Effects of medical nutrition therapy compared with general nutritional advice on nutritional status and nutrition-related complications in esophageal cancer patients receiving concurrent chemoradiation: A randomized controlled trial

Abstract

OBJECTIVE:

The purpose of this randomized controlled trial study was to assess the effects of medical nutrition therapy (MNT) compared with general nutritional advice (NA) on nutritional status in esophageal cancer (EC) patients during Chemoradiation (CRT).

METHOD:

The sample includes one hundred newly diagnosed patients with EC. The MNT group received individualized nutritional therapy. The NA group received general nutritional advice at the beginning of the participation. Patient-Generated- Subjective Global Assessment (PG-SGA), anthropometric indices, body composition, dietary intake, laboratory tests, and nutrition-related complications were assessed.

RESULTS:

Forty-nine cases were in the MNT group. The MNT group had significantly more favorable energy (26.4±14.1 vs. 18.2±11.2 kcal/kgw.day) and protein (1±0.6 vs. 0.7±0.4 g/kgw.day) intake than the NA group at the final evaluation. The PG-SGA score diminished but not significantly in both groups (11±6 vs. 12±6). As compared to the NA group, patients in the MNT group experienced more frequently no weight loss (21% vs. 11%) or mild weight loss (40% vs 35%) during the treatment. Meanwhile, moderate weight loss was more frequently observed in the NA group (26% vs. 44%). In the MNT group, those with severe weight loss had not proper adherence to the nutritional protocol. Mid-upper arm circumference, body composition, laboratory tests, physical performance, and nutrition-related complications were not significantly different between the two groups.

CONCLUSION:

As compared to general NA, MNT improved energy and macronutrients intake in patients with EC undergoing CRT which resulted in less severe weight loss and potentially better nutritional status.

Keywords

Esophageal cancer nutritional assessment medical nutrition therapy nutritional advice randomized controlled trial

1 Introduction

Esophageal cancer (EC) usually has a dire prognosis with an aggressive nature. The two most common pathologies are adenocarcinoma and squamous cell carcinoma (SCC) [1]. EC is the eighth most common cancer and the sixth leading cause of cancer death in the world with a 5-year survival rate of less than 20% [2, 3]. Although the prevalence of some cancers is expected to decrease in the future, it is projected that the EC prevalence will increase by 140% by 2025 [4]. The records in the United States displayed 17,650 new cases and 16,080 deaths from EC in 2013 [5]. The prevalence of EC varies by geographic region, as the highest incidence of SCC (as the most common form of EC) has been reported in Asia, especially in China and the Middle East, with 100 cases per 100000 annually [6]. In Iran, EC accounts for 9% of all types of cancers and 27% of gastrointestinal cancers, indicating a relatively high prevalence rate in this region [7, 8].

The prevalence of malnutrition in patients with gastrointestinal cancers has been reported to be around 85%, indicating the importance of nutritional monitoring in these cases [9, 10]. The etiology of malnutrition is multifactorial and can be attributed to treatment complications or the nature of cancer itself [11]. Patients with significant weight loss and low muscle strength are more prone to treatment complications. Therefore, nutritional interventions like oral nutrition supplements (ONS) may improve treatment tolerability, clinical status, and even survival [12 –15]. Medical nutrition therapy is standardized, systematic, and individualized nutrition management including individualized energy and protein requirement calculation, dietary plan, nutrition education, ONS, and pharmacotherapy for nutrition-related complications. Few studies have assessed the effects of medical nutritional therapy on nutritional and clinical status in EC patients and no randomized controlled trial has demonstrated, so far, the effect of nutritional intervention on survival.

This randomized clinical trial has conducted to compare the effects of medical nutritional therapy with general nutritional advice on weight loss, Patient-Generated Subjective Global Assessment (PG-SGA), and other nutritional status and clinical outcomes in EC patients during CRT.

