Dietary sources of vitamin A and retinol activity equivalences (adapted from [5, 6]).
\r\n\tAll book chapters are produced by forward-thinking specialists in the area of renewable energy and smart grids, with detailed analysis and/or case studies. This book is intended to serve as a reference for graduate students, academics, professionals, and system operators.
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"66221",title:"Vitamin A in Health and Disease",doi:"10.5772/intechopen.84460",slug:"vitamin-a-in-health-and-disease",body:'Vitamin A in health and disease chapter intends to introduce general information of vitamin A with specific focus mainly on its dietary recommendations and its importance to human health. In line with this, continuous monitoring of vitamin A status that determines deficiency or toxicity state that could significantly affect human health along with prevention efforts is also described.
Vitamin A is a fat-soluble vitamin and also comprises of a group of unsaturated nutritional organic compounds. These compounds include preformed vitamin A that exist in the form of retinol (alcohol), retinal (aldehyde), retinoic acid (irreversibly oxidized form of retinol) and several pro-vitamin A carotenoids (mainly β–carotene). The preformed vitamin A can only be obtained from the diet in food of animal origin and is the most abundant form of vitamin A in the human body. Retinol is a yellow fat-soluble substance, an absorbable form of vitamin A present in animal food sources. This chemical structure makes it poorly soluble in water but easily transferable through membrane lipid bilayers. Retinol is an alcohol and is known to be unstable. Vitamin A is mainly found in human tissues in the form of retinyl esters, which explains why the vitamin is commercially produced and administered as esters of retinyl acetate or palmitate. Retinyl esters will subsequently be converted into retinols in the small intestine [1, 2]. The pro-vitamin A comes from plant-derived foods primarily in oils, fruits and vegetables. β-Carotene is the major source of vitamin A precursor from plants and is represented as two connected retinyl groups. The molecules contribute to the body’s total vitamin A level. All forms of vitamin A have a β-ionone ring, which is attached to an isoprenoid chain (retinyl group). Both of these structural moieties are essential for the vitamin to exert biological activity. The β-ionone ring containing carotenoids include α-carotene, β-carotene and the xanthophyll β-cryptoxanthin [2].
Vitamin A can be found in a variety of foods. The bioavailability of carotenoids in food is variable because the efficacy of metabolic processes that convert carotene into retinol varies from one person to another. Table 1 shows important dietary sources of vitamin A. Foods rich in retinol include meat, butter, retinol-enriched margarine, dairy products and eggs, while foods rich in β-carotene include vegetables and fruits (e.g. sweet potatoes, carrots, dark-green leafy vegetables, sweet red peppers, mangoes, melons). Several processed foods have been fortified with vitamin A and are good sources of the vitamin, such as cornflakes, malted milk powder and milk powder [2, 3, 4]. Foods containing pro-vitamin A carotenoids tend to have less biologically available vitamin A but are more affordable than animal products especially in the diets of economically deprived populations.
Food category | Vitamin A (μg retinol equivalent/100g) |
---|---|
Meat/poultry/fish | |
Liver (ox/beef, chicken) | 9000–16,000 |
Egg, whole (duck, hen) | 208–304 |
Chicken, duck (thigh) | 50–69 |
Fish, mackerel, Indian/Spanish | 8 |
Vegetables | |
Carrot, raw | 835 |
Sweet potato | 709 |
Spinach | 469 |
Broccoli | 31 |
Fruits | |
Mango | 54–214 |
Papaya | 55–193 |
Apricot | 96 |
Watermelon | 28–68 |
Processed Food | |
Butter | 200–684 |
Cheddar cheese | 117–265 |
Full cream milk powder | 400 |
Malted milk powder | 711 |
Retinol, in the form of retinyl esters, and pro-vitamin A carotenoids enter the human body as a component of nascent chylomicrons secreted into the lymphatic system. Most dietary retinol (in chylomicrons and chylomicron remnants) is taken up by the liver, which is the major site of retinol metabolism and storage. Once circulating retinol is absorbed from the intestine, it will bind primarily to a protein called retinol-binding protein (RBP). The RBP will enter and leave the liver several times daily due to its lipophilic properties in a process known as retinol recycling. The retinol will bind to a cellular RBP (CRBP-I or CRBP-II) and can then be esterified by enzyme lecithin: retinol acyltransferase (LRAT), which enables the vitamins to be interconvertible, i.e. the stored ester and circulating retinol form. The storage efficiency and retinol catabolism are dependent on vitamin A status. Low retinol stores are associated with reduced storage efficiency and decrease the absolute catabolic rate [2].
To express the vitamin A activity of carotenoids in diets on a common basis, a concept of the retinol equivalent (RE) was introduced [7]. Based on this concept, the relationships among food sources of vitamin A were established as shown below:
1 μg retinol | = | 1 μg RE |
---|---|---|
1 μg β-carotene | = | 0.167 μg RE |
1 μg other pro-vitamin A | = | 0.084 μg RE |
A new term, retinol activity equivalent (RAE), was introduced in order to express the activity of carotenoids after taking into account new research on vitamin A activity of carotenoids [8, 9]. Specific carotenoids/retinol equivalence ratios are defined for pro-vitamin A carotenoids, which account for the less efficient absorption of carotenoids and their bioconversion to retinol. Recent work has shown that the absorption of carotenoids, the vitamin A precursors, is only half of as much as that previously considered. Institute of Medicine established the following conversion factor equivalents:
1 μg retinol | = | 1 μg RAE |
---|---|---|
1 μg β-carotene in oil | = | 0.5 μg RAE |
1 μg β-carotene in mixed foods | = | 0.083 μg RAE |
1 μg β-carotene and other pro-vitamin A carotenoids in mixed foods | = | 0.042 μg RAE |
The use of SI units (weight and molar) is strongly recommended to replace the use of IU in many databases to decrease confusion and overcome limitations in the nonequivalence of the IU values for retinol and β-carotenes. The conversion factors to be used are as follows:
1 IU retinol | = | 0.3 μg retinol |
---|---|---|
1 IU β-carotene | = | 0.6 μg β-carotene |
I IU retinol | = | 3.0 μg β-carotene |
Vitamin A is an essential micronutrient required in small amounts by human throughout the life cycle to perform multiple metabolic functions. It is important for growth and development, the maintenance of immune function and maintenance of epithelial cell integrity, good vision, reproduction as well as lipid metabolism. Vitamin A is also an important antioxidant, a property shared with vitamins E and C, respectively [3]. New biological functions of vitamin A such as lipid metabolism, insulin response, energy balance and the nervous system are continuously being discovered.
Vitamin A has long been known to play a critical role in vision. Night blindness or reduced vision ability under dim light is a very early and purely subjective symptom of vitamin A deficiency (VAD). In the eye, the 11-cis retinal binds to protein, term opsins, to form both the rhodopsins (rods) and iodopsins (cones) visual pigments [10]. Light that enters the eyes will isomerise the bound 11-cis retinal to all-trans form which initiates excitation of the photoreceptor cell. This isomerisation reaction will trigger nervous signal and passes along the cranial ‘optic nerve’ destined for the visual centre of the cerebral cortex that translates into a picture [11, 12]. A vitamin A metabolite, retinoic acid (RA), is essential for the normal functioning of the immune system [13]. Retinol and its derivatives function as an immune enhancer that potentiates the antibody response; at the same time it maintains and restores the integration of all mucosal cells and their functions. Retinols are also required for the development of leukocytes that play a major role in mounting an immune system. The major site of vitamin A action in the immune response is thought to be the T helper cell and T lymphocytes cell. The retinol derivative ‘4-hydroxyretinoic acid’ rather than retinoic acid is important in this aspect [14].
