Gamma Knife Radiosurgery - LGK Society€¦ · literature. Several thousand articles have now been published related to outcomes of Gamma Knife Radiosurgery (GKRS) since the first

1

Gamma Knife Radiosurgery:

A Review of Epidemiology and Practice

2014

2

Table of Contents

Introduction ............................................................... 4

Summary of Treatable Conditions ............................. 5

Vascular Abnormalities .............................................. 6AVMs ......................................................................................................6Cavernous Malformations .............................................................7Dural AV Fistulas (DAVFs)...............................................................8

Benign Tumors............................................................ 9Vestibular Schwannomas (Acoustic Neuroma) ...................9Meningiomas .................................................................................. 10Pituitary Adenomas ...................................................................... 10

Malignant Tumors .................................................... 12Brain Metastases ............................................................................ 12Glial Tumors ..................................................................................... 12Nasopharyngeal Carcinomas ................................................... 13

Functional Disorders ................................................ 14Movement Disorders ................................................................... 14Epilepsy .............................................................................................. 14Behavioral Disorders ..................................................................... 15Trigeminal Neuralgia .................................................................... 15

Tables ........................................................................ 17

References ................................................................ 20

3

Gamma Knife Radiosurgery:A Review of Epidemiology and Practice

Acknowledgement: This report represents an update and revision of the initial data compiled by Dr. Jeremy Ganz.

The authors are indebted for his pioneering work estimating the potential role of Gamma Knife surgery.

Author

Travis M. Hamilton, BS

Michigan State University,

College of Human Medicine,

Lansing, Michigan, U.S.A.

Author

Hideyuki Kano, M.D., Ph.D.

Department of Neurological Surgery,

University of Pittsburgh School of Medicine,

Pittsburgh, Pennsylvania, U.S.A.

Author

L. Dade Lunsford, M.D.

Department of Neurological Surgery,

University of Pittsburgh School of Medicine,

Pittsburgh, Pennsylvania, U.S.A.

4

Epidemiology of Conditions Treated Using Leksell Gamma Knife®

4

1. Epidemiological studies are set up to examine a given disease.

2. GKRS is appropriate for a subset of the total number of patients.

3. The indications for GKRS are increasing because of advances in imaging and the GKRS technology itself. In most societies,

structural brain issues such as tumors and vascular malformations are recognized at earlier stages because of the widespread

availability of MRI. However, earlier recognition does not always mean that GKRS or any other treatment option is required, since

indications vary related to volume, anatomic location, age of the patient, symptoms or signs present at the time of diagnosis,

and risks of more invasive options. The natural history of some tumors is such that in some patients no intervention is needed.

4. The incidence of disease in a given population may vary widely depending on the geographical area and the socioeco-

nomic status of that area.

The following are some of the factors studied by epidemiology: 1. The study of the course, or natural history, of diseases

2. To determine the frequency of diseases in populations

3. To identify the patterns of disease occurrence

4. To identify risk factors for and potential causes of disease

5. To evaluate the effectiveness of preventative and treatment measures

The following are considered in estimating the number of indications suitable for treatment with Gamma Knife Radiosurgery:1. The incidence of a relevant disease in a population. – How many new cases a year are suitable for GKRS?

2. The prevalence of a relevant disease. – What is the total number of cases in a given population?

The basis of this report

A reasonable estimation of the number of cases treatable by Gamma Knife are provided in the Summary Table on the following page. However,

in addition, tables reporting the average number of cases treated each year at certain high volume Gamma Knife centers is provided on pages

17-19, using data from centers in North America, Europe and Asia. Data from such high volume centers is dependent on the referral patterns to

those specific institutions and may not reflect the effect of the increasing number of GKRS units in these geographical areas.

IntroductionThe purpose of this report is to update information related to the multiple uses of Leksell Gamma Knife® based on data available in the published

literature. Several thousand articles have now been published related to outcomes of Gamma Knife Radiosurgery (GKRS) since the first Gamma

Knife system became operational in 1967. This report will not attempt to summarize that extensive literature but rather provide a broad overview

of the state of Gamma Knife use as of 2014.

Estimations of the role of GKRS are not always easy because:

5 5

Summary of Neurological Disorders Treatable with Leksell Gamma Knife

Treatable Indication Annual Incidence

(per million)

Prevalence

(per million population)

% Indicated for Gamma

Knife treatment

Annual Gamma

Knife cases (per million)

Benign Tumors

Meningioma 74.4975 (Wiemels, Wrensch &

Claus, 2010)50 36.7

Pituitary tumor 31.2757 (Gruppetta et al.,

2013)15 4.7

Vestibular Schwannoma 19 200 (Lin et al., 2005) 80 15.2

Craniopharyngioma 1.8 NA 20 0.36

Malignant Tumors

Metastases83 - 143

(Veldhuis et al., 2012) NA 90 74.7 - 128.7

Anaplastic Astrocytoma 3.7 NA 20 0.74

Glioblastoma 31.9 280 20 6.38

Nasopharyngeal Cancer7

(J. T. Lee & Ko, 2005)NA 10 0.7

Lymphoma 4.4 NA 10 0.44

Vascular Abnormalities

Arteriovenous Malformations

8.9 - 13.4 (Laakso & Hernesniemi, 2012)

180 (Bowden et al., 2014)

70 6.23 - 9.38

Cavernous Malformations4.3

(Smith & Scott, 2010)