2 Materials and methods

2.1 Patients and study design

This randomized controlled trial (RCT) recruited 100 newly diagnosed EC patients admitted from February 2018 to February 2019 to Reza Radiation Oncology Center (RROC), Mashhad, Iran. This study was approved by the Mashhad University of Medical Sciences (MUMS) research ethics committee (ethics committee code: IR.MUMS.fm.REC.1395.111). This trial was registered in the Iranian Registry of Clinical Trials (IRCT) (IRCT ID: IRCT2016112931161N1). Written informed consent was obtained from all participants before the study. We followed the Consolidated Standards of Reporting Trials (CONSORT) 2010 for reporting this randomized trial [16].

We recruited patients over 18 years old with newly pathologically-confirmed esophageal carcinoma who were a candidate for radiotherapy (RT) or chemoradiation (CRT), while patients with confirmed distant metastases, adjacent tracheal, main vessels or vertebral involvement, a history of other cancers, concurrent disabling diseases such as chronic heart failure (CHF), chronic renal failure, chronic obstructive pulmonary diseases (COPD), liver failure, Acquired Immune Deficiency Syndrome (AIDS), active rheumatic diseases as well as those who had previously received oncological treatments were excluded. All patients were assessed at the beginning and the end of the CRT course. The information regarding demographic and disease-related data, anthropometric and dietary assessment, PG-SGA, clinical evaluation, and laboratory tests were recorded. The patients were randomly assigned to the MNT or NA groups using sequenced opaque sealed envelopes. The random sequence was achieved by www.randomization.com and printed in papers. Then, the papers were kept in opaque envelopes respectively by a third person and were sequentially numbered. Patients in both groups visited every two weeks during cancer treatment and were monitored for dietary intake and nutrition-related complications.

2.2 Nutrition intervention

The MNT group received an individualized dietary plan, nutrition education, as well as pharmacotherapy for nutrition-related complications, and if they could not meet their required energy intake, ONS was provided by the investigator. Energy and protein requirements were calculated as 25–30 kilocalories per kilogram of body weight per day and 1.2–1.5 grams per kilogram of weight per day [17]. ONS (Fortimel, Nutricia, Netherlands) was prescribed if patients received less than 90% of daily energy intake requirements through their dietary plan. Multivitamin and mineral supplements were prescribed at the recommended daily intake (RDA) dosage if needed [17]. When the patients were unable to have 60 percent of their energy requirements orally, they were recommended for enteral nutrition. When the patients could not meet their nutritional needs by oral and enteral nutrition, partial parenteral nutrition was considered according to their calculated daily energy and protein requirements. If the patients could not have any oral intake and enteral nutrition, total parenteral nutrition was administered [17]. Nutrition-related complications were managed by diet modification as well as medications. Pharmacotherapy was prescribed for symptom relief according to National Comprehensive Cancer Network (NCCN) guidelines, as follows: anorexia (Megestrol acetate), nausea and vomiting (Metoclopramide or Ondansetron), constipation (Polyethylene glycol, Lactulose, or Magnesium hydroxide), diarrhea (if not bacterial, Loperamide), gastritis or gastroparesis (proton pump inhibitors or H2 blockers), mouth mucositis (Nystatin) [18]. Esophagitis was also relieved by a medication recommended by a local guideline.

The NA group received general dietary advice at the beginning of the treatment which included explaining the importance of proper nutrition and regular food intake during cancer treatment. The patients were allowed to receive medications for symptom relief, ONS, or artificial nutrition prescribed by the oncologists during the treatment course.

2.3 Anthropometric, nutrition and dietary assessment

The demographic information including socioeconomic status [19] was directly collected from patients. The information regarding patients’ past medical history, tumor site, pathological type, pathology, diagnosis duration (according to pathology date), treatment type including RT or CRT, RT dosage, RT completion, and RT delay were also obtained.

