Pre-operative immunomodulatory nutrition and post-operative outcomes of surgical treatment of gastrointestinal surgery: a systematic review

INTRODUCTION

Malnutrition is a well-evident phenomenon in cancer patients, specifically gastrointestinal cancers.¹ It is also associated with an undeniable high risk of morbidity and mortality. The overall incidence of malnutrition in cancer patients is 40 to 80%, 20% of them die due to malnutrition-related causes.^2-4

The cause of malnutrition in cancer patients is multifactorial. Treatment modality largely influences the nutritional status of the patients. The prevalence of malnutrition differs among different groups of patients of the same type of cancer-based on their treatment modality. This is mainly due to side effects related to the treatment including nausea, vomiting, diarrhea, stress esophagitis, stress gastritis, and dysphagia.^2-4

The type of cancer is also a determining cause of malnutrition. A study found that the highest prevalence of malnutrition was in pancreatic cancer (85%) followed by stomach (65-85%).² The high prevalence in gastrointestinal tumors is also caused by the tumor itself rather than the other factors; the gastrointestinal tumors interfere with the eating process.^1,2

Malnutrition in the gastrointestinal tumor was associated with decreased quality of life, increased resistance to treatment, increased risk of toxicity from chemotherapy, high morbidity, and mortality rates.^3,5-7 Malnutrition also affects immunity against tumors causing a decreased immune response to mitogens, dysfunction of phagocytes, cell-mediated immunity, decreased cytotoxic T-cell activity, and impaired inflammatory response.⁸

Moreover, malnutrition was associated with decreased wound healing and increased postoperative complications. It is mainly due to an increased catabolic process after surgical treatment. That was evident in many studies that found that malnutrition was associated with worse outcomes after surgical treatment.⁹ That is why the concept of immunomodulatory nutrition has gained worldwide recognition recently.

Immunomodulatory nutrition is specific nutrition containing nutrition components that increase the immunity of cancer patients.^8,10 It acts through modulation of immune cells and inflammatory response increasing the healing power after surgery.^4,7,8,10 Despite no specific determination of the ingredients of the immunomodulatory nutritional diet, it is usually composed of omega-3, arginine, glutamine, and nucleotides.¹⁰

Other constituents that may be added or not are vitamin C, E, selenium, or beta carotene.¹⁰ The choice of Arginine among other amino acids is mainly due to its effect on wound healing and growth. The nucleotides are essential as usual diet would be deficient in essential nucleotide components for the salvage pathway of nucleotide synthesis. This addition enhanced the production of IL-2 and increased T-cell response.^3,8,10 Based on animal studies, the effect of immunomodulatory nutrition is only evident when it is given three days before the surgery.¹¹ Furthermore, to obtain the full effect, it should be administered up to five days post-operative.¹¹

The effect of immunomodulatory nutrition on the postoperative outcome is still under debate. More research is needed to understand its effect and whether it should be recommended or not for preoperative preparation of gastrointestinal tumors surgery.

METHODS

Database search

A comprehensive search approach was used to identify randomized controlled trials from five databases PubMed, Google Scholar, SCOPUS, ISI web of science, and Cochrane Collaboration. The keywords used were (‘pre-operative’ or ‘pre-op’ or ‘peri-operative’) and (‘immunomodulatory nutrition’ or ‘pharmacononutrition’ or ‘immune nutrients’ or ‘immune modulating nutrients’ or ‘dietary supplements’ or ‘oral supplement’ or ‘enteral nutrition’ or ‘nutritional support’ or ‘arginine’ or ‘omega-3 fatty acid’ or ‘glutamine’ or ‘enteric feeding’ or ‘diet therapy’ or ‘nutrition feed’ or ‘nutrition disorders’) and (‘gastrointestinal surgery’ or ‘surgeries’ or ‘post-operative’). We restricted our search to human studies.

Inclusion and exclusion criteria for screening

Specific inclusion criteria were used to identify high quality and studies that fulfill the goals of this study. Inclusion criteria were (i) randomized controlled studies that assess the efficacy of pre-operative immune modulating nutrition on mortality rates of patients; (ii) all enrolled patients should be aged 18 years or more undergoing gastrointestinal surgery.

We excluded any studies that assessed the efficacy of pre-operative immune modulating nutrition against diet with supplements. The pre-operative immune modulating nutrition includes combinations of arginine, glutamine, ω-3 fatty acids, and nucleotides provided as part of oral supplementation or enteral nutrition and should be given pre-operatively at least three days before surgery to be fully effective.

