worldwide variance in the potential utilization of gamma ... · american providers was 46%, while...

clinical articleJ neurosurg (Suppl 1) 125:160–165, 2016

The first prototype Leksell Gamma Knife (GK) unit was introduced into clinical practice in 1967, and by 2016 the uses for GK radiosurgery (GKRS) have

expanded dramatically. GKRS has been used across the world (at more than 300 centers) for primary or adjuvant management of both benign and malignant brain tumors, vascular malformations, and select medically refractory functional disorders (such as tremor, epilepsy, and obses-sive compulsive/anxiety disorders). As the role of GKRS continues to expand, there remains considerable diversity of opinion regarding the appropriate use of GKRS for var-ious intracranial conditions.

The present report describes both the consensus and the variance in the estimated role of GKRS in centers across the world. Using epidemiological data and patient spec-trum data from the 2014 Leksell Gamma Knife Society,

an estimate of the potential underuse of this technology was made.

MethodsUsing the membership database of the Leksell Gamma

Knife Society, more than 300 providers at high-volume GK centers across the world were surveyed. The physicians tar-geted were the chief neurosurgeon/director of the GK cen-ters, medical physicists, and radiation oncologists. Eighty responses were collected at the end of the designated 2-week period. Fourteen of these responses were exclud-ed because respondents failed to complete the survey or misinterpreted the instructions. Sixty-six responses were included in the final analysis. The countries represented include the US, Belgium, Canada, Chile, China, Croatia,

abbreviationS AVM = arteriovenous malformation; CBTRUS = Central Brain Tumor Registry of the US; CM = cavernous malformation; DAVF = dural arteriovenous fistula; GK = Gama Knife; GKRS = Gamma Knife radiosurgery; TN = trigeminal neuralgia; VS = vestibular schwannoma.SUbMitteD June 3, 2016. accePteD July 8, 2016.inclUDe when citing DOI: 10.3171/2016.7.GKS161425.

Worldwide variance in the potential utilization of Gamma Knife radiosurgery travis hamilton, bS,1 and l. Dade lunsford, MD2

1Michigan State University College of Human Medicine, Lansing, Michigan; and 2Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

obJective The role of Gamma Knife radiosurgery (GKRS) has expanded worldwide during the past 3 decades. The authors sought to evaluate whether experienced users vary in their estimate of its potential use.MethoDS Sixty-six current Gamma Knife users from 24 countries responded to an electronic survey. They estimated the potential role of GKRS for benign and malignant tumors, vascular malformations, and functional disorders. These estimates were compared with published disease epidemiological statistics and the 2014 use reports provided by the Leksell Gamma Knife Society (16,750 cases).reSUltS Respondents reported no significant variation in the estimated use in many conditions for which GKRS is performed: meningiomas, vestibular schwannomas, and arteriovenous malformations. Significant variance in the esti-mated use of GKRS was noted for pituitary tumors, craniopharyngiomas, and cavernous malformations. For many cur-rent indications, the authors found significant variance in GKRS users based in the Americas, Europe, and Asia. Experts estimated that GKRS was used in only 8.5% of the 196,000 eligible cases in 2014.conclUSionS Although there was a general worldwide consensus regarding many major indications for GKRS, sig-nificant variability was noted for several more controversial roles. This expert opinion survey also suggested that GKRS is significantly underutilized for many current diagnoses, especially in the Americas. Future studies should be conducted to investigate health care barriers to GKRS for many patients.http://thejns.org/doi/abs/10.3171/2016.7.GKS161425Key worDS stereotactic radiosurgery; Gamma Knife; epidemiology; percentage utilization; percentage indication for treatment; intracranial disorders

©AANS, 2016J neurosurg Volume 125 • December 2016160

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gamma Knife utilization

J neurosurg Volume 125 • December 2016 161

Czech Republic, Ecuador, Egypt, Hong Kong, India, Italy, Japan, Malaysia, Mexico, Morocco, Norway, Philippines, Republic of Korea, Russia, Spain, Taiwan, Turkey, and Venezuela.