Bodyweight was measured using a calibrated scale with an accuracy of 0.5 kg and an upper limit of 150 kg (Seca 510 scale, Germany). Each patient was asked to stand barefoot at the center of the scale base, wearing light clothes. Height was measured using a stadiometer attached to the wall (Seca 206 stadiometer, Germany). Patients stood barefoot with their heels close together, their back straight and arms extended vertically along the body. Body mass index (BMI) was calculated by dividing the patients’ weight (in kilograms) by the square of their height (in meters). Weight loss (WL) was defined as either mild (<5% loss in 1 month or 6–10% in 6 months), moderate (5–10% loss in 1 month or 10–20% in 6 months), and severe (>10% loss in 1 month or >20% in 6 months). Mid-upper arm circumference (MUAC) was measured by a flexible tape. Patients were told to bend their left arm, and the mid-point between olecranon and acromion process was marked with a pen. Then, the patients were asked to hang their arm straight and the tape was wrapped around the marked point.

Body composition was assessed using a bioelectric impedance analyzer (Tanita BC-418, Japan). Patients were asked to stand barefoot on the device with light clothes, holding the device handles. Fat mass percentage of total body mass and fat-free mass (in kilograms) were measured. The fat-free mass index (FFMI) was calculated as fat-free mass (in kilograms) divided by the square of the height (in meters). According to the Global Leadership Initiative on Malnutrition (GLIM) criteria for the diagnosis of malnutrition, FFMI of less than 17 kg/m² in men and 15 kg/m² in women is considered as reduced muscle mass [20].

Dietary intake was recorded using a 24-hour food recall. Macro and micronutrients were assessed by Nutritionist 4 software (Version 7, N-squared computing, OR, USA).

PG-SGA was used for nutritional status assessment by a trained nutritionist [21]. PG-SGA has been validated in Farsi [22, 23]. Visual analog scale (VAS) was used for pain level assessment [24]. The physical condition of patients was assessed through the Karnofsky performance status scale, which is a validated tool for the evaluation of physical performance [25] and muscle strength [26, 27]. Handgrip strength was measured using a dynamometer (Jamar, USA). The measurements were also compared with locally validated cut-offs according to age and sex [28].

2.4 Laboratory tests

The patients had to be fasting for 12 hours before sampling. Urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, serum albumin, cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL) were measured by the autoanalyzer device (Alpha classic- AT plus). Complete blood count (CBC) was measured by Sysmex KX-21N (Japan) and quantitative C-reactive protein (CRP) was measured by the ELISA test.

2.5 Sample size and statistical analysis

The sample size was calculated according to Isering et al. study [29] which reported the PG-SGA score to be 8.4±4.3 and 4.8±5.6 in the intervention and control groups, respectively. Considering a difference of 3, SD = 5, α= 0.05, and power = 80%, the sample size was calculated 45 in each group. With a 10 % drop out rate, the final sample size was estimated as 100 cases. All the data were collected and analyzed using SPSS V.22. (SPSS Inc., Chicago, IL, USA). The prevalence rates were calculated using descriptive statistics. The normal distribution checked by the Kolmogorov–Smirnov test and histogram chart with the normal curve. Parametric and non-parametric tests were used for analytic statistics accordingly. P-values less than 0.05 were considered statistically significant.

3 Results

A total of 100 patients with a male to female ratio of 51/49 and a mean age of 67.2±12.1 (range; 35–96) were enrolled. Figure 1 shows the CONSORT flow diagram of the study selection and process. The general characteristics of the patients and the information regarding oncological treatments are shown in Table 1.

Fig. 1

CONSORT Flow Diagram.

