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State of the Art of Gamma Knife Radiosurgery
An Overview of Current Practice and Review of the 17th International Leksell Gamma Knife Society Meeting2014
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Selected videos and PDFs of most of the presentations given at the 17th International Leksell Gamma Knife Society may be accessed at
www.lgksociety.com. For more information on the subject matter contained herein, please contact [email protected].
State of the Art of Gamma Knife Radiosurgery 2014An Overview of Current Practice and Review
of the 17th International Leksell Gamma Knife Society Meeting
The Leksell Gamma Knife Society gratefully acknowledges the significant contributions of
Bodo Lippitz, (clinical content), MD and Ian Paddick, (physics content), MS to the development of this report.
Authors’ addresses:
Bodo Lippitz, M.D. Ian Paddick, MS
Professor of Neurosurgery Bupa Cromwell Hospital
Bupa Cromwell Hospital SW50TU London
SW50TU London United Kingdom
United Kingdom Medical Physics Limited
Interdisciplinary Center for Radiosurgery Hamburg
Mörkenstr.47
22767 Hamburg Germany
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Table of Contents
Introduction _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 6Brain Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 8
Improved Detection of Metastases: Time-Delayed MRI and NEMO _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 10Feasibility of Gamma Knife Treatment of Multiple Brain Metastases and Comparison with Alternative Technologies _ _ _ 10Metastases and Quality of Life_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 11Metastases: Age _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 12Large Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 12Cystic Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 13Brainstem Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 13Calvarial Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 13Adjuvant Gamma Knife Radiosurgery for Resected Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 14Multiple Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 15Metastases Grading Scales _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 15Metastases and Adverse Radiation Eff ects _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 16Post-Treatment PET _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 17Treatment of Adverse Radiation Eff ects: Bevacizumab _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 17Targeted Therapy and Radiosurgery _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 18Lung Cancer _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 18Iressa (Gefi tinibTM) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 19Melanoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 19Breast Cancer _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 19Colorectal Cancer _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 20Other Primary Cancer Types _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 20Cost and Reimbursement _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 20
Vascular Malformations _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 22AVM: General Outcome _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 22Unruptured Cerebral Arteriovenous Malformations _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 23Large AVM _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 23Pediatric and Adolescent Patients _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 24Treatments of AVMs During Pregnancy _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 24AVM: Adverse Radiation Eff ects _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 24Cavernous Malformtions _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 25
Meningioma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 26Long Term Follow-Up _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 27Hypofractionation_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 27
Vestibular Schwannoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 28Hearing Preservation and Threshold Doses _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 30Hypofractionation_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 31Surgical Resection plus Gamma Knife _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 32Neurofi bromatosis Type 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 33Malignant Transformation _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 33
55
Pituitary Adenoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 34Non-Secreting Pituitary Adenoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 34Secreting Pituitary Adenomas _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 35Threshold Doses for Radiation-Induced Optic Neuropathy _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 35
Other Benign Tumors _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 36Central Neurocytoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 36Facial Schwannoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 36Trigeminal Schwannoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 36Glomus Tumors _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 36Craniopharyngioma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 36
Glioma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 38Malignant Glioma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 38Low-Grade Gliomas _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 41
Functional Disorders _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 42Trigeminal Neuralgia _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 42Glossopharyngeal Neuralgia _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 44Gamma Knife Thalamotomy _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 45Imaging and Thalamotomy _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 46Imaging Accuracy _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 47
Fractionation _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 48Ophthalmologic Indications_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 49
Orbital Lesions _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 49Ophthalmologic Indications: Stenopeic Eye Fixation _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 49Glaucoma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 49
Novel Approaches _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 50Gamma Knife Hypophysectomy for Cancer Pain _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 50Modern Genetic Approaches to Glioma _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 50A Stem-Cell Based Surgical Transplantation Therapy for Parkinsons Disease _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 50Focused Ultrasound: The New Frontier? _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 52Neuro-Immunology and Therapeutic Radiation _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 52
Physics and Radiobiology _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 54Brain Doses from the Treatment of Multiple Metastases _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 54Technological Developments _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 55Accuracy of Co-Registration _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 56Target Outlining _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 56Radiobiology _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 57
New and Ongoing Studies _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 58References _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 60Indications Treated 1968 to 2013 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 65
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Clinical OverviewBodo Lippitz, MD
IntroductionThis section is a summary and analysis of the clinical proceedings of the 17th International Meeting of the Leksell Gamma Knife
Society held in New York in May, 2014. A total of 300 abstracts were presented refl ecting the current stage of development and
research in Gamma Knife radiosurgery.
Although it would have been an option to analyze the proceedings of the current meeting only according to the most novel
trends or according to the largest studies or randomized trials, the variety of indications for Gamma Knife radiosurgery (GKrS)
demands a broader view. The focus of this review is a general overview plus recording and preservation of scientifically and
practically valuable data that were presented at the meeting. Hence, for practical reasons, doses, volumes and the length of
follow-up are generally included when provided in a cited presentation. When greater discrepancies between abstract and
slides were noted, the data from the slides were cited, since it was assumed that they represent the more recent analyses.
Due to space and format, not all presentations appear in this summary. In such a review it is virtually impossible to summa-
rize presentations that provide a general overview of a specifi c fi eld. The result is that several of highly relevant comprehen-
sive reviews cannot be included here, since the complexity of the topic would not allow a short summary in the given space.
Very few and generally those that represent a novel approach, were selected; in some cases these presentations were not
even associated with radiosurgery.
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Indications treated worldwide 1991-2013
Leksell Gamma KnifeTreatments by indication worldwide 1991 - 2013
3
44%
37%
12%
7%
0%
Malignant TumorsBenign TumorsVascular disordersFunctional disordersOther disorders
354,605295,840
96,86254,957
3,057
68-100% sites reporting
Leksell Gamma KnifeTreatments by indication worldwide 1991 - 2013
3
44%
37%
12%
7%
0%
Malignant TumorsBenign TumorsVascular disordersFunctional disordersOther disorders
354,605295,840
96,86254,957
3,057
68-100% sites reporting
Malignant Tumors 354,605
benign Tumors 295,840
Vascular disorders 96,862
Functional disorders 54,957
Other disorders 3,057
Indications treated worldwide 1991-2013
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Vascular disorders
Other disorders
Malignant tumors
Functional disorders
Benign tumors
7.0 11.3 16.7 26.7 40.458.1
78.5100.5
125.2152.4
180.8214.0
252.5
298.7
347.6
401.2
451.1
504.0
553.4
610.3
674.3
740.2
68-100% sites reporting1991 re�ects cumulative numbers
810.4
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Vascular disorders
Other disorders
Malignant tumors
Functional disorders
Benign tumors
7.0 11.3 16.7 26.7 40.458.1
78.5100.5
125.2152.4
180.8214.0
252.5
298.7
347.6
401.2
451.1
504.0
553.4
610.3
674.3
740.2
68-100% sites reporting1991 re�ects cumulative numbers
810.4
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Vascular disorders
Other disorders
Malignant tumors
Functional disorders
Benign tumors
7.0 11.3 16.7 26.7 40.458.1
78.5100.5
125.2152.4
180.8214.0
252.5
298.7
347.6
401.2
451.1
504.0
553.4
610.3
674.3
740.2
68-100% sites reporting1991 re�ects cumulative numbers
810.4
7
The Leksell Gamma Knife Society Meeting provided many practical hints for daily clinical practice, but apart from the detailed review, it is
tempting to see if there are more general tendencies that can be sensed through the abundance of data. Several comprehensive trends
increasingly appear to materialize:
1. Larger study groups are being established to organize retrospective and prospective trials that will change daily
clinical practice through large numbers and higher quality evidence. Examples are the European Gamma Knife Society
(EGKS) meningioma analysis, the North American Gamma Knife Consortium (NAGKC) studies and the studies conducted
by the Japanese Leksell Gamma Knife Society (JLGK) Study Group.
2. Gamma Knife radiosurgery has become an inherent component in the treatment of neurological
conditions and clinical practice and scienti� c studies increasingly integrate radiosurgery in a combined
approach. This is true in surgery, where Leksell Gamma Knife® provides the ability to reduce the morbidity of the
intervention or in chemotherapy, where Gamma Knife treats brain metastases that are inaccessible for medication.
Hence, even cancer patients with brain metastases can benefi t from recent progresses in targeted systemic therapy
with improved life expectancy.
3. The fact that the number of brain metastases is not directly related to the patient’s prognosis is now being
realized. The logical conclusion is the necessity to treat all of these metastases eff ectively in order to maintain the
patient’s quality of life. Important studies have now provided the necessary data. It has now been realized that the
previously assumed limitation of radiosurgical indications that was based on a defi ned number of brain metastases,
was a mere artifact of previous study designs. This conclusion will lead to an exponential increase of patients with brain
metastases being treated with stereotactic radiosurgery.
4. The trend toward fractionated stereotactic radiosurgery that was visible at the two recent ISRS meetings has not
quite reached the Gamma Knife community, although an increasing number of studies document fractionation
schemes in larger benign and malignant tumors.
5. The radiosurgical salvage treatment of anaplastic gliomas and glioblastomas has recently been cleared by the
FDA and a number of studies show reproducible results that demonstrate that Gamma Knife radiosurgery can be an
additional treatment option in this otherwise highly problematic condition.
6. Lesioning in functional neurosurgery has maintained its role, since deep brain stimulation is associated
with high costs, maintenance problems and speci� c side e� ects. A majority of functional neurosurgeons is still
applying lesioning techniques and the number of functional lesioning procedures appears to be increasing again. Leksell
Gamma Knife® has become an important non-invasive alternative in lesioning and results document a clinical effi cacy
identical to invasive methods.
7
8
0.5 1.2 2.3 4.4 7.3 11.6 17.123.8
32.12.0
5.66.1
82.2
100.5
120.3
142.1
163.1
185.3
205.0
226.8
251.9
278.2
305.6
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Leksell Gamma KnifeMetastatic tumor - Cumulative worldwide
Thousands
468-100% sites reporting1991 reflects cumulative numbers
Thousands
Metastatic tumor – Cumulative worldwide
An eff ective therapy and local tumor control is paramount for
the patient’s prognosis and quality of life. In practice, conven-
tional fractionated whole brain radiotherapy (WBRT) is still
frequently applied as a standard therapy of brain metasta-
ses, but side eff ects and lack of sustained local effi cacy could
outweigh potential benefits: The median survival of patients
with brain metastases treated with WBRT appears to be very
limited and was less than 4.5 months in 8 out of 9 studies in
1925 out of 1971 reported patients. In patients with adverse
prognostic features there was no signifi cant diff erence between
best supportive care and 20 Gy WBRT and only slight and clini-
cally irrelevant diff erences in the 30 Gy WBRT group (median 2.2
vs. 1.7 months).
These results match the recently published interim data from
the QUARTZ Trial (Quality of Life after Radiotherapy for Brain
Metastases), a randomized Phase III trial of patients with inop-
erable NSCLC brain metastases showing a median survival of
49 days after optimal supportive care plus WBRT. On the other
hand, WBRT must be considered insuffi cient in patients with a
better systemic prognosis, since prospective and randomized
studies showed that WBRT provided only limited local control
over the treated brain metastases with complete or partial
responses in 24-55%. WBRT in brain metastases of colorectal
cancer (3 Gy x 10) achieved a local control of 17% at six months.
8
Brain MetastasesAccording to conservative estimates, about 8% of cancer
patients will develop brain metastases, which often cause the
leading symptoms in cancer. Chemotherapy has signifi cantly
improved the prognosis of patients with cancer but generally
fails in the treatment of brain metastases. Hence, many chemo-
therapeutical regimens are not applicable in the presence of
brain metastases.
9
The application of focal radiation using Gamma Knife radio-
surgery (GKRS) has changed these previously rather negative
perspectives in a fundamental way. Reproducible tumor control
after radiosurgery underlines that physically focused and stereo-
tactically applied radiation can overcome several limitations
of fractionated radiotherapy. This insight has signifi cantly infl u-
enced treatment recommendations and guidelines that have
recently been published to define the criteria for treatment of
brain metastases from a surgical, radiotherapeutical and radio-
surgical perspective. In practical terms radiosurgery is still an
unusual treatment, as only 6.1% of 7684 patients with non-small
cell lung cancer who were diagnosed with brain metastases in
the US between 2000 and 2007 had billing codes for stereotactic
radiosurgery, while radiosurgery was signifi cantly associated with
increasing year of diagnosis, higher socioeconomic status and
admission to a teaching hospital.