Emails with a link to the survey (SurveyMonkey) were sent to providers at these GK centers. The survey included questions regarding the incidence of various intracranial disorders treated at each center. Supplementary questions attempted to gather a perspective on the types and num-bers of cases treated at each responding center. In addition, we used various epidemiological resources to estimate the number of GKRS-appropriate diagnoses by region. Sta-tistics on incidence for each disorder were obtained from updates of the WHO, Central Brain Tumor Registry of the United States (CBTRUS), Brain Tumor Registry of Japan, Cancer Research of the United Kingdom, and various published articles identified using MEDLINE (PubMed). Search criteria for PubMed included the terms “Stereotac-tic radiosurgery,” “Gamma-Knife,” “epidemiology,” “in-cidence,” and all MeSH (medical subject headings) terms for the condition of interest and countries. Only articles published in English were included. Incidence data were extracted and consolidated on a spreadsheet by the review author. Responses were collected within a 2-week period. Statistical analyses of the responses were performed using an Excel spreadsheet, SPSS (version 23, IBM Corp.) and other statistical software. Population statistics were based on current worldwide reports of 529 million individuals in North America, 743 million in Europe, and 4026 million in Asia (including Japan).

resultsgKrS for benign tumors

The annual incidence of benign brain tumors in North America, Europe, and Asia ranged from 17 to 81 indi-viduals per million.3,6,7,10,13,15 The average estimate of ap-

propriate cases for treatment with GKRS among North American providers was 46%, while European and Asian providers regarded 57% and 53% of cases, respectively, to be appropriate. Among the 29,404 cases of benign con-ditions treated in 2014, the most common tumors treated were meningiomas (44% of the total amount), followed by vestibular schwannomas (VSs; 29%), pituitary adenomas (15%), and other rare tumors (22%). The maximum esti-mated number of individuals with commonly treated be-nign tumors appropriate for GKRS in Europe was 34,304 and in North America was 26,227. Providers in Asia es-timated that 157,900 benign tumors were appropriate for GKRS. Based on the total number of cases actually treated with GKRS and the estimated number of appropriate indi-viduals, North American centers treated up to 17% of all potential cases, while European centers treated 27% and Asian centers treated 8% of potential cases.

Variance was noted in the estimated role of GKRS for the relatively uncommon craniopharyngioma, a tumor es-timated to be diagnosed in 1 to 6 per million persons per year.5,8,11,12,14,15 Providers in North America estimated that 17% of cases were treatable. In contrast, providers in Eu-rope and Asia suggested 46% and 31% of cases, respec-tively, were appropriate for GKRS. The total number of cases that were estimated to be appropriate for treatment was 540 in North America, 2051 in Europe, and 7488 in Asia. In comparison, a total of 396 patients with cranio-pharyngiomas were treated by GKRS worldwide in 2014. The estimated utilization of GKRS for other benign neo-plasms was 26% in European centers compared with 14% in the Americas, and 4% in Asia (Fig. 1).

gKrS for Malignant tumorsThe annual incidence of metastatic brain tumors was

550 per million in the US and Asia.4,6 In European coun-tries, brain metastases occurred in 10%–40% of individu-

Fig. 1. Estimated role for GKRS based on geography. Survey results from Asia, North America, and Europe are represented based on average percentage of indication for various intracranial disorders. The error bars represent the standard error of the mean (SEM). AV = arteriovenous.


t. hamilton and l. D. lunsford

J neurosurg Volume 125 • December 2016162

als diagnosed with systemic cancers.9,16 At an annual esti-mated incidence of 2536 metastatic brain cancers per mil-lion per year (http://globocan.iarc.fr), the total estimated number of brain metastasis cases in Europe ranged from 195,591 to 752,685. Experts in all 3 regions estimated that an average of 62% (58%–65%) of all brain metastases were eligible for GKRS. In North America, 189,118 in-dividuals with metastases were believed appropriate for GKRS, while 14 million patients were eligible in Asia, and 1.8 million patients were eligible in Europe. In contrast, a total of 31,592 individuals with malignant tumors (in-cluding brain metastases) were actually treated by GKRS worldwide in 2014 (North America, 10,035; Europe, 5968; Asia, 15,589; Fig. 2).