Books, review articles, letters to the editor, editorial reports, case reports, and conference abstracts and duplicates were excluded.

Screening for studies

The retrieved studies from each database were screened based on inclusion and exclusion criteria. First, title/abstract screening was conducted by three independent reviewers. The included studies were then screened thoroughly to make sure it fulfills the target of this review. Each study was reviewed thoroughly to extract and build a qualitative review.

Quality assessment of the included papers

The quality of included studies was evaluated by three reviewers using ‘The Cochrane Collaboration's tool for assessing the risk of bias’.¹² It has seven specific domains including sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other sources of bias.²⁷ The answers were categorized as ‘low risk,’ ‘high risk,’ or ‘unclear risk’ of bias.

RESULTS

Search results and risk of bias

The search performed on five databases yielded 2582 studies, of which only 23 fulfilled the inclusion criteria and were used for qualitative evidence synthesis (Figure 1).

Nine studies have a low risk of bias, six studies had a high risk of bias, and the remaining studies had high risk in some domains Figure 2. Most studies had high risk in the allocation domains Figure 2. Only three studies had an unknown bias in the first domain.^13-15

Patient characteristics

Two studies investigated the effect of immunomodulatory diet in esophageal carcinoma, three studies for gastric cancer, five studies for colorectal carcinoma, two studies for pancreatic cancer and liver cancer.^{13-18,20-24,26} The remaining studies had non-specific gastrointestinal tumors (Table 1). The patients' age ranged from 55 to 65 years old. There were only eleven studies that assessed the malnutrition status of the patients preoperative. All studies administered the treatment seven days before the surgery except thirteen studies.^{13-15,19,22-24,26-31}

Efficacy of pre-operative immune-modulating nutrition in patients undergoing surgery for gastrointestinal cancer

Immune markers

Many studies measured the efficacy of immunomodulatory nutrition on the immune status of the patients. There were no unified immune markers, and each study used specific markers. Aida et al measured the immune response by measuring the rate of Th1/Th2 differentiation.¹⁴ It was measured through the measurement of the expression level of the mRNA of T-bet. T-bet is a T-box protein expressed in T cells; it has a modulatory effect for enhancing the development of T-cells.³² In addition, it modulates the action of IL-2 and Th-2 cytokines.³²

In this study, they found that T-bet expression was increased in the immunomodulatory groups indicating enhancement of the immune response.¹⁴ Moreover, they measured the PGE2, which was significantly lower in the treatment group indicating a less inflammatory response. PGE2 is one of the proinflammatory cytokines and has an important role in T helper cell differentiation. It is synthesized from arachidonic acid, which is found to be inhibited by the action of the immunomodulatory diet.³³

Another study found that in contrast to the control group, the treatment group has significantly higher polymorphonuclear cells phagocytic capability indicating higher innate immunity. Furthermore, IL-6 was significantly less in the treatment group and returned to normal earlier than the control group. They also measured the delated hyperimmune response and found it less in the treatment group.^24,34

Ding et al measured the immune response in the form of the level of IgG, IgA, CD4+T cell/ CD8+T cell, which is significantly increased in the treatment group. They also assessed the IL-6 level in the treatment group and was significantly decreased; it also rapidly decreased back to normal than the control group.¹⁸ Gade et al discovered significantly less TNF-alpha postoperative indicating the immunomodulatory effect of the diet. In the same context, Huang et al found significantly higher immune markers e.g. lymphocytes, CD3, CD4, CD8, and natural killer cells in the treatment group.³⁵

Nakamura et al measured the level of polymorphonuclear leukocyte-elastase and interleukin-8 and found a significant decrease in the treatment group. They also found a decrease in inflammatory markers and downregulation of cytokine receptors in the treatment group.³¹ These results are consistent with Okamoto et al and Migaki et al who also proved that there was decreased inflammatory markers in treatment group.^20,26

On the contrary, Russel et al found no significant change of the white cell count and total lymphocytes or markers of inflammation like C-reactive protein, tumor necrosis factor-α, IL-8, and IL-10.¹³ Other studies measured CRP as an indication of the inflammatory status of the patients. Fujitani et al found no significant difference in CRP.

Meanwhile, Gade et al found that there was a significant decrease of endotoxin and CRP in the treatment group implying better immune response. Xu et al also proved that cellular immunity was activated in the immunomodulatory nutrition group as evidenced by an increased CD4/CD8 ratio in the treatment group.