According to an international online practice survey in 2010 with
445 responses, 93% from radiation oncologists, 78% of respon-
dents would still use WBRT alone for initial treatment of two to
four brain metastases in patients with a KPS of 70 and active,
uncontrolled extracranial disease.
The trends for Gamma Knife radiosurgery indications over time
are well refl ected by a review of indications and clinical practice
at the Cleveland Clinic, where a signifi cant change in indications
was seen between 2002-12. Until 2012, the number of patients
who underwent Gamma Knife treatment increased from 148 to
349 and the increase in total patients (201 more in 2012 than
2002) is almost completely accounted for by the parallel increase
in patients treated for metastasis. The metastasis subgroup
showed a concurrent increase in mean number of metastases
treated per patient. Despite a decrease in per patient billing of
36%, case volume and indications suggest an estimated total bill-
ing increase of 150% between 2002 and 2012.1
10
Improved Detection of Metastases: Time-Delayed MRI and NeMODue to the improved image quality in immobilized patients
in stereotactic frames and due to the use of increased doses
of Gadolinium, frame-based stereotactic MRI studies detect
generally 34-40% more metastases than anticipated from diag-
nostic studies.2,3 A supporting study was presented showing
that 6% of patients had an increased number of lesions on the
day of GK than on pre-operative imaging when the slice thick-
ness decreased from 3-5 mm to 1-2 mm.4
The T2-weighted images from the 7T brain MRI reveal detailed
microvasculature and the internal contents of supratentorial
brain tumors better than that of the 1.5T brain MRI. However,
for brain tumors located in parasellar areas or areas adjacent to
major cerebral vessels, flow-related artifacts are exaggerated
in the 7.0T brain MRIs. For brain tumors adjacent to skull base,
susceptibility artifacts in the interfacing areas of paranasal sinus
and skull base hampered the acquisition of detailed images and
information on brain tumors in the 7.0T brain MRIs.5
Contrast enhancement of metastases is a dynamic process. For
example, delaying imaging for 10-25 minutes after contrast
administration reveals additional brain metastases in a substan-
tial number of patients and permits radiosurgical treatment for
all detectable tumors. Between the 1st and 3rd scan 15 minutes
after contrast administration, 41.2% of subjects had new brain
metastases identified, with an increase range of 1-14.6
When the goal is to improve tumor detection in the follow-up,
identifying additional brain metastases or areas of subtle tumor
growth in benign brain tumors, a simple method can be help-
ful: subtracting prior (old) high-resolution MR images from new
strereotactic MR images creates New-Minus-Old (NeMO) fusion
images, thus highlighting areas of change that developed in
the time interval between the two scans. After reviewing 100
new-old subtraction-fusion images, 33 additional brain metas-
tases most commonly near dura and blood vessels were identi-
fied from 24/100 radiosurgery sessions.7
Feasibility of Gamma Knife Treatment of Multiple Brain Metastases and Comparison withAlternative TechnologiesSeveral studies compared the radiation dose exposure to normal
brain in Gamma Knife compared with various alternative radia-
tion techniques and demonstrated that Leksell Gamma Knife®
was superior in reducing the dose to normal structures. Differ-
ent quality metrics were used to compare radiosurgery plans
for multiple metastases generated for treatment with Leksell
Gamma Knife Perfexion (GKP) and single-isocenter volumetric
modulated arc radiosurgery (VMAS). Plans that showed similar
dose conformality and PTV coverage, also showed significant-
ly increased low-dose spillage for single-isocenter volumet-
ric modulated arc radiosurgery plans.8 The peripheral normal
brain tissue doses were lowest for the Gamma Knife Perfexion
and highest for TrueBeam FFF and CyberKnife treatment plans.
Comparing the volumes of normal brain receiving 12 Gy, True-
Beam FFF, Novalis and Cyber-Knife were 180-290% higher than
Gamma Knife Perfexion.9 Each successive hardware/software
version generally showed an improvement to the treatment plan
in terms of coverage, selectivity and PCI.
11
Plans produced with Leksell GammaPlan® 10.1 were better with
regard to all planning parameters.10 A typical SRS case is unlikely
to reach the whole brain limit of 800cGy even when 35 mixed
lesions or 68cc were treated.11 During treatment of multiple
brain metastases the Gamma Knife Perfexion gave low doses
to the brain (mean 1.03 Gy, median 0.90 Gy). No correlation
was found between the mean dose to the head and the total
number of metastases treated. The conclusion was that radio-
surgery for multiple lesions, when performed with the Gamma
Knife, exposes the normal brain to relatively low doses, which
allows even multiple treatments if necessary.12
Dose-Volume Histograms for Linac WBRT 30 Gy, Tomotherapy 30 Gy with 10 Gy boost and Gamma Knife treatment of 28 brain metastases (18 Gy min dose, 11.4 cc total volume) From Ian Paddick12
Metastases and Quality of LifePatients receiving stereotactic radiosurgery alone were at
significantly lower risk of a decline in learning and memory
function by 4 months when compared to patients undergoing
additional WBRT. The conclusion from this study was interpret-
ed as level I evidence to support the use of stereotactic radio-
surgery alone.13 Fractionated cranial irradiation causes a nega-
tive impact on health-related quality of life scales particularly
due to fatigue and hair loss and causes cognitive dysfunction
immediately after the beginning of radiotherapy. Subacute
radiation effects on verbal memory function are observed, both
after therapeutic and prophylactic cranial irradiation. These
effects were more pronounced in patients with above-aver-
age performance at baseline. A recently published prospective
randomized EORTC phase III trial with 359 patients showed that
WBRT after surgery or radiosurgery of brain metastases nega-
tively impacted the health-related quality-of-life14. Delayed
significant CNS toxicity 12 months after fractionated radiothera-
py is a known phenomenon. It was shown in a smaller prospec-
tive study after Gamma Knife treatment for brain metastases
that quality of life parameters remained either unchanged or
improved in patients who had no evidence of intracranial or
extracranial tumor progression15.
It can be considered as proven that GKRS allows the mainte-
nance of the quality of life in patients with brain metastases.
Supporting evidence was presented in 317 patients who
underwent Gamma Knife treatment for brain metastases and
completed initial quality of life (QOL) questionnaires at 3, 6, and
12 months posttreatment. QOL is largely preserved following
GKRS (with or without surgery), with statistically significant
improvements measured throughout the first year of follow-
up. In contrast, patients undergoing whole brain radiother-
apy in addition to GKRS experienced initial improvement and
subsequent decline in QOL through the first post-treatment
year16. Another study confirmed these results in 97 consecutive
patients with 1-6 brain metastases and showed that quality of
life remained stable for at least 12 months following GKRS. The
highest QOL is seen for patients with improved or stable cere-
bral symptoms, reflecting local tumor control17.
12
Metastases: AgeThree published randomized controlled trials ((EORTC 22952-
26001, JRSOG99-1 and MDACC NCT00548756) compar-
ing patients assigned to SRS alone vs. SRS plus WBRT for
newly diagnosed 1 to 4 brain metastases were individually
under-powered for overall survival (OS) comparisons. The raw
individual patient data from 364 patients receiving either SRS
alone or SRS plus WBRT were reevaluated in a meta-analysis.
The result showed a statistically significant favorable treatment
effect on overall survival for patients age ≤50 years who had
been treated with stereotactic radiosurgery alone. In this age
group, distant brain relapse rates were not increased, despite
omission of upfront WBRT. According to this re-evaluation of
prospective randomized data, WBRT offered no advantage in
this age group18.
On the other hand, treatment results after SRS for brain metas-
tases in patients over age 80 (n=165) were compared with
the outcome of patients who were 65-79 years old (n=1181).
Although post-SRS median survival time in patients over age 80
(5.3) was shorter than patients 65-79 years old (6.9), this difference
was not statistically significant. Competing risk analyses showed
that the two groups did not differ significantly in cumulative inci-
dences of local recurrence, repeat SRS, neurological deterioration
or SRS related complications. Hence, older patients do not appear
to be poor candidates for SRS19.
Large metastasesThere is a general agreement that larger brain metastases
with a clinically relevant mass effect should be removed surgi-
cally as single session radiosurgery in larger brain metastases
can be associated with side effects due to later formation of
edema. These difficulties in the radiosurgical treatment of
large volumes were documented in series of 143 patients with
single large brain metastases (>10 cc), where in 37% local tumor
progression and/or increase in perilesional edema was seen
after radiosurgery20. The alternatives for larger brain metas-
tases are the surgical resection or the recently applied hypof-
ractionated stereotactic radiosurgical therapy. A three-staged
gamma knife treatment for large brain metastases (>10cc in
volume) has been proposed using a prescription dose of 10 Gy
in three fractions21. A study was presented where the efficacy of
3-staged radiosurgery compared with 2-staged stereotactic radi-
ation therapy in 211 large brain metastases: 124 metastases in 119
patients were treated with 2-staged SRT (Group A) and 87 lesions
in 83 patients were treated with 3-staged SRT (Group B). The
prescribed dose was 26 to 28 Gy in 2 fractions with 2-4 weeks
interfraction in Group A, (n= 124); and 30 Gy in 3 fractions with 2
weeks interfraction in Group B (n=87). The mean tumor volume
was 18.6 cc (range 10.0 to 51.1). The median overall survival peri-
od was 7.4 and 9.7 months in groups A and B, respectively. The
results revealed that the treatment result of 2-staged SRT would
be equivalent to 3-staged SRT22. Unfortunately the study did not
provide data concerning morbidity or ARE22.
13
Cystic MetastasesCystic brain metastases (n=37) showed actuarial local
tumor control rates of 92.9% and 82.2% at 6 and 12 months,
respectively. Adequate doses should be applied, since local
12-month-tumor control rates of lesions treated with margin
doses <15 Gy were 64% whereas 91% of metastases that had
been treated with prescription doses >15 Gy were controlled23.
Cystic metastases of colorectal origin demonstrated the best
treatment response of the cystic component, signifi cantly high-
er than metastases from the breast, but not the lung24.
Brainstem MetastasesBrainstem metastases (n=28) that were treated with a median
dose of 17 Gy showed a crude local control rate of 88%, but an
actuarial overall survival at one year of only 13% with a median
overall survival of 4.6 months25. Very similar results were shown
in another study: at an average GKRS prescription dose of 17
Gy, local tumor control was achieved in 91% and the post-GKRS
overall survival at 6-months was 42%, at 12-months 22%. There
were no serious complications of GKRS26.
Calvarial MetastasesCalvarial metastases are unusual targets in radiosurgery and
are often declined since there is uncertainty concerning thresh-
old doses for the skin. In seven patients with calvarial lesions
treated with GKRS, a novel technique was utilized with bolus
placement over the site of treatment (median prescription dose
15 Gy). The 1-year local control rate was 88.9%. None of the
patients treated to calvarial sites in this study had worsening of
their local symptoms after radiosurgical treatment or suff ered a
complication due to this particular treatment technique (data
from slide)27.
Gamma Knife radiosurgery plans for a patient with a history of breast cancer with three concurrent metastases to the calvarial bones with extension through the inner table into the underlying dura. The superfi cial border of the bolus skin-equivalent layer is outlined in red. From Rupesh Kotecha27
14
Adjuvant Gamma Knife Radiosurgery for Resected MetastasesDue to high risk of local recurrence and an increasing reluctance
to prescribe postoperative conventional fractionated radiother-
apy, the perioperative radiosurgical treatment of brain metasta-
ses is increasingly discussed. The question whether treatment
results differ between pre-operative and post-operative SRS
was analysed based on comparison of 209 patients who under-
went post-operative SRS with 17 patients with pre-operative
SRS. The median survival times after treatment were 9.8 months
in post-operative SRS and 10.3 in pre-operative SRS. The two
groups did not differ significantly in cumulative incidences of
neurological death, local recurrence, neurological deteriora-
tion, remote recurrence and re-SRS. However, the crude rate of
subdural seeding in pre-operative SRS (5.9%) was significantly
lower than that in post-operative SRS (31.1%, p=0.03), but this
difference was not shown to be statistically significant using the
competing risk analysis (p=0.07)28.
The suspicion of an increased leptomeningeal seeding after
surgical removal of brain metastases was confirmed by another
study of 330 patients with a minimum follow-up of 3 months
with no prior whole brain radiation or stereotactic radiosurgery
who had been treated for brain metastases with Gamma Knife.
The 3-year Kaplan-Meier estimate for development of menin-
geal spread was 19% for those patients who underwent prior
surgery vs. 8% for those who did not (p=0.02). On multivari-
ate analysis of primary histology and prior surgical resection,
only prior surgical resection remained predictive of meningeal
spread (p=0.02)29.