The annual incidence of glioblastomas in Asian coun-tries varies from 8 to 16 per million persons but occurs at an incidence of 32 to 174 per million in North America and Europe. Respondents from both Europe and Asia es-timated that 17% of glioblastomas were appropriate for GKRS treatment. American experts believed that GKRS was appropriate in 12% of cases. Based on expert opinion, the number of estimated cases per year should be 10,951 in Asia, 11,045 in North America, and 20,685 in Europe. The actual number of reported glioblastomas treated in Asia was 669, while 397 and 262 patients with glioblastomas

were treated in North American and Europe, respectively, in 2014.

Among all malignant tumors (brain metastases and glioblastomas), North American centers currently treat 5.3% of all eligible cases, while both European and Asian centers treat fewer than 1% of estimated eligible cases (Fig. 2). We found no significant variance among survey respon-dents regarding the appropriate use of GKRS for menin-giomas.

gKrS for vascular DisordersIn North America, between 2 and 14 per million pa-

tients will be diagnosed with intracranial arteriovenous malformations (AVMs) annually. Population studies con-ducted in Scotland estimated the annual incidence of in-tracranial AVMs in the general population to be 23 per million.1,2 Both European and Asian experts suggested that 67% of AVMs were eligible for treatment, as opposed to experts in the Americas suggesting that 49% of AVMs were appropriate for GKRS.

We found a greater variance between regions regard-ing the role of GRKS for the treatment of both cavern-ous malformations (CMs) and dural arteriovenous fistulas (DAVFs). Both European and American providers es-timated that 8% of CMs were appropriate for GKRS. In

Fig. 2. Percentage utilization of GKRS based on histology. Incidence data extracted from published data were used in conjunction with the estimated indication for brain disorders to calculate the estimated annual caseload. The percentage of estimated cases was compared with the actual number of cases treated to calculate the percentage of utilization. NA = North America.




contrast, experts in Asia estimated that 26% of cases were appropriate for GKRS. Additionally, 39% of DAVFs were believed appropriate for treatment in Asian GK centers, while only an average of 18% were regarded to be appro-priate in Europe and the Americas.

Including all types of vascular malformations, an es-timated 3163 individuals in North America, 11,621 in Europe, and 35,066 in Asia were deemed appropriate for GKRS in 2014. North American centers treated up to 24% of appropriate cases, while European and Asian centers treated 18% and 11%, respectively.

gKrS for Functional DisordersThe annual incidence of functional disorders (tremor,

trigeminal neuralgia, epilepsy, and behavioral disorders, such as medically refractory obsessive compulsive disor-der, anxiety, and depression) considered appropriate for GKRS, range from 120 to 2000 per million per year in the US and Europe.5,8,11,12,15 Our respondents suggested that an average of 52% of all functional disorders were eligible for treatment with GKRS. All surveyed providers indicated that an average of 2% of behavioral disorders were treat-able with GKRS (Table 1).

The total number of functional disorders estimated to be treated annually in North America was 243,340, pri-marily trigeminal neuralgia and tremor. European centers estimated 683,560 cases and Asian centers over 3.5 mil-lion cases were appropriate for GKRS annually. Based on the 2014 reported GK use data, less than 1% of individuals with appropriate functional disorders were treated.

A significant variance was observed among regions re-garding the role of GKRS for medically refractory essen-tial or parkinsonian tremor. North American surveys esti-mated that 13% of patients with tremor were appropriate for treatment, compared with 6% estimated as appropriate in Asia and 7% in Europe.

Discussionworldwide consensus for the role of gKrS

Surveys were sent to 300 high-volume GK centers across the world regarding the treatment patterns in their practices. Participants in the survey represented providers with extensive experience at their practice sites. Respon-dents were asked to estimate the percentage of patients with various intracranial tumors, vascular malformations, or functional disorders suitable for GKRS at their site. Of these conditions, 19 disorders were identified and distrib-uted into categories, including benign tumors, malignant tumors, vascular malformations, and functional disorders.

