Nutritional values of Prosopis flour compared with plain white wheat flour.
\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:"62401",title:"Prosopis cineraria as an Unconventional Legumes, Nutrition and Health Benefits",doi:"10.5772/intechopen.79291",slug:"prosopis-cineraria-as-an-unconventional-legumes-nutrition-and-health-benefits",body:'The continuous world population growth, inadequate protein sources, exorbitant cost of animal protein are considered the main reasons for malnutrition and undernourishment among people living in many developing countries around the world. To meet the increasing demand of protein, alternative strategies and unconventional sources of protein for human and animal nutrition have been considered recently.
Trees of Prosopis genus, which belongs to the Leguminosae family, are one of the most important source of proteins in arid and semi-arid regions. Its capability to stand heat and tolerate drought, salt, and alkalinity make Prosopis cultivated and distributed in many areas around the world especially India, America, GCC, and MENA [1]. According to the recent studies, the species Prosopis cineraria has significant contribution in the farm economy and rural area development. Undoubtedly, it shares with other Prosopis species numerous characteristics, uses and effects, i.e., chemical composition, types of phytochemical components, and health effects. Prosopis cineraria has been valued by different communities and cultures for the versatility of all its parts and named as “the Wonder Tree” or “King of Desert” [2] or “the Golden Tree of Indian deserts” [3]. The tree parts including leaves, pods, seeds and barks has been used in many ways as food, i.e., flour, drink, vegetable, and gum. Leaves and pods are used for ruminant and animal feed. Prosopis cineraria extensively used in traditional medicine to cure many diseases such as ailments like leprosy, dysentery, asthma, leucoderma, dyspepsia and earache [4, 5, 6]. Barks are used for non-nutritional purposes, i.e., wood, tanning, fuel, firewood and charcoal. The Prosopis cineraria has many chemical constituents as alkaloid, steroids, alcohol and alkane.
Despite its fabulous importance in local culture, there is minimal aware by the developed communities about P. cineraria as unconventional legumes. Therefore, authors present a comprehensive chapter about this important tree from all aspects including traditional uses, biological and phytochemical investigation.
The genus Prosopis L. belongs to Leguminosae family, subfamily Mimosoideae and accommodates 44 species of which 40 are native to North and South Americas, three originate in Asia, and one comes from Africa [7, 8, 9]. Trees of Prosopis L. are widespread in Western Asia, Africa and arid and semi-arid regions in the Americas and Australia.
The species P. cineraria is native to dry and arid regions of Arabia and India [10]. Its main population is center on the Thar Desert of India and Pakistan, with less dense populations occur in the Arabian Peninsula, Iran, and Afghanistan [11]. It is considered the national tree of the United Arab Emirates [12]. P. cineraria is known as Ghaf in Arabic, Khejri in Indian, and Jand in Pakistan.
P. cineraria is an evergreen, thorny tree, 10–25 m in high. The stem is commonly straight, un-branched for several meters with a gray roughish, exfoliated bark (Figure 1). The branches are slender, drooped giving the canopy a rounded appearance with short triangular spines (3–6 mm long) between leaves nodes. At the time of no grazing the lower branches can reach to the ground. Leaves are gray-green, alternate usually divided into two pinnae, each pinna has 7–14 pairs of oblong, oblique, apex leaflets. The mid-rib nearer the upper edge, is sessile.
The tree of Prosopis cineraria, flower, leave and pods.
Flowers are small, yellow or creamy white, nearly sessile in slender pedunculated axillary spikes 5–13 cm long. Pods are yellow to reddish brown with cylindrical shape and slightly curved; 10–20 cm long and 0.5–0.8 cm thick. Seeds 10–25, oblong or rhomboidal, brown, smooth, with a moderately hard taste [13, 14]. The tap root of P. cineraria penetrates vertically up to 20 m but can reach water at an extraordinary depth of 53 m or more [15]. Flowering and fruiting period is varied between locations and weather condition and generally from February to May after the new flush of leaves. The pods are mature almost after 2 months.
P. cineraria is a xerophytic plant that is well adapted to dry and arid environment. Under the conditions of drought, the tree produces more flowers and fruits [16]. In areas of its natural distribution, the annual rainfall ranges between 100 up to 500 mm annually, whereas the optimum density is confined to areas receiving 350–400 mm [17]. The climate is characterized by extremes summer temperature varies from about 40–48°C [18]. It can tolerate frost and withstand low temperature less than 10°C in the winter season.
