A Narrative Review of Nutritional Therapy for Gastrointestinal Cancer Patients Underwent Surgery

Abstract

Background: Patients with gastrointestinal cancer often suffer from malnutrition during tumor progression. Malnutrition is associated with postoperative complications and decreased quality of life. Supporting cancer patients with proper nutrition is vital for improving their prognoses.

Method: Google scholar and PubMed database searches were performed. Selection criteria included gastrointestinal cancer, surgery, ω − 3 fatty acids, randomized clinical trials from 2007 to August 2022.

Conclusion: Nutritional therapy includes nutritional counseling, enteral nutrition, parenteral nutrition, and oral nutritional supplements. Immune nutrients like glutamine and ω-3 fatty acid have been demonstrated with benefits in reducing inflammatory responses and postoperative complications, regulating immune function and improving prognosis.

Keywords:

• gastrointestinal cancer
• surgery
• malnutrition
• nutrition therapy
• immunonutrition

1. Introduction

Cancers of the stomach and colon are the fifth and third most common types, respectively, and the third and fourth leading causes of cancer-related deaths worldwide [1]. Surgery is currently the mainstay of treatment for patients gastrointestinal(GI) cancer without distant metastases [2]. Patients with locally advanced GI cancer are treated with postoperative chemotherapy. However, because of inadequate nutritional intake caused by primary anorexia or GI symptoms, systemic inflammation syndrome and alternative substance metabolism caused by cancer, cancer patients have a malnutrition rate of 20%–70%, and that in upper GI cancer patients is up to 60.2% [3, 4]. Among patients receiving postoperative chemotherapy, gastrointestinal toxicity such as nausea and vomiting is a common complication. Treatment-induced GI mucositis and changes in the composition of the microflora could result in absorption and other intestinal function dysregulation and increase the rate and severity degree of malnutrition [5]. For GI cancer patients, malnutrition contributes to loss of weight and muscle [6], reduced immune function, more postoperative infections [7], increased chemotherapy toxicity [5], dose reductions and delays or cessation of chemotherapy [5], lower quality of life [8], prolonged length of stay (LOS) and higher mortality [7]. However, 25.5%–34.0% of patients who are well-nourished received improper nutritional therapy while 41.8%–59.1% of those with malnutrition received no nutritional support at all according to a survey [9, 10]. Delivery of proper nutrition support to patients with malnutrition can increase energy intake and body weight, reduce of mortality and nonelective hospital readmission rates, improve survival and prognosis and save the cost of disease as well [11–13].

2. Method

Google scholar and PubMed database searches were performed. Selection criteria included gastrointestinal cancer, surgery, ω − 3 fatty acids, randomized clinical trials from 2007 to August 2022.

3. Definition of malnutrition

Malnutrition can be diagnosed by the following two criteria according to ESPEN: 1) BMI < 18.5 kg/m²; 2) Weight loss (unintentional)>10% indefinite of time, or > 5% over the past three months combined with either BMI < 20kg/m² if < 70years old, or FFMI < 15 and 17 kg/m² in women and men, respectively, or BMI < 22kg/m² if > 70 years old [6]. It is important to conduct a nutritional assessment by any validated malnutrition screening tools, such as Nutrition Risk Screening 2002 (NRS-2002) [14], Malnutrition Universal Screening Tool (MUST), Patient-Generated Subjective Global Assessment (PG-SGA), Mini Nutritional Assessment (MNA) [6]. The goal of nutritional therapy is to enhance immune function and nutritional status, which will ultimately improve the prognosis for cancer.

