Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

3. Skull Base and CNS Glial Tumors

Ugur Selek • Eric L. Chang


• Image-guided radiotherapy started to be utilized over the last decade initially as forward-planned three-dimensional conformal radiation therapy (3DCRT) and later evolved toward inverse-planned delivery of intensity modulated radiation therapy (IMRT) and volumetric arc radiation therapy (VMAT). Stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), and proton-beam therapy also critically rely on image guidance for target and critical structure delineation.

• Radiotherapy of skull base and posterior fossa tumors is challenging because of the close proximity of the tumors to radiosensitive structures such as lens, eyes, optic pathways, auditory apparatus, and brain stem. These critical structures also play a role in treatment planning of glial tumors which could arise from any lobe of the brain.

• The limiting factor in dose delivery is the tolerance of normal tissue to radiation; the goal is to give the appropriate dose necessary to control the tumor while preserving the surrounding normal tissues within their respective tolerance doses.

• Owing to the variety of tumors affecting the skull base (Table 3-1), a unified classification system has not been established. Therefore, general classifications are being based on either the location or the biologic behavior of the tumor.

• We review the complex anatomy of the skull base to serve as a guide for delineating target and normal tissue, as well as offering several examples.


• The base of the skull can be divided into the anterior, middle, and posterior cranial fossa (Fig. 3-1).

• Anterior cranial fossa (Fig. 3-1) is formed anteriorly by orbital plates of the frontal bone, and the cribriform plate of the ethmoid bone, and posteriorly by the posterior edge of the lesser wing of the sphenoid bone and anterior margin of the chiasmatic groove. Below is the anterior skull base mainly separating frontal base and paranasal sinuses and involving critical structures such as the frontal lobe, the orbits, and the optic nerves. The planum sphenoidale is a flat region separating the cribriform area of the ethmoid bone anteriorly from the chiasmatic sulcus posteriorly. The cribriform plate transmits the olfactory nerve and the anterior ethmoidal nerve.

• The chiasmatic sulcus is a linear, transversely oriented depression through which the optic canals enter the intracranial compartment at its lateral margins. Optic nerves combine at the optic chiasm, which is superior to the sella turcica in the suprasellar cistern at the base of the brain. The optic tract courses dorsolaterally around the hypothalamus and the rostral part of the cerebral peduncle.

• Middle cranial fossa (Fig. 3-1) is formed anteriorly by the posterior edge of the lesser wing of the sphenoid bone, the anterior clinoid process, and the anterior ridge of chiasmatic groove, and posteriorly by the petrous ridge of the temporal bone. The central skull base can be organized roughly into three regions. The midline is formed mainly by the sphenoid bone (sella and sphenoid sinus), covered by dura and bearing two important embryological structures: the notochord and Rathke’s pouch. Just lateral to the midline is the sagittal plane of the foramina and fissures (medial middle fossa, cavernous sinus, Meckel’s cave). Further laterally is the greater wing of the sphenoid with no fissures or foramina (sphenoid wing, lateral middle fossa). This area is closely related to the pterygomaxillary region and the infratemporal fossa.

• The Meckel’s cave (MC) and the cavernous sinus (CS) are the anatomical structures connecting most of the foramina. MC is a loose dural sleeve around the trigeminal nerve and the gasserian ganglion. The CS is a venous sinusoid structure located between the layers of dura, bordering the pituitary fossa and the body of the sphenoid. The CS lies superomedially to MC, extending anteriorly. The ophthalmic branch (V1) of the trigeminal nerve passes through the CS to the superior orbital fissure (SOF) as the maxillary division (V2), and with a shorter course in the CS enters the foramen rotundum (FR). The mandibular division of trigeminal nerve does not truly enter the CS after exiting MC. The oculomotor (III), trochlear (IV), and abducens (VI) nerves traverse the CS to exit at the SOF. The internal carotid artery also traverses the CS after exiting the petrous carotid canal.

• The optic canal and SOF open into the orbit. Just caudal to the SOF, the FR lies in a posterior-anterior orientation through the skull base. The FR passes from the CS to the pterygopalatine fossa (PPF) (Fig. 3-2), entering the fossa at the level of the inferior orbital fissure (IOF). The V2 (maxillary) division of the trigeminal nerve, carried through the FR, crosses the upper part of the fossa and enters the orbit through the IOF. It becomes the infraorbital nerve in the floor of the orbit and exits through the infraorbital foramen to the face.

• The pterygoid canal (PC, vidian canal) is inferomedial to the FR, transmitting the pterygoid nerve and artery from the anterior wall of foramen lacerum to the PPF.

• The foramen ovale (FO) is anterior and medial to the foramen spinosum (FS) (Fig. 3-3). The FO transmits the V3 (mandibular) division of the trigeminal nerve into the masticator space, as well as the accessory meningeal artery and the lesser superficial petrosal nerve. The FS transmits the middle meningeal artery and the recurrent branch of the mandibular nerve.

• The PPF is an important landmark that provides pathways for tumor spread by its connections: via the PC and FR to the central skull base and middle cranial fossa; via the IOF to the orbit; via the pterygomaxillary fissure to the infratemporal fossa; via the sphenopalatine foramen to the nasal cavity; and via the pterygopalatine canals to the oral cavity.

• Posterior cranial fossa, containing the cerebellum and brain stem, is formed by the dorsum sellae and clivus of the sphenoid, the occipital bone, the petrous and mastoid temporal bone, and the mastoid angle of the parietal bone. Cranial nerves VII–XII exit in this fossa.

• The jugular foramen is situated between the lateral occipital bone and the petrous temporal bone (Fig. 3-1). Above the jugular foramen is the internal acoustic meatus, which transmits the facial and acoustic nerves and the internal auditory artery.


3.1. Meningioma

• Meningiomas represent approximately 15% of primary brain tumors and occur with an annual incidence ranging from <1 to >6 per 100,000.1,2

• They arise from the arachnoidal cells of the meninges.3 The peak incidence is during the sixth and seventh decades of life.

• The ratio of males to females ranges from 1:1.4 to 1:2.8.1,4,5

• Most meningiomas occur along either the convexities or the parasagittal plane. Six morphologic variants defined by the World Health Organization (grade II: atypical, clear cell, chordoid; grade III: anaplastic, papillary, rhabdoid) are associated with aggressive clinical behavior and increased recurrence and metastasis.6

FIGURE 3-1. Base of skull. (A) Outer surface. (B) Inner surface. (From Anatomical Chart Company copyright © 2008, Lippincott Williams & Wilkins. All rights reserved.)

FIGURE 3-2. Foramen rotundum (white arrow) and pterygo-palatine fossa (star, PPF) demonstrated in axial CT slide with head and neck bone image resolution.

FIGURE 3-3. Foramen ovale (arrow) and foramen spinosum (star) demonstrated in axial CT with head and neck bone image resolution.

FIGURE 3-4. Right-sided petroclival meningioma with a characteristic dural-based tail appearance and parasellar and cavernous extension in axial (left) and coronal (right) T1 MRI with gadolinium.

• Although skull base origin is infrequent, they may arise from any part of the sphenoid such as the greater wing, the planum sphenoidale, the tuberculum sellae, the walls of the CS, petrous apex or clivus (petroclival), parasellar regions (Fig. 3-4), the optic sheath, the petroclinoid, or the trigeminal nerve.