Along with its role in vision and immune system, vitamin A has also been shown to be actively involved in the production of red blood cells, which are derived from stem cells that depend upon retinoid for their proper differentiation. Vitamin A also appears to facilitate the mobilisation of iron stores to the developing erythrocytes where it is incorporated into haemoglobin, the oxygen carrier complex protein [15]. In addition, vitamin A (retinol, retinoic acid, all-trans retinal) is an important signalling molecule that affects gene expression and is called ‘retinoid-controlled genes’ which are involved in the differentiation and development of foetal and adult tissues, stem cell differentiation, apoptosis, support of reproductive and immune functions and regulation of lipid metabolism and energy homeostasis [16]. Retinol and retinoic acid also play a vital part in the development of human embryo and differentiation of three germ layers and propagation of the signalling process in the formation of the neural tube, organogenesis and development of limbs during embryogenesis. There are two main types of high-affinity receptor for trans- and cis-retinoic acid isomers within the nucleus cells of vertebrates including mammals. Each set of these receptors has six different domains which are involved in gene expression [17].
In terms of skin health, the isoform retinoic acid will switch on genes that differentiate immature skin cells into mature epidermal cells. Vitamin A and its metabolites have also been shown to improve photo-aged and chronologically aged skin pathologies. They promote the deposition of new collagen fibres and prevent degradation occurring in such skin types [11]. Growth hormone is a peptide hormone that stimulates growth (anabolic metabolite), cell reproduction and cell regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesised, stored and secreted by the somatotropic cells within the lateral wings of the anterior pituitary gland. The availability of vitamin A is necessary for expression of many genes including those human growth hormones [11].
Studies showed that vitamin A in the form of retinol is required for maintenance of adult mammalian spermatogenesis. Spermatogenesis is the production and development of sperm. It is a process which sperm cells undergo a series of cellular changes and divisions in order to fully develop. The cell begins as a spermatogonium and the undeveloped diploid sperm cell and ends as four spermatids. These spermatids form fully developed sperm cells that comprise semen. Retinoid acid is an essential regulator of gametogenesis both in male and female gametes, such that they can enter meiosis [18]. Antioxidant activity is another identified vital role, where the presence of vitamin A or β-carotene in small doses showed anticancer effect. It appears to stem from its ability to scavenge for reactive oxygen species (ROS) and can improve immune function in addition to eliciting an anti-proliferative effect through the retinoic acid receptor (RAR) and retinoid X receptor (RXR). ROS are the most important free radical in biological system and harmful by-products generated during the normal cellular functions. In this way, they can block certain carcinogenic processes and thus inhibit tumour cell growth [11, 19].
Vitamin A status of a specific population is important to better understand health status of the community in that particular area. VAD can lead to many health consequences, with children, pregnant and lactating women known to be the prominent groups suffering from VAD in many low-income countries [20]. Its prevalence of deficiency in a population is assessed by specific indicators/biomarkers [21].
There are several indicators/biomarkers to detect VAD. The ‘gold standard’ method to assess vitamin A status is through the direct measurement of liver reserves of vitamin A through biopsy, since in human, vitamin A is stored abundantly (>90%) in the liver [22]. A study in average-weight individuals for 4 months had shown that an estimated cut-off at 0.07 μmol/g liver was able to protect them from any clinical signs of VAD [23]. Unfortunately, this method is not feasible for population evaluation [24, 25]. Therefore, other various methods are being proposed to assess and monitor VAD based on their different aspects. The two different ways include biological (clinical, functional, histological) and biochemical indicators [26]. In 2010, liver reserves of vitamin A were plotted against the commonly used indicators to define the range of liver reserves associated with the specific indicators. It was later updated in 2015 as presented in Figure 1 [27].
The definition of vitamin A status assessed by using vitamin A indicators associated with vitamin A concentration in the liver. In 2010, 0.7–1 μmol/g was considered adequate, but this range is considered high (updated in 2015) until more biologically meaningful data are generated.
Biological indicators consist of clinical, functional and histological components. The clinical indicators are xerophthalmia where it consists of two words, ‘xeros’ (dry) and ‘ophthalmia’ (eye), which refers to specific eye diseases caused by VAD [28]. It is classified into several groups with night blindness being the earliest ocular sign of VAD. The xerophthalmia classifications and its associated criteria of public health problems by WHO are highlighted in Table 2.
Xerophthalmia classifications | Symbol | WHO criteria | Epidemiological aspect | Method of assessment |
---|---|---|---|---|
Night blindness | XN | >1% | Difficult for children below 2 years, highly specific, less sensitive | Survey/questionnaire |
Conjunctival xerosis | X1A | Not applicable | Not a reliable indicator of prevalence | Clinical examinations |
Bitot’s spot | X1B | >0.05% | Common in men, mostly occur in preschool children. Usually associated with history of X1A and night blindness | |
Corneal xerosis | X2 | >0.01% | A mild superficial haze due to obvious corneal change | |
Corneal ulceration/keratomalacia (<1/3 corneal surface) | X3A | >0.01% | Rapidly induced by VAD and measles infection | |
Corneal ulceration/keratomalacia (≥1/3 corneal surface) | X3B | >0.1% | Irreversible stage even with supplementation | |
Corneal scar | XS | >0.05% | Bilateral with onset before 5 years | |
Xerophthalmic fundus | XF | Not applicable | Rare manifestation of VAD |
Xerophthalmia classifications and its associated criteria of public health problem as per WHO (adapted from [57]).
Night blindness (XN) or poor adaptation to the dark is a functional indicator of VAD, which is assessed by taking a history from mothers and both pregnant and lactating women. The cut-off point to indicate the deficiency in mothers and children (age 24–71 months) is ≥1% report history of night blindness [29]. Night blindness occurs if vitamin A is seriously depleted since it is responsible for vision under very low illumination [30].
Signs of chronic, long-standing VAD of xerophthalmia are conjunctival xerosis (X1A) and Bitot’s spots with conjunctival xerosis (X1B). In general, a very bright torchlight in natural light is used to examine the eyes [29]. Conjunctival xerosis or drying can occur in both eyes where eyes turn dry and non-wettable with wrinkle presence at the temporal conjunctiva [31, 32]. Bitot’s spots are the accumulation of fine white foamy cheesy material comprising keratin, on the conjunctival surface [28].
Signs of acute, sudden onset of VAD are corneal xerosis (X2), corneal ulceration with xerosis (X3A), keratomalacia (X3B) and xerophthalmia fundus (XF). Corneal xerosis (X2) is drying of the cornea due to the lack of mucus and tears (wetting agent) because glands in the conjunctiva are no more functioning normally [33]. Lesions on the cornea become denser, and stromal oedema starts to develop during corneal xerosis. The cornea appears to be granular, rough and blurry when examined using a hand light [32]. At this stage, treatment with vitamin A will heal the eyes within 1 to 2 weeks without leaving any scars. Corneal ulceration with xerosis (X3A) is permanent destruction of all or some parts of the corneal stroma which are prominent. Ulcers may be shallow but usually become deep if it penetrates into the cornea. Vitamin A therapy can cure superficial ulcer, leaving small scars, while deeper ulcers and perforations form dense scars [28].