4. Therapy for GI cancer patients underwent surgery

The forms of nutritional support preoperatively include nutrition counseling, oral nutritional supplements (ONS), artificial nutrition includes enteral nutrition (EN) and parenteral nutrition (PN). The dosage of nutrition therapy should depend on energy requirements and nutrition elements. Total energy requirement of cancer patients is suggested ranging from 25 to 30 kcal/kg/day. The dosage of protein intake should be 1.0–1.5 g/kg/day, 1.2–1.5 g/kg/day for chronically ill older patients [15]. All energy and protein intakes through oral, EN, and PN should be calculated. Besides, micronutrient is at a risk of deficiency in malnutrition patients. According to ESPEN recommendations, minerals and vitamins should be given to cancer patients in proportions that roughly correspond to the recommended dietary allowance (RDA), but avoid using high-dose micronutrients unless there are specific deficiencies [15].

4.1. Nutritional counselling

Nutrition counseling is the first and the most common choice of nutrition support which involves nutritional history, diagnosis, and nutrition treatment to relieve symptoms and increase energy intake in order to keep up with or work on healthful nutritional status [15]. Critical elements of nutrition counseling include communicating to patients the reasons and goals for dietary advice, and motivating them to adjust to their disease’s changing nutritional demands [3].

4.2. Oral nutritional supplements

ONS are made to provide nutrient-dense, high-energy liquids that can be prepared as drinks or added to drinks and foods [16]. For all patients identified as malnourished or could not meet their energy needs by normal diet, ONS is suggested. What’s more, for patients who are about to undergo surgery, ONS enhanced with immune-modulating elements such arginine, nucleotides, and omega-3 fatty acids is recommended for 5–7 days before to surgery to improve patients’ nutritional condition, boost immune function, minimize postoperative inflammatory response, and improve cancer prognosis [16–18]. It can significantly reduce hospital (re)admissions as well, especially in older patients [19]. While significant differences in postoperative complications and body weight did not be found in the recent meta-analysis, which is consistent with Reece et al. [16, 20].

Most of GI cancer patients underwent nutritional treatment were unable to achieve their energy requirements via normal oral diet for a long period, putting them at risk of postoperative malnutrition after discharge [17]. For these patients, they are suggested to continue nutritional follow-up after discharge [17]. We conducted six randomized controlled trials (RCTs) [21–26] to investigate the use of ONS for 6–12 weeks in postoperative gastric and colorectal cancer patients. The outcomes demonstrated that ONS administration following surgery can lessen body weight loss [21–23], improve nutritional outcomes such as body mass index (BMI) and skeletal muscle index (SMI) [24–26], lessen the occurrence of sarcopenia and chemotherapy modifications like delay, dosage reduction, or termination [25, 26].

4.3. Enteral nutrition

Patients who are unable to eat for more than a week or whose estimated energy intake is less than 60% of their demand for more than 1–2 weeks are deemed to have inadequate food intake and artificial nutrition is recommended [15]. Enteral nutrition is more consistent with physiological processes. So, if possible, it is preferred during perioperative in major abdominal surgery.

Early enteral nutrition contributes to more increase in the level of nutritional and immune indicators and body weight, shortener of the LOS, reduction of the risk of postoperative complications and promotion of the functional recovery of the digestive system as well [27, 28].

Recent years, early oral feeding attracted attention, and many studies were conducted. Results of most studies suggested that early oral feeding can shorten the LOS, save cost, improve clinical outcomes, and have no negative effects on healing of anastomoses in patients underwent colorectal [17, 29–31]. Even after partial or total gastrectomy, early oral feeding can be safe, feasible and associated with several potential benefits without increasing clinical complications [32–36]. However, a multicenter RCT found that early oral feeding did not show an advantage in shortening the LOS in patients underwent distal gastrectomy (DG) and it increased postoperative complications rate in DG (P = 0.045) on the contrary [37]. More conclusive study is necessary to firmly prove the potential benefits of early oral eating for GI surgery patients. Post-discharge enteral feeding is helpful in boosting calorie intake in patients undergoing upper GI cancer surgery, but there is no discernible benefit in tiredness, quality of life, or health economics [38].

