Nutritional Deficiencies in Radiotherapy-Treated Head and Neck Cancer Patients

Nutritional deficiencies (malnutrition, cachexia, sarcopenia, and unfavorable changes in the body composition) developing as a side effect of radiotherapy (RT) currently represents a significant but still inaccurately studied clinical problem in cancer patients. The incidence of malnutrition observed in head and neck cancer (HNC) patients in oncological radiology departments can reach 80%. The presence of malnutrition, sarcopenia, and cachexia is associated with an unfavorable prognosis of the disease, higher mortality, and deterioration of the quality of life. Therefore, it is necessary to identify patients with a high risk of both metabolic syndromes. However, the number of studies investigating potential predictive markers for the mentioned purposes is still significantly limited. This literature review summarizes the incidence of nutritional deficiencies in HNC patients prior to therapy and after the commencement of RT, and presents recent perspectives for the prediction of unfavorable nutritional changes developing as a result of applied RT.


Head and Neck Cancer
Head and neck cancer (HNC) consists of a group of malignant neoplasms, mainly squamous-cell carcinomas (approx. 90% of tumors), that are heterogeneous with regard to their anatomical location, etiology, and clinical presentation, occurring in the mouth, throat, larynx, salivary glands, paranasal sinuses, and ear [1,2]. HNC forecasts are unfavorable, predicting a systematic increase in the number of cases and deaths. In the United States, over 65,000 new HNC cases and 14,500 deaths were estimated for 2020, which constitutes a 33.3% and 28.8% increase, respectively, compared to 2010 [3][4][5][6].
HNC is characterized by an unfavorable prognosis and the percentage of 5-year survival in this group of patients, regardless of the stage of cancer progression, which also depends on the anatomical location of the tumor, its degree of differentiation, the treatment used, and the clinical-demographic characteristics of the patient, does not usually exceed 30-40% [7,8]. In addition, development of the disease is promoted by risk factors to which residents of both developing and developed countries are exposed. The most important ones are smoking tobacco, regular alcohol consumption, and oncogenic human papilloma virus (HPV) infection resulting from risky sexual behavior and genetic alterations [9][10][11][12][13].
The choice of the HNC treatment method depends on the anatomical location, clinical stage, and histological differentiation of the tumor, as well as the clinical and demographic features of the patient, including age, fitness, the presence of comorbidities, and the nutritional status. In addition to surgical treatment, radiotherapy (RT) constitutes essential and routine HNC treatment, and in advanced stages of the disease, it is often supplemented with chemotherapy (CRT). If radical RT is used as the sole method of treatment or in combination with chemotherapy, conventional radiation doses are used (1 fractional dose: 1.8-2.0 Grey (Gy)/day for 5 days a week in a treatment regimen lasting 5-7 weeks (total dose of about 70 Gy)). This allows the achievement of therapeutic effects comparable to The disturbance of said balance by changing cellular metabolism in favor of catabolic processes leads to a gradual disruption of the quantitative and qualitative composition of energy-providing substances in the body, which leads to an impaired function of cells, tissues, and organs, and, consequently, the whole body, with effects of varying intensity occurring in cancer patients [32]. In light of recent studies, disorders of the catabolicanabolic balance in the course of neoplastic disease are attributed to both the developing cancer and the body of the patient trying to defend themselves against the "intruder". The developing tumor initially mainly consumes the energy substrates circulating in the host's blood-carbohydrates, fats, and proteins-to satisfy hyper anabolic processes that enable rapid and uncontrolled cell proliferation and, hence, a tumor mass increase. Along with the disease progression in the patient's body, the cancer's metabolic needs also increase, which requires the supply of increasing amounts of energy and building materials [33]. At this stage, the energy needs of the tumor can only be meet by the release of fats and proteins stored in the patient's adipose and muscle tissues under the influence of lipolytic and proteolytic factors secreted by cancer cells [34]. On the other hand, the body, which is being gradually cut off from the supply of energy-providing substances, is forced to cover its own energy requirements at the expense of a further loss of adipose and muscle tissues. In addition, in response to the developing pathology, the patient's body produces a number of pro-inflammatory cytokines (IL-1, IL-6, and TNF-α) [35]. Although they act as alarm and defense mechanisms of the body, their long-term release and persistently high level in the body lead to a negative effect on adipose and muscle tissue, as well as liver and brain functions. Currently, many researchers postulate the development of generalized inflammation as one of the key mechanisms leading to the development of malnutrition and cachexia [36,37]. According to clinical observations and the confirmed adverse effect of the applied therapy, the current definition of nutritional disabilities should be supplemented by the unfavorable effect of the therapy (surgery, chemotherapy, RT, and CRT) on the nutritional status of cancer patients. The mechanism of malnutrition and cachexia in neoplastic diseases postulated by most researchers and definition complemented by the impact of RT on the nutritional status of the HNC patients are presented in Figure 1. The result of the above-described metabolic disorders developing under the influence of the ongoing cancer process is disruption of the body's caloric balance, the development of inflammation, a loss of cell mass, and a change in the body composition that can lead to the development of malnutrition or wasting of the body [39,40].

