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Chapter 91

Radiotherapy of Nonmalignant Diseases

Karen M. Winkfield, MD, PhD; Jose Bazan, MD; Iris C. Gibbs, MD; Tony Y. Eng, MD; Charles R. Thomas, MD

Karen M. Winkfield, MD, PhDHarvard Medical SchoolDepartment of Radiation OncologyMassachusetts General Hospital100 Blossom Street, Cox 3Boston, MA 02114Email: [email protected]: 617-724-1159Fax: 617-726-3603

Jose G. Bazan, MD, MSDepartment of Radiation OncologyStanford University875 Blake Wilbur DriveStanford, CA 94305-5847Email: [email protected]: 650-725-4021Fax: 650-725-8231

Iris C. Gibbs, MDAssociate ProfessorStanford University875 Blake Wilbur Drive MC:5847Stanford, CA 94305-5847Email: [email protected]: 650-725-4021Fax: 650-725-8231

Tony Y. Eng, MDProfessor and Vice ChairThe University of Texas Health Science Center at San Antonio& Cancer Therapy and Research CenterRadiation Oncology Department7979 Wurzbach RoadSan Antonio, TX 78229Email: [email protected]

Charles R. Thomas, Jr., MD**Professor and ChairDepartment of Radiation MedicineOHSU Knight Cancer InstituteMail Code KPV43181 SW Sam Jackson Park RoadPortland, Oregon, USA 97239-3098Email: [email protected] 503-494-8758 Fax 503-346-0237

**Corresponding Author; will review proofs.

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Benign diseases generally include a class of localized tumors or growths that have a low

potential for progression, and do not invade surrounding tissue or metastasize to distant sites.

Pathologically, they are composed of well differentiated cells that are considered non-malignant

and usually do not require any treatment. However, clinically, not all benign diseases have

benign consequences. Some untreated benign diseases can produce bothersome mass or secretory

effects. Others can be locally aggressive and cause secondary debilitating symptoms.

For example, Grave’s ophthalmopathy can lead to local pain and visual impairment without

therapeutic intervention;1 a hormonally active pituitary adenoma may cause growth abnormality

in addition to blindness;2 desmoid tumors, can be locally persistent even after surgical resection

and some desmoids therefore are managed aggressively, similar to their malignant counterparts

and may require adjuvant radiation therapy after radical resection.3

Documented empirical use of radiation in imaging and the treatment of benign diseases

or conditions occurred soon after the discovery of x-rays by Wilhelm Röntgen in 1895.4 An

estimate of over a million Americans, mostly young adults and children, received x-ray

treatments to the head and neck region for benign conditions between 1920 and 1960. The

painless x-ray treatment and its visible efficacy led to many benign conditions being treated with

radiation, such as acne, body hair, scalp ringworm, enlarged tonsils, enlarged thymus, enlarged

lymph neck nodes, whooping cough, and others. Radiation therapy was used in some instances

due to a lack of effective alternative therapies.7

Over the past decades, advances in medical and surgical therapies have provided new

treatment options for many diseases. With improved awareness of late radiation sequelae on

normal tissue, particularly radiation carcinogenesis, there has been a gradual decline in the use of

radiation therapy for treatment of benign conditions. However, with modern radiation therapy

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techniques and better understanding of radiobiology, judicial use of radiation still provides good

local control in and relief of associated symptoms from a variety of benign diseases.

Radiobiological effects on benign diseases

The precise radiobiological mechanisms of radiation effects on benign diseases are not

well defined. Radiation is believed to work through a complex of multicellular interactions that

affect different cell types in our body system.8 Specific cellular and functional mechanisms

depend on the specific disease and site. While most benign lesions have no known stimuli or

causes, some benign lesions may be triggered by trauma as seen in keloid formation after body

piercing, or heteroptopic bone formation after surgery. In conditions that arise following trauma,

local inflammation and repair occur, which is often characterized by stimulation of growth

factors and accelerated cellular proliferation. For example, in the development of keloids,

fibroblast proliferation is responsible for most of the hyperproliferative process. Even with the

lower doses commonly used in benign diseases, radiotherapy is clinically effective in inhibiting

cell proliferation and suppressing cell differentiation without inducing cell death as is typically

seen with tumoricidal doses of radiation. Yet, radiation can induce apoptosis in selected target

cells by influencing the expression of cytokines in macrophages, leukocytes, endothelial, and

other cells, and thereby modulating the inflammatory cascade.

Among the major sites of radiation effects are the blood vessels; vascular endothelial

cells respond rapidly to radiation damage by up-regulating the cytokine-mediated cellular

reactions responsible for inflammatory tissue response. Low-dose irradiation (<12 Gy) exerts

anti-inflammatory effects on the endothelial cells of capillaries and mononuclear cells of the

immune system.9

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Cell adhesion molecules, selectins, are mobilized to the cell membrane and change the

capillary permeability allowing the inflammatory cells (lymphocytes, macrophages, monocytes)

to migrate into interstitial space. The anti-inflammatory effect is attributed to the modulation of

cytokine and adhesion molecule expression on the activated endothelial cells and leukocytes.

These cells are known to be radiosensitive. They express proinflammatory cytokines (e.g.,

interleukin-1, interleukin-6) or necrosis factors (e.g., tumor necrosis factor-α), which influence

the complement cascade and enzymes of inflammatory reaction. Interleukin-1 stimulates the

production and release of proinflammatory prostaglandins leading to a change in synthesis of

inducible nitric oxide synthetase.

The radiation-induced modulation of nitric oxide production and oxidative burst in

activated macrophages and native granulocytes lead to modification of the immune response and

inflammatory process as well as clinical analgesic effects. Although endothelial cells possess a

high proliferative potential and are sensitive to radiation damage at high doses, they are not

prone to rapid mitotic radiation death at low doses.

Chronic inflammatory processes are triggered by antigen-antibody reactions and

mediated by mononuclear peripheral blood cells in the immune system. Ionizing radiation helps

suppress some of these cell populations, such as T lymphocytes, in the inflammation process or

modulate their effects. While low doses of radiation can exert anti-inflammatory response in

inflammatory tissue, high doses of radiation as used in malignant tumors can elicit pro-

inflammatory effects and fibrotic change in normal tissue.10 At higher single or total doses,

endothelial cell damage can lead to sclerosis and obliteration of blood vessels. In vascular

disorders such as hemangiomas or arteriovenous malformations, high radiation doses may induce

occlusion of pathologic vessels. In addition to inhibition of cell proliferation, cell killing may

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play a part in the management of benign meningiomas, pituitary adenomas, or neuromas where

higher, tumoricidal doses of radiation may be required.

Risk of second malignancies

The induction of cancer or genetic defects by radiation exposure is attributed to stochastic

effects where there is no threshold level of radiation exposure below which cancer induction or

genetic effects will not occur. Increasing the radiation dose or the volume of exposure will

increase the probability that a cancer or genetic effect will occur. Sometimes, the radiation

effects are difficult to separate from inherent genetic effects. For example, in patients with

retinoblastoma, the Rb1 gene plays an important role in the development of radiation-induced

sarcomas. In a study of 384 retinoblastoma patients treated with radiation, the actuarial risk for

developing a sarcoma in the treatment field 18 years after treatment was 6.6.11 In another study

of 693 patients, the cumulative risk for any sarcoma 50 years after radiotherapy was 13.1%.12

Although most sarcomas were within the irradiated fields, 18 out 69 sarcomas developed outside

of the treatment fields. The RB1 mutations appear to have a genetic pre-disposition to

developing sarcoma especially after radiation exposure.

The risk of the induction of secondary tumors was overestimated in the past.13 Trott and

Kamprad used the epidemiological data from long-term follow-up studies on patients treated

with radiotherapy for benign diseases to estimate the risk of cancer induction.14 Taking all known

modifying and organ-specific factors into account, including doses of radiation and volume

irradiated, the estimated absolute lifetime risk for sarcoma induction was < 0.0001% for 1 Gy

and a 100- cm2 field. Table 1 lists the absolute lifetime risk for other malignancies.

Jansen et al. applied the effective dose concept and estimated the carcinogenic risk in

patients after radiotherapy of benign diseases (heterotopic ossification, omarthritis, gonarthrosis,

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heel spurs and hidradenitis suppurativa).15 Special risk modifying factors, including age at

exposure and gender, were taken into account. For an average-aged population, the estimated

number of radiation-induced fatal tumors was between 0.5 and 40 persons per 1000 patients

treated. The range of effective doses was also found to be large (5–400 mSv). In addition to age

and gender, the individual risk also depends on individual inherent sensitivity, anatomic site,

type of disease, and treatment technique, such dose and fractionation.

Indication for Radiotherapy

The majority of benign diseases can be classified as inflammatory, degenerative,

hyperproliferative, or functional. Therefore therapeutic approaches vary widely and are

regionally customized, in part because of geographic traditions and differences in clinical

training. Radiation treatment of benign diseases is less commonly used in the United States than

in some other parts of the world where variation in indications and treatment schedules are

institutionally based.16 Within Germany, a pattern of care study revealed significant geographic

and institutional differences.17 Although most radiation treatments for benign disease are

delivered in the low dose range (<10-15 Gy), the prescribed dose varied widely and

inconsistently within geographic regions and between institutions.

Degenerative processes in tendons, ligaments, and joints can cause pain by chronic

inflammation and trigger secondary functional impairment of the involved musculoskeletal

system. Although radiation does not halt the degenerative process, it may reduce the

inflammation and provide partial or complete pain relief. This clinical effect is well-established

in reports of osteoarthritis, synovitis, and bursitis, where low-dose radiation therapy has

improved the function of affected joints.

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Benign diseases may have a significant effect on self-image and -esteem because of

cosmetic appearance (e.g. facial keloids, juvenile angiofibroma) or lasting impact on quality of

life because of chronic pain or other secondary symptoms (e.g. heterotopic bone, macular

degeneration). When benign diseases become locally invasive with aggressive growth,

therapeutic intervention can prevent or limit functional loss of organs. In rare cases of large

hemangioma with associated thrombocytopenia and consumption coagulopathy (Kasabach-

Merritt syndrome), potentially fatal complications can occur, and timely therapeutic intervention

can be life-saving.19

Although there is a lack of an international consensus, the German Working Group on

Radiotherapy of Benign Diseases published their consensus guidelines for radiation therapy of

nonmalignant diseases. The guidelines were to serve as a starting point for quality assessment,

prospective clinical trials, and outcomes research.18 In brief, treatment is indicated when benign

diseases are symptomatic or potentially symptomatic. When other methods are unavailable or

have failed, radiation therapy should be considered. As medical professionals, we remain

mindful of therapeutic gain and potential treatment side effects and complications. A thorough

risk-benefit analysis is always pertinent. Organ-specific acute and chronic toxicities including

potential effects on fertility and induction of secondary tumors in the future must be explained to

and discussed with patients, especially those who are young and have a long life expectancy.

Informed consent that is required for all medical interventions is certainly required for treatment

of benign diseases and should be obtained prior to the delivery of radiation therapy.

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The current chapter covers some of the more common benign conditions that we still

encounter in the practice of radiation oncology. Details on the therapeutic approaches and data

on radiation dose regimens for different benign diseases are summarized in the individual

corresponding sections.

Benign Neoplasms of the Brain, Head and Neck

Non-malignant tumors of the central nervous system (CNS) and neck can lead to severe, life-

threatening symptoms due to pressure and mass effect on critical structures from tumor growth.

However, depending on their growth rate and location, the surrounding tissue may also well

adapt and lead to a delay in the clinical diagnosis.

Meningioma

Background and Clinical Aspects

Meningiomas are the most common benign tumors of the CNS. The incidence peaks in

the 7th decade of life with a 2:1 female-to-male predominance. The majority (>90%) of

meningiomas are benign and classified by the World Health Organization (WHO) as grade I

tumors.20 WHO grade II meningiomas (atypical, clear cell or chordoid) have a higher tendency

for local recurrence, and WHO grade III/malignant meningiomas (anaplastic, rhabdoid,

papillary) are exceedingly rare.

The most common presenting symptom is headache, but patients may present with other

localizing symptoms depending on the tumor location. The radiographic diagnosis of

meningioma is often made on CT or MRI imaging based upon the appearance of a

homogeneously and intensely enhancing extra-axial mass with or without the presence of a dural

tail.

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Surgical Management

Surgical resection is the treatment of choice for the majority of patients as this will

relieve symptoms and also provide a pathologic diagnosis. The primary goal of surgery is to

remove as much tumor burden as possible while minimizing the risk of neurologic deficits

(maximal safe resection). Gross total resection (GTR) is generally attempted for patients with

tumors in locations such as the convexity and olfactory groove. After GTR, the relapse rate is as

low as 10%, but depends upon the Simpson classification, which grades tumors according to

extent of resection and degree of dural involvement (Table 1).23 Local recurrence rates are as

high as 40% for patients with incomplete resection,23 though these rates can be substantially

reduced with the use of adjuvant radiotherapy.