Early oral feeding and EN has been suggested by ESPEN and ERAS, while the early feeding intolerance and the poor compliance resulted by it are the main barriers to administration of early enteral nutrition [17, 39]. Patients who have undergone a radical gastrectomy have a feeding intolerance rate of 49.3%, which is the dominant independent factor for postoperative complications in colorectal [40, 41]. Measures such as choosing appropriate feeding routes, maintaining good oral hygiene, and proper positioning for tube feeding can reduce the occurrence of feeding intolerance [42]. A recent study attempted to improve early feeding intolerance with ONS for 7 days preoperatively, but the results were negative [43]. Further researches are need to identify definitive mechanisms of feeding intolerance, propose more effective ways and more appropriate nutritional preparations to reduce its incidence.

4.4. Parenteral nutrition

Parenteral nutrition can provide adequate macronutrients and micronutrients through intravenous route which may allow for improving nitrogen balance efficiently and immune function, decreasing postoperative complications [44]. The effects of total parenteral nutrition on the gastrointestinal tract, however, such as a reduction in brush-border hydrolase, microvillus height and nutrient transporter activity, are associated with bacterial translocation (BT) and the recovery of intestinal function [45]. There are many studies have demonstrated that EN has more benefits over PN both in pre- and post-of operation [46–48]. But when oral/EN could not achieve adequate energy or there are contraindications to EN such as intestinal obstruction and intestinal ischemia, parenteral nutrition is needed to be administration as soon as possible.

Appropriate parenteral nutrition prior to surgery is vital. A period of 7–14 days of preoperative PN is advised, especially for patients who have significant nutrition risk or malnutrition [17]. A substantial decrease in postoperative overall problems (RR 0.64, 95%CI 0.46 to 0.87) was seen in a Cochrane study of preoperative PN in patients having gastrointestinal surgery [49]. 10 days preoperatively and 9 days postoperatively of PN were able to lower the mortality rate and the complication risk by almost one third in severely malnourished, GI cancer patients [50].

5. Immunonutrition

Immunonutrition, which includes glutamine, arginine, nucleotides and omega-3 fatty acids, has attracted more and more attention, especially for perioperative nutrition management between cancer patients in recent years. It can modulate host immune systems and inflammatory response [51]. The advantages of oral/enteral formula enhanced with immunonutrients have been demonstrated in several researches. Data on supplementing arginine or nucleotides as a single item are scarce for arginine and nucleotides are mainly mixed in enteral nutrition preparations. Supplementations of glutamine and omega-3 fatty acids are easily available recently and mainly administrated through parenteral route.

5.1. Glutamine

Glutamine is a conditionally necessary amino acid that can improve nitrogen balance, enhance muscle protein synthesis and decrease protein loss. A retrospective study of 1950 patients found that parenteral glutamine supplementation of 0.05–0.49 g/kg/day postoperatively resulted in a reduced drop in serum albumin levels (−0.6 vs. −1.1 g/dL; P < 0.001) [52]. The significance of glutamine to cell survival and proliferation in vitro was first described by Ehrensvard et al. [53] Glutamine can enhance immunome function, such as regulate T-lymphocyte proliferation and facilitate the differentiation of B-lymphocytes into cells that produce and secrete antibodies [54]. A RCT conducted glutamine with a dose of 0.5 g/kg/day from 1 day preoperatively to the 3rd postoperatively revealed that perioperative parenteral nutrition enriched with dipeptide glutamine meliorates postoperative immunodepression and reduces the LOS [55]. An animal study found that total parenteral nutrition (TPN) enriched glutamine can significantly attenuate the TPN-associated loss of epithelial barrier function (EBF) and TPN-associated intestinal mucosal atrophy, which is confirmed in a clinical research investigation of patients with advanced gastric cancer [56, 57]. Wang et al. reported that patients with advanced gastric cancer accepted parenteral nutrition support enhanced with glutamine of 0.4 g/(kg·day) can effectively protect the intestinal mucosal barrier function and improve the level of MMP-2 and MMP-9 during perioperative chemotherapy [57]. It should be emphasized that MMP-2 and MMP-9 can affect the progression of gastric cancer and there is a positive correlation between intestinal permeability and the levels of MMP-2 and MMP-9 in the intestinal mucosa according to animal researches [57, 58]. Besides, glutamine may function as a motility-recovery agent following gastrectomy according to Mochiki et al. [59] More high-quality researches are required to determine the exact effect and optimal dosage of glutamine after gastrointestinal surgery. Currently, no definite recommendation for the oral glutamine supplementation has been proposed.