Keratomalacia (X3B) means softening of the cornea, and it is a rare stage of xerophthalmia. The cornea may become thickened and melt away due to a progression of necrosis or death of tissue, affecting the collagen in the cornea [32]. Blindness is usually inevitable, although other eyes and the lives of children can be instantly saved by vitamin A therapy. Keratomalacia is also usually associated with secondary eye infections but can be treated with an antibiotic [28]. Xerophthalmia fundus (XF) is the appearance of small yellowish lesions on the fundus of the eye, which occurs due to the loss of pigment from the retinal pigment epithelium caused by VAD. The lesions are sometimes accompanied by blind spots or scotomas, congruent with their distribution on the retina [34]. The healing or end result of corneal ulceration and keratomalacia is corneal scars (XS). Scars are left on the cornea with varying densities, known as staphyloma (permanent bulging of the damaged cornea) or phthisis bulbi (shrunken globe), whereby the contents of the intraocular are gone and can lead to blindness [28].
The morphological changes of epithelial cells from the conjunctiva surface can be assessed using a piece of filter paper. Normal conjunctiva cells show an abundance of mucin-secreting goblet cells and small epithelial cells. However, if there is a deficiency in vitamin A, the goblet cells and mucin droplets will reduce, and the epithelial cells become enlarged, separated and flattened [29]. Histological indicators include conjunctival impression cytology (CIC) and impression cytology with transfer (ICT). Assessing VAD using both techniques requires standard pore size filter paper, slides and a simple light microscope. The method involves gently applying a filter paper on the surface of the conjunctiva for 2–3 seconds, and after removal, it is placed in fixative and stained to differentiate the goblet cells from the endothelial cells. The eye is classified as normal or abnormal based on the number of goblet cells, which is counted under a microscope [35]. The differences between the two techniques are ICT only require single staining while CIC include extra processing steps for fixing, staining and mounting specimens. Comparatively, the CIC technique is more efficient in transferring cells of high quality from filter paper to slide [29].
Biochemical indicators include serum and breast milk retinol concentrations, relative dose response (RDR) test, modified relative dose response (MRDR) test and isotope dilution (ID) assay.
Serum retinol concentrations are among the most common method used to identify populations at risk of VAD [36]. They are determined using high-performance liquid chromatography (HPLC). The current cut-offs for VAD are <0.70 μmol/L, while severe VAD is classified below 0.35 μmol/L [21]. However, this indicator is affected by infections [37], inflammation and inadequate intakes of protein, zinc or energy, which are needed for retinol-binding synthesis [38]. Therefore, before using serum retinol concentration to assess VAD in a population, these factors should also be taken into consideration. In addition, serum retinol concentrations are homeostatically controlled over a broad range of body store and only decline when the liver reserves are very low [39]. Serum retinol concentrations should be used in conjunction with another biological indicator or when four or more of the following risk factors are detected in the population being assessed [40]. These risk factors include:
Infant mortality rate and under 5 years old mortality rate are >75 of 1000 and >100 of 1000 live births, respectively.
Less than 50% of children of 12–23 months old have full immunisation coverage.
The prevalence of breastfeeding in 6-month-old infants are <50%.
Among 75% of children (1–6 years old) have median dietary intakes <50% of the recommended safe levels of intake.
The prevalence of 2-week period of diarrhoea is ≥20%.
Fatality rate of measles cases is ≥1%.
More than 50% of women (15–44 years old) have no formal schooling.
Less than 50% of households has a safe water source (e.g. boiled, treated, filtered, properly stored).
Breast milk retinol concentration is a unique indicator in lactating women. It has also been proposed as a measure of the population status of vitamin A, since the probability of infant and children at risk of VAD is very high if the lactating women are of a community with marginal vitamin A status [41]. Vitamin A deficiency is considered a moderate public health problem if the prevalence of inadequate milk retinol concentrations (≤1.05 mmol/L or ≤8 mg/g milk fat) is ≥10–<25% [29]. The breast milk samples are easier to obtain, and the concentration of retinol in milk can be determined after saponification by HPLC, similar to those used to determine serum retinol [42].
The test principle of the RDR is on the basis that when vitamin A undergoes depletion, apo-retinol-binding protein (apo-RBP) accumulates in the liver. In this test, a challenge dose of retinyl ester is given to the subject, and blood samples are withdrawn prior to dosing (baseline) and 5 hours after dosing. The retinol from retinyl ester will bind to the excess RBP and is released into serum as holo-retinol/retinol-binding protein complex (holo-RBP-retinol complex). A percentage change is measured as per Eq. 1 where RDR ≥ 20% indicates VAD [35].
where, [A5] is the serum retinol concentration at 5-hr post-dosing; and [A0] is the serum retinol concentration just before dosing (baseline).
MRDR is a modified test of RDR using 3, 4-didehydroretinyl acetate (DRA) as the challenge dose, followed by a high-fat snack to ensure adequate absorption. In this method, a single blood sample is taken after 4 to 7 hours dosing [43]. In parallel to retinyl esters, DRA is hydrolysed to 3, 4-didehydroretinol (DR) within small intestine, taken up by enterocytes and esterified to form various didehydroretinyl esters. The esters are de-esterified to form DR in the liver, which can bind to apo-RBP and be released into serum or can be re-esterified and stored in stellate cells. The only difference between DR and retinol is the presence of a double bond located in the 3–4 position on β-ionone ring of DR. This structural difference can be separated using HPLC due to their difference in polarity. The MRDR value, which is used to indicate liver reserves, is the ratio of DR to retinol in serum [27]. The ratio of 3, 4-didehydroretinol (DR) to retinol is calculated, and the value of ≥0.06 indicates VAD in children [44]. The MRDR test has been widely used to diagnose a subclinical vitamin A status.
Of all the indicators available, the most accurate method to indirectly measure the vitamin A storage in the liver known till now is the isotope dilution assay [45, 46, 47]. Isotope dilution assay could detect a full range of vitamin A content in the body from deficient state up to the toxic level [48]. This test involves blood sample collection before and after the administration of a stable isotope tracer (deuterated or 13C-labelled retinyl acetate) at an appropriate equilibration period. The variations in the equation and assumptions used in the calculation are dependent on the study design based on the population assessed. The method of mass spectrometry used, the dosage size given to the subjects and the time allowed for equilibration were also taken into consideration when calculating the total body reserve in the ID test [41]. The ID assay is determined as shown in Eq. 2.
where:
a is the amount of dose absorbed and stored (dose × absorption rate).
b is the baseline total body reserves of vitamin A.
c is the total body reserve in μmol after the dose (c = a + b).
where Fa, Fb and Fc are the abundance of isotopes [13C/total C; At %/100; R/(R + 1)] from dose, baseline serum and serum after the dose.
Routine monitoring of vitamin A status serves as an important measure in the determination of toxicity due to excessive intake or deficiency in a population. Under circumstances where dietary consumption does not meet the recommended criteria, this could lead to vitamin deficiency or toxicity depending on whether the vitamin consumption is insufficient or in excess, respectively. Various health implications have been reported as a consequence of both vitamin deficiency and excess, as discussed below.