The tree grows on a variety of soils. It is seen at its best on alluvial soils consisting of various mixtures of sand and clay [19]. In arid areas, the growth is better in dune lows than in sandy plains. Good drainage is very essential. P. cineraria can grow under highly saline and alkaline soils. However, it relatively salt tolerant at seed germination whereas seedling emergence was found to be reduced to 50% in soil with a salinity of 7.6 dS m−1 and a further increase in salt concentration was detrimental to seed germination [20].
P. cineraria is a multipurpose tree that holds an important role in the rural economy in many arid regions, particularly in the Arabian Gulf and the northwest arid region of Indian sub-continent. Historically, the Bedouin and Indian uses all its part in their traditional lifestyle [21, 22, 23]. It is used as a folk remedy for various diseases and conditions [24].
The unripe pods are used for making curry and pickle. The green pods are consumed as vegetables. The flour of mature pods is used for cookies preparation and other local dishes. The leaves and dry pods are annually harvested for cattle and sheep feed, where an adult tree produce 2–5 kg/year dry pods. A resin occurring naturally on the tree, known as mesquite gum, is also occasionally eaten by people [25].
P. cineraria as a leguminous tree has importance in improving soil fertility through fixing atmospheric nitrogen. Litter fall production for P. cineraria and decomposition rate are considered the highest comparing with other arid trees, and that build up soil organic matter contents under its canopy, increase soluble calcium and available phosphorus and decrease soil pH [26, 27]. Therefore, farmers tend to grow field crops under its canopy to boost the growth and productivity of their crops.
The rounded shape crown provides the shade and shelter for animals and wildlife during hot season. It is widely used for sand dune stabilization program because of it is deep mass root system which enable plant not to compete with others for moisture and nutrients [28]. It provides good quality resources of wood for basic construction and fuel for people in the desert regions.
P. cineraria is one of major bee foraging plant in the Arabian Gulf [29], it supports honey bees with long and abundant flowering and honey produced is of a good quality.
Numerous people around the world, especially in Africa and Asia, are suffering from protein deficiency due to lack of protein-rich food. P. cineraria have 16.5–18.25% protein content compared with 25.47% in Acacia nilotica and 38.89% in Acacia senegal [30]. On other hand, legumes contain 18–35% protein [31], and cereals contain 10–15% protein [32]. Therefore, Prosopis seeds are considered a potential and cheap source of protein for industrial use, especially in developing Afro−Asian countries and can be an alternate protein source for solving the protein-energy-malnutrition problem. The protein content, P. cineraria contains reasonable amount of ash (5.34%), and fiber (20.93%) [33, 34, 35]. Chemical composition of pods is varied between individual trees that it influenced by a wide range of environmental factors. The P. cineraria pods have low moisture content (8.55%) that may be advantageous in increasing of the pods shelf-life, 18% protein, 1.89% oil, 5.34% ash and 20.93% fiber [34]. The P. cineraria seed contains 10.6% oil, 28.6% of the oil are saturated fatty esters, 68.3% are unsaturated fatty esters, and 3.1% are methyl hydroxy fatty ester. Moreover, the seed oil is rich in oleic acid (31.3%) along with linoleic acid (32.1%). Oil and seeds of P. cineraria show an absence of keto, cyclopropenoid, and epoxy fatty acids or any evidence for the presence of trans-unsaturation or the presence of conjugation. In addition, the tree leaves have a good source of macro minerals as calcium (2.43%), phosphorus (0.16%) and potassium (0.41%). So, it can be used as good food during the mineral deficient periods [36].
Besides the ecological value of P. cineraria tree, there are significant utilizations centered on its use for human food, animal feeds, medical purposes and many other applications. The multipurpose and added value usages of P. cineraria tree; barks, pods, and leaves; will be discussed with regards to its health benefits and nutraceutical effects as follow:
P. cineraria tree are extensively used as human food in many area especially arid land region and semi-desert as Arizona, India, California, South America and northwestern Mexico. There are diverse uses of the P. cineraria tree parts; dried and undried pods, green and dry leaves, and seeds; in human food. It is interesting to note that studies did not refer to the presence of cyanogenic or toxic compounds in Prosopis parts as seeds or pods till now [37, 38, 39]. The P. cineraria food applications include:
Leguminous Prosopis trees play a great role in feeding human in dry area to prevent protein and mineral deficiency especially during famine period. In these area, people used to eat unripe green pods of P. cineraria that selling in their market as vegetables and children eat its ripe fruits [2, 33, 40, 41]. In addition, green and unripe pods are also used in the preparation of pickles and curries [3].