Table 1

General, tumor and treatment characteristics of study participants

Variables	MNT Group (n = 49)	NA Group (n = 51)
Age (years)^$^*	65.8±12.0	68.6±12.1
Sex (male)	30 (61.2%)	21(42.2%)
Education
Illiterate	30 (61.2%)	39 (76.5%)
Primary education	19 (38.8%)	9 (17.7%)
Academic education	0	3 (5.8%)
Living area (Rural)	30 (61.2%)	31 (60.8%)
Marital status (Married)	40 (81.6%)	41 (80.4%)
Occupation
Housewife	12 (24.5%)	19 (37.3%)
Employed	27 (55.1%)	20 (39.2%)
Retired	10 (20.4%)	12 (23.5%)
Economic Status
Low	35 (71.4%)	42 (82.4%)
Moderate	13 (26.6%)	5 (9.8%)
High	1 (2%)	4 (7.8%)
Food availability
No need for assistance	26 (53.1%)	32 (62.7%)
Has somebody for food preparation	23 (46.9%)	19 (37.3%)
Needs help but nobody is available	0	0
Smoking	5 (10.2%)	5 (9.8%)
Substance Addiction	12 (24.5%)	15 (29.4%)
Cancer self-awareness	45 (91.8%)	48 (94.1%)
Medical history
Diabetes	7 (14.3%)	4 (7.8%)
Cardiovascular diseases	6 (12.2%)	9 (17.6%)
Hypertension	16 (32.7%)	22 (43.1%)
Hyperlipidemia	8 (16.3%)	12 (23.5%)
Diagnosis duration (months)^$^*	1.1±0.2	1.1±0.4
Tumor sites
Upper	3 (6.1%)	5 (9.8%)
Middle	20 (40.8%)	17 (33.3%)
Lower	26 (53.1%)	29 (56.9%)
Tumor pathology
Squamous cell carcinoma (SCC)	45 (93.8%)	45 (88.2%)
Adenocarcinoma	3 (6.9%)	6 (11.8%)
Treatment type
Radiotherapy	7 (14.3%)	6 (11.8%)
Chemoradiation	42 (85.7%)	45 (88.2%)
Radiotherapy total dosage (Grays)^$, *	51.3±7.2	53.4±6.9
Radiotherapy completion	46 (93.9%)	47 (92.2%)
Radiotherapy Delay
Due to disease	6 (12.2%)	6 (11.8%)
Due to technical problem	4 (8.2%)	10 (19.6%)
Monitoring sessions^# , *	4 (3–5)	4 (3–5)

Values are reported N (%). ^$value reported in mean±standard deviation; ^#value reported in median (25th–75th percentile). ^*P-value obtained from independent sample t-test; and the other tests are Chi-square or Fisher tests. There was no significant difference at primary evaluation in all variables between groups (p-value > 0.05). Abbreviations: MNT, medical nutrition therapy; NA, nutrition advice.

The two groups did not differ significantly in regards to clinical, demographic, dietary intake, PG-SGA, body composition, laboratory tests, and nutrition-related complications. The dietary intake among groups is revealed in Table 2. The mean duration of patients’ assessment was 44±13 days. The MNT group had significantly better energy (26.4±14.1 vs. 18.2±11.2 Kcal/kg/.day), protein (1±0.6 vs. 0.7±0.4 g/kgw.day), fat (52±37 vs. 30±20 g/day), and carbohydrate (183±104 vs. 130±84 g/day) intake than the NA group at the final evaluation. The PG-SGA score, anthropometric indices, and patients’ physical condition are also illustrated in Table 2. There was no significant difference in the PG-SGA score between groups at the final evaluation (11±6 vs. 12±6). The PG-SGA did not change significantly from the primary to the final evaluation in either group. The NA group experienced relatively more weight loss during treatment (2.6±2.4 vs. 2.4±3.6 kg); however, this difference was not statistically significant (P = 0.80). Figure 2 reveals the weight loss intensity in both groups. Patients in the MNT group compared to the NA group showed more commonly no weight loss (21% vs. 11%) or developed only a mild WL (40% vs. 35%). Meanwhile, moderate WL was more frequent in the NA group (26% vs. 44%). A total of 11 cases experience severe weight loss. Among six cases who developed severe weight loss in the MNT group, four patients declined to undergo Jejunostomy despite not being able to take their dietary requirements orally, and 2 cases were not adherent to the prescribed oral supplementation. There was no significant difference in MUAC, fat mass percentage, FFMI, and handgrip strength between groups at the final evaluation (P-value > 0.05). Meanwhile, significant reductions in these indices were observed in both groups from primary to final evaluation; except for fat mass percentage which did not reduce significantly in the MNT group as opposed to the significant reduction observed in the NA group (Table 2). The Karnofsky scores and pain VAS did not change significantly during the treatment in either group. RT completion and RT delay were not significantly different between the two groups.