Dietary source of vitamin A is generally available in various forms, of which the preformed retinol from animal-based source (eggs, liver, dairy) is the most bioavailable form of vitamin A. Plant-based food sources are rich in pro-vitamin A; however, populations that are dependent solely on these sources are at higher risk of VAD since its absorption is reliant on various factors [49, 50]. VAD is commonly associated with decreased immunity and higher risk of night blindness [51]. It is worthwhile to note that this deficiency is highly prevalent in countries with an alarming increase of diabetes especially among those of lower income group in United States as well as Asian developing countries [51, 52].
Vulnerability to VAD differs according to specific life stages that include infancy, childhood and pregnancy. VAD in neonates is highly related to insufficient vitamin A in breast milk or formula milk. Apart from dietary shortage, VAD could have also been triggered by reduced intestinal absorption of vitamin A. Prolonged deprivation of body requirements for vitamin A leads to vitamin A deficiency disorders (VADDs) that affects gastrointestinal, renal, musco-skeletal organ systems as well as harming growth and development [53]. Xerophthalmia and anaemia are two most common examples of VADDs. In line with vitamin A roles as immunity enhancer, its deficiency is often associated with an increased risk of infections [54, 55]. Respiratory tract infections and diarrhoeal diseases are the most common form of infections with high incidence of mortality along with marked susceptibility to severe measles infection [55, 56, 57]. The representation of VADD association to risk of mortality is presented in Figure 2 below.
Representation of VADDs in relation to risk of mortality (adapted from [53]).
Xerophthalmia refers to a spectrum of ocular manifestations due to VAD and varies according to its severity and age. It is characterised by pathological dryness of the conjunctiva and cornea that turns out as a leading cause of childhood corneal blindness, especially in nutritionally deprived populations [58]. All of such signs encompass those involving impaired retinal sensitivity to light (night blindness) and epithelial disruptions of the cornea and conjunctiva (conjunctival xerosis, Bitot’s spot, corneal xerosis and keratomalacia) [59, 60]. The classifications of xerophthalmia stages in order of severity based on WHO criteria are shown in Table 2 (Section 3.1.1).
Xerophthalmia can occur in any age group with higher possibilities in preschool-age children, adolescents and pregnant women. In line with greater requirements for growth, children are more prone to VAD and xerophthalmia [61]. The initial symptoms of VAD are characterised by impaired adaptation to dark, which starts when the serum retinol concentration falls below 1.0 μmol/L and becomes more often when it falls lower than 0.7 μmol/L. A further drop in serum retinol concentration level below 0.35 μmol/L leads to more frequent and severe xerophthalmia condition [62, 63]. The incidence of xerophthalmia is often associated with higher risk of mortality [57].
Night blindness is generally the earliest manifestation, and it is indicated by vision limitation under dim light and is both a sensitive and specific indicators for low serum retinol levels [63, 64]. Vitamin A in the form of retinal within the eyes combines with opsin to form rhodopsin, which is the photosensitive visual pigment of rods. Rhodopsin level decreases when vitamin A is deficient, and this impairs the rod function causing night blindness [61]. Bitot’s spot is the representation of opaque whitish deposits on the scleral conjunctiva, which is the most characteristic sign of problems related to VAD. Conjunctival xerosis is already present at this stage, with the conjunctiva appearing dry and dull. Under conditions where VAD persists, corneal xerosis (hazy cornea) occurs, followed by keratomalacia (liquefaction of part or all cornea) [61].
Several risk factors have been associated with onset of VAD and xerophthalmia based on epidemiological findings. These include demographic, geographic, childhood, parents and household factors. The mechanism of these factor effects on the prevalence of xerophthalmia is summarised in Table 3.
Risk factors | Epidemiological findings | References |
---|---|---|
Demographic | Higher prevalence is observed in neonates, preschool children and pregnant women as they are more vulnerable to be deficient | [57, 65] |
Geographic | VAD and xerophthalmia are generally more prevalent in rural areas due to variations of vitamin A-rich food sources, supplementation efforts, limited access and climate changes | [57, 66, 67, 68] |
Childhood | Breastfed children are at minimal risk of infections and xerophthalmia compared to the non-breastfed children | [57, 69] |
Parental | Education literacy is important since it is highly protective against xerophthalmia development and VAD in preschool children | [57, 70] |
Household | Poor hygiene, inefficient water supply and cultural and behavioural practices of a family can increase the risk of xerophthalmia. Its prevalence is higher in lower socioeconomic status areas | [57, 70, 71, 72, 73, 74] |
Risk factors associated with prevalence of VAD and xerophthalmia.
On another note, the increase in supply and consumption of fortified foods and supplements led to intake of preformed vitamin A at higher than the recommended level [75]. The side effects of vitamin A excess could occur in two forms, known as hypervitaminosis A and hypercarotenemia [76].
Hypervitaminosis A can occur due to both acute and chronic intoxications that generally result from excessive intake of vitamin A from nutritional supplements and foods rich in vitamin A [76]. Acute toxicity occurs when adults and children ingest more than their respective recommended dietary allowance within few hours or days, while chronic toxicity results from prolonged consumption of preformed vitamin A over the months or years. However, acute conditions create minimal consequences to human health compared to those under chronic toxicity [77, 78]. Vitamin A, being an essential fat-soluble micronutrient, is quickly absorbed upon ingestion, although it is only cleared slowly from the body. Under such conditions, toxicity could arise either from high-dose exposure or low intake over short or prolonged duration, respectively [79]. Chronic hypervitaminosis A leads to various clinical manifestations that include xerosis, epistaxis, alopecia, weakness and fatigue, bone and joint pain, insomnia, drowsiness, anorexia, bulging fontanelle in infants as well as psychiatric symptoms [76].
Previous research findings have shown that elevated serum concentrations of vitamin A is highly associated with risk of hip fracture [80, 81]. This association is supported by evidence of rat-based experimental studies that demonstrated excessive intake of vitamin A leads to increased bone resorption and less formation at the outer surface that results in bone narrowing [82, 83]. In contrast, the mechanism takes place in opposing effect on the bone marrow surface, where an increase in vitamin A intake reduces bone resorption while increasing its formation. This contradictory effect takes place by the action of vitamin A or its metabolites on osteoblasts at the outer surface together with indirect effect on bone marrow surface [83, 84].
Hypercarotenemia, which is also referred to as carotenemia or carotenodermia, is a benign phenomenon characterised by pigmentation of the skin. The yellow-orange pigmentation is a result of carotene deposition at the stratum corneum, which is the outermost layer of epidermis [76]. Hyperlipidaemia, consumption of excessive carotene or failure of converting carotenes into vitamin A are conditions that lead to the onset of carotenemia. In view that there is a direct relationship between β-carotene and β-lipoprotein, other medical conditions that are associated with hyperlipidaemia also could lead to this pigmentation. Those conditions include diabetes mellitus, nephrotic syndrome and hypothyroidism. Apart from these, patients suffering from liver disease are also at higher risk of carotenemia due to the impaired conversion of β-carotene into vitamin A [76]. In contrast to hypervitaminosis A, there are no clear indications of carotenemia to health, and the pigmentation could disappear within weeks to months along with a steady decrease in β-carotene concentration [76, 85].
