Parenteral nutrition with n-3 polyunsaturated fatty acids on nutrition inflammatory and immune status of gastrointestinal cancer patients: Meta-analysis

Abstract

BACKGROUND

The incidence of malignant tumors in the digestive system is increasing and is a threat to human health. However, the long duration from tumor detection to radical resection, stress responses due to surgical trauma, and insufficient nutritional intake increases the risk of malnutrition, immune function reduction, postoperative complications, and intestinal dysfunction among patients.

AIM

To systematically investigate the association of parenteral nutrition enriched with n-3 polyunsaturated fatty acids (PUFAs) with the nutritional status of patients after gastrointestinal treatment.

METHODS

Randomized controlled trials associated with PUFA-enriched parenteral nutrition administration in patients with digestive system malignancies were retrieved from online databases such as PubMed, EMBASE, ScienceDirect, Cochrane Library, China Knowledge Network, China VIP, Wanfang, and China Biomedical Literature Database, with the retrieval time from database inception to present. Two researchers independently extracted data. Each article’s bias risk was assessed by referring to the Cochrane Handbook version 5.3 criteria and RevMan5.4 was used for data analysis.

RESULTS

This meta-analysis involved six randomized controlled trials involving a total of 505 cases. Random-effects model analysis indicated remarkably better improvements in various inflammatory factors in the study group (P < 0.05). Meta-analysis of nutritional indicators revealed that the study group had higher total protein, albumin, and prealbumin levels, as well as lower transferrin levels compared to the control group (P < 0.05). Meanwhile, meta-analysis of T-cell subsets revealed no remarkable inter-group difference in post-treatment CD8⁺ cells (P > 0.05). Moreover, the meta-analysis identified a notably lower incidence of adverse reactions in the study group (P < 0.05).

CONCLUSION

Administration of PUFAs helps improve the nutritional status of patients with digestive malignancies in the perioperative period. It promotes immune function recovery, reduces the inflammatory response, and decreases the risk of adverse effects. These beneficial effects make it worth investigating and promoting their use in appropriate patient populations. However, further validation via high-quality studies with long intervention time and extended follow-up periods is required.

Key Words: N-3 polyunsaturated fatty acids; Gastrointestinal cancer; Parenteral nutrition; Maintenance therapy; Nutritional status; Meta-analysis

Core Tip: Nutritional support is an important measure that can improve immunity, reduce the incidence of infectious or non-infectious complications, and enhance the prognosis of patients with malignant tumors. In this study, we conducted a meta-analysis of randomized controlled trials in patients with digestive system malignancies who received n-3 polyunsaturated fatty acids to resolve these ambiguities and evaluate the clinical significance of n-3 polyunsaturated fatty acids in these patients.

INTRODUCTION

Malignant tumors pose a major threat to human life and health[1]. Medical technology is constantly advancing; however, a considerable number of people still die from malignant tumors each year. The incidence of malignant tumors in the digestive system accounts for > 60% of all malignant tumors, and its fatality rate remains high[2-4]. Several factors affect the survival of patients with malignant tumors, including pathological stage, postoperative complications, immune regulation, psychological and nutritional status, and other factors[5]. Relevant studies have revealed that approximately 40%-80% of tumors are associated with malnutrition[6].

Malignant tumors of the digestive system are those that occur in the digestive tract and digestive organs. They are categorized based on the pathology type, such as adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, undifferentiated cancer, etc[7]. Malignant tumors of the digestive system cause structural changes in the digestive tract and insufficient digestive juice secretion, directly affecting nutrient intake and absorption, leading to malnutrition. During anti-tumor therapy, patients are more likely to have gastrointestinal-related complications, such as loss of appetite, diarrhea, nausea, vomiting, and abdominal distention; thus, malnutrition is especially prominent in these patients[8,9]. Patients who develop malnutrition demonstrate weight loss (WL), infection susceptibility, and anemia-related complications. Malnutrition not only affects treatment effectiveness and patient prognosis, but also decreases their quality of life, characterized by reduced body function and loss of some or all social functions.