Meningiomas tend to be highly vascularized tumors. In select patients, preoperative

embolization is used to decrease blood loss and improve the extent of resection.

Active Surveillance

Asymptomatic patients with small meningiomas may be observed clinically. At the time

of tumor growth or the development of symptoms, patients can be treated with surgery or

radiation therapy. The safety and reasoning for this approach was established in a large

retrospective series from Japan that demonstrated that the majority of patients do not require

intervention in the short-term.26

Systemic Therapy

Interest in the use of medical therapy to treat meningiomas stems from the observation

that up to 67% of meningiomas express the progesterone receptor or androgen receptor, and

approximately 10% express the estrogen receptor.27 However, response rates to anti-hormonal

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agents are low. Overall, studies that have investigated the role of chemotherapy, such as

hydroxyurea, in the management of recurrent disease have demonstrated little efficacy.27

Radiotherapy

Primary radiotherapy (RT) is indicated for tumors in locations in which complete

resection is not feasible (i.e. optic nerve, cavernous sinus, major venous sinus) or for patients

who are poor surgical candidates. Adjuvant RT is indicated for patients with STR, recurrent

disease, or for WHO grade II/III tumors. RT techniques include conventionally fractionated

three-dimensional conformal radiotherapy (3DRT), conventionally fractionated intensity-

modulated radiation therapy (IMRT), frame-based or linear accelerator-based fractionated

stereotactic radiotherapy (FSRT), stereotactic radiosurgery (SRS), or protons and heavy ions.

The MRI sequences that best delineate the gross tumor volume (GTV) should be

coregistered with the treatment-planning CT scan for optimal treatment planning and delivery.

Particularly for patients receiving FSRT or SRS, it is important that a neuroradiologist and

neurosurgeon be involved in assisting with GTV delineation, as enhancement from residual

tumor versus postoperative change is often difficult to ascertain.

For 3DRT or IMRT treatments, the clinical target volume (CTV) is constructed by adding

a 1-2 cm symmetric margin around the GTV, respecting normal tissue boundaries. An additional

3-5 mm is added for the final planning target volume (PTV). These margins may be modified

based on institutional policy and other considerations, such as the availability of daily image

guidance (i.e. kV imaging or cone-beam CT).

For benign meningiomas, the typical dose prescription to the PTV is 50-54 Gy given in

1.8-2 Gy daily fractions. Retrospective data suggests that local control is inferior for patients

treated with doses of <52 Gy 28. For patients with more aggressive histology (WHO grade II/ III

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tumors), the GTV is expanded by at least 2 cm with a higher dose prescription in the range of

59.4 – 63 Gy. Several modern series of radiotherapy show 5- year local control rates ranging

approximately 89 – 98%, with 3-dimensional conformal therapy demonstrating local control

rates greater than 95% (Table 2).28-32

Since meningiomas are frequently well-circumscribed and non-invasive tumors, SRS and

FSRT are increasingly being used in their treatment. The decision to fractionate depends largely

upon tumor size and proximity to critical structures, such as the optic apparatus or brainstem.

Typical dose prescriptions for frame-based SRS range from 12-16 Gy prescribed to the 50%

isodose line (IDL) and 14-18 Gy prescribed to the 80% IDL for a frame-less robotic radiosurgery

platform. In patients with tumors that require fractionated treatment, dose prescriptions vary and

are dependent upon the individual case. For example, at our institution we often treat primary or

residual meningiomas of the convexity and skull base to 15-18 Gy in 1-2 fractions. Additionally,

we have treated a select group of perioptic tumors, including meningiomas, with a prescription of

24-30 Gy in 3-5 fractions (to the 80% IDL) with high rates of tumor control and visual

preservation (Figure 1).33 Recent non-randomized, prospective evidence indicates that FSRT

should be the treatment of choice for optic nerve sheath meningiomas due to the high rate of

preservation of visual acuity.34

Reported results with SRS are excellent, with 5-year local control rates as high as 98-

100% (Table 2).35-44 DiBiase et al. demonstrated that male gender, conformality index <1.4 and

size > 10 mL predict for worse outcome after SRS.45 The DiBiase paper also showed improved

disease free survival in patients in which the dural tail was covered as part of the target volume.45

The benefit of including the dural tail has to be weighed against the risk of toxicity from

increasing the target volume for each individual case.

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Due to their physical properties, protons and heavy ions (i.e. carbon) are attractive

choices for the treatment of meningiomas, particularly for those located near critical structures.

Several studies have shown excellent local control rates with the combination of protons and

photons or protons alone.46-49 In the study by Weber, patients were treated to a median dose of

56 Cobalt Gray Equivalents (GyE) given in 1.8 – 2.0 GyE per day.48

Pituitary Adenoma


Pituitary adenomas comprise 10-15% of all intracranial tumors. Approximately 75% of

these tumors are functional (secretory) thereby producing increased amounts of hormones.

Prolactinomas and growth-hormone (GH)-secreting adenomas are the most frequently

encountered. Functional adenomas are more common in women, while non-functioning and

GH-secreting adenomas are more common in men.

Adenomas are often classified by size with a picoadenoma < 0.3 cm, microadenoma < 1

cm and macroadenoma > 1cm. Macroadenomas may exert mass effect upon the optic chiasm

leading to the classic sign of bitemporal hemianopsia. Headaches are seen in approximately 20%

of patients. If the adenoma extends to the cavernous sinus, cranial nerve deficits may be present.

Involvement of the hypothalamus by the adenoma results in hypopituitarism.

Patients with functional adenomas present with signs and symptoms that correspond to

the excess hormone: galactorrhea, amenorrhea, diminished libido and infertility in patients with

prolactinomas; acromegaly or gigantism in patients with GH-secreting adenomas; Cushing’s

disease in ACTH-secreting adenomas; hyperthyroidism in patients with TSH-secreting

adenomas. In patients who have had bilateral adrenalectomy, up to 40% will develop Nelson’s

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syndrome, which is characterized by an ACTH-secreting adenoma and increased skin

pigmentation secondary to increased release of alpha-melanocyte-stimulating hormone.

In addition to history and detailed physical examination (H&P), workup of a pituitary

tumor includes laboratory analysis of pituitary hormone levels, contrast enhanced MRI with thin

slices through the pituitary (Figure 2A-B), and tissue diagnosis to rule out other causes of

pituitary masses including craniopharyngioma, meningioma, suprasellar germ cell tumor,

metastatic disease, or a benign lesion (i.e. cyst).

Surgical Management

Surgery is generally the treatment of choice for pituitary adenomas. Surgery provides

immediate relief of compressive symptoms and helps to decrease hormone secretion. The most

common surgical technique is through a transsphenoidal approach. In some cases, a more

aggressive surgery (i.e. frontal craniotomy) may be indicated for patients with extensive

intracranial and skull based involvement. Overall, local control rates range from 50-80% after

surgery alone for both functioning and non-functioning adenomas.50 In patients that continue to

have abnormally elevated hormones after surgical resection, adjuvant treatment with

pharmacotherapy and/or radiation therapy is pursued.

Pharmacotherapy

Pharmacotherapy, such as bromocriptine and cabergoline for prolactinomas, octreotide

for GH-adenomas and TSH-adenomas, and ketoconazole for ACTH-adenomas, is often used as

an adjunct to surgery for patients with functioning adenomas. With the exception of

prolactinomas, the use of these drugs as monotherapy is generally not curative. Prolactinomas

can often be managed with pharmacotherapy alone, but a high proportion of patients are unable

to tolerate bromocriptine for long periods of time due to nausea, headache and fatigue.

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Radiotherapy

Except for medically inoperable patients in which RT is used in the primary setting, the

role of RT is generally in the adjuvant setting with the following indications: recurrent tumor

after surgery; persistence of hormone elevation after surgery; residual disease after

STR/debulking procedure. Tumor growth control is excellent, particularly for patients with non-

functioning adenomas.51-53 Endocrine control, as demonstrated by normalization of pituitary

hormone levels, for functioning adenomas takes years to develop. Growth hormone levels

stabilize quickest at a median of 2 years after radiation therapy and is slowest for TSH-secreting

adenomas 54. Pharmacologic therapy should be discontinued one to two months prior to the

initiation of RT based on evidence demonstrating lower RT sensitivity with concurrent medical

treatment 55.

RT techniques include 3DRT, IMRT, single-fraction SRS and FSRT. Delineation of the

GTV (or preoperative GTV in the case of GTR) should be performed by co-registration of the

postoperative MRI to the treatment planning CT scan.

For 3DRT and IMRT, the CTV is constructed by adding 1-1.5 cm to the GTV; an

additional 3-5 mm is added to the CTV to create the PTV. These margins may be modified

based on institutional policy and other considerations, such as the availability of daily image

guidance. Non-functional adenomas are typically prescribed a dose of 45-50.4 Gy given in 1.8-

2.0 Gy daily fractions (Figure 2C-E). Higher doses in the range of 50.4-54 Gy are recommended

for secretory adenomas.

SRS remains an attractive option for the treatment of pituitary adenomas. General

principles apply in that FSRT is used over SRS for large lesions (i.e. > 3 cm) or lesions near

critical structures (i.e. <1-2 mm from the chiasm). Similar to 3DRT/IMRT, higher doses are

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needed for functional adenomas compared to non-functional adenomas. Numerous retrospective

studies have demonstrated excellent local control rates of 92-100% for non-functional adenomas

using doses of 14-25 Gy (at the edge of the tumor) in a single fraction.56 Commonly used

prescriptions are 16-20 Gy in a single fraction for non-functional adenomas and 20-25 Gy in a

single fraction for functional adenomas using a frameless robotic radiosurgery platform.

Craniopharyngioma


Craniopharyngiomas make up 6-10% of pediatric CNS tumors, or approximately 300-350

cases per year in the US. The median age of diagnosis is 5-10 yrs with a second peak in patients

>40 years old.

These benign tumors are epithelial, arising from remnants of Rathke’s pouch

(hypophyseal-pharyngeal duct) and are most commonly located in the suprasellar region, though

they may be found in the sella proper. Craniopharyngiomas generally abut the hypothalamus

and third ventricle. Histologically, they are divided into the adamantinomatous and squamous

subtypes. The adamantinomatous subtype is characterized by a solid and cystic pattern with the

well-known description of “machine oil-like” cystic fluid.

Presenting signs and symptoms include headache, nausea and vomiting, bitemporal

hemianopsia, endocrine dysfunction (diabetes insipidus, dwarfism, fat tissue disturbance, adrenal

cortical insufficiency). The most common hormone deficiency is lack of GH. The workup is

similar to that of pituitary adenoma and includes H&P, pituitary hormone levels, and brain MRI

with thin slices through the sella (Figure 3).

Surgery

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The primary goal of surgery is complete resection. However, GTR may be associated

with high rates of neurologic sequelae including visual impairment and panhypopituitarism. In

order to minimize morbidity, most patients are treated with maximal safe resection followed by

adjuvant RT.

In some cases, intralesional bleomycin may be directly injected into the cyst to decrease

the rate of cyst recurrence.

Radiotherapy

Radiation therapy is often used in the adjuvant setting. In select patients (i.e. < 3 years

old), observation following a subtotal resection may be an option as local control rates are

similar with RT at the time of relapse (‘salvage’ RT) compared with adjuvant RT with no

compromise in overall survival 57.

RT techniques include 3DRT, IMRT, FSRT, proton therapy, and intralesional RT with

beta-emitting isotopes (Yttrium-90, Phosphorous-32). The GTV is the postoperative residual

tumor volume, including the cyst wall, if present. The postoperative MRI should be fused with

the treatment planning CT scan for optimal target delineation. A margin of 1-1.5 cm is added to

the GTV to create the PTV. Dose prescriptions for 3DRT and IMRT are typically 54 Gy given

in 1.8 Gy daily fractions.

Fractionated proton radiotherapy has demonstrated excellent results. The Loma Linda

series treated 15 patients to a total dose of 50.4-59.4 GyE given in 1.8 GyE daily fractions 58.

Local control was achieved in 14 out of 15 patients with few long-term complications. In a

series from the Massachusetts General Hospital (MGH), no failures were seen in 24 patients that

received fractionated proton radiotherapy to a total dose of 52.2-54 GyE in 1.8 GyE per fraction

59.

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It has been well established that cysts may regrow during the several weeks of

fractionated treatment. The MGH proton study recommends that re-imaging (CT or MRI if cyst

is not well visualized on CT) should be performed within two weeks of the treatment planning

scan and every two weeks thereafter; for large cysts or those that demonstrate growth during RT,

weekly re-imaging is recommended 59. The emergence of image-guided radiotherapy techniques

now allows for the convenient monitoring of cyst re-growth with cone beam CT scans while

patients are on the treatment table.

SRS and SSRT have been used with success in the treatment of craniopharyngioma. In

one series from Stanford using a frameless robotic platform 60, 16 patients were treated

postoperatively with doses of 18-38 Gy given over 3-10 fractions prescribed to mean IDL of

75%. Local control was 91% in this cohort of patients with no visual or neuroendocrine

complications. Similar results have been demonstrated with use of a frame-based platform 61-64.

