Short summary

Within the last 20 years, robotic-assisted surgery has become more widespread among several surgical specialties. There is no solid scientific evidence for the routine use of robotic-assisted surgery in colon cancer surgery, but it has been implemented increasingly.

To date, there are no randomized studies comparing the systemic inflammatory response in colon cancer surgery performed by robotic-assisted or laparoscopic method. In order to investigate the systemic and peritoneal stress-induced response in robot-assisted and laparoscopic colon surgery, it is our intention to perform a blinded, controlled randomized study.

Rationale

A decreased systemic inflammatory response is associated with less risk of surgical complications, and the possibility of improved long-term oncological outcomes. This is due to a cascade of neuroendocrine, metabolic, and immunological factors.

The surgical trauma initiates the production of macrophages, mast cells, monocytes, and lymphocytes that are predominantly produced in the peritoneal fluid, and has a protective effect through persistent intraperitoneal phagocytosis.

Postoperatively the amounts of proinflammatory cytokines - mainly tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 - will increase intraperitoneally. An additional benefit of laparoscopic surgery is a further decreased stress response by a depression of intraperitoneally decreased cytokine concentrations due to the use of carbon dioxide which mediates an increased production of proinflammatory cytokines.

In the systemic acute inflammatory reaction, a release of proinflammatory cytokines (IL-1, IL-6, and TNF-alpha) occurs as a part of wound healing by producing acute phase reactants (C-reactive protein (CRP), fibrinogen, and complement C3) as a reaction to the initiated surgical trauma.

In the case of high concentrations of proinflammatory cytokines (predominantly IL-6) and lack of compensatory expression of anti-inflammatory cytokines, it may cause systemic inflammatory response syndrome (SIRS).

There is a direct correlation between high concentrations of proinflammatory cytokines and an increased mortality rate. Both robotic-assisted and laparoscopic colon surgery is categorized as minimally invasive, and there is a focus on enhanced recovery after surgery (ERAS) in order to minimize the risk of postoperative complications, morbidity, and hospitalization time.

It has been shown that robotic-assisted colorectal surgery has positive effects in terms of faster establishment of bowel function and shorter hospital stay compared to laparoscopic surgery.

Through more gentle manipulation of the tissue during the surgical procedure, better visualization, tremor reduction, as well as better hemostasis control, it is conceivable that robotic-assisted surgery results in a reduced surgical trauma thereby minimizing the inflammatory stress response compared to the laparoscopic method.

However, the evidence is limited regarding differences in the inflammatory stress response caused by robotic-assisted and laparoscopic colon surgery.

The aim of this study is to evaluate the peritoneal and systemic inflammatory stress response induced by robotic-assisted or laparoscopic surgery for elective colon cancer resections in a prospective, randomized design.

Description of the cohort

Study material will consist of a total of 50 patients randomized in the period March 1, 2021 - September 1, 2022 for robotic-assisted respective laparoscopic surgery.

Inclusion criteria:

Elective robotic-assisted or laparoscopic surgery for colon cancer, age ≥ 18, ASA-score ≤ 3, UICC-stage ≤ 3, endoscopic suspected colon cancer, histologically verified adenocarcinoma, signet ring cell carcinoma, undifferentiated cancer, medullary carcinoma, or another malignant tumor type originating from colon. Patients must give informed written consent, patients must be able to understand

Danish language

Exclusion criteria:

Previous history of colon resection, previous open major abdominal surgery with exception of open appendectomy and cholecystectomy, locally advanced tumors without curative intervention, tumors that requires en-bloc multivisceral resection, clinical or radiological evidence of metastatic cancer disease, competing invasive cancer disease, synchronous colonic cancer, pregnancy, history of psychiatric or addictive disorder that would prevent the patient from participating in the trial, emergency colon surgery, co-existing inflammatory bowel disease, co-existing immunological disease that requires ingestion of systemic immunomodulatory drugs (DMARD - disease-modifying anti-rheumatic drugs), corticosteroids and biologic disease-modifying anti-rheumatic drugs.

Routine use of NSAID is not considered an exclusion criterion

Data and biological material

In order to examine the systemic and peritoneal inflammatory stress response induced by the surgical procedures, blood sampling, and peritoneal microdialysis will be performed.

Peritoneal microdialysis:

Patients will have a 61 high cut off microdialysis catheter (CMA 61; CMA Microdialysis AB, Stockholm®, Sweden) inserted intraperitoneally at the end of the operation. Since the microdialysis catheter is thin (1mm), no further incisions are needed as one of the already existing incision sites can be used. The catheter will be perfused with an isotone perfusion fluid (Dextran) used for microdialysis, with a flow rate of 0,3 l/min. The catheter membrane allows large molecules to diffuse into the perfusion fluid due to its permeability as it mimics a capillary. The peritoneal fluid will be collected from the abdominal cavity once daily for 3 days. The peritoneal fluid will be collected in NUC-vails and stored at -80 degrees Celsius. A cytokine panel (V-plex human cytokine 30 plex - Mesoscale ®, US ) will consist of; Eotaxin, Eotaxin-3, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-α, TNF-β, VEGF-A as well as IL-1RA and CRP (V-plex cytokine IL-1RA - Mesoscale ®, US).

Blood samples in order to investigate the systemic inflammatory stress-response:

Patients will have venous blood taken preoperatively and once daily basis postoperatively for 3 days in separator gel collection tubes, after which the samples will be centrifuged. The remaining amount of serum fluid will be pipetted and transferred to cryotubes. The samples will immediately thereafter be frozen to -80 degrees Celsius. The samples will be stored in a biobank with unique identification numbers. In addition, blood samples will be collected in PAX-gene tubes (Preanalytix, Switzerland) daily for 3 days. This is in order to perform a blood gene expression profiling of the measured cytokine levels. The same panel of cytokines will be measured as described above.

Collaborating researchers and departments

Department of surgery, Hospital of Southern Jutland, Denmark

• Department of Clinical Biochemistry, Hospital of Southern Jutland, Denmark
• Neurobiological research unit, University of Southern Denmark, Denmark
• Department of surgery, Odense University Hospital