Dietary factors are highly correlated with VAD, especially with increasing requirements at different stages of life. Apart from these, sociocultural factors (intra-household distribution, gender preference) and other economic constraints to achieve adequate dietary requirements for well-being are where a high prevalence of deficiency occurs that leads to prevention efforts. The undertaken prevention efforts should also cater to reduce infectious disease apart from improving vitamin A levels [53]. The prevention approach includes dietary diversification, fortification as well as supplementation. The feasibility of applying each preventive strategy concurrently is somehow dependent on deficiency prevalence and severity as well as infrastructure, financial capacity, potential benefits and safety [86]. In addition, it is also necessary to understand that the success of each preventive programme is interrelated to all levels, inclusive of family, community, district, national and global [53].
Dietary diversification refers to efforts of increasing vitamin A intake from commonly accessible and easily available food sources. This approach is deemed feasible provided there is diverse, affordable and continuous supply of vitamin A-enriched dietary sources. Extended breastfeeding is also regarded an important dietary intervention measure, especially as a first-line defence and protection for infants and young children against xerophthalmia. A combined approach of weaning with a routine provision of vitamin A-enriched sources (fruits, vegetables, eggs and others) has proven effective in increasing serum levels of retinols among children [87]. However, under circumstances that the dietary supply is inadequate, home or community gardening will be a good alternative in ensuring food security. In addition to food security, this effort is viable for income generation as well as providing nutritional education to the community. The attempt to involve community-level participation is vital for behavioural adaptation that could considerably improve vitamin A status [53].
Fortified foods have been a common intervention globally in combating multiple nutrient deficiencies. The effectiveness of fortification-based intervention is highly dependent on few factors. These include the fortified food vehicle that are widely consumed by high-risk groups, incurs minimal cost and is of a high quality along with centralised processing and distribution [53]. Comparatively, preventive measure via food fortification is much more beneficial and effective than either dietary diversification or vitamin A capsule distribution. Numerous food sources have been subjected to fortification, and these range from oils, flours, cereals, rice, infant formula and also beverages. As such, fortification relates to exploitation of current fortified food consumption patterns towards enhancing vitamin A status [53].
Vitamin A supplementation at high dosage is the most widely practiced prevention measures throughout the world. The supplementation is channelled on an interval basis with a designated duration. This mode of prevention comprises community involvement and efforts to provide vitamin A supplements to nutritionally vulnerable groups, especially preschool children and mothers. The rationale for high-dose supplementation of vitamin A is based on the assumption that this fat-soluble compound will be stored in the liver and is released together with the transport proteins as per body tissue requirement [53].
Vitamin A is one of the fat-soluble vitamins that are vital for various biological roles in the human body, as it is essential for embryogenesis up to adulthood. It can be sourced from both animal-based (preformed vitamin A) and plant-based (pro-vitamin A) foods. The evaluation of whether a population is vitamin A deficient or excess is determined by status monitoring. Biological and biochemical indicators are the most widely applied parameters in assessment of vitamin A status. Vitamin A deficiency or toxicity state arises under conditions where the dietary intake does not comply with recommended levels. It is crucial to note that both conditions could lead to various health complications with VAD leading to mainly xerophthalmia, increased infection risk and anaemia, while toxicity could result in chronic hypervitaminosis and hypercarotenemia. In line with this, prevention efforts that could improve vitamin A status are widely explored. Dietary diversification, fortification and supplementation are the three main approaches that are widely applied for this purpose. These continuous efforts are believed to be able in improving vitamin A status among the vitamin A-deficient populations.
Utmost appreciation is conveyed to the Director General of Health Malaysia and the Director of Institute for Medical Research (IMR) for giving permission for this manuscript to be published as a book chapter. Special thanks to all staff of the Nutrition Unit, IMR, for their continuous support.
It is declared that there is no conflict of interest involved in the publication of this book chapter.
apo-RBP | apo-retinol-binding protein |
CIC | conjunctival impression cytology |
CRBP | cellular retinol-binding protein |
DR | 3, 4-didehydroretinol |
DRA | 3, 4-didehydroretinyl acetate |
Holo-RBP-retinol complex | holo-retinol/retinol-binding protein complex |
HPLC | high-performance liquid chromatography |
ICT | impression cytology with transfer |
ID | isotope dilution |
LRAT | lecithin: retinol acyltransferase |
MRDR | modified relative dose response |
RA | retinoic acid |
RAE | retinol activity equivalent |
RAR | retinoic acid receptor |
RBP | retinol-binding protein |
RDR | relative dose response |
RE | retinol equivalent |
ROS | reactive oxygen species |
RXR | retinoic X receptor |
VAD | vitamin A deficiency |
VADDs | vitamin A deficiency disorders |
XF | xerophthalmia fundus |
XN | night blindness |
XS | corneal scars |
X1A | conjunctival xerosis |
X1B | Bitot’s spots with conjunctival xerosis |
X2 | corneal xerosis |
X3A | corneal ulceration with xerosis |
X3B | keratomalacia |
The transition in the 1990s from conformal 3D radiotherapy to intensity-modulated intensity radiotherapy (IMRT) allowed the high-dose irradiation of volumes with irregular shapes [1, 2]. The use of radioprotective agents and radiosensitizers is another strategy to maximize the effect of radiotherapy. Recently, interest has focused on the design of irradiation protocols that exploit the differences in biology in terms of the response to irradiation between tumor cells and normal tissues [2, 3].
From the clinical point of view, tissue radiosensitivity is reported as the difference in the degree of response at the same dose of irradiation or at different doses required to produce the same response to different subjects. The radiosensitivity and radioresistance of the different types of tissues is determined by the mitotic rate and the cellular repopulation, being proven that the cells with low rates of repopulation are more radioresistant. Especially for cells with long post-mitotic life, for which the main mechanism of radiation induced hypoplasia and atrophy, is death in interphase, the response is obtained only at high doses of radiation [1, 2, 4].
With all the technical and ballistic advances in the planning and delivery of radiation therapy that has occurred in over 100 years since the use of radiation in anticancer treatments, it has not been possible to obtain a perfect therapeutic ratio for which the irradiation of healthy tissues tends to zero. Historically, the first initiative to guide doctor radiation oncologists was the publication of Rubin and Cassarett, a collection of reports on toxicities and doses to which they were reported. The 1980s were a significant evolution in the field of radiation oncology, the radiotherapy being transformed from a two-dimensional (2D), based on the approximate evaluation of the position of the radiosensitive organs based on the anatomical landmarks and subsequently of the 2D simulator with conventional radiographs, to a three-dimensional (3D/volumetric) process. This evolution has shown that previous knowledge about tumoricidal doses and tolerance of radiosensitive organs to irradiation does not present accuracy and new information is needed regarding partial organ volumes and toxicities [2, 5].
In this context, a scientific committee has carried out an extensive review on the dose data received from different organs and toxicities, reaching the consensus to evaluate the data using a volumetric division of organs in one-third, two-thirds, and the whole organ. The consensus of eight experts from reference centers in the United States was published under the name “Emami Paper.” The paper was a reference for assessing the risk of toxicity associated with doses, but being a literature review until 1991, it contained data from the previous 3D-CRT technology. Another limitation of the study was the evaluation of toxicities after conventional irradiation (2 Gy/fraction), and at that time neither the dose-volume histograms were routinely used in dosimetry. From the clinical point of view, only the most severe toxicity was evaluated, without any grading system for these adverse effects [1, 2, 6, 7].
