Cancer is one of the biggest public health concerns, and the overall burden of cancer will continue to increase due to population aging [1]. Colorectal cancer is the third most prevalent cancer among males and females in Korea, with an age-standardized incidence rate of 24.4 per 100,000 [1]. The primary treatment for colorectal cancer consists of radical surgery and neoadjuvant and adjuvant treatments. However, immunosuppression can be caused by surgical stress, leading to postoperative development of inflammatory and infectious complications [2]. In particular, colorectal cancer has a high rate of surgical complications, such as anastomotic leakage, which may lead to poor oncological outcomes [3]. Hence, it is important to minimize the surgical stress associated with colorectal cancer surgery and enhance surgical outcomes.

Nutrition plays a very important role in colorectal cancer surgery. Cancer patients have a higher nutritional risk rate, ranging from 26% to 76%, compared with the general population [3]. Cancer patients are susceptible to malnutrition since the secretion of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, is promoted by the tumor, causing muscle wasting, changes in liver metabolism, and fat depletion [4]. In addition, colorectal cancer can cause symptoms such as anorexia, diarrhea, and intestinal obstruction, increasing the vulnerability to malnutrition [5]. Previous studies have shown that nutritionally high-risk patients have more complications, increased morbidity, and prolonged hospital stays [6]. However, many previous reports have shown that proper nutritional support improves the results of abdominal surgeries [7,8]. Therefore, perioperative nutritional support is crucial for patients with colorectal cancer.

The current European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend oral nutritional supplements (ONS) for patients undergoing major abdominal surgery, and immunonutrition supplements, including arginine, ω-3 fatty acids, and nucleotides, are preferred [9,10]. However, despite several previous randomized controlled trials (RCTs) that have reported the effect of preoperative immunonutrition on the outcomes of abdominal surgery [11,12], immunonutrition is still controversial due to the possibility of publication bias and heterogeneity in the previous studies [13,14].

This review aims to summarize the current evidence of using preoperative immunonutrition before colorectal cancer surgery.

The term “immunonutrition” is used for solutions enriched with nutrients that stimulate the host immune response and improve control of the inflammatory response [15]. These nutrients include glutamine, arginine, polyunsaturated fatty acids, nucleotides, taurine, vitamins, and trace elements such as zinc and selenium. However, immunonutrition generally refers to supplements containing a high protein content and arginine, ω-3 fatty acids, and nucleotides. Currently, immunonutrition only exists in the form of enteral supplements [15]. The most frequently assessed such product in previous studies is Impact^® (Nestlé Health Science). However, this supplement is not available in Korea. Newcare Enhancer^® (Daesang Life Science) is one of the immunonutrition products available in Korea and includes a high protein content, arginine, and ω-3 fatty acids.

L-arginine is an essential amino acid involved in various metabolic pathways, such as the synthesis of nitric oxide, proteins, creatine, and urea [16]. Arginine exhibits several immunostimulatory effects, such as promoting the proliferation of T lymphocytes and enhancing the functional capabilities of macrophages and natural killer cells [17]. Omega-3 fatty acids are a subgroup of polyunsaturated fatty acids that primarily consist of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid [18]. The presence of ω-3 fatty acids decreases the production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, and increases the secretion of anti-inflammatory factors, such as IL-10 and prostaglandin D3 [18], which can impede the adhesion of lymphocytes to monocytes and diminish antigen-stimulated lymphocyte proliferation [17,19]. Nucleotides and their metabolites can stimulate lymphocyte proliferation, which also impacts the immune function of macrophages and natural killer cells [17]. Due to these mechanisms, immunonutrients have the potential to offer sufficient support in preventing malnutrition and modulating favorable immune responses.

Guidelines for perioperative immunonutrition are described in Table 1. In summary, the guidelines commonly recommend preoperative ONS for better surgical outcomes [9,20]. For patients with severe malnutrition, one to two weeks of nutritional therapy is strongly recommended before major surgery [9]. For those who do not meet the energy needs provided by a normal diet, preoperative ONS, preferably immunonutrition, is recommended for five to seven days preoperatively [9].