Cystic craniopharyngiomas may also be managed by the use of intralesional radioactive

isotope injection using a beta-emitter. Typical prescriptions range from 200-250 Gy prescribed

to the cyst wall. Optimal results are seen in patients whose tumors have one cyst and lack a large

solid component .

Acoustic Neuroma (Vestibular Scwhannoma)


Acoustic neuromas (AN) represent 5-8% of primary CNS brain tumors. They are derived

from Schwann cells of the neurilemma of the vestibulocochlear nerve (CN VIII). The vast

majority of cases (90%) are unilateral and sporadic. Bilateral acoustic neuromas occur in about

10% of cases and are associated with the autosomal dominant disorder Neurofibromatosis Type

II.

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Symptoms include sensorineural hearing loss, tinnitus, and vertigo. Hearing loss is

correlated more with tumor location (intracanalicular) rather than tumor size In a minority of

patients (5%), facial nerve symptoms may be present. As the AN grows, it may affect the

trigeminal nerve (CN V) and brainstem.

During the initial workup, physical examination should include the Rinne test (air

conduction > bone conduction on the affect side) and Weber test (vibratory sound louder on the

unaffected side) to test for sensorineural hearing loss, as well as detailed examination of CN V

and CN VII. All patients should undergo audiometry when the diagnosis of AN is suspected;

this will often reveal asymmetric hearing loss more prominent at high frequencies as well as

impairments in speech discrimination score. Imaging should include a contrast-enhanced MRI

with thin-slices through the internal auditory canal. The entire neuraxis should be imaged in

patients with NF-2.

Surgery

For many years, the standard treatment for patients with AN was microsurgical resection,

either via a translabrynthine approach or middle cranial fossa approach. Surgery remains the

preferred treatment for patients with large, symptomatic lesions. Hearing preservation is

approximately 50-60% after surgery, and facial nerve preservation ranges from 80-90% .

Active Surveillance

Observation is appropriate management for asymptomatic patients with small tumors.

Serial MRI and audiometry (at least once per year) should be performed in this patient cohort for

surveillance. Treatment is initiated when the lesion demonstrates rapid and significant growth or

when the patient becomes symptomatic.

Radiotherapy

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RT in the form of SRS or FSRT is an option for the primary treatment of AN, often with

higher rates of hearing preservation and facial nerve presentation compared with surgery. Proton

therapy has also been used to treat AN.

SRS doses using frame-based platforms are generally 12-13 Gy prescribed to the 50%

IDL. Although earlier studies demonstrated lower hearing preservation rates with higher SRS

doses 69, current results are significantly improved. Flickinger demonstrated local control rate of

98.6%, hearing preservation rate of 70.3%, 4.4% rate of trigeminal neuropathy, and no incidence

of facial nerve dysfunction 70. Using a frameless robotic radiosurgery platform to treat 383 ANs

to a dose of 18-21 Gy given in 3 fractions, Stanford demonstrated 98% local control, 76%

hearing preservation, 2% incidence of trigeminal nerve dysfunction (transient in 4 of the 8

affected patients), and no facial nerve dysfunction 71.

Common dose prescriptions employing FSRT include 25 Gy in 5 fractions, 30 Gy in 10

fractions, and 50-55 Gy in 25-30 fractions. A non-randomized, prospective trial compared SRS

(10-12.5 Gy) to FSRT (20-25 Gy in 5 fractions). This study demonstrated comparable rates of

local control, hearing preservation, and CN V and CN VII preservation between the two groups

72.

Proton beam SRS has also been used to treat AN, though with low rates of hearing

preservation compared to other RT techniques. In a series from MGH, 88 patients were treated

to a median dose of 12 Gray Equivalents (GyE) given in a single fraction prescribed to a median

IDL of 70%. Tumor control rates at 2 and 5 years were 95.3% and 93.6%, respectively. Facial

and trigeminal nerve preservation rates were 90%. Only 33% of patients retained serviceable

hearing 73. In a study of FSRT using proton beam, local control was excellent but the hearing

preservation rate was also poor at 42% 74.

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Chordoma


Chordomas are rare, slowly growing midline tumors originating from the embryonal

notochord rests in the skull base (35%), vertebral column (15%), or sacral regions (50%). The

most common sites of skull based tumors include the clivus, dorsum sella and nasopharynx.

Patients typically present with signs and symptoms attributable to the primary site of the

tumor. Workup includes MRI with contrast enhancement. CT may complement MRI to assess

for local bony destruction. A biopsy is necessary primarily to distinguish chordoma from

chondrosarcoma, which has a better prognosis, and other malignancies. In children, biopsy is

essential to distinguish chordoma from rhabdomyosarcoma, which can frequently present in the

same location.

Surgery

Complete surgical resection is the mainstay of treatment. However, due to their location,

GTR is often not possible. Relapse rates are as high as 50% even after surgical resection with

negative margins 75. Poor prognostic factors include large tumors, recurrent tumors, older age,

and presence of necrosis on biopsy 76-78.

Systemic Therapy

Approximately 25% of chordomas metastasize to the lungs, liver or bone. In these

patients, or in patients with recurrent disease after surgical resection and radiation therapy,

molecularly targeted agents may be considered. Several small studies have demonstrated some

benefit to the use of imatanib or the combination of imatanib and sirolimus in this situation 79-81.

Radiotherapy

21

Adjuvant radiation therapy is indicated to reduce recurrence rates for skull-based

chordomas. Retrospective data suggests that salvage RT is inferior to adjuvant RT with 5 and 10

year overall survival rates of 50% and 0%, respectively, for those treated with salvage RT

compared to 80% and 65%, respectively, for patients treated with adjuvant RT 82. RT techniques

for treatment of skull-based chordomas include conventionally fractionated EBRT and IMRT,

fractionated charged particle therapy (protons, carbon ions), and FSRT.

Determination of the GTV should be made by co-registration of the preoperative and/or

postoperative MRI to the treatment planning CT scan. Particularly for pediatric cases in which

IMRT will be used with tight margins, a neuroradiologist should be available at the time of

treatment planning to assist in creating the GTV. Margins for CTV should be 1-2 cm with an

additional 3-5 mm for the PTV. Dose prescriptions to the PTV for patients receiving photon-

based treatment should be at least 60 Gy given in 1.8 – 2.0 Gy daily fractions.

Proton-based therapy can achieve higher doses with good results. In a series of 195

chordomas treated at the MGH, 5 yr PFS was 70% with doses of 63-79.2 GyE given in 1.8-2.0

GyE daily fractions 83 . Loma Linda examined 33 cases of chordomas treated with a median of

70 GyE and found 76% 5-year local control and 79% 5-yr overall survival 78.

In a report of 96 chordomas treated using carbon ion therapy at the University of

Heidelberg with median total dose of 60 GyE (range, 60-70 GyE) delivered in 20 fractions

within 3 weeks, good local control rates of 81% at 3 years and 70% at 5 years were observed 84.

There was a trend to improved local control in patients that received >60 GyE.

FSRT and SRS are less well established than charged-particle therapy. The North

American Gamma Knife Consortium published the experience of 71 patients that underwent

Gamma Knife SRS as primary, adjuvant or salvage therapy for skull base chordomas 85. The

22

median dose to the tumor margin was 15 Gy (range, 9-25 Gy). 5-year local control was 66% for

the entire cohort (69% for the no prior RT group and 62% for the prior RT group). Debus et al.

reported on 37 patients with chordomas treated with FSRT to a median dose of 66.6 Gy given in

1.8 Gy daily fractions; the target volume was encompassed by 90% of the dose 86. Local control

was 82% at 2 years and 50% at 5 years.

Glomus Tumor/Chemodectoma/Paraganglioma


Glomus tumors are rare, benign tumors that occur at the along the carotid artery near the

bifurcation (carotid body tumor), the jugular bulb (glomus jugulare), or the middle ear (globus

tympanicum). The peak age is in the fifth decade of life. Bilateral or multiple tumors occur in

10-20% of affected patients.

Symptoms include headache, cranial nerve dysfunction, dysphagia, pulsatile tinnitus,

vertigo, and large, pulsating masses in the neck. In rare cases, patients present with episodic

hypertension which may be related to the secretion of vasoactive substances by the tumor. In

this situation, urine and serum metanephrines should be measured. The clinical presentation

coupled with imaging (high-resolution CT, MRI, and/or angiography) often establishes the

diagnosis. In patients in which multiple tumors are suspected, imaging with

metaiodobenzylguanidine (MIBG) may be useful.

Surgery

In the carotid region, primary tumor resection after previous embolization is the therapy

of choice. At the skull base or tympanum, neurosurgical intervention is often deferred due to the

high rates of complications, including stroke and cranial nerve injury 87.

Radiotherapy

23

RT is indicated for patients with tumors in unsuitable locations (i.e. skull-base), as

adjuvant therapy after STR, or as salvage therapy at the time of relapse after surgery. RT

techniques include conventionally fractionated 3DRT/IMRT, SRS and FSRT.

The diagnostic MRI should be co-registered with the treatment planning CT scan. The

GTV is delineated and 1-1.5 cm is added for clinical and setup margin. With conventional

techniques, doses are often 45-55 Gy given in 1.8-2 Gy daily fractions with local control rates

near or greater than 90% in several series 88-91.

Results with SRS have been comparable to that of conventionally fractionated RT. Using

a frame-based platform, reported tumor margin doses range from 12.5 – 20 Gy prescribed to the

50% IDL 92-94 and 15 – 25 Gy for linac-based SRS 87. Local control rates in these series range

from 90-100%. A recent meta-anlaysis of SRS published by the Johns Hopkins Hospital

reviewed 335 patients treated with SRS across 19 different studies 95. In the eight studies with

median follow-up of greater than 3 years, clincal control was 95% and tumor control was 96%.

The control rates were equal amongst patients treated with linac-based platforms and frame-

based platforms. Complications were rare and often transient in each of the studies examined.

On the basis of these findings, the authors advocate for the use of SRS as primary treatment of

glomus jugulare tumors 95.

Juvenile Nasopharyngeal Angiofibroma (JNA)


JNA is a rare, benign, vascularized tumor in the head and neck, affecting mostly male

adolescents. JNAs develop from the sphenoethmoidal suture and spread from the nasal cavity to

the sphenopalatine foramen and pterygopalatine fossa. Other routes of local spread include the

paranasal sinuses, infratemporal fossa, orbital space, and middle cranial fossa.

24

Symptoms initially include recurrent epistaxis and impaired nose breathing. As local

extension occurs, patients may develop facial swelling, orbital symptoms (blindness), cranial

nerve deficits, and headaches from intracranial extension.

Diagnosis is often made with the clinical presentation and CT or MRI-based imaging.

Biopsy may cause massive bleeding. Numerous staging systems are used to categorize the

tumors based on extent of local extension, including the Chandler, Radkowski, and Fisch

systems (Table 3, 96-98).

Surgery

Surgery combined with embolization is the preferred treatment. Through surgery, most

JNAs without intracranial extension (i.e. Chandler stage I-III) have local control rates of near

100%. In patients with intracranial extension, complete resection is often not possible.

Radiotherapy

Tumors with intracranial extension or tumors in patients that are medically inoperable are

generally treated with RT as the primary modality. Indications for postoperative RT include

relapse after surgery. Fractionated IMRT is currently the RT technique of choice to limit

collateral radiation to critical structures near the target volume.

The PTV is generally treated to 30-50 Gy given in fraction sizes of 2-3 Gy per day. In

modern series, local control rates range from 85-100% (Table 4, 99-102). After RT, JNA remission

is slow, and late recurrences may occur.

Langerhans Cell Histiocytosis (Histiocytosis-X)


Langerhans Cell Histiocytosis (LCH) is a rare disorder that affects approximately 300

individuals with a higher incidence in children (3-5 per million) than adults (1-2 per million).

25

Age is an important prognostic factor with children having better outcomes than adults. In the

past, it was felt that children younger than two years old were felt to have a poor prognosis, but

recent data from the LCH-II study now refute that point 103.

The disease is due to an accumulation and/or proliferation of cells that phenotypically

resemble the Langerhans skin cell and can cause tissue damage by production of cytokines and

infiltration. The actual Langerhans cell is a myeloid dendritic cell that expresses the same

antigens (CD1a and CD207) as the Langerhans skin cell 104. On electron microscopy, Birbeck

granules are the classic finding.

LCH can affect a variety of organ systems. Patients are typically stratified into groups

based on the extent of disease: single-system disease at a single site, single-system disease

involving multiple sites, or multisystem disease. The clinical presentation is dependent upon the

sites of disease. Involvement of the skeletal system is the most common site for children and

may manifests as pain, palpable mass, or motion deficit, or chronic otitis in the case of mastoid

or middle ear involvement. Bony lesions from LCH are predominantly lytic in appearance, and

the skull is the most frequently involved bony structure.