1000-40,000 (.1% -4%) (Kondziolka, Monaco &

Lunsford, 2013)15 0.645

Dural AV Fistulas1.7

(Ghobrial et al., 2013)NA 50 0.85

Functional Disorders

Trigeminal Neuralgia126 - 289

(Reddy & Viswanathan, 2014; Zakrzewska & McMillan, 2011)

700 50 63 - 144.5

Tremor (Parkinson’s Disease)

120 - 146 (Caslake et al., 2013; Duncan et al.,

2014; Johnson, Diener, Kaltenboeck, Birnbaum, & Siderowf, 2013)

3,150 (Pringsheim et al., 2014)

15 18 - 21.9

Tremor (Essential Tremor)237

(Zesiewicz, Chari, Jahan, Miller & Sullivan, 2010)

3,000 – 4,000 (Zesiewicz et al., 2010)

50 118.5

Epilepsy450

(Ngugi et al., 2011)5,000-9,000

(Kaiboriboon et al., 2013)5 22.5

Behavioral Disorders160 - 2000

(Veldhuis et al., 2012),*

23,000 (“Behavioral Health US

report - 2012,”)2 3.2 - 40

Other /Rare Tumors

Chondrosarcoma 0.1

NA

10 .01

Chordoma

0.2 - .8 (“Behavioral Health US report -

2012,” ; “CBTRUS Statistical Report 2004-2008,” ; Chambers et al., 2014; Nguyen & Chang, 2008)

10 .02 - .08

Ependymoma 4.2 10 .42

Hemangioblastoma1.7 (“CBTRUS Statistical

Report 2004-2008,”)20 .34

Hemangioma 2.6 1 .026

Glomus Tumor 0.77 (Gandia-Gonzalez et al., 2014) 75 .58

Choroid Plexus Tumor 0.5 5 .025

Central Neurocytoma0.21 – 1.05 (Sharma, Deb,

Sharma & Sarkar, 2006)10 .021 - .105

Total 374-553

6

AVMsTo understand all the aspects of AVMs, it must be remembered

that a variety of specialties are involved in AVM management

and each may have some treatment bias based on their prior

education and experience. There are neurosurgeons, neurol-

ogists, pediatricians, radiologists, radiation oncologists, and

endovascular specialists who provide AVM care. A decision to

recommend treatment of an AVM is based on anatomic loca-

tion, symptoms, signs, and various angioarchitecture features

that provide a basis for deciding to treat versus continue obser-

vation.

Most centers believe that the annual risk of AVM hemorrhage

varies between 1 and 4% per year and that the annual mortality

risk for patients with an AVM is 1%. This data comes from

natural history data developed in Finland with a homogeneous

population. For patients who have had a bleeding event, the

risk of a rebleed in the first 6 months may be 10%, as described

by Pollock et al. from earlier data from the University of Pitts-

burgh. On the low end, a small volume AVM without prior

bleeding may have a risk of 1% per year. Some feel that deep

AVMs have a higher risk of bleeding, but this may be a selec-

tion bias issue caused by the fact that most deep AVMS are

discovered only after a hemorrhage. In contrast, lobar or more

superficial cortical AVMs may be discovered after a seizure or in

patients with headache.

The recently published ARUBA trial unfortunately provided a

confusing outcome because patients randomized to observa-

tion fared better at 3 years than patients who underwent some

form of intervention – most of which were embolization proce-

dures. Since each embolization may be associated with 10%

morbidity and 1% mortality, it is not surprising that no clinical

equipoise could be expected in this poorly designed clinical

trial. The broad consensus among those who provide care for

AVM patients remains that the ARUBA trial revealed no useful

information to assist in clinical decision making. In addition,

the trial may further confuse third party insurance payors, who

prefer to manage patients with the lowest cost initial treatment

(i.e., do nothing).

Today, almost all the risk assessments published are based

on the behavior of AVMs which have either bled or caused

epilepsy. An article by Laakso et al. has identified a range of inci-

dence rates of .89 to 1.34 per 100,000, which is consistent with

the published data available (ApSimon, Reef, Phadke, & Popovic,

2002; Brown, Wiebers, Torner, & O’Fallon, 1996; Hillman, 2001;

Laakso & Hernesniemi, 2012; Stangerup & Caye-Thomasen,

2012; Stapf et al., 2003).

A report from Linköping, Sweden takes advantage of Scandi-

navia’s stable population and excellent health care documen-

tation. This report was a prospective study of nearly 1,000,000

patients over a 10 year period. The importance of this study is

that it was prospective and nobody was lost to follow-up. From

the point of view of GKRS, the great majority of the patients

(84.5%) of the AVMs were Spetzler Grades 1 to 3. These are

the lesions suitable for GKRS. Current knowledge indicates that

approximately 10 cases per million AVMs are suitable for GKRS.

The problem with AVMs is their high mortality and morbidity if

untreated as mentioned above and documented by Lasko et al.

Today it is estimated that the risks of a treatment are consider-

ably lower than the risk of the untreated disease. Thus, for the

time being the tendency will continue to treat asymptomatic

lesions aggressively, especially in younger patients because of

the risks if a lesion were to rupture.

Vascular Abnormalities

7

Management today depends on who has the primary respon-

sibility for the patient. In general there is an urge to treat

symptomatic cases because of the acknowledged risks of the

untreated lesions. Clinicians who cannot themselves treat the

patient (neurologists, pediatricians) have in the past advocated

a conservative watch and wait policy for all patients. More

recently, such physicians are now convinced that symptomatic

lesions should be treated.