• Skull base meningiomas extend along the dural surfaces or intraosseously. Penetrating through bone may cause a substantial extracranial mass.

• As arachnoid cells accompany the cranial nerves, meningiomas can be found adjacent to and traversing various neural foramina.7

3.2. Esthesioneuroblastoma

• Esthesioneuroblastoma (olfactory neuroblastoma, neuroendocrine carcinoma) constitutes 1% to 5% of all malignant neoplasms of the nasal cavity.8;9 It originates from the basal cells of the olfactory epithelium in the upper third of the nasal septum, the cribriform plate, or the superior turbinates (Fig. 3-5). It has a spectrum of neural and epithelial differentiation.10,11

FIGURE 3-5. Postsurgical resection of right-sided esthesioneuroblastoma with a residual right medial orbital mass (white arrow) in axial (left) and coronal (right) T1 MRI with gadolinium. Postoperative cystic areas are marked (stars) in coronal section.

• It has a fairly equal distribution between sexes, with a slight male predominance. The mean age at diagnosis is 45 years, with a bimodal distribution with peaks of incidence in the second and fifth decades of life.12

• Early symptoms are usually nasal obstruction or epistaxis. Periorbital swelling and hyposmia are also common.

• Advanced age, brain involvement, high histologic grade, and advanced Kadish stage (Table 3-4) are major prognostic factors. Polin et al. reported that, in their experience at the University of Virginia, advanced Kadish stage was associated with a slightly higher rate of disease-related mortality, but not with disease-free survival.13

• Synchronous cervical lymph node metastases incidence is 17% to 47%.14

• Distant hematogenous metastases are not usual at presentation, but may occur after relapse. Metastases occur mainly to the lung, bone, bone marrow, or skin.9

3.3. Chordoma

• Chordomas represent approximately 1% of all malignant bone tumors and arise from remnants of the notochord. The terminus of the notochord is in the sphenoid bone, so skull base chordomas arise in the region of the clivus (Fig. 3-6).

• Thirty-five percent of chordomas occur in the skull base, 50% in the sacrococcygeal region, and 15% in the spine.15

• Most chordomas in the craniovertebral area are diagnosed in persons aged 30–50 years, while sacrococcygeal chordomas have their peak incidence at 40–60 years of age.

FIGURE 3-6. Left-sided chordoma tumor (black stars) with compression of brain stem in axial (left) and coronal (right) T1 MRI with gadolinium.

• Male predominance has been reported,15 while in another series, the gender distribution was even.16

• The three pathologic subtypes are described as classic (most common), chondroid (mostly in the skull base), and dedifferentiated (rare, but poor prognosis).15,17

• Distant metastases, more common in sacral and vertebral chordomas than in skull base chordomas, occur in the lungs, bones, lymph nodes, liver, and skin.1820 Intradural metastases may appear following surgical resection of skull base chordomas, but are rare.21

3.4. Glomus Jugulare Tumor

• Glomus jugulare tumor (GJT)—also known as paraganglioma or chemodectoma—is a rare tumor with an incidence of about 1 per 1,000,000 population.22

• It is the most common neoplasm of the middle ear.23,24 It is the most commonly diagnosed neurotologic neoplasm after acoustic neuroma, and originates from special neural crest elements called paraganglion cells, which, along with autonomic ganglion cells, form the paraganglia. It is composed of two types of cells: chief cells and sustentacular cells (modified Schwann cells).

• It is part of the diffuse neuroendocrine system. The chief cells of the glomus body are nearly identical to the chromaffin cells of the sympathetic ganglia and contain osmiophilic granules similar to those implicated in catecholamine storage.25,26 Glomus bodies may function in a manner similar to that of the carotid body as chemoreceptors, responding to alterations in blood pH and oxygen and carbon dioxide tensions, as well as affecting systemic blood pressure through the release of various transmitters.

• Glomus bodies have a rich blood supply and are innervated by either the tympanic branch of the glossopharyngeal nerve (Jacobsen’s nerve) or the auricular branch of the vagus nerve (Arnold’s nerve).25

• Although usually benign and slow growing, they are destructive. In about 3% of patients, the tumor is malignant.25

• A very strong female predominance of 4:1 to 6:1 has been reported.27,28

• Typically, these tumors develop during the fifth and sixth decades of life.27

• GJTs have their epicenter in the region of the jugular bulb. Neurovascular structures within the hypoglossal canal, jugular foramen, and temporal bone can be affected (Fig. 3-7).

• Generally, patients with a GJT exhibit tinnitus; cephalagia; hyperacusis; anacusis; dizziness; or multiple injuries of cranial nerves VII, VIII, IX, X, XI, and XII.

3.5. Medulloblastoma

• Medulloblastoma represents 20% of childhood brain tumors. The median age at diagnosis of childhood medulloblastoma is 6 years, and approximately 25% occur in children younger than 3 years. Medulloblastoma in adults occurs predominantly in the third to fifth decades of life and constitutes 10% to 20% of medulloblastomas.

• Headaches, vomiting (a sign of increased intracranial pressure), and ataxia are the classic presenting triad of posterior fossa tumors.

• Most often arising in the cerebellar vermis (Fig. 3-8), the tumor grows to fill the fourth ventricle and frequently attaches to the brain stem. It has a characteristic seeding tendency associated with subarachnoid dissemination through the cerebrospinal fluid (CSF). Subarachnoid disease is detected in 20% to 25% of cases at diagnosis.29,30

FIGURE 3-7. Left-sided glomus jugulare tumor (black stars) with extension to mastoid air cells, infratemporal fossa, cerebellopontine angle, and cavernous sinus in axial (left) and coronal (right) T1 MRI with gadolinium.

3.6. Glial Tumors

• Glial tumors are primary central nervous system neoplasms of neuroglial cells such as astrocytes or oligodendrocytes demonstrating various characteristics as low-grade gliomas (LGG) with slower growth pattern and high-grade gliomas (HGG) with rapid progression.

3.6.1. Low-Grade Glial Tumors

• LGG account for approximately 10% of primary CNS tumors.31 Histologic subtypes of LGG include pilocytic astrocytomas (PA) classified as WHO Grade I, diffuse infiltrating LGG such as oligodendrogliomas, and mixed oligoastrocytomas classified as WHO Grade II.32 Grade II defines well-differentiated gliomas without demonstration of mitoses, nuclear pleomorphism, anaplasia, vascular proliferation, and necrosis.

3.6.2. High-Grade Glial Tumors

• Glioblastoma (GB) and anaplastic gliomas account for approximately one-third of primary brain tumors.31 GB is the only WHO grade IV glioma that is astrocytoma with nuclear atypia, mitotic activity, vascular proliferation, and necrosis.32 Anaplastic gliomas classified as WHO grade III tumors include anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA), anaplastic oligodendroglioma (AOD), and anaplastic ependymoma.32 AA exhibits mitoses but no endothelial proliferation or necrosis. AOD is an oligodendroglial tumor with focal or diffuse histologic malignancy features and a less favorable prognosis than that of grade II oligodendroglioma.