Cutaneous involvement affects primarily the skin of the scalp and groin and resembles a

seborrheic dermatitis. Patients with cranial involvement (posterior pituitary or hypothalamus)

may present with diabetes insipidus (DI). The disease may also involve the cervical lymph

nodes. Pulmonary involvement is more typically seen in adults. Hepatomegaly, splenomegaly,

bone marrow infiltration and involvement of the gastrointestinal tract are further potential sites

of disease.

Evaluation of the patient with suspected LCH should include complete history and

physical examination. Routine laboratory work should include CBC with differential. Patients

26

that have symptoms of DI should also undergo a water restriction test. A skeletal survey with or

without bone scan should be performed to assess for potential lytic lesions. Further imaging with

CT of the head should be performed in patients with skull, orbital or mastoid involvement. MRI

of the head is indicated for patients with diabetes insipidus and those suspected of having brain

parenchymal disease involvement. CT of the chest is performed to evaluate patients with

pulmonary involvement. An MRI abdomen should be performed for patients with palpable

hepatomegaly or splenomegaly.

Management Principles

Treatment of LCH depends upon the site and extent of disease. Asymptomatic lesions

may be observed. For patients with involvement of only the skeletal system, treatment options

include curettage, excision, or intralesional steroid injection. Response rates with curettage or

excision alone range from 70-90% 105. Single system multifocal bone disease may be effectively

treated with corticosteroids or chemotherapy, such as vinblastine. For skin only disease, topical

nitrogen mustard and methotrexate are considered effective treatments.

In patients with multi-system disease with symptoms (fever, pain, failure to thrive) or

organ dysfunction, treatment with systemic therapy is indicated. In LCH-II, all patients received

initial treatment with prednisone and vinblastine and were randomized to intensification with or

without etoposide . The patients treated with intensification demonstrated superior rapid

response rates and decreased mortality rates compared to the standard arm 106. Exogenous ADH

(vasopressin) is used to treat children with DI.

Radiotherapy

Due to the excellent response rates to non-radiotherapeutic measures, the role of RT in

the treatment of LCH bony lesions has decreased. Indications for radiation therapy to bony sites

27

include relapse after surgery, no signs of clinical healing after other interventions, pain relief,

potential compromise of critical structures from an expansile lesion (i.e. cord compression), or if

the bony site is not amenable to other local therapies. Collapsed vertebral lesions should not be

irradiated unless they are painful. DI is another recognized potential indication for treatment

with RT. When the decision is made to treat, 3DRT should be the technique of choice.

The target volume for patients with bony disease should encompass the abnormality seen

on imaging with a small margin. For children, low doses on the order of 5-10 Gy given in 1.5-2

Gy daily fractions should be sufficient to control most bony lesions. Higher doses can be used in

adults. In an early study by Smith, 92% of patients received total doses in the range of 4.5 – 10

Gy with an 87% local control rate 107. UCLA found local control rates of 88% with doses in the

range of 6 Gy – 15 Gy for previously untreated lesions and 8 Gy- 15 Gy for recurrent lesions 108.

The target volume for patients receiving treatment for DI should encompass the

hypothalamus and pituitary gland. The recommended prescribed dose is 15 Gy in 1.5 Gy daily

fractions. In a report from the Mayo Clinic, 36% of 28 evaluable patients responded to

radiotherapy 109. The response rates were 60% (3 of 5 patients) in those treated with more than

15 Gy compared to 30% (7 of 23 patients) treated with doses of less than 15 Gy. Six patients

had a complete response to therapy, five of whom received treatment within 14 days from

diagnosis of DI.

Controversy still remains regarding the role of RT in the management of DI. In a

retrospective series from MGH, 14 of 17 patients with DI received irradiation to the

hypothalamic-pituitary axis 110. Only two of these patients had a complete response (cessation of

ADH therapy), and no patients had a partial response. The others argue that treatment of DI

from LCH is “no longer justified 110”.

28

Vascular Disorders

Vascular disorders are broadly categorized into vascular tumors, most commonly benign

hemangiomas, and vascular malformations, including arteriovenous malformations (AVMs) and

cavernous hemangiomas. Radiosurgery has emerged as an important and common treatment

option for AVMs. While radiation was used commonly in the past to treat hemangiomas in

children, the recognition of late effects associated with radiotherapy, especially secondary

malignancies, has rendered this practice less common.

Arteriovenous Malformations (AVM)


Intracranial AVMs are congenital vessel abnormalities consisting of widened arteries

connected to the normal capillary bed. The nidus of an AVM is made up of tangled arteries and

veins that are connected by one or more fistulas. The overall prevalence is low, affecting

approximately 18 in 100,000 individuals with age at presentation typically between 20-40 years

old.

Clinical concern comes from the high risk of bleeding, estimated to be 2-4% per year.

Approximately 50% of patients present with hemorrhage and 50% present with non-focal

(headache, nausea) symptoms or incidentally found focal neurologic deficits. The risk of death

per bleed is up to 10% and approximately 30% have serious morbidity associated with each

bleed.

Diagnostic imaging includes angiography, which is invasive but allows for full grading of

the AVM according to the Spetzler-Martin Scale. MRI, MR angiography, and CT angiography

are non-invasive and complementary studies that may be used to visualize the AVM.

Surgery

29

The goal of any therapy for AVM is to completely obliterate the nidus. Partial

obliteration of the nidus does not decrease the bleeding risk. Complete surgical excision

provides immediate cure but carries a risk of intraoperative bleeding, ischemic cerebrovascular

accident, infection and death. Surgery is particularly indicated for AVMs in superficial,

noneloquent regions of the brain. Endovascular therapy (embolization) is not curative, but may

be used to decrease the risk of intraoperative bleeding or to decrease the size of the nidus before

planned radiotherapy.

Radiotherapy

SRS is the radiation modality of choice for the treatment of AVMs. SRS is indicated

mostly for lesions in deep or eloquent regions of the brain, and is particularly safe and successful

for lesions that are <3 cm. Unlike surgery, the time to obliteration ranges from 1-4 yrs after

SRS, so the patient remains at a continued bleeding risk. Even with time, Maryuma et al.

demonstrated that the bleeding risk is not completely eliminated, but reduced by approximately

88% 111.

Based on the Flickinger dose-response data, typical prescriptions for treatment of AVM

are 21-22 Gy prescribed to the 50% IDL for frame-based radiosurgery (Table 5) 112. The

prescription should be lowered for AVMs near the brain stem or larger lesions (> 3cm). For

linac based SRS, prescriptions generally range from 16-24 Gy in a single fraction to 20-22 Gy in

2 fractions for spinal AVMs (Figure 4) 113.

Hemangioma/Kasabach-Merritt Syndrome


Hemangiomas are dynamic vascular tumors characterized by a proliferative phase

followed by an involution phase. Approximately 20% of hemangiomas are present at birth,

30

while the remaining 80% usually form within the first few weeks of life. Most hemangiomas

present no problems to the patient and require no treatment. The spontaneous involution rate is

approximately 10% per year 114. However, potential complications that may require treatment

include obstruction of vision (eyelid hemangioma), ulceration and infection, cosmetic deformity

from a facial hemangioma and high-output cardiac failure.

Previously, it was felt that extremely large hemangiomas predisposed patients to the

Kasabach-Merritt syndrome (KMS). This syndrome consists of platelet trapping and destruction

within the vascular tumor with a resultant consumptive coagulopathy (disseminated intravascular

coagulation, DIC) that can be life-threatening. It is now recognized that this phenomenon is

associated with a type of vascular tumor known as the Kaposiform hemangioendothelioma, and

not the classical infantile hemangioma 115.

Systemic Therapy

Treatment options for hemangiomas include local and systemic pharmacotherapy, laser

therapy and surgery. Glucocorticoids have been the mainstay of systemic treatment for patients

with hemangiomas. However, long-term use of steroids in children leads to many complications,

including growth retardation, metabolic disorders, cushingoid facies, personality changes, and

increased risk of infections. Recently, propranolol has been recognized as a potential therapeutic

agent for hemangiomas. The first report of its use was published in the New England Journal of

Medicine in 2008 when two patients with hemangiomas with resultant heart failure were treated

with propranolol and were noted to have softening, change in color, and ultimately regression of

the lesions 116. Both of these children were able to sustain a clinical response even after being

weaned off of steroids. Additional studies of propranolol have shown promising results with

31

most children exhibiting significant regression of their lesions and the ability to wean off of

steroids without a rebound effect 117.

For patients with KMS, vincristine and interferon-alpha have been used, particularly in

situations in which a quick clinical response is needed or when the disease has become refractory

to steroids and propranolol. Patients with KMS should also be managed with supportive

measures, such as blood and/or platelet transfusions, as needed.

Patients with small lesions may be candidates for local therapy, such as intralesional or

topical steroids. Topical timolol is also being investigated, given the promising results seen with

propranolol 118. Select patients may be candidates for treatment with pulse-dye laser or

excisional surgery.

Radiotherapy

Radiotherapy is indicated only in patients that have exhausted all other treatment options.

When RT is used, responses are often quick and dramatic. With low dose RT (i.e. <10 Gy),

scarring should be minimal, but patients must be followed closely for secondary malignancies.

The CTV should include the clinically visible and palpable lesion with margin. Imaging

of the affected area with MRI is useful to delineate the depth and full extent of disease.

Although there are no prospective trials to guide total dose and daily dose, most reports have

used fractionation schedules of 100-300 cGy per day to a total dose of 10 Gy or less . When

patients have not responded to low-dose RT, higher doses may be used to achieve a response.

Functional Disorders

Stereotactic radiosurgery is widely used for the treatment of benign tumors. However, a

significant number of patients benefit from the use of SRS to treat functional disorders such as

trigeminal neuralgia, tremors, and epilepsy. Over the past several years, there have been

32

increasing reports of the use of SRS for the treatment of refractory psychiatric disorders

including obsessive-compulsive disorder and major depressive disorder.

Trigeminal Neuralgia (Tic Douloureux)


Trigeminal neuralgia (TN) is a common problem that affects approximately 15,000

patients each year in the United States. There is a slight female predominance (1.5:1). The

disorder is currently classified into Type I TN and Type II TN, which is based on pain

characteristics, as opposed to the traditional classification system which divided patients into

idiopathic TN versus secondary TN 120-122. Patients with Type I TN describe pain as being

predominantly (>50%) sharp, lancinating and shock-like with pain-free intervals. Patients with

type II TN predominantly experience burning, aching or throbbing pain. This system also carries

prognostic significance, with Type I TN patients more likely to be pain-free and have longer

disease control than patients with Type II TN after decompression 120.

The classic clinical feature is recurrent episodes of sudden, brief, severe, stabbing or

lancinating pain in the area of the trigeminal nerve sensory distribution. It is most commonly

unilateral, but some cases are bilateral. Common triggers for attacks include talking, chewing,

brushing teeth and cold air. The diagnosis is often suspected on the basis of the above clinical

symptoms, but an MRI brain should be performed to rule out structural abnormalities that may

be causing secondary TN.

Medical Therapy

TN is first treated with pharmacotherapy, with carbamazepine being the most common

and extensively studied agent. Oxcarbazepine is an option for patients who are unable to tolerate

33

carbamazepine. Numerous other agents have been used to treat carbamazepine-refractory

patients including lamotrigine, neurontin, pimozide, tizanadine, and topiramate.

Surgery

In patients that have medically refractory disease, microvascular decompression is the

treatment of choice for immediate relief of symptoms. Other options include rhizotomy with

either radiofrequency ablation, glycerol injection or balloon compression.

Radiotherapy

SRS has emerged as a successful and minimally invasive procedure to treat classical TN.

Treatment planning involves fusion of a contrast-enhanced MRI with thin cuts to the treatment

planning CT scan. The target for SRS varies from the root entry zone of the trigeminal nerve as

it enters the pons to the semilunar ganglion 123-129. Typical doses using a frame-based

radiosurgery platform are 70-90 Gy, prescribed to the 50% isodose line. This dose range is

largely based on a trial that prospectively assigned patients to low-dose (60-65 Gy) or high-dose

(70-90 Gy) SRS and demonstrated higher rates of pain relief in the high-dose arm (72% vs. 9%

for patients treated with ≥70 Gy vs. <70 Gy), with a median time to pain relief of 1 month 125.

The main concern with treating larger segments of the nerve with higher doses of

radiation is the delayed onset of facial numbness. This is based on a prospective study by

Flickinger et al. that randomized patients to 75 Gy targeted to a shorter (1 isocenter) or longer (2

isocenters) segment of the trigeminal nerve 130. The rates of pain relief were surprisingly

identical between the two groups. There was a trend towards a higher-incidence of numbness or

paresthesias in the two-isocenter patients, and overall, the nerve length irradiated was

significantly correlated with the development of numbness and paresthesias. However, in a

report by Adler et al., 46 patients received treatment with a frameless robotic radiosurgery

34

platform to a 6-mm segment of the trigeminal nerve with a mean marginal prescription dose of

58.3 Gy and mean maximal dose of 73.5 Gy 131. In this cohort of patients, 85% experienced a

complete response and at a mean follow-up of 15 months, 96% reported excellent or good

outcomes. Only 15% of patients experienced ipsilateral facial numbness.