Some vascular neurosurgeons prefer craniotomy for lobar

smaller volume AVMS. However, data accumulated over the

past 30 years indicates that stereotactic radiosurgery (SRS) is

often the preferred treatment option based on obliteration

and complication rates. There will be cases where combination

treatments will be preferable. Interventionally trained endovas-

cular surgeons, neurologists, or radiologists may begin with

embolization as that is the technique at their disposal. However

increasing data suggests that AVM management decisions

should be made by multidisciplinary teams with all methods at

their disposal. Several publications now indicate that the results

of SRS are worse in patients who underwent initial emboliza-

tion. Newer methods of AVM embolization include the use of

liquid polymerization agents that significantly degrade MRI, CT,

and angiographic imaging of the residual AVM.

GKRS results are best (highest obliteration rates and lowest

complication rates) for smaller volume AVMs, typically less

than 10 cc in volume. Over recent years the volume of lesions

treated has been increased and gradually management criteria

are being established for these larger lesions (Kano, et al. JNS

Part 6). The results are not as good with larger AVMs since both

the obliteration rates are lower and the complication rates are

higher. For otherwise untreatable AVMS both dose staging

( treating the entire volume with more than one session ) or

volume staging (treating separate volumes with higher doses in

2 or more sessions) have been proposed. Results are related to

volume, dose, location, and perhaps patient age.

In conclusion, current evidence indicates that there are at least

8 to 14 patients per million per year who could be treated

with GKRS. In the US, approximately 10,000 new AVM patients

per year will be diagnosed. In pediatric age groups, the most

frequent reason for diagnosis is a brain hemorrhage. In adults

imaging may define an AVM during the course of an evaluation

for headache or new onset of a seizure. GKRS appropriate AVM

patients at busy referral centers may vary between 36 - 99 per

year (Table 1).

Cavernous MalformationsAfter the widespread availability of MRI was complete, an

important subclass of vascular malformations has been recog-

nized with increasing frequency. Previously called angiograph-

ically occult vascular malformations, cavernous malformations

(Cav mals, cavernomas, and cavernous angiomas) have been

diagnosed frequently both in sporadic form and in a geneti-

cally linked form. Selective gene changes have been found in

the familial variant. Many cavernous malformations are found

in conjunction with adjacent developmental anomalies (DVAs),

which represent aberrant but common venous drainage

patterns of normal brain. Some hypothesize that cavernous

malformations form because of obstruction outflow channels

of the DVA.

The annual risk of a cavernous malformation bleeding event

is approximately 0.5% per year in patients whose cavernous

malformation has been found incidentally on imaging and has

never bled. Most studies show that a new bleed rate increases

to 1-4% per year after an initial hemorrhage. A small group of

such patients have multiple bleeding events. After two or more

bleeds, the annual bleeding risk increases to as high as 33%

each year. For patients with subcortical lesions that are acces-

sible easily using image guidance, craniotomy and resection is

quite feasible especially if the patient has lesional associated

epilepsy. Most cavernous malformations are observed until

rebleeding events are confirmed. In patients with deep seated

lesions not located on a cortical, pial, or ependymal surface,

8

GKRS has been indicated. Treatment reduces the repeated

hemorrhage risk to less than 1% per year after the initial two

year latency interval after radiosurgery. GK radiosurgery is

performed with MRI localization and the target lies within the

hemosiderin rim defi ned by MRI. The total number of eligible

patients is unclear. At the University of Pittsburgh Medical

Center (UPMC) Gamma Knife facility, cavernous malformations

represent 1% of the clinical experience. Almost all patients have

had 2 or more bleeding events, which establishes the clinical

behavior as more aggressive in terms of rebleed risks.

Dural AV Fistulas (DAVFs)Patients with spontaneous development of dural arterio-

venous fi stulas, or those that develop after prior venous outfl ow

thrombosis, require intervention if the fistula is associated

with cortical venous drainage, intractable pulsatile tinnitus, or

severe ocular proptosis, pain and chemosis (in the case of a

DAVF of the cavernous sinus). Many such patients are treated in

conjunction with post radiosurgery DAVF embolization in order

to achieve both early clinical response (embolization) and main-

tenance of long term occlusion (radiosurgery). The incidence

of these vascular anomalizes is unclear. During a 27 year ex-

perience with DAVFs constituted less than 0.5% of the patients

treated at the UPMC Gamma Knife facility.

1

0%

Malignant Tumors

Benign Tumors

Vascular disorders

Func7onal disorders

Ocular disorders

354,535

295,563

96,802

59,951

3,054

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Indications treated worldwide 1968-2013

Vascular disorders – Accumulated number of patients treated worldwide

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Vascular disorders case mix 1968-2013