FIGURE 3-8. Medulloblastoma of the cerebellar vermis (black stars) in sagittal (left) and coronal (right) T1 MRI with gadolinium.

• All high-grade gliomas express vascular endothelial growth factor (VEGF) as well as oligodendrocyte lineage transcription factor 2 (OLIG2); besides, there have been genetic alterations leading to primary GB, secondary GB, and AOA.33 MGMT promoter methylation and IDH1 mutational status allow for stratification of glioblastoma patients into prognostically distinct subgroups.34


4.1. Signs and Symptoms

• Common presenting symptoms of skull base tumors are orbitofrontal headaches due to involvement or stretching of the dura and visual disturbances due to involvement of optic nerves or neural contents of the cavernous sinuses.

• Frontal base and paranasal extension may cause olfactory and frontal syndromes, such as increased intracranial pressure, seizures, or personality changes for subfrontal tumors and loss of sensation of smell, nasal obstruction, rhinorrhea, or epistaxis for paranasal involvement.

• Tumors affecting the sella turcica and sphenoid sinus cause chiasmatic or hypothalamic symptoms. Chiasmatic involvement results in vision loss due to hemianopsia, either unilateral or bitemporal. Endocrinologic symptoms such as diabetes insipidus, amenorrhea, impotence, or pituitary apoplexy can be observed in cases of pituitary or hypothalamic involvement.

• Tumors involving the lateral middle fossa, infratemporal fossa, or sphenoid wing may extend into the orbit and induce exophthalmus, diplopia, or unilateral vision loss.

• Medial middle fossa tumors, including those of the CS and MC, may present as dysfunction of one or more of the upper cranial nerves (III, IV, V1–3, VI). Tumors in this area may encase or constrict the carotid artery in the parasellar region causing cerebral ischemia.

• Petroclival–clival involvement may result in cranial nerve deficits, cerebellar signs, corticospinal tract involvement, or increased intracranial pressure.

• Internal auditory canal or cerebellopontine angle involvement may cause hearing loss, or deficits secondary to cerebellar or brainstem compression.

• Different lobes involved with high-grade glial tumors may initiate various signs and symptoms such as seizures, hemiparesis, mental status lability, urinary incontinence for the frontal lobe; seizures, language/reading/calculation disturbances for the parietal lobe; seizures, aphasia, emotional disturbances for the temporal lobe; seizures and visual changes for the occipital lobe; etc.

4.2. Physical Examination

• Evaluation requires clinical examination for cranial neuropathy and imaging evidence for extent of disease in patients known to have a skull base lesion. Physical examination is based mainly on the general neurologic examination, including cranial nerves for signs of skull base lesions and basic cerebellar functions for signs of posterior fossa tumors.

4.3. Imaging

• Neuroimaging is critical for pretreatment planning and posttreatment surveillance.35 Detection of differential features might predict tumor histology and help in delineation. Important features include calcification, mineralized matrix, hyperostosis, enhancement pattern, flow voids on magnetic resonance imaging (MRI), and hypervascularity on computed tomography (CT).

• CT scan and MRI are, in most cases, complementary in diagnosis and treatment of skull base tumors.

• CT scan is superior for detecting calcification in the tumor as well as slight cortical erosion or frank bony destruction.

• MRI is better for detecting soft tissue details such as intracranial extension, compression, involvement of the neural foramina, perineural tumor spread, vascular encasement, and thrombosis.

• A slow-growing or more benign process usually presents with remodeled or pushed away bony structures. A more aggressive lesion should be favored if there is gross destruction of bone (chewed up, moth-eaten).

• Most tumors affecting bone replace healthy bone marrow (T1 hyperintense on MRI) with isointense tumor.

• Bony hyperostosis associated with a soft-tissue tumor usually suggests meningioma, and occasionally more malignant tumors such as esthesioneuroblastoma. Hyperostosis without a soft tissue component may be fibrous dysplasia, Paget’s disease, or osteoblastic metastasis (e.g., prostate cancer).

• Clinical correlation is required to identify extension, such as denervation (masticator musculature problems: MC or FO; ipsilateral tongue paralysis: hypoglossal canal).

• Clival tumors with gross destruction, bony fragments, and bright signal on T2-weighted MRI suggest chordoma.

• A jugular foramen origin with a moth-eaten bony pattern, with or without cranial neuropathy or tinnitus, suggests a GJT.

• Nondestructive enlargement of a neural foramen or transforaminal tumor extension suggests schwannoma or meningioma.

• An enhancing tumor in the internal auditory canal, presenting with sensorineural hearing loss (SNHL), very strongly suggests acoustic schwannoma.

• Tumor involvement of the sella, parasellar region, and/or suprasellar cistern, with central skull base destruction, should prompt consideration of invasive pituitary adenoma.

• A review of imaging characteristics of selected tumors is given in Table 3-2.

4.4. Staging

• Meningioma: Intracranial meningiomas are generally staged according to the extent of surgical resection (Table 3-3).48

• Esthesioneuroblastoma: Kadish et al.49 developed a staging system, which has been modified by Morita et al.,12 based on anatomic extension of the tumor beyond the nasal cavity (Table 3-4).

• Chordoma: Various classification schemes based on location have been proposed: clival, parasellar, and sellar;50 basiocciput-caudal and basisphenoid-rostral;51 and, of greatest help in the choice of surgical approach, superior, middle, and inferior clival.52

• Glomus Jugulare Tumor: Several classification systems have been proposed over the years. The most recent and widely used systems are the Fisch classification53 (Table 3-5), revised in 1981, and the Glasscock and Jackson classification, based on site and extent of the tumor.54

• Medulloblastoma: The most widely used classification is the Chang operative staging system (Table 3-6).55 The degree of residual tumor and presence or absence of subarachnoid or extraneural metastases determine stage.

• Glial tumors: The WHO grading establishes a malignancy scale based on histologic features (Table 3-7)32,56. The low grade constitutes grades I and II, and high grade, III and IV.


5.1. Meningioma

• The treatment of choice is complete surgical excision, but this is not always possible, as 20% to 50% of meningiomas are located in the skull base and may not be amenable to a safe surgical approach.57

• Surgical literature reports permanent cranial nerve deficits in 22% to 91% of patients undergoing surgical resection for petroclival meningiomas; an average of 54% develop new onset of neurologic symptoms after surgery.5862

• To reduce the risk of neurologic deficit, a subtotal resection is often accepted. However, adjuvant therapy is usually required in these cases, since an estimated 10% to 56% of patients develop recurrence after subtotal resection.6365In a number of series, fractionated radiotherapy significantly increased tumor control rates after subtotal resection of meningiomas.6669

• Goldsmith et al. found 5-year progression-free survival rates of 87% for benign and 45% for malignant meningiomas treated with radiation after subtotal resection, and a 5-year progression-free survival rate of 98% in a subset of patients with benign lesions treated in the era of CT-/MRI-based planning.67

• Smaller series looking specifically at malignant or atypical meningiomas, including data from our own institution, have also demonstrated a benefit from radiation.70,71

• Similarly, stereotactic radiosurgery has been used in the treatment of meningiomas. Recently, Kondziolka et al. reported a 93% clinical tumor control rate in a series of 99 patients with a minimum of 5 years of follow-up, and recommended gamma knife treatment for lesions <3 cm in diameter with regular borders that do not compress the optic chiasm.72

• Skull base meningiomas that appear progressive in serial imaging or are symptomatic deserve treatment. Surgery is the first step if operable with minimal toxicity. Adjuvant radiotherapy (3DCRT, IMRT, or stereotactic radiosurgery) is indicated for WHO grade-II and -III meningiomas, even with gross total resection (GTR), and for WHO grade I tumors after subtotal resection (STR) if future salvage gross total resection seems not possible.