Currently, nutritional support is the most important approach used to improve immunity, reduce the incidence of infectious or non-infectious complications, shorten hospital stays, improve patient prognosis, and reduce medical expenses. Patients with malignant tumors exhibit varying degrees of low immune function; however, the nutritional support therapy predominantly used in the clinic cannot improve immune function postoperatively. Recent studies have revealed that specific nutrients regulate immune function and inflammatory response, maintain nitrogen balance, and promote protein synthesis and secretion. As indispensable fatty acids, n-3 polyunsaturated fatty acids (PUFAs) contain alpha-linolenic acid, eicosatetraenoic acid, and docosahexaenoic acid (DHA). In the human body, PUFAs exhibit anti-inflammatory and anti-thrombotic effects, blood lipid reduction, blood vessel dilation, retinal function 2 maintenance, and memory function improvement[10,11]. As important immune nutrients, PUFAs are used in critical diseases to prevent cardiovascular and anti-thrombotic diseases and to improve hypercoagulability. Previous meta-analyses have identified a role for PUFAs in patients with critical illness and cardio-cerebrovascular diseases[12,13]. Clinical studies have demonstrated that adding PUFAs to nutritional support reduced cachexia symptoms in patients with advanced malignant tumors, reduced WL, and even helped with weight gain. In vivo and ex vivo experiments revealed that PUFAs increase lipid peroxide production in tumor cells by changing the structure and function of tumor cell biofilm, thereby promoting tumor cell apoptosis and having an overall anti-tumor effect[14].

Studies have demonstrated that omega-3 PUFAs have inhibitory and lethal effects on various tumors, such as colorectal, prostate, and breast cancers[15]. However, some studies have reported that the effects of PUFA supplementation on patients with advanced malignant tumors are quite different[16]. The assessment and application of immunonutritional therapy/support have largely been overlooked[17]. So far, the European Society for Clinical Nutrition and Metabolism guidelines have recommended general immunonutrition support for malnourished patients with cancer[18], which coincides with enhanced recovery plans after surgery[19]. Alpha-linolenic acid, eicosapentaenoic acid, and DHA are the primary components of n-3 PUFAs[20]. Several studies have confirmed that PUFA-enriched parenteral nutrition remarkably improved the nutritional status of patients after gastrointestinal treatment, but these studies have various research designs and assessment indicators. Furthermore, current clinical studies are heterogeneous in study populations, study designs, sample quantities, and systematic approaches. Accordingly, this meta-analysis systematically, quantitatively, and comprehensively discusses the results of similar independent papers to evaluate the clinical value of PUFA-enriched enteral nutrition in patients after gastrointestinal treatment.

MATERIALS AND METHODS

Literature sources and retrieval methods

Literature was retrieved by searching online databases, such as PubMed, EMBASE, ScienceDirect, Cochrane Library, China Journal full-text Database, VIP full-text Database, Wanfang Database, and Chinese Biomedical Literature data, as well as relevant Chinese journals, conference papers, and degree papers. Online searches were supplemented with literature tracing, using free words plus subject words with the following keywords: PUFAs, parenteral nutrition, digestive system, malignant tumor, nutritional status, immune function, and parenteral nutrition from papers published between January 2010 and March 2022.

Literature selection criteria

Literature eligibility criteria were as follows: (1) Research type: This meta-analysis analyzed all randomized controlled trials (RCTs, in Chinese) associated with PUFA-enriched parenteral nutrition in patients with digestive system malignant tumors at home and abroad; (2) Participants: Patients with digestive system malignancies (e.g., esophageal, gastric, colorectal, liver, gallbladder, pancreatic cancers) were diagnosed based on gold standard pathological examination; and (3) Intervention: The study group was supplemented with PUFAs in addition to routine nutritional support, whereas the control group received only routine nutritional support. Literature exclusion standards were as follows: (1) Non-RCTs; (2) Incomplete data report or unusable data; (3) Studies with repetitive research content; (4) Research with insignificant efficacy; and (5) Patients not diagnosed as malignant using the gold standard, those diagnosed with benign tumors, and those without digestive malignancies.

Quality assessment and data retrieval were as follows: (1) Bias risk assessment: Bias risk assessment was performed using the tool recommended in Cochrane System Review Manual 5.3; and (2) The literature scanning and data retrieval process involved two researchers that independently screened papers, extracted data, assessed quality, and cross-checked the results. Any disagreement was resolved either by discussion or judgment from a third researcher. Data management and extraction were performed using the document management software NoteExpress and Microsoft Excel. In the case of incomplete data documented in the literature, the authors were contacted for additional information. The following data were extracted from publications: (1) Basic information: Author(s), publication time, and sample size; (2) Intervention: Plan and treatment course; and (3) Outcome measures.