Leksell Gamma KnifeVascular disorders - Cumulative patients treated Worldwide

3.6 5.3 6.7 8.911.5

14.718.1

21.224.5

27.730.9

34.738.6

43.849.1

54.759.9

65.270.2

76.4

83.1

89.9

96.8

-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13

Thousands

268-100% sites reporting1991 reflects cumulative numbers


3.6 5.3 6.7 8.911.5

14.718.1

21.224.5

27.730.9

34.738.6

43.849.1

54.759.9

65.270.2

76.4

83.1

89.9

96.8

-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13

Thousands



3.6 5.3 6.7 8.911.5

14.718.1

21.224.5

27.730.9

34.738.6

43.849.1

54.759.9

65.270.2

76.4

83.1

89.9

96.8

-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13

Thousands


9

Vestibular Schwannomas (Acoustic Neuroma)Traditionally the incidence of vestibular schwannomas (VS) has

been thought to approximate 1 per 100,000 (Tos, 1992). During

the last 25 years these tumors are recognized more often,

when the tumor volume is smaller. The introduction of MRI has

permitted the diagnosis of such smaller volume tumors often

in patients with minor symptoms of disequilibrium or hearing

dysfunction. The number of tumors found incidentally has

suggested that the actual incidence may be higher, perhaps 20

per 100,000. However, in the view of Tos et al. there are inherent

errors in deriving epidemiology fi gures from post mortem and

temporal bone studies which indicate a very high prevalence.

This is attributed partly to case selection and partly to the

discovery of tumors that may not be clinically signifi cant.

A recent article published by Stangerup et al in 2012, summa-

rized the natural history and epidemiology of these tumors, and

suggested that the incidence of VS peaked in 2004 at an esti-

mate of 24 VS/million/year. Since then, there has been a slight

decrease and stabilization in the identification of new cases

found to be at a rate of 19 VS/million/year by the end of 2008.

The sudden increase since 1976 and stabilization of incidences

by 2008 has been attributed to the improvement of diagnostic

equipment, increased access to healthcare, and awareness of

the general population (Stangerup & Caye-Thomasen, 2012).

A review article by Schmidt et al. published in 2012 suggested that

estimates of the prevalence of incidental VS (as verifi ed by MRI in

non-symptomatic patients) is 0.02% of the general population.

The article compared the pre alence rates of two major articles

published in 2000 and 2005. The former study examined patients

with VS symptomology and proposed a prevalence of 0.07%,

a result signifi cantly higher than the accepted article in 2005.

The statistical diff erences are believed to be attributed to the

number and duration of MRI studies and inclusion/exclusion

criteria for VS symptoms (Lin, Hegarty, Fischbein, & Jackler,

2005; Schmidt et al., 2012).

Since approximately 75% of VS patients are treatable by GKRS

and using an incidence of 19 patients per million, we can esti-

mate that approximately 14.25 patients per million inhabitants

are candidates for Gamma Knife surgery. This suggests that

GKRS is appropriate for one patient per a 100,000 population.

Management of VS continues to generate some controversy.

One of the reasons for this is the improved surgical results

during the microsurgical era. Total tumor removal plus cranial

nerve preservation, without additional complications remains

an important goal. Publications from busy centers of excellence

suggest that the results of surgical removal have signifi cantly

improved over the last 20 years. During the last 25 years GKRS

also has become a frequently applied intervention, with more

than 100,000 patients worldwide who have undergone this

non-invasive treatment option. Since facial neuropathy has

been virtually eliminated and hearing preservation rates may

approximate 50-70% of patients after GKRS, the controversy

related to the use of radiosurgery has largely abated. Contro-

versy still exists about the timing of intervention and the relative

benefi t of early SRS for newly diagnosed patients vs. watchful

waiting. Tumor growth rates under observation are estimated

at 1-2 mm per year, although tumor volume doubling times

have been suggested as 2.3 years. Today the majority of vestib-

ular schwannomas that are discovered in higher economic

status countries are small and suitable for GKRS.

The recent literature has concentrated on hearing preserva-

tion. The ability to preserve hearing after treatment of a VS is

a development of the past 10 years and the results have greatly

improved. Today 50-70% of patients who undergo GKRS can

Benign Tumors

10

expect to maintain hearing at the pre-treatment level. There

is a gradual but growing interest for the planned treatment of

symptomatic larger tumors with subtotal resection followed by

GKRS instead of attempting to initially remove the whole tumor.

This is logical if facial nerve function is to be preserved. There

have also been a number of papers in recent years providing

evidence that the retreatment of VS by GKRS is safe and effec-

tive. In less wealthy countries where larger tumors are discov-

ered later in the disease course, the combined approach of

microsurgical debulking followed by GKRS is attractive option

that should be encouraged to reduce morbidity and improve

patient quality of life. At busy referral centers between 28 and

150 patients each year may be referred for GKRS (Table 2).

MeningiomasMeningioma is the most frequently reported histology in

reports on all primary brain and CNS tumors (between 13 and

25% of patients who are diagnosed with brain tumors). In the

largest compilation of data on primary brain and CNS tumors

in the United States, including 4 years of incidence data (2006

- 2010) from 50 collaborating cancer registries, it was reported

that the total incidence of both low grade and higher grade

meningiomas was 74.4 patients per million (Ostrom et al., 2013).

Anatomically located skull base meningiomas are often suitable

for GKRS because of the higher incidence of surgical compli-

cations after microsurgery for many skull base meningiomas.

Convexity or falcine meningiomas may be suitable for GKRS

as well, but most patients with symptomatic larger tumors

generally are considered for craniotomy and resection as

the first line option in patients eligible for general anesthesia

and resection. The ratio of non-basal to basal meningiomas

is 2.3/1. This would give an incidence based on the Central

Brain Tumor Registry of the United States (CBTRUS-2013) of

32/million per year where GKRS may be a first line manage-

ment option. In addition, treatable non-basal meningiomas

include residual or recurrent tumors after initial attempted

resection. Depending on patient age, presentation, and symp-

toms or signs, some patients with basal meningiomas warrant

observation until symptoms develop or repeat imaging

defines additional tumor growth. The total number of menin-

gioma patients for whom GKRS may be indicated varies from

33 - 88 per 1,000,000 per year (Table 3).