Table 2

Components of dietary intake, anthropometric indices and clinical status of participants who received either MNT or NA

Variables	MNT Group			NA Group			P-value^b
	Primary evaluation	Final evaluation	Change^a	Primary evaluation	Final evaluation	Change^a
	(n = 49)	(n = 47)		(n = 51)	(n = 46)
Energy Intake (Kcal/kgw.d)	17.4±9.6	26.4±14.1	8.8±15.4^**	16.3±9.4	18.2±11.2	1.2±14.4	0.003
Protein Intake (g/kgWday)	0.6±0.4	1.0±0.6	0.3±0.7^**	0.5±0.4	0.7±0.4	0.1±0.5	0.005
Carbohydrate (g/day)	128±60	183±104	57±100^**	116±72	130±84	10±111	0.04
Fat (g/day)	39±41	52±37	12±55	32±25	30±20	–2±33	0.001
MUFA (mg/d)	10±12	13±10	3±16	8±7	8±6	–3±9	0.005
PUFA (mg/d)	4±5	6±5	3±6	3±3	4±5	1±6	0.012
Fiber (g/d)	5±4	7±5	3±5	4±3	5±4	1±5	0.045
Phosphor (mg/day)	576±302	866±457	303±589	493±337	632±395	109±494	0.012
Iron (mg/day)	3.4±2.5	7.7±7.4	4.5±7.6	2.6±2.4	3.6±2.7	0.9±3.7	0.001
Zinc (mg/day)	3.5±2.1	7.4±5.8	3.8±6.5^**	3.2±2.7	4.0±2.9	0.8±4.2	0.001
Calcium (mg/day)	458±298	919±564	461±724^*	472±350	631±402	159±554	0.007
Magnesium (mg/day)	132±65	189±110	59±132	109±66	133±70	18±96	0.007
Vitamin C (mg/day)	98±102	103±97	11±106^*	78±74	104±96	24±103^*	0.94
Vitamin E (mg/day)	2.5±2.9	6.2±5.9	4.0±6.6	2.1±2.3	2.9±2.5	0.7±3.1	0.001
Vitamin A (μg/day)	166±140	248±261	84±317	197±192	174±179	–32±233	0.13
Vitamin D (IU/day)	14.9±22.2	39.9±52	24.9±56.1^*	17.9±29.4	22.6±29.0	4.8±31.6	0.058
PG-SGA score	13±6	11±6	–1±4	14±5	12±6	–1±6	0.97
BMI (kg/m²)	22.1±4.8	21.2±4.5	–0.9±1.3^**	21.8±4.3	20.7±4.4	–1.1±1.0^**	0.62
Weight (kg)$	56.9±13.5	54.5±12.3	–2.4±3.6^**	53.7±12.7	51.1±12.6	–26±2.4^**	0.80
MUAC (cm)	26.2±4.1	25.4±3.9	–0.7±1.4^**	25.7±3.6	24.4±3.7	–1.3±1.6^**	0.20
Fat Mass (%)	22.4±10.5	21.45±10.5	–0.9±4.2	22.0±10.3	19.9±10.8	–2.1±4.7^*	0.63
FFMI (Kg/M²)	17.1±2.5	16.4±2.3	–0.8±1.3^**	17.1±2.0	16.5±2.1	–0.5±1.0^*	0.78
Handgrip strength (kg)	43±21	39±20	–4±9^*	39±19	35±21	–4±7^*	0.40
Karnofsky	81±13	78±16	–3±14	82±12	79±15	–4±13	0.96
Pain VAS	2±3	3±3	1±3	2±2	3±3	1±4	0.97

All values are means±standard deviations. The normal distribution checked by the Kolmogorov–Smirnov test and histogram chart with the normal curve. ^aP-value comparison within groups obtained from paired-samples t-test: ^*P-value < 0.05; ^**p-value < 0.001. ^bP-value comparison between the groups obtained from independent-samples T-test. There was no significant difference between groups at primary evaluation in all variables (P-value > 0.05). ^$This comparison between the groups was done for the latest month weight loss. Abbreviations: MNT, medical nutrition therapy; NA, nutrition advice; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; PG-SGA, Patient-Generated - Subjective Global Assessment; BMI, body mass index; MUAC, mid-upper arm circumference; FFMI, fat-free mass index; VAS, visual analog scale.

