Immunonutrition of perioperative therapy for colorectal cancer

Abstract

Immunonutrition, a modified nutritional formula that involves the addition of glutamine, arginine, omega-3 fatty acids, nucleotides, and other potential compounds to the diet, has proven its potential for use in immunomodulation and protein metabolism improvement. Its clinical benefits include shortening hospital stays and lowering surgical infectious complications in upper gastrointestinal surgery. However, the use of perioperative immunonutrition is rare among colorectal cancer patients undergoing surgical intervention. Colorectal cancer is one of the most common cancers around the world, but its malnutrition rate is not high in comparison with other cancers (eg, gastric cancer or esophageal cancer). Furthermore, the surgical modality for the majority of colorectal cancer patients involves minimal invasive surgery (MIS), which enhances recovery speed. It is an interesting clinical question whether or not perioperative immunonutrition supplementation for colorectal cancer patients undergoing MIS causes extraclinical impacts. The immunomodulation effect of CD4⁺ T cells has been proven in colorectal patients undergoing elective surgery. In recent years, there have been several prospective randomized studies elucidating the clinical effects of immunonutrition on colorectal cancer patients undergoing surgery in Western countries. These studies have generally found that perioperative immunonutrition was associated with a lower rate of surgical infectious complications even in normo-nourished patients undergoing MIS. The use of perioperative immunonutrition provides clinical benefits according to high-quality studies. However, most results come from Western countries, and its effect needs to be validated in Asian countries.

1. Introduction

Colorectal cancer is the third most common type of cancer and the second most common etiology of cancer-related deaths worldwide.^[1] Although genetic abnormalities play an important role in the occurrence of colorectal cancer, several elements of a so-called Western lifestyle are associated with its development, such as a lack of regular physical activity, obesity, a diet low in fruit/vegetables, and high-fat and low-fiber diet.^[2] Surgery in conjunction with chemotherapy is usually prescribed as a curative treatment. With the advancement of instruments and the application of minimal invasive surgery, the outcomes have improved significantly in the modern era, leading to lower rates of surgical complications and better patient quality of life (less wound pain, shorter hospital stay, and earlier recovery of bowel function).^[3]

Malnutrition has been considered a risk factor for surgical complications among patients with major trauma,^[4] breast cancer,^[5] hepatocellular carcinoma,^[6] and pancreatic cancer.^[7] Malnutrition is less common in colorectal cancer patients than in gastric or periampullary cancer patients,^[8] whereas overweight is more common, which may contribute to the occurrence of medical complications due to the associated cardiovascular dysfunction and poor physical reserve capacity. Further, colorectal patients who are overweight or obese carry 20%–50% higher odds of developing surgical site infection (SSI) after colectomy compared with normal-weight patients.^[9] The reasons why colectomy is associated with increased rates of SSI include contamination and immunosuppression due to surgical stress or cancer cachexia.^[10] As the occurrence of SSI causes both prolonged hospital stays and increased medical costs,^[11] an effective strategy to prevent SSI can reduce healthcare costs by as much as US $27,000 per patient.^[12]

Immunonutrition is a modified nutritional formula that involves the addition of glutamine, arginine, omega-3 fatty acids, nucleotides, and other potential compounds to the diet that has become popular since the 1990s.^[13] The guidelines from both the American Society for Parenteral and Enteral Nutrition^[14] and the European Society for Clinical Nutrition and Metabolism^[15] recommend the use of immunonutrition for cancer patients undergoing major surgery. Notably, the evidence supporting the guidelines mostly comes from randomized clinical trials conducted with upper gastrointestinal tract cancer patients. According to these studies, the perioperative use of immunonutrition helps decrease infectious complications, especially in the SSI.^[16] At present, few studies have elucidated the benefits of immunonutrition for colorectal cancer patients undergoing colectomy. The main aim of this mini-review is to investigate whether the current academic evidence supports the use of perioperative immunonutrition to improve surgical outcomes and enhance recovery for this population.

2. Trends of Associated Published Articles

Studies focused on the administration of perioperative immunonutrition in colorectal cancer patients have become more and more common over the past 20 years. Using the PubMed database, the search terms (“colorectal cancer” OR “colorectal carcinoma”) AND (“immunonutrition”) AND (“preoperative” OR “perioperative” OR “postoperative”) were used to conduct a thorough review of the relevant studies. The search was conducted on August 10, 2022. Figure 1 illustrates the trends of the published articles. As we know, immunonutrition may have the potential to modulate immunologic and inflammatory responses, which may augment host defense mechanisms and improve surgical outcomes. From the clinical experiences of cancer patients other than colorectal cancer patients, the clinical studies emphasize some of the study aims, including change in the immune system, timing of the supplementation of immunonutrition, and surgical outcomes. The next paragraph presents the evolution of high-quality research on the application of perioperative immunonutrition in colorectal cancer patients undergoing colectomy over time. To ensure sufficient evidence quality, only prospective studies (randomized controlled trials and prospective cohort studies) are described in the following section.