Table 1

Recommendations from current guidelines on the use of perioperative immunonutrition

Guidelines	Recommendations
ESPEN guideline: clinical nutrition in surgery [9]	- Peri- or at least postoperative administration of a specific formula enriched with immunonutrients (arginine, ω-3-fatty acids, ribonucleotides) should be given to malnourished patients undergoing major cancer surgery. There is currently no clear evidence for the use of these formulae enriched with immunonutrients vs. standard ONS exclusively in the preoperative period - Patients with severe nutritional risk shall receive nutritional therapy prior to major surgery even if operations including those for cancer must be delayed. A period of 7–14 days may be appropriate - When patients do not meet their energy needs from normal food, they should be recommended ONS unrelated to their nutritional status during the preoperative period - Preoperatively, ONS shall be given to all malnourished cancer and high-risk patients undergoing major abdominal surgery. A special group of high-risk patients are elderly people with sarcopenia - Immune modulating ONS including arginine, ω-3 fatty acids, and nucleotides can be preferred and administered for 5–7 days preoperatively - Preoperative enteral nutrition/ONS should preferably be administered prior to hospital admission to avoid unnecessary hospitalization and to lower the risk of nosocomial infections
Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: SCCM and ASPEN [20]	- We suggest that immune-modulating enteral formulations (arginine with other agents, including EPA, DHA, glutamine, and nucleic acid) not be used routinely in the MICU. Consideration for these formulations should be reserved for patients with traumatic brain injury and perioperative patients in the SICU - We suggest that immune-modulating formulations containing arginine and fish oil be considered in patients with severe trauma - Based on expert consensus, we suggest the use of either arginine-containing immune-modulating formulations or EPA/DHA supplements with standard enteral formula in patients with traumatic brain injury

ESPEN = European Society for Clinical Nutrition and Metabolism; ONS = oral nutritional supplements; SCCM = Society of Critical Care Medicine; ASPEN = American Society for Parenteral and Enteral Nutrition; EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; MICU = medical intensive care unit; SICU = surgical intensive care unit.

According to previous meta-analysis, preoperative immunonutrition has a significant effect on reducing the incidence of infectious complications and hospital stay durations following major abdominal surgery [13,14,21]. A recent meta-analysis reported that utilization of preoperative immunonutrition resulted in a reduction of infectious complications (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.38–0.71, P<0.0001) and decreased length of hospital stay (weighted mean difference: –1.57 days, 95% CI –2.48 to –0.66, P=0.0007) compared with the control group; however, it did not have an impact on noninfectious complications or mortality [21]. Based on these observations, the study concluded that preoperative immunonutrition should be prescribed routinely in patients undergoing surgery for gastrointestinal cancer [21]. However, the included studies had several shortcomings, such as small sample sizes, conflicts of interest, and limited generalizability [14]. Most importantly, the majority of the included studies that reported a significant association between preoperative immunonutrition and postoperative complications were industry-funded trials, raising concerns about the potential for publication bias [14]. Recently, a non-industry-funded RCT was conducted by Lee et al. [22] and compared 79 patients who received preoperative immunonutrition with 82 control patients. The results showed that the incidence rates of infectious (17.7% vs. 15.9%, P=0.751) and total (31.6% vs. 29.3%, P=0.743) complications did not differ between the two groups. Based on these results, the study concluded that routine administration of preoperative immunonutrition cannot be justified for colon cancer surgery. However, an updated meta-analysis [23], including the above RCT by Lee et al. [22], reported that immunonutrition was effective in reducing complications and hospital stay in patients undergoing surgery for gastrointestinal cancer. Recently, Slim et al. [24] conducted an umbrella review, including 20 meta-analysis, which reported that perioperative immunonutrition was beneficial in terms of reducing postoperative infectious complications (OR 0.60, 95% CI 0.54–0.65) in visceral surgery.

