will meet weekly. The Trial Steering Committee (TSC), will consists of representatives from participating institutions. This will be a decision-making committee, responsible for the scientific conduct of the study. The TSC will meet every 3 months, ensure that the trial is conducted in accordance with relevant principles and provide overall supervision.
Frequency and procedures for auditing trial conduct
The IRB of each participating institution will continue to review the trial. The TSC will check the consent forms, compliance with the protocol, the planned surgical interventions, and quality of data collected in the case report forms at least annually.
Composition of the data monitoring committee, its role and reporting structure
The Data Safety and Monitoring Board (DSBM) is independent from the sponsor, has not worked with the study team, and does not have competing interests. The DSBM will meet every 6 months to review the study procedures and adverse events.
Plans to promote participant retention and complete follow‑up
During follow-up, several strategies such as collecting detailed contact preferences and sending text messages in advance will be used to maximize participant retention. Up to five contact attempts will be made before participants are considered lost to follow-up.
Sample size estimation
This study aimed to test the superiority of non-muscle cutting transverse incision over midline incision, and the sample size was estimated based on the primary outcome (incidence of incisional hernia at 12 months after surgery). Our previous retrospective study showed that the incidence of incisional hernia was 2.4% in non-muscle cutting transverse incision, and 14.9% in midline incision.(6) For this study, a conservative estimate rounded these incidences up to 2.5% and 15%, respectively. The required sample size for a superiority trial was determined to be 168 patients using power analysis (power = 80%, ɑ=0.05, two-sided) and dropout rate was anticipated as 10%. Finally, a total of 174 patients are required for randomisation.
Statistical analysis
Data analysis will be performed using intention-to-treat (primary analysis), followed by as-treated principles (secondary analysis). All baseline and outcome data will be presented using frequencies with proportions for categorical variables, and means with standard deviations for continuous data (or medians with interquartile ranges if more appropriate). To determine the balance between the two groups, patients will be compared with respect to baseline characteristics including age, sex, American Society of Anesthesiologists classification, preoperative treatment (none, radiotherapy, or chemotherapy), comorbidities, medication, history of previous abdominal surgery, location of tumour (right/left), and baseline SF-12. The primary outcome (incidence of incisional hernia) will be analysed using the chi-square test. The primary outcome will be analysed using a generalised linear regression model, with the control of important potential confounders to the treatment effect. Secondary outcomes will be analysed using the chi-square test for categorical variables (i.e.type of operation, type of resection, type of anastomosis, incidence of 30-day postoperative complications, histologic type, and tumour depth) and Student’s t-test or Mann–Whitney U test for quantitative variables (i.e. operative time, length of hospital stay, blood loss, postoperative pain scores, tumour size, and number of lymph nodes) as appropriate. In accordance with symptoms, each incision type will be evaluated during follow-up after surgery. However, it is not expected that there will be missing data relating to the primary outcomes. For other possible missing data, multiple imputation will be made, based on the assumption that the data is missing at random.
Subgroup analyses will be conducted for each randomization straum. The results will be evaluated at a significance threshold of p < 0.05 (two-sided). All statistical analyses will be performed using R statistical software, version 3.4.3 (R Foundation for Statistical Computing).
Patient and public involvement
Patients and/or the public were not involved in the planning, conduct, reporting, or dissemination of this study at any stage.
Ethics and dissemination
This trial has been approved by the Institutional Review Board (IRB) of CNUHH for clinical trials (IRB No. CNUHH 2021-009) on 19 January 2021 and the IRBs of each participating institution. The current study protocol version is 2.2, which was approved on 21 April 2021. The study protocol has been registered within the Clinical Research Information Service (KCT00006082) on 12 April 2021. This study will be conducted in accordance with the tenets of the Declaration of Helsinki and its amendments. Investigators will provide patients with complete written and oral information on the two types of incision and the process of the trial prior to their participation. All participants will voluntarily join the study and can cease at any time without any consequence. We plan to disseminate this information to the relevant patients and healthcare professionals. When requested by the participants, we plan to educate them on the trial results during their regular hospital visit at the outpatient clinic. The results will be published in a peer-reviewed journal and presented at pertinent national and international scientific meetings as posters or oral presentations. If a suitable research and data-protection strategy is agreed upon, study data may be made available after a request to the principal investigator has been made.