The next decades have brought a revolution in terms of oncological treatments. A multidisciplinary approach has become a standard in oncology, and sequential and increasingly concomitant therapeutic associations are increasingly used. In terms of technology, most cobalt units have been replaced with linear accelerators, and radiotherapy planning based on CT simulation has become standard. 3D-CRT and IMRT techniques based on IGRT have been widely implemented, and delineation of tumor target volumes using CT, MRI, and PET-CT imaging has become a standard. The complexity and the large number of factors that influence the response to the irradiation of the tumors and the probability of the complications of the normal tissues have made it necessary to develop predictive models for the clinical complications associated with the radiation therapy. The large number of data reported in relation to the different toxicities and conditions of registration make analysis difficult to identify value parameters. A group of clinicians and researchers performed a retrospective analysis called “Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC).” The aim of this approach was to review the available literature on the correlation of dose-volume parameters with the complications of normal tissues, the study being the analysis of the literature of the last 18 years. The paper QUANTEC, resulting from the collective effort of 57 experts, appears with the support of the American Association of Radiation Therapy (ASTRO) and American Association of Medical Physics (AAPM) and is published in the supplement of the journal “International Journal of Radiation Oncology, Biology, Physics” (the Red Journal) [2, 5, 6, 7, 8].
The QUANTEC group aimed to provide a reliable prediction at the time of radiotherapy planning of the risk of occurrence of toxicity depending on the volume parameters extracted from the dose-volume histograms.
Although these publications contain a comprehensive review of scientific papers of the information published in order to be a guide for clinicians, the use of this guide cannot substitute for the judgment of the radiation oncologist clinician, considering the large number of intrinsic and extrinsic factors on which the radiosensitivity of each organ depends [7, 8].
There is no model that accurately predicts normal tissue responses to irradiation for routine clinical use, most models being more descriptive than predictive. The use of the multi-leaf collimator (MLC) allowed a better dosimetric coverage of the target volumes also offering a significant reduction in the irradiation of the healthy tissue from the proximity of tumors.
The isoeffect formula for conversion to standard fractionation is commonly used in cases where another fractionation scheme (hypofractionation or hyperfractionation) is used to assess the toxicity risk according to the “QUANTEC” data:
The α/β index is calculated based on information from cell survival curves on in vitro cell cultures, assigning values for the α/β ratio, and using these values to calculate a normal dose of tissue tolerance may be risky in estimating clinical complications [2, 7, 9].
Organs at risk (OAR) are those organs that if irradiated can be structurally and functionally affected. The structures that are in the proximity of the irradiated volume or by their anatomical function are defined as OAR, receive a certain dose during the treatment. These OAR’s have been divided from the radiobiological/functional point of view into serial organs and parallel organs. The spinal cord is the most relevant example of OAR with serial architecture. Each subunit of the spinal cord is vital to the functioning of the entire organ. The parallel structural organization is based on the functional independence of the subunits. The impairment of a limited number of structures does not compromise the function of the whole organ; the dysfunction occurs if a large number of subunits have been affected, because the remaining functional ones do not have sufficient compensatory capacity. An example of an organ with parallel architecture would be that of the parotid glands. In these cases the average dose absorbed throughout the organ is the most significant predictor of toxicity [5, 7, 8].
Using a Lyman mathematical model and the algorithm proposed by Kutcher and collaborators, a radiobiological model was proposed based on extrapolation of Emami guides to any dosimetric distribution, using dose-volume histograms (DVH). The Lyman-Kutcher-Burman (LKB) model was and is one of the most used radiobiological mathematical models, but the multitude of factors involved in producing toxicities made this model an ideal one, without being implemented in clinical practice as a standard. The QUANTEC is one of the most valuable analyzes on dose-volume parameters based on numerous retrospective studies. However, the therapeutic and technical diagnostic advances in the multimodal treatment of the pathological pathology make it necessary to update and validate new recommendations regarding the dose-volume parameters correlated with toxicities [7, 8, 9, 10].
With the implementation of inverse planning techniques (IMRT and volumetric intensity-modulated volumetric arc therapy (VMAT)), it became necessary to define a risk-exposed volume (RVR) in order to obtain an optimal dose distribution using the planning software, trying to limit the risk of developing high-dose regions outside the target volume. ICRU83 defines RVR as the difference between the volume included in the external contour and the volumes CTV and OAR. With the implementation of IMRT, the dose received by RVR can be a predictor of the risk of radioinduced carcinogenesis, and a reduction of large volumes receiving low doses is necessary. In fact, there are numerous intrinsic and extrinsic factors that influence the radiosensitivity of each tissue/organ, related to the patient (age, comorbidities, Karnofsky score/ECOG performance status) and dependent on the radiosensitivity of each organ (serial dose-effect organization, the most eloquent case being of the spinal cord, parallel radiobiological organization volume-effect structure as in the case of liver and lungs, mixed serial and parallel organization described in the literature in the case of kidneys), but it is also influenced by the previous treatments applied. Radiotherapy treatment influences the response of radiosensitive organs by parameters as the maximum dose, average, minimum, dose rate, general treatment time, irradiation beam energy, and irradiated volume. Systemic treatments (radiosensitizing and radioprotective agents, chemotherapy, biological and immunotherapy) influence the tissue radiosensitivity and determine the variability of the different responses at the same irradiation dose. The most recent studies show the involvement of molecular and genetic profiles in radiosensitivity. According to Emami and QUANTEC studies, cerebral radionecrosis usually occurs late from 3 months up to a few years after radiotherapy with initially a 5% risk at 5 years after treatment at a dose of 60 Gy received by one-third of the brain by standard fractionation. Using the ratio
Toxicity by spinal cord irradiation is also severe, and myelopathy is often disabling. For a ratio
Radiation-induced optic neuropathy (RION) is severe toxicity leading to a rapid assessed blindness. Emami’s recommendations are TD 5/5 of 50 Gy for the entire organ.
Based on the QUANTEC review, a dose of 50 Gy received by the whole organ is associated with <1% risk of toxicity, and the risk increases from 3–7% for doses between 55 and 60 Gy, the increase in toxicity rate being significant for doses greater than 60 Gy [2, 7, 8].
For the radiotherapy of thoracic tumors, radiation-induced pneumonitis is one of the most common toxicities in patients treated with radiation for cancers of the lung, breast, and other mediastinal tumors, often being the dose-limiting toxicity. Parameter V20 was identified as the most significant predictor of pneumonitis.
Radiation-induced pericarditis is associated with increased levels of mortality, the most relevant cardiac toxicity of irradiation. It was considered that the pericarditis risk is less than 15% when the mean pericardial dose was <26Gy, another dosimetric constraint considered predictive for pericarditis being V30 (pericardium) <46% in the case of breast cancers irradiation [2, 7].
Radiation-induced liver disease (RILD) usually occurs between 2 weeks and 3 months after radiation therapy. Emami guideline estimates an associated risk of <5% toxicity for an average dose of ≤30 Gy received by the liver, with a reduction to a maximum of 28 Gy required in patients with pre-existing liver disease.