Statistical analysis

RevMan version 5.3 was used for data meta-analysis. Count and measurement data were indexed by relative risk and mean difference, respectively. The point estimate of each effect and its 95% confidence interval (CI) were provided. Heterogeneity testing was performed using the χ²-test, whereas heterogeneity assessment utilized I². The fixed-effects model was adopted in the case with no heterogeneities. Subgroups, sensitivity, and descriptive analyses were used and the random-effects model (REM) was adopted if heterogeneities were present. Publication bias was analyzed using Eggers’s test. A P value of < 0.05 indicates statistical significance.

RESULTS

Literature retrieval results and literature inclusion information

After eliminating duplicate articles, 628 of the 1732 papers retrieved through computer database retrieval were obtained. A preliminary reading of titles and abstracts was performed to exclude irrelevant research, reviews, case reports, and noncontrol papers, yielding a total of 208 articles. Of the initial 173 articles, the full text of 167 was carefully read, eliminating those with defective data or no main outcome measures. Finally, six RCTs, totaling 505 samples, remained for meta-analysis (Table 1)[21-26].

Table 1 Basic characteristics of papers included.

Ref.	Country	N, C/T	Intervention method, C	Intervention method, T	Outcome measure	Research type	Random	Blinded
Teng et al[21], 2016	China	40/40	Routine parenteral nutrition	Routine parenteral nutrition + PUFAs	1, 2, 3, 4	Forward-looking	Yes	No
Hu et al[22], 2018	China	20/20	Routine parenteral nutrition	Routine parenteral nutrition + PUFAs	1, 2, 3	Forward-looking	Yes	No
Song et al[23], 2018	China	34/34	Routine parenteral nutrition	Routine parenteral nutrition + PUFAs	1, 2, 3, 4	Forward-looking	Yes	No
Qin et al[24], 2019	China	50/50	Routine parenteral nutrition	Routine parenteral nutrition + PUFAs	2, 3	Forward-looking	Yes	No
Zhu et al[25], 2012	China	29/28	Routine parenteral nutrition	Routine parenteral nutrition + PUFAs	3	Forward-looking	Yes	No
Mo et al[26], 2012	China	80/80	Routine parenteral nutrition	Routine parenteral nutrition + PUFAs	1, 2	Forward-looking	Yes	No

“1” represents inflammatory factor level; “2” represents nutritional status index; “3” represents immune function index; and “4” represents adverse reaction. C: Control groups; T: Research groups; PUFA: N-3 polyunsaturated fatty acids.

Methodological quality evaluation

All six RCTs reported patients’ baseline status. Random assignment was indicated in all six RCTs, and the random method was not described in 2 of the 6 articles. Each trial provided detailed intervention measures, which were prospective studies. These six RCTs failed to provide a detailed description of the blinding method, as well as the number and reasons for loss to follow-up or withdrawal, with the Jadad scale revealing a score of < 2 points for their methodological quality (Figure 1).

Figure 1 The risk of bias. A: The risk of bias graph for quality assessment in randomized controlled trials; B: The summary of risk-of-bias assessments.

Results of meta-analysis

Inflammatory factor level: As mentioned above, we included six RCTs, which involved a total of 505 samples. Meta-analysis of inflammatory factors included C-reactive protein (CRP, I² = 0%, Z = 7.34, P < 0.00001), procalcitonin (I² = 54%, Z = 1.68, P = 0.01), and interleukin-6 (IL-6, I² = 29%, Z = 2.72, P = 0.007) after treatment. REM analysis revealed I² = 93% and 95%CI: -0.50 to 0.04 (P = 0.007), indicating remarkably better improvements in various inflammatory factor levels in the study group (P < 0.05). Hence, PUFA-enriched parenteral nutrition reduced the inflammatory response of patients after maintenance therapy for gastrointestinal malignancies (Figure 2A).

Figure 2 Forest plot. A: Forest plot for differences in inflammatory factors between experimental group and control group after treatment; B: Forest plot for difference of nutritional status indicators after treatment between experimental group and control group; C: Forest plot for difference of T lymphocyte subsets after treatment between experimental group and control group; D: Forest plot for the incidence of adverse reactions after treatment between experimental group and control group. CI: Confidence interval; CRP: C-reactive protein; PCT: Procalcitonin; IL: Interleukin; TP: Total protein; ALB: Albumin; TF: Transferrin; PA: Prealbumin.

