Oral nutrition supplement improves nutrition and inflammation of cancer patients by regulating iron metabolism

ABSTRACT

The relationship between cancer and iron metabolism has received more attention, but there is less research on nutritional support to improve the nutritional and inflammatory status of cancer patients by regulating iron metabolism. A survey was conducted involving 90 patients with lung cancer. The control group was given routine hospitalization diet and the oral nutrition supplement (ONS) group was given oral nutrient solution on the basis of routine hospitalization diet. It lasted for 2 weeks. The changes of iron metabolism, nutritional status, and inflammatory indicators of the two groups were compared. After 2 weeks of intervention, the levels of ALB and PA in the ONS group were increased than that in the control group (P < .05), the inflammation was significantly decreased in the ONS group (P < .05), and the levels of Hb, SI, and TIBC in the ONS group were higher than that in the control group, while the SF was significantly reduced (P < .05). ONS could improve iron metabolism, nutritional status, and inflammatory levels. We speculate that the decrease in inflammation may be due to the changes of iron metabolism, thereby improving nutritional status. It may become a new target for tumor treatment.

KEYWORDS:

• Oral nutrition supplement
• nutritional status
• inflammation
• iron metabolism

Introduction

Iron is an essential trace element in various cell processes, and it plays a key role in cell metabolism and growth. The abnormal iron metabolism increased the risk of tumorigenesis and promotes tumor growth. It may promote the occurrence of tumor by inducing the production of free radicals and subsequent cell damage,^[1] and act as a nutrient to promote the proliferation of tumor cells.^[2] In the process of canceration, cells change the way of iron metabolism, resulting in high consumption of iron.

Malnutrition is a risk factor of the poor prognosis, and in this case, the way of iron acquisition, storage, efflux, and regulation is disturbed. Many guidelines recommend oral nutrition supplement (ONS) provision to increase oral intake in malnourished cancer patients during treatment, which is the preferred route of feeding.^[3] ONS is important as a means to compensate for the reduction in food intake, which can prevent nutritional deterioration during the process of cancer treatment.^[4] The purpose of nutritional therapy is to improve the metabolism and nutritional status of patients.^[5]

At present, the research on the relationship between cancer and iron metabolism is extensive, mostly the relationship between etiology and disease. However, most cancer patients are at a low level of iron metabolism and it can affect the prognosis of patients. Therefore, how to use this “double-edged sword” during cancer treatment is an urgent problem to be solved. Few reports have described the effects of oral nutrition supplementation on clinical outcomes by regulating iron metabolism in cancer patients. Thus, our aim was to investigate the beneficial effects of ONS on lung cancer patients undergoing chemotherapy by regulating iron metabolism. This study contributes to understand the relationship between ONS and iron metabolism in cancer patients and provide new ideas for improving the nutritional status of cancer patients by regulating iron metabolism.

Materials and methods

Study population

Ninety non-small-cell lung cancer patients were selected from March 2020 to December 2021. All of the subjects were divided into the ONS group (n = 45) and the control group (n = 45) according to whether they accepted ONS. Reasons for patients to refuse ONS: ①economic reasons; ②poor appetite caused by cancer treatment and unable to add ONS; ③do not recognize the effect of ONS.

All patients were given routine hospitalization diet. The ONS group received 2 ONS packs daily for 2 weeks, while the control group did not. The control group was matched regarding demographics, tumor stage, and tumor site for comparison. The chemotherapy protocol and other clinical treatments of the two groups of patients were consistent. This study conducted according to the Declaration of Helsinki and was approved by the Ethics Committee of the Yuhuangding Hospital (The clinical trial registration number: ChiCTR-TRC-2021016415).

Hospitalization diet

The hospitalization diet was uniformly prepared and distributed by the hospital canteen. All patients could complete daily intake of the hospitalization diet. The recommended calorie intake was set at 25 kcal/kg and protein at 1.0 g/kg.^[6]

Oral nutrition supplement

The ONS used in this study was the “Nutren Optimum” (Nestlè Health Science) and it contains 250 kcal energy, 29.3 g carbohydrate, 10.2 g protein and 9.6 g fat per pack. The expected daily nutritional intake in the ONS group was 500 kcal energy, 58.5 g carbohydrate, 20.4 g protein and 19.3 g fat per two ONS packs.

Data collection

Data regarding diagnosis, gender, age, Body Mass Index (BMI), and biochemical tests were collected from medical records. The focus was on the nutrition, inflammation, and iron metabolism indicators of patients at the 1st day, 7th day, and 14th day to monitor the changes. These data included total protein (TP), albumin (ALB), prealbumin (PA), hemoglobin (Hb), serum iron (SI), serum ferritin (SF), total iron-binding capacity (TIBC), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP).

Statistical analysis

The values were reported as mean ± standard errors or percentages, which were conducted in all the statistical analyses in SPSS 22.0. The linear mixed models were used to compare differences between groups (day 1, 7, and 14). The model included the time as a categorical variable and we treated the group x time interaction as the fixed effect in the model. Statistical significance was verified at a p-value of <0.05.