Radiation-induced renal dysfunction is manifested in a variety of ways, from clinical symptoms to biochemical or imaging changes, most commonly with decreased creatinine clearance or even renal failure. An average dose of 18 Gy is considered to be associated with a 5% risk of toxicity at 5 years, with limitation to an average dose of 20 Gy being considered a feasible option in clinical practice [2, 5, 7].
Treatment toxicity for pelvine tumors includes femoral neck and head necrosis, associated with possible fracture. Factors such as osteoporosis and androgen treatment in the background increase the risk of irradiation toxicity. A 52 Gy dose for the entire femoral head was considered the recommended limit according to Emami publication, limiting the dose below 50 Gy and reducing the risk of neck/femoral neck necrosis to <5%. However, there are studies that report toxicities for large doses delivered on smaller volumes [7, 9, 13].
Without proposing to present all the recommendations of these guides, we have exemplified some recommendations and their predictive value on the toxicities for radiotherapy of tumors of the cervical, thoracic, abdominal, and pelvic regions.
The development of mathematical models in cancer biology and radiotherapy treatment is a step motivated by the desire to evaluate the probability of tumor control and the probability of healthy tissue complications. The technical evolution of radiotherapy and the complexity of the treatment plans have led to the emergence of increasingly complex treatment plans, with unpredictable difficulty to evaluate dose distributions. The desire to obtain an optimal plan and to increase the tumor control, limiting the risk of complications at the lowest possible level, has oriented the research toward the development of radiobiological models with a predictive value of the tumor response and the toxicity rate. The development of radiobiological models originated three decades ago, but in recent years efforts have been intensified to introduce these models into clinical practice. The inability to consider variables as clinical data and histological type of tumor made it difficult to introduce these models as standard in the process of evaluating treatment plans. However, some producers have included radiobiological models in commercial TPS that use DVH curves in the treatment plan and biological parameters such as histologic type and characteristics of nearby healthy tissues to calculate tumor control probability (TCP) and normal tissue complication probability (NTCP). The radiobiological models included in the TPS software are based on the Poisson TCP model and the LKB model for the calculation of NTCP [9, 14].
Although not yet implemented as a standard of assessment in clinical routine, TCP and NTCP models offered the radiation oncologist and medical physicist a useful tool in evaluating treatment plans and selecting the best treatment plan but also in evaluating geometrical errors and in comparison of the most modern radiotherapy techniques.
Dosimetric comparisons between treatment plans have been used extensively in validating treatment plans generated by the inverse planning techniques IMRT and VMAT, determining according to EMAMI/QUANTEC recommendations and the latest RTOG recommendations the possibility of reducing the risk of toxicities associated with irradiation. The use of radiobiological models has shown a small benefit in TCP and a significant reduction of NTCP when using the IMRT technique in prostate cancer radiotherapy. TCP/NTCP models were also used to compare sequential IMRT plans with SIB-IMRT plans. The use of the boost integrated in the VMAT technique demonstrated the ability to reduce the average dose received by the rectum and bladder by 13 and 17% [2, 7, 15].
Also the use of radiobiological models can highlight the percentage with which the TCP value increases by increasing the dose to a certain value. In the case of comparative VMAT single-arc vs. VMAT double-arc treatment plans, the use of NTCP radiobiological models revealed similar values regarding the risk of radionecrosis of the femoral heads, on irradiation plans for prostate cancer although the dosimetric distribution is significantly different between the two plans. However, some authors report lower mean NTCP values for VMAT double-arc plans.
Biological optimization based on NTCP of treatment plans has become a feasible alternative, based on dose-volume optimization, demonstrating the possibility to reduce up to 3 times the doses received by the parotid glands in the case of locally advanced nasopharynx cancers treated by IMRT technique [16, 17].
Patient repositioning based on imaging guidance is routinely performed in most radiotherapy centers using modern radiotherapy techniques using daily setup and four-dimensional computer tomography (CBCT) images performed with onboard imaging (OBI) systems which are increasingly used to compare planned and treated target volumes. TCP and NTCP radiobiological models can be used to evaluate the effect of systematic and random errors on the probability of tumor control and on the risk of toxicity, using information from the DVH curves. Some authors have used EPID portal dosimetry to check the dose received by critical organs as heart for the purpose of evaluating NTCP [2, 16, 17, 18].
Another direction of interest was the evaluation with the help of the NTCP of the advantage of the new four-dimensional computer tomography (4D-CT) technology in radiotherapy planning. The radiobiology studies proved a minor benefit in TCP in many situations. This evaluation has the role to give a suggestive image of the situations in which the 4D-CT technique offers a clear advantage over 3D image-based planning. Reposition during treatment is made according to the geometric variations of the target volumes and to the changes in the anatomical conformation of the body. The adjustments in treatment position using CBCT imaging is often used without being able to accurately estimate the consequences from the point of view of toxicities and tumor control [2, 18, 19, 20].
Currently, replanning of treatment using weekly CBCT imaging for radiotherapy patients can be done during the course of treatment, to provide a more accurate dose and to avoid erroneous treatment due to daily movement of organs. Adaptive radiation therapy is defined as changing the radiological treatment plan delivered to a patient during a course of radiation therapy to take into account temporal changes in anatomy, such as tumor contraction, weight loss, or internal movement, etc. However, the biological consequences of this intervention during the course of treatment may remain unclear to some practitioners. The clinical impact of adaptive radiotherapy has been evaluated using biological modeling of bladder cancer. In the Wright et al. study, various adaptive planning target volumes (PTV) were generated from the inter-fractional variation of the bladder observed in the first four CBCT sessions. In addition to IMRT plans that deliver 60 Gy to a given PTV, simultaneous integrated impulse (SIB) plans have been generated. For uniform clonogenic cell density throughout the bladder, TCP ranged from 53–58% for 60 Gy planes, while it was between 51 and 64% for SIB planes. They showed that dose tracking and TCP calculation can provide additional information on standard criteria, such as geometric coverage for selected cases [20, 21, 22, 23].
It is assumed that the use of IGRT can lead to an improvement in TCP by increasing the PTV dose coverage in daily treatment while decreasing NTCP by using low uncertainty CTV-PTV margins in the case of prostate cancer radiotherapy, demonstrating the ability to improve therapeutic for both IMRT and 3D-CRT plans.
With all the efforts made to develop radiobiological models, they remain ideal models. Including the individual biological parameters of the patients in the treatment decision will contribute to the understanding of differentiated response of tumors to radiotherapy and will be able to transform these models into feasible models applicable in clinical practice. The number of malignant stem cells and their intrinsic cell radiosensitivity, cell repopulation, tumor and tissue hypoxia, and the ability of tumor cells to reoxygenate and repair DNA damage are factors whose introduction into the radiobiological mathematical models will increase the accuracy of each case of tumor control and toxicity predictions. Thus, a step forward will be taken in the use of these models in clinical practice within the concept of personalized medicine, modulating the treatment for each patient in order to obtain the best therapeutic ratio.
Identifying new biomarkers to guide radiotherapy tailored to each case depending on the radiosensitivity of tumor cells and healthy tissue requires the identification of a large number of pre-therapeutic factors with predictive value on tumor toxicity and control. If the data obtained from the tumor histology and the patient performance status and comorbidities are taken into account in the evaluation and pre-therapeutic optimization of the plans, the biological parameters of the tumor are rarely considered in the modulation of the treatment. Also, early response to imaging-evaluated therapy may be a predictive factor of tumor control [2, 23, 24, 25].