Nutritional index: We then performed meta-analysis of the post-treatment nutritional indexes of the 505 samples. We analyzed serum total protein (TP, I² = 0%, score: 5.92; P < 0.00001), albumin (ALB, I² = 75%, Z = 2.42; P = 0.02), transferrin (TF, I² = 98%, Z = 0.37; P = 0.71), and prealbumin (PA, I² = 99%, Z = 0.85, P = 0.40) by REM (I² = 99%, 95%CI: 0.30-1.60, P = 0.004). We observed higher TP, ALB, and PA and lower TF in the study group compared to the controls (P < 0.05). These data suggest that PUFA-enriched parenteral nutrition may improve the nutritional status of patients compared to conventional parenteral nutrition (Figure 2B).

T-cell subsets: Meta-analysis of T-cell subsets after treatment analyzed CD3⁺ (I² = 25%, Z = 4.58, P < 0.00001), CD4⁺ (I² = 0%, Z = 5.35, P < 0.00001), CD8⁺ (I² = 78%, Z = 0.59, P = 0.55), and CD4⁺/CD8⁺ (I² = 0%, Z = 25.24, P < 0.00001) subsets of T-cells. REM analysis revealed an I² value of 77% and a 95%CI of 0.34-1.07 (P < 0.00001). CD3⁺, CD4⁺, and CD4⁺/CD8⁺ populations were notably higher in the study group (P < 0.05), whereas the post-treatment CD8⁺ levels were not different between the study and control groups (P > 0.05). These data indicate that n-3 PUFA-enriched parenteral nutrition remarkably improves patient immunity compared to conventional parenteral nutrition (Figure 2C).

Incidence of adverse reactions: Finally, we performed meta-analysis on post-treatment adverse reactions. The results indicated that increased body temperature (I² = 0%, Z = 1.42, P = 0.16), diarrhea and abdominal distension (I² = 0%, Z = 1.39, P = 0.17), nausea and vomiting (I² = 0%, Z = 1.62, P = 0.11), and rash (I² = 0%, Z = 1.39, P = 0.17) were the most frequent adverse reactions. Fixed-effects model analysis revealed an I² of 0% and 95%CI of 0.16-0.70 (P = 0.004), with a remarkably lower incidence of adverse reactions in the study group (P < 0.05). These data suggest that PUFA treatment with routine parenteral nutrition could remarkably reduce the incidence of adverse reactions in patients with gastrointestinal malignancies (Figure 2D).

DISCUSSION

WL and malnutrition are the most prevalent problems in patients with malignant tumors. The degree of WL is primarily related to tumor staging and location. WL rates range from 10% to 83% in patients with tumors, most predominantly in gastrointestinal tumors, pancreatic cancer, head and neck tumors, etc. A previous study revealed a 40%-80% incidence of malnutrition in patients with tumors[27]. Furthermore, 50%-80% of patients with tumors develop cachexia due to persistent skeletal muscle loss, a condition that cannot be fully reversed by routine nutritional support and that leads to progressive dysfunction. Many studies have revealed that malnutrition has an adverse effect on the clinical outcomes of patients with tumors[28,29], thereby increasing the risk of postoperative mortality and the likelihood of complications and/or prolonged hospital stays. Increasingly more studies have demonstrated that reasonable nutritional therapy can improve the clinical outcome of patients by reducing the incidence of complications, decreasing hospitalization duration, decreasing hospitalization costs, improving patient quality of life, and enhancing their prognosis[30].