Results

Baseline information

The baseline information of all enrolled patients is presented in Table 1. It demonstrated no significant differences in the baseline characteristics of the two groups (P > .05).

Table 1. Baseline data of patients with lung cancer.

	The Control group (n=45)	The ONS group (n=45)	P
Age	59±6	61±6	0.198
Gender (male)	26 (58%)	24 (53%)	0.254
BMI (kg/m^2)	18±3	19±3	0.315
Hb (g/L)	102±6	103±5	0.262
SI (μmol/L)	9±3	10±3	0.634
SF (ng/ml)	396±24	410±24	0.458
TIBC (μmol/L)	49±7	49±6	0.275
TP (g/L)	59±5	57±5	0.467
ALB(g/L)	34±5	33±5	0.512
PA(mg/L)	125±15	119±15	0.384
TNF-α (pg/ml)	19±4	21±4	0.722
IL-6 (pg/ml)	23±6	25±6	0.164
CRP (mg/L)	14±1	15±2	0.216

Values are presented as mean ± SD. BMI: Body Mass Index; Hb: hemoglobin; SI: serum iron; SF: serum ferritin; TIBC: total iron-binding capacity; TP: total protein; ALB: albumin; PA: prealbumin; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; CRP: C-reactive protein.

C-2: All data must be presented with appropriate decimal point based on the standard deviation. For examples:

1. 78.99 ±8.67 should be 79 ± 9

2. 78.99 ±0.67 should be 79.0 ± 0.7

3. 78.99 ±0.073 should be 78.99 ± 0.07

Check all tables

Comparison of nutritional status

As shown in Table 2, compared with the control group, there was no significant difference in these indicators at 1st day and 7th day (P > .05). But at 14th day, the levels of ALB and PA in the ONS group were higher than that in the control group (P < .05). However, we did not observe the significant changes in TP and BMI.

Table 2. Comparison of nutritional status between two groups.

	time	The ONS group (n=45)	The Control group (n=45)	P-time	P-group	P-time×group interaction
TP (g/L)	1st day	57±5	59±5	0.217	0.045	0.281
	7th day	56±5	56±5
	14th day	59±8\^a	56±4^a
ALB (g/L)	1st day	33±5	34±5	0.286	0.034	0.304
	7th day	33±5	32±4
	14th day	37±5^a	33±4^b
PA (mg/L)	1st day	119±15	125±15	0.424	0.017	0.425
	7th day	129±16	126±15
	14th day	155±23^a	117±25^b
BMI (kg/m^2)	1st day	19±3	18±3	0.289	0.163	0.386
	7th day	19±3	18±3
	14th day	19±3^a	18±4^a

Values are presented as mean ± SD. TP: total protein, ALB: albumin, PA: prealbumin, BMI: body mass index; Groups sharing the same superscript (a or b) have no significant difference from each other in the post hoc analysis (p ≥ .05)

Comparison of inflammation

The TNF-α, IL-6, and CRP were assessed to monitor inflammation changes. As shown in Table 3, there was no difference between the two groups at 1st day and 7th day (P > .05). However, compared with the control group, the inflammation was significantly decreased in the ONS group at 14th day (P < .05).

Table 3. Comparison of inflammation between two groups.

	Time	The ONS group (n=45)	The Control group (n=45)	P-time	P-group	P-time×group interaction
TNF-α (pg/ml)	1st day	21±4	19±4	0.413	0.018	0.412
	7th day	18±4	19±4
	14th day	10±4^a	18±4^b
IL-6 (pg/ml)	1st day	25±6	23±6	0.207	0.022	0.657
	7th day	18±4	20±4
	14th day	12±4^a	21±4^b
CRP (mg/L)	1st day	15±2	14±1	0.472	0.039	0.285
	7th day	12±2	15±2
	14th day	9±1^a	14±3^b

Values are presented as mean ± SD. Hb: hemoglobin, SI: serum iron, SF: serum ferritin, TIBC: total iron-binding capacity; Groups sharing the same superscript (a or b) have no significant difference from each other in the post hoc analysis (p ≥ .05)

Comparison of iron metabolism

The Hb, SI, SF, and TIBC were assessed to monitor iron metabolism changes. As shown in Table 4, compared with the control group, there was no significant difference in these indicators at 1st day and 7th day (P > .05). But at 14th day, the levels of Hb, SI, and TIBC in the ONS group were higher than that in the control group, while the SF was significantly reduced (P < .05).

Table 4. Comparison of iron metabolism between two groups.