5.2. Omega-3 (ω-3) fatty acid

Omega-3 (ω-3) fatty acid is one of polyunsaturated fatty acids (PUFAs), which mainly includes α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is rich in nuts and seeds, and EPA and DHA are mainly found in fish oil [60]. ω-3 fatty acid can modulate immune system and reduce inflammatory reaction. In the initiation of acute inflammatory response, it modulate inflammatory reaction mainly through decreasing the secretion of pro-inflammatory factors like IL-1β, IL-6 and TNF-α, increasing the production of anti-inflammatory cytokine IL-10 and prostaglandin D3 which can reduce the neutrophil adhesion and transmigration [60]. During the post-acute phase, ω-3 fatty acid can be used to produce maresins, protectins and resolvins, which are called resolution specialized pro-resolving mediators(SPMs) [61]. Besides, ω-3 fatty acid can optimize the omega-6/omega-3 balance. Omega-6 PUFAs, such as arachidonic acid (AA) and linoleic acid (LA), can be metabolized to proinflammatory factors, specifically prostaglandin E2, thromboxanes, leukotriene B4, lipoxins [62, 63]. A high ratio of omega-6/omega-3 is considered as a critical condition with proinflammatory potential. A recent high quality meta-analysis investigated about omega-6 sparing benefits of parenteral lipid emulsions on critically sick patients showed that omega-6 FA reducing lipid emulsions in PN can decrease the hospital and ICU LOS, 28-day mortality, and mechanical ventilation [64]. What’s more, they demonstrated that lipid emulsions with fish oil and lower omega-6 FA decrease the occurrence of nosocomial infections. Omega-3 PUFA also can regulate intestinal inflammatory response and enhance anti-stress ability, resulting in reducing the occurrence of diarrhea, bloating and diarrhea and improving postoperative enteral feeding tolerance [65].

Cause the benefits of ω-3 fatty acids in reducing the inflammatory response and regulating the immune response, several researches have been done to observe the effect of fish oil on clinical outcomes in GI cancer patients underwent surgery. Studies demonstrating parenteral fish oil’s benefit for GI cancer patients are summarized in Table 1. The advantages of omega-3 fish oil are related to the dosage and time point of use. In previous studies, the dose of omega-3 fish oil was 0.08–0.20 g/kg/day. A multi-center study with 661 patients have shown that when 0.10–0.20g/kg/d omega-3 fish oil was provided, the prognosis of severe patients can be significantly improved [77]. More high-quality studies are required to demonstrate the effectiveness in GI cancer patients and determine more precise optimal dosages and time point of use.

Table 1. Effectiveness of parenteral fish oil on gastrointestinal cancer patients.