In addition, they found decreased complement 3, complement 4 in the treatment group indicating decreased inflammatory conditions.³⁶ Post-operative immunoglobulin G (IgG) was significantly higher in the treatment group.

Infectious complications

Infectious complications are very common after gastrointestinal surgery. Four studies found there was a decrease in the number of wound abscess, peritoneal abscess, sepsis, enteritis, and pneumonia in the treatment group.

However, it was non-significant.^14,19,22,25 Notwithstanding, subgroup analysis in Campillo et al found that patients with rectal cancer have a significantly lesser infectious rate in the immunomodulatory nutritional diet. Two studies showed that both treatment and control groups had the same rate of infectious complications.^17,27 In contrast to the previous finding, Horie et al and Moriya et al implied that it only significantly decreased surgical site infections, specifically superficial incisional surgical site infections.^15,23 In addition, four studies found that there was a significant decrease in infectious complications, including sepsis, abdominal abscess, and enteritis. It also decreased the dosage and duration of antibiotics.^16,24,30,36 Okamoto et al proved also that there is not only decreased the risk of infectious diseases, but also the duration of the infections.²⁰

Non-infectious complications

Non-infectious complications were assessed in many studies. The non-infectious complications comprise a wide range of diseases. It was defined clearly in Xu et al, and we explained it in Table 2. Other reported non-infectious complications included pancreatic fistula, delayed gastric emptying, chylous ascites, intra-abdominal bleeding, sterile pancreatic fistula, presacral sterile hematoma, heart failure, myocardial infarction, pulmonary embolism, pleural effusion, transient renal failure, anastomotic rectal bleeding, delayed gastric emptying, anastomotic insufficiency, and aspiration/ARDS.

Most studies revealed that these complications were not decreased in the treatment group and were approximately the same as the standard care group. On the contrary, Braga et al reported a significantly less anastomotic leak in the treatment group.^24,34 In addition, Gade et al found that there was significant weight gain in the treatment group.²⁵ Another study found that there was a higher rate of diarrhea in the control group.³⁵

However, three studies found that post-operative non-infectious complications decreased in the treatment group more than the control group, yet non-significant decrease.^17,23,26 Xu et al found that there was a significantly higher weight loss in the control group than the treatment group. Furthermore, the incidence of stoma fistula was significantly decreased in the treatment group.³⁶

Length of stay

Most studies did not find any significant difference between the immunomodulatory nutrition group and the control group, which was explained by the non-significant difference of infectious and non-infectious complications between the two groups.

However, five studies found that the group that received a preoperative immunomodulatory diet had a significantly less post-operative length of stay.^{22,24,25,30,34} These five studies showed significantly better outcomes in the treatment groups, which may explain their significant beneficial effect of the immunomodulatory diet on the length of stay. Notwithstanding, more investigations are needed to understand the difference in these results.

Biochemical markers

Some studies measured different biochemical markers for more accurate identification of the efficacy of the immunomodulatory diet. Aida et al. measured the serum eicosapentaenoic acid and eicosapentaenoic acid/arachidonic acid ratios and found it was significantly higher in the treatment group.¹⁴ This corresponds to findings by Russel et al, who found the plasma ratio of (eicosapentaenoic acid plus docosahexaenoic acid) to arachidonic acid was higher in the immunomodulatory group. Ding et al found a significant increase in pre-albumin and albumin in the treatment group compared to the control group indicating better nutritional value status.¹⁸ However, they did not find a significant difference between the treatment and control group regarding blood sugar, hepatic and renal functions, and electrolytes.

Similarly, Okamoto et al measured the serum concentrations of prealbumin, and transferrin, albumin, choline-esterase, and total cholesterol did not show any significant differences.²⁰ On the contrary, Huang et al found that liver enzymes returned to normal rapidly compared to control.³⁵ Another biochemical process that was measured was protein turn-over. Two studies measured retinol-binding protein as an example of rapid protein turnover.^16,31 It was higher in the treatment group indicating rapid protein turnover. This phenomenon was not explained and why it happened in treatment groups. Seven days after the surgery, Xu et al found that there was increased prealbumin and transferrin in the treatment group.³⁶

Gastrointestinal microperfusion

Braga et al measured intra-operative colonic microperfusion and found that treatment groups who received pre-operative or peri-operative immunomodulatory diet had significantly better microperfusion as also evidenced by higher O₂ tension. They considered this as a good sign for anastomotic leak healing.²⁴

Mortality

All studies assessed the death rate in the treatment group compared to the control group. There was no significant difference between the treatment and control groups. There was also no significant difference between peri-operative and pre-operative treatment.