Pituitary AdenomasThe most recent publication investigating the epidemiology of

pituitary adenomas by Aflorei et al., summarized articles rele-

vant to the incidence rates and prevalence data since 2006.

Individual reports made in 2010 and 2013 suggest the inci-

dence to vary between 40 and 42.7/million. The prevalence of

pituitary tumors ranges from 68 – 94 per 100,000 during the

interval between 2006 and 2010 (Aflorei & Korbonits, 2014;

Daly et al., 2006; Fernandez, Karavitaki, & Wass, 2010; Fontana &

Gaillard, 2009; Gruppetta, Mercieca, & Vassallo, 2013; Raappana,

Koivukangas, Ebeling, & Pirila, 2010).

Prior autopsy studies have shown that up to 30% of normal

patients may have incidental pituitary lesions (including

adenomas, Rathkes cleft cysts, craniopharyngiomas). A report

from Finland gives a documented incidence of approximately

40 patients per million. To understand these tumors properly

they have to be considered as two types. Patients with larger

tumors that compress adjacent structures, such as the optic

chiasm or extend laterally into the cavernous sinus, usually

require initial surgery. Most such tumors are not endocrine

active, but may lead to gradual pituitary hormone loss as the

tumor damages normal gland function. Some pituitary tumors

are endocrine active, and produce an excess of a specific

hormone that may impact quality of and length of life if left

untreated. There are three most commonly recognized endo-

crine active pituitary tumors: prolactinomas (making excess

prolactin – PRL), growth hormone – GH secreting tumors that

lead to clinical acromegaly, and ACTH producing tumors that

lead to Cushing’s disease, a condition that reflects the excess

ACTH production leading to hypercortisolism caused by

excess steroid production by the adrenal glands. PRL affects

menstruation and fertility in women and potency in men.

A macroadenoma is a tumor that has a maximum diameter

12

Brain MetastasesGamma Knife Radiosurgery has been used in almost one

million patients worldwide and has sparked a revolution in the

management of cancer that has spread from a site in the body

to the brain. Non-small cell lung, breast, renal, and melanoma

represent the largest number of such cancers. While originally

applied to patients only with a single brain metastasis as an

alternative to craniotomy and removal (followed by whole

brain radiation therapy or WBRT), GKRS is now used for patients

with one or many brain metastases. Increasing evidence indi-

cates that control of brain disease is possible in more than 80%

of patients and that death from CNS progression has been

reduced to < 20% of patients who undergo GKRS for metastatic

brain cancer. The important issue for GKRS is the total volume

of all brain metastases to undergo treatment, not the number

of such metastases.

A number of figures from the literature are quoted but the most

reliable number seems to be the figure of 170,000 new cases

per year are diagnosed each year in the United States (esti-

mated by the RTOG). This gives an incidence of 550 per million

per year. In the US the estimated number of patients who are

diagnosed with brain metastases ranges between 120,000

and 300,000 new patients per year. An accurate estimate of

the incidence of brain metastases is unknown. However an

article published in 2012, reviewing both population-based and

autopsy studies, estimated the incidence of brain metastases

among cancer patients as 9.6%. This estimate was based on a

study by Barnholtz-Solan et al, who examined patients from

the Metropolitan Detroit Cancer Surveillance System (patients

with melanoma, breast, renal, or colorectal cancer from 1973

to 2001). Population-based studies conducted between 1935

and 2000 estimated an annual incidence of brain metastases

ranging from 8.3 to 14.3 per 100,000 population (Nayak, Lee, &

Wen, 2012).

Increasingly, GKRS has replaced both upfront craniotomy and

the reflex initial use of WBRT in patients with newly diagnosed

brain metastatic disease. Craniotomy and tumor removal is

normally considered now in patients with large tumors, usually

solitary, associated with symptomatic mass effect, especially in

patient with no known cancer diagnosis. WBRT is used upfront

in patients with miliary brain metastases or those who present

with imaging criteria of carcinomatous meningitis. Increasingly,

tumor bed GKRS has replaced WBRT in those patients who

have undergone craniotomy and tumor removal or debulking.

Appropriate GKRS patients with brain metastases vary between

115 and 325 a year (Table 6) at busy GKRS referral centers.

Glial TumorsData from the 2014 CBTRUS registry estimates that the annual

number of new cases of primary brain and CNS tumors across

49 included states and the District of Columbia will be 66,240

(22,810 malignant; 43,430 non-malignant). Thus, the incidence

rate of all primary benign and malignant brain tumors is 21.03

cases per 100,000 person-years (13.77 for benign and 7.27 for

malignant tumors). Annually, in the US approximately 15,000

new brain gliomas will be diagnosed, and over half of these are

malignant (anaplastic astrocytoma or glioblastoma).