The question if the previous surgical resection improves the
outcome, was studied in a matched-pair analysis was performed
in 90 patients who underwent resection followed by radiosur-
gery to the tumor bed (SURG+SRS) who were matched (1:1) with
patients who underwent SRS alone (Gamma Knife or CyberKnife,
follow-up ≥3 months and KPS score of ≥70).
Patients were matched according to age, tumor size, and histol-
ogy. Local control was not statistically different between the
two groups (87% for SURG+SRS and 71% for SRS alone). Similar-
ly, regional CNS control and overall survival were not different.
However, the rate of radiation necrosis was higher in SURG+SRS
compared with SRS alone, 22% vs. 4% respectively (p=0.003).
The conclusion was that surgery followed by SRS to the tumor
bed did not improve local control or survival compared to SRS
alone but did increase the risk of radiation necrosis30.
When GKRS is applied to the resection cavity (n=76) without
prior WBRT (median 16 Gy, median volume 8.6 cc), a crude fail-
ure rate of 25% was shown. The 1-year local control for treat-
ment volume over 10 cc was 64% versus 82% for treatment
volume under 10 cc (p = 0.059)31. A similar local tumor control
rate of ca 75% after Gamma Knife radiosurgery to the postoper-
ative resection cavity was shown in another study: (Data from
presented slides) (n=118; mean cavity volume 13 cc, average
marginal dose 18 Gy.) It was interesting that margin dose > 16
Gy yields better local control and increasing delay between
surgery and SRS increased recurrence32.
Factors for tumor recurrence: margin dose > 16 Gy yields better local control and increasing delay between surgery and SRS increased recurrence; from Christian Iorio-Morin32
15
Multiple MetastasesAmong the very relevant data presented at the meeting were
the results from the Japanese multi-institutional retrospective
cohort study that showed that patient survival was indepen-
dent of number of brain metastases. Similarly, the group had
previously shown in a Japanese multicenter study with 1194
patients (JLGK0901) that stereotactic radiosurgery without
WBRT in patients with 5-10 brain metastases is non-inferior to
radiosurgery in patients with 2-4 brain metastases33. Overall
survival did not differ between the patients with 2-4 tumours
and those with 5-10 metastases. The proportion of patients
who had one or more treatment-related adverse event of any
grade did not differ significantly between the two groups of
patients with multiple tumours.33
The conclusion of the study presented at the Gamma Knife
Society Meeting was that patients with 10 or more brain
metastases are not unfavorable candidates for a treatment
with stereotactic radiosurgery alone. A case-matched study
was conducted using the propensity score matching method
with 720 selected patients. Patients with 2-9 brain metastases
were compared to patients with 10 and more brain metastases.
There was no significant difference in post-SRS median survival
times between the cohorts, incidences of neurological death
were very similar, with no significant difference in neurological
survival, neurological deterioration or SRS-related complica-
tions. The conclusion was that treatment results after radiosur-
gery were not inferior in patients with 10 or more brain metas-
tases as compared to patients with 2-9 brain metastases34.
Survival times were significantly longer following Gamma Knife
radiosurgery (GKRS) compared to fractionated whole brain
radiotherapy (WBRT) in retrospective study of 866 patients
with ≥3 brain metastases (6.4 vs.2.4 months, p<0.0001). There
was no significant difference in survival times between 3-4 and
>4 BM neither following GKS nor following WBRT confirming
that the number of brain metastases had no predictive power.
Patient selection, longer survival among the more recently
treated patients and better local tumor control following GKS
are all factors that may have contributed to this difference35.
Metastases Grading ScalesThe diagnosis-specific Graded Prognostic Assessment (DS-GPA)
is a prognostic index for patients with brain metastases. A
multi-institutional retrospective database of 3940 patients
from 11 institutions was analyzed using univariate and multi-
variate analyses to identify prognostic factors associated with
outcomes by primary site and treatment. Significant prognostic
factors were used to define the DS-GPA prognostic indices. A
GPA of 4.0 correlates with the best prognosis and 0.0, the worst.
According to this analysis, significant prognostic factors varied
by diagnosis36:
• For lungcancer,prognosticfactorswereKarnofsky
performance status (KPS), age, presence of extracranial
metastases, and number of brain metastases
• Formelanomaandrenalcellcancer,prognosticfactors
were KPS and the number of brain metastases.
• Forbreast cancer,prognostic factorswere tumor
subtype, performance status and age.
• Forgastrointestinalcancer,theonlyprognosticfactor
was the KPS36.
The validity of the DS-GPA was then tested in an indepen-
dent Japanese study of 179 patients with brain metastasis
from breast cancer undergoing Gamma Knife radiosurgery.
The conclusion in this series was that DS-GPA appeared to not
be applicable, since the only significant difference was found
between groups 2 and 337. Another study tested the validi-
ty of 6 grading systems in patients undergoing Gamma Knife
radiosurgery in 2645 patients with brain metastases. The grad-
ing systems were the original recursive partitioning analysis
(RPA, Gaspar, 1997), score index for stereotactic radiosurgery
(SIR, Weltman, 2000), basic score for brain metastases (BSBM,
Lorenzoni, 2004), modified-RPA (m-RPA, Yamato, 2013), qualita-
tive survival score (QSS, Serizawa, 2013) and diagnosis-specific
graded prognostic assessment (DS-GPA, Sperduto, 2011). The
authors concluded that BSBM and QSS appeared to be good,
while DS-GPA was less applicable to brain metastasis patients
treated with GKS than the other systems. According to this
evaluation, SIR and m-RPA appear to be the most useful grad-
16
ing systems for all cancer types and showed highly statistically
significant differences for overall survival38. Another group test-
ed the validity of 4 grading systems (RPA, SIR, BSBM,GPA) in 389
evaluable patients confirming the usefulness of all 4 systems of
classification to be used to select patients for radiosurgery. The
BSBM score and the GPA model were seen to be as powerful
as the RPA and SIR systems. BSBM and SIR scores remain signif-
icant after a multivariate backward elimination39. The validity of
grading scales in the specific situation of a radiosurgical retreat-
ment was specifically tested based on 746 patients from the
Japanese prospectively accumulated database. RPA, SIR, BSBM
and the Modified RPA showed statistically significant differ-
ences in median survival time with no or minimal overlapping
of 95% confidence intervals between any two pairs of groups.
Differences between the GPA 3.5 - 4.0 and GPA 3.0 groups
however, did not reach statistical significance40.
Since classical indices rather predict survival than neurolog-
ical outcome, Toru Serizawa proposed the modified BSBM
(m-BSBM) by adding 4 brain factors to the original BSBM. The
conclusion after verification in 2645 patients was that the new
index appeared to be excellent for predicting both qualitative
survival and neurological survival41.
Metastases and Adverse Radiation EffectsThe tumor volume is the primary limiting factor in radiosurgery
since the volume of the irradiated healthy brain in the penum-
bra of the metastasis increases when larger metastases are
treated. This can result in formation of a local edema around
the irradiated target, typically 6-9 months after radiosurgery.
This effect is generally transient, but may require steroid medi-
cation and in rare cases a surgical intervention. Adverse radia-
tion effects are generally seen in larger metastases or unconfor-
mal treatments and are uncommon when metastases smaller
than 2.5 cm are treated. A detailed dose/volume analysis was
carried out and was related to the MRI follow-up in 124 patients
surviving more than 9 months with 173 metastases larger than
10 mm. There were adverse radiation effects in 20.2% and local
recurrences in 11.6%. As an objective representation of the
prescribed dose, the dose given to 95% of the volume (V95)
was measured, which according to logistic regression is a signif-
icant factor for recurrence. The conclusion is that the number of
adverse radiation effects can be further reduced, when dose/
volume relations are taken into consideration. The dose given
to 95% of the volume (V95) and ratio between V10Gy and
tumor volume (KARE factor) serve as an empirical algorithm for
the approximation for the ideal dose range in the Gamma Knife
treatment of brain metastases avoiding both adverse radiation
effects and local recurrences42. Another study analysed clinical
parameters as predictors of dexamethasone use after stereo-
tactic radiosurgery in a retrospective analysis of 162 patients
with brain metastases (on a multivariable model). Dose volume
relations were not taken into consideration. 29% of patients
had steroid use post-SRS. Patients not requiring steroids or with
decrease in steroid use after radiosurgery were more likely to be
male, >=56 years old, with smaller tumors (<2.0 cm), have no
brain mets at initial diagnosis, and had controlled EDS43. Despite
anecdotal evidence that treatment related imaging changes
may be greater after immunotherapy, there was no statistical-
ly significant association between treatment with traditional
chemotherapy, immunotherapy, or targeted therapy and devel-
opment of radiation necrosis44.
17
Post-Treatment Imaging PETImaging during follow-up is essential to differentiate between
uncomplicated cases, adverse radiation effects and recurrences.
Unfortunately, standard MRI is insufficient for this differenti-
ation. Alternatively, 11C-Methionine proved useful for differ-
ential diagnosis between radiation injury and recurrence. The
negative predictability on tumor recurrence in [11C]methionine
PET-CT was 85.7% in a small series, and the positive predictabil-
ity 77.4%47. Similarly, another series showed that the sensitivity
and specificity for radiation injury in Methionine-PET was 87.0%
and 71.4%, respectively. The lesion that accumulated FDG had
an 88.9% possibility of recurrence48.
Treatment of Adverse Radiation Effects: BevacizumabThe standard treatment for radiation induced edema and
adverse radiation effects is a steroid medication with all its
well known side effects during long-term administration. As an
alternative, Bevacizumab has been suggested as a new treat-
ment modality for adverse radiation effects due to its ability to
block the effects of vascular endothelial growth factor (VEGF) in
leakage-prone capillaries. In a small series of 10 patients where
Bevacizumab was used in otherwise poorly controlled symp-
tomatic adverse radiation effects (5 mg/kg 2-3-week interval;
administered over 90 minutes), MRI analysis revealed an aver-
age reduction (of edema) 48.3% in T2-weighted images (data
from slides) and Dexamethasone reduction in all patients with
significant clinical improvements in 90%.49
Successful treatment of adverse radiation effects with Bevacizumab. From Tang Xuqun49
18
Targeted Therapy and RadiosurgeryErlotinib is a reversible tyrosine kinase inhibitor acting on the
epidermal growth factor receptor (EGFR), similar to Gefitinib
(Iressa), which was the first drug of this type. It was shown
that Erlotinib was well tolerated in combination with WBRT
for the treatment of brain metastases with response rates up
to 86%50. Similarly, Lapatinib is a tyrosine kinase inhibitor that
interferes with the HER2/NEU and EGFR pathways and is used
in HER2-positive breast cancer. In patients with brain metasta-
ses, objective CNS responses have been described in 65.9%51.
Ipilimumab is a monoclonal antibody that targets CTLA-4,
which is expressed on a subset of activated T-cells as a negative
regulator of T-cell activation. Blockade of CTLA-4 potentiates an
antitumor immune response and leads to tumor regression52.
The use of ipilimumab in a supportive treatment paradigm of
radiosurgery for brain oligometastases was associated with
an increased median survival from 4.9 to 21.3 months, with a
2-year survival rate of 19.7% versus 47.2%53. Ipilimumab is the
first agent to show overall survival benefit in patients with
advanced melanoma52. Approximately 50% of patients with
cutaneous melanoma have a mutation in BRAF kinase, lead-
ing to constitutive activation of the mitogen-activated protein
kinase pathway and unregulated cell growth. Selective inhib-
itors of the mutated BRAF kinase produce response rates of
approximately 50% and recently the BRAF inhibitor Dabrafenib
was approved for use in patients with metastatic melanoma54.
These new compounds for targeted chemotherapy provide
an obviously novel and highly effective approach in cancer
patients and stereotactic radiosurgery offers the technology for
a corresponding effect against brain metastases. The combi-
nation of these therapeutic approaches promises a prognostic
break-through in selected oncological patients55.
Lung CancerIn 817 patients with NSCLC treated by GKRS median overall
survival from diagnosis of brain metastasis was 68.8 weeks.
Patients with EGFR or ALK mutation had a better prognosis56.
Similar results were seen in 757 patients undergoing GKRS with
a median survival time of 12.8 months (range 0.7-166) from the
diagnosis of brain metastasis and a local tumor control rate of
92.5%. Survival time after SRS was decreased in patients treated
with prior whole brain radiation (median 7.5 months) compared
to SRS alone (median 10.2 months)(p=0.006)57. A more negative
prognosis was described in patients with squamous cell carci-
noma when compared to adenocarcinoma58.