CONCLUSION

Based on the systematic review of the randomized-controlled trials investigating the efficacy of immunomodulatory nutrition on the outcome of the surgery, immunomodulatory nutrition had enhanced the immune status of the patients and enhanced renal and liver functions. Furthermore, they decreased weight loss and inflammatory biomarkers. However, its effect on the infectious and non-infectious complications are still under debate. The length of postoperative hospitalization was decreased in some cases, but not in all cases. For mortality, immunomodulatory nutrition showed no significant difference from the control group. Despite its failure to prove any favorable outcome on the survival rate, it must be taken seriously for its immune-stimulant effect.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Meyenfeldt M. Cancer-associated malnutrition: an introduction. Eur J Oncol Nurs. 2005;9(2):35-8.
2. 2. Borum P. Disease-Related Malnutrition: An Evidence-Based Approach To Treatment. The American J Clinic Nut. 2004;79:1128-9.
3. 3. Zhang L, Lu Y, Fang Y. Nutritional status and related factors of patients with advanced gastrointestinal cancer. Br J Nutr. 2014;111(7):1239-44.
4. 4. Lis CG, Gupta D, Lammersfeld CA, Markman M, Vashi PG. Role of nutritional status in predicting quality of life outcomes in cancer--a systematic review of the epidemiological literature. Nutr J. 2012;11:27.
5. 5. Farreras N, Artigas V, Cardona D, Rius X, Trias M, González JA. Effect of early postoperative enteral immunonutrition on wound healing in patients undergoing surgery for gastric cancer. Clin Nutr. 2005;24(1):55-65.
6. 6. Zheng C, Chen T, Wang Y, Gao Y, Kong Y, Liu Z, Deng X. A randomised trial of probiotics to reduce severity of physiological and microbial disorders induced by partial gastrectomy for patients with gastric cancer. J Cancer. 2019;10(3):568-76.
7. 7. Chen DW, Wei FZ, Zhang YC, Ou JM, Xu J. Role of enteral immunonutrition in patients with gastric carcinoma undergoing major surgery. Asian J Surg. 2005;28(2):121-4.
8. 8. Sax HC. Immunonutrition and upper gastrointestinal surgery: what really matters. Nutr Clin Pract. 2005;20(5):540-3.
9. 9. Farreras N, Artigas V, Cardona D, Rius X, Trias M, González JA. Effect of early postoperative enteral immunonutrition on wound healing in patients undergoing surgery for gastric cancer. Clin Nutr. 2005;24(1):55-65.
10. 10. Calder PC. Immunonutrition. May have beneficial effects in surgical patients. British Med J. 2003;327.
11. 11. Palombo JD, Michele SJ, Lydon EE, Gregory TJ, Banks PL, Forse RA, et al. Rapid modulation of lung and liver macrophage phospholipid fatty acids in endotoxemic rats by continuous enteral feeding with n-3 and gamma-linolenic fatty acids. Am J Clin Nutr. 1996;63(2):208-19.
12. 12. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:5928.
13. 13. Russell K, Zhang HG, Gillanders LK, Bartlett AS, Fisk HL, Calder PC, et al. Preoperative immunonutrition in patients undergoing liver resection: A prospective randomized trial. World J Hepatol. 2019;11(3):305-17.
14. 14. Aida T, Furukawa K, Suzuki D, Shimizu H, Yoshidome H, et al. Preoperative immunonutrition decreases postoperative complications by modulating prostaglandin E2 production and T-cell differentiation in patients undergoing pancreatoduodenectomy. Surgery. 2014;155(1):124-33.
15. 15. Horie H, Okada M, Kojima M, Nagai H. Favorable effects of preoperative enteral immunonutrition on a surgical site infection in patients with colorectal cancer without malnutrition. Surg Today. 2006;36(12):1063-8.
16. 16. Kanekiyo S, Takeda S, Iida M, Nishiyama M, Kitahara M, Shindo Y, et al. Efficacy of perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy. Nutrition. 2019;59:96-102.
17. 17. Mudge LA, Watson DI, Smithers BM, Isenring EA, Smith L, Jamieson GG, et al. Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer. Br J Surg. 2018;105(10):1262-72.
18. 18. Ding D, Feng Y, Song B, Gao S, Zhao J. Effects of preoperative and postoperative enteral nutrition on postoperative nutritional status and immune function of gastric cancer patients. Turk J Gastroenterol. 2015;26(2):181-5.