According to 2012 data from CBTRUS, the prevalence rate for

all primary brain tumors (benign and malignant) is 221.8 per

100,000. It is estimated that more than 688,096 persons were

living with a diagnosis of primary brain tumor in the U.S. in

2010. The prevalence rate for primary malignant brain tumors

is 61.9 per 100,000 and for primary benign brain tumors is

177.3 per 100,000. Since glioblastomas (GBM) represent 45.2%

of malignant tumors, it can be estimated that the prevalence

of GBM is 28 per 100,000. It is estimated that in the year 2010

in the U.S. more than 138,054 and 550,042 persons were living

Malignant Tumors

14

Movement DisordersGamma Knife can be used to perform a VIM thalamotomy

primarily for tremor reduction in patients with essential tremor

or tremor predominant Parkinson’s disease (PD). Both multi-

center and single center experience has been reported using

modern localization techniques with MRI when feasible,

but also CT imaging when patients are not eligible for MRI.

Outcomes suggest that 70-80% of patients will have contra-

lateral tremor suppression with a single 4mm isocenter of

radiation (130-140Gy) delivered to the thalamic VIM nucleus.

Clinical benefit ensues in 6-12 months. Between 4-6% of

patients may have an larger than expected lesion detected

at follow-up imaging and may have associated neurolog-

ical symptoms or signs develop related to treatment effects

encroaching on the internal capsule laterally or sensory

thalamic nucleus (VPL ) posterior to the VIM nucleus. Intra-

operative physiological confirmation is not performed during

GK thalamotomy. In patients who have excellent benefit and no

new side effects, a contra lateral thalamotomy can be consid-

ered no sooner than 12 months after the initial procedure.

Studies published in the past two years investigating the

age-adjusted incidence of Parkinson’s disease in the English

and Scottish populations reported annual rates of 12 and 14.6

per 100,000 respectively. A 2003 US study on the economic

model and burden of PD reported an annual incidence rate of

13.3 per 100,000 per year (cited in 2013 article.) The Parkinson’s

Disease Foundation 2013 Fact Sheet suggests there are 60,000

new cases identified per year in America (20/100,000/yr).

Prevalence data was obtained from a recent study (2014) which

performed a systematic review and meta-analysis on 219

articles. 47 articles that obtained prevalence data based on a

two-stage identification procedure which identified individ-

uals with PD in the general population. The studies spanned

all major continents/geographical regions including Europe

(11 articles), Africa (5), Australia (4), South America (4), and

North America (2). The prevalence of PD in the general popu-

lation, stratifying individuals from age 40 – 80+ was estimated

to be 315 per 100,000 population (95% CI 113, 873 I2 94.5)

(Pringsheim, Jette, Frolkis, & Steeves, 2014).

Available patients with medically refractory tremor appropriate

for GKRS vary between 5 and 13 per year (Table 8).

EpilepsyGamma Knife Radiosurgery has been used in carefully

selected patients with mesial temporal lobe epilepsy as

an alternative to amygdalohippocampectomy performed

via craniotomy and microsurgical resection. The Radiosur-

gery or Surgery for Epilepsy (ROSE) clinical trial was initially

funded by NIH and will be completed under the auspices

of the North American Gamma knife Consortium (NAGKC).

Isolated case reports have described the use of GKRS for

other brain epileptic sites confirmed by appropriate neuro-

physiological studies. GKRS callosotomy has been reported

for use in patients with drop attack epilepsy. Most patients

undergoing GKRS for epilepsy are treated for seizure disor-

ders in the context of imaging defined lesions such as AVMs,

cavernous malformations, and lower grade glial neoplasms.

There are on average 9 patients each year who undergo

epilepsy GKRS at busy referral centers (Table 9). The selection

of options to manage patients with epilepsy requires multi-

disciplinary input. GKRS is used most often in patients whose

seizure disorder occurs in the context of a known brain mass

or vascular malformation. Radiosurgery for non-structural

related epilepsy is currently under evaluation at selected

GKRS sites.

Functional Disorders

15

There are several studies that review the epidemiology of

epilepsy as stratified by socioeconomic status, age, race and

geographic location. To gain a comprehensive understanding

for the incidence and prevalence in the general population, a

meta-analysis and systematic review of the epidemiology of

epilepsy was reviewed. In the review, 33 studies were used to

determine these statistics based on the level of development

of the country (high income vs. low income). The mean inci-

dence of epilepsy for both high and low income countries was

50.4 per 100,000 per year (High income = 45; Low income =

81.7) (Ngugi et al., 2011). Other studies have noted an annual

incidence rate between 15 and 71/100,000 in the United

States. Another epidemiological study published in 2013 by

Kaiboriboon et al estimated the prevalence of epilepsy to

be 5 – 9 per 1000 in the United States (Kaiboriboon, Bakaki,

Lhatoo, & Koroukian, 2013).

Behavioral DisordersBetween February 2001 and April 2003, over 9,000 English

speaking US adults from the US National Comorbidity Survey

Replication were interviewed to determine the epidemiology

of mental illness in the United States. Face to face interviews

based on the WHO World Mental Health survey version of

the Composite International Diagnostic Interview were used

to assess 19 specific DSM-IV diagnoses. The disorders exam-

ined includes: anxiety disorder (panic disorder, generalized

anxiety disorder, agoraphobia without panic disorder, specific

phobia, social phobia, post-traumatic stress disorder, obsessive

compulsive disorder, separation anxiety disorder), mood disor-

ders (major depressive disorder, dysthymia, bipolar disorder I

or II), impulse-control disorders (oppositional-defiant disorder,

conduct disorder, attention-deficit/hyperactivity disorder,

intermittent explosive disorder), and substance use disorders

(alcohol and drug abuse and dependence). It was estimated

that the 12-month prevalence of moderate to serious cases

represented 14% of the population. The current estimate for

all mental disorders in the general US population is 30% (for a

12-month DSM-IV disorder)(Kessler, Chiu, Demler, Merikangas, &

Walters, 2005).