In brain metastases of small cell lung cancer the established
treatment is the use of WBRT, but it has been shown previous-
ly that Gamma Knife appears to be as effective in SCLC as in
NSCLC59, 60. A study was presented after radiosurgery of (less
than 10) SCLC brain metastases (n=41, 79% evaluated), the
12-month rates of local control failure was 14% and the median
survival time 8.1 months61.
In 1999, the World Health Organization categorized large cell
endocrine carcinoma (LCNEC) as a variant of large cell carcino-
ma. Although LCNEC of the lung is categorized among NSCLC,
the biological behavior of LCNEC tumors is very similar to that
of small cell lung carcinomas. In 18 patients treated GKRS, the
overall median survival for patients with brain metastases from
LCNEC of the lung was 12.6 months. Local tumor control was
achieved in all 15 patients with imaging follow-up62.
19
Iressa (GefitinibTM)The outcome of patients with brain metastases from non-small
cell lung cancer treated either by WBRT followed by GK, or by
IRESSA, or by the combination of GK and IRESSA was evaluat-
ed based on the records from the National Health Insurance
Research Database of Taiwan. WBRT was the first line treatment
for nearly all patients. Of the 60,194 patients with newly diag-
nosed NSCLC, 23,874 (39.6%) developed brain metastases. The
median survival after the diagnosis of brain metastases was
0.53 years for WBRT, 1.01 years for WBRT+IRESSA, 1.46 years for
WBRT+ GKRS and 2.25 years for WBRT+IRESSA+GKRS, respec-
tively (p<0.0001) showing extended survival for patients receiv-
ing GKRS or IRESSA63. Results from a smaller retrospective anal-
ysis of 161 patients (from slide) did not support the conclusion
of the previous analysis: There was no significant difference in
overall survival rates after application of Gefitinib or Erlotinib
alone or in combination with WBRT or GKRS64. Because Temo-
zolomide (TMZ) and Erlotinib (ETN) cross the blood brain barrier
and have documented activity in NSCLC, a phase III study was
designed to test whether these drugs would improve the OS
associated with WBRT+SRS. 126 patients with NSCLC (1-3 BM)
were randomized and showed qualitatively different median
survival times (13.4 mo for WBRT+SRS, 6.3 mo for WBRT+SRS+T-
MZ and 6.1 months for WBRT+SRS+ETN), although the differ-
ences were not statistically significant. Performance status at 6
months was better in the WBRT+SRS arm. Because the analysis
was underpowered, these data suggest but do not prove that
increased toxicity was the cause of inferior survival in the drug
arms. So far neither this, nor any other phase III randomized
controlled trial, has shown chemotherapy improves survival for
patients with brain metastases65.
MelanomaIn patients with brain metastases from malignant melano-
ma treated with GKRS (n=102; mean tumor volume 6.0 cm3,
prescription dose 20 Gy: range: 15-24), local control was
achieved in 94% and the median overall survival was 6.4
months from the radiosurgical treatment and 53.0 months from
the diagnosis of the primary melanoma. Intratumoral hemor-
rhage was seen in 11% and adverse radiation effects in 9%, but
rates for tumor hemorrhage appeared to be similar before and
after radiosurgery (data from slides)66.
Eleven percent of patients developed intratumoral hemorrhage and 9% adverse radiation effects, but rates for tumor hemorrhage appeared to be similar before and after radiosurgery (data from slides) from Pavel Ivanov 66
Breast CancerIn GKRS for brain metastases from breast cancer (n=90), use
of anti-HER2 targeting agents, volume ≤1.2cc, and prescribed
dosage ≥18Gy were predictive factors for local tumor control
(according to slides)67.
20
Colorectal CancerIn patients with brain metastases from colorectal carcinoma
treated with GKRS (n=51; mean tumor volume 5.2 cm3 (range,
0.01-45.5 cm3), mean prescription dose 19.4 Gy, range, 5-23 Gy),
the actuarial local tumor control rates were 78.6% and 72.9% at
6 and 12 months after GKRS, respectively. Median overall surviv-
al time after GKRS was 11.0 months68. Another series showed
a comparatively short median short survival of 4.3 months
(range, 0.2-26.5 months) in patients with brain metasases from
colorectal carcinoma (n=188; median prescription dose 18 Gy:
range: 10-25 Gy)69.
Other Primary Cancer TypesHepatomas are rare (but in Korea the 4th common prima-
ry tumor in men) and rarely metastasizes to the brain. These
tumors are usually diagnosed with intratumoral bleeding. In
patients with brain metastases from hepatoma treated with
GKRS, tumor growth was controlled in 79.6% (cited from slide)
(followed n=49/73; mean volume 7348 mm3, range: 187-33700
mm3, prescription dose 23.2 Gy, range: 15-32)70.
In patients with brain metastases from esophageal carcinoma
treated with GKRS, the median survival time from the diagnosis
of brain metastasis was 8 months and median survival from SRS
was 4.2 months, corresponding to a 6-month survival of 45%
and a 12-month survival of 19% after SRS (n=26; mean tumor
volume 5.7 cm3, range 0.5-44 cm3, prescription dose 17 Gy:
range: 12-20Gy)71.
In patients with brain metastases from hepatocellular carcino-
ma treated with GKRS, the median overall survival time after
GKS was 5.0 months (n=14; mean tumor volume 8.16 cm3,
mean prescription dose 18.7 Gy)72.
Cost and ReimbursementCost containment is an essential issue in healthcare, and
treatment methods that are based on outpatient proce-
dures or short-term hospitalizations are gaining momen-
tum in the current environment of decreasing ward capac-
ity. Neurosurgery is a good example of this development,
with a striking trend towards minimally invasive methods.
The widespread implementation of Gamma Knife radiosur-
gery has started to replace previously invasive resections
of AVM, skull base tumors, acoustic neuromas and brain
metastases. While cost considerations may not directly influ-
ence individual treatment decisions, economic compar-
isons can be highly relevant in the regional determina-
tion of ward capacity. Treatment options are also validated
according to economic standards.
In a comparison of costs, 40 patients were treated with LINAC-
based SRS and 61 patients were treated with the Leksell
Gamma Knife Perfexion. In unadjusted analysis, there was a
small not statistically significant difference in median overall
survival between the Gamma Knife and LINAC-based radio-
surgery groups in favor of the Gamma Knife (12 months vs. 7.8
months respectively, p<0.01). The cost associated with actual
SRS delivery was higher for Gamma Knife (incremental cost
difference of $11,058 per patient, p<0.001). However, Gamma
Knife SRS was associated with lower periprocedural costs than
LINAC-based SRS ($8832 vs. $14934, p=0.002), as well as lower
lifetime costs ($100,961.70 vs $173,429.30 per life-year saved,
p=0.04). The cost-effectiveness of Gamma Knife was enhanced
as the number of lesions treated rose. The conclusion of the
study was that Gamma Knife radiosurgery was associated with
better cost-effectiveness than LINAC-based SRS with a cost-sav-
ings of approximately $70,000 per life-year saved73.
21
In another analysis, treatment costs in 289 patients with brain
metastases were computed from a Medicare payer perspec-
tive including initial and salvage therapies for brain metas-
tases, hospitalizations, management of complications, and
imaging. Average treatment cost and average cost per month
median survival were compared between SRS alone, SRS+W-
BRT, or Surgery + SRS. The overall survival was not significant-
ly different with median survivals of 9.8 months, 7.4 months,
and 10.6 months, respectively. Despite an increased need for
salvage therapy, the average cost per month median survival
was $2,382/ month for SRS alone, $3,106/month for SRS+W-
BRT, and $4,380/month for Surgery+SRS (p=0.004). SRS alone
had an incremental cost-effectiveness ratio of $181 per month
improvement in overall survival. The conclusion was that
patients with brain metastases initially treated with stereotac-
tic radiosurgery alone, received more cost-effective care than
SRS+WBRT despite an increased need for salvage therapy74.
22
The overall bleeding rate was 2.25% (mean volume 8,957 cm3,
mean marginal dose 21.4 Gy, mean follow-up 41.8 months)76.
In another study of 97 AVM patients treated with GKRS, MRI
showed the AVM occlusion in 64% (mean nidus volume 2.71cc,
mean prescription dose 22.5Gy)77.
When MR criteria were applied to document the treatment
eff ect, the obliteration rate was reported to be 94% and hence
unusually high (n=99, median volume 6.25 cm3, median
prescription dose 21 Gy)78.
Even for highly eloquent locations such as the post-geniculate
visual pathway, it was shown that 82% of patients receiving 22
Gy or greater had complete obliteration, and GKRS provided
an eff ective treatment with a relatively high rate of visual fi eld
preservation (n=171; median target volume 6.0 cm3; median
prescription dose 19 Gy)79. AVMs with a volume <5 cm3 had
an obliteration rate of 60% at 3 years and 79% at 4 years. The
actuarial rates of visual defi cit were 3% at 3 years, 5% at 5 years
and 8% at 10 years. The annual hemorrhage rate during the
latency interval was 2% and no hemorrhages occurred after
confi rmed obliteration79. In periventricular AVM (n=188), the
actuarial rates of total obliteration were 32% at 3 years, 55%
at 4 years, 60% at 5 years, and 64% at 10-years. Permanent
neurological deficits due to adverse radiation effects (ARE)
developed in 4%. 13% sustained a hemorrhage during the
initial latency interval after SRS indicating an annual hemor-
rhage rate of 3.4% prior to obliteration80.
When ar terial aneur ysms coexist together with AVM,
combined management should be considered. Many of these
aneurysms are treated with embolization combined with
GKRS for an AVM. In a series of 10 associated aneurysms that
had remained untreated after GKRS, 4 intranidal aneurysms
and 4 flow-related distal aneurysms regressed completely;
2 fl ow-unrelated aneurysms were not changed in size81.
Vascular Malformations
22
AVM: General OutcomeIn a larger retrospective analysis of 401 patients with AVMs who
were treated with GKRS, the overall angiographic obliteration
rate was 77.2%, and was 88.8%, 59.7%, and 22% for small, medi-
um and large AVMs.
AVM: General OutcomeIn a larger retrospective analysis of 401 patients with AVMs who
were treated with GKRS, the overall angiographic obliteration
rate was 77.2%, and was 88.8%, 59.7%, and 22% for small, medi-
um and large AVMs.
3.55.2 6.6
8.711.2
14.217.3
20.223.2
26.129.0
32.235.6
39.9
44.2
48.752.9
57.261.2
66.2
71.3
76.5
81.7
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Leksell Gamma KnifeArteriovenous malformation - Cumulative worldwide
Thousands
368-100% sites reporting1991 reflects cumulative numbers
Thousands
Arteriovenous malformation – Cumulative worldwide
23
Unruptured Cerebral Arteriovenous MalformationsThe necessity to treat unruptured AVM has been questioned
in particular with regard to the ARUBA study82 as discussed in
great detail by Gary Steinberg83. It was emphasized that the
very short follow-up period of the ARUBA study is a serious
issue which caused criticism raising the question as to whether
any preliminary result of the study can be evaluated at all at this
early time point. The unusually and unacceptably high compli-
cation rate in the interventional arm is another unclear issue83.
In this context, the presented retrospective study of Gamma
Knife SRS in 276 patients with unruptured AVMs is important
(median follow-up: 49 mo, median nidus volume 4.4 cm3). The
rates of obliteration were 64%, 80% and 88% at 3, 5 and 7 years,
respectively. Permanent adverse eff ects were observed in 2.9%.
The annual hemorrhage rates after SRS were 0.84% during the
latency interval, which decreased to 0.29% after obliteration.
Deep venous drainage was the only factor associated with
hemorrhage after SRS84.
Large AVMIt is well known that large AVM have a reduced chance of
obliteration and increased risk for side effects after single
session radiosurgery. Consequently, it was shown that giant
AVMs which had been treated with Gamma Knife showed a
complete obliteration rate of only 36%, and a subtotal oblitera-
tion (>70%) of 36% and partial obliteration of 28%. (n=11, mean
AVM volume 41 cc, mean prescription dose 14.2 Gy)85. Similar-
ly, in pediatric AVM with volumes >10cc, the obliteration rate
after single treatments was only 25% with high risk for perma-
nent complications in 37% and bleeding in the latency period
(data from slide)86.