• Radiation therapy can be delivered as 3DCRT, IMRT, SRS, FSRT, or proton-beam therapy.

• Recommended dose is 50 to 54 Gy in 25–30 fractions for grade I [clinical target volume (CTV) = contrast-enhancing gross tumor volume (GTV) in T1 weighted MRI), and 57 to 60 Gy in 30–33 fractions for grade II to III tumors. Recommended SRS dose (up to 3 to 4 cm) is 12 Gy in 1 fraction when the tumor is adjacent to critical structures such as the brainstem or optic nerves, and 12 to 18 Gy (higher for grades II to III) for others clear from critical structures (18 Gy if <1 cm, 16 Gy if 1 to 3 cm, 12 to 14 Gy if >3 cm) (Fig. 3-9).7379

• The European Organisation for Research and Treatment of Cancer (EORTC) has launched the phase II trial 22042-26042,80 focusing only on WHO grade II and III tumors, which examines the utility of adjuvant postoperative high-dose fractionated radiotherapy. Patients with WHO grade II tumors are stratified into two groups based upon the Simpson grade (SG) of resection; SG 1–3 are treated with fractionated radiotherapy to 60 Gy, and SG 4 or 5 are treated with 60 Gy plus a boost of 10 Gy. Patients with WHO grade III tumors are also similarly separated into two groups for a descriptive observational study.

• The Radiation Therapy Oncology Group (RTOG) has launched phase II trial 053981 for all grades of meningioma through three groups based on the likelihood of tumor regrowth after surgery risk. Group I tumors (WHO grade I after any degree of surgical resection) are observed postoperatively without adjuvant therapy until recurrence. Group II tumors (recurrent grade I or newly diagnosed grade II following SG 1–3) are treated with conformal or intensity modulated radiotherapy (IMRT) to 54 Gy in 30 fractions. Group III tumors (any grade III, any recurrent grade II, or any newly diagnosed WHO grade II following SG 4 or 5) are treated with IMRT to 60 Gy in 30 fractions.

5.2. Esthesioneuroblastoma

• Preferred treatment in localized tumors is en bloc craniofacial resection of the tumor, cribriform plate, and overlying dura.82

• In advanced disease, preoperative radiotherapy with or without chemotherapy is preferred. An initially planned combination of surgery followed by postoperative radiotherapy may be another option.

• Cyclophosphamide, vincristine, and doxorubicin are generally preferred for concomitant radiotherapy. Platinum-based chemotherapy is preferred for advanced, high-grade tumors.

• Primary radiotherapy is preferred only in selected patients who are ineligible for surgical resection.

• Positive surgical margins are the most significant predictor of progression and decreased overall survival rates in the experience of many centers.8386

• Radical surgery alone is not enough to avoid local recurrences; adjuvant postoperative high-dose radiotherapy has achieved high local control rates (92%) in a recently reported series.8688

• Nearly one-half of the recurrences occur >5 years after diagnosis.89 Recurrence rates range from 30% to 70%.

• Estimated survival rates are 74% to 87% at 5 years and 54% to 60% at 10 years. Five-year survival rate following local recurrence is 82% after salvage therapy.

• We recommend as radical a surgical procedure as possible with preoperative or postoperative radiotherapy (dose ~60 Gy) and concomitant chemotherapy, as aggressive, multimodality treatment is supported by the findings of many centers.13,86,90,91

• The efficacy of IMRT on tumors of nasal cavity and paranasal sinuses are more commonly reported in recent series.92102

5.3. Chordoma

• Wide or complete resection is the treatment of choice, but is not feasible in most cases. Adjuvant radiation has been advocated for patients with positive surgical margins and residual disease.103105

FIGURE 3-9. Two separate right posterior and anterior frontal meningiomas radiosurgically treated with a single fraction of 16 Gy.

• Munzenrider and Liebsch suggested that charged particle beams are ideal for treating skull base chordomas because such beams can deliver precise, high-dose radiation to localized areas of disease while sparing surrounding normal structures.106 Proton–photon therapy was recommended by both Borba et al. and Habrand et al. for intracranial tumors in children.107,108 The 5-year actuarial survival rate was reported as 68%, while the disease-free survival rate was 63% for intracranial chordomas.

• Romero et al. and Klekamp et al. produced comparable results with high-dose fractionated conventional radiotherapy.109,110 Romero et al. showed that prognosis for patients with microscopic residual disease given 48 Gy postoperative radiotherapy was better than for those who received <40 Gy. Klekamp and colleagues reported that postoperative radiation doses of 60 to 70 Gy assured a significantly longer recurrence-free interval in contrast to suboptimal excision without radiotherapy.

• IMRT, which can deliver precise, high-dose radiation while sparing surrounding normal structures, has not yet been reported to emphasize the comparison in results.

• The use of charged particle radiotherapy with protons as the postoperative treatment in single-institutional retrospective studies suggests better results as compared to the use of conventional photon irradiation; the former yields better 10-year outcome with relatively few significant complications despite the higher doses delivered with this therapeutic modality.111,112

• We prefer, if possible, to prescribe 66 to 70 Gy in 2 Gy/fraction given by IMRT, FSRT, or proton radiotherapy (Fig. 3-10).

5.4. Glomus Jugulare Tumor

• Management of jugular paraganglioma historically has shown a pendulum swing away from virtually exclusive primary surgery to more of primary radiation therapy, with a very recent moderating trend toward selecting treatment according to patient profile.

FIGURE 3-10. Proton radiotherapy for clivus (A) and parasellar (B) chordoma cases delivered 70 Gy while sparing brainstem with a sharp dose decrease.

• The goal of surgery is complete tumor removal, whereas the goal of conventionally fractionated, external beam radiation therapy and stereotactic radiosurgery is long-term tumor control by preventing tumor growth and regional extension that could lead to progressive symptoms and neurologic deficits.

• Local tumor control rates after total surgical removal vary from 0% to 90%.113 Surgical removal can be associated with considerable morbidity and mortality.114118 In general, gross total surgical resection has been accomplished in 40% to 80% of cases in different series.119121

• Progressive growth of GJTs was arrested by conventional external beam radiation therapy at rates of local control ranging from 85% to 100%, with reversal of symptoms in some patients, and complication rates of 0% to 10%.122125

• Despite the inherent limitations and biases of retrospective, predominantly single-institution reported series, surgery and radiation therapy appear to have similar rates of long-term local control (~90%). This is true even though patients treated with radiation therapy generally have larger or more infiltrative tumors that are not readily subject to surgical resection. Disease-related mortality is only limited to a few patients with residual or recurrent tumor, irrespective of the mode of treatment. Therefore, treatment of GJTs should focus primarily on decreasing morbidity.