The most important issue with immunonutrition is the choice patients, which is controversial. According to the current ESPEN guidelines, preoperative ONS is recommended for patients who do not meet their energy needs from a normal diet regardless of nutritional status, and immunonutrition is preferred [9]. The latest ESPEN practical guidelines for clinical nutrition in surgery presented a flow scheme outlining perioperative nutrition therapy and included detailed indications for preoperative ONS [25]. The ESPEN recommends immunonutrition for patients at risk of malnutrition (nutritional risk screening score 3–5 by Nutrition Risk Screening [NRS] 2002) and general ONS for no-risk patients (NRS 2002 score<3) [25]. However, the level of evidence for these recommendations is low [9,25]. Although there is growing evidence that perioperative immunonutrition in visceral surgery is beneficial [21,23,24], it is difficult to draw solid conclusions because the designs of the previous studies are heterogenous and the characteristics of the included patients are diverse. In particular, the proportion of patients with nutritional risk varies by studies [21,23], making it difficult to determine the immunonutrition before surgery. According to a recent meta-analysis, there have been four studies that have provided relevant data on malnourished patients [23]. Although the meta-analysis has reported that preoperative immunonutrition in malnourished patients significantly reduced the occurrence of infectious complications, this finding is slightly dubious due to the inclusion of older studies, the presence of variations in the patient groups, and the timing of immunonutrition [23]. Further RCTs focusing on preoperative immunonutrition in nutritionally high-risk patients are warranted. A multicenter RCT on the impact of preoperative immunonutrition on the outcomes of colorectal cancer surgery patients at risk of malnutrition is about to start in Korea (CRIS no. KCT0008382) available from: https://cris.nih.go.kr/.

According to the findings of recent animal studies, 72 hours was necessary to observe the effects of enteral-administered immunonutrition on macrophage phospholipid profiles [21]. Since notable disparities in infectious complications were primarily observed in studies where immunonutrition was administered for 5 to 7 days prior to surgery, this is the currently recommended optimal duration of preoperative immunonutrition [9,15,25]. In previous RCTs, the typical recommendation for preoperative immunonutrition was 750–1,000 mL/d [21]. However, there are other studies using a lower dose of 400 mL/d [12,22]. The current ESPEN guidelines do not specify the optimal amount of immunonutrition, and they only recommend a duration of 5 to 7 days preoperatively [9].

Compliance with immunonutrition is essential since oral intake may be impeded by psychosocial factors, such as anxiety and depression, anorexia, or obstructive symptoms in patients with colorectal cancer [15,26]. Additionally, ensuring consistent adherence to the recommended immunonutrition intake is challenging as it is prescribed prior to hospital admission with the goal of minimizing avoidable hospital stays and preventing hospital-acquired infections [22]. According to a previous RCT, 42% of the included patients were considered preoperative ONS noncompliant [27]. Therefore, it is crucial to determine the suitable amount of immunonutrition that can be effectively incorporated alongside three meals. To enhance compliance, some authors have suggested consuming the immunonutrition in a cooled state either after or with each of the three meals [15].

There are unresolved practical inquiries regarding the implementation of preoperative immunonutrition, including the optimal timing, duration, and amount; identifying the surgical specialties that would benefit most; and evaluating the effectiveness of immunonutrition within enhanced recovery after surgery protocols [24]. Future prospective RCTs are needed to address these questions.

Preoperative immunonutrition can be a potential strategy for enhancing the outcomes of colorectal cancer surgery. Providing specific immunonutrients to patients before surgery can improve their immune function and reduce the risk of infectious complications. However, more research is needed to refine and optimize the preoperative immunonutrition protocols.

Conceptualization: SYL, HP, CHK, HRK. Writing – original draft: SYL, HP. Writing – review & editing: all authors.

The authors of this manuscript have no conflicts of interest to disclose.

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