The role of GKRS for meningiomas, metastatic tu-mors, and AVMs had the highest consensus among centers worldwide. There was an overall similarity in treatment indications observed among these conditions. Among be-nign conditions, a mean of 51% (range 48%–53%) of me-ningiomas and 70% (range 67%–73%) of VSs were esti-mated to be appropriate for GKRS in all regions surveyed. Experts agreed that an average of 62% (range 58%–64%) of brain metastases and 15% (range 12%–17%) of glio-blastomas were suitable for GKRS (Table 1).

Treatment indications for all common and rare malig-

nant tumors demonstrated no significant variance in treat-ment patterns. For patients with trigeminal neuralgia (TN), respondents generally agreed that approximately 52% of patients with refractory TN were eligible for GKRS.

worldwide variance in the estimated role of gKrSIn contrast to the general agreement about the role of

GKRS for meningiomas and schwannomas, considerable differences existed among sites in regard to the manage-ment of pituitary tumors and craniopharyngiomas. Pitu-itary tumors account for as many as 20% of all intracrani-al neoplasms. Experts in North America considered only 23% of cases treatable with GKRS. European and Asian experts estimated that 38% and 46% of cases were eligible for treatment, respectively. Furthermore, craniopharyngi-omas are relatively rare tumors found in approximately 2 patients per million annually. Because a significant num-ber of these cases occur in the pediatric population, most centers subscribe to the concept of an initial attempt at gross-total resection. Based on our survey, North Ameri-can experts estimated that 17% of craniopharyngiomas should be treated with GKRS. Asian and European ex-perts indicated 31% and 46% of cases should be treated with GKRS, respectively.

The role of GKRS in treating CMs and DAVFs in Asia far exceeded its use relative to countries in Europe and the Americas. An average of 8% of CMs and 18% of DAVFs were suitable for treatment with GKRS in North Ameri-can and Europe. However, Asian experts estimated 26% of CMs and 38% of DAVFs were appropriate for treat-ment. Based on the Leksell Gamma Knife Society annual reports, Asian countries treated a total of 1045 CMs and DAVFs, while the combined European and North Ameri-can cases totaled 497 in 2014. The degree of use of GKRS for treating intractable tremor and behavioral disorders also varied considerably between American, European, and Asian sites.

Study weaknesses and Future DirectionsWe asked experienced providers at 66 GK centers to

determine the various roles for radiosurgery for a wide va-riety of current indications. These respondents represent-ed the “expert panel.” Epidemiological incidence data for many medical conditions are difficult to obtain or validate in smaller and developing countries outside of the Ameri-cas and Europe. Furthermore, the data that are available are rarely up to date. We found relatively few publica-tions from Asian countries regarding disease incidence and prevalence. We found that the pooled worldwide data in English totaled almost 4 billion individuals. Coun-tries like India and China, which are the most populated countries in Asia, also did not have national brain tumor registries from which to extrapolate data. In effect, data from smaller countries such as Japan were used to repre-sent larger countries in many instances. Further statistical stratification between Japanese data and other Asian coun-tries should be conducted to determine any differences in epidemiology and percentage indication.

There were also differences among regions with re-gard to disorders that were less commonly encountered.


t. hamilton and l. D. lunsford

J neurosurg Volume 125 • December 2016164

tabl

e 1.

Perc

enta

ge in

dica

tion

for i

ntra

cran

ial d

isord

ers b

ased

on

hist

olog

y

Trea

tmen

t In

dicati

on

North

Ame

rica (

n = 29

)As

ia (n

= 26

)Eu

rope

(n =

8)M

ean %

In

dicate

d for

GK

Trea

tmen

t ±

SDSE

M

Med

ian %

In

dicate

d for

GK

Trea

tmen

t (ra

nge)

Mea

n %

Indic

ated f

or

GK Tr

eatm

ent

± SD

SEM

Med

ian %

In

dicate

d for

GK

Trea

tmen

t (ra

nge)

Mea

n %

Indic

ated f

or

GK Tr

eatm

ent

± SD

SEM

Med

ian %

In

dicate

d for

GK

Trea

tmen

t (ra

nge)

Benig

n tum

ors

M

ening

ioma

47.9

± 22

.58.