Figure 1: Trend of published articles regarding application of perioperative immunonutrition in general (blue) and in colorectal cancer patients (red) (2022: only enrolled January to September). The search terms (“immunonutrition”) AND (“preoperative” OR “perioperative” OR “postoperative”) AND (“colorectal cancer” OR “colorectal carcinoma”) AND (“immunonutrition”) AND (“preoperative” OR “perioperative” OR “postoperative”) were used, respectively.

3. Review of High-Quality Articles

One randomized double-blind clinical trial (RCT) used four groups to investigate not only the impact of immunonutrition on the surgical outcomes between preoperative use and perioperative use but also the differences between immunonutrition and conventional treatment (no supplementation).^[17] It concluded that preoperative immunonutrition with a formula enriched with oral arginine and n-3 fatty acids decreases the infection rate and that prolonged immunonutrition supplementation during the postoperative period has no additional benefit.^[17] The change in immune response after surgery caused Th-2 dominance, which is associated with early cancer recurrence and infectious complications.^[18] Matsuda et al.^[19] conducted a prospective observation study investigating whether 5-day preoperative immunonutrition supplementation (arginine, ω-3 fatty acids, and ribonucleic acid) corrected the imbalance of type 1/2 CD4⁺ T cells (Th1/Th2), which showed that preoperative immunonutrition was beneficial for correcting the impaired Th1/Th2 balance on both postoperative day (POD) 0 and at the end of the postoperative period (POD 14). With the popularity of minimally invasive surgery for colectomy, we may wonder whether immunonutrition still improves surgical outcomes for this population. Finco et al.^[20] conducted an RCT to answer this question, which proved that perioperative immunonutrition was useful for enhancing the abilities of the perioperative immunologic cells by improving the cleansing and relaxation of the intestines. Further, another RCT found that perioperative supplementation with immunonutrients lowered surgical wound infection rates in colorectal cancer patients undergoing colorectal surgery.^[21] Furthermore, a multicenter RCT found that perioperative supplementation with immunonutrition had the benefit of reducing infectious complications, even with the implementation of enhanced recovery after surgery protocols.^[22] Finally, the role of arginine in enhancing natural killer cell function in colorectal surgery has been showcased in a single-center translational RCT study.^[23]Table 1 summarizes the study designs in these articles.

Table 1 - Effect of Perioperative Immunonutrition Supplementation on Colorectal Cancer Patients Undergoing Colectomy

Authors	Braga et al., 2002[17]	Matsuda et al., 2006[19]	Finco et al., 2007[20]	Moya et al., 2016[21]	Moya et al., 2016[22]	Angka et al., 2022[23]
Study design	Randomized controlled trial	Prospective observation study	Randomized controlled trial	Randomized controlled trial	Randomized controlled trial	Randomized controlled trial
Study place	Italy	Japan	Italy	Spain	Spain	Canada
No. study groups	4	2	2	2	2	2
Sample size	200	36	28	128	264	24
Formula compounds	Arginine, 12.5 g/L; omega-3 fatty acids, 3.3 g/L	Arginine, omega-3 fatty acids, and RNA (IMPACT)	Arginine, omega-3 fatty acids, and RNA (IMPACT)	ATEMPERO	ATEMPERO	Arginine, 4.2 g/85 g (EMN, Enhanced Medical Nutrition)
Timing and duration
Preoperative	5 d; 1 L/d	5 d; 750 mL/d	6 d; 750 mL/d	7 d; 800 mL/d	7 d; 800 mL/d	5 d; 12.6 g arginine per day
Postoperative	5–7 d	No use	No use	5 d; 800 mL/d	5 d; 800 mL/d	5 d; 12.6 g arginine per day
End points	Infectious complications	Th1/Th2 balance	No. immune cells	Infectious complications	Infectious complications	NK cell cytotoxicity
Suggestion	Recommend	Recommend	Recommend	Recommend	Recommend	Recommend

4. Considerations for Immunonutrition

There are a few special considerations that we must bear in mind before recommending that patients undergo immunonutrition supplementation. First, immunonutrition with arginine is contraindicated in patients with shock or concomitant hemodynamic instability because arginine causes vasodilatation.^[24] Second, glutamine supplementation should be avoided in patients with moderate to severe renal or hepatic insufficiency, who may have poor prognoses.^[25] Third, the administration of immunonutrition during the postoperative period may be specifically selected for malnourished subjects.^[24] Fourth, there are many commercial formulae for immunonutrition, but most lack academic evidence for their efficacy. As medical professionals, we should suggest a formula to patients with sufficient high-quality evidence for its efficacy. Fifth, one main criticism goes that few studies demonstrate clinical benefits other than preventing surgical infectious complications. There are some explanations for this negative result, including that different study populations have different percentages of malnourished patients, different formulae, and different definitions of complications.^[26] Further prospective studies should be conducted to provide new information for the surgical community.

5. Conclusions

This mini-review demonstrates the current academic evidence elucidating the impact of perioperative immunonutrition supplementation on colorectal cancer patients receiving colectomy. Preoperative use is recognized as the most efficient strategy to improve surgical outcomes, especially for the prevention of surgical infectious complications. Prolonged use during the postoperative period should be considered if patients are malnourished. However, more high-quality studies should be conducted in the future so that immunonutrition can be upgraded to a more imperative role: pharmaconutrition.