Epilepsy


Epilepsy is a disorder characterized by recurring seizures. It affects 0.5-1% of the

population, and its etiology is unknown in the vast majority of cases. The clinical presentation of

patients with seizures is broad, depending on the type of seizure and the area of the brain

involved. Seizures are generally classified into simple versus complex (loss of consciousness)

and generalized vs. partial (affecting only one focus in the brain).

Nonradiotherapeutic Treatment

Anti-epileptic drugs are the treatment of choice for patients with epilepsy. Surgery is an

option for patients that develop medically-refractory disease, particularly for temporal lobe

epilepsy 132.

Radiotherapy

SRS may be an alternative to surgery in medically-refractory epilepsy for patients that are

not surgical candidates. In a multi-instutional study, Regis et al. and colleagues treated 20

patients with SRS for intractable mesial temporal lobe epilepsy 133. The mesial temporal lobe

was treated to a dose of 24-25 Gy in a single fraction with Gamma Knife. At a follow-up of 2

years, 65% of the patients were seizure-free. However, there was a one-year lag between

treatment and maximal effect, and there was a transient increase in seizures before the seizures

started to diminish. In a study by Barbaro et al., 30 patients were randomized to low dose (20

35

Gy) or high dose (24 Gy) radiosurgery targeting the amygdala, hippocampus and

parahippocampal gyrus 134. At 3 years, the seizure-free rate was 67% among all patients with a

trend towards a higher response rate (77% versus 59%) and earlier responses in the high dose

compared to the low dose group of patients. No serious toxicity was reported in the study.

In general, the use of SRS to treat epilepsy is not routine, and non radiosurgical options

should be employed first. Further study is needed to establish the long term safety and efficacy

of SRS in the treatment of epilepsy.

Parkinson’s Disease


Parkinson’s disease (PD) results from the loss of dopaminergic neurons in the substantia

nigra. It is a debilitating and progressive neurodegenerative disorder that affects approximately 1

million people in the US. The hallmark clinical symptoms include masked facies, resting

tremor, slow movements, shuffling gait and muscle rigidity. Some patients also develop

dementia as part of the disorder.


Pharmacotherapy with dopamine agonists and other compounds is the treatment of choice

for patients with PD. Once refractory to medical therapy, surgery (thalamotomy or pallidotomy)

may be used to remove the overactive brain nuclei. Deep brain stimulation is another invasive

procedure done under stereotactic guidance that can be used in medically refractory PD.

Radiotherapy

Patients that are poor candidates for surgery may receive SRS for the treatment of

medically-refractory PD. To relieve tremor, the target is the ventralis medialis nucleus with a

36

dose in the range of 120-180 Gy. Young et al. reported a long-term success rate of 80-90% in

relieving symptoms from PD-tremor with a very low rate of permanent complications .

Mixed results have been found with regards to the treatment of PD-related

akinesia/dyskinesia/rigidity. Treatment entails targeting the globus pallidus internus

(pallidotomy) with doses in the range of 120 – 180 Gy. Rand et al. reported that 4 of 8 patients

received relief in rigidity with no serious complications 137. However, Friedman et al. achieved a

response in only 1 of 4 patients while causing dementia and psychosis in the only patient

responder 138. Young et al. 139 treated 29 patients with SRS pallidotomy with 80% success rate at

mean follow-up of 2 years and only 1 (3.4%) complication at 9 months (homonymous

hemianopia).

Psychiatric Disorders


Psychiatric disorders such as obsessive-compulsive disorder (OCD), bipolar disorder, and

major depressive disorder are debilitating illnesses. Radiosurgery has been used for the

treatment of some of these psychiatric illnesses, with the majority of the experience in patients

with OCD. OCD is characterized by intrusive thoughts (obsessions) that lead to repetitive

behaviors (compulsions).

Nonradiotherapeutic treatment

The combination of pharmacotherapy (i.e. selective serotonin reuptake inhibitors) and

behavior therapy is the treatment of choice for patients with mood disorders and OCD. Surgical

management and deep brain stimulation are used for extreme and severe cases.

Radiotherapy

37

Patient selection for the use of SRS to treat psychiatric disorders is complex. Friehs et al.

recommends that such patients must be enrolled on an institutional protocol after carefully being

evaluated by a multidisciplinary team 140. Similar strict criteria were used by Kondziolka et al.

141.

The treatment of OCD involves targeting the bilateral anterior capsules to a total dose of

120-140 Gy (Figure 5). Kondziolka et al. delivered a maximum dose of 140 or 150 Gy to the

anterior limb of the internal capsule in 3 patients 141. At a minimum follow-up of 28 months, all

patients noted significant functional improvements with no treatment related complications. In a

pilot study by Lopes et al., 5 patients were treated with SRS to a maximum dose of 180 Gy to the

anterior limb of the internal capsule 142. At 3 years, 3 patients had a complete response to

treatment, and one patient had a partial response based on changes in scores on an OCD

assessment tool. Based on these findings, the group has opened a double-blind, randomized

controlled study on the use of SRS to treat refractory OCD 142.

Summary

SRS is a well-established, safe and effective treatment modality for TN. Its use in the

treatment of PD, epilepsy, and psychiatric disorders remains an active area of investigation with

limited data to support the widespread use of SRS in these situations. In particular, patients with

psychiatric disorders should only be treated with SRS as part of a strict institutional protocol.

Diseases of the Eye and Orbit

Ptyergium


Pterygium is a chronic fibrovascular and degenerative process that arises from the

conjunctival-corneal border that extends from the nasal corner of the eye to the cornea. Its name

38

(“pterygium”) refers to the shape of the tissue, which is wing-like. The exact prevalence of this

problem is unknown, but it is well established that the frequency is higher in tropical regions.

Most patients are asymptomatic and present for medical attention on the basis of cosmetic

concerns, but symptoms may include redness and irritation of the eye. Pterygium may impair

vision by producing an irregular astigmatism as it grows onto the cornea.

Surgery

Treatment is indicated when vision is threatened and less commonly to improve

cosmesis. The treatment of choice for pterygium is surgical excision with an adjunct to help

improve local control rates (i.e. sliding conjunctival flap; rotational conjunctival autograft; free

conjunctival or limbal autograft). Intraoperative or postoperative mitomycin C has also been

used to improve local control rates, though this leads to increased risk of scleral ulceration,

secondary glaucoma, iritis, and cataracts.

Radiotherapy

Local radiation therapy with Strontium-90 plays an important role as an adjunct to

surgery to prevent relapse. Outcomes with radiotherapy have been excellent at decreasing

relapse rates.

The first prospective, randomized study comparing postoperative radiation to observation

after surgery was performed by de Kaizer et al. 143. In this study, 19 pterygia were treated with

bare scleral excision with a recurrence rate of 68% at 4 months compared to no recurrences in

the 18 pterygia treated with postoperative fractionated irradiation (3 x 10 Gy, once a week).

Numerous retrospective studies have also demonstrated the efficacy of postoperative radiation in

preventing recurrence of pterygium, including large series of 1,300 pterygia by Van de Brenk et

39

al. 144 and 825 pterygia by Paryani et al. 145, both of which showed a low recurrence rate of 1.7%

using fractionated radiotherapy.

In 2004, a European randomized trial compared single-dose (as opposed to fractionated)

postoperative radiotherapy (25 Gy) compared to sham RT 146. Patients that received radiotherapy

had a local control rate of 93.2% compared to 33.3% in the placebo arm, indicating that single-

dose radiotherapy is effective. In another randomized study, Viani et al. compared low

fractionation dose (2 Gy in 10 fractions) to high fractionation dose (5 Gy in 7 fractions) beta

radiotherapy in the postoperative settings 147. Control rates were similar between the two groups

(93.8% vs. 92.3%) with a significantly lower incidence of poorer cosmesis, photophobia, eye

irritation and scleromalacia in the low fractionation dose arm.

Choroidal Hemangioma


Choroidal hemangiomas (CH) are rare vascsular tumors that arise from the choroid. CH

can be classified as circumscribed, which occur in older patients or diffuse, which are associated

with the Sturge-Weber Syndrome.148

Clinically, these lesions are often asymptomatic, but patients may present with a visual

disturbance by several mechanisms, including retinal detachment, macular edema, and retinal

pigment changes.149 Lesions are detected on fundoscopic exam. Further workup includes

ultrasonography, angiography with fluorescent dyes, and CT or MRI.

Surgery

Amongst the surgical treatment options available, choroidal hemangiomas that are not

near the central visual structures (macula and papilla) are often treated with photodynamic

therapy (PDT) with a low rate of complications.148 Other treatment modalities include laser

40

photocoagulation and transpupillary thermotherapy. In general, radiation therapy is preferred

over PDT for the treatment of diffuse CH, though several small studies have reported

encouraging results with the use of PDT.148

Radiation Therapy

RT is indicated to treat lesions near the macula and papilla and in cases that did not

respond to other therapeutic maneuvers. RT techniques to treat CH include conventional 3DRT,

proton beam therapy, and brachytherapy.

Typical dose prescriptions for 3DRT are 18-20 Gy for circumscribed CH and 30 Gy for

diffuse CH given in 1.8-2 Gy daily fractions. Schilling irradiated 36 circumscribed CH with 20

Gy in 10 fractions.150 Retinal reattachment occurred in 64% of the cases with improved vision in

50% and stable vision in 50%.

Fractionated proton radiotherapy doses range from 16.4-30 Gy in four fractions.151-153 In

the study by Zografos et al., all 54 cases experienced retinal reattachment and visual acuity was

improved in 70%.153 A recent study from Paris also demonstrated a 100% rate of retinal

reattachment and substantial improvement in visual acuity using proton beam therapy.154

Plaque brachytherapy using Cobalt-60, Iodine-125, or Ruthenium-106 has been used to

treat circumscribed lesions. Typical doses prescribed to the apex of the lesion range from 25-50

Gy. Each isotope has advantages and disadvantages depending on the physical properties (i.e.

energy, half-life), and there is no evidence to support the use of one over the other.

Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading causes of blindness in the

developed world.157 The development of AMD is dependent on age, with a prevalence of up to

35% in the eighth decade of life. External beam radiotherapy with photons or protons and

41

brachytherapy have been used in the past to treat macular degeneration. Overall, results of

radiotherapy in the management of this disease have been mixed. A Cochrane meta-analysis in

2010 analyzed 14 randomized trials utilizing RT as a treatment for AMD and concluded that the

review “does not provide convincing evidence that radiotherapy is an effective treatment for

neovascular AMD 158.” Given that there is no clear benefit or indication for RT, its use should be

limited for the treatment of AMD.

Graves Ophthalmopathy


Graves opthalmopathy (GO), also referred to as Graves orbitopathy or thyroid eye

disease, is an autoimmune disorder affecting the musculature of the orbits. The presence of

activated T-lymphocytes leads to an inflammatory reaction secondary to the release of cytokines.

It is estimated that up to 50% of patients with Graves disease will develop orbitopathy, but 10%

of patients are euthyroid and some are hypothyroid at presentation 1. Smoking is the greatest risk

factor for the development of GO, and also predicts for a poorer response to therapy 1.

A multidisciplinary team including an opthamologist, endocrinologist and radiation

oncologist should be involved in the evaluation of the patient with GO. Clinical features of

patients with GO include proptosis (measured by the Hertel exopthalmometer on physical exam),

photophobia, upper eyelid retraction, periorbital edema (due to the accumulation of collagen and

hyaluronin, which attract water), conjunctival erythema, and tearing, and visual impairment

(Figure 6A-B). Patients may complain of a “gritty” sensation in their eyes. Several

classification systems are available to document the extent of disease, though the one favored at

our institution is the SPECS Opthalmic Index (Table 6), which assigns a score of 1-3 on the basis

42

of 6 categories: Soft tissue involvement, Proptosis, Extraocular movements, Corneal

involvement, and Sight (visual acuity).

Imaging studies, such as CT or MRI will demonstrate abnormalities, including

enlargement of the extraocular muscles and fatty infiltration, in 70-80% of cases 1. The most

commonly involved muscles include the inferior and medial rectus muscles 159.

Management Overview

Treatment options for GO include glucocorticoids, orbital radiotherapy, and surgery

(orbital decompression, eye muscle surgery, eyelid surgery). Smokers should be encouraged to

quit. Prior to the initiation of treatment, the patient’s thyroid function should be normalized, as

this may help improve the GO 160. Radioiodine therapy, but not antithyroid drugs, may cause

worsening of GO . Once thyroid function is stabilized, the treatment of GO depends upon the

severity of the disease.

Medical Management (Glucocorticoids)

Glucocorticoids (GCs) are a mainstay of treatment for GO. Immediate treatment with

high dose steroids (IV or oral) is required for patients whose vision is threatened by optic

neuropathy.163 GCs may also be used to treat patients with moderate to severe active

ophthalmopathy.163

Surgery

In the event that GCs fail to improve optic neuropathy, urgent orbital decompression is

necessary . Another indication for urgent orbital decompression is exposure keratopathy not

relieved by local measures 164. In order to improve extraocular muscle function and cosmesis,

other procedures such as strabismus surgery and lid surgery may be performed. It is

recommended that the GO be inactive for at least 6 months before pursuing these procedures.164

43

Radiotherapy

Indications for RT in the management of GO have been outlined by Donaldson et al. and

include (Table 7): inducing clinical regression, improving functional deficits, improving

cosmesis, and avoiding side effects of other treatments 166.