Vascular Malformations
3.55.2 6.6
8.711.2
14.217.3
20.223.2
26.129.0
32.235.6
39.9
44.2
48.752.9
57.261.2
66.2
71.3
76.5
81.7
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Leksell Gamma KnifeArteriovenous malformation - Cumulative worldwide
Thousands
368-100% sites reporting1991 reflects cumulative numbers
24
The alternative is volume- or dose-staged radiosurgery. In 63
patients with large AVM (>10 mL) treated with volume-staged
stereotactic radiosurgery (VS-SRS), decreasing treatment
volume per stage allowed higher dose per fraction without
increasing complications. With reduction of the treated median
volume per stage from 15 to 6.8 ml and increase of the median
dose from 15.5 Gy to 17 Gy, the rates of near-obliteration were
increased from 24% to 42% (p=0.0001). The conclusion was
that patients with large AVM should be considered for VS-SRS
and be treated with doses of at least 17 Gy87.
Other preliminary results in a small study may suggest that
staged dose radiosurgery provides more promising results in
terms of obliteration than staged volume radiosurgery in large
AVMs (volume >15 cc). (data from slides) (mean AVM volume
15.8 cc, mean prescription dose 14.5 Gy)88.
Pediatric and Adolescent PatientsHigh rates of complete obliteration and very low frequency of
permanent morbidity or severe bleedings during the latency
period encourage a widespread application of radiosurgery in
pediatric and adolescent patients affected with cerebral AVMs.
A retrospective series which studied the outcome of GKRS in
a series of 100 pediatric and adolescent patients with AVMs,
demonstrated that angiographically documented actuarial
cAVM obliteration rates were 73% and 86% at 3- and 5-years,
respectively (mean cAVM volume 4.99 cc; prescription dose 19.8
Gy). Permanent symptomatic GK-related complications were
observed in 6% of cases with surgical removal of post-radiosur-
gical imaging change needed in 3 cases. Hemorrhage during
the latency period occurred in 8% of patients89. Very similar
results were reported in another study of Gamma Knife radio-
surgery in 75 children with AVM, where nidus obliteration was
achieved in 81% with marginal dose > 20Gy being a favorable
factor for obliteration (median target volume was 1.9 cm3; medi-
an prescription dose 20Gy). Actuarial obliteration rates at 3 and
5years after SRS were 70% and 87%, respectively and 4% devel-
oped treatment related neurological deterioration (median 9
months). Annual bleeding rate after SRS was calculated as 0.3%90.
Treatments of AVMs During PregnancyThe risk of hemorrhage in patients who become pregnant
during the latency interval following GKRS for AVMs was eval-
uated in 253 women of childbearing age with 828.7 patient-
years of follow-up. The data showed that pregnancy appears
to be a risk factor for AVM bleeding. Prior to obliteration, twenty
hemorrhages occurred in non-pregnant patients equating to
an annual hemorrhage rate of 2.5% for non-pregnant women
in the latency interval. Eighteen pregnancies occurred and two
patients had hemorrhages, yielding an annual hemorrhage rate
of 11.1% for women who became pregnant in the latency inter-
val after SRS91.
AVM Adverse Radiation EffectsIn a large retrospective series of 1426 GKRS procedures
performed for AVMs at the University of Virginia, a total of
33.8% of nidi developed radiation-induced imaging changes, in
19.7% classified as Grade I, in 11.5% as Grade II, and in 2.6% as
Grade III. The median duration from GKS to the development
of radiation-induced imaging changes was 13 months (range
2-124 months). The overall incidence of symptomatic imaging
changes was 8.6%92. The focus of a series from the University
of Pittsburgh were the associated symptoms and symptomat-
ic adverse radiation effects that were described in 6% of 879
patients treated for AVM with GKRS (median target volume
3.4cc, median margin dose 20 Gy). Overall rates of symptom-
atic ARE were 2.7% at 1 year, 5.1% at 2 years, 6.0% at 3 years,
and 6.9% at 5 years and rates of permanent symptomatic ARE
were 0.7% at 1 year, 1.8% at 2 years, 1.9% at 3 years, and 2.7%
at 5 years93. Among 817 patients, 23 were identified who had
developed late cysts after GKRS for AVM. Cyst formation was
detected from 1.1 to 16 years (mean 5.4 years) after GKS. Histo-
logical examination in 14 cases showed dilated capillary vessels
with wall damage such as hyalinization and fibrinoid necrosis,
marked protein exudation, and hemorrhage94.
25
Cavernous MalformationsCurrently there are three options for cavernous malformations:
operative resection, radiosurgery or no active treatment at all.
As one of the earlier analyses of radiosurgery for cavernous
malformation , Kondziolka et al published two studies where
initially the natural history of cavernous malformation was
defined95: In patients without a prior bleed, the prospective
annual rate of hemorrhage rate was 0.6% and patients with
prior hemorrhage had an annual bleed rate of 4.5%. The same
group in Pittsburgh demonstrated elegantly that the propor-
tion of patients with hemorrhage after radiosurgery was signifi -
cantly reduced, but in the first 2 years after radiosurgery, an
annual hemorrhage rate of 12.3% per year was still found. Only
in the 2- to 12-year interval after radiosurgery, the annual bleed-
ing rate decreased to 0.76% per year96.
In cavernous malformations it is important to differentiate
between annual bleeding risk in randomly found cavernous
malformations and the rebleeding risk for cavernous malforma-
tions that have bled before. Furthermore the bleeding risk per
patient should be differentiated from bleeding risk per lesion
before and after treatment. A specific example from a recent
paper shows an annual bleeding rate of 2.9% until the fi rst hemor-
rhage, and an annual risk for rebleeding of 30.5% until treatment.
Within 2 years after radiosurgery there was a reduced rebleed risk
of 15%, which fell to 2.4% per patient year thereafter97.
The provided radiosurgical data are generally interpreted as
evidence for a reduced risk for rebleeding after initial hemor-
rhages, whereas it appears difficult to find arguments that a
treatment-induced signifi cant improvement actually occurs in
incidental cavernous malformations.
A presented study of cavernous malformations analysed the
outcome after conservative treatment or surgery, showing an
annual rate of hemorrhage until the fi rst event from of 1.7 and
1.8% respectively. Rebleedings occurred in many cases of conser-
vative group, whose annual rate of hemorrhage was 10.2% per
year after the first event, 19.7% after the 2nd event. In surgery
group, the rate was only 1.9% per year after 1st event, and 2.7%
per year after the surgery for cavernous malformations98.
In a joint retrospective study 334 cases of cavernous malforma-
tion were collected from 23 Gamma Knife centers all over Japan
(mean lesion size: 14.8 mm, mean marginal dose: 14.6 Gy). A
dose dependent response was confi rmed with more frequent
complications occurring at a marginal dose over 15Gy, and in
cavernous malformation with more than 15mm in diameter.
The rates of annual hemorrhage were estimated to be 6.7%
during first 2 years after radiosurgery and 3.3% thereafter.
Rebleeding rates appeared to be lower at prescription doses of
>15 Gy; diff erences however, were not statistically signifi cant99.
Statistically insignifi cant correlation between rebleeding and dose in Gamma Knife treatment of cavernous malformations; From Yoshihisa Kida 99
Very similar bleeding rates after Gamma Knife were reported
in another study where the authors reported 92 symptomatic
patients with brainstem cavernous malformations who were
treated microsurgically (n = 43) or radiosurgically (n = 49) at a
median margin dose of 12 Gy (6-16 Gy). In the first two years
after GKRS the hemorrhage rate was 2.6% but dropped to
0.6% after the fi rst two years. It was notable, that for surgically
treated patients with residual lesions the annual postoperative
hemorrhage rate was 8.8%100.
26
Leksell Gamma KnifeMeningioma - Cumulative worldwide
Thousands
168-100% sites reporting1991 reflects cumulative numbers
0.6 1.1 1.8 3.1 5.1 7.39.9
12.815.9
19.322.6
26.631.3
36.8
43.1
50.2
56.8
64.2
71.6
80.3
90.4
100.9
112.8
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
In certain anatomical locations the complete surgical removal
of meningiomas can be associated with a major postopera-
tive neurological defi cit. Hence, the consequence of the close
involvement of relevant and sensible structures is an incom-
plete tumor resection in order to preserve the neurological
function. Long term follow-up studies have demonstrated
that incompletely resected skull base meningiomas carry a
significant risk for symptomatic recurrences. Gamma Knife
radiosurgery has an important role to complete microsurgery
in these cases through provision of a postoperative long-term
tumor control.
Under the auspices of the European Gamma Knife Society
(EGKS), a retrospective observational analysis of 4565 consec-
utive patients harboring 5300 benign meningiomas was
performed by 15 participating centers. All patients were treat-
ed with Gamma Knife radiosurgery (median tumor volume 4.8
cm3, median prescription dose 14 Gy, median imaging follow-
up was 63 months). Detailed results from 3768 meningiomas
(71%) were analyzed. The volume of treated tumors decreased
in 58%, remained unchanged in 34.5%, and increased in
7.5%, thus providing a control rate of 92.5%. Five- and 10-year
progression-free-survival rates were 95.2% and 88.6%, respec-
tively. Tumor control was higher for imaging defi ned tumors vs
grade I meningiomas, for female vs male patients, for sporadic vs
multiple meningiomas, and for skull base vs convexity tumors.
Permanent morbidity rate was 6.6% at the last follow-up101.In a
group of 722 patients, it was shown that the relative risk for an
aggravation of a peritumoral edema after GKS was 4.58 times
higher when a meningioma presented with peritumoral edema
Meningioma
26
Thousands
Meningioma – Cumulative worldwide
Within recent years, there has been a modification in clinical
neurosurgical approaches of meningioma: a shift away from
aggressive surgical solutions toward disease management
with lower invasiveness. The current priority emphasizes the
patient’s quality of life and avoidance of postoperative defects.
One of the critical anatomical regions is the skull base, particu-
larly the cavernous sinus and the petroclival region, but even
the complete surgical resection of meningioma of the falx can
be very complicated when the sagittal sinus is infi ltrated.
27
Meningioma at the time of radiosurgery when deterioration can be expect-
ed in 60%. In the group of meningioma without initial peritu-
moral swelling, the edema occurred in 13.1%107. A higher rate
of side eff ects was described in a smaller retrospective analysis
showing that 18.7% developed new T2 signal change sugges-
tive of edema with 10.8% being symptomatic with headache,
fatigue or ataxia (data from slides). (75 followed out of 170 treat-
ed patients, median follow-up 36.2 months, average tumor
volume 5.2 cm3)108.
The dural tail (DT) has been described as a common feature in
menigiomas. The necessity to include the dural tail in Gamma
Knife radiosurgery is still a matter of debate. Gamma Knife
radiosurgery was performed in 471 menigiomas with dural tails
in 209 (44%) tumors (median prescribed dose of 13 Gy, medi-
an follow-up 48 months). Only the part of the dural tail closely
related to the tumor mass was included in the target defini-
tion. Since no tumor growth was found outside the target in
the dural tail during the median follow-up up 48 months, the
conclusion was made that is not necessary to include the entire
dural tail of meningiomas in Gamma Knife radiosurgery109.
Long Term Follow-UpWith regard to the very slow growth rate of meningioma,
however, it is essential to provide long-term data in order to be
able to predict the outcome with regard to local control, remote
control and potential late side effects. So far, only very few
published studies had followed meningioma patients for more
than 5 years after radiosurgical treatment. As one of the longest
available follow-up investigations of patients with meningi-
omas, 86 patients have been followed after treatment with
Gamma Knife radiosurgery with a median follow-up period of
10 years documenting a persistent high local tumor control,
which was only slightly lower than in other published obser-
vations with shorter follow-up. Tumor control was achieved in
87.8% of meningiomas. For the follow-up potential very long
latencies to recurrences have to be taken into consideration; the
median time between initial treatment and recurrence was 5.8
years and out of fi eld recurrences were documented at a medi-
an of 7.5 years in 15.1% of patients. Meningiomas treated with a
prescription dose of > 13.4 Gy experienced a signifi cantly lower
rate of local recurrences (7.1% vs 24% p=0.0096)110.
HypofractionationIn larger meningiomas, the treatment alternatives are either
a partial tumor resection and adjuvant Gamma Knife radio-
surgery or the recently applied hypofractionated stereotactic
radiosurgical treatment. In 42 patients with meningiomas who
underwent fractionated Gamma Knife radiosurgery, the local
control rate of tumor was 97.2% and the symptomatic control
was 94.4%. Median dose of 6 Gy was delivered over median of
2.7 fractions (median tumor volume 15.2 ml, range: 2.1-53.2 ml,
median follow-up up 32.8 months). Tumor volume decreased
(>25%) in 22.2%, remained stable in 75%, and increased (>25%)
in 2.8%111. Similarly, in perioptic meningioma, the established
threshold doses for optic nerves may not allow eff ective single
session treatments which require prescription doses >14 Gy.