	Time	The ONS group (n=45)	The Control group (n=45)	P-time	P-group	P-time×group interaction
Hb (g/L)	1st day	103±5	102±6	0.325	0.027	0.327
	7th day	110±6	102±6
	14th day	126±6^a	99±5^b
SI (μmol/L)	1st day	10±3	9±3	0.179	0.038	0.545
	7th day	12±4	10±4
	14th day	16±5^a	10±3^b
SF (ng/ml)	1st day	410±24	396±24	0.354	0.044	0.694
	7th day	358±24	381±25
	14th day	305±23^a	378±25^b
TIBC (μmol/L)	1st day	49±6	49±7	0.471	0.013	0.513
	7th day	55±6	45±7
	14th day	68±5^a	42±7^b

Values are presented as mean ± SD. Hb: hemoglobin, SI: serum iron, SF: serum ferritin, TIBC: total iron-binding capacity; Groups sharing the same superscript (a or b) have no significant difference from each other in the post hoc analysis (p ≥ .05)

Discussion

Iron is an momentous micronutrient, which plays different roles in the occurrence and progression of tumors, including oxygen transport, heme synthesis, DNA and RNA synthesis, cellular respiration, the activity of numerous enzymes, and immune function.^[7] The cancer patients require sufficient nutritional intervention for a better prognosis,^[8] because chemotherapy increases the risk of malnutrition and weight loss. We hypothesized that ONS could help cancer patients maintain nutritional status by regulating iron metabolism. We demonstrated that ONS indeed improved iron metabolism in cancer patients along with an improvement of the nutritional status and a decrease in inflammatory levels.

On the one hand, the intercostal muscles and the immune system can be weakened by the malnutrition,^[9] on the other hand, the survival and recovery of the cancer patients can be influenced by the nutritional alterations.^[10] Therefore, the appropriate nutritional therapy is important for cancer patients. The patients should be treated with ONS when possible and it is viewed as the priority.^[3] In this study, all patients received the same hospitalization diet except for the supply of ONS. We found that there was no significant difference in nutritional status after 7 days. It may be due to insufficient intervention time and also because the protein synthesis is inhibited due to inflammation. However, the levels of ALB and PA in the ONS group were significantly increased after 14 days. It demonstrated that ONS could help improve the nutritional status of patients. However, there is a study that could not demonstrate the efficacy of an ONS and they speculated that it was due to decreased of a regular diet by adding the ONS.^[11] According to a study, about 58% of patients with non-small cell lung cancer lose weight before treatment and usually gain weight during chemotherapy.^[12] Another study found a significant decline in body weight loss for patients who tolerated >200 kcal/d compared with those who could not consume it.^[13] In this research, there are no significant differences in BMI. This might be due to the short intervention time in this study.

Inflammation is a key part of the etiology of the cancer and it is also one of the major targets for nutritional intervention.^[14] In this study, we found that the level of inflammation decreased significantly after 14 days of intervention. Previous studies have shown that the specific microenvironment changes in lung tissue and the oxidative stress might be the reasons of the progression of cancer and disorders in the immune system.^[15] The effects of IL-2 and TNF-α on iron metabolism could lead to the decrease of serum iron and the increase of ferritin in cancer patients.^[16] That is consistent with our research. Many cancer patients have high ferritin concentrations, which is related to poor patients’ prognosis.^[17,18] In this study, we found that after 14 days of intervention, the SF of patients in ONS group decreased significantly. TIBC reflects the level of transferrin. Transferrin delivers iron to all tissues for erythropoiesis.^[19] The levels of Hb, SI, and TIBC in the ONS group were increased significantly at the end point.

The proliferation is associated with the biosynthesis of proteins and nucleic acids, so the acquisition of energy is important for cancer patients. Mitochondria can generate energy and are the principal organelles for the metabolism of iron.^[20] A study shows that low carbohydrates availability can impair iron regulation.^[21] In this study, we found that both inflammatory and cancer can impact iron balance, and this is consistent with previous research results.^[22,23] In our study, the ONS group increased the supply of carbohydrate and total energy, and the results were consistent with the above. Iron is necessary for immunity, and iron deficiency can lead to impaired cellular immunity.^[24] The relationships could be complex among iron metabolism, cancer, and inflammation, and we speculate that the ONS regulated iron metabolism to improve immune status and inhibit inflammation.

For patients with iron deficiency anemia, oral iron therapy is the main method. However, it can increase the oxidative stress and inflammation.^[25] In contrast, intravenous iron has fewer iron gastrointestinal adverse reactions and better tolerance.^[26] The development of enteral nutrition preparations rich in iron but able to reduce gastrointestinal irritation is a direction of product development and research in the future, which may make it a new target for cancer nutrition therapy.

The limitation of this research was that the intervention time was short for us to monitor the effect of ONS on other indicators. In addition, we did not inspect the patient’s diet completion, although they promised verbally that they would consume the daily diet provided by the hospital and not eat other foods during the intervention. Third, we did not monitor the changes in the patient’s muscle mass. The bioelectrical impedance analysis is helpful to adjust the dietary composition according to the changes of the patient’s body composition as soon as possible. Fourth, the large-scale researches are required to confirm our findings because the sample size has a limited statistic power.

The authorship statement

Xuelong Li and Changxing Cui equally contributed to the conception and design of the research; Wenjing Gong contributed to the design of the research; Guangrun Li contributed to the acquisition and analysis of the data; Fubo Song and Peng Huang contributed to the interpretation of the data. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.

Acknowledgments

This work was funded and supported by Projects of medical and health technology development program in Shandong province (No. 202203100434).

Disclosure statement

No potential conflict of interest was reported by the authors.