Overview of Important “Organs at Risk” (OAR) in Modern Radiotherapy for Head and Neck Cancer (HNC) Overview of Important “Organs at Risk” (OAR) in Modern Radiotherapy for Head and Neck Cancer (HNC)

With the advent of highly conformal and adaptive radiotherapy techniques, the sig- nificance of accurate delineation of organs at risk (OARs) is becoming more and more important. Techniques such as Intensity modulated radiotherapy (IMRT) and intensity/ volumetric modulated arc therapy (VMAT) has allowed for improved dose conformation within the target. It has also allowed for steep dose gradients around the target for better normal tissue sparing. The accurate contouring and delineation of the OARs are thus warranted as variation in delineation has been systematically reported in studies. All these facts have led to the development of contouring guidelines for OARs in various sites. Head and neck cancers (HNC) are a perfect example where outcome and quality of life (QOL) balance remains a therapeutic challenge. There are several OARs and thus the accurate delineation following a standard guideline becomes more important. This chapter looks into the published guidelines for the delineation of such structures.


Introduction
The variation in the contouring and delineation of the different OAR's has been systematically reported in studies [1]. We will be discussing the standard available guidelines and a simple practical way to delineate OAR's in modulated radiotherapy for HNC. The OAR's have been divided into five subgroups viz. optic structures, salivation related structures, structures related to swallowing, brachial plexus and intra-cranial structures.

Optic structures 2.1. Eye ball
The entire eye ball is to be contoured as a single structure. The entire retina is to be included.
For contouring of substructures of the eye the European particle therapy network (EPTN) has put forward a consensus based atlas based on CT and MRI [2].

Cornea
The cornea is located anterior to the vitreous humor, iris, lens and ciliary body [2]. It can be delineated in MRI or CT and is contoured with a 2-3 mm brush.
RT can injure the cornea by damaging the deeper layers of stroma, but in most cases the acute toxicity is as a result of loss of tear film [3].
Dose recommendation: < 40 Gy. Edema of the corneal stoma appears at a dose of 40-50Gy, but is usually transient. With doses of 60 Gy the chance of corneal ulceration is increased to 17-20% which increases further if chemotherapy is added.

Retina
It is the innermost layer of the globe and is about 0.25 mm in thickness and is not usually visualized in a standard MRI [2]. Contoured using a 3 mm brush, the retina covers the posterior 5/6th of the globe. The optic nerve is not contoured along with it [4].
Dose recommendations: Dmax-45Gy. Acute retinal toxicity is not reported. Being a part of the central nervous system, the retina behaves as a late reacting tissue [3]. Usually there is a latent period of 6 months to 3 years before the onset of clinically significant retinopathy. The mean latent period is 19 months [5].

Lens
Biconvex structure in the aqueous humor, it is clearly visible in CT [2]. The structure is about 10 mm in diameter seen in the coronal plane.
Dose recommendations: Dmax-5 to 10 Gy. Acute lens toxicity is not reported. A single dose of 2 Gy can cause cataract, but is usually visually insignificant. [3] The time of onset is dose related. For doses in the range of 2.5-6.5Gy, the latency is 8 yrs. with the possibility of 33% progressive cataract, whereas doses of 6.5-11.5Gy, the latency reduces to 4 years with the 66% risk of progressive cataract.

Optic nerve
While moving craniocaudally, optic nerve is seen below the superior rectus. The nerve is 2-5 mm thick and is delineated from the posterior margin of retina and continued along its course posteriorly till it merges with the optic chiasm after passing through the superior orbital fissure.

Optic chiasm
A small structure is usually confined to 2 or 3 slices in the superior-inferior direction. Better demarcated in MRI, the chiasm is situated about 1 cm superior to the pituitary gland. Laterally it is bounded by the carotid arteries. It is better visible in MRI with a high signal on T1. A good landmark to look for is the pituitary stalk. It lies just posterior to the chiasm and appears hyperintense even on plain CT [7]. On average it measures 8 x 14 mm (APxTrans) and is about 2-5 mm thickness in the super-inferior dimension [7].
It should be kept in mind that, the chiasm should be contoured in continuity with the optic nerves.