The Problem of Malnutrition in HNC Patients
For decades, the presence of cancer cachexia was considered an obvious consequence of the ongoing neoplastic process in the body. Over the years, however, significant differences have been observed in the response to treatment and the survival of patients suffering from cancer cachexia compared to patients with a normal nutritional status, despite similar clinical-demographic characteristics. Unlike cachexia, sarcopenia was previously matched with an older age. Nevertheless, 22.5% of cancer patients present a risk for sarcopenia. Alarmingly, the prevalence of sarcopenia in HNC patients has been demonstrated to be high, although there is considerable between-study variation (16-71%). We now know that malnutrition, sarcopenia, and cachexia in cancer patients constitute an unfavorable clinical factor associated with deterioration in the quality of life and a worse response to the applied therapy, as well as a shorter survival time [41]. Malnutrition of various degrees is reported in 50-80% of cancer patients, and about 20-30% of patients in the terminal stage of the disease do not die of cancer, but due to long-term wasting of the body, which is no longer able to support the functions of vital organs due to the depletion of energy substrates [42,43].
HNC patients are at a very high risk of developing malnutrition, and about 60,000-90,000 patients die from cancer cachexia every year. The high rate of malnutrition in this group of patients is affected by the anatomical location of the tumor, the degree of its infiltration of the structures responsible for providing food to the body, and the toxicity of the applied therapy [42,44]. Approximately 50-70% of HNC patients are diagnosed with malnutrition of varying degrees, and progressive weight loss is often one of the first visible signs of cancer [45]. Although there are diagnostic tools based on clinical scales (Subjective Global Assessment-SGA and Malnutrition Universal Screening Tool-MUST), anthropometric measurements (BMI), electrical bioimpedance (BIA), or dual energy X-ray absorptiometry (DXA), which are able to detect malnutrition, sarcopenia, or cachexia with various degrees of sensitivity and specificity before or after treatment, there are still no objective predictive markers that would allow patients at the highest risk of developing malnutrition or cachexia during therapy to be initially selected [46][47][48]. The prevalence of malnutrition in RT-naïve HNC patients is summarized in Table 1.

Nutritional Deficiencies in HNC Patients Treated with RT
Malnutrition, cachexia, and sarcopenia developing as a side effect of cancer treatment is currently a significant but still inaccurately studied clinical problem in cancer patients. RT or CRT, which are characterized by a high aggressiveness in the destruction of tumor tissue, unfortunately also damage healthy tissues, which results in either the development of malnutrition or intensification of the already existing malnutrition, leading to cachexia [61,62]. The negative effect of therapy on the nutritional status of HNC patients is confirmed by the high percentage of malnutrition (44-88%) found after the completion of treatment in this group of patients. RT toxicity leads to gastrointestinal disorders, such as vomiting, diarrhea, xerostomy, stomatitis, and taste disorders, as well as a loss of appetite and anorexia. In addition, the side effects of RT or CRT are associated with a negative impact on the patient's mental condition. Patients may feel anxious or unwilling to eat as they associate eating with physical pain that accompanies biting, chewing, and swallowing [21,63]. These side effects of RT lead to a significant reduction in the supply of food and energy. This promotes the intensification of catabolic processes within the organism, which results in a gradual loss of body mass and its remodeling (changes in the body composition) associated with progressive proteolysis and/or lipolysis of muscle and/or fat tissue [64,65]. The most recent meta-analysis conducted demonstrated an unfavorable impact of RT-based therapy on sarcopenia incidence; its prevalence ranged from 6.6 to 64.6% pre-treatment and 12.4 to 65.8% post-treatment [66]. However, the incidence of malnutrition observed in HNC patients in oncological radiology departments can reach 80% [67,68]. The presence of malnutrition, cachexia, and sarcopenia is associated with an unfavorable prognosis of the disease, a higher mortality, and deterioration of the quality of life. Therefore, it is necessary to identify patients with a high risk of the mentioned metabolic syndromes [68]. The problem of malnutrition developing as a result of treatment and its impact on the patient's life and treatment results is so important that, based on the above clinical observations, the classical definition of malnutrition and cachexia has been expanded to also include other factors (the applied therapy) conducive to their development beyond the factors related to the presence of a tumor and metabolic disorders in the body. It is believed that any involuntary weight loss ≥ 5% within 1 month is a reliable indicator of malnutrition associated with hospitalization and the applied treatment [69,70]. This emphasizes that the therapy and adverse effects associated with it may significantly increase the dynamics of malnutrition development, even in short periods of time, such as the duration of radical RT (5-7 weeks). The prevalence of nutritional deficiencies developing in the course of RT ispresented in Table 2.