RT is generally administered with 3DRT. Both orbits, including the entire length of the

extraocular muscles, are treated to a total dose of 20 Gy in 2 Gy fractions using opposed lateral

fields with the isocenter placed a few millimeters posterior to the lenses using a beam-split

technique (Figure 6C).

In a double-blind, placebo-controlled study, untreated euthyroid patients with GO were

randomized to oral steroids or 20 Gy orbital irradiation 167. Both groups experienced response

rates of 50%, with greater improvements in eye motility and fewer side effects in the radiation

arm 167. Two prospective studies have demonstrated a benefit of the combination of steroids and

radiation compared with single modality treatment .

For patients with progressive GO, retrospective data suggests that orbital RT is an

effective treatment modality. Marquez et al. reviewed the records of 197 patients treated at

Stanford, all of whom received 20-30 Gy to the bilateral retrobulbar region 170. Outcomes

assessed included SPECS score and patient satisfaction. There was a 96% overall response rate

and 98% patient satisfaction rate with the largest improvements in soft tissue findings (89%),

extraocular muscle dysfunction (85%), and corneal abnormalities (96%).

Reactive Lymphoid Hyperplasia/Orbital Pseudotumor

Background and Clinical Presentation

Disease of the lymphoid tissue in the orbit is rare, and may include orbital pseudotumor

( OP) or malignant lymphomas. OP is an inflammatory condition of unclear etiology that affects

44

the soft tissue of the orbits, most often unilaterally 159. Most patients present between the 5th and

6th decades of life 171.

Clinical features of OP include periorbital edema, retrobulbar pain, extraocular muscle

dysfunction, palpable mass and exophthalmos 159. Symptoms usually develop acutely. Imaging

with CT or MRI of the orbits should be obtained for further evaluation. Imaging findings

include enlarged extraocular muscles, optic nerve thickening, and infiltrates in the retrobulbar

adiopose tissue with enhancement after administration of iodinated contrast or gadolinium 159.

Biopsy should be obtained to establish the diagnosis, especially for lesions that are easily

accessible.

Medical Therapy

Corticosteroids are the treatment of choice for the majority of patients. Response rates

for optic neuropathy are as high as 92% with an overall response rate of 78% 159. However, only

33% of patients experience long-term control with a single course of steroids 172.

Surgery

Surgical excision may be used for easily accessible lesions. Relapses are common after

surgery.

Radiation Therapy

Indications for RT include recurrent lesions after surgery, steroid-refractory lesions, and

lesions not amenable to other treatments. The RT technique of choice is 3DRT.

A planning CT should be obtained and co-registered with the diagnostic MR or

diagnostic CT to delineate the target volume, when visible. Unilateral treatment is typically

performed with a single lateral field or with an anterior and lateral field, weighted more heavily

laterally. Bilateral orbital involvement is treated in a manner similar to GO. Occasionally,

45

superficial lesions may be treated with electrons. Typically, the prescription dose is 20 Gy

given in 10 fractions 159.

In a modern retrospective series from the University of Oklahoma, 20 orbits in 16

patients were treated with RT for OP 173. With a mean dose of 20 Gy in 10 fractions, 87.5% of

the patients experienced a response (clinical improvement and/or tapering of corticosteroid

dose). Corticosteroid use was stopped or reduced in 81% of the patients. No significant late

effects were reported.

Benign Diseases of Soft Tissue & Bones

General Overview of Inflammatory Conditions of Joints and Tendons

The role of radiation therapy in the treatment of benign inflammatory conditions

involving the joints and/or tendons is controversial. Osteoarthritis (OA), tendonitis, bursitis,

rotator’s cuff syndrome and tennis elbow are examples of inflammatory conditions for which

radiation therapy has been used in the past. These soft tissue syndromes may result from

repetitive activities that cause overuse or injury to the joint areas, incorrect posture, stress on the

soft tissues due to an abnormal or poor positioned joint or bone or other diseases, such as

autoimmune diseases or infection.

Although the cause of each disorder may be different, the clinical presentation and

general treatment plan are frequently similar. Symptoms include pain, swelling, or inflammation

in the tissues and structures around a joint, such as the tendons, ligaments, bursae, and muscles.

Treatment generally involves a combination of exercise, lifestyle modification, and analgesics. If

pain becomes debilitating, joint replacement surgery may be used to improve the quality of life.

46

In rare instances, low-dose radiation therapy (<10-15Gy) can be employed. The low dose

required to improve symptoms suggests the possible mechanism of action for radiation therapy

(Table 9).

Osteoarthritis

OA is the most common joint disorder. It presents with pain associated with cartilage

destruction, bone modification, and structural changes of capsule and synovia. Symptoms are

caused by reactive inflammation of joint surface and joint capsule lining (synovia). While in

many instances the cause of OA is unknown, age is a major risk factor. Other risk factors include

obesity, bone fracture or joint injury whether by an accident of overuse from work or sports, and

other medical conditions.

Nonradiotherapeutic treatment

Hunter, et al. provide a general overview of the diagnosis, investigation, and treatment of

OA.174 The treatment of early OA is intended to reduce the primary symptoms of joint pain and

stiffness with the goal of maintaining and improving the functional capacity of the affected

joint(s).175 Exercise, weight reduction, and joint braces, among other measures have shown some

success at unloading damaged joints and improving symptoms. For osteoarthritis of the hip and

knee, exercises that strengthen muscles and improve aerobic condition are most effective.178

Oral analgesics are the mainstay of treatment for OA. While acetaminophen is frequently

offered due to its relative safety and effectiveness, a non-steroidal anti-inflammatory drug

(NSAID) may be added or substituted.179 NSAIDs can be used in patients with symptomatic OA

of the hand, hip, or knee. The goal is to administer the lowest effective dose for the shortest

duration .The use of stronger analgesics, such as weak opioids and narcotic, may be considered

when other methods have been ineffective or if certain drugs are contraindicated.176 Glucosamine

47

and chondroitin sulfate are over-the-counter remedies that are frequently used to reduce pain, but

their efficacy has not been proven.180 Corticosteroids and other analgesics may be injected

directly into the joint; injections may temporarily reduce swelling and pain. Acupuncture and

other complementary and alternative treatment modalities have been used but their efficacy has

yet to be proven.181

Surgery is reserved for patients with severe OA and those who have not responded to

non-invasive therapies. Total or partial joint replacement is most commonly used for OA

involving the knee, hip and shoulder, and is considered when structural damage is visible on X-

rays. However, there are modern surgical procedures that can obviate or delay the need for joint

replacement, including osteotomies, joint resurfacing.182 Joint fusion or arthrodesis may be used

to treat arthritis of the spine, ankles, hands, and feet. Arthroscopy, or arthroscopic surgery, is a

minimally invasive surgical procedure that can be used to examine and treat the interior surface

of a damaged joint. Arthroscopic procedures can help relieve pain for a short time and allow the

joints to move better. While arthroscopy may delay the need for joint replacement surgery it

does not improve the arthritis itself.183

Radiotherapeutic Options

In non-surgical candidates, low-dose RT may be considered if pharmacotherapy has

failed. RT can lead to primary freedom from pain and secondary to improved joint function.184

Several single-institution studies have been published that report long-term pain relief and

functional gain in 50% to 75% of patients. In Germany, a pattern of care study investigated the

use of RT for the treatment of OA of the knee (gonarthrosis) from the years 2006 to

2008.185Almost 80% of institutions in Germany have used RT to treat OA in the two-year period

analyzed. Treatment of 4,544 patients was performed annually at 188 institutions. The median

48

total dose was 6 Gy (range 3-12 Gy), with a median single dose of 1 Gy (0.25-3 Gy). Long-term

clinical outcomes were available in 5,069 cases. The majority of patient experienced pain

reduction for at least 3 months but pain management for up to 12 months was reported. In 30%

of patients, a second course of RT was used for inadequate pain response or early pain

recurrence.185

As with arthroscopy, radiation may reduce pain and pain-related dysfunction, but it does

not improve the arthritis itself. Due to its efficacy and relative safety, RT may provide an

alternative to conventional conservative treatment for patients who are not surgical candidates.

Diseases of Connective Tissue and Skin

DesmoidTumors


Desmoid tumors (also called aggressive fibromatosis or deep musculoaponeurotic

fibromatosis) are benign tumors of connective tissue tumors that arise from muscle fascias,

aponeuroses, tendons, and scar tissue. They are slightly more predominant in females and tend to

occur during the third and fourth decades of life, although children and the elderly can be

affected. In the general population, desmoids are rare; the estimated incidence is 2–4 per million

per year. Genetic factors, trauma, and/or surgery predispose the development of desmoids. Most

desmoids arise sporadically, however, approximately 2% are associated with familial

adenomatous polyposis (FAP). Desmoid tumors affect between 10 to 20 percent of patients with

FAP. The development of desmoid tumors in patients with FAP is called Gardner's syndrome.

Tumors can develop anywhere in the body, but most commonly involve in the

trunk/extremity, abdominal wall, and intraabdominal sites, including the bowel and mesentery.

49

Approximately 30% of patients with desmoid tumors have a history of prior. Sporadic cases

commonly involve the extremities, the shoulder girdle, and the buttock.187 In patients with FAP,

intraabdominal desmoids predominate and tend to be associated with surgical sites and

anastomoses following colectomy.188 Desmoid tumors in women can occur during or after

pregnancy, and therefore may be associated with high estrogen states. Women who have been

pregnant are more likely to have abdominal desmoid tumors that develop within 10 years of the

last pregnancy.189

Although desmoids have no known potential for metastasis or dedifferentiation, they are

locally aggressive and commonly have a high rate of recurrence even after complete resection.

Diagnostics work-up with MRI helps to estimate size and infiltration into other organs and

should be obtained prior to incisional biopsy that is obtained to confirm diagnosis.


Observation is a viable option for stable, asymptomatic desmoids. Treatment is indicated

for symptomatic patients, if there is risk to adjacent structures, or to improve cosmesis. Complete

resection of the tumor with negative microscopic margins is the treatment of choice for most

desmoid tumors. Due to the size and infiltrative nature of extraabdominal desmoids, resection

may require skin grafting or flap reconstruction. Desmoid tumors have a high rate of recurrence

following even complete surgical removal, and the contribution of incomplete resection to local

recurrence rates is unclear.190 Furthermore, resection does not appear to affect survival, which is

not surprising in view of the histologically benign nature of desmoids. Given these issues, the

overall surgical strategy should be an attempt at complete removal using function-preserving

surgical approaches to minimize major morbidity (functional and/or cosmetic).191

50

While extra-abdominal desmoid tumors can generally be treated effectively with local

therapy, surgical intervention tends to be counterproductive in intraabdominal variants,

especially the ones associated with FAP. In some instances, systemic therapy may achieve

significant and durable cytoreduction, obviating the need for resection. Patients with desmoid

tumors have been treated with non-steroidal anti-inflammatory drugs (NSAIDs). The most

widely used NSAID for treatment of desmoid tumors is sulindac. Hormonal agents such as

tamoxifen, raloxifene and progesterone have been used, often in combination with NSAIDs.

Tamoxifen has been used most widely and is typically prescribed at doses similar to those used

for breast cancer (10mg daily). Much higher doses (120mg daily) have been recommended,192

but high-dose tamoxifen is difficult to tolerate and there is no evidence to suggest that higher

doses of tamoxifen are better than lower doses.

A variety of palliative chemotherapeutic regimens have been used.193-196 With the waxing

and waning natural history of desmoids, it is difficult to say whether systemic therapy provides

much benefit over observation. In one series, 142 patients presented with either a primary (n =

74) or recurrent (n = 68) desmoid tumor. Eighty-three patients were treated with observation

along, and 59 received either hormone therapy or chemotherapy. There was no statistically

significant difference in progression-free between the two groups.

Desmoid tumors also respond to the tyrosine kinase inhibitor imatinib. The response is

thought to be due to expression of one of Gleevec’s molecular targets, PDGF receptor, on

desmoid tumors.199 In a phase II clinical trial to assess the efficacy of imatinib (400 mg/day for 1

year) in the treatment of progressive and recurrent aggressive fibromatosis, the 2-year

progression-free and overall survival rates after the use of imatinib were 55% and 95%,

respectively.198

51

Intralesional injections200 and radiofrequency ablation201 have also been used. Although

the techniques led to some tumor shrinkage, the experience to date is limited and the long-term

results are not yet known.