In the US, Gamma Knife is considered as a treatment for severe

behavioral disorders such as treatment resistant obsessive

compulsive disorders (OCD) that have failed extensive trials of

both drug and behavioral therapies. Based on the limited data,

3 articles defining the annual incidence of obsessive compul-

sive disorder have been identified. The best estimate on the

incidence on OCD in the general population ranges from

.016% - .2% (Veldhuis et al., 2012). A prospective trial based on

the Zurich population of Switzerland estimated an unweighted

cumulative incidence of OCD to be 5.1% (Fineberg et al., 2013).

According to the Substance Abuse and Mental Health Report in

2012, the prevalence of Obsessive Compulsive Disorder in the

US was 2.3% of the general population (“Behavioral Health US

report - 2012”) GKRS can be part of the treatment options for

these refractory disorders at centers with experienced psychi-

atrists who agree that medical and behavioral options have

been exhausted.

Trigeminal NeuralgiaThe initial treatment of trigeminal neuralgia (TN) is medical with

agents such as carbamazepine, oxcarbazepine, or gabapentin.

These medications do not work in all patients or if they work

initially, the effect can diminish over time. For medically refrac-

tory patients or those intolerant of side effects of such medi-

cine, microvascular decompression (MVD) remains the current

‘gold standard’ surgical intervention for patients who eligible for

craniotomy. Percutaneous treatments using glycerol rhizotomy,

radiofrequency, or balloon assisted rhizotomy are alternative

strategies as well. GKRS has been shown to be reliable and safe

alternative in many published reports. Outcomes are best when

patients have not already failed prior surgical procedures. Pain

relief after GKRS typically occurs 2-4 weeks after the procedure.

A study from Italy suggested that the prevalence of TN was

100-200 per million. The incidence is 50-200 per million in

patients over age 60.

16

European population based studies in the UK and Netherlands

suggest that the annual detection rate is significantly higher

and ranges between 126 - 289 cases per million (Reddy &

Viswanathan, 2014; Zakrzewska & McMillan, 2011).

In a prospective UK study, a General Practice Linkage Scheme

with the National Hospital for Neurology and Neurosurgery

(NHNN) was used to ascertain all cases of neurological disorders

over an 18-month period in an unselected urban population of

100,230 patients registered, based on 13 general practices in

the London area. In three of these practices (27,657 persons),

lifetime prevalence was also assessed. Registration of patients

began in 1994; this report covers the period from January 1,

1995 to July 1, 1996. This survey does not include the small

number of patients who are in long-stay hospitals for severe

neurological problems. The age- and sex-adjusted incidence

rate of TN was reported as 8 per 100,000 per year. The lifetime

prevalence was reported as 0.7 per 1000 population. This is the

first large, prospective UK study measuring the burden of all

serious neurological conditions in the community in over 30

years. In another report the incidence of trigeminal neuralgia is

approximately 4 to 5 in 100,000.

A German, population-based study conducted in 2011 esti-

mated the lifetime prevalence of trigeminal neuralgia to be

.3% (10 of 3336; 95% CI [0.1% - 0.5%]). Another study focusing

on the Egyptian population (published in 2013) estimated an

age specifi c, life-time prevalence rate among subjects over 30

years of age was 29.5/100000 (95% CI 22.3 – 34.7) (n = 4/13285

persons) (El-Tallawy et al., 2013).

At busy LGK centers, approximately 25-87 patients with Trigem-

inal Neuralgia are treated annually (Table 10).

Indications treated worldwide 1968-2013

Functional disorders – Accumulated number of patients treated worldwide

1

Trigeminal Neuralgia 52.2

Epilepsy 2.9, 5%

Parkinson’s Disease 2.0, 3%

68-‐100% sites repor1ng

Other IndicaBons 3.0, 5%

Functional case mix 1968-2013

Leksell Gamma KnifeFunctional disorders - Cumulative patients treated Worldwide

0.2 0.2 0.3 0.5 1.0 1.8 3.14.9

7.09.3

12.014.8

18.1

22.3

26.5

30.7

34.4

38.7

42.2

46.0

50.1

54.7

60.0

-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13

Thousands



3.6 5.3 6.7 8.911.5

14.718.1

21.224.5

27.730.9

34.738.6

43.849.1

54.759.9

65.270.2

76.4

83.1

89.9

96.8

-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13

Thousands


1

0%

Malignant Tumors

Benign Tumors

Vascular disorders

Func7onal disorders

Ocular disorders

354,535

295,563

96,802

59,951

3,054

��"��


3.6 5.3 6.7 8.911.5

14.718.1

21.224.5

27.730.9

34.738.6

43.849.1

54.759.9

65.270.2

76.4

83.1

89.9

96.8

-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13

Thousands


17

Tables

Location Treatment Period Number of patients Number per year

Prague (Liscak et al., 2007) 1992 - 2000 330 41.25

Seoul (Han et al., 2008) 1997 - 2004 277 39.5

Pittsburgh (Kano et al., 2012) 1987 - 2014 1,130 52.4

Virginia (Ding, Yen, Xu, Starke & Sheehan, 2014) 1989 - 2012 1,450 63

New Dheli (Thapa et al., 2009) 2000 - 2008 790 98.8

Tokyo (Izawa et al., 2009) 1991 - 2002 396 36

Taipei (Luo et al., 2013) 2002 - 2011 523 58.1

Osaki (Jokura et al., 2009) 1991 - 2004 534 41.1

Table 1. AVM patients treated


Pittsburgh (Lunsford, Niranjan, Flickinger, Maitz & Kondziolka, 2005)