• A primary surgical approach is recommended for younger patients with lesions that are readily resectable without significant neurologic impairment. This approach avoids the small risk of radiation-induced second malignancy.

• Involvement of the internal carotid artery (demonstrated by balloon occlusion test), contralateral SNHL, bilateral tumors with contralateral deficits of the lower cranial nerves, concerns of venous return, and poor medical condition are common causes for inoperability and therefore are indications for primary definitive radiotherapy.

• We recommend a conventionally fractionated IMRT approach for most patients whose tumors are irregularly shaped and are in close proximity to radiosensitive normal structures. A dose of 45 to 50 Gy (1.8 to 2 Gy/fraction) is prescribed, encompassing radiographically visible tumor as CTV plus a 3-mm margin for setup uncertainty, making up the planning target volume (PTV).

5.5. Medulloblastoma

• The initial goal is maximal surgical resection for both treatment and reestablishing CSF flow. Gross total resection (>90% of the tumor removed, with <1.5 cm2 residual) generally is limited only by substantial invasion of the tumor into the brain stem or infiltration into the peduncle. Gross or near total resection is achieved in 90% of children with medulloblastoma older than 3 years in the USA.126

• MRI brain imaging within the immediate postoperative period (1 to 3 days) is important to define postoperative residual effect, which is a reliable prognostic factor.126

• Neuraxis staging is recommended 10 days or longer after surgery to eliminate the confusion between findings and postoperative debris. A contrast-enhanced spinal MRI and subsequent lumbar CSF cytologic studies are standard.

• Categorization into standard (or average-risk) and poor-risk disease guides the treatment decision. Average-risk is defined as patients older than 3 years with posterior fossa tumors who underwent total or “near-total” (<1.5 cm2 of residual disease) resection with no dissemination.55,127

• Postoperative management currently consists of radiotherapy and chemotherapy.128

• Radiotherapy requires systematic inclusion of the entire subarachnoid space-craniospinal irradiation (CSI) followed by a boost to the posterior cranial fossa. The conventional dose to the neuraxis has historically been 36 Gy (1.8 Gy/day). Gross total resection and postoperative CSI yield a 5- to 10-year progression-free survival rate of approximately 65%.129133

• Pediatric Oncology Group and Children’s Cancer Group conducted a randomized study that compared CSI at doses of 36 and 23.4 Gy in average-risk medulloblastoma, and established a standard of removing >90% tumor with less than 1.5 cm2 of residual disease.133 Reduced-dose neuraxis irradiation (23.4 Gy) was associated with higher risk of early relapse and early isolated neuraxis relapse, and lower 5-year rates of event-free survival96 and overall survival than observed with standard irradiation (36 Gy). Mature analysis has confirmed these results but has showed that, with time, the differences are less pronounced (8-year analysis of EFS).

• The combination of reduced-dose CSI (23.4 Gy) and cisplatin-based chemotherapy has been shown to be comparable to conventional CSI dose alone.134 However, metastatic disease at presentation requires a dose of 36 to 39 Gy to the neuraxis.

• Boost to the posterior fossa is defined as irradiation of the entire infratentorial volume. The current effort is to use a 3D conformal approach to spare the auditory apparatus and, when possible, the pituitary hypothalamic region. The cumulative dose for boost is 54 to 55.8 Gy.

• Reduction of the boost volume from the posterior fossa to just the tumor bed has been an active area of research.135 Merchant et al. prospectively investigated the reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) together with dose-intensive chemotherapy for average-risk medulloblastoma and concluded that there was a 13% reduction in posterior fossa volume receiving >55 Gy, as well as significant reductions in temporal lobes, cochleae, and hypothalamus doses.135

• IMRT tumor bed boost has been investigated as a method to minimize ototoxicity and other morbidity associated with full posterior fossa irradiation without compromising tumor control.136 In a baseline study, Paulino et al. compared posterior fossa boosts with tumor bed boosts using 2D radiotherapy techniques; the cochlea was in the treatment field of all patients, regardless of which target volume was selected.137,138 This study suggested that IMRT can decrease auditory dose rather than size of the target volume. Additional studies with IMRT have demonstrated much lower doses of radiation to the auditory apparatus, while still delivering full doses to the desired target volume.136,139

• A recent study by Paulino et al. reported that tumor boost with IMRT to a 2-cm margin around the surgical bed was associated with excellent local control and did not result in excess posterior fossa failures outside of the tumor bed.140

• The IMRT to reduce ototoxicity seems not to cause any decline in nonverbal intellectual abilities, visual-spatial skills, processing speed, or fine motor dexterity in comparison to conformal radiotherapy.141

• Proton radiotherapy has become very appealing recently due to the fact that protons were found to be superior to IMRT, based on substantially improved nontarget tissue sparing on hearing, endocrine, and cardiac function achieved with protons.142,143

5.6. Low-Grade Gliomas

• Indolent natural history of LGG raises the controversy in its management as to whether an aggressive approach with surgical intervention is required in the case of small and asymptomatic disease and whether adjuvant radiotherapy needs to be immediate or delayed.

• Evidence is in favor of a maximal and safe resection to increase the progression-free survival.144148 The extent of surgical resection might be independently associated with survival.146

• EORTC 22845 trial investigated immediate RT of 54 Gy or no radiotherapy until progression following initial biopsy or subtotal resection on 311 patients, which demonstrated significantly prolonged progression-free survival (median 5.4 vs 3.7 years) and improved seizure control with immediate postoperative radiotherapy, despite the same overall survival (7.4 vs 7.2 years).149 The lack of overall survival benefit gives the flexibility to individualize the radiotherapy recommendation based on prognostic factors including recurrent or progressive disease, age ≥40 years, tumor >6 cm, tumor crossing the midline, pure astrocytic histology, persisting disease-related neurological symptoms (seizures etc.), or MIB-1 >3%.148,150153

• For LGG, 50.4 to 54 Gy in 1.8 to 2 Gy/fraction is the current standard dose, and dose escalation has not been correlated with survival benefit.152,154,155 EORTC 22844 trial compared 59.4 Gy (1.8 Gy/fraction) and 45 Gy (1.8 Gy/fraction) following surgery or biopsy and revealed no significant outcome differences between arms.154 NNCTG/RTOG/ECOG multicenter trial evaluated 64.8 Gy versus 50.4 Gy demonstrating no improvement in the survival rate with dose escalation but increased rate of radiation necrosis (5.0% vs 2.5%).152

• As no evidence has been demonstrated of routine postoperative chemotherapy prolonging survival significantly in LGG patients, RTOG 98-02 triaged a group of patients with unfavorable prognosis (aged ≥40 years or with a subtotal resection/biopsy alone) to postoperative RT (54 Gy, 1.8 Gy/fraction) plus six cycles of procarbazine, lomustine, vincristine (PCV) versus the same radiotherapy without chemotherapy and revealed that adjuvant PCV chemotherapy increased the progression-free survival.156.

• The Phase II RTOG 0424 trial, of which the results are pending, evaluated the role of radiotherapy (54 Gy, 1.8 Gy/ fraction) and concurrent temozolomide (TMZ) in selected high-risk subsets (with at least three of the risk factors: age ≥40, largest diameter of tumor ≥6 cm, tumor crossing midline, astrocytoma subtype, preoperative neurological function status >1) of adults with LGG.