Reference	Disease	Sample	Dose of fish oil	Time point	outcome
Ma, C.-J., et al. [66]	Gastric (26) and colorectal (73) cancer	99	0.08–0.15 g/kg BW/day	day −1 up to postoperative day 7	Net decrease of free fatty acids was significantly greater in the study group, while the net increase of triglycerides and decrease of high-density lipoprotein were remarkably lower. The two groups did not differ notably in terms of pro-inflammatory markers, other laboratory parameters, or adverse events.
Wei, Z., et al. [67]	Gastric cancer	46	0.2 g/kg BW/day	6 days postoperative	The levels of inflammatory markers and rate of complication were significantly decreased in the intervention group. No significant difference between the two groups in terms of nutritional status, liver function, or renal function.
de Miranda Torrinhas, R. S. M., et al. [68]	Stomach (38) and Colon (25) cancer	63	0.2 g/kg BW/day	3 days preoperative	Significant increase in IL-10 levels on day 3, decrease in IL-6 and IL-10 levels on day 6, lower decrease in leukocyte oxidative burst, maintenance of HLA-DR and CD32-expressing monocyte percentage, increase in CD32 neutrophil expression in the experiment group. No difference in the length of ICU and hospital stay or frequency of post-operative infections.
Makay, O., et al. [69]	Gastric cancer	26	0.2 g/kg BW/day	5 days postoperative	No statistically significant differences in serum lactate levels, other biochemical parameters, length of hospital stay, complications, or mortality.
Jiang, Z. M., et al. [70]	Colonic (64) and other gastrointestinal (79) cancer	203	0.2 g/kg BW/day	7 days postoperative	Significantly reduction SIRS and length of hospital stay, and a more normalization of CD4^+/CD8^+ in the treatment group.
Liang, B., et al. [71]	Colorectal cancer	42	0.2 g/kg BW/day	7 days postoperative	Significantly depression in serum IL-6 levels and increasing in the ratios of CD4^+/CD8^+ in the study group. No statistically significant difference in mortality or the occurrence of infectious complications.
Wang, D., et al. [72]	Gastric cancer	47	0.2 g/kg BW/day	5 days postoperative	Significantly depression in TNF-α, CRP, IL-1, IL-6 levels and SIRS rate, increasing in IL-10 and nutrition proteins levels, shorter bowel sound recovery time and earlier passage of flatus in experiment group. No statistically significant difference in occurrence of complications.
Wang, J., et al. [73]	Gastric (22) and colonic cancer (29)	63	Not clear	5 days postoperative	Significantly increasing in LB5/ LB4 and significant decreases in TNF-α, IL-6, and nuclear factor-kB in the study group. There were no differences in the distribution of the T-cell subpopulation and the changes of VEGF, CRP, IL-10, IL-8, IL-1 between the two groups.
Ma, C. J., et al. [74]	Gastric (4) and colonic cancer (29) and other gastrointestinal tumors (7)	40	Not clear	5 days postoperative	Significantly decrease in postoperative low-density lipoprotein levels in the study group. The two groups did not differ in terms of laboratory parameters, metabolic parameters, proinflammatory cytokine levels, clinical outcomes, or adverse events.
Xu, L. N., et al. [75]	Gastric Cancer	70	10g/day	14 days postoperative	Average NK cell activity was noticeably higher and TNF-α gene promoter methylation rates were lower in the ω-3 group. No appreciable variations in the serum levels of TNF-α, albumin, prealbumin, or in the number of NK cells between the two groups.
Yang, J., et al. [76]	Gastric Cancer	120	0.2 g/kg BW/day	5 days postoperative	Significantly increased in the immune parameters and nutritional parameters and lower inflammatory indicators, lower rate of postoperative complications, shorter time to first aerofluxus and defecation of the n-3 PUFAs group. No differences in the 30-day unplanned readmission rate, postoperative hospital stay, or need for further operation between the two groups.

6. Conclusion

Patients with gastrointestinal cancer often suffer from malnutrition which associated with worse prognosis. Nutritional therapy includes nutritional counseling, enteral nutrition, parenteral nutrition, and oral nutritional supplements. Immune nutrients like glutamine and ω-3 fatty acid have been demonstrated with benefits in reducing inflammatory responses and postoperative complications, regulating immune function and improving prognosis. This review summarizes the current nutritional therapy and various nutritional issues in GI cancer surgery (Figure 1). More well-developed studies are demanded to be demonstrated to explore more efficient and meaningful nutritional treatment options.

Figure 1. Conclusion of nutritional therapy process and methods.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Key Research Projects of Department of Science and Technology of Sichuan Province, China under Grant NO. 2018SZ0136; Key Research Projects of Department of Science and Technology of Sichuan Province, China under Grant NO. 2022YFS0164.