N-3 unsaturated fatty acids are immunonutrients that have drawn a great deal of attention. They are indispensable fatty acids, containing linolenic acid, eicosatetraenoic acid, and DHA. They help increase the synthesis rate of ALB and regulate the immune status of the body and have an anti-tumor effect, which has been widely promoted[31]. Epidemiological research data have demonstrated that long-term high n-3 unsaturated fatty acid level intake remarkably reduced the incidence of breast and colon cancer[32]. Further, n-3 unsaturated fatty acids help improve the cachexia of advanced tumors and prolong patient survival[33]. The literature included in this study includes randomized control groups with high-quality double-blinded, multi-centered studies, indicating that the clinical value of PUFA-enriched parenteral nutrition for patients with gastrointestinal malignancies has been recognized by a wide range of scholars. TP and ALB are both important proteins in the body, which reflect the synthetic ability of the liver in the early stage and thus the patient’s nutritional status. In this study, we analyzed six RCTs, totaling 505 samples. Meta-analysis of nutritional indicators after treatment indicated higher TP, ALB, and PA levels and lower TF levels in the study group. This indicated that n-3 PUFA-enriched parenteral nutrition helps improve patients’ nutritional status better than conventional parenteral nutrition alone.

Related studies have revealed higher CRP, IL-6, tumor necrosis factor α, and other inflammatory indexes in patients with malignant tumors with nutritional risk than in those without nutritional risk, indicating the involvement of inflammatory response in the malnutrition process. Meta-analysis of inflammatory factors such as CRP, procalcitonin, and IL-6 after treatment revealed remarkably better inflammatory factor alleviation in the study group, implying that n-3 PUFA-enriched parenteral nutrition helps reduce the inflammatory response of patients after maintenance gastrointestinal therapy. Inflammation is a fundamental pathological process caused by damage due to various inflammatory cytokines. The existence of inflammatory reactions alters nerves, body fluids, tissues, and metabolic disorders. Inflammatory reactions have been prevalent in patients with malignant tumors[34,35], accompanied by tumor invasion, metastasis, and other aspects. Malignant tumors can induce an inflammatory microenvironment in the body, which improves the local inflammatory response. In the meantime, there is a complex association between malignant tumors, platelets and white blood cells, which increases the release of tumor-related inflammatory cytokines and further promotes inflammatory reaction occurrence. Inflammation occurrence increases the oxygen consumption and catabolism of the body and aggravates patient nutrient consumption.

Moreover, n-3 PUFAs are an important part of immune nutrition, which not only provides patients with the calories required by parenteral nutrition but also regulates their immune function. Some studies have revealed that PUFAs shift receptor proteins to non-functional areas by changing the fat environment of membrane fat microregions, causing immune regulation. Some scholars believe that PUFAs are crucial in the immune system by regulating dendritic cells. In this study, we conducted a meta-analysis of T-cell subsets after treatment. CD3⁺, CD4⁺, and CD4⁺/CD8⁺ T cell populations were remarkably increased in the study group, whereas no remarkable intergroup difference was identified for the posttreatment CD8⁺ levels. Altogether, PUFA-enriched parenteral nutrition remarkably improved patient immunity compared to conventional parenteral nutrition. The role of PUFAs in regulating immune cell function includes the following primary aspects: (1) PUFAs remarkably reduce the proliferative response and IL-2 level of antigen-specific CD4⁺ T lymphocytes; (2) n-3 PUFAs remarkably increase the ratio of plasma free fatty acids and monocyte n-3 and n-6 lipids, while remarkably inhibiting the release of tumor necrosis factor α, IL-1, IL-6, and IL-8 upon endotoxin stimulation; and (3) PUFAs down-regulate the phenotypes of CD18, CD54, CD11a, and major histocompatibility complex of rat dendritic cells and affect antigen presentation, thus improving the body’s immune function[36].

PUFAs exhibit a remarkable effect on the perioperative application of colon cancer radical surgery; however, they may also cause adverse effects. The meta-analysis of post-treatment adverse reactions revealed a lower incidence of adverse reactions in the study group, indicating a remarkably reduced risk of adverse reactions under PUFA intervention based on routine parenteral nutrition. Therefore, in clinical application, PUFAs can be administered at an appropriate time based on specific patient conditions. The limitations of this study include the following: (1) The number of included studies is relatively small due to the rigorous inclusion and exclusion criteria; and (2) Follow-up research is warranted due to the failure to determine the source of heterogeneity through subgroup analysis. To provide more clinical evidence for future applications of n-3 PUFAs in patients with digestive system malignant tumors, more high-quality RCTs are needed.

CONCLUSION

PUFAs exhibited remarkable clinical effects on patients with digestive system malignant tumors, which effectively reduced inflammatory reactions, regulated T-cell subsets, improved immune status, and avoided adverse conditions. It is worth advocating for in clinical practice.