Prediction of Nutritional Deficiencies Developing during the RT Course
Assessment of the risk of cancer malnutrition, sarcopenia or cachexia at the stage of RT planning in HNC patients seems to be crucial for determining the patient's further prognosis, the success of the applied therapy, and the risk of early and long-term effects of its toxicity [88]. The currently available predictive tools-the patient's clinical features (age, smoking, and socioeconomic status), anthropometric measures (body weight, and BMI), clinical scales (Nutritional Risk Score-NRS-2002), or laboratory tests (markers of inflammation and the albumin level)-are insufficient for predicting the development of malnutrition during RT [54,67,81,[89][90][91]. The more reliable tools for the prediction of RTinduced changes in body composition demonstrate parameters derived from BIA, mainly the phase angle (PA), whose value is decreased in malnourished/cachectic patients [92]. For cachexia and sarcopenia detection, the most reliable tools are computed tomography (CT) and DXA [90,91]. The skeletal muscle index (SMI) is a measure of sarcopenia that can be obtained from diagnostic imaging studies, mainly CT. SMI measurement can be used globally to select patients for potential suitable therapy, and patients with a low SMI are more likely to be sarcopenic. Patients with a low SMI also had a significantly poorer prognosis than others, especially those who received definitive RT. SMI measured prior to RT can serve as a prospective biomarker of RT-induced sarcopenia. By establishing the optimal cut-off value, the changes in SMI noted during the therapy course can be considered as alternatives for the diagnosis of sarcopenia in routine examinations (ROC value > 0.9) [93][94][95]. In light of recent research in the field of genetics and molecular biology, more attention is being paid to molecular markers (gene polymorphisms, the expression of non-coding RNA, and epigenetic alterations), which can be very useful for diagnostic and predictive and prognostic purposes in cancer patients [96]. However, in the literature to date, there are very limited study results assessing the predictive value of molecular markers of malnutrition and cachexia developing during radical RT treatment in cancer patients, including HNC patients. The high application potential of the above markers also highlights the need to test their ability to detect and predict malnutrition, cachexia, and changes in body composition, while assessing the disturbance of their function (intensification or weakening) seems to be key to understanding the pathological mechanism of the development of both metabolic syndromes. This is justified by the molecular background leading to malnutrition, including the development of inflammation and fat and protein metabolism disorder as a result of increased lipolysis and proteolysis leading to quantitative and qualitative changes in the body composition [97]. The above-described processes are controlled by proteins, which demonstrate differences in the level of their activity as a result of the presence of, among others, polymorphisms in the genes encoding them or disorders in the mechanisms controlling their expression (microRNA and long non-coding RNA (lncRNA) expression). The intensification of the above mechanisms may be the result of the presence of a tumor, the patient's response to the pathological condition, or induced by the applied therapy. To date, many single nucleotide polymorphisms (SNPs) that regulate the activity of proteins involved in the development of inflammation and the regulation of metabolic pathways of sugars, fats, and proteins have been identified, and their presence may predispose patients to the development of cancer malnutrition or cachexia [98]. Recent studies have also proven the key role of microRNA molecules in regulating fat metabolism and, above all, in the mechanism of muscle atrophy and regulation of the severity of the inflammatory response in the body [99,100]. Moreover, RT affects the changes in the microRNA expression signature measured prior to and after the commencement of therapy [101]. Non-anthropometric factors demonstrating prospective utility in the prediction of nutritional deficiencies developing during RT in HNC patients are summarized in Table 3. Table 3. Tools/markers used in prediction of RT-induced malnutrition, cachexia, and body composition changes in HNC patients (anthropometric measurements and clinical scales were excluded).