• The Phase III EORTEC 2203 study, which is continuing accrual, evaluates the role of radiotherapy alone (50.4 Gy, 1.8 Gy/fraction) versus TMZ alone in selected LGG patients (if ≥1 of the following criteria: age ≥40 years, radiologically-proven progressive lesion, new or worsening neurological symptoms other than seizures only such as focal deficits, signs of increased intracranial pressure, mental deficits, intractible seizures.)

• Patients with PA are recommended radiotherapy only in case of symptomatic residual or progressive tumor and when resection is not feasible.

• Patients with LGG are recommended observation after gross total resection (complete elimination of the preoperative FLAIR signal abnormality based on MRI performed within 48 h after surgery), while patients aged ≥40 years might be individualized for consideration of radiotherapy. LGG with residual or progressive disease are candidates for radiotherapy, especially when the safe GTR is not feasible; these patients could also be enrolled for chemotherapy trials.

5.7. High-Grade Gliomas

• Current standard initial approach for all high-grade glial tumors is maximal safe resection.157 Concurrent chemoradiotherapy followed by adjuvant chemotherapy is standard in GB, while a standard of care for the other high-grade gliomas has not been firmly established.

• The current standard for all high-grade gliomas is 60 Gy in 2 Gy/fraction, and dose escalation has not been correlated with improvement in survival.158,159

• Beneficial effects of radiotherapy with concomitant and adjuvant temozolomide (TMZ) versus radiotherapy alone on survival in glioblastoma are evident with phase III verification.160165 Overall survival was 27.2% at 2 years, 16.0% at 3 years, 12.1% at 4 years, and 9.8% at 5 years with temozolomide, versus 10.9%, 4.4%, 3.0%, and 1.9%, respectively, with radiotherapy alone, and benefit of combined therapy was demonstrated in all clinical prognostic subgroups, as well as in patients aged 60 to 70 years. The strongest predictor for outcome and benefit from temozolomide was methylation of the MGMT promoter. Recursive partitioning analysis (RPA) continues its prognostic significance overall as well as in patients receiving RT with or without TMZ for GB, particularly in classes III and IV.161

• Schedules of dose-dense TMZ (7 days on and 7 days off, at 150 mg/m2 per day) and metronomic TMZ (21 days on and 7 days off, at 100 mg/m2 per day) in GB management are being tested in patients with newly diagnosed GB.166 RTOG 0525 was reported in abstract form at ASCO 2011 and showed no benefit following concurrent chemoradiation therapy of administering adjuvant dose-dense TMZ over adjuvant standard TMZ administration of 5 days in every 28 days.

• Three-dimensional CRT (3DCRT) has long been compared with IMRT in high-grade gliomas verifying the superiority of IMRT.167171 A recent systematic review demonstrated that “dose bath” theory was not real, as all IMRT techniques (VMAT, IMRT, etc.) have very similar quality of dose distribution.172

• IMRT treatment for high-grade gliomas allows for improved target conformity and better critical-tissue sparing without increasing integral dose and the volume of normal tissue exposed to low doses of radiation.170,172

• The current standard for first-line treatment in anaplastic gliomas is radiotherapy or chemotherapy.173 The optimal role of chemotherapy in anaplastic gliomas and sequencing is unresolved.158 Selected patients with anaplastic gliomas could be treated with combination chemotherapy (procarbazine, lomustine, vincristine; PCV) or TMZ as initial therapy after surgical resection, or as adjuvant therapy after radiotherapy.158 Based on the results of the EORTC 26951 study,201 the current standard for first line treatment in anaplastic oligodendroglial tumors (AOD) is radiotherapy with adjuvant PCV chemotherapy. Also, a recent unplanned subgroup analysis in RTOG 94-02202found that neoadjuvant PCV and radiotherapy may be an especially effective treatment for patients with 1p/19q codeleted AO/AOA.

• The NOA-04 phase III trial tested efficacy and safety of radiotherapy followed by chemotherapy (with procarbazine, lomustine, and vincristine, or temozolomide) at progression with the reverse sequence in a limited number of patients with newly diagnosed anaplastic gliomas.174 Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. Median time to treatment failure (chemo: 43.8 months vs RT: 42.7 months), progression-free survival (chemo: 31.9 months vs RT: 30.6 months), and 4-year overall survival (chemo: 64.6% vs RT: 72.6%) were similar for the initial radiotherapy and initial chemotherapy arms (PCV is more toxic than Temozolomide). IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas showed the same, better prognosis than that of anaplastic astrocytomas.

• EORTC has launched a phase III trial on concurrent and adjuvant temozolomide chemotherapy in non-1p/19q deleted anaplastic glioma (the CATNON intergroup trial)175 in order to assess whether concurrent radiotherapy with daily TMZ improves overall survival, besides whether adjuvant TMZ improves survival as compared to no adjuvant TMZ.


6.1. Target Volume Determination

• For IMRT, a general strategy described in RTOG protocols is to encompass at least 95% of the PTV. It is also important to avoid delivering <93% of the prescribed dose to >1% of the PTV or >110% of the prescribed dose to >20% of the PTV.

• Adequate immobilization is crucial so as not to underdose the target or overdose the organs at risk because of the tight PTV for steep dose gradients.

• Imaging characteristics of skull base tumors are important in target delineation as summarized in Table 3-2.

• The target volume specification for definitive and postoperative IMRT for skull base tumors is summarized in Table 3-8.

6.2. Target Volume Delineation

• In patients receiving postoperative IMRT, CTV1 encompasses residual tumor (GTV) and the surgical bed with invasion of soft or bone tissue by the tumor. CTV2 includes primarily the prophylactically treated area or adjacent tissue the assigned dose of which is lower owing to tolerance constraints, such as the brain.

• In patients receiving definitive IMRT, CTV1 is defined as GTV with 0- to 10-mm (occasionally 20 mm) margins based on clinical and radiological justification. In general, because most skull base tumors are benign, including meningiomas (WHO grade I), schwannomas, GJTs, pituitary adenomas, and juvenile angiofibromas, CTV1 is equal to GTV. However, other meningiomas (WHO grades II to III), chordomas, chondrosarcomas, adenoid cystic carcinomas, and esthesioneuroblastomas are low-grade malignant tumors for which a margin over GTV is required for CTV1. CTV2 includes primarily the prophylactically treated area or an adjacent tissue the assigned dose of which is lower owing to tolerance constraints, such as the brain.

• PTV margin is CTV plus 0.3 to 0.5 cm in general depending on the clinic quality assurance end-to-end tests for image guidance. PTV margins may be designed smaller in case of using SRS or FSRT, depending on the setup accuracy of the stereotactic system (typically 0.2 cm).

• Figure 3-11 shows CTV delineation in a 64-year-old woman with right petroclival meningioma who presented with progressive visual deficit in the right eye. MRI revealed a lesion in the right CS with multiple dura-based tails along the tentorium.