Fig. 2

Weight loss (WL) intensity in MNT (medical nutrition therapy) and NA (nutritional advice) groups at the final evaluation.

Nutrition-related complications at the baseline and end of cancer treatment course are reported in Table 3. The most common complications which lead to food intake reduction were dysphagia (80%), constipation (40%), and anorexia (32%). There was no significant difference in terms of complications between the MNT and NA groups.

Table 3

Nutrition-related complications of participants who received either MNT or NA

Variables^∗	MNT Group		NA Group
	Primary evaluation	Final evaluation	Primary evaluation	Final evaluation
	(n = 49)	(n = 47)	(n = 51)	(n = 46)
Dysphagia	39 (79.6%)	26 (55.3%)	36 (70.6%)	26 (56.5%)
Anorexia	15 (31.9%)	15 (31.9%)	14 (30.4%)	11 (23.9%)
Nausea	9 (18.4%)	6 (12.8%)	3 (5.9%)	3 (6.5%)
Vomiting	2 (4.1%)	1 (2.1%)	1 (2.0%)	1 (2.2%)
Constipation	19 (40.4%)	11 (23.4%)	19 (41.3%)	14 (30.4%)
Diarrhea	0	0	0	0
Mouth sores	1 (2.0%)	0	0	1 (2.2%)
Dry mouth	3 (6.1%)	3 (6.4%)	1 (2.0%)	2 (4.3%)
Dyspepsia	10 (21.3%)	8 (17%)	13 (28.3%)	12 (26.1%)
Dysgeusia	7 (14.3%)	7 (14.9%)	9 (17.6%)	7 (15.2%)
Esophagitis	10 (21.3%)	15 (31.9%)	8 (17.4%)	15 (32.6%)
Oral mucositis	1 (2.0%)	1 (2.1%)	0	2 (4.3%)
Dysosmia	1 (2.0%)	2 (4.3%)	1 (2.0%)	2 (4.3%)
Early satiety	7 (14.3%)	9 (19.1%)	6 (11.8%)	5 (10.9%)

All values are reported n (%). ^*The symptoms were considered if they led to intake reduction. P-value comparison between groups obtained from Mc Nemar test. There was no significant difference at primary and final evaluation in all variables between groups (P-value > 0.05). P-value comparison within groups obtained from the Chi-square test. There was a significant reduction in dysphagia during chemoradiation in the MNT group (P-value = 0.019). There was no other significant difference in all variables within groups during the intervention (P-value > 0.05). Abbreviations: MNT, medical nutrition therapy; NA, nutrition advice.

Laboratory tests of participants at the baseline and end of cancer treatment course are shown in Table 4. There was no significant difference in laboratory tests between the two groups. WBC, total lymphocyte count, hemoglobin, hematocrit, platelets, and total protein decreased significantly from primary to the final evaluation in both groups. Albumin was also decreased in both groups (p-value = 0.054)

Table 4

Biochemical and hematological indices of participants who received either MNT or NA