Tool/Marker Role in Prediction of RT-Induced Nutritional Deficiencies
Phase angle (PA) [52] The risk of malnutrition/cachexia developing during CRT increased by 1.71 per mean PA decrease by one unit PA [92] Patients with low PA had 9.3-fold higher chance of BMI reduction below 18.5 kg/m 2 and over 5.9-fold and 4.2-fold higher chance of lean mass (LM) and FM reduction after therapy end compared with patients with a high PA value pre-albumin [81] Decrease of > 15% in pre-albumin level was more likely to be malnourished (OR = 2.442) after RT commencement. Pre-albumin level predicts weight loss during RT pre-albumin [83] The percentage of weight loss during RT negatively correlated with pre-albumin concentration, but not with other nutrition parameters 3-hydroxybutyrate (3HB) [102] 3HB is a relatively sensitive marker that allows earlier identification of the HNC at higher risk of > 10% weight loss during RT/CRT Patients with CC genotype had a significantly higher chance of BMI decrease < 18.5 kg/m 2 (underweight) following RT (OR = 23.0) and lower total protein and albumin concentration in the blood compared to carriers of CT and TT genotypes

SELP-2028 C/T [104]
The chance of losing ≥ 10% body weight and the development of cachexia during radical RT in patients with CC and CT genotypes was five times higher than TT genotype carriers (OR = 5.0) The dynamics of the adipose tissue lipolysis during RT was the highest in patients with AA genotype. They lost an average of 37.01% FM, while patients with GA and GG genotypes only lost an average of 7.73% FM. The risk of losing ≥20% or ≥30% FM during RT in AA genotype carriers was over five and over two times higher, respectively, than in men with GA and GG genotypes (OR = 5.78 and OR = 2.28).

ITGAM-323G>A [106]
The presence of the A allele of the ITGAM significantly (over 14-fold) reduced the risk of severe disturbances in nutritional status assessed according to the SGA scale (OR = 0.07) during RT miRNA-130a [78] Patients with low miRNA expression had over a three-fold higher risk of BMI decrease below 18.5, over six-fold higher risk of losing over 5% of body weight, and higher risk of > 10% weight reduction OR = 14.18, after the RT miRNA-181a + PA [107] Patients with simultaneous presence of low PA and high miRNA expression were at a significantly higher risk of decreasing the FFMI < 14.9 kg/m 2 (OR = 5.14), FFM < 44.7 kg (OR = 6.20), and lean mass (OR = 10.0) during RT Elevations in inflammatory cytokines and impairments in leptin/ghrelin functioning are associated with symptoms of cancer cachexia. Moreover, leptin level can decrease after the commencement of RT [108]. In another study, leptin increased cell proliferation and migration, as well as the colony-forming ability, despite the suppressive effect induced by RT [109]. These findings suggest that "hunger hormones" can also be attractive and prospective markers of post-RT nutritional deficiencies. Based on recent clinical experience, it is important to assess a patient's susceptibility to developing nutritional deficiencies in the course of RT. Therefore, detailed nutritional screening is required during therapy planning. Apart from molecular markers and body composition analysis, clinical factors are still useful for cachexia prediction. Recent studies demonstrated that patients with an older age (>70 years), loss of appetite, swallowing difficulty, poor performance status, and high Nutritional Risk Score (NRS) are at a higher risk of cachexia. Regarding sarcopenia in RT-treated HNC patients, it was found that sarcopenic individuals were more likely to be older (66 vs. 62 years, p < 0.001) or have a worse performance status (according to ECOG-WHO), and they were less likely to have a tumor located in the larynx, stage I or II disease, or p16-positive oropharyngeal cancer [110]. Clinical symptoms along with body composition evaluation and molecular marker assessment could allow a detailed insight into a patient's condition and should be considered during nutritional screening prior to therapy. It could exclude selected patients from therapy, for whom the therapy complications could be worse than the benefits [111,112]. The assessment of molecular changes seems to be primarily useful because of its ability to objectively reflect the body's condition at the cellular level, including the nutritional status and mechanisms controlling this process. Cellular metabolism disorder and damage to healthy tissues exacerbated by the effect of ionizing radiation can be noted much earlier at the molecular level, days or even weeks ahead of the appearance of clinical symptoms of malnutrition.