• Figure 3-12 shows CTV1 and CTV2 delineation in a 66-year-old man following surgical removal of a recurrent esthesioneuroblastoma after initial resection. The patient originally presented with headaches and a large olfactory groove tumor and underwent resection. The tumor recurred after 1.5 years at the right ethmoid and medial orbit. While the right medial orbital mass was partially removed, a small portion of this mass remained. Adjacent brain tissue and paranasal sinuses under risk, in which the tumor did not recur, were also treated to a lower dose as CTV2.

FIGURE 3-11. Delineation of CTV (CTV = GTV) of a petroclival WHO grade I meningioma. RE, right eye; LE, left eye; CTV, clinical target volume; BS, brainstem.

FIGURE 3-12. Delineation of CTV1 and CTV2 of an esthesioneuroblastoma. CTV1 is composed of residual tumor and operative bed, which had initial recurrence. CTV2 is the area of first primary tumor before surgical resection and areas deemed at risk for recurrence. GTV, gross tumor volume; CTV1, clinical target volume 1; CTV2, clinical target volume 2; RL, right lens; LL, left lens; RE, right eye; LE, left eye; RON, right optic nerve; LON, left optic nerve; P, pituitary gland; BS, brainstem; PG, parotid gland; PF, posterior fossa.

FIGURE 3-13. Delineation of CTV (CTV = GTV) of chordoma tumor involving clivus. CTV, clinical target volume; RE, right eye; LE, left eye; RON, right optic nerve; BS, brainstem.

• Figure 3-13 shows CTV delineation in 25-year-old woman with a clival chordoma who presented with headache, pain in her eyes and head, dragging of her right leg and arm, and slurred speech. She underwent a left orbital craniotomy with partial resection of the clival chordoma and decompression of the brain stem and optic nerve. She was referred for radiation therapy after tumor progression in the upper clivus involving the sella and sphenoid sinus caused marked compression and mass effect in the upper left pons.

• Figure 3-14 shows CTV delineation in a 43-year-old woman with a GJT who presented with 20% loss of hearing in the left ear and double vision. The MRI demonstrated an expansile lesion consistent with a glomus tympanicum involving the mastoid air cells, the infratemporal fossa, the cerebellopontine angle, and the CS.

• Figure 3-15 shows CTV1 and CTV2 delineation in a 16-year-old boy with medulloblastoma who presented with worsening headaches, neck pain, and nausea with associated symptoms of tripping easily and dropping objects. MRI defined an enhancing tumor of the cerebellar vermis with hydrocephalus for which he underwent gross total resection. CTV1 is the tumor bed after resection. CTV 2 is the whole posterior fossa, which is similar to a “Mexican hat” in appearance in the coronal beam eye view (Fig. 3-16).

6.2.1. Target Volume Delineation for Glial Tumors

• PTV margin is CTV plus 0.3 to 0.5 cm in general depending on the clinic quality assurance end-to-end tests for image guidance. PTV margins may be designed smaller in case of using SRS or FSRT, depending on the setup accuracy of the stereotactic system (typically 0.2 cm). Low-Grade Glial Tumors

• The GTV of PA in MRI is defined as T1 contrast enhancing lesion together with the cystic component; and FLAIR/T2 abnormality with T1 contrast enhancing lesion is used for GTV of LGG.

• The CTV delineation remains similar in PA and LGG: CTV = (GTV + 0.5 cm). High-Grade Glial Tumors

• The delineation remains similar in GB and other high-grade gliomas.

• The relationship between recurrence pattern and peritumoral edema in GB has not been defined clearly. The rationale for including peritumoral edema is the belief that it can contain high concentrations of tumor cells.176Peritumoral edema might be the result of mass effect and vascular permeability factors secreted by the visible tumor, and there is a higher concentration of infiltrating tumor cells in close proximity to the GTV.177 While the RTOG defined the initial field as the peritumoral edema + 2 cm to 46 Gy and the boost field as GTV + 2.5 cm to 60 Gy,178,179 the inclusion of peritumoral edema within the CTV has not been universally adopted such as in the University of Texas M. D. Anderson Cancer Center (MDACC; they define CTV as the GTV + 2 cm and PTV as CTV + 0.5 cm; Fig. 3-17). We have demonstrated before that CTV delineation based on a 2-cm margin rather than on peritumoral edema did not seem to alter the central pattern of failure for patients with GB.180 This constant 2-cm margin resulted in a smaller median percent volume of the brain being irradiated to 30, 46, and 50 Gy in comparison to theoretical RTOG definition of CTV with the inclusion of peritumoral edema in patients with peritumoral edema of >75 cm3.

FIGURE 3-14. Delineation of CTV (CTV = GTV) of glomus jugulare. CTV, clinical target volume; RE, right eye; LE, left eye; BS, brainstem; P, parotid gland; PF, posterior fossa; SC, spinal cord.

FIGURE 3-15. Delineation of CTV1 and CTV2 of medulloblastoma. Whole posterior fossa is defined as CTV2. Surgical bed in posterior fossa, which initially contained the tumor, is defined as CTV1. CTV1, clinical target volume 1; CTV2, clinical target volume 2; VIII, 8th cranial nerve; ME, middle ear apparatus.

• Determination of beam arrangements is an empirical process in general, and optimization of the plan with optimal conformality is difficult to achieve as a standard. Therefore, regional CNS class solutions have been implemented at our institution due to the fact that user-defined plans were inferior to those generated using class solutions in terms of mean brain dose, brain V30, and RTOG conformality index; besides, the use of class solutions could lead to higher reproducible efficiency, consistency, and time conservation for treatment planning (Fig. 3-18A,B).181

• A phase III trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma enrolled patients in RTOG and EORTC groups with different radiotherapy contouring guidelines.182 RTOG used a schema with the cone down technique where CTV is not defined: PTV to 46 Gy (GTV1 T2 + T1 with contrast + 2 cm) and boost PTV of 14 Gy to total 60 Gy (GTV2 T1 with contrast + 2.5 cm); EORTC used a schema without a cone down: GTV (T1 with contrast—without edema—on pre- or postoperative MRI), CTV 60 Gy (GTV + 2–3 cm as T2 abnormality is included within the margin).182

• Current delineation practice in MD Anderson Cancer Center is based on the simultaneous integrated boost technique with two CTV volumes in 30 weekdays following determination of GTV as T2/FLAIR (to be distinguished from high T2 signaling vasogenic edema which should be excluded) and T1 postcontrast tumor and surgical cavity. CTV 60 Gy (GTV + 0.5 cm) and CTV 50 Gy (GTV + 2 cm) are also defined in Figure 3-19.

6.3. Normal Tissue Delineation

• Normal tissue delineation is shown in Figures 3-16 and 3-20 through 3-22.

• Optic nerves are delineated starting from the eye and ending at the apex of the optic canal (Fig. 3-20).

FIGURE 3-16. Delineation of posterior fossa (PF) and brain stem (BS).

• The optic chiasm can be difficult to delineate accurately. The oblique take off of the chiasm posteriorly from the optic nerves must be appreciated (Figs. 3-20 and 3-21A,C). Optic pathways are delineated starting from the optic canal, extending through the infundibulum or pituitary stalk in the suprasellar cistern to the rostral part of the cerebral peduncle (Fig. 3-21B).