The alternative is a multi-session radiosurgery with Gamma
Knife which appeared to be safe in a series of 97 patients with
perioptic meningioma immediately adjacent to the anterior
visual pathway (mean tumor volume was 8,28 cc (range 0,33-
34,2 cc, mean follow-up 26,4 months). Gamma Knife radiosur-
gery was delivered in three sessions with a mean prescription
dose of 6,8 Gy per session (range 6-7 Gy) and a mean total
prescription dose of 20.4 Gy (range 18-21 Gy). Maximum dose
to the optic apparatus was always below 7 Gy for each session.
At last follow-up, tumor volume was unchanged in 50,5%,
decreased in 47,4% and increased in 3,1%. 5.4% developed new
cranial nerves palsies following GKS, 35.1% had an improve-
ment of previous palsies. Among all patients with visual defi cits
at GKS 23.8% had an improvement while it worsened in 2.4%112.
28
0.9 1.5 2.2 3.4 4.86.6
8.710.7
13.015.6
18.221.3
24.528.4
32.6
37.3
41.9
46.9
51.5
57.2
63.6
70.3
77.7
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Leksell Gamma KnifeVestibular Schwannoma - Cumulative worldwide
Thousands
268-100% sites reporting1991 reflects cumulative numbers
A review of 23 articles representing 2204 patients revealed an
overall facial nerve preservation rate of 96.2% after Gamma
Knife113 and a review of 45 articles representing 4234 patients
showed an overall hearing preservation rate of 51% after radio-
surgery114.
A recent study compared the outcome after treatment of
acoustic neuroma with open surgical resection or Gamma
Knife. The mean hospital stay was 2.5 days (2–5 days) in the
Gamma Knife group and 12.5 days (10–30 days) in the surgery
group. Hearing was preserved in 17 out of 28 patients with
functional hearing 2 years after Gamma Knife treatment, while
hearing could not be preserved in any patient after open surgi-
cal resection115.
A large group of patients was presented who had undergone
GKRS as primary treatment for vestibular schwannoma. The
main limitation of the present study was that a detailed radio-
logical follow-up was only available in 60.7% (210/346) and
audiometrical follow-up in 41.3% (143/346). Tumor control was
achieved in 97.11% of followed patients. Overall functional hear-
ing preservation rate at long-term follow-up was 47.5%; in GR 1
patients, this value increased to 72.2% (median tumor volume
1.2cc, range 0.014-14.3 cc; median prescription dose 13 Gy)116.
Vestibular Schwannoma
28
Thousands
Vestibular Schwannoma – Cumulative worldwide
In vestibular schwannoma, Gamma Knife is highly effective
in stopping potential tumor growth while preserving normal
facial function and hearing. The goal of every acoustic neuroma
management is to provide the best outcome with the lowest
possible risk level. The long-term results after Gamma Knife
treatmentl is comparable and often even superior to the best
results with open microsurgical techniques. The functional
results after Gamma Knife are signifi cantly superior to conven-
tional surgical results. Average tumor control >95% is reported
in the majority of published series.
29
To clarify the appropriate length of follow-up after GKRS, a
presented series analyzed changes in MRI and clinical status
more than 10 years after the treatment in 80 patients with
unilateral vestibular schwannomas. Despite initial marked
tumor response for more than 10 years after GKRS, surgi-
cal removal was necessary in 3.8% (3/80) at 143, 151 and 167
months. No new cranial nerve symptom without tumor growth
and no malignant transformation of the tumor were observed
more than 10 years after GKRS117.
Tumor volume is considered as the main limitation for single
session radiosurgery. Hence it is essential to defi ne the specifi c
maximum doses and volume for a safe treatment. 90 patients
with large vestibular schwannomas (>25 mm) treated with
GKRS, showed significant tumor volume reduction in 87.8%
and overall tumor control in 94.5% (mean tumor volume 5.98
cc, median prescription dose 13 Gy, mean follow-up period 67.9
months). Eleven patients developed hydrocephalus at follow-
up requiring a ventriculo-peritoneal shunt. The conclusion was
that Gamma Knife radiosurgery is a safe and eff ective treatment
even for larger vestibular schwannomas118.
Vestibular Schwannoma
30
Hearing Preservation and Threshold DosesThe doses applied to the cochlea could have a potential impact
on hearing deterioration after GKRS. Actuarial incidences of
hearing preservation were 51% and 26% at the 60th and 120th
post-SRS months. Mean cochlear dose higher than 4.2 Gy and
maximum cochlear dose higher than 6.9 Gy were significantly
associated with post-SRS hearing worsening. Age and tumor
size were further factors (n=131, median tumor volume 2cc,
prescription dose 12 Gy)119. The outcome after low-dose GKRS
was described in retrospective study of unilateral vestibu-
lar schwannoma that showed that tumor control rate was
not significantly related to radiation doses (>=12 Gy vs. >=11
Gy-12Gy vs. <11 Gy). The conclusion was that Gamma Knife
radiosurgery achieved high percentage of tumor control and
good hearing preservation even when doses of less than 12
Gy were applied (105 patients, mean follow-up 76 months,
median tumor volume 5.05 cc, median tumor dose 11.4 Gy)120.
This result is potentially important with regard to a study that
showed in a multivariate analysis, that patients receiving a
marginal dose of >12Gy were over 7 times more likely to devel-
op non-serviceable hearing121. Tumor marginal dose >12Gy and
cochlea max dose were jointly significantly associated with the
development of non-serviceable hearing121. But even more rele-
vant, patients with a pretreatment speech discrimination score
(SDS) of >70% were 11.1 times less likely to develop nonservice-
able hearing following SRS. In this study neither mean cochle-
ar dose nor modiolar point dose were associated with hearing
preservation at any threshold121. Similar results were shown in
a prospectively analyzed series of 94 patients with vestibular
schwannoma treated with GKRS where patients in GR class 1 &
2 retained serviceable hearing in 67.2% of the cases. The mean
maximal dose received by the cochlea in patients in GR class 1
and 2 was 4.2 Gy. Among the patients with a follow-up of at
least one year, those with Koos I tumors had the highest proba-
bility (100%) to maintain identical level of hearing122.
The conclusion should be that Gamma Knife radiosurgery
allows hearing preservation in patients with smaller vestibular
schwannoma with good initial hearing. The consequence is the
recommendation of an early radiosurgical treatment before the
hearing has deteriorated.
The topographical factors associated with hearing function
after GKRS was analysed in 102 consecutive patients with
vestibular schwannomas (mean prescription dose 11.9 Gy).
Within the mean follow-up of 55 months, the crude tumor
growth control was 92%. Hearing was preserved in 57% of
patients with initially serviceable hearing. It was suggested that
presence of intrameatal tumor extension up to the fundus may
be associated with somewhat greater risk of functional deterio-
ration after irradiation123.
This potential relation of tumor location to functional status
was further analysed in 176 patients with unilateral acoustic
neuromas treated in Pittsburgh, where the potential prerequi-
sites for hearing deterioration according to MR prior to Gamma
Knife stereotactic radiosurgery were tested. It was confirmed
that tumor volume in the internal auditory canal significantly
correlated with GRC hearing. Hearing worsened as the total
tumor volume increased. However, even small tumors frequent-
ly presented with major hearing impairment, but the concept
that hearing would be worse when the lateral tumor margin
reached the cochlea was not supported124.
Even with the most conformal SRS devices available, and
specific “cochlea shielding” strategies, there is still very little
that can be done to limit dose to the cochlea when the tumor
extends to the fundus of the internal auditory canal121. Jeffrey
Jacob asked the provocative question if – by reporting cochlea
dose as it relates to hearing outcome – we may only be report-
ing what we can measure rather than what is truly impacting
outcome121.
31
Preserved hearing with regard to Pre-SRS SDS; from Jeff rey Jacob121
Preserved hearing with regard to mean cochlear volume dose <5Gy vs ≥5Gy. from Jeff rey Jacob121
HypofractionationA potential treatment option for larger vestibular schwannom-
as is fractionated or hypofractionated stereotactic radiosurgery
which was analysed in a small study of 79 patients with 49
patients with acoustic neuromas, where 49 received fraction-
ated stereotactic radiosurgery (average: 3 fractions, mean dose
18 Gy, mean volume 2.4 cc) and 30 patients who received single
fraction radiosurgery (mean dose 12.5 Gy, mean volume 1.8cc,
median f/u for Group A was 39 months and for Group B 18
months). In this small series with short follow-up, fractionated
radiosurgery achieved tumor control in 92%. A total of 65% had
no change in useful hearing. The results were similar for single
fraction radiosurgery with tumor control rates of 90% and
maintained useful hearing in 67%. The results were interpreted
that a multi-fractionated stereotactic treatment regimen had
no benefi ts in the treatment of an acoustic neuroma125, but the
follow-up in this study was too short to allow conclusions with
regard to tumor control.
32
Surgical Resection Plus Gamma KnifeRadiosurgery has opened a new paradigm of functional integ-
rity in the management of vestibular schwannoma with the
consequence of classical neurosurgical results being ques-
tioned as to their inherent perioperative morbidity. The result
is the comparatively new approach of a safe and partial tumor
removal that allows the preservation of functions combined
with radiosurgery of the remaining tumor to prevent further
growth. A series form Lausanne was presented that had
prospectively analyzed this combined approach, i.e., the
planned subtotal resection followed by Gamma Knife radiosur-
gery on the postoperative residual tumor for the management
of 16 large skull-base lesions, including vestibular schwanno-
mas (mean presurgical tumor volume: 16 cc). Postoperative
status showed no facial nerve defi cits. Five patients with useful
pre-operative hearing underwent surgery with the aim to
preserve cochlear nerve function; of these patients, 4 remained
in GR class 1 and one lost hearing126.
Yoshiyasu Iwai evaluated the functional preservation of hearing
in planned partial surgical resection followed by GKRS in 40
patients of large unilateral vestibular schwannomas with inten-
tional partial tumor removal for functional preservation (mean
maximum tumor diameter: 35.1 mm, range 25-52 mm). GKRS
was performed 3-6 months after surgical resection. (median
tumor volume at GKS was 3.3 cm3 and prescription dose 12 Gy,
mean follow-up 63 months). The combined approach allowed
the functional preservation of the facial nerve in 95% at the fi nal
follow-up. Among the patients with some hearing preservation
before surgery, 73% maintained same hearing levels (<20 dB
deterioration) after surgical resections. At the last follow-up,
45% had maintained the same hearing levels as before GKRS127.
Planned subtotal resection followed by Gamma Knife radiosurgery on the postoperative residual tumor. From Yoshiyasu Iwai127
33
Neurofibromatosis Type 2In patients with neurofibromatosis type 2 (NF2) who were stud-
ied with a very long mean observation period of 112 months
at the Beijing Neurosurgical Institute, the overall tumor control
rate was 88.6% and hearing preservation rate was 37.2% and
the rate of transient or permanent facial paralysis was unusu-
ally high with 10.3%128. In another study from the Shanghai
Gamma Hospital with 113 patients treated with GKRS for
vestibular schwannomas associated with NF2 (median tumor
volume 3.2 cc, mean follow-up time 35 months), the radio-
graphic control rate was 82% at 2 years and 67% at 5 years and
the hearing preservation rate was 44% at 5 years. Even here,
there was an unusually high rate of 31% of new partial facial
weakness. The authors reported that 34/35 of these cases were
unrelated to radiation toxicity--a statement that would require
a more detailed analysis129. It should be noted that a previous-
ly published long term series with 122 tumours in 92 patients,
(906 patient-years of follow-up) described a 5% risk for facial
palsy. Furthermore, it was estimated that 8 years after radiosur-
gery for NF2 VS, 50% will be well controlled and 20% of patients
will have required further treatment130.
Malignant TransformationThe significance of radiation in the induction of malignancy
in vestibular schwannoma after radiosurgery is still not quite
clear, although a number of case reports have been published.
Michael Torrens described a new case of verified induction of
malignant peripheral nerve sheath tumor (MPNST) in a vestib-
ular schwannoma. This patient is the 26th reported case of
verified malignant transformation after radiation. Eight of the
cases were patients with NF2. Additional 20 cases of malignant
transformation have been reported in patients who had not
been irradiated before. The author drew the conclusion that
despite recent reports of malignant transformation in vestib-
ular schwannoma after radiation, only in NF2 cases the inci-
dence of malignancies appears to be notable in relation to the
numbers treated. Radiation treatment including SRS can poten-
tially induce malignancy in vestibular schwannoma, but the risk
appears to be small in the region of 0.01% – 0.02%. This has
to be compared with a realistic mortality rate after craniotomy
of at least 1%131.