Nutritional Support in RT-Treated HNC Patients
There are limited data concerning the predictive value of nutritional support in RTtreated HNC patients, because most studies have focused on the treatment methods of post-RT nutritional deficits. However, according to nutritional management guidelines, nutritional intervention should be part of the management of RT-treated HNC patients. Nutritional intervention should be tailored to meet the needs of the patient and be realistic for the patient to achieve. Individualized nutritional intervention either during planning or for early stage RT may be beneficial in terms of decreasing the impact of its side effects, as follows: Decreasing unintended weight loss; improving dietary intake and quality of life; reducing acute toxicities and treatment interruptions; and positively affecting the survival. It is recommended that nutritional intervention takes place before RT is started and continued during and after treatment [113,114]. For these goals, the three main methods of nutritional support are oral, enteral, and parenteral. Parenteral nutritional support is rarely used in the HNC setting; however, it should be considered if required [115]. Current guidelines from the ESPEN recommend that ambulating patients with HNC should receive 1.2 to 2 g/kg/day of protein and 30 to 35 kcal/kg/day of energy daily [116]. Truly, such timely nutritional intervention can improve the curative effect for patients undergoing RT by the effective prevention of weight loss and muscle wasting. In a recent study concerning the energy intake in RT-treated HNC patients, it was found that an increased energy intake during RT can reliably reduce the post-treatment prevalence of severe malnutrition and increase the number of well-nourished individuals [55]. Prospective and retrospective trials in HNC undergoing RT demonstrated that enteral nutrition compared with oral feeding reduces weight loss, the frequency and duration of treatment interruptions, and the rate of hospital admission [117,118]. In HNC patients treated with either RT or CRT, individualized dietary counseling was beneficial for the quality of life, but the impact of tube feedings was not conclusive [119]. The latest findings also suggest a significant role of controlled physical exercises and rehabilitation in the curation of post-RT malnutrition, sarcopenia, and cachexia. However, a meta-analysis did not confirm the beneficial combina-tion of nutritional support with controlled physical activity regarding patients' nutritional benefits [112]. Moreover, dietetic counseling alone or associated with supplementation by enteral nutrition for three months was not able to prevent a loss of muscle strength and body weight during RT [113].

Conclusions
Malnutrition, cachexia, sarcopenia, and body composition changes are some of the major issues in RT-treated HNC patients. Unfortunately, there are a lack of established clinical guidelines allowing the successful management of HNC patients undergoing RT intervention. Data from oncology departments of European hospitals prove that only 30-60% of cancer patients at risk of malnutrition receive nutritional support in the form of oral supplementation, as well as parenteral or enteral nutrition [68]. By selecting a risk group using a molecular analysis of patients who have a high chance of development or progression of malnutrition during RT, it may be possible to make decisions regarding the introduction of nutritional treatment at the planning stage of therapy or parallel to treatment. In addition, using molecular markers to select patients at a high risk of developing both malnutrition syndromes during RT may help answer the questions of why some patients do not receive a full course of treatment (disqualification during treatment), the results of treatment are unsatisfactory, and the percentage and severity of complications are higher than expected. The development of treatment-induced malnutrition or cachexia may also be an unfavorable factor associated with the risk of early death, despite radical treatment. Molecular markers can be evaluated in a non-invasive manner based on blood sample testing, which may allow the assessment or monitoring of the patient's nutritional status at various stages of the therapeutic procedure. Determining the specific genotype and changes in the level of expression of microRNA and lncRNA circulating in blood in patients with HNC at the therapy planning stage can be a reliable and clinically attractive non-invasive predictive marker of malnutrition and/or cachexia, which may develop during RT before the first clinical symptoms occur. Early nutritional intervention can improve the curative effect for patients undergoing RT by the effective prevention of weight loss and muscle wasting.

Conflicts of Interest:
The authors declare no conflict of interest.