Lacrimal gland
Freedman et al. [8] has given a step-by-step instruction to contour the lacrimal gland. The contour starts by identifying the mid portion of the gland and thereafter tracking it superiorly and inferiorly.
Superior extend corresponds to the super-lateral corner of orbit, just below the orbital rim. Inferiorly it does not extend below the level of insertion of lateral rectus.
Dose recommendations: Dmean <30 Gy. Doses above 40 Gy have shown to steeply increase the incidence of dry eye while doses above 57-60Gy can cause permanent loss of tearing [9].
The details are given in  Overview of Important "Organs at Risk" (OAR) in Modern Radiotherapy for Head and Neck Cancer (HNC) http://dx.doi.org/10.5772/intechopen.80606

Parotids
Parotids are contoured based on the guidelines given by Water et al. [10] ( Table 1). It is to be noted that in 20% of the cases, the parotid gland extends anteriorly over the surface of the masseter muscle following the parotid duct and in the anterior direction the deep lobe of the parotid gland may extend alongside the medial border of the mandible gland may extend   alongside the medial border of the mandible. The external carotid artery, the retromandibular vein and the extracranial facial nerve are enclosed in the parotid gland.
The external carotid artery (ECA), retromandibular vein and the extra-cranial part of facial nerve are enclosed in the gland. If contrast agents are used, the vessels can be clearly demarcated and can be avoided from the gland contour. But as contrast administration is not routinely practiced, and to make the contouring practice uniform, it is recommended to include the vessels within the gland contour.
Dose recommendations: severe xerostomia or salivary output <25% of baseline can be avoided if at least one parotid is restricted to a mean dose <20 Gy or both parotids restricted to <25 Gy [11].

Submandibular gland
Situated in the floor of the mouth, it is a predominantly serous gland having a large superficial lobe and a small deep process separated by the fibers of mylohyoid. In most cases the gland is hypo dense on CT and can be easily demarcated.
Dose recommendations: if deemed oncologically safe, the mean dose to the submandibular gland, restricted to 35Gy may reduce xerostomia symptoms [11].

Sublingual gland
Sublingual gland is the smallest of the three major salivary glands. It is a predominantly mucus gland, situated in the anterior part of oral cavity in the sublingual space.

Extended oral cavity
The extended oral cavity is contoured partly based on the work by Hoebers et al. [12] excluding the lips and buccal mucosa [4]. It includes the space posterior to the arch of mandible and maxilla. Posteriorly it is limited by the uvula, soft palate and the base of tongue.

Soft palate
Soft palate contains numerous minor salivary glands. It is better seen in the sagittal sections by a thin air line separating it from the tongue inferiorly. As the salivary glands are distributed along the length of the soft palate, the entire soft palate is contoured including the uvula.
Dose recommendations: oral cavity dose should be kept as low as possible. Seeking for V45 < 40% and V50 < 20% limits mucositis and improves QoL [12].

Other minor salivary glands
These glands are distributed along the inner aspects of lips and buccal mucosa between the mucous membrane and the muscle layer. Maximum depth from the mucosal surface is about 4 mm with lower lip glands deeper than the upper ones.

Lower lip glands
The upper and posterior limit of the lip is better identified in sagittal sections. The lower limit corresponds to the caudal limit of teeth sockets or the cranial mandibular body (in case of edentulate mandible) [10].

Upper lip glands
As of the lower lip, the lower and posterior extend is more easily made out in the sagittal plane. Cranially it extends till the nasal spine [10].
Dose recommendations: seek for a lip dose less than the oral cavity dose. A mean dose of 30Gy and 50 Gy for oral cavity and non-oral cavity cancers respectively would be preferable.
Orbicularis oris muscle can be used to delineate the glands anteriorly.

Glands of buccal mucosa
The glands of buccal mucosa are difficult to distinguish. The cranial, caudal and medial borders are better visualized in the coronal plane.
The abovementioned have been summarized in Table 1: salivation-related structures.

Pharyngeal constrictor muscles
Pharyngeal wall has two layers of muscle ( Table 2). The outer circular layer which are the pharyngeal constrictor muscles (PCM) and inner longitudinal muscles which are levators (stylopharyngeus and palatopharyngeus). PCM has three parts-superior, middle and inferior constrictor. The caudal ends of the levators blend with the PCM. These muscles are usually hard to differentiate from PCM and are not contoured differently.

Superior PCM
They originate from sphenoid bone from its pterygoid hamulus and insert to the median raphe. Different authors have put forward different levels in regards to its cranial border. Generally, cranial border of the superior PCM is taken as the caudal tip of the pterygoid plate, i.e., the pterygoid hamulus. The lowest fibers of the superior PCM are separated by the muddle PCM by stylopharyngeus and glossopharyngeal nerve. These fibers also overlap onto the upper fibers of middle PCM. As these changes are hardly made out in CT, most authors define the lowest limit of the muscle as the cranial border of hyoid bone. But this can lead to missing of half of middle PCM. Thus, the cranial border can be considered at the lower border of second cervical vertebra.

Middle PCM
The fibers originate from the greater and lesser horns of hyoid bone and insert along the median raphe. The upper fibers overlap, therefore these boundaries are arbitrary. The upper border is taken as the lower border of superior PCM. Lower border corresponds to the lower border of hyoid bone.