9033

4572

550

(10–

90)

52.0

± 19

.610

.2161

1002

50 (8

–90)

52.5

± 12

.818

.6170

2128

50 (3

0–70

)

Pitui

tary

tumo

r22

.8 ±

18.9

4.23

7918

216

20 (5

–75)

38.4

± 25

.87.5

4420

4322

30 (5

–90)

45.6

± 28

.516

.1702

1277

40 (1

5–90

)

VS68

.3 ±

25.8

12.6

9516

729

80 (6

–95)

67.2

± 20

.713

.202

3575

677

.5 (6

–95)

73.1

± 11

.325

.921

9858

275

(50–

90)

Cr

aniop

hary

ngiom

a17

.2 ±

17.1

3.197

0260

2210

(0–7

5)30

.6 ±

23.4

6.011

7878

1927

.5 (0

–90)

45.6

± 27

.016

.1702

1277

50 (5

–80)

Mali

gnan

t tumo

rs

Met

asta

ses

64.0

± 30

.511

.895

9107

875

(0.75

–100

)65

.1 ±

29.8

12.78

9783

8980

(0–9

5)58

.1 ±

33.2

20.6

0283

688

70 (0

.8–9

9)

Gliob

lastom

a11

.5 ±

12.1

2.137

5464

685 (

1–50

)16

.6 ±

12.7

3.26

1296

6615

(0–5

0)15

.5 ±

18.7

5.496

4539

017.5

(1–5

0)Va

scula

r abn

orma

lities

AV

M48

.7 ±

24.9

9.052

0446

150

(3–8

5)67

.3 ±

25.2

13.2

2200

393

77.5

(5–9

5)67

.5 ±

14.9

23.9

3617

021

65 (5

0–90

)

CM7.5

± 8.

01.3

9405

2045

5 (0–

30)

26.2

± 26

.25.1

4734

7741

20 (0

–80)

9.0 ±

8.1

3.191

4893

6210

(0–2

0)

DAVF

19.3

± 20

.43.

5873

6059

510

(0–7

0)37

.8 ±

28.3

7.426

3261

330

(0–1

00)

17.6

± 26

.56.

2411

3475

210

(0–8

0)

TN60

.1 ±

27.0

11.17

1003

7265

(13–

100)

43.9

± 27

.08.

6247

5442

40 (1

–90)

51.3

± 3

5.8

18.19

1489

3672

.5 (5

–80)

Func

tiona

l diso

rder

s

Trem

or (P

arkin

son’s

dise

ase)

12.9

± 17

.02.

3977

6951

75 (

0–50

)6.0

± 8.

71.1

7878

1925

1 (0–

30)

7.0 ±

11.6

2.482

2695

040.

5 (0–

30)

Be

havio

ral

1.9 ±

3.3

0.35

3159

851

0.5 (

0–10

)1.3

± 2.

70.

2554

0275

0 (0–

10)

3.8 ±

10.6

1.347

5177

30 (

0–30

)Ot

her/r

are t

umor

s

Chon

dros

arco

ma25

.8 ±

33.

34.7

9553

9033

10 (0

–100

)34

.8 ±

28.4

6.83

6935

167

25 (0

–80)

37.1

± 25

.613

.1560

2837

50 (0

–60)

Ch

ordo

ma32

.1 ±

35.7

5.780

6691

4515

(0–1

00)

34.0

± 25

.86.

6797

6424

427

.5 (0

–80)

27.1

± 23

.69.6

0992

9078

30 (0

–50)

Ep

endy

moma

18.2

± 20

.83.

3828

9962

810

(0–9

0)29

.9 ±

22.2

5.87

4263

261

20 (0

–80)

34.4

± 30

.512

.1985

8156

25 (5

–80)

He

mang

ioblas

toma

31.8

± 24

.85.