34
In pituitary adenomas, medication and microsurgery are typically
used as fi rst-line treatments. When hormone-producing tumors
cannot be removed completely or when the tumor recurs after
surgery, further treatment is imperative in order to stop excess
hormone secretion. Previously, fractionated radiotherapy has
been applied as alternative treatment, which is currently thor-
oughly questioned due to a long latency to achieve endocrine
normalization, high risk of delayed radiation induced pituitary
dysfunction and even secondary tumor development.
Gamma Knife radiosurgery is ideally suited in this situation since
the required high radiation doses can be applied locally with
an extreme precision while complex treatment planning helps
to protect the surrounding structures. In these cases, Gamma
Knife radiosurgery has been shown to normalize the excessive
hormone production and stop further tumor growth.
Typically, high prescription doses of 25 Gy are applied in
hormonally active pituitary adenoma. However, not all series
could establish a relation between dose and outcome. After
radiosurgery, the elevated hormone levels generally decrease
slowly within several months. Due to this known latency
period, however, stereotactic radiosurgery is generally not
preferred over a surgical resection, which ideally provides
immediate endocrine normalization. Several studies indicate
that withdrawal of anti-secretory medication prior to radiosur-
gery improves the chance of endocrine remission.
Non-Secreting Pituitary AdenomaIn cases of smaller non-secreting pituitary adenoma, Gamma
Knife radiosurgery appears to be a safe option providing consis-
tent and reproducible tumour control with very low risk for
immediate side eff ects. The risk of developing pituitary endocri-
nological defi cits is estimated at 32% 5 years after radiosurgery.
In general, radiosurgery is applied for remnant tumors after a
surgical resection. With regard to the predictable outcome
and low level of side eff ects however, Gamma Knife radiosur-
gery can be considered even as a fi rst line treatment in smaller
non-secreting pituitary adenoma.
Under the auspices of the North American Gamma Knife
Consortium (NAGKC), nine Gamma Knife centers retrospec-
tively combined their outcome data in a very large series of
512 patients with non-functional pituitary adenomas (median
prescription dose 16 Gy, median follow-up 36 months). Prior
resection had been performed in 479 patients and prior fraction-
ated external beam radiotherapy applied in 34 patients. Actuarial
tumor control was 98%, 95% and 91% at 3, 5 and 8 years post-
radiosurgery.
New or worsened hypopituitarism after radiosurgery was
noted in 21.1% of patients, with thyroid and cortisol defi ciencies
reported as the most common post-radiosurgery endocrinop-
athies. New or progressive cranial nerve defi cits were noted in
9.3% of patients; 6.6% had worsening or new onset optic nerve
dysfunction. No patient died as a result of tumor progression135.
A large series from the Ospedale San Raffaele in Milano was
presented with 238 patients with a diagnosis of non-function-
ing pituitary adenoma (NFPA) and secreting pituitary adenoma
(SPA) in 249 patients. All patients had been treated surgically
and were treated with GKRS for residual pituitary tumor (medial
marginal dose 15.4 Gy for NFPA and 23.1 Gy for SPA, the dose to
the optic pathways <10 Gy, mean FU after GKRS 68.75 months).
Only 5.1% showed recurrences and of those, 72% were outside
the radiation fi eld. Current doses were found to be adequate for
growth control, since only 1.4% developed in-fi eld recurrences
following GKRS136.
Pituitary Adenoma
34
35
Secreting Pituitary AdenomasWhen compared with a second transsphenoidal adenomectomy, a high-
er recurrence-free interval was shown after Gamma Knife treatment
of patients with relapse of Cushing’s disease (n=52), who had random-
ly undergone either second surgery or GKRS as the next therapeutic
approach137. In a series of 91 patients with functional pituitary microade-
nomas, the hormone level was normalized in 42.8% patients, partly recov-
ered in 25.3% and showed no change 16.5%, and increased 15.4%. For
56 patients with prolactin secreting microadenomas, the serum prolac-
tin decreased in 41.1% patients138. Similarly others reported a biochem-
ical remission occurred in 45.3% (58/128) at mean prescription doses of
26Gy, with highest success rate being among ACTH secreting adenoma
patients. Hormonal normalization occurred at a mean of 20.4 months
(6-84 months), the earliest among prolactinoma patients139. In a series
with 128 pituitary microprolactinoma treated with GKRS serum prolactin
normalised or decreased in 87% (prescription dose 23 Gy)140.
Threshold Doses for Radiation-Induced Optic NeuropathyThe radiosurgical and radiotherapeutical dose thresholds for visual
complications have been defi ned based on relatively small series using
older technology. Data that further define the dose thresholds for the
optic nerves and defi ne the boundaries of single session radiosurgery are
highly relevant. The following study aimed at determining the dose-vol-
ume tolerance of the optic nerves and chiasm in 116 patients with
pituitary adenomas treated with GKRS without previous radiation. The
median maximum point dose to the anterior visual pathways was 9.2 Gy
(2.4-14.5), 64% of measured sides received > 8 Gy, 35% of sides received
> 10 Gy and 12% of sides received > 12 Gy. While formal ophthalmologi-
cal testing after SRS was not available for 19%, it appeared as noteworthy
that no tested patient had a documented decline in their visual function
after SRS. The 95% confi dence interval of developing a radiation-induced
optic neuropathy at the 8-Gy, 10-Gy, and 12-Gy volumes in this series were
0-3.0%, 0-5.4%, and 0-14.8%, respectively. The conclusion of the authors
was, that the anterior visual pathways in patients without prior radiation
treatments can safely receive radiation doses up to 12 Gy with a low risk of
radiation-induced optic neuropathy141. These data will have to be confi rmed
in larger studies before they can be applied safely in clinical practice.
36 36
Other Benign Tumors
36
Central NeurocytomaA retrospective analysis of 36 patients with central neurocyto-
ma who had been treated with GKRS in 12 institutions in Japan
was presented with cumulative local tumor control rates of 94%
and 86% at 5 and 10 years, respectively. Three patients devel-
oped distant dissemination (mean tumor volume 6.4 ml, mean
prescription dose 15 Gy, mean follow-up 57.5 months)132.
Facial SchwannomaTen cases of facial schwannomas were reported: marginal dose
of 12 Gy, mean clinical and radiological follow-up 44.6 months.
Overall tumor control rate was 100%. Postoperative facial palsy
was seen in 20% of patients (transient: 10%). Hearing deteriora-
tion was seen in 20%133.
Trigeminal SchwannomaIn one of the largest series of trigeminal schwannomas in
53 patients treated by GKRS, the actuarial 5- and 10-year
progression-free survival rates were 90% and 82%, respec-
tively (median tumor volume 6.0 cm3, median marginal doses
14 Gy, median follow-up period 98 months). The conclusion
was that GKRS can be an acceptable alternative to surgical
resection in patients with trigeminal schwannomas. However,
large tumors compressing the brainstem with deviation of the
fourth ventricle should be removed surgically134.
Glomus TumorsA retrospective study analysed the outcome in 44 patients
with glomus tumors; open surgery had preceded radiosurgery
in 46%, embolization in 17% and fractionated radiotherapy in
4% (mean tumor volume 3.6 cm3, range: 0.2-24.3 cm3, medi-
an prescription dose 20 Gy, range: 10-30 Gy). With a median
follow-up period of 110 months, tumor size decreased in 77%,
showed no change in 20% and increased in 2%. A prescription
dose of > 15 Gy is recommended (data from slides)75.
CraniopharyngiomaIn patients with craniopharyngioma treated with GKRS, tumor
progression free survival rate was 72% after 5 years and 38%
after 10 years follow-up (n=113, median tumor volume 5.6cc,
median prescription dose 12 Gy, follow-up 41 months).
Although 9 patients died during follow-up, mortality was relat-
ed to tumor progression in only 4 patients142. Tumor control
rate was 79.2% in another study of craniopharyngioma (n=24,
mean volume 2.5 ml, mean prescription dose 11.96 Gy, mean
follow-up period 64.1 months). Actuarial survival was 96% and
80% after 5 and 8 years, respectively, however, PFS was 79.5%
and 53% after 5 and 8 years. Two patients died of hypothalamic
invasion of tumor at 14 and 8.5 years after the diagnosis143.
37
Long-term follow-up after Gamma Knife treatment of a glomus tumor; from Roman Liscak75
A prescription dose of > 15 Gy is recommended for the treatment of glomus tumors (data from slides) from Roman Liscak75
38
After standard fractionated radiotherapy, 77%-90% patients
relapse within 2 cm of the original glioblastoma within 20-40
weeks. The median survival time after reoperation of recurrent
glioblastoma can be estimated with 3.5-9 months, provided
that the patients are in good preoperative clinical condition.
Stereotactic radiosurgery has been used as the treatment for
glioblastoma as up-front treatment or for recurrent tumors.
When compared to other technologies, Leksell Gamma Knife is
superior in terms of radiation dose gradients and accuracy.
In the current literature, salvage stereotactic radiosurgery was
used in 16 studies and 643 patients in the treatment of glioblas-
toma recurrences. Overall survival was reported in 11 studies
(422 patients) as ranging between 16.7-33.2 months.
In 9 out of these 11 studies comprising 88% of published
patients (370/422 patients) the overall median survival ranged
between 18 and 33.2 months, which is more favorable than
the outcome in the best prognostic group of glioblastoma
patients (RPA class 3) after conventional treatment. There were
14/16 studies comprising 590 patients that reported the surviv-
al specifi cally after radiosurgical treatment for the glioblastoma
recurrence ranging between 6.5 and 30 months. In 10 out of
those 14 studies representing 82% of published patients who
had been treated with salvage radiosurgery (486/590), the
median survival was 10-30 months after the recurrence, which
compares favorably to the outcome after reoperation of recur-
rent glioblastoma (3.5-9 months), the treatment with temozolo-
mide and the median overall survival on bevacizumab after
glioblastoma recurrence (4.5 months).
Glioma
38
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0.3 0.8 1.32.4
4.1
5.9
7.8
9.4
11.2
13.0
14.8
16.8
18.7
20.722.1
23.825.1
26.427.6
29.1
30.832.2
33.6
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Thousands
Glial tumor – Cumulative worldwide
Malignant GliomaTumor recurrence after initial standard therapy of glioblasto-
ma is virtually inevitable. Even after resection and fractionat-
ed radiotherapy of glioblastoma, the outcome is poor with a
reported median overall survival of 9-12 months.
39
For patients with recurrent glioblastoma the outcome
after use of stereotactic radiosurgery appeared to be at
least equivalent to repeated surgical resection and more
effective than chemotherapy alone. Hence the retrospective
evidence shows that stereotactic salvage radiosurgery in gener-
al and Gamma Knife radiosurgery in particular off ers a safe and
eff ective minimally invasive treatment strategy for glioblasto-
ma recurrences in a situation when only very few alternative
options exist.
Christopher Duma described that glioblastoma multiforme
cells migrate along predictable white matter pathways; his
hypothesis is that this spread may be blunted by high-dose,
single-fraction radiation. He claims that it has been shown that
glioblastoma cells will undergo apoptosis if rendered unable
to migrate. The hypothesis is that targeting white matter path-
ways, adjacent to the original enhancing tumor site (“Leading
Edge”© GKRS) should improve survival for patients with glio-
blastoma. A total of 109 patients with newly diagnosed glio-
blastoma were treated with GK radiosurgery to the “Leading
Edge”© of tumor cell migration as defi ned as the region outside
the enhancing, tumor nidus, defi ned by FLAIR MRI and/or MR
spectroscopy. Subjectivity in choosing the ”Leading Edge” is
the main limitation of the technique. A median volume of 33.5
cm3 of tissue was targeted using a median prescription dose of
8 Gy. The overall median survival from time of diagnosis was
23 months and 43% were still alive at 2 years, 19% at 3 years,
12% at 5 years. Admission and mannitol for radiation induced
edema was necessary in 9% and permanent complications
were seen in 6%144. In this context it is interesting to see an in
vitro study that showed that low-dose gamma knife radiation
of 6~8Gy could even increase the invasive ability of glioma cell
lines (U87 and U251)145.
