Improved Gastrectomy Outcomes With Omega-3s

A controlled trial involving gastric cancer patients

By Jenna Bailey, ND, FABNO

REFERENCE

Yang J, Zhang X, Li K, et al. Effects of EN combined with PN enriched with n-3 polyunsaturated fatty acids on immune related indicators and early rehabilitation of patients with gastric cancer: a randomized controlled trial. Clin Nutr. 2022;41(6):1163-1170.

STUDY OBJECTIVE

To evaluate the effect of adding omega-3 polyunsaturated fatty acids (PUFA) to usual postsurgical nutritional care in individuals undergoing gastrectomy for gastric cancer

KEY TAKEAWAY

The addition of n-3 polyunsaturated fats to parenteral nutrition in combination with enteral nutrition following gastrectomy improves immune parameters, inflammatory markers, and nutritional parameters and reduces postoperative complications.

DESIGN

Prospective, randomized, controlled trial with patients undergoing elective radical gastrectomy at the West China Hospital of Sichuan University

PARTICIPANTS

Investigators recruited 123 patients with biopsy-confirmed gastric adenocarcinoma, aged 18 to 80 years with a mean age of 57.8 ± 10.5 years. A total of 120 patients completed the study: 60 in the control group and 60 in the study group (male=82; female=38). There were no significant differences between the study and control groups in regard to gender; age; weight; body mass index (BMI); tumor location; tumor, node, metastasis (TNM) stage; or surgical parameters. There were also no significant differences in baseline parameters (immune function, inflammatory markers, and nutrition markers).

INTERVENTION

The intervention period consisted of the 5 days immediately postoperative. Both the study group and the control group received the same base of enteral nutrition (EN) plus parenteral nutrition (PN). The study group received n-3 polyunsaturated fatty acids in their PN. EN was 500 mL of 5% glucose and sodium chloride through a nasojejunal tube starting day 1. Day 2 EN was an enteral Specifically for gastric cancer, we have seen complication rates decrease from around 28% to 10% with these “ fast-track procedures.”

nutrition emulsion (Huarui). Researchers calculated energy requirements based on ideal weight x 30 kcal/kg/d. PN was given via peripheral or central venous routes starting day 1 postop. Both groups received Kaviven™ PI (Huarui). The study group additionally received 0.2 g/kg/d of 10% fish oil fat emulsion (Omegaven®, Huarui), which contained 1.25 to 2.82 g eicosapentaenoic acid (EPA) and 1.44 to 3.09 g docosahexaenoic acid (DHA; 10 g/100 mL).

STUDY PARAMETERS ASSESSED

Investigators assessed the following through fasting blood collected the day before surgery and again on postoperative days 1, 3, and 5: • Immune parameters: lymphocyte count (LYM), cluster of differentiation 3+ (CD3+), CD4+, CD8+, and CD4+/

CD8+ • Inflammatory indicators: white blood cells (WBC),

C-reactive protein (CRP), interleukin 6 (Il-6), tumor necrosis factor alpha (TNF-α) • Nutrition parameters: hemoglobin (Hb), total protein (TP), albumin (Alb), prealbumin (PAB), and transferrin (TAF) • Incidence of postoperative complication Secondary endpoints included: • Time to first aerofluxus (flatus) and defecation • Postoperative length of stay • Rate of unplanned 30-day readmission • Unplanned reoperation after surgery

PRIMARY OUTCOME

To assess the effect of n-3 PUFA–enriched PN on immune- and inflammatory-related indices compared to PUFA PN without n-3.

KEY FINDINGS

Findings revealed statistically significant differences in several immune parameters (LYM, CD3+, CD4+, and CD4+/CD8+; no difference in CD8+ between groups), as well as improvement in inflammatory indicators (CRP, IL-6, and TNF-α; CRP in study group lower than in control group at days 3 and 5 postop; TNF-α in study group lower than in control group at day 5 postop), and nutrition parameters (total protein P level in study group higher than in control group at day 5 postop; Alb and PAB in study group higher than in control group at days 3 and 5 postop). Additionally, there were fewer postoperative complications in the study group (4 cases) compared to usual care (12 cases; P=0.032). For secondary outcomes, there was a statistically significant decrease in time to flatus and defecation for the study group (P=0.044 and P=0.002, respectively). Researchers saw no differences in postoperative length of stay or the rate of unplanned 30-day readmission or reoperation between the 2 groups.