Radiation therapy is a viable option for inoperable patients and may also be used in

combination with surgery or chemotherapy. Spear, et al. retrospectively compared the efficacy

of surgery alone, radiation alone and combined modality therapy (radiation and surgery) in the

treatment of desmoid tumors.202 Five-year local control rates among surgery, radiation therapy,

and combined modality groups were 69%, 93%, and 72%, respectively. The study

recommended radiation doses of 60 to 65 Gy for inoperable or recurrent desmoids. However,

long-term results at another institution show increased post-treatment toxicity in patients who

receive RT doses greater than 56 Gy.

Young age (≤ 30-years) was also associated with increased late toxicity. In a

retrospective study of 30 patients under the age of 30, younger age (<18) is associated with

inferior local-regional control following RT. Although actuarial control rates were better with

RT doses of ≥ 55 Gy almost 50% of patients experienced grade 3-4 complications, including

pathologic fractures, impaired range of motion, pain, and in-field skin cancers.204 Since long-term

results suggest that unresectable tumors respond to 56 Gy with a 75% expectation of local

control, the lower dose may be more appropriate.

When an R0 resection is not possible, doses of 50 Gy postoperatively should be given to

improve local control. RT is often not considered for intraabdominal tumors because of the dose

and increased field size required increase risk of bowel injury. Due to the complexities involved

in managing the disease, a multidisciplinary approach must be taken.205

52

Peyronie’s Disease


Peyronie's Disease (also known as "Induratio penis plastica" is a chronic inflammatory

connective tissue disorder involving the penile tunica albuginea that results in tissue proliferation

and the development of hard plaques, most commonly on the dorsal surface of the penis, which

may cause a curvature and changes in the length or circumference of the penis while erect.

Symptoms may lead to difficult intercourse, penile pain, and erectile dysfunction.

Peyronie’s disease affects up to 10% of men, although a recent population based study

suggests the condition may be underreported in the United States.206 While peyronie’s can affect

teenagers, peak incidence of Peyronie’s is between 40 to 60 years of age. The cause is unknown,

but diabetes mellitus and arterial and venous vascular disease are risk factors, along with an

assumed genetic predisposition. The disorder results in pain, abnormal curvature, erectile

dysfunction, indentation, loss of girth and shortening. Slow progression over several months is

typical, but spontaneous remission may occasionally occur.


Results of non-surgical treatment of peyronie’s diease are mixed and are controversial.

Some success has been reported with Vitamin E supplementation, but results have not been

confirmed in larger studies.209 A combination of Vitamin E and colchicine may delay disease

progression.210 Other agents that specifically target inflammatory pathways have also shown

mixed benefit, including, TGFβ1 inhibitors,211 Coenzyme Q10,212 and sildenafil, among others.213

Topical therapies have largely been ineffective, but penile injection with Verapamil or

53

collagenase, intended to break up scar tissue formed by the inflammation, have shown some

efficacy.214 Physical therapy and extracorporeal shock treatments have also had limited benefit.

Surgical options for Peyronie's disease are complex procedures that should only be

performed by experienced urologists, and are reserved for patients not responding to other

therapies.215 Although the non-surgical treatments discussed may not reliably treat the disease,

they can be used to stabilize the scarring process and may result in some reduction of deformity.

A combination of non-surgical techniques may have even more efficacy.216


The largest experience with the use of RT in the treatment of peyronie’s disease has been

in Europe. Retrospective studies symptom improvement with the use of RT. Although some

studies suggested improvement in curvature,217 the majority of studies suggest that radiation

therapy primarily provides relief of pain associated with peyronie’s disease. These data suggest

that the benefit of RT might best be in the treatment of early stages of disease, when radio-

responsive inflammatory cells and fibroblasts are still active in the disease. There may be little

improvement in penile contracture once the plaques have fully formed.

As with radiation therapy for other rare benign conditions, the treatment regimens for

peyronie’s disease vary among institutions.17 A survey of European practices show that most

practices give a total dose of approximately 20Gy (3-30Gy) in 2Gy fractions (range 0.5-8) Gy.

Most of the institutions used electrons (n = 44), however, orthovoltage was still used at a number

of practices (n = 32). One retrospective study from the Netherlands indicated that low dose RT,

either 13.5 Gy (9 x 1.5 Gy, 3 fractions per week) or 12 Gy (6 x 2 Gy, daily fractions) resulted in

54

pain relief in the majority of the 179 patients evaluated.217 Sexual dysfunction was a reported

side effect, although this is confounded by the underlying disease.

As experimental model improve our understanding of the pathogenesis of the peyronie’s

disease, the use of radiation therapy may further decline, as concern regarding radiation

induction of fibrosis surface and new more effective therapies to emerge.

Dupuytren’s Contracture


Dupuytren’s contracture, also known as Morbus Dupuytren (MD) and Morbus

Ledderhose (ML) depending on involvement of the hands or feet, respectively, is a connective

tissue disorders that affects the palmar or plantar fascia. Incidence increases after the age of 40

and the condition affects men more often than women. While there is a familial disposition,

alcohol abuse, diabetes mellitus, epilepsy, and other conditions, are associated. Initially, there is

an inflammatory proliferative phase with fibroblast activity.

In the early stage, subcutaneous nodules appear, which may be fixed to the overlying

skin. As the disease progresses, cords develop and become visibly predominant. With further

progression, the cords reach the periosteum of the bones and lead to the characteristic appearance

of palmar or plantar contraction. The fourth/fifth phalanges of the hand (MD) or the first/second

toes of the foot (ML) are most commonly affected digits (Fig. 14). With increased thickening of

the fascia and progressive contracture, the fingers and toes begin to curl, resulting in impaired

function. Flexion contractures in the metacarpal or proximal interphalangeal joints lead to

difficulty grabbing (MD) or walking (ML).

55


Excision of diseased cords and fascia via limited or selective fasciectomy is widely

considered the gold standard treatment for Dupuytren’s contracture. A 20-year review of open

surgery for Dupuytren's contracture showed that major complications occurred in 15.7% of cases

and wound complications were seen in 22% of cases.222 Even with excellent surgical resection,

relapse is common, with 30% to 50% recurrence rate at 3 years.

Modern minimally-invasive techniques have substantially reduced the complication rates.

Percutaneous needle fasciotomy is a technique where cords are weakened through the insertion

and manipulation of a small 25 Gauge needle mounted on a 10 ml syringe.223 The procedure is

performed under local anesthesia and patients may return to full usage of the affected limb

within 24 hours. Since the cords and nodules are not fully excised, minimally invasive surgery

has an even higher recurrence rate that surgical excision. A randomized study comparing

percutaneous needle fasciotomy with limited fasciectomy showed a85% recurrence rate after 5

years with the minimally invasive procedure.224

During the early stage of Dupuytren’s, medication (steroids, allopurinol, nonsteroidals

vitamin E) may provide benefit, but the effects are temporary. Injectable collagenase extracted

from Clostridium histolyticum has been approved for the treatment of Dupuytren's contracture.

Injection of small amounts of the enzyme collegenase weaken cords by breaking the peptide

bonds in collagen.225 Treatments should only be applied by an experienced provider, as the

amount of enzyme injected varies depending on the affected joint and also has a very high

recurrence rate.

56


Several clinical trials support the concept of prophylactic radiation therapy in the

treatment of Dupuytren’s contracture.228-231 Radiotherapy is effective for prevention of disease

progression in early stages of disease when only small lumps or cords are present and only

moderate extension deficits (≤10 degrees) are present. Treatment can be administered with either

electrons or orthovoltage radiation and a variety of dose levels have been used. Since the target

cells are proliferating and radiosensitive fibroblasts and inflammatory cells, low dose radiation

therapy can be applied.

In a recent prospective trial involving 129 patients, two different dose regimens were

compared for safety and efficacy. In group A, 63 patients received 10×3 Gy (30 Gy) via a split

course (5×3 Gy) separated by 8 weeks; in Group B, 66 patients were treated with 7×3 Gy (21

Gy) delivered over 2 weeks. There was no difference in treatment outcome between the two

groups. Regardless of dose regimen, approximately 90% of patients had stable or improved

disease. Overall and mean number of nodules, cords, and skin changes decreased at 3 and 12

months. There was an 8%treatment failure rate at 1 year. Acute toxicity was more pronounced in

group B, but long-term toxicity was comparable and included dryness, desquamation, skin

atrophy, and altered sensation. Although long-term results of this study are pending, prior

retrospective data indicated that prophylactic RT is well tolerated by patients and is effective at

prevents disease progression. Irrespective of dose regimen, appropriate immobilization and

shielding of unaffected joints is required (Fig 8).

57

Keloids and Hypertrophic Scars


Keloids are an excessive tissue proliferation about scars after skin injury from surgery,

heat, chemical burns, inflammation (e.g., acne), or even spontaneous proliferation. They differ

from hypertrophic scars by their typical infiltrative growth pattern, causing local pain and

inflammatory reactions, and sometimes long-term progression; hypertrophic scars show

thickening without surrounding reaction and can flatten spontaneously. Keloids appear mostly in

the upper body and in regions with high skin tension (e.g., sternum, earlobes). The cause is still

unknown, although there is a genetic and race-specific predisposition that is already noted during

adolescence. Keloids at the earlobe after piercing are typical. In some patients the resulting

lesions are severely disfiguring and painful (Fig. 9). Recurrence is common after treatment


Silicone bandages, pressure dressings, and cryosurgery have all been used to treat for

keloids with varying efficacy.232-234 Intralesional injections remain the first-line therapy for most

keloids. Corticosteroids, 5FU, and verapamil have all been directly injected into keloid lesions

with symptom improvement. Up to 70% of patients respond to intralesional corticosteroid

injection with flattening of keloids, although the recurrence rate is high in some studies (up to 50

percent at five years).235

Surgical excision may be indicated if injection therapy alone does not result in

improvement. In patients treated with excision alone, recurrence rates range from 45-100%,236

therefore excision is typically combined with peri-operative postoperative injections of either

triamcinolone or interferon.235

58


Radiotherapy should be considered in cases of repeat recurrences postoperatively or

where there is a high-risk of recurrence (e.g., marginal resection, large lesion, unfavorable

location). Primary RT can be considered in instances where resection would result in functional

impairment and in actively proliferating disorders within about 6 months after the triggering

trauma. Because proliferating fibroblasts and mesenchymal and inflammatory cells are the target

cells for RT, fully matured keloids have minimal response to RT alone. Prophylactic RT

immediately following excision is most effective and reduces the risk of recurrence to 20% to

25% in most series.

RT is initiated 24 hours after surgery. The target volume is limited to the scar plus a 1-cm

margin; lead shielding can be constructed to protect normal tissue. An analysis of multicenter

data on the use of post-operative RT for earlobe keloids show that higher dose per fraction and

use of deeper penetrating electrons is preferable to standard 2 Gy fractionation schemes or use of

brachytherapy techniques that have rapid dose fall off.237 Radiation dose is typically 12 to 20 Gy,

delivered in 3 or 4 fractions within 1 week.238 Single-fraction RT with 7.5 to 10 Gy is also

effective.239 Clinical end points are long-term control, low relapse rate, and good cosmesis.

Diseases of Bone

Gorham-Stout Syndrome

Gorham-Stout Syndrome, also known as disappearing bone disease or essential

osteolysis, is a rare bone disorder of unknown etiology. It is characterized by painless bone

destruction due to progressive proliferation of small blood or lymph vessels. There may also be

59

significant osteoclast activation. The symptoms are nonspecific, but include muscular weakness,

limb tenderness, and pathologic fracture occurring minimal trauma. Involvement of the cervical

spine or skull base could be fatal. Case reports indicate limited efficacy of systemic therapies

such as zoledronic acid and interferon-alpha. Radiation therapy has also been used. Heyd, et al.

completed a national patterns-of-care study and literature review that summarizes the scant data

available for this rare disorder.244 The 38 articles listed therein provide evidence from treatment

of 44 patients that conventionally fractionated external beam RT (total dose of 36 to 45 Gy) may

prevent disease progression in 77% to 80% of cases.

Pigmented villonodularsynovitis

Pigmented villonodular synovitis or tenosynovial giant cell tumor is a rare proliferative

disorder of synovial tissue. Symptoms include sudden onset, unexplained joint swelling and pain

that frequentlyinvolves a single joint. The knee and foot are most commonly affected, but there

are reports of shoulder, hand, and hip involvement.245 Decreased motion, joint stiffness, and

increased pain occur as the disorder progresses. Surgical resection with either synovectomy or

joint replacement is the treatment of choice.

Radiation therapy is indicated in cases of diffuse disease, bulky disease resulting in bone

destruction, or in the rare instance of multiple recurrences after resection. Although intra-

synovial injection of radioactive isotopes post-operatively has been used in the past for high-risk

patients,248 most institutions use external beam radiation therapy. RT to a dose of 35 to 50 Gy

has been effective. MRI is essential for delineating disease pre- and post-operatively. Final dose

of RT should be tailored to amount of residual disease.251

60

Vertebral Hemangiomas

Hemangiomas are benign proliferations of blood vessels that can affect any tissue and are

typically asymptomatic. About 50% of hemangiomas involving the vertebral body are associated

with pain and therefore may require treatment. Treatment options include surgical resection or

more conservative interventions such as vetebroplasty or intralesional injections.252 Radiation

therapy either alone or post-operatively has been successful in reducing pain caused by vertebral

hemangiomas.253 In this study, a total of 84 patients with 96 symptomatic lesions were irradiated

for a symptomatic vertebral hemangioma. At a median 68 months follow-up, 90% of patients had

either complete or partial pain relief. Radiation doses ≥34 Gy resulted in significantly improved

pain relief. A total radiation dose of 36-40 Gy delivered in 2 Gy per fraction has been

recommended.254

Heterotopic Ossification


Heterotopic ossification (HO) is a common complication of total hip arthroplasty, hip

trauma, or acetabular fracture. HO occurs when the soft tissues around the hip become ossified.