Inferior PCM
The thickest of the three constrictors, the inferior PCM has two parts-the thyropharengeal part which originate from the oblique line of thyroid cartilage and the cricopharyngeal part which originate from the lateral part of thyroid cartilage. Most authors delineate these two structures separately. The thyropharyngeus is referred to as inferior PCM and the latter is referred to as cricopharyngeal muscle. As functionally these muscles are different, they are contoured differently.
The inferior PCM is starts cranially from the caudal end of middle PCM, usually one slice below the caudal end of hyoid. The caudal border corresponds to the upper border of cricoid, just below the level of arytenoid.
Anteriorly, the inferior PCM attaches to the posterior edge of thyroid cartilage, which can be recognized easily on CT, while the posterior border is defined by the prevertebral muscles.

Cricopharyngeus
Delineation starts cranially one slice below the level of arytenoids which also corresponds to the lower limit of inferior PCM. The contour continues till the lower end of cricoid cartilage.

Esophageal inlet muscles (EIM)
Levendag et al. [10] recommends contouring the proximal 1 cm of esophagus as a separate structure. The cranial border starts from the caudal end of cricopharyngeus.

Cervical esophagus (CE)
The contouring of CE varies from authors [13,14]. For the purpose of consistency the upper border of CE starts 1 cm below the esophageal inlet muscles and end at the level of sternal notch.

Base of tongue (BOT)
The delineation of BOT has been provided by three authors. All of them are consistent with the cranial extend defined as just below the soft palate. As this boundary is difficult to identify in CT, the lower end of anterior tubercle of C1 vertebra (which corresponds to the same level) may be taken for the demarcation. The three authors vary in the definition of the lower extend. The lower limit of hyoid [13], the vallecular and the first slice of epiglottis [14] are mentioned, but for consistency, we follow the upper end of body of hyoid as the lower caudal limit of BOT.

Contouring of larynx structures
Freedman et al. [15] has provided a 3 step method to delineate larynx.
Step 1 and 3 identifies the cranial and caudal limit of larynx. The contouring starts form the slice just below the caudal edge of hyoid and ends where the cricoid cartilage is seen as a complete ring.
Step 2 mentions the circumference limits of the larynx. The anterior border corresponds to the inner surface of the thyroid cartilage. The posterior border in the upper part corresponds to the lateral surfaces of the aryepiglottic folds and the posterior surface of the mucosa covering the arytenoids. In the lower part it corresponds to the posterior surface of the cricoid cartilage. The pyriform sinus is not to be included in the contour.
The above guidelines contour the larynx as a single structure. As the larynx consists of subglottic, glottic and the supraglottic area, several authors have delineated these sub-sites separately. The supraglottis includes the epiglottis, the aryepiglottic folds, the arytenoids, and the false vocal cords. The glottis is composed of the true vocal cords and the subglottis extends from lower end of glottis to lower edge of cricoid.
The delineation of supraglottis and glottis is based on the function of the two subsites. While the supraglottis includes the muscles responsible for the closure of larynx, the glottis part is responsible for the movement of the vocal cords.

Supraglottic larynx
The contour includes the supraglottic adductors (oblique arytenoids and aryepiglottic muscles) and epiglottis. The cranial border is the tip of the epiglottis and the contour continues inferiorly till the upper edge of arytenoid cartilage.

Glottis
The contour starts from the upper end of arytenoid cartilage and ends caudally at the lower edge of the cricoid. Only the soft tissue is contoured (except for the arytenoids). The cricoid and the thyroid cartilage should be excluded.

Dose recommendations:
To minimize laryngeal edema, the volume of larynx receiving 50 Gy and mean dose should be kept as low as possible, ideally ≤20% and 40 Gy respectively [16].
The above has been summarized in Table 2: Swallowing related structures.

Brachial plexus
Guidelines for contouring brachial plexus has been put forward by Hall et al. They have put forward step-by-step technique. The contour starts form the neural foramina of C5-T1.
It extends from outer edge of spinal canal to the space between anterior and middle scalene. Where no spinal foramina was present, only the space between anterior and middle scalene is contoured. The middle scalene will end in the region of the subclavian neurovascular bundle.
In the lower part, the brachial plexus is contoured in the posterior aspect of neurovascular bundle in the inferior and lateral aspect one to two slices below the clavicle.
Dose recommendations: Dmax <60Gy. Emami et al. [17] has suggested TD 5/5 for the entire brachial plexus to be 60Gy. More recent studies with longer follow-up (upto 20 years) have shown that the risk of plexopathy keeps rising even after 5 yrs. and may not be apparent until 20 years after radiation [18].