The Prosopis pods consist of three parts, mesocarp (56% of the pod) that grind to produce flour, endocarp (35%) that discard as waste alongside seeds (9%). People used the flour to make bread, cake, chapatti by mixing with wheat flour and sweets [40]. The Prosopis flour contains a high level of proteins (62%), dietary fiber (25%) and low content of total carbohydrate and fat in addition to dominant amounts of free polyphenol and carotenoids compounds as shown in Table 1 [42]. Prosopis flour is gluten-free, and a premium source of calcium, potassium, magnesium, zinc, and iron, in addition to amino acids such as lysine that is low in other cereals [11, 43]. Prosopis flour has a unique combination taste that has been variously described as; sweet or slightly nutty, with a sweet chocolate or coffee flavor, with a pleasant hint of caramel or molasses, with a hint of cinnamon as it contains many volatile components, i.e., γ-nonalactone, 5,6-dihydro-6-propyl-2H-pyran-2-one, 2,6-dimethylpyrazine, and methyl salicylate [44]. Therefore, only 10 to 25% flour is generally used in combination with other flours because above than 25%, the taste becomes too strong for most palate. While, the desirable degree of browning for different bakery products was obtained using different adding concentration, i.e., biscuits (5%), breads (10%), pancakes (15%) and chapatti (50%).
Compounds | Prosopis flour | Plain white wheat flour |
---|---|---|
Energy (kcal/100 g) | 361 | 338 |
Carbohydrate (g/100 g) | 69.2 | 72.2 |
Total sugars (g/100 g) | 13.0 | 1.5 |
Fiber (g/100 g) | 47.8 | 3.2 |
Protein (g/100 g) | 16.2 | 9.4 |
Fat content (g/100 g) | 2.12 | 1.3 |
Saturated fatty acids (g/100 g) | 0.6 | 0.2 |
Nutritional values of Prosopis flour compared with plain white wheat flour.
The dried pods are used to make flour after collecting pods directly from the tree or from pods that have recently fallen to the ground. Sometimes they store the dried pods to provide food year round. The flour particle size is varied depending on the grinding processing, e.g., pounded using pestle and mortar produces coarse powder, while using stone grinding produces a fine powder.
The Prosopis flour assist the diabetic patient through helping maintain a healthy insulin system in those people not affected by blood sugar troubles because of two reasons: firstly, the Prosopis flour requires a longer time to be digested compared with other grains, i.e., it needs 4 to 6 hours compared to 1 to 2 hours needs for wheat flour to be digest. This help to sustains constant blood sugar over time and prevents hunger. Secondly, the pods contain fructose, which the body can process without insulin [45].
In many places, the Prosopis species are used to make fermented, non-fermented beverages, and syrup [46, 47, 48, 49, 50]. Nutritious syrup is produced by boiling the clean green pods in water after breaking them into small pieces. Beans should be simmered for 2 hours with continuous adding a small amount of water to avoid burning. Followed by mashing the pods to release more of the sweet pulp with simmering for further few minutes. The juice then sieved through strain and kept in clean containers to be used directly as a drink. Or more sugar can be added to the juice and boil to produce unique flavor syrup [51].
In addition to the previous uses, amber colored gum is produced from the P. cineraria tree. This gum has similar properties to the gum produced from acacia tree [40]. Its exudate gum is liquid, water soluble and slowly hardening. Moreover, this genus is not the only source of gum. A galactomannan types interesting gum that called vinal gum is produced from P. ruscifolia [52].
P. cineraria is an important feed species under traditional livestock production systems in the arid regions. Leaves and pods are highly palatable, nutritious and eaten readily by camels, cattle, sheep and goats.
The leaves contained 12.1% crude protein, 20.1% crude fiber, 3.2% ether extract and 12.2% ash [53]. The ripened pods contained 91% dry matter, 13.5% crude protein, 14.3% crude fiber, 1.3% ether extract and 5.2% ash [54]. Feeding P. cineraria to sheep did not cause overt health problems such as diarrhea or impaction. Though, it is not advisable to use leaves as a sole feed for animal as it contain 8–10% tannins [55]. Increasing Prosopis tannin in the diet reduce animal intake, digestibility of nutrients and body weight gain in sheep [54, 56] and goats [57]. In general goat showed superior efficiency in utilizing P. cineraria leaves than that in sheep [58]. However, feeding Prosopis tannin at 23 and 45 g/kg dry matter in the ration of lambs and kids can achieve maximum microbial protein synthesis under intensive feeding system. Beyond this level, Prosopis tannins will have anti-nutritional effects [59].