Following trauma, primitive mesenchymal cells in the surrounding soft tissues are transformed

into osteoblastic tissue that then forms mature bone. The hip is the most common joint affected;

HO typically occurs around the femoral neck and adjacent to the greater trochanter. The risk

factors for development of HO are unknown, but the incidence is greater in men and occurs in

more than 80% in patients who have a history of ipsilateral or contralateral HO. It is also more

common in patients with a known history of osteoarthritis, ankylosing spondylitis, diffuse and

61

Paget’s disease.255 Hip stiffness is the primary symptom and the diagnosis is made

radiographically. Pain is typically not associated with HO.

62


The treatment for HO is surgical excision followed by some form of HO prophylaxis.

Prophylaxis is only applied to patients at high risk for developing HO. A meta-analysis showed

that NSAIDs are effective in reducing the risk of post-operative HO.256 Indomethacin is the most

commonly used NSAID for HO prophylaxis. Indomethacin is a prostaglandin synthase inhibitor

that also suppresses mesenchymal cells. The limited data available have not shown a clear

benefit to the use of selective cyclooxygenase-2 inhibitors in HO prophylaxis. Bisphosphonates

have been used for prophylaxis because they delay mineralization of osteoid and appear to have

some efficacy in preventing HO if used at the appropriate time. In one study, the cost of

bisophosphonate use was prohibitive for routine use when compared to indomethacin.259


63

External-beam radiation is an effective method for prevention of HO after total hip

arthroplasty. Prophylactic radiation therapy for the prevention of HO has been used sine the

1970s. A single fraction of 700 or 800 cGy to the at-risk region (Figure 17) is recommended and

should be delivered in the peri-operative period, either preoperatively (within 24 hours) or

postoperatively (within 72 hours).260-262 When comparing radiation therapy and NSAIDs, there is

no clear benefit for use of one modality over another. A prospective, randomized study

demonstrated that radiation therapy and indomethacin are both effective in the prevention of

postoperative HO.263 Although one meta-analysis of seven randomized studies concluded that

radiotherapy is more effective than NSAIDs for HO prophylaxis,264 a more recent analysis of 9

studies involving 1295 patients found no statistically significant difference between the two.265

An economic analysis using the same 9 studies and the meta-analysis suggest that radiation

therapy is not cost effective when compared to use of NSAIDs.266 This analysis has yet to be

validated.

64

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266. Vavken P, Dorotka R. Economic evaluation of NSAID and radiation to prevent heterotopic ossification after hip surgery. Arch Orthop Trauma Surg. Sep 2011;131(9):1309-1315.

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Table 1. The estimated absolute lifetime risk for malignancies after radiation therapy for benign diseases

Types Absolute lifetime riskSkin (basal cell carcinoma) 0.1% for 100-cm2 field

Osteosarcoma < 0.0001% for 1 Gyand a 100- cm2 Field

Leukemia 1% for 1 Gy TBI

Brain tumor 0.2% after 20 Gy for endocrine orbitopathy

Thyroid carcinoma 1% per Gy for children < 10 years

Breast Carcinoma 5% for one breast, 1 Gy, age < 35 (< 3% for age 35–45)

Lung carcinoma 1%. within 25 years after a mean lung dose of 1 Gy

Table 2: Simpson grading system for postoperative meningiomas with associated rates of recurrence.Simpson Grade Description Recurrence RateI Complete mascropic tumor

removal with adherent dura as well as the possibly affected part of the cranial calotte

8.9% (8/90 patients)

II Complete mascroscopic tumor removal with adherent dura via diathermia

15.8% (18/114 patients)

III Complete mascrospic tumor removal without adherent dura or possibly additional extradural parts

29.2% (7/24 patients)

IV Partial macroscopic tumor removal while leaving intradural tumor parts

39.2% (20/51 patients)

V Simple decompressive and bioptic removal of tumor

88.9% (8/9 patients)

*Adapted from Simpson23

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Table 3: Clinical outcomes of stereotactic radiosurgery or external beam radiotherapy (with or without surgery) for meningiomas in modern series.Study (year) Patient No. Radiation S+R/R Dose (median

or mean)Local Control (%)

Ganz et al. (2009) 37

97 SRS NA 12 Gy 100% (2 yrs)

Takanisha et al. (2009) 43

101 SRS 24%/76% 13.2 Gy 97% (1 yr)

Han et al. (2008) 38

98 SRS 36%/64% 12.7 Gy 90% (5 yrs)

Iway et al. (2008) 40

108 SRS NA 12 Gy 93% (5 yrs), 83% (10 yrs)

Kondziolka et al. (2008) 42

972 SRS 49%/51% 14 Gy 87% (10 yrs)

Davidson et al. (2007) 35

36 SRS 100%/0% 16 Gy 100% (5 yrs)95% (10 yrs)

Feigl et al. (2007) 36

214 SRS 43%/57% 13.6 Gy 86.3% (4 yrs)

Hasegawa et al. (2007) 39

115 SRS 57%/43% 13 Gy 87% (5 yrs)73% (10 yrs)

Kollova et al. (2007) 41

368 SRS 30%/70% 12.5 Gy 98% (5 yrs)

Zachenhofe et al. (2006) 44

36 SRS 70%/30% 17 Gy 94% (9 yrs)

Goldsmith et al. (1994) 28

117 EBRT 100%/0% 54 Gy 89% (5 yrs)77% (10 yrs)

Mendenhall et al. (2003) 29

101 EBRT 35%/65% 54 Gy 95% (5 yrs)92% (10 yrs)

Nutting et al. (1999) 31

82 EBRT 100%/0% 55-60 Gy 92% (5 yrs)83% (10 yrs)

Vendrely et al. (1999) 32

156 EBRT 51%/49% 50 Gy 79% (5 yrs)

*Adapted from Minniti et al.30 Abbreviations, S=surgery; R=radiation; SRS = stereotactic radiosurgery; EBRT = external beam radiotherapy

Table 4: Chandler staging system for Juvenile Nasopharyngeal Angiofibroma.Stage DescriptionI Confined to nasopharynxII Extension into nasal cavity and/or sphenoid

sinusIII Extension into ≥ 1 of the following: cheeks,

infratemporal fossa, pterygomaxillary fossa, ethmoid sinus, maxillary antrum

IV Intracranial extension

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*Adapted from Chandler et al.96 Please see references [97] and [98] for the Fisch and Radkowski staging, respectively.

Table 5: Clinical results of radiotherapy in Juvenile Nasopharyngeal AngiofibromaStudy No.

PatientsStudy Period

Dose (Gy) Local Control

Side Effects

Chakraborty et al. (2011) 99

9 2006-2009 30-46 87.5% (2 yrs)

No late toxicity

Mcafee et al. (2006) 101

22 1975-2003 30-36 90% (10 yrs) Cataracts (6), transient CNS syndrome (2), “in field” BCC (2)

Lee et al. (2002) 100

27 1960-2000 30-55 85% (5 yrs) 15% late toxicity (growth retardation, panhypopituitarism, TLN, cataracts)

Reddy et al. (2001) 102

15 1980-1991 30-35 85% (5 yrs) Cataracts (3), CNS syndrome (1), BCC (1)

Abbreviations: CNS=central nervous system; BCC=basal cell carcinoma; TLN=temporal lobe necrosis

Table 6: Flickinger’s predicted rates of in-field AVM obliteration based on the minimum dose within the target volume.

Minimum Dose to Target (Gy) Predicted AVM obliteration Rate (%)27 9925 9822 9520 9017 8016 7013 50

*Adapted from Flickinger et al., Figure 2.112

Table 7: SPECS classification system for Graves’ ophthalmopathy.Clinical Feature Grade 1 (1 point) Grade 2 (2 points) Grade 3 (3 points)S (soft tissue involvement)

Minimal objective symptoms: redness, chemosis, slight periorbital edema

Moderate objective symptoms: redness, chemosis; moderate periorbital edema

Severe objective symptoms: conjunctival exposition, prominent periorbital edema

P (proptosis) >20-23 mm 24-27 mm >27 mmE (eye muscle Rare diplopia; none in Frequent diplopia; Severe constant

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dysfunction) parimary position moderate mobility impairment

muscular dysfunction

C (corneal involvement)

Slight corneal changes and no symptoms

Prominent corneal changes and moderate symptoms

Keratitis or other severe eye symptoms

S (sight loss) 20/25 – 20/40 20/45 – 20/100 >20/100

Table 8: Clinical guidelines for use of radiotherapy in Graves’ ophthalmopathy (GO)Radiotherapy Goal Precondition/Indications ContraindicationsInduce clinical regression Pretherapeutic diagnostics:

evidence of autoimmune thyroid disease; CT/MRI

Stable GO without clinical progression

Reduce/eliminate functional deficits

Ophthalmologic diagnostics: documented progressive disease

Lack of euthyrosis

Improve cosmetics/esthetics Subjective/objective findings: evidence of functional deficits and disorders

“Cosmetic” indication alone without functional impairment

Avoid/decrease undesired effects of other measures

Exclusion of risk factors: no other eye disease (i.e. diabetic retinopathy)

No consent to planned therapy

*Adapted from Donaldson et al.166

Table 9. Radiation therapy mechanism of action dose concepts

Mechanisms of Action Single Dose (Gy) Total Dose (Gy)

Cellular gene and protein expression (e.g., eczemas) <2.0 <2

Inhibition of inflammation in lymphocytes (e.g., in

pseudotumororbitae)

0.3–1.0 2–6

Inhibition of fibroblast proliferation (e.g., in keloids) 1.5–3.0 8–12

Inhibition of proliferation in benign tumors (e.g., in

desmoids)

1.8–3,0 45–60

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FIGURE LEGENDS

Figure 1: Radiosurgery treatment plan of a patient with a right optic nerve sheath meningioma treated to a dose of 24 Gy in 3 fractions. The lesion is intensely enhancing on the post-contrast stereotactic MRI sequences. Panel 1 demonstrates the dose-volume histogram for the patient. The maximum dose to the ipsilateral optic nerve was 22.3 Gy. Panels 2-4 demonstrate the isodose curves for the treatment in the axial, sagittal and coronal planes. The 100% (24 Gy) isodose line is green, the 88% (21 Gy) isodoseline is in orange and the 50% (12 Gy) isodose line is blue.

Figure 2: A-B) A recurrent non-functioning pituitary adenoma seven years after surgical resection in the axial (A) and coronal (B) planes. The yellow arrows denote invasion into the left cavernous sinus. C-E) Rapid arc intensity-modulated radiotherapy treatment plan for the same patient in the axial (C), coronal (D) and sagittal (E) planes. The PTV (purple shaded area) was prescribed 50.4 Gy in 28 fractions.

Figure 3: Axial, coronal, and sagittal MRI images of a patient with multicystic (yellow arrows) craniopharyngioma prior to treatment.

Figure 4: A) Stereotactic radiosurgery plan for an AVM (red) in the dorsal pons treated with 22 Gy in 2 fractions. The prominent streak artifacts are present due to embolization one year prior to treatment. B) CT angiogram of the same patient used to assist in defining the AVM nidus (red contour).

Figure 5: Stereotactic MRI sequences (Panel 1) demonstrating the contoured anterior limbs of the internal capsule bilaterally and the corresponding treatment plan for the right internal capsule (Panel 2) for a patient with refractory obsessive-compulsive disorder. The right internal capsule was prescribed 70 Gy to the 50% isodose line (140 Gy maximum dose) in a single fraction.

Figure 6: A-B) 50-year old woman with Graves’ ophthalmopathy before (A) and after (B) treatment with corticosteroids and radiotherapy for prominent eyelid edema and strabismus. C) 3D-conformal radiotherapy treatment plan for a patient with Graves’ ophthalmopathy. The isocenter (yellow arrow) is placed a few mm posterior to the lenses (magenta), and the opposing fields are beam split anteriorly (white arrows). The extraocular muscles are contoured in red. The color wash display demonstrates that less than 10% of the dose reaches the lens.

Figure 7: Dupuytren’s contracture of both hands and the left foot [Use figure from previous version of chapter].

Figure 8: Immobilization for treatment of Dupuytren’s contracture with electrons.

Figure 9: A: Keloid behind left earlobe. B: Status of keloid following resection plus 4 × 4 Gy radiotherapy. [Use figures from previous version of chapter].

Figure 10: Typical treatment field for HO.

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