Ear structures
Ear structures (both the middle ear and inner ear) should be contoured using the bone window.

Middle ear
The eustachian tube (ET), tympanic cavity and the mastoid air cells (M) may be contoured separately based on the CT/MRI anatomy.
Dose recommendations: ET D 30 < 52Gy; M D 0.05cc < 41 Gy. Based on the study by Yao et al. [19], dose to 30% of ET and 0.5 cc of mastoid volume were the main predictors of severe ear disorders. Doses above these are associated with increase in grade 2 ear disorders post RT.

Cochlea
It is a small spiral structure of about 0.6cm 3 volume located in the petrous part of temporal bone. The small bony cavity can be visualized better with a setting of 120/1500 on CT. The structures of inner ear are visualized more in T2 weighted MRI images. The semicircular canals should not be contoured.
Dose recommendations: Dmean <45 Gy. In children it is advisable to keep it below 35 Gy. [20]

Vestibular and semicircular canal
Arranged in 3 planes, the canals are contoured in bone window (120/1500). They are located lateral and superior to the cochlea.

Brain stem
Brain stem comprises of midbrain, pons and medulla. The cranial extend starts from the level of inferior section of lateral ventricle. The organ is better visualized better in MRI. The contour extends till the level of the tip of dense of C2 vertebra or foramen magnum.

Midbrain
It starts from the nigral substance of the cerebral peduncle and ends upper border of pons.

Pons
Better visualized as an oval structure in sagittal sections, it is easily delineated.

Medulla
Medulla starts from the lower end of pons to the lever of tip of dense of axis.
Dose recommendations: Dmax-54 Gy. The entire brain stem can be treated to a dose of 54 Gy with little risk of serious side effects. [21]. Mean time of onset of symptom is 17 months (range 4.5-19 months). Smaller volumes (1-10 cc) may be irradiated to 59Gy at fractionations ≤2Gy [22].

Pituitary gland
A small gland, it is difficult to visualize in CT, but sella turcica can be used as a surrogate marked and the inner boundary of the same can be contoured for its delineation. The gland lies immediately below the brain and is connected to the hypothalamus by its stalk.
CT density of pituitary gland is similar to brain. Upon contrast administration, the gland may become more hyperintense than brain due to the rich vascular supply.
Dose recommendations: DMax 45Gy (for pan hypopituitarism, lower for Growth hormone (GH) deficiency). The anterior pituitary has 5 different types of cells, each with different radiosensitivity. Most sensitive is the GH axis followed by the gonadotropin, ACTH and TSH axis. GH deficiency has been noted in relatively lower doses, and has been reported for TBI for doses as low as 10 Gy [23], but the incidence increases substantially after 30 Gy where the incidence can be as high as 50-100%.

Temporal lobe
Contouring of temporal lobe should include the hippocampus, parahippocampal gyrus and the uncus. The basal ganglia and insula are excluded from the contour. Cranially it starts for the superior end of sylvian fissure and ends inferiorly at the base of middle cranial fossa. Medial boundary is marked by cavernous sinus, sphenoid sinus and the sylvian fissure and laterally by the temporal bone.

Discussion
The modern radiotherapy in HNC have revolutionized treatment outcome especially in terms of acute and late toxicity. It thus brings about a clear change in treatment outcome. One important aspect in preserving the QOL is the OAR's. We, as radiation oncologist are much aware about the importance of accurate delineation of these structures. Only an accurate delineation can lead to effective sparing and thus a desirable outcome in terms of QOL. There were several isolated guidelines available. In this chapter we tried to summarize all the available guidelines. For certain organs like temporal lobe, multiple guidelines are available in the literature. We have tried to incorporate them together to put forward a single uniform consensus. Having said that the delineation and the attempted dose constraints should also be evaluated based on the target volume and tumor control. In case of parallel structures, the target volume coverage should be made priority and the risks and side effects of the same should be communicated to the patients. In such cases the volume of OARs outside the planning target volume (PTV) may be delineated separately and similar dose constrains may be aimed for. It should also be kept in mind that even with the most sophisticated of technologies, not all of the dose constraints might not be achieved due the basic physics of the photon beam. In such situations a trade-off should be agreed upon. However, such liberties, should not be attempted with serial structures like spinal cord and brain stem. Organs such as these should always be given hard constraints. If the PTV is overlapping such structures, under dose the area is accepted.

Conclusion
The chapter summarizes basic day to day information for a radiation oncologist to delineate OAR's in HNC radiotherapy. There are several updates and the readers are encouraged to go through them at a regular interval. We will be publishing a detail clinical end point based acute and late toxicities of these OAR's at a later date.