The development, validation, and integration of imaging biomarkers using CT, PET-CT, and MRI to improve the response to radiotherapy are part of the areas of interest of clinical and preclinical studies, this research directive being integrated under the name of “radiomics.” There are two directions for using predictive biomarkers for individualized treatment, to choose the treatment offered to a patient (e.g., intensifying and choosing a multimodal therapy for a hypoxic tumor with radiation and chemotherapy resistance factors or de-escalating treatment for tumors with radiosensitivity-associated factors such as HPV viral etiology for head and neck cancers). The modulation of the treatment by altered therapeutic and fractional associations (hypo- and hyperfractionation) aims to obtain a higher TCP with the limitation of NTCP of the tissues from the vicinity of target volumes, avoiding the risk of toxicity [2, 24, 26, 27].
Biomarkers can also be used for early evaluation of therapeutic outcomes to decide whether to discontinue or continue a therapeutic procedure or modify the initial treatment, but validating some biomarkers and including them in radiobiological models that are part of the clinical decision algorithm is still a strategy used only in preclinical and clinical studies. Regarding systemic therapy significant progress has been made, by discovering new therapeutic targets that have changed the clinical oncological practice, making it necessary to identify biomarkers to guide the therapeutic decision. HER-2 and hormone receptor status evaluated at breast cancer patient biopsy is currently used for therapeutic protocol decision, EGFR mutation targets treatment for targeted molecular therapy in lung cancer, KRAS mutational status is integrated into colorectal cancer treatment to allocate patients for anti-EGFR therapies for KRAS wild-type tumors, PD-L1 expression becomes a marker of response to immunotherapy in more and more nonplastic locations, and even though we have presented only a few suggestive examples, there is an increasing number of biomarkers with potential predictive for response to radiotherapy [2, 5, 27, 28].
Radiation oncology has a long history of research into understanding the implications of genetics in the variation of the response to treatment for each patient in order to personalize the therapy. The identification of new biological signaling pathways will explain the variation in the individual response of some tumors to irradiation. The use of elements from the genetic signature of each patient could constitute biomarkers of the clinical response to irradiation by modifying radiosensitivity of the tumor and healthy tissue. Since 1936 the different effects for subjects of irradiation with an identical radiation dose have been demonstrated by the occurrence of early skin toxicity, the near-Gaussian frequency distribution of individual sensitivity being highlighted. Subsequent research has shown the involvement of genetic syndromes in the early onset of toxicities, with the subtraction of cell hypersensitivity to irradiation, caused by affecting the DNA chain repair mechanisms. In addition to the ATM gene associated with ataxia-telangiectasia syndrome, other genes such as NBS1, LIG4, and MRE11 have been linked with syndromes associated with high radiosensitivity, caused by impaired DNA chain repair mechanisms [29, 30].
Modern radiobiology research has highlighted the applicability of genomics in predicting the adverse effects of radiotherapy, based on the application of genomics in radio-oncology. Advances in high-throughput approaches will support increased understanding of radiosensitivity and the development of future predictive analyses for clinical application. There is an established contribution of genetic risk factor to adverse radiotherapy reactions. The radiosensitivity of an individual is an inherited polygenic feature, and in order to elucidate the genomic involvement in radiosensitivity, the Radiogenomics Consortium was set up to allow large data cohorts for research development, and the REQUITE project would collect standardized and genotyped data for∼5000 patients [31]. Linking their information with the dosimetric data will lead to the generation of multivariable models that can be used in the clinic, identifying new genes that have an impact on the radiosensitivity of the toxicity pathogenesis and the tests that will be incorporated into the clinical decision-making process [30, 32].
The development in the last decades of imagistic techniques and their noninvasive or minimally invasive character allowed the dynamic evaluation of the changes of the biological characteristics of the tumor. Molecular imaging brings pre-treatment information but also has the ability to evaluate the changes produced by the treatment since the first irradiation fractions. CT and MRI imaging already has a significant role in radiotherapy planning, CT simulation becoming a standard, and MRI imaging contributes to a more precise delineation of tumor invasion into adjacent organelles. The increasing use and availability of PET-CT imaging and its inclusion in treatment planning make it possible to use different tracers as a biomarker of tumor radiosensitivity in click practice [33]. 18F-Fluorodeoxyglucose (18F-FDG) is one of the most used biomarkers in experimental and clinical investigations, the SUV values before and during the treatment being investigated as possible biomarkers of the treatment by chemotherapy and radiotherapy. The concept of “biological dose painting” is based on the delimitation of target volumes on functional criteria; the irradiation of a tumor with different doses and the escalation of the doses in areas with high uptake of 18F-FDG were discussed with the introduction of IMRT and VMAT techniques that allow the irradiation with different doses of some subvolumes from the target volume. 18F-FDG can identify tumor regions with high cell density and radioresistant regions due to hypoxia. Identifying the most common relapses after radiotherapy in the areas with higher uptake of 18F-FDG is a new argument for dose escalation in these regions.
The observation that in several cases of locally advanced cancers the tumor control after irradiation was not satisfactory made necessary a careful analysis of the areas where recurrence occurs. The analysis of the characteristics of the tumors with recurrence risk revealed an increased risk for the hypoxic regions or with an increased number of clonogens with proliferation capacity. One of the strategies used to control the tumor response is to use the boost on subvolumes with radioresistance pattern, considering the results of the studies that prove the survival rates associated with better locoregional control [34, 35].
The use of routine boost for all patients is a controversial topic. For head and neck cancers and for prostate cancer, there was a benefit in escalating doses by 10–20% in the topographic regions of the tumor with an increased risk of recurrence. An EORTC trial shows a minor benefit of breast boost but with a significant increase in toxicity rate.
Using radiobiological models, an increase of up to 20% of the TCP was observed in the case of a 10–30% dose escalation on a sub-volume of 60–80% of the primary tumor target volume. The introduction of IGRT and PET-CT hybrid imaging opens the horizons of a new challenge, the topographic identification of the region where the boost will be made, based on the clinical rationale balancing the benefit and the toxicities.
Adaptive risk optimization uses a biological objective function instead of an objective function based on dose-volume constraints, maximizing TCP for different regions of the tumor with recurrent risk while also minimizing NTCP for risk organs [2, 26, 36].
The tendency to include biological information in radiotherapy will lead to the use of cellular, molecular, and physiological characteristics in the treatment planning. PET-CT radiotracers 18F-FMISO-PET,60Cu-ATSM-PET, and blood oxygen diffusion (BOLD)-MRI are frequently investigated in translational research related to tumor hypoxia. Investigation of tumor proliferation proved benefits from 18F-labeled fluorotime (FLT) as a biomarker.
The development of multivariable radiobiological models and dose prescription protocol based on functional data obtained from hybrid imaging is part of the tendency to include modern radiotherapy in the precision medicine trend, exploiting variations in tumor radiosensitivity and healthy tissues in clinical practice [2, 21, 37, 38].
The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
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\\n\\nWe started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\nIn the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n2004
\n\n2005
\n\n2006
\n\n2008
\n\n2009
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