9107

8066

925

(0–9

0)36

.5 ±

24.9

7.170

9233

7929

.3 (5

–90)

44.4

± 29

.615

.7446

8085

37.5

(10–

100)

He

mang

ioma

16.3

± 3

0.03.

0297

3977

75 (

0–10

0)44

.9 ±

37.5

8.82

1218

075

50 (0

–100

)40

.0 ±

22.4

14.18

4397

1650

(0–5

0)

Centr

al ne

uroc

ytoma

25.8

± 24

.14.7

9553

9033

20 (0

–80)

38.4

± 31

.47.5

4420

4322

30 (5

–100

)34

.4 ±

29.5

12.19

8581

5620

(5–9

0)

Hema

ngiop

ericy

toma

35.0

± 27

.36.

5055

7620

830

(0–9

5)39

.2 ±

30.4

7.701

3752

4640

(5–1

00)

41.4

± 22

.914

.680

8510

650

(5–7

5)




Because these differences may be attributed to genetic/environmental factors affecting epidemiology, physician training, or barriers to appropriate health care, such issues warrant further investigation. The reasons for this vari-ance in consensus on the role of the GK for less common indications may include insufficient scientific literature to support an expanding role, training bias, and incomplete cost-effectiveness analyses that compare various therapeu-tic options, such as microsurgery, radiation therapy, and radiosurgery. Access to radiosurgical technology may also limit its application in some countries.

conclusionsThere is a general consensus among experts regarding

treatment indications for commonly encountered disorders. We found common agreement regarding the role of GKRS for common problems, such as brain metastasis, meningio-mas, and schwannomas. Regional differences were noted in less common tumors, vascular malformations, and func-tional disorders. The variance in estimated role, actual use, and potential use of GKRS warrants further analysis. Significant barriers to the application of this technology—which has roles in benign and malignant brain disease, vascular malformations, and select functional disorders—should be evaluated in each region. Additional publica-tions, long-term outcome data, cost-effectiveness analysis, and education of neurosurgical and radiation oncology pro-viders may provide further impetus for expanding the role of GKRS worldwide. In addition, radiosurgery can be per-formed by various linear accelerator platforms in addition to the GK. Treatment of patients by staged radiosurgery or hypofractionated techniques may also expand the fu-ture role of radiosurgery for both common indications with little variance in estimated roles, as well as even rarer in-dications for which significant variance in its role remains.

acknowledgmentsWe thank Grand Rapids Medical Education Partners (GRMEP)

for their assistance with the statistical analysis of the data. We also thank Drs. Kendra Davis and Kristia Hamilton for their contribu-tions to manuscript preparation.

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3. Cea-Soriano L, Wallander MA, García Rodríguez LA: Epi-demiology of meningioma in the United Kingdom. Neuro-epidemiology 39:27–34, 2012

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14. Nielsen EH, Feldt-Rasmussen U, Poulsgaard L, Kristensen LO, Astrup J, Jørgensen JO, et al: Incidence of craniopharyn-gioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults. J Neurooncol 104:755–763, 2011

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DisclosuresMichigan State University College of Human Medicine Academic Research Enhancement Funding for Students was provided for this research. Dr. Lunsford is a consultant for and a stockholder in Elekta AB.

author contributionsConception and design: both authors. Acquisition of data: both authors. Analysis and interpretation of data: both authors. Draft-ing the article: both authors. Critically revising the article: both authors. Reviewed submitted version of manuscript: both authors. Approved the final version of the manuscript on behalf of both authors: Hamilton. Administrative/technical/material support: Lunsford. Study supervision: both authors.

Supplemental informationPrevious Presentations“Survey results on subjective percent indication for treatment with Gamma Knife Radiosurgery” was presented as an electronic poster at the 18th Annual Leksell Gamma Knife Society Meeting, Amsterdam, The Netherlands, May 15–19, 2016.

correspondenceTravis Hamilton, 15 Michigan St. NE, Grand Rapids, MI 49503-2532. email: [email protected].


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