TRANSPARENCY

No conflicts of interest.

PRACTICE IMPLICATIONS & LIMITATIONS

In 2020, gastric cancer was the 5th most common cancer and the 4th leading cause of death worldwide (accountable for about 7.7% cancer deaths1), which amounts to about 1.1 million new cases and 770,000 deaths attributable to the disease. It is predicted that by 2040 there will be about 1.8 million new cases and 1.3 million deaths. Unfortunately, survival rates remain low as the disease is often found in an advanced stage. We are now also seeing, similarly to other tumor types, a rise in cases among younger individuals (aged less than 50 years). There are many modifiable risk factors including smoking, alcohol consumption, intake of salt-preserved foods, obesity, and reflux.2

Although there have been advances in treatment, surgery remains the only treatment offered with curative intent. However, 5-year survival for stage I resected gastric cancer is only 70%, and for stage IIB and beyond, 5-year survival is less than 30%.3 Risk for postoperative complications following total gastrectomy has been found to be as high as 36% and mortality rate as high as 4.7% in the 30 days following surgery.4 So how can we reduce these complications and improve morbidity and mortality rates for these individuals, especially given that surgery and anesthesia can also cause immunosuppression and increased inflammation?5

Researchers have found several relatively simple and clinically applicable tools that can help predict complications in individuals undergoing gastrectomy.

Prior to surgery, a low prognostic nutritional index (PNI) is associated with a lower 5-year overall survival. The PNI is equal to 10 x serum albumin value (g/dL) + 0.005 x total lymphocyte count in the peripheral blood (per mm3). PNI values less than 46 were associated with a 21.1% 5-year overall survival, and PNI values greater than 46 were associated with a 54.15% 5-year overall survival.6 Screening individuals before surgery may allow for improving their PNI and subsequently their postoperative course and overall survival, especially given the high (66.7%–80.4%) incidence of malnutrition in individuals with gastric cancer and the almost 2-fold increased risk for postoperative complications associated with malnutrition.7

C-reactive protein (CRP) has also been found to be an independent risk factor for predicting complications following total gastrectomy. A retrospective study found that CRP was elevated on day 3 postop in 60.4% of the patients who developed complications.8

Surgical practices are changing, and we are seeing more fast-track procedures that allow for higher carbohydrate and protein intake in the preoperative period, in addition to higher oral intake in the postoperative period and implementation

of parenteral nutrition when oral intake is not adequate. Specifically for gastric cancer, we have seen complication rates decrease from around 28% to 10% with these fast-track procedures. Additional factors that play a role are optimal pain control, improving gut function, and protecting gut mucosal barrier.9 Adequate intake of n-3 PUFAs can modify all those factors. The authors of the current study under review write:

“n-3 PUFAs in gastrointestinal cancer cannot only reduce inflammatory reactions, and improve the postoperative curative effect, but also improve immune suppression. The possible mechanism has been discussed, EPA and DHA could regulate the immune inflammatory response by enhancing T cell function, and B cell function, altering membrane fluidity, lipid peroxide formation, and eicosanoid production; regulating of gene expression and subsequently inhibiting many aspects of inflammation, including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of proinflammatory cytokines.”