Variables	MNT Group			NA Group
	Primary evaluation	Final evaluation	Change	Primary evaluation	Final evaluation	Change
	(n = 49)	(n = 47)		(n = 51)	(n = 46)
WBC (cells/mm³)	7684±2700	4046±3000	–3637±3800^**	7564±2600	4089±2700	–3475±2900^**
TLC (cells/mm³)	2154±817	731±442	–1423±911^**	1849±727	708±448	–1140±842^**
Hemoglobin (cells/mm³)	12.6±1.7	11.6±1.8	–1.0±1.2^**	12.4±1.7	11.4±1.5	–1.0±1.5^**
Hematocrit (g/dL)	37.7±4.5	34.4±4.8	–3.3±3.7^**	37.3±4.3	34.2±4.1	–3.1±4.3^**
MCV (fL)	84.9±7	85.3±7	0.4±6	85.1±7	86.2±6	1.2±4
MCH (pg)	28.4±3	28.8±3	0.4±2	28.3±3	28.8±3	0.5±1^*
RDW (%)	13.7±2.3	16.0±2.8	2.4±1.9^**	13.5±1.9	15.9±2.9	2.3±2.5^**
Platelets (per mm³) (*1000)	304±80	227±84	–767±75^**	287±87	212±83	–755±93^**
Urea (mg/dL)	29±10	38±16	9±12^**	31±11	32±14	1±15
Creatinine (g/dL)	1.09±0.24	1.08±0.30	–0.01±0.26	1.04±0.19	1.01±0.20	–0.03±0.25
CRP (mg/dl)	14.7±19.4	16.5±20.9	1.8±28.4	12.1±14.7	15.1±13.3	3.1±17.2
ALT (units/L)	17±11	22±10	5±15^*	16±9	20±14	5±10^*
AST (units/L)	21±5	24±10	5±11	21±7	24±9	3±8^*
Total protein (g/dL)	7.2±0.4	6.7±0.6	–0.5±0.7^**	7.1±0.6	6.7±0.6	–0.4±0.7^**
Albumin (g/dL)	3.9±0.3	3.8±0.3	–0.1±0.3	4.0±0.4	3.7±0.4	–0.3±0.4^**
Cholesterol (mg/dL)	182±39	188±50	7±43	190±41	188±44	–2±37
Triglyceride (mg/dL)	106±45	116±53	6±45	97±29	116±41	19±38^*
LDL (mg/dL)	110±28	116±31	6±31	108±32	110±32	3±31
HDL (mg/dL)	38.5±6.7	38.5±5.7	0.05±8.5	38.8±5.0	38.8±5.9	0.0001±7.5

All values are means±standard deviations. The normal distribution checked by the Kolmogorov–Smirnov test and histogram chart with the normal curve. P-value between groups comparison obtained from independent-samples T-test. There was no significant difference at primary evaluation in all variables between groups (P-value > 0.05). There was a significant difference at the final evaluation in urea between groups (p-value = 0.046). There was no other significant difference at the final evaluation between groups (P-value > 0.05). P-value within groups comparison at final evaluation obtained from paired-samples t-test: ^*P-value < 0.05; ^**p-value < 0.001. Abbreviations: MNT, medical nutrition therapy; NA, nutrition advice; WBC, white blood cells; TLC, Total lymphocyte count; WL, weight loss; FFMI, fat-free mass index; VAS, visual analog scale; BMI, body mass index; PG-SGA, Patient-Generated - Subjective Global Assessment; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RDW, red blood cell distribution width; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

4 Discussion

This study showed that patients with esophageal carcinoma undergoing CRT who received medical nutrition therapy had more favorable nutritional intake and experienced less weight loss as compared to cases who received only general nutritional advice. Despite higher energy and macronutrients and some micronutrients intakes in the MNT group, no statistical differences were noted between two groups in terms of Weight loss, PG-SGA, MUAC, muscle strength, physical performance, nutrition-related complications, and laboratory tests at the final evaluation. Some studies have shown that effective and timely nutritional interventions in patients with EC can improve quality of life and increase survival [17]. A study conducted by Cong et al. on 50 EC patients undergoing CRT revealed that as compared to the control group, patients who received nutrition support had improved nutritional status indices including weight, albumin, pre-albumin, and transferring levels as well as lower rates of cancer treatment side effects [30]. As compatible with our results, Isering et al. showed in a trial that patients with head and neck and gastrointestinal cancer who received MNT for 12 weeks had better total energy and protein intake than those who received only usual care (UC). In this study, the usual care constituted general nutritional advice and a booklet that were provided at the beginning of the treatment [31]. However, in contrast, our results, in this study, the PG-SGA score was improved in the MNT as compared to the UC group. This difference might be explained by the fact that in contrast to the Isering study, our MNT and NA groups had the same monitoring sessions.