1987 – 2014 1,670 55.3

Taipei (Chung et al., 2010) 1993 - 2009 513 32.1

Prague (Liscak, Vladyka, Urgosik, Simonova& Vymazal, 2009)

1992 – 2001 351 39

Beijing (Sun & Liu, 2012) 1994 - 2001 200 28.6

Brussels (Delbrouck et al., 2011) 2000 - 2011 415 37.7

Tokyo (Hayashi et al., 2013) 2002 - 2011 260 28.8

Komaki (Hasegawa et al., 2013) 1991 - 2000 440 48.8

Seoul (Han et al., 2012) 1998 - 2009 739 67.2

Tohoku (Murakami, Jokura, Kawagishi, Watanabe & Tominaga, 2011)*

1994 - 2006 449 37.4

Minnesota (Jacob et al., 2014) 2007 - 2011 105 26.25

Marseille** 1994 - 2014 3,000 150

Table 2. Vestibular Schwannoma patients treated

* Includes Seiro-machi, Aoba-ku, Sendai and Miyagi Japan** Personal communication – publication pending

18


Prague (Kollova et al., 2007) 1992 - 2005 1,149 88.4

Sheffield (Malik, Rowe, Walton, Radatz & Kemeny, 2005)

1994 - 2000 309 51.5

Pittsburgh (Kondziolka et al., 2008) 18 Year period 972 54

Mayo (Pollock et al., 2012) 1990 - 2008 602 33.4

Tokyo (Monson, 2000) 2006 - 2008 163 81.5

Table 3. Meningioma patients treated

Tumor Type Treatment Period Number of patients

Non Functional 37.0 82%

Prolactinoma 51.0 75% of male patients

Acromegaly 8.5 78%

Cushing’s Disease 3.0 39%

Table 4. Incidence and distribution of Pituitary Adenoma types


Virginia (Xu, Lee Vance, Schlesinger & Sheehan, 2013)

1994 - 2006 469 39.1

Marmara (Pamir, Kilic, Belirgen, Abacioglu & Karabekiroglu, 2007)

1997 - 2004 360 51.4

Prague (Vladyka et al., 2000) 5 years 163 32.6

Mayo (Pollock, Link, Leavitt & Stafford, 2014) 2007 - 2012 163 32.6

Table 5. Pituitary Adenoma patients treated


Tilburg (Hanssens, Karlsson, Yeo, Chou & Beute, 2011)

2002 - 2009 835 119

Marmar (Serizawa et al., 2010) 1998 - 2009 1,918 174

Milan (Franzin et al., 2008) 2001 - 2005 680 170

Tokyo (Yamamoto et al., 2013) 1998 - 2011 2,553 196.4

Tokyo (Takakura et al., 2013) 1993 - 2011 3,095 171.9

New Haven (Nath et al., 2014) 2004 - 2010 690 115

Seoul (M. H. Lee, Kong, Seol, Nam & Lee, 2013) 2008 - 2009 258 129

Pittsburgh (Luther et al., 2013) 2002 - 2014 4,000 325

Table 6. Brain Metastases patients treated

19

Table 7. Glial Tumor patients treated


Marseille, Prague, Graz (Regis et al., 2004) 1996 - 2000 21 5.3

Table 9. Epilepsy patients treated

Table 10. Trigeminal Neuralgia patients treated

Table 8. Movement Disorders patients treated


Cleveland (Einstein et al., 2012) 2002 - 2007 35 (GBM) 7

Tokyo (Tamura et al., 2010) 2000 - 2006 8 (grade3), 24 (GBM) 5.3

Seoul (Kong et al., 2008) 2000 - 2006 49 (grade3), 65 (GBM) 18.2

Virginia (Dodoo et al., 2014) 2001 - 2007 20 (grade3), 35 (GBM) 9.2

Pittsburgh (submitted) 1987 - 2008 297 (GBM) 14.1


Pittsburgh (Kooshkabadi, Lunsford, Tonetti, Flickinger & Kondziolka, 2013)

1996 - 2011 86 5.7

Kuala Lumpur (Lim et al., 2010) 2006 - 2008 18 9

Seattle (R. F. Young, Li, Vermeulen & Meier, 2010) 1994 - 2007 172 13.2


Chengdu (Li, Wang, Liu, Zhong & Mao, 2012) 2005 - 2010 129 25.8

Marseille (Regis et al., 2009) 1992 - 2005 334 25.7

Pittsburgh (Kondziolka et al., 2010) 1992 - 2014 1,100 50

Winston-Salem (Lucas et al., 2014) 1999 - 2008 777 86.3

Lexington (B. Young, Shivazad, Kryscio, St Clair & Bush, 2013)

1996 - 2009 315 24.2

Marseille (Tuleasca et al., 2012) 1992 - 2010 737 41

Virginia (Sheehan et al., 2010) 2004 - 2008 106 26.5

20

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Gamma Knife Radiosurgery - LGK Society€¦ · literature. Several thousand articles have now been published related to outcomes of Gamma Knife Radiosurgery (GKRS) since the first