• Brain stem is delineated from the foramen magnum (medulla oblongata) between the basilar artery and cerebellum (pons and medulla oblongata) to the mesencephalon (cerebral peduncle) (Fig. 3-16).

• Auditory structures are delineated at the level of the internal acoustic meatus involving middle ear structures such as the cochlea (Fig. 3-22).

6.4. Suggested Target and Normal Tissue Doses

• All plans should be calculated with tissue homogeneity correction.183,184

FIGURE 3-17. Depiction of the M. D. Anderson Cancer Center method for target volume delineation of primary (A) and boost (B) volumes. GTV, gross tumor volume; CTV, clinical target volume; PTV, planning target volume.

FIGURE 3-18. (A) When comparing conformality indices for the frontal, temporal, parietal/occipital, and brainstem regions, the class solution plans were consistently better than the user-defined plans.

6.4.1. Lacrimal Gland and Cornea

• Lacrimal gland atrophy and loss of glandular function can be observed, leading to dry eye syndrome if tolerance limits are exceeded. Chronic irritation of the cornea by the eyelid may trigger corneal laceration and possible ulceration with opacification and neovascularization.

• Experience of the University of Florida with dose–response relationship for dry eye complications demonstrated no injury at doses <30 Gy.185 The incidence of injury was 5% to 25% in the 30 to 40 Gy range, but it increased rapidly at doses >40 Gy, and was 100% at doses ≥57 Gy.

• Jiang and colleagues suggested that visual impairment from corneal injury is most likely the combined result of radiation on the cornea and lacrimal gland injury.186 The 2-year incidence of visual impairment was 81% to 88% at lacrimal gland doses of 56 to 74.5 Gy and corneal doses of 31 to 41 Gy, while it was 17% at lacrimal gland doses of 42 to 45 Gy and corneal doses of 23 to 30 Gy. The median time to visual injury was 9 months.

6.4.2. Lens

• The lens is the most radiosensitive organ in the body. It is enclosed in a capsule and consists largely of fiber cells covered anteriorly by epithelium. When there is radiation injury to the dividing cells of the lens, aberrant fibers migrate toward the posterior pole, where they constitute the beginning of a cataract.

• Cataractogenic doses were reported as 2 Gy for a single fraction, 4 Gy for multiple fractions given over a period ranging from 3 weeks to 3 months, and 5.5 Gy for multiple fractions given over a period longer than 3 months.187The latent period was 8 years and 7 months for doses from 2.5 to 6.5 Gy, and 4 years and 4 months for doses from 6.51 to 11.5 Gy.

6.4.3. Optic Pathway

• Series from the University of Texas MDACC revealed that visual impairment from damage to the optic nerve and chiasm occurred at a median of 27 months (range, 7 to 50 months) after radiotherapy.186 At doses <56 Gy, optic neuropathy was not observed; the incidence remained <5% at 10 years with doses up to 60 Gy in fractions not exceeding 2.5 Gy. The incidence of optic neuropathy increased steeply at doses >60 Gy to 34% at 10 years. Optic chiasm injury was not observed at doses <50 Gy, and the actuarial rate of optic chiasm complications at 10 years was only 8% for doses of 50 to 60 Gy in fractions of ≤2.6 Gy.

FIGURE 3-19. (A) Delineation with preoperative and postoperative fusion MRI in a supraventricular right paracentral frontal lobe glioblastoma case. (B) CTV 60 Gy and CTV 50 Gy delineation.

FIGURE 3-20. Delineation of optic nerves and chiasm. RL, right lens; LL, left lens; RE, right eye; LE, left eye; RON, right optic nerve; LON, left optic nerve; BS, brainstem; OC, optic chiasm.

FIGURE 3-21. Delineation of CN VIII and middle ear apparatus including cochlea (star). IAC, internal acoustic canal; VIII, 8th cranial nerve; ME, middle ear apparatus.

FIGURE 3-22. Optic tract appearance in (A) sagittal beam eye view (OC) and in (B) coronal (star, OC; yellow outline) and (C) sagittal MRI (OC, red arrow and outline). BS, brainstem; OC, optic chiasm; ON, optic nerve.

• University of Florida also reported increased incidence of optic neuropathy for doses above 60 Gy.188 With doses of ≥60 Gy, the incidence at 15 years was 11% for fractions of <1.9 Gy, but 47% for fractions ≥1.9 Gy.

• Dose to the optic nerves and chiasm should be limited to <54 Gy, as dose is restricted to 10 Gy for lenses. If GTV is in close proximity, the dose to the optic pathway is limited to 60 Gy with <10% informed consented risk of blindness. The risk of toxicity increases markedly for doses of >60 Gy at approximately 1.8 Gy/fraction and at >12 Gy for single-fraction radiosurgery.189

6.4.4. Brain Stem

• Debus et al. reported that tolerance of fractionated radiotherapy by the brain stem appears to be a steep function of tissue volume included in the high-dose regions rather than the maximum dose of radiation to the brain stem alone.190 Increased risk of brainstem toxicity was significantly associated with maximum dose to the brain stem; volume of the brain stem receiving ≥50 Cobalt Gray equivalent (CGE), ≥55 CGE, and ≥60 CGE; the number of surgical procedures; and presence of diabetes or hypertension.

• The brain stem generally is restricted to a dose of not higher than 54 Gy, if possible, but smaller volumes of the brainstem (0.9 cc) may be irradiated to maximum doses of 60 Gy for ≤2 Gy/fraction where the risk appears to increase markedly at doses of >64 Gy.191

6.4.5. Auditory Structures

• A dose–response relationship for radiation-induced SNHL seems to be evident. The threshold occurs at approximately 50 to 60 Gy over 5 to 6 weeks. No hearing loss was defined in children with acute leukemia after prophylactic cranial irradiation of 24 Gy in 12 fractions.192 Evans et al. detected no hearing impairment in the irradiated ear as compared with the nonirradiated one following unilateral radiotherapy of 55 to 60 Gy over 5 to 6 weeks for parotid carcinoma.193 However, Grau et al. tested hearing at baseline before irradiation and after irradiation, revealing an 8% (1 out of 13 patients) incidence of SNHL at doses of ≤50 Gy and 44% (8 out of 18 patients) at doses of ≥59 Gy.194

• SNHL due to radiation is usually reported within 6 to 12 months after radiotherapy.194 Higher hearing frequencies are affected in about 25% to 50% of patients after curative doses of >50 to 60 Gy.195197

• Platinum agents also cause cumulative dose-related bilateral and irreversible ototoxicity.198200 High-risk criteria, namely, young age, presence of a central nervous system tumor, and prior cranial irradiation, apply to the vast majority of medulloblastoma patients. The negligible risk of hearing loss after treatment with cisplatin alone at doses of 90 to 360 mg/m2 increases to 60% to 80% when combined with prior radiation.199

• IMRT has the advantage of sparing the cochlea and eighth cranial nerve. Huang and colleagues noted that the conformal technique of IMRT delivered only 68% of the total prescribed dose (36.7 vs 54.2 Gy) to the auditory apparatus, while still delivering the full dose to the desired target volume.136 Their findings suggest that, despite higher doses of cisplatin and radiotherapy before cisplatin therapy, treatment with IMRT can achieve a lower rate of hearing loss.


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