19. 19. Fujitani K, Tsujinaka T, Fujita J, Miyashiro I, Imamura H, Kimura Y, et al. Prospective randomized trial of preoperative enteral immunonutrition followed by elective total gastrectomy for gastric cancer. Br J Surg. 2012;99(5):621-9.
20. 20. Okamoto Y, Okano K, Izuishi K, Usuki H, Wakabayashi H, Suzuki Y. Attenuation of the systemic inflammatory response and infectious complications after gastrectomy with preoperative oral arginine and omega-3 fatty acids supplemented immunonutrition. World J Surg. 2009;33(9):1815-21.
21. 21. Sørensen LS, Rasmussen SL, Calder PC, Yilmaz MN, Schmidt EB, Ussing O. Long-term outcomes after perioperative treatment with omega-3 fatty acid supplements in colorectal cancer. BJS Open. 2020;4(4):678-84.
22. 22. Campillo MDC, Martín FJ, Amo SM, Casanova RD. A randomized controlled trial of preoperative oral immunonutrition in patients undergoing surgery for colorectal cancer: hospital stay and health care costs. Cir Cir. 2017;85(5):393-400.
23. 23. Moriya T, Fukatsu K, Okamoto K. LB022-SUN: Effects of Preoperative use of an Immune-Enhancing Diet on Postoperative Complications and Long-Term Outcome: A Randomized Clinical Trial in Colorectal Cancer Surgery in Japanese Patients. Clin Nutrit. 2014;33:247.
24. 24. Braga M, Gianotti L, Vignali A, Carlo VD. Preoperative oral arginine and n-3 fatty acid supplementation improves the immunometabolic host response and outcome after colorectal resection for cancer. Surgery. 2002;132(5):805-14.
25. 25. Gade J, Levring T, Hillingsø J, Hansen CP, Andersen JR. The Effect of Preoperative Oral Immunonutrition on Complications and Length of Hospital Stay After Elective Surgery for Pancreatic Cancer--A Randomized Controlled Trial. Nutr Cancer. 2016;68(2):225-33.
26. 26. Mikagi K, Kawahara R, Kinoshita H, Aoyagi S. Effect of preoperative immunonutrition in patients undergoing hepatectomy; a randomized controlled trial. Kurume Med J. 2011;58(1):1-8.
27. 27. Pabst U, Lange J, Maurer C, Bucher C, Schreiber V, Schlumpf R, et al. Short-term preoperative supplementation of an immunoenriched diet does not improve clinical outcome in well-nourished patients undergoing abdominal cancer surgery. Nutrition. 2013;29(5):724-9.
28. 28. Klek S, Szybinski P, Szczepanek K. Perioperative immunonutrition in surgical cancer patients: a summary of a decade of research. World J Surg. 2014;38(4):803-12.
29. 29. Giger U, Büchler M, Farhadi J, Berger D, Hüsler J, Schneider H, et al. Preoperative immunonutrition suppresses perioperative inflammatory response in patients with major abdominal surgery-a randomized controlled pilot study. Ann Surg Oncol. 2007;14(10):2798-806.
30. 30. Gianotti L, Braga M, Nespoli L, Radaelli G, Beneduce A, Carlo V. A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gastrointestinal cancer. Gastroenterology. 2002;122(7):1763-70.
31. 31. Nakamura K, Kariyazono H, Komokata T, Hamada N, Sakata R, Yamada K. Influence of preoperative administration of omega-3 fatty acid-enriched supplement on inflammatory and immune responses in patients undergoing major surgery for cancer. Nutrition. 2005;21(6):639-49.
32. 32. Oh S, Hwang ES. The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. J Immunol Res. 2014;2014:589672.
33. 33. Maseda D, Johnson EM, Kirk L, Aronoff DM, Crofford LJ. T cell function during intestinal immune responses. J Immunol. 2017;198(1):200-15.
34. 34. Braga M, Gianotti L, Nespoli L, Radaelli G, Carlo V. Nutritional approach in malnourished surgical patients: a prospective randomized study. Arch Surg. 2002;137(2):174-80.
35. 35. Huang D, Sun Z, Huang J, Shen Z. Early enteral nutrition in combination with parenteral nutrition in elderly patients after surgery due to gastrointestinal cancer. Int J Clin Exp Med. 2015;8(8):13937-45.
36. 36. Xu J, Zhong Y, Jing D, Wu Z. Preoperative enteral immunonutrition improves postoperative outcome in patients with gastrointestinal cancer. World J Surg. 2006;30(7):1284-9.