Yang et al investigated the use of n-3 PUFA–enriched parenteral nutrition in combination with enteral nutrition on days 1 to 5 following gastrectomy in individuals with gastric adenocarcinoma. Individuals in the study arm were given 0.2 g/kg/d of 10% fat oil emulsion containing 1.25 to 2.82 g EPA and 1.44 to 3.09 g DHA (10 g/100 mL).10 If we were to translate this into an oral dose for a 150-pound individual, this would be anywhere from 1.7 to 3.8 g EPA and 1.95 to 4.2 g DHA. Fortunately, achieving these doses would be attainable with commercially available omega-3 fatty acids with high concentrations of EPA and DHA. Enteral supplementation and parenteral supplementation have been shown to increase EPA in plasma cell membranes, though incorporation was slower with enteral supplementation.11

The individuals who received n-3 PUFA–enriched parenteral nutrition had improved immune parameters, inflammatory indicators, and nutritional markers. Additionally, they had fewer postoperative complications. There was also a decrease in time to first flatus and defecation but no difference in postoperative length of stay. Unfortunately, parenteral nutrition is often underused in the postoperative setting, especially in individuals who receive enteral nutrition but remain undernourished.12

Although we rarely have the opportunity to influence the postoperative course while an individual is inpatient, it would seem that in the case of gastrectomy, recommending postoperative oral n-3 PUFAs would be not only safe but beneficial for these individuals. Using tools such as the PNI and CRP may be useful predictive markers for those who may benefit the most from supplementation. Additionally, given that about 60% of patients will undergo surgery to treat their cancer, healthcare providers should consider n-3 PUFAs across tumor types in the postoperative setting.

REFERENCES

1 Mocan L. Surgical management of gastric cancer: a systematic review. J Clin Med. 2021;10(12):2557. 2 Yang J, Zhang X, Li K, et al. Effects of EN combined with PN enriched with n-3 polyunsaturated fatty acids on immune related indicators and early rehabilitation of patients with gastric cancer: a randomized controlled trial. Clin Nutr. 2022;41(6):1163-1170. 3 Mocan L. Surgical management of gastric cancer: a systematic review. J Clin Med. 2021;10(12):2557. 4 Bartlett E, Roses R, Kelz R, Drebin J, Fraker D, Karakousis G. Morbidity and mortality after total gastrectomy for gastric malignancy using the American College of Surgeons National Surgical Quality Improvement Program Database. Surgery. 2014;156(2):298-304. 5 Kim R. Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence. J Transl Med. 2018;16(1):8. 6 Jiang N, Deng JY, Ding XW, et al. Prognostic nutritional index predicts postoperative complications and long-term outcomes of gastric cancer. World J Gastroenterol. 2014;20(30):10537-10544. 7 Yang J, Zhang X, Li K, et al. Effects of EN combined with PN enriched with n-3 polyunsaturated fatty acids on immune related indicators and early rehabilitation of patients with gastric cancer: a randomized controlled trial. Clin Nutr. 2022;41(6):1163-1170. 8 Okubo K, Arigami T, Matsushita D, et al. Clinical impact of creatine phosphokinase and c-reactive protein as predictors of postgastrectomy complications in patients with gastric cancer. BMC Cancer. 2021;21(1):95. 9 Feng F, Ji G, Li JP, et al. Fast-track surgery could improve postoperative recovery in radical total gastrectomy patients. World J Gastroenterol. 2013;19(23):36423648. 10 Yang J, Zhang X, Li K, et al. Effects of EN combined with PN enriched with n-3 polyunsaturated fatty acids on immune related indicators and early rehabilitation of patients with gastric cancer: a randomized controlled trial. Clin Nutr. 2022;41(6):1163-1170. 11 van der Meij BS, van Bokhorst-de van der Schueren MA, Langius JA, Brouwer IA, van Leeuwen PA. n–3 PUFAs in cancer, surgery, and critical care: a systematic review on clinical effects, incorporation, and washout of oral or enteral compared with parenteral supplementation. Am J Clin Nutr. 2011;94(5):1248-1265. 12 Yang J, Zhang X, Li K, et al. Effects of EN combined with PN enriched with n-3 polyunsaturated fatty acids on immune related indicators and early rehabilitation of patients with gastric cancer: a randomized controlled trial. Clin Nutr. 2022;41(6):1163-1170.