Despite the economic importance of Prosopis spp. as food, plants have been used in traditional medicine to treat various human ailments since ancient history. Prosopis spp. is one of these plants that possess many medicinal properties and used to cure many diseases. Studies showed that leaves and seeds were largely used to treat many diseases such as diarrhea, inflammation, measles, diabetes and prostate disorders [4, 5].
The pods of P. cineraria contain alkaloids (good anesthetic and spasmolytic activity), Saponin (boost immunity system of the body, lowering the cholesterol level in the body and reducing the risk of intestinal cancer), and tannins (produce anthelmintic activity). In addition to the mineral content as zinc (relevant to the nutritional aspect as zinc supplementation in diabetes mellitus have antioxidant effect), magnesium (important for proper functioning of every organ like heart, muscle, and kidney), iron (used in anemia, tuberculosis and growth disorder), calcium and phosphorous (useful for the bone, teeth, and ligament related disorder) [17, 60].
Moreover, studies show that the alkaloid mixture of P. cineraria in a dose of 1 mg/kg decreased the blood pressure and immediate mortality of dogs. In contrast, extensive damage to the liver, spleen, kidney, lung, and heart was observed on histological examination of mice given the same alkaloid mixture [61].
Studies show that the methanolic extract of Prosopis pods has antimicrobial activity against Candida albicans [62]. And the aqueous and methanolic extracts of stem bark have moderate antibacterial activity at a dose of 250 μg/ml. In addition to the previous effects, the methanolic extract shows significant action on all pathogens. This antibacterial activity of Prosopis spp. is due to the presence of flavonoids and tannins [63].
Many researchers illustrated that the bark extract of the P. cineraria have abundant activity in lowering blood sugar level by 27.3%, in addition, to significant decrease in body weight (29.6%) in diabetic rats when a dose of 300 mg/Kg mice body weight are given orally in daily base for 45 days [6, 64] explained the effect of the Prosopis extracts is due to activate the surviving of the β cells of the islets of langerhans and producing an insulinogenic effect.
The 70% hydroalcoholic bark extract dose of 500 mg/Kg BW of albino male New Zealand white rabbits reduced significantly the serum total cholesterol by 88%, LDL-C by 95%, triglyceride by 59%, VLDL-C by 60% and ischemic indices compared to hypercholesterolemic control [64, 65, 66].
A study on P. cineraria illustrated that a dose of 200 and 400 mg/Kg BW of hydroalcoholic extract of leaves and bark have a significant antitumor activity against Ehrlich ascites carcinoma tumor model. In addition, the methanolic extract of the P. cineraria leaves shows significant radical scavenging activity. This effect is due to the inhibition of cell proliferation even through inducing the cell death and/or extending the time for cell proliferation [67].
Studies show that aqueous extract of the P. cineraria leaves have a significant antidepressant effect on mice and a similar effect of the antidepressant drugs. This is due to the presence of some phytochemicals as saponins, flavonoids, glycosides, alkaloids, and phenolic compounds in these extracts [5].
Toxicity effect of 50% Hydroalcoholic extracts of Prosopis (at dose ranged between 50 and 2000 mg/Kg BW) through oral route of rats did not show any significant effects in breathing, behavior, sensory nervous system responses, cutaneous effects or had any mortality recorded within 24 h after treatments [6]. Further studies are required to determine the toxicity effects of the Prosopis extracts that might show adverse effects when consumed because it contains piperidine alkaloids [68].
These are not the only uses of the P. cineraria tree. The good bark considered a good source of woods that can be used to make tool handles, boat frames, posts, and houses. While the poor or bad quality bark can be used as timber [40]. In India; especially in the Punjab region; the purplish brown bark used as fuel, firewood and used to produce high-quality charcoal. Leaf galls of P. cineraria tree can be used also for tanning. While, leaves can be used as a source of compost on the agricultural field and flowers are considered a good source for honey bee forage. The produced honey is light yellow with pleasant taste and slight aroma and generally of good quality [69].
There are few studies on the chemistry and bioactive compounds of Prosopis species have been published recently. Studies referred to the secondary metabolites compounds in plants that are considered bioactive compounds and has diverse antinutritional and nutraceutical features. Therefore, it can be potential as a source of bioactive products and used in functional products. Refs. [61, 84, 85, 86] mentioned that Prosopis spp. tree generally contains various phytochemical compounds as tannins, 5-hydroxytryptamine, isorhamnetin-3-diglucoside, L-arabinose, quercetin, apigenin, and tryptamine. Studies conducted on phytochemical compounds of P. cineraria showed that each part of the plant contains different types of these compounds (Tables 2 and 3).