Glioma
40
Patients with recurrent glioblastoma were retreated with
low-dose GKRS (median prescription dose 10Gy) after failed
multimodal treatment including surgical resection, chemother-
apy and fractionated external beam radiation therapy. Average
time from first surgery to GKRS was 17 months. (n=42, median
target volume 5.1ccm) Median overall survival was 25.6 months
from time of diagnosis, 19% showed radiation induced edema,
2.4% necrosis and 2.4% cysts. Median survival after first GKRS
was 9.6 months146. Higher doses were applied in 18 patients
with recurrent GBM treated with GKRS. The treatment target
consisted in the contrast-enhancing lesion on MRI imaging
(median treatment volume 7.3 cc, median marginal dose 18 Gy).
Similar to the previous study, median overall survival time was
12 months following GKRS treatment. The local recurrence rate
was 50% at 3 months, and 76% at 6 months. Only one patient
developed significant toxicity with surgically resected radia-
tion necrosis following GKRS147. A higher rate of side effects
was reported in another study of 55 patients with high grade
glioma (WHO III and WHO IV) who had been treated with GKRS
for local recurrences at higher doses (median tumor volume
5.2 cc, prescription dose: 20 Gy). In 40%, there were secondarily
increasing contrast enhancing lesions that were considered as
adverse radiation effects. Median survival in WHO III patients
after GKRS of the recurrences was 24.2 months and median
survival in WHO IV was 11.3 months148. A similar rather positive
survival time of 20.2 months since initial diagnosis was shown
in another study with 63 patients with recurrent GBM: Median
survival following GKRS salvage therapy was 9.9 months for all
patients with KPS being a significant predictor of survival.
The outcome appears to be promising when compared to
an expected survival of 11.2 months for patients in Class IV
after conventional therapy149. A similar survival was reported
in 33 patients with WHO grade IV gliomas who were treated
with GKRS, the average post-GK and overall survival was 15.8
months and 40.1 months respectively. In WHO grade III gliomas,
the average post-GK and overall survival was 34.9 months and
136.4 months respectively. Even here, 67% patients showed
edema after GKRS, with 14/33 requiring dexamethasone150.
The conclusion is that Gamma Knife radiosurgery may be an
additional option in the treatment of recurrent malignant glio-
ma and glioblastoma with promising overall survival in a situ-
ation that otherwise is considered untreatable. Further infor-
mation is required to define the ideal imaging modality, the
target and doses, since the low-dose studies appear to provide
a similar treatment effect at a lower risk for radiation induced
side effects.
41
Low-Grade GliomasPilocytic astrocytoma (WHO grade I) are generally surgical-
ly resected. However, due to the generally central and often
eloquent tumor location, a significant number of patients are
considered inoperable or are left with postoperative tumor
remnants. Gamma Knife radiosurgery is a low invasive treat-
ment option for this relatively rare indication in an otherwise
complicated clinical situation. The long-term-outcome of 30
patients with pilocytic astrocytoma treated with GKRS (median
prescription dose 10 Gy) and median clinical and radiological
follow-up of 12.2 years and 10.9 years, respectively, showed a
local control of the solid tumor component in 90% and a 93%
survival at the end of the follow-up period151. A virtually iden-
tical tumor control rate of 93.5% was achieved in 46 patients
with pilocytic astrocytomas after GKRS at a mean follow-up of
48 months (mean tumor volume 5.5 cc, mean prescription dose
13.1 Gy). In 11/18 patients, where cysts were present at GKRS,
the cysts increased and 4 out of 45 patients developed new
cysts. Seizures improved in 6/15 patients. Associated clinical
deterioration occurred in 15.6% which was temporary in all but
one case (cited according to slide)152.
Stereotactic fractionated radiotherapy was used in 102 patients
with pilocytic astrocytomas (mean dose 54.8 Gy), while 54
patients underwent single session Gamma Knife treatment
(mean dose 17 Gy) with a median follow-up of 34.7 months.
Tumor control was achieved in 79.8%. In the vast majority of
patients (23/28), where tumor volume enlarged during the
follow-up, the increasing size was the result of enlargement
of cystic components153. Similarly, 19 patients were treated in 5
fractions (1 fraction per day), and 5 patients received single frac-
tion treatment for pilocytic astrocytoma and were followed for
a minimum of 10 years at the Na Homolce Hospital in Prague.
Patients slept with the stereotactic frame attached (maximum 4
nights). The median target volume was 2.7 cc (range 0.2-25 cc)
and the median minimal total target dose (for all fractions) was
25 Gy. Complete regression occurred in 40% and partial regres-
sion in 40%. Overall detected surviving fraction after 10 years
was 96%. Later progression of cysts was seen in 16% (cited
from slides)154.
In conclusion, Gamma Knife radiosurgery allows the long-term
tumor control in pilocytic astrocytoma with minimal morbidity.
Cyst development is rather frequently seen during follow-up
and may require separate treatment.
42
0.0 0.1 0.1 0.2 0.3 0.7 1.52.8
4.56.4
8.8
11.3
14.3
18.0
21.8
25.5
29.0
33.0
36.1
39.6
43.3
47.5
52.2
-91 -92 -93 -94 -95 -96 -97 -98 -99 -00 -01 -02 -03 -04 -05 -06 -07 -08 -09 -10 -11 -12 -13
Leksell Gamma KnifeTrigeminal neuralgia - Cumulative worldwide
5
Thousands
68-100% sites reporting1991 reflects cumulative numbers
These bursts are often triggered by a light touch around the
mouth or face or by talking, eating, or brushing one’s teeth.
Usually pain occurs on just one side of the face. Often the pain
responds to medication, but sometimes the dose has to be
increased and unpleasant side effects can occur. An invasive
and generally surgical procedure is recommended for patients
who continue to experience severe pain or side effects from
medications. Gamma Knife radiosurgery achieves similar results
without open surgery and without general anesthesia. Gamma
Knife radiosurgery is the most recent and least invasive neuro-
surgical treatment for trigeminal neuralgia. Through focal irradi-
ation of the trigeminal nerve close to the brain stem the facial
pain can be treated successfully without impairment of other
nerve functions.
Signifi cant pain relief can be achieved in 73% of patients at 1
year, in 65% at 2 years, and in 41% at 5 years, respectively155.
Most published series show a similar outcome with signifi cant
pain relief between 73 and 86% of patients after the Gamma
Knife intervention. After radiosurgery, about 10% of patients
may be mildly affected by facial paraesthesias. In a present-
ed retrospective study 130 patients with essential Trigeminal
Neuralgia were followed up at least 5 years after GKRS and 66%
were completely pain free at the last follow-up up (90 Gy at
maximum dose, one shot of 4 mm collimator)156. Patients with
previous surgical microvascular decompression (MVD) appear
to have a lower chance of being pain free after GKRS compared
to patients without previous MVD history: Retrogasserian GKRS
after previous MVD (n=45) showed an initial pain free rate of
77.8%, and the probability of remaining pain free at 3, 5 and 10
years was 66.5%, 59.1% and 44.3%, respectively157.
42
Thousands
Trigeminal Neuralgia – Cumulative worldwide
Functional DisordersTrigeminal NeuralgiaTrigeminal neuralgia is a disorder of the fi fth cranial (trigeminal)
nerve that causes sudden bursts of intense, stabbing, electric
shock-like facial pain. The pain is located in the areas supplied
by the trigeminal nerve in the face.
43
The optimal target position in trigeminal neuralgia has been
discussed with regards to pain relief and side eff ects, and it has
been claimed that facial hypoaesthesia after GKRS could be
avoided through a more anterior placement of the isocenter
creating a longer distance towards the root entry zone at the
brain stem. This was studied in 106 patients where the dorsal
root entry zone was targeted with a maximum dose of 90 Gy. It
appeared that the pain relief and pain recurrence was not infl u-
enced by diff erences in distance between the target and brain
stem, while radiation-induced facial hypoesthesia appeared to
result from a more proximal target158.
Volume diff erences between aff ected and unaff ected trigem-
inal nerves have been described, and the volume of the
trigeminal nerve on the aff ected side was shown to be signifi -
cantly smaller than the volume of the unaff ected side, but the
evaluation of nerve volumes along their course through the
pontocerebellar cistern (n=55) did not support the hypothe-
sis that volume changes are a predictive factor for successful
treatment by GKRS159. Another study documented no statis-
tically signifi cant diff erences in cross sectional areas or nerve
volumes between aff ected and unaff ected trigeminal nerves
and no diff erence in cross sectional area at the root entry-zone,
midpoint, nerve entry point to Meckel’s cave, or nerve volume
between normal and aff ected nerves (n=68)160.
Functional Disorders
44
Radiobiological aspects suggest an infl uence of the radiation
dose rate on the outcome after radiosurgery161. Hence, the clin-
ical impact of the radiation dose rate was tested in 497 patients
with classical trigeminal neuralgia who had been treated with
GKRS at a median maximum dose of 85 Gy. Patients were divid-
ed into 2 groups: a low dose rate group (LDR, 0.891-2.513 Gy/
minute; n=210) and a high dose rate group (HDR, 2.514- 4.099
Gy/minute; n= 208). A total of 50.5% were pain free in the LDR
group and 49.5% in the HDR group, respectively (p=0.69) and
20.1% developed new or increased facial sensory dysfunction
and 33.8% had a recurrence. However, within the tested range
between 0.891 and 4.099 Gy/minute, the variation in dose rate
did not affect the rate of freedom of pain, the onset hypoes-
thesia or the probability of recurrence after GKRS for trigeminal
neuralgia162.
In cases of recurrent pain, GKRS can be repeated. It can be esti-
mated that 83% of patients will experience pain relief from a
second GK procedure with side eff ects in 10.5% including facial
numbness, corneal dryness and diffi culty swallowing; however,
only 5% of these patients found these eff ects to be bothersome
(n=38). The conclusion was that repeat GKRS proved to be
eff ective with an acceptable risk of side eff ects163.
In patients with multiple sclerosis-related trigeminal neuralgia
the outcome of GKRS has been reported to be less favorable
which is in line with the results of all other treatment modal-
ities in this condition. While 90.7% (39/43) of these patients
were initially pain free within a median of 30 days, 61.5%
experienced a pain recurrence after a median delay of 16
months and hence their probability of remaining pain free at
1, 3 and 5 years was 71.8%, 43.1% and 38.3%, respectively. The
high rate for the recurrence of the trigeminal pain is specifi c
to this clinical entity164..
Glossopharyngeal NeuralgiaEven glossopharyngeal neuralgia has been treated with GKRS.
in a small study all patients (n=5) improved between 3 and 6
months after treatment, three cases are without pain and with-
out medication. No neurological deficit has been observed
after the treatment. The glossopharyngeal nerve was targeted
in the jugular foramen, a maximum dose of 90 Gy was adminis-
trated with a 4 mm collimator165.
Target point for glossopharyngeal neuralgia treated with GKRS in CT and ”FIESTA” MR sequences (General Electric®). From Roberto Martinez Alvarez 165
45
Gamma Knife ThalamotomyLesioning in functional neurosurgery has maintained an
important role in the treatment of movement disorders and a
variety of lesioning technologies are still available. A worldwide
survey of a total of 353 neurosurgeons from 51 countries who
had operated on 13,200 patients showed that ablative surgery
is still used by about 65% of neurosurgeons, regardless of their
country’s economic status171. The current options for lesioning
procedures were reviewed by Takaomi Taira172.
Gamma Knife provides a non-invasive option for functional
lesions in movement disorders and even in selected cases of
psychosurgery. The neurological outcome after unilateral VIM
Gamma Knife thalamotomy for Parkinsonian’s or essential trem-
or was evaluated in 95 treated patients showing that 75% of
patients clinically responded to thalamotomy. The mean clin-
ical improvement score was 61.5%. One very large lesion was
described but excluded from the analysis. The conclusion
was that VIM Gammaknife thalamotomy is a safe and effec-
tive option for intractable tremor173. Virtually identical results
were reported in a series from Warsaw, after Gamma Knife
thalamotomy for the treatment of Parkinsonian and essential
tremor, where 76% of patients became tremor free or nearly
tremor free (n=48, median radiation dose 130 Gy). Two types
of tissue reaction were observed on follow-up MR imaging:
an oval necrotic lesion up to 5-7 mm without surrounding
edema and a complex irregular shaped necrosis with thalamus/
midbrain edema. In the group of the last 18 patients, DTI was
utilized analysis to visualize internal capsule fibers that are in
the vicinity of VIM nucleus174. Another series with 20 patients
who underwent Gamma Knife VIM thalamotomy (130 Gy, single
4 mm collimator) showed signifi cant tremor relief in 85%, with
complete relief in 50%175.
Patients with essential tremor either only or predominantly
aff ecting axial structures, including the head and neck, voice
or lower jaw, respond to staged bilateral Gamma Knