Prevention and Management of Acute and Late Toxicities in Radiation Oncology: Management of Toxicities in Radiation Oncology 3030377970, 9783030377977

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Prevention and Management of Acute and Late Toxicities in Radiation Oncology Management of Toxicities in Radiation Oncology Gokhan Ozyigit Ugur Selek Editors

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Prevention and Management of Acute and Late Toxicities in Radiation Oncology

Gokhan Ozyigit  •  Ugur Selek Editors

Prevention and Management of Acute and Late Toxicities in Radiation Oncology Management of Toxicities in Radiation Oncology

Editors Gokhan Ozyigit Chair and Professor Department of Radiation Oncology Hacettepe University, Faculty of Medicine Ankara Turkey

Ugur Selek Chair and Professor Department of Radiation Oncology Koc University, Faculty of Medicine Istanbul Turkey

ISBN 978-3-030-37797-7    ISBN 978-3-030-37798-4 (eBook) https://doi.org/10.1007/978-3-030-37798-4 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To our patients from whom we have learned to excel.

Preface

The role of radiation oncologists in multidisciplinary care is gradually becoming essential and more involved in patient care in the current era of improving technology and individualized management. As the patients’ awareness and their participation in treatment decisions increase, the clinicians have been discussing more and more about the quality of life issues in addition to outcome matters. Therefore, acute and late toxicity management is more crucial than ever in our clinical practice in comparison to a decade ago. We have planned to provide a structured and comprehensive book to deliver a current evidence-based and/or practice-proven management tool to feel confident in prescribing the innovative treatments with a goal of functionally unimpaired patient during and after radiotherapy. In this context, our book covers prevention and current management of acute and late toxicities of radiation therapy in a wide range of malignancies, while each chapter focuses on a particular anatomic site with information on normal sectional anatomy, contouring of target volumes and organs at risk, dose constraints, the pathophysiology of radiation toxicity, and treatment approaches for each potential toxicity; given under the variability of planning and delivery of intensity-modulated radiation therapy, volumetric modulated arc therapy, stereotactic radiosurgery, and stereotactic body radiotherapy. Overall, this book will enable the selection of appropriate, evidence-based management options in individual patients who experience radiation toxicities, taking into account the organ-specific pathophysiology of radiation injury, for practicing clinical and radiation oncologists, radiotherapists, fellows, residents, and nurses. We hope to encourage the clinicians through practical and theoretical aspects of acute and late toxicity management in modern radiation oncology, and we extend our most sincere gratitude to our patients, who stand side by side with us to fight with their cancer, and who teach us invaluable lessons to brace our faith to succeed. Ankara, Turkey Istanbul, Turkey 

Gokhan Ozyigit Ugur Selek

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Acknowledgments

The editors are indebted to Gesa Frese and Wilma McHugh from Springer DE and Niveka Somasundaram and Mariesha Justin from SPi Global/Springer Nature for their assistance in preparing Prevention and Management of Acute and Late Toxicities in Radiation Oncology. We extend our most sincere gratitude to our colleagues and friends at Hacettepe University, Koç University, and Baskent University as well as our families.

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Contents

1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology ��������������������������������������������������������������������������������   1 Guler Yavas and Gozde Yazici 2 Toxicity Management for Head and Neck Tumors in Radiation Oncology-I������������������������������������������������������������������������������  59 Sezin Yuce Sari 3 Toxicity Management for Head and Neck Tumors in Radiation Oncology-II��������������������������������������������������������������������������������������������������  85 Pervin Hurmuz 4 Toxicity Management for Thorax Tumors in Radiation Oncology �������� 107 Teuta Zoto Mustafayev and Banu Atalar 5 Toxicity Management for Upper Abdomen Tumors in Radiation Oncology �������������������������������������������������������������������������������� 171 Zumre Arican Alicikus and Barbaros Aydin 6 Toxicity Management for Pelvic Tumors in Radiation Oncology������������ 231 Nilufer Kılıc Durankus, Duygu Sezen, Ugur Selek, and Yasemin Bolukbasi 7 Toxicity Management for Other Sites in Radiation Oncology���������������� 267 Cagdas Yavas and Melis Gultekin

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1.1

Anatomy

The central nervous system (CNS) consists of the brain and the spinal cord (SC). The spinal cord is a single structure, whereas the adult brain can be defined by four major regions: the cerebrum, the diencephalon, the brain stem, and the cerebellum. The main functions of the CNS include receiving, processing, and responding to sensory information.

1.1.1 Brain Embryologically, the brain is composed of the prosencephalon (forebrain), the mesencephalon (midbrain), and the rhombencephalon (hind brain). The prosencephalon forms the two hemispheres (telencephalon) and the diencephalon (interbrain) during the later stages of embryogenic life [1]. The weight of the brain changes from birth through adulthood. At birth the brain weighs less than 400 g, but by the beginning of the second year of life it weighs around 900 g, and the adult brain weighs between 1250 and 1450 g [2]. The cerebrum is the largest region of the human brain and the two hemispheres together account for 85% of the brain mass. The interbrain (diencephalon) is the part that links the two hemispheres of the brain. The diencephalon has four regions: the epithalamus, thalamus, G. Yavas Faculty of Medicine, Department of Radiation Oncology, Selcuk Meram University, Konya, Turkey G. Yazici (*) Hacettepe University, Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey e-mail: [email protected] © Springer Nature Switzerland AG 2020 G. Ozyigit, U. Selek (eds.), Prevention and Management of Acute and Late Toxicities in Radiation Oncology, https://doi.org/10.1007/978-3-030-37798-4_1

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hypothalamus, and subthalamus. Each cerebral hemisphere is divided into five lobes entitled as: the frontal, parietal, temporal and occipital lobes, and the insula. The surfaces of the cerebral hemispheres are formed by highly folded collection of gray matter, few millimeters in width, named as the cerebral cortex. Although it is only 2–4 mm in thickness, the gray matter accounts for 40% of total brain mass. The inner region of the cortex is a central core of white matter that consists solely of neuronal pathways. Deep within the cerebral white matter is an important region of the cerebrum, a group of sub-cortical gray matter known as “basal nuclei.” The basal nuclei are composed of the caudate nucleus, putamen, and globus pallidus which are important regulators of skeletal muscle movements [3]. The cavities within the cerebral hemispheres are called as the right and the left lateral ventricles, which communicate with the third ventricle via interventricular foramen (foramen of Monro). The first and the second ventricles lie within the hemispheres of the brain, and the third ventricle is located in the interbrain. The space between the pons, bulbus, and the cerebellum is called as the fourth ventricle. These ventricles are continuous with one another and with the central canal of the spinal cord. The inner surface of the ventricles is lined by ependymal cells, and protruding into each ventricle is a choroid plexus which functions in the production of cerebrospinal fluid (CSF). About 300–400  mL of CSF is produced daily. The CSF forms a liquid cushion for the brain, and helps to nourish the brain. The brain and spinal cord is covered by three membranes which are called the meninges. The dura mater is the outermost layer of the meninges, lying directly underneath the bones of the skull and vertebral column. Inside the dura mater there is the arachnoid mater. Arachnoid mater consists of layers of connective tissue. It is avascular, and does not receive any innervation. Underneath the arachnoid mater is the sub-arachnoid space which contains CSF. The pia mater is located underneath the sub-arachnoid space. It is very thin, and is tightly adhered to the surface of the brain and spinal cord. It follows the contours of the brain. Like the dura mater, pia mater is highly vascularized with blood vessels perforating through the membrane to supply the underlying neural tissue. Therefore the dura mater and pia mater are very sensitive to pain.

1.1.2 Brain Stem The brain stem (BS) is composed of the mesencephalon, the pons, and the medulla oblongata. The BS begins inferior to the thalamus and is positioned between the cerebrum and the spinal cord. The mesencephalon is a relatively narrow band of the BS surrounding the cerebral aqueduct (of Sylvius), extending from the diencephalon to pons. The pons is thicker portion of the brainstem, and is about 25–30 mm in length. The pons bulges from the midbrain and medulla and is separated from them by the superior and inferior pontine sulci. Posteriorly it is surrounded by the cerebellum, and they unite through the middle cerebellar peduncles. The medulla oblongata is the caudal portion of the BS [2].

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1.1.3 Spinal Cord The spinal cord runs through the spinal canal from the cranial top portion of the atlas down to the L1–2 intervertebral disc in adults. It may extend below to L3 vertebral body in children. The spinal cord ends at the level of the L1 vertebral body, and the roots extend caudally in the cauda equina to exit in the appropriate intervertebral foramina. It is 45 cm long, 30 g in weight, and approximately 1 cm in diameter [2, 4]. The spinal cord in the spinal canal is surrounded by meninges. Dorsal and ventral roots course through the intervertebral foramina.

1.1.4 Orbita (Eye, Retina, Lens) The orbits are conical structures surrounding the organs of vision. The shape of the orbit resembles a four-sided pyramid. Orbit supports the eye and it protects this vital structure. The volume of the orbital cavity in an adult is roughly about 30 cc. The globe of the eye, or bulbus oculi, is a bulb-like structure consisting of a wall enclosing a fluid-filled cavity. The adult eyeball is spherical in shape, and is 24 mm in length antero-posteriorly. The anterior segment of the eyeball consists of the structures ventral to the vitreous humor, including the cornea, iris, ciliary body, and lens (crystalline lens). The pupil serves as an aperture which is adjusted by the surrounding iris, acting as a diaphragm that regulates the amount of light entering the eye. Both the iris and the pupil are covered by the convex transparent cornea. The cornea is the major refractive component of the eye due to the huge difference in refractive index across the air-cornea interface. The lens is a transparent, biconvex structure. Lens and the cornea refract light to focus on the retina. The lens is made of transparent proteins called “crystallins.” It is approximately 5 mm thick and has a diameter of about 9 mm for an adult [5]. The posterior segment of the eyeball is located posteriorly to the lens, and it includes the anterior hyaloid membrane, the vitreous humor, the retina, and the choroid. The retina is the light-sensitive tissue that lines thinner surface of the eye. In embryogenesis both the retina and the optic nerves originate from the diencephalon and should therefore be considered as part of the CNS.

1.1.5 Optic Pathway The optic pathway consists of the series of cells and synapses that carry visual information from the environment to the brain for processing. It includes the retina, optic nerve, optic chiasm, optic tract, lateral geniculate nucleus, optic radiations, and striate cortex. The optic nerve is the second cranial nerve, responsible for transmitting the sensory information for vision. The optic nerves are surrounded by the cranial meninges. The optic nerves progress from the posterior aspect of the globe,

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angle up through the optic canals, and unite to form the optic chiasm. At the chiasm, fibers from the nasal (medial) half of each retina cross over to the contralateral optic tract, while fibers from the temporal (lateral) halves remain ipsilateral. Each optic tract travels to its corresponding cerebral hemisphere to reach the lateral geniculate nucleus. From the lateral geniculate nucleus, the signals continue to the primary visual cortex, where further visual processing takes place [6].

1.1.6 Hippocampus The hippocampus has a distinctive, curved shape that has been likened to the sea-­ horse monster of Greek mythology and the ram’s horns of Amun in Egyptian mythology. The literature describes considerable age and diseasespecific variability in hippocampal size (range 2.8–4.0 cm3) and location. The hippocampus is located in the medial temporal lobe of the brain. It is a paired structure, with mirror-­image halves in the left and right sides of the brain. It consists of ventral and dorsal portions, both of which share similar composition but are parts of different neural circuits. It belongs to the limbic system (Latin limbus  =  border) which includes the hippocampus, cingulate cortex, olfactory cortex, and amygdala. It plays important roles in long-term memory and spatial navigation [7].

1.1.7 Pituitary Gland The pituitary gland (hypophysis cerebri) is a small organ situated in a depression of the sphenoid bone at the base of the skull called the “sella turcica.” Anatomically, the pituitary gland is related superiorly to the optic chiasm, inferiorly to the sphenoid sinus, and laterally, on either side, to the cavernous sinus and the structures contained within. The pituitary gland measures approximately 10 × 13 × 6 mm, weighs about 500 mg, and occupies most of the volume of the sella turcica. The gland consists of two anatomically and functionally distinct regions, the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis). Between these lobes lies a small sliver of tissue called the intermediate lobe. The adenohypophysis is originated from the Rathke’s pouch, an ectodermal diverticulum from the roof of the stomodeum, whereas the neurohypophysis is derived from the diencephalon. The adenohypophysis is divided into the pars anterior (anterior lobe) and the pars intermedia (intermediate lobe). The neurohypophysis consists mainly of the “pars posterior” (posterior lobe), part of the infundibular stem and the median eminence. The adenohypophysis secretes several hormones (somatotropin, gonadotropins, thyrotropin, adrenocorticotropin, prolactin, lipotropic hormones, and endorphins), whereas the posterior pituitary essentially stores vasopressin and oxytocin, secreted by the supraoptic and paraventricular nuclei of the hypothalamus [8].

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Contouring

Over the past decades a great deal of progress has been made in the field of radiation oncology as the profession has switched from 2-dimensional to 3-dimensional to intensity modulated and stereotactic techniques. Radiation-related side effects can be improved by avoiding critical structures called organs at risk (OARs) with the help of these technical developments. The comprehensive identification and delineation of OARs are vital to the quality of radiation therapy treatment planning and the safety of treatment delivery. The delineation of intracranial OARs is one of the most crucial points in the planning of brain tumors since RT to the brain may cause serious side effects. Moreover, accurate delineation of OARs is essential for the inverse-planning process of intensity modulate radiotherapy (IMRT). In some situations changes in anatomy because of the possible tumor extension necessitates a basic understanding of normal anatomy. During the delineation of intracranial OAR using contrast-enhanced computed tomography (CT) scans together with magnetic resonance imaging (MRI) allows better visualization and definition when compared to using CT alone. For example, in order to delineate spinal cord accurately, especially for stereotactic planning, a high-resolution T2-weighted MRI is recommended. Moreover during the delineation of optic chiasm and optic nerves using a high-resolution T1- or T2-weighted MRI rather than planning CT helps better and easier delineation. It is very important to contour on appropriate density windows for each tissue. The structures should be reviewed in the coronal and sagittal planes when contouring on axial slices to verify completeness of coverage in all dimensions [9].

1.2.1 Brain The delineation of the brain consists of the small brain vessels, cerebellum, CSF and excludes the brainstem and large cerebellar vessels, including the sigmoid sinus, transverse sinus, and superior sagittal sinus (Figs. 1.1 and 1.2). CT bone settings in addition to brain soft tissue 350/40 WW/WL-settings are recommended. The carotid canal and cavernous sinus which are located in the middle cranial fossa are not recommended to be included [9–11].

1.2.2 Brain Stem The cranial boarder of the brainstem (BS) is defined as bottom of optic tract or the disappearance of posterior cerebral artery which is the bottom of the lateral ventricles, and the caudal border is defined as the tip of the dens of C2 (cranial border of the spinal cord). For delineation of BS, MRI is recommended; however, the bottom section of the lateral ventricles is easily visible on both MRI and CT (Fig.  1.3). Visualization of sagittal plane may be helpful when defining the BS. From cranial to caudal, BS may be divided into three parts during contouring: the midbrain, pons,

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Fig. 1.1  Delineation of the brain as normal structure

and medulla oblongata [10–12]. Cochlea should also be delineated in pontocerebellar region (Fig. 1.4).

1.2.3 Spinal Cord For delineation of the spinal cord accurately, especially for stereotactic planning, a high-resolution T2-weighted MRI or CT myelogram is recommended. The spinal cord should be delineated instead of whole spinal canal. For CNS tumors, the cranial border of the spinal cord is defined at the tip of the dens of C2, which is the caudal border of the BS, and the caudal border at the upper edge of T3 [11].

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Fig. 1.2  Delineation of the cerebellum as normal structure

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Fig. 1.3  Delineation of the brain stem as normal structure

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Fig. 1.4  Delineation of the cochlea as normal structure

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1.2.4 Orbita (Eye, Retina, Lens) Cornea can be easily delineated using 2–3 mm brush on both MRI and CT scans (Fig. 1.5). Lens, which is up to 10 mm in diameter, is a biconvex, avascular, non-­ innervated, encapsulated body composed entirely of epithelial cells and fibers. The lens can be easily delineated on CT [10, 11]. The posterior segment of the eyeball includes the anterior hyaloid membrane, vitreous humor, retina, and choroid [10, 11]. The retina is approximately 0.25 mm thick, and covers the posterior 5/6 of the globe, extending nearly as far as the ciliary body. The retina can be delineated on both MRI and CT using a 3 mm brush. The anterior border of the retina is between the insertion of the medial rectus muscle and the lateral rectus muscle, posterior to the ciliary body. The optic nerve is excluded from this contour. On axial images the anterior limit of the retina is between the insertion of the medial rectus muscle and the insertion of the lateral rectus muscle, posteriorly to the ciliary body [10, 11, 13]. Lacrimal glands should also be delineated (Fig. 1.6).

Fig. 1.5  Delineation of the orbita

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Fig. 1.6  Delineation of the lacrimal glands

1.2.5 Optic Pathway The optic nerve is thin, usually 2–5 mm thick, and is clearly identifiable on CT. Using both CT and T1- and T2-weighted imaging/fast fluid-attenuated inversion recovery imaging of MRI is recommended for the accurate delineation of the optic nerve. Depending on the orientation of the scan plane relative to the brain, the optic nerve and chiasm can appear on multiple images (Fig. 1.7). The optic nerves should be delineated all the way from the posterior edge of the eyeball, through the bony optic canal to the optic chiasm. It is crucial to delineate the optic apparatus in continuity, since gaps in the structures will result in omission of the dose from the missing volume for that structure’s dose–volume histogram. The optic chiasm is usually 2–5 mm thick, and is located in the sub-arachnoid space of the supracellar cistern 1 cm superior to pituitary gland. Internal carotid artery forms the lateral boarder of the optic chiasm. It is demarcated inferiorly by the third ventricle. The pituitary stalk is the most important landmark since it is located just behind the crossing of the fibers. Pituitary gland is easily visible in T1-weighted MRI images because it shows hyperintense signals. Although it can be visible on both CT and MRI scans, a T1-weighted MRI with axial, sagittal, and coronal sections is recommended for better delineation [10, 11, 13].

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Fig. 1.7  Delineation of optic pathway

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1.2.6 Hippocampus During the recent years, the accurate delineation of the hippocampus (dentate gyrus) has been increasingly important since both the clinical and preclinical evidence suggest that irradiation to hippocampal dentate gyrus can cause neurocognitive impairment. The hippocampus is delineated as the gray matter medial to the medial boundary of the temporal horn of the lateral ventricle bordered medially by the quadrigeminal cistern as described by Gondi et al. [14] (Fig. 1.8). At the level of the curve of the temporal horn which is also called as uncal recess, the hippocampus is easily visible because it is the gray matter included in the curve and is bounded anteriorly, laterally, and medially by the CSF in the temporal horn. Amygdala, which is a gray matter located medially to the temporal horn of the lateral ventricle is easily distinguished from the hippocampus at this level. The amygdala should be excluded from the contour of the hippocampus [13]. The boundary between the hippocampus and the amygdala is not clearly visible in the more caudal slices. The hippocampus is mainly composed of gray matter therefore for the delineation of

Fig. 1.8  Delineation of the hippocampus

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hippocampus T1-weighted MRI scan is recommended. Very thin slice-thickness (1–2 mm) is necessary to visualize the hippocampus. In sagittal view it is easy to visualize “banana” shape hippocampus.

1.2.7 Pituitary Gland The pituitary gland is oval-shaped structure which is craniocaudally up to 12 mm, and is located in the sella turcica. The pituitary gland is one of the smallest OARs; therefore, it is difficult to visualize it on CT images (Fig. 1.9). The lateral border of the pituitary gland is formed by the cavernous sinuses. The inner part of the sella turcica can be used as surrogate anatomical bony structure. It is better to define the pituitary gland in the sagittal images [11, 13].

1.3

Pathophysiology

Despite the significant advances in limiting overt neurotoxicity, cognitive dysfunction is still a major problem particularly for childhood CNS tumors. During the last decades the researchers focused on identifying the primary cause of tissue damage. However, the data indicates that the response of the CNS to RT is a continuous and interacting process. Although the exact mechanism is not clear, the clinical and scientific evidence helps us to understand the pathophysiology of radiation-induced brain injury. The CNS is particularly more vulnerable to ionizing irradiation when compared to other tissue types. The ionizing irradiation may cause direct or indirect DNA damage, but it may also cause a metabolic stress, which is very harmful for the CNS [15]. Understanding the mechanisms of radiation-induced CNS toxicity may help to develop strategies to either increase the radiation tolerance or treat CNS alterations caused by ionizing radiation. The etiology of radiation-induced CNS toxicity is a multifactorial process that is influenced by patient-related factors including age, medical comorbidities, psychological and genetic predispositions, characteristics of the underlying malignancy, and any additional injuries caused by other treatment modalities such as surgery and chemotherapy [16]. The radiation-induced CNS injury is described in three phases from the radiobiological perspective: acute (within days to weeks after irradiation), early delayed (within 1–6 months post-irradiation), and late or late delayed (>6 months post-irradiation). The Radiation Therapy Oncology Group (RTOG) describes acute injury based on the clinical time expression as the injury occurring during or within 90 days of RT. Acute injury includes seizure, coma, and paralysis which are considered to be secondary to edema and disruption of the blood–brain barrier (BBB). The corticosteroid treatment improves the acute neurologic changes. Late toxicities include headache, lethargy, and severe CNS dysfunctions such as partial loss of power and dyskinesia, and coma, and occur after

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Fig. 1.9  Delineation of the pituitary gland

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90  days of RT.  Radiation-induced late toxicities are probably associated with increased intracranial pressure caused by the persistent vasogenic edema resulting from BBB damage [17]. Larger fraction sizes and compressed fractionation schedules are known to contribute negatively to the CNS toxicity. RTOG prospectively compared different whole brain RT fractionation schedules in patients with symptomatic brain metastases with respect to the impact on overall survival [18]. Multiple fractionation schedules ranging from 10  Gy in a single fraction to up to 40  Gy delivered over 20 fractions were delivered. Most fractionation schedules were not significantly different in terms of overall survival times, except the delivery of 10 Gy in a single fraction. 10 Gy to the entire brain in single fraction was determined to be significantly detrimental. It can be interpreted from these data that, above a certain threshold, larger fractionation sizes has detrimental impact on radiation-induced brain injury when the treatment volumes are equivalent. Among the varieties of radiation-induced CNS toxicities, it is the late delayed effects that cause severe and irreversible neurological consequences. After the exposure of ionizing radiation, late delayed effects within the CNS have been attributable to both the parenchymal and vascular injury involving the oligodendroglial cells, neuronal progenitors, and vascular endothelial cells [19]. Late delayed toxicity of CNS irradiation may be presented with different scenarios including demyelination, proliferative and degenerative glial reactions, endothelial cell loss, and capillary occlusion. Therefore a single mechanism cannot explain these complex alterations. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum, and cortex; (4) generalized alterations of cytokine expression [20]. These four contributing factors can be explained with (1) the vascular hypothesis, (2) parenchymal hypothesis, (3) the dynamic interactions between multiple cell type’s hypothesis, and (4) molecular mechanisms.

1.3.1 Vascular Hypothesis The vascular hypothesis argues that vascular damage leads to ischemia with secondary white matter necrosis. Death of endothelial cells is an early event in small vessels which may be responsible for the initial edema [21, 22]. After the early changes of the vascular wall there is progressive loss of endothelia. Thrombocytes adhere to exposed matrix which leads to the formation of thrombi. Thrombi occur within weeks and months after RT.  After this, abnormal endothelial proliferation is observed. In the acute and subacute phases of vascular damage the most prominent findings are altered permeability of the vascular wall and BBB breakdown, and in the late phase the important findings are telangiectasia, hyalinosis, and fibrinoid deposits in the vessel wall.

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1.3.2 Parenchymal Hypothesis 1.3.2.1 Oligodendrocytes Since the white matter necrosis after RT is associated with demyelination, the parenchymal hypothesis initially focused on the oligodendrocytes as they are required for the formation of myelin sheaths. The progenitor cells of oligodendrocytes, known as O-2A cells, give rise to mature oligodendrocytes. It has been proposed that the radiation-induced loss of O-2A progenitor cells leads to failure to replace oligodendrocytes that eventually results in demyelination and white matter necrosis. It has been shown that the oligodendrocytes are the most radiosensitive type of glial cells, with cell death occurring rather early after relatively low doses of irradiation. Therefore, the data seemed to be consistent with the white matter selectivity of radiation-induced brain injury. However, the time course of oligodendrocyte depletion after irradiation was not consistent with that of white matter necrosis during the development of late delayed effects [19, 20]. 1.3.2.2 Astrocytes Astrocytes have many functions besides their supportive role, including modulation of synaptic transmission and secretion of neurotrophic factors such as basic fibroblast growth factor to promote neurogenesis. Astrocytes are vital for the protection of endothelial cells oligodendrocytes, and neurons from oxidative stress. It has been suggested that hippocampal astrocytes are capable of regulating neurogenesis by instructing the stem cells to adopt a neuronal fate [23]. In response to injury, astrocytes exhibit two common reactions: in acute phase cellular swelling (radiation-­induced edema), and in chronic phase hyperplasia and hypertrophy. In chronic phase astrocytes undergo proliferation, exhibit hypertrophic nuclei/cell bodies, and show increased expression of glial fibrillary acidic protein (GFAP) [24–26]. These reactive astrocytes secrete a host of pro-inflammatory mediators such as cyclooxygenase (Cox)-2 and the intercellular adhesion molecule (ICAM)-1, which lead to the infiltration of leukocytes into the brain via BBB breakdown [25–27]. 1.3.2.3 Microglia Microglia are the immune cells of the brain. After injury, microglia become activated. Activated microglia can proliferate, phagocytose, and exacerbate the injury by the production of reactive oxygen species (ROS), lipid metabolites, and hydrolytic enzymes. Although microglial activation plays an important role in phagocytosis of dead cells, sustained activation is believed to contribute to a chronic inflammatory state. In-vitro studies suggested that activated microglia leads to a remarkable increase in expression of pro-inflammatory genes TNFα, IL-1β, IL-6 and Cox-2, and the chemokines. In particular, excessive generation of ROS from the injured and/or pro-inflammatory cells has been implicated in the development of late delayed effects of the ionizing radiation [27–29].

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1.3.2.4 Neurons The neurons, which are located in the gray matter, were initially thought to be a radioresistant. Therefore the neurons were believed to play no role in radiation-­ induced CNS injury. However, studies have demonstrated radiation-induced changes in hippocampal cellular activity, synaptic efficiency/spike generation, and neuronal gene expression [30–32]. In addition, the chronic and progressive cognitive dysfunction following cranial irradiation was shown in both children and adult patients in clinical studies; therefore, the neurons should be sensitive to radiation.

1.3.3 Neuronal Stem Cells/Neurogenesis The hippocampus plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory. The dentate gyrus, which is a part of hippocampus is a highly dynamic structure and a major site of postnatal/adult neurogenesis. Residents in the hippocampus are neuronal stem cells, self-renewing cells capable of generating neurons, astrocytes, and oligodendrogliocytes. High doses of radiation produce overt histopathological changes such as demyelination and vasculopathies within the brain parenchyma, but lower doses produce cognitive dysfunction without inducing obvious morphological changes. Although the pathogenesis of radiation-induced cognitive dysfunction is unknown, recent studies suggest that it may involve impaired neurogenesis within the subgranular zone (SGZ) of the dentate gyrus [19, 33, 34].

1.3.4 D  ynamic Interactions Between Multiple Cell Types Hypothesis The radiation-induced late CNS injury is a dynamic process between the multiple cell types of the CNS. Oligodendrocytes, astrocytes, microglia, neurons, and vascular endothelial cells are not only passive bystanders that merely die from radiation damage but rather act as participants in an orchestrated response to radiation injury [28, 35].

1.3.5 Molecular Mechanisms There are many suggested molecular mechanisms involved in the radiation-induced CNS toxicity including: (a) apoptosis and neurogenesis inhibition, (b) excessive production of cytokines and chemokines, (c) VEGF, hypoxia and blood–brain barrier disruption, (d) radiation-induced ROS generation.

1.3.5.1 Apoptosis and Neurogenesis Inhibition Radiation-induced apoptosis is primarily related to mitochondrial damage followed by caspase activation. In addition, ATM gene is required for the regulation of

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apoptosis in some part of the brain including hippocampal dentate gyrus, external granular layer of the cerebellum and retina. In preclinical studies it has been demonstrated that apoptosis occurs in the young adult rat brain after ionizing radiation, and leads to damage in hippocampal neurons which eventually is associated with cognitive decline [20, 36, 37].

1.3.5.2 Excessive Production of Cytokines and Chemokines Among the numerous pro-inflammatory cytokines and chemokines IL-1, IL-6, TNF-α, and TGF-β are the ones that are excessively produced immediately after radiation exposure to brain tissue [20]. Although there are many studies providing the evidence that the expression of TNF- α is directly activated by ionizing radiation, limited evidence is available with respect to the pathways describing the TNF-α gene induction in response to radiation [38]. All of these cytokines and chemokines in the irradiated tissue perpetuate and augment the inflammatory response for long periods of time, causing to possible chronic inflammation and radiation-­ induced CNS injury. 1.3.5.3 VEGF, Hypoxia, and Blood–Brain Barrier Disruption The endothelial cell density after RT is reduced which gradually diminishes the integrity of BBB. This causes vasogenic edema, inflammation, and tissue hypoxia. Hypoxia causes induction of HIF-1α and VEGF. VEGF augments the vascular permeability which eventually causes disruption of BBB, worsening vasogenic edema, inflammation, and tissue hypoxia. All of these cascades further increase the VEGF concentrations. Eventually VEGF concentrations become sufficient to increase endothelial proliferation and angiogenesis which leads to a dramatic increase in endothelial cells. This situation is referred as “conditional renewal.” All of these cascades end with white matter necrosis. Reports suggesting that anti-VEGF therapy can normalize BBB function in microvessels damaged during radiosurgery in the human brain and suggest that manipulating the VEGF signaling cascade may be a useful strategy for mitigating late delayed injuries resulting from brain radiation as well [19, 39]. 1.3.5.4 Radiation-Induced ROS Generation Reactive oxygen species (ROS) include free radicals, oxygen ions, and both inorganic and organic peroxides. ROS are highly reactive since they have unpaired electrons in their shells. In normal situation, the antioxidant systems protect cells against oxidative damage. However, under stress, ROS levels can increase dramatically, overwhelming antioxidant systems and resulting in significant injury to tissues. This condition is called as “oxidative stress.” Increased levels of ROS might arise from macrophages, infiltrating activated leukocytes, and neurons. Tissue hypoxia resulting from vascular damage is another source of ROS generation. Moreover pro-­inflammatory cytokines and growth factors increase intracellular ROS generation [19]. The brain is very vulnerable to oxidative stress. When compared to other cells, neurons and glial cells contain relatively low levels of antioxidant enzymes

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including catalase, glutathione peroxidase, and superoxide dismutase (SOD). Additionally, myelin membranes contain relatively high levels of peroxidizable fatty acids which make them highly susceptible to ROS. Strategies to block effector molecules or to reduce oxidative stress are attractive approaches for mitigating radiation-­induced toxicity [19, 39].

1.3.5.5 Brain Radiation-induced brain toxicity has been classified into three phases: acute, early delayed (subacute), and late delayed injury. These phases were first described by Sheline [40]. Acute brain injury occurs during and/or in days to weeks after irradiation. Early delayed brain injury is seen 1–6 months post-irradiation; however, some other researchers consider this time course as 6–12  weeks. Late delayed injury, which is the most severe, often irreversible and progressive form of the injury usually develops >6 months after irradiation. The most common acute reactions associated with brain irradiation include headache, nausea, drowsiness, and sometimes worsening of neurologic symptoms, fatigue, hair loss (alopecia), skin erythema (radiation dermatitis). Acute side effects are usually transient and self-limiting [41–43]. The initial vascular injury causes platelet aggregation and thrombus formation in microvessels within weeks to months. Furthermore early vascular injury causes degenerative structural changes in white matter. General neurologic deterioration during early delayed period (2–6 months after RT) is probably due to transient, diffuse demyelination. Many focal neurologic signs following irradiation of intracranial tumor have been attributed to intralesional reactions, probably indicative of tumor response or perilesional reactions including edema and demyelination. Periventricular white matter lesions start to appear on conventional MR imaging or CT during this interval, even with standard fractionated partial brain RT [41]. Similar to acute toxicities, early delayed side effects are usually reversible and resolve spontaneously. Late delayed side effects are of the most concern when discussing radiation-­ induced brain toxicity. Unlike acute and early delayed side effects, late delayed toxicity is largely progressive and irreversible. Due to the limited lifespan of many adult brain tumor patients receiving irradiation to the brain, it is largely unknown what the long-term consequences of most treatments would be after many years. The classical late effect following brain irradiation is either localized or multifocal necrosis, often associated with high-dose and large brain-volume treatment. Complications include worsening neurologic signs and symptoms, seizures, and increased intracranial pressure [41]. Both conventional and more precise treatments including stereotactic radiotherapy (SRT) and stereotactic radiosurgery (SRS) have the potential to produce late delayed side effects such as cognitive alterations in short-term memory and concentration, and in rare cases dementia. Radiation-­ induced neuropsychological function and cognition deficits evolve in a biphasic pattern with a subacute transient decline corresponding to more common symptoms, followed by a late delayed irreversible impairment several months or years later in a much smaller proportion of surviving patients [44].

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1.3.5.6 Brain Stem Brainstem injury patients may exhibit III-XII cranial nerve palsy as well as long-­ beam (cone and sensory system) and cerebellar injury symptoms. The pathophysiology of the brain stem injury is similar to brain injury [45]. Patients have no clinical symptoms in mild cases; serious complaints vary and include limb weakness, hemiplegia, gait instability, temperature sensory disturbance, diplopia, dysarthria, tongue, and facial paralysis. One severe clinical manifestation of brain stem injury is syncope. Damage to descending sympathetic nerve fibers, which anatomically run along the brain stem, may result in syncope or Horner syndrome. Some patients may recover from the disease after their brainstem suffers mild radiation injury, while others may need earlier medical intervention to alleviate their symptoms. However, patients who develop severe radiation brainstem injuries have a poor prognosis due to the lack of effective medical therapies [46]. 1.3.5.7 Spinal Cord The most common early delayed side effect of the spinal cord is transient myelopathy, particularly in the cervical and thoracic spine. The most common pathophysiology of the transient myelopathy is believed to be demyelination on the posterior columns. Lhermitte’s sign, or “transient radiation myelopathy,” which is characterized by an electric shock sensation that radiates down the spine and extremities on flexion of the neck, is a relatively infrequent sequela of irradiation of the cervical spinal cord. It is a self-limiting condition and most patients improve during the course of several months to a year. Although Lhermitte’s sign is rarely a precursor of myelitis, there have been some reports of patients who developed radiation myelopathy after experiencing Lhermitte’s sign. In general, the Lhermitte’s sign that predated true radiation myelitis is later in onset than the usual latency period of 2–4 months [46]. Late effects to spinal cord are less common and highly severe. A progressive myelopathy syndrome can be seen, initially presenting with a partial cord involvement and progressing to a total transverse myelopathy. Irreversible radiation myelopathy usually is not seen earlier than 6–12 months after the completion of treatment. Typically, half of the patients who develop radiation-induced myelopathy in the cervical or thoracic cord region will do so within 20 months of treatment and 75% of cases will occur within 30  months. The signs and symptoms are typically progressive over several months, but acute onset of plegia over several hours or a few days is also possible. The diagnosis of radiation myelopathy is one of exclusion; a history of radiation therapy in doses sufficient to result in injury must be present. The region of the irradiated cord must lie slightly above the dermatome level of expression of the lesion; the latent period from the completion of treatment to the onset of injury must be consistent with that observed in radiation myelopathy; and local tumor progression must be ruled out. Radiation myelopathy is a diagnosis of exclusion, and patients must be evaluated for tumor progression and paraneoplastic syndromes with MRI of the cord [47, 48].

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1.3.5.8 Orbita (Eye, Retina, Lens) Radiation-induced orbital injury is composed of a wide variety of clinical conditions from transient eyelid erythema and a mild conjunctivitis to corneal perforation and complete loss of vision, with or without loss of the globe (Fig. 1.10). Long-term radiation effects of the human ocular adnexa are manifest by a spectrum of changes. Among these alterations are loss of meibomian glands and ducts, loss of distal glands with persistent remnants of ducts and acini, squamous metaplasia of the meibomian glands and dilated ducts filled with keratin. Late conjunctival alterations include chronic conjunctivitis, focal loss of epithelial cells, and squamous metaplasia [49]. Radiation-induced retinopathy histologically resembles diabetic retinopathy. Histologic examination reveals several consistent findings including thickening of arteriolar capillary walls, accumulation of fine fibrillar material within the walls of the vessels, myointimal proliferation, swelling of the endothelium, an enlarged elastic lamina, narrowing and occlusion of the vessel lumen, degeneration of the media and adventitia, and swelling and loss of muscular, elastic, and collagenous components. In clinic, radiation retinopathy can manifest by many disorders including cotton wool spots, macular edema, exudates, microaneurysms, telangiectasia, retinal hemorrhages, proliferative neovascularization, vitreous hemorrhage, and pigmentary changes [49]. Cataract is a well-known radiation complication. According to the anatomic location cataracts are classified into three types including, nuclear, cortical, and posterior subcapsular types. Nuclear and cortical cataracts develop from pathologic changes within the lens fiber cells; on the other hand, posterior subcapsular cataracts are associated with abnormalities at the germinative zone of the lens. Among the three different cataract types, the posterior subcapsular cataract is the one that is Fig. 1.10  A patient with eyelid erythema and a mild conjunctivitis after radiotherapy

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most commonly associated with ionizing irradiation [50]. Radiation damage to the germinative zone of lens epithelial cell DNA is probably responsible for most post treatment cataracts. In addition to DNA damage, direct cytoplasmic effects, such as disruption of membrane channels, protein cross-linking, and ion pump abnormalities are also important in radiation-induced cataract progression [49, 51].

1.3.5.9 Optic Pathway The most frequent clinical symptoms of radiation-induced optic neuropathy are sudden, painless, and irreversible loss of vision in one or both eyes 3  months to 9 years after RT. The changes are similar to those associated with brain radionecrosis. Pathological specimens have revealed thickened blood vessels, endothelial cell proliferation occluding vessel lumens, and demyelinization [49, 51]. 1.3.5.10 Hippocampus The hippocampus is central to short-term declarative memory and spatial information processing. Hippocampus consists of the dentate gyrus, CA3, and CA1 regions. The dentate gyrus is a highly dynamic structure and it is an important site of postnatal/adult neurogenesis. The hippocampus is consisted of neuronal stem cells that are self-renewing cells capable of generating neurons, astrocytes, and oligodendrocytes. Neurogenesis depends on the presence of a specific neurogenic microenvironment. Both astrocytes and endothelial cells can regulate neurogenesis [23, 52]. Hippocampus is particularly vulnerable to ionizing radiation. Hippocampal dysfunction is characterized by a progressive decline in the learning, memory, and spatial information processing abilities. Although the pathophysiology of radiation-induced cognitive dysfunction has still been unknown, recent evidences suggest that it may involve impaired neurogenesis within the subgranular zone of the dentate gyrus. Whole brain radiotherapy doses as low as 2 Gy are sufficient to reduce the rate of proliferation among neuronal progenitors within the subgranular zone [53]. The cellular mechanisms underlying the vulnerability of hippocampus remain to be elucidated [53–55]. Although the neuronal progenitors within the subgranular zone of the dentate gyrus are highly radiosensitive, direct effects of radiation on synaptic plasticity in the hippocampus or in other limbic or paralimbic structures may also be involved [19]. 1.3.5.11 Pituitary Gland The pituitary gland is an endocrine gland essential for the regulation of many physiological processes including growth, thyroid gland function, reproduction, and lactation. The pituitary gland is controlled in large part by the hypothalamus, a region of the brain that lies just above the pituitary. The pituitary gland is linked to the hypothalamus through the pituitary stalk. The hypothalamic–pituitary unit is a particularly radiosensitive region in the CNS. The clinical scenarios include panhypopituitarism, hypothalamic hypopituitarism, and hypothalamic hypogonadism. Pediatric patients are more vulnerable to

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pituitary dysfunction than the adult patients. The most common clinical condition for the pediatric patients is growth hormone deficiency revealing short stature and retarded growth [56]. Growth hormone deficiency is usually the first and frequently is the only manifestation of neuro-endocrine injury following cranial irradiation. GH axis is followed by the gonadotrophin, adrenocorticotrophic hormone (ACTH), and thyroid-stimulating hormone (TSH) axes; these observations in humans have been reproduced in animal models [57, 58].

1.4

Dose Constraints

Despite the increasing number of patients treated with RT for CNS tumors, limited evidence is available about the relationship between dose and toxicity. In addition, technological advances in the field of radiation therapy have emerged new treatment strategies, including stereotactic radiosurgery (SRS) and stereotactic cranial radiotherapy (SCRT), and these treatment methods require new dose restrictions for organs at risk (OAR) (Table 1.1). Seminal papers by Rubin [59] and Emami [60] provided rational guidelines for the dose tolerance limits of normal tissues under conventional fractionation. In 2006, leaders in the American Association of Physics in Medicine (AAPM) and American Society of Therapeutic Radiology and Oncology (ASTRO) recognized that an increasing amount of dose/volume/outcome data for normal tissues had been generated. The joint efforts of the radiation oncologists and physicist (ASTRO-­ AAPM), called as “Quantitative Analysis of Normal Tissue Effects in the Clinic” (QUANTEC), updated the recommendations of Emami et al. using models for normal tissue complications for most sites [61, 62]. The QUANTEC papers essentially present a critical review of the literature on radiation dose/volume/outcome for normal tissue, and attempt to quantitatively analyze these data and present recommendations on dose-volume limits for normal tissue toxicity. Nonetheless QUANTEC provides limited evidence with respect to dose constraints for SRS and SCRT. Later when the clinical data emerged, new proposals defining dose/volume/toxicity for SRS and SCRT are developed. The radiation tolerance to CNS may be affected from a number of parameters, including total dose, dose per fraction, total treatment time, fractionation schedule, volume, host-related factors (age, comorbid diseases such as diabetes mellitus), radiation quality (linear energy transfer = LET), and adjunctive therapies. RTOG/EORTC acute and late radiation morbidity scoring criteria are summarized in Table 1.2.

1.4.1 Brain Although the brain is composed of different anatomical regions including the gray matter, white matter, and nuclei, dose constraints to brain is uniformly applied to

5 cm TD5/5: 50 Gy TD50/5: 70 Gy

Spinal cord

Lacrimal gland

TD5/5 = 60 TD50/5 = 75

20 cm TD5/5: 47 Gy Cauda equina: TD5/5: 60 Gy TD50/5: 75 Gy

10 cm TD5/5: 50 Gy TD50/5: 70 Gy

TD5/5: 35 Gy TD50/5: 50 Gy

TD5/5 = 50 TD50/5 = 65

3/3 TD5/5 = 45 TD50/5 = 60

TD5/5 = 53 TD50/5=

Emami dose limits (Gy) 1/3 2/3 TD5/5 = 60 TD5/5 = 50 TD50/5 = 75 TD50/5 = 65

Brain stem

Organ Brain

Myelopathy risk: Dmax = 50 Gy: 0.2% Dmax = 60 Gy: 6% Dmax = 69 Gy: 50%

QUANTEC dose limits Symptomatic necrosis risk: Dmax