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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.
2
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
3
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
4
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
5
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,
6
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.
7
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.
8
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.
9
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
10
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
11
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.
12
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
Background and Clinical Aspects
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
13
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.
14
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
15
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
Background and Clinical Aspects
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
16
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.
17
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)
Background and Clinical Aspects
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.
18
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
19
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.
20
Chordoma
Background and Clinical Aspects
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
Background and Clinical Aspects
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)
Background and Clinical Aspects
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)
Background and Clinical Aspects
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)
Background and Clinical Aspects
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
Background and Clinical Aspects
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)
Background and Clinical Aspects
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
Background and Clinical Aspects
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
Background and Clinical Aspects
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.
Nonradiotherapeutic Treatment
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
Background and Clinical Aspects
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
Background and Clinical Aspects
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
Background and Clinical Aspects
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
Background and Clinical Aspects
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
Background and Clinical Aspects
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.
Nonradiotherapeutic Treatment
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.
Radiotherapeutic Options
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
Background and Clinical Aspects
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.
Nonradiotherapeutic Treatment
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
Radiotherapeutic Options
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
Background and Clinical Aspects
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
Nonradiotherapeutic Treatment
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
Radiotherapeutic Options
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
Background and Clinical Aspects
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
Nonradiotherapeutic 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
Radiotherapeutic Options
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
Background and Clinical Aspects
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
Nonradiotherapeutic Treatment
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
Radiotherapeutic Options
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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263. Kienapfel H, Koller M, Wust A, et al. Prevention of heterotopic bone formation after total hip arthroplasty: a prospective randomised study comparing postoperative radiation therapy with indomethacin medication. Arch Orthop Trauma Surg. 1999;119(5-6):296-302.
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264. Pakos EE, Ioannidis JP. Radiotherapy vs. nonsteroidal anti-inflammatory drugs for the prevention of heterotopic ossification after major hip procedures: a meta-analysis of randomized trials. Int J Radiat Oncol Biol Phys. Nov 1 2004;60(3):888-895.
265. Vavken P, Castellani L, Sculco TP. Prophylaxis of heterotopic ossification of the hip: systematic review and meta-analysis. Clin Orthop Relat Res. Dec 2009;467(12):3283-3289.
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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