Ravasco et al. conducted two separate randomized clinical trials on patients with colorectal and head and neck cancers to compare three methods of individualized dietary counseling, oral supplementation (provided 400 kcal/day energy and 20 gr/day protein) and a regular diet of usual food (ad libitum group). In both studies, energy and protein intake were significantly higher in the intervention groups (individualized dietary counseling and oral nutrition supplement) than ad libitum. The protein intake was higher in patients receiving ONS than those who were provided with individualized dietary counseling; however, the effect of dietary counseling was more constant after three months in comparison with the ONS group [32, 33].

Some previous studies have shown that nutritional interventions in patients with gastrointestinal cancers can be effective in improving nutritional status and weight gain [29 , 32–34]. In our study, both NA and MNT groups showed increased protein, carbohydrate, and energy intake at the final evaluation as compared to primary evaluation. This result shows that even general nutritional advice could be beneficial in improving nutritional status in patients receiving CRT. However, significantly higher carbohydrates, protein, and energy intake were shown in the MNT group.

Cancer treatments including radiotherapy and chemotherapy put patients at risk for malnutrition and reduce anthropometric indices such as weight, BMI, MUAC, and body fat percentage; however, as compatible with our results, previous studies have also proved that proper nutritional interventions can improve, or at least modifies the patients’ nutritional status [35, 36]. In this study, there was a better result in the fat mass percentage in the MNT group rather than the NA group (P = 0.151 vs. 0.006).

At the beginning of our study, the most common nutrition-related symptoms were dysphagia, anorexia, constipation, dyspepsia, esophagitis, and nausea. There was no significant difference between the frequency of these symptoms in the two groups, indicating nutritional intervention, either MNT or NA, can help improve these clinical symptoms. Only, dysphagia significantly improved in the MNT group (p-value = 0.019). Dysphagia, a common symptom in EC, is an important cause of malnutrition; therefore, timely nutritional intervention is crucial in improving the nutritional status in these patients [37]. Alongside our results, Cong et al. study proved that nutritional support can reduce treatment-related complications, improve treatment tolerability, and finally enhance nutritional status in patients with EC undergoing CRT [30].

Cancer treatments including radiotherapy and chemotherapy can alter hematological parameters [38]. In our study, the average WBC, total lymphocyte count, hemoglobin, and platelets decreased significantly from the primary to the final evaluation in both groups. Vasson et al. In a study on 37 patients with EC and head and neck cancers undergoing CRT, revealed that nutrition therapy can improve nutritional status as well as nutritional related laboratory tests such as albumin and total protein levels [39].

5 Conclusion

MNT compared with NA could improve energy and macronutrients intakes in EC patients; however, there was no significant difference in terms of clinical nutritional status. Therefore, it seems nutritional intervention (MNT or NA) and the presence of a nutrition specialist can help to better cope with treatment complications and improve nutritional status.

Author contributions

SM, AN, MST, AGM, FVT, SE, MN, MGM, ME, MKR, and FB designed the research. SM carried out the study. SM, NP, AN, MST, MGM, FB, SE, ME, and MKR conducted the library search, wrote the manuscript, and participated in the drafting and editing the manuscript. SM and NP designed the tables. and SM, ME, MKR, and SE participated in the statistical analysis. All of the authors read and approved the final manuscript.

Conflict of interest

The authors declare that there are no Conflicts of interest.

Footnotes

Acknowledgments

This paper is taken from a Ph.D. thesis on the same topic (code number: 941765). This research was funded by grants from Mashhad University of Medical Sciences, Deputy of Research and Cancer Research Center, and Reza Radiotherapy and Oncology Center (RROC). The formula was provided by Nutricia company. We thank the authorities of RROC for their cooperation and all the kind staff who facilitated the data collection procedure. The help of clinical research development units of Ghaem hospital and Akbar hospital is also appreciated. Also, we appreciate the patients who participated in this study.

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