Plant part | Chemical constituent present | Medicinal effect |
---|---|---|
Flowers | Patuletin glycoside patulitrin, luteolin and rutin sitosterol, and spicigerine. Flavone derivatives Prosogerin A and Prosogerin B | -Flowers are known as an anti-diabetic agent. -Flowers can be mixed with sugar when administered orally prevent miscarriage. -It contains Patulitrin3, 5, 6, 3, 4-pentamethoxy-7-hydroxy flavone which has significant activity against Lewis lung carcinoma in vivo. References: [70, 71] |
Leaves | -Alkaloid: spicigerine -Steroids: campesterol, cholesterol, sitosterol, stigmasterol, actacosanol -Alcohol: octacosanal, triacontane-1-ol, Tricosan-1-ol, -Alkane: hentriacontane, Diisopropyl-10,11-dihydroxyicosane-1,20-dioate References: [6, 72, 73, 74, 75, 76] | -Leaf paste of P. cineraria is applied on boils and blisters, including mouth ulcers in livestock and leaf infusion on open sores on the skin -Smoke of the leaves is considered good for eye troubles and infections. References: [72, 77, 78, 79, 80] |
Seeds | Prosogerin C, Prosogerin D, Prosogerin E, gallic acid, patuletin, patulitrin, luteolin, and rutin | |
Pods | 3-benzyl-2-hydroxy-urs-12-en-28-oic acid, maslinic acid-3 glucoside, linoleic acid, prosophylline, 5,5′-oxybis-1,3-benzenediol, 3,4,5-trihydroxycinnamic acid 2-hydroxyethyl ester and 5,3′,4’trihydroxyflavanone 7-glycoside | -Dry pods help in preventing protein calorie malnutrition and iron calcium deficiency in blood. References: [3, 64] |
Barks | Hexacosan-25-on-l-ol, a new keto alcohol along with ombuin and a triterpenoid glycoside.vitamin K1, n-octacosyl acetate, the long-chain aliphatic acid. Presence of glucose, rhamnose, sucrose and starch | -Bark used in the treatment of asthma, bronchitis, dysentery, leucoderma, leprosy, muscle tremors and piles. -Different extracts of stem bark possessed a weak antibacterial activity. References: [81, 82, 83] |
Phytochemical constituents of the Prosopis cineraria.
Phytochemicals | Plant parts | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Flower | Leaf | Pod | Seed | Stem | ||||||
Aqueous | Ethanol | Aqueous | Ethanol | Aqueous | Ethanol | Aqueous | Ethanol | Aqueous | Ethanol | |
Carbohydrates | + | + | — | — | +++ | +++ | + | + | — | — |
Proteins | — | — | + | + | ++ | ++ | + | + | — | — |
Tannin | — | — | + | + | + | + | + | + | — | — |
Flavonoids | ++ | +++ | + | + | + | ++ | ++ | ++ | + | — |
Cardia glycoside | — | — | — | — | + | + | — | — | — | — |
Alkaloids | ++ | ++ | ++ | ++ | ++ | ++ | ++ | + | — | — |
Terpenes | — | — | + | + | + | + | + | ++ | + | + |
Steroids | + | + | +++ | +++ | — | — | + | ++ | — | — |
Concentration of phytochemicals of different parts of Prosopis cineraria among different solvents (water and ethanol extracts) [87].
+; low concentration, ++; moderate concentration, +++; high concentration, −; absent.
P. cineraria is a naturalized constituent of many natural and cultivated ecosystems in the world. Its value, however, lies not only in its ability to thrive under adverse conditions, but also it provide wide range of useful product. In this unifying review, it was shown the morphological trait, ecological and economical importance in addition to the nutritional value and health benefits.
The authors tried to drag the attention toward this significant tree as alternative type for the traditional legumes and possibility to use it as a source of protein in free-gluten products and functional foods which can be added value in food product development.
Future efforts are required to be focus on integrated management of P. cineraria in their natural ecosystem and implement environmental conservation strategies for achieving sustainable uses and maintain its benefits to livelihood and coming generation.
Authors would like to thank Abu Dhabi Food Control Authority, UAE.
The authors declare that there are no conflicts of interest regarding the publication of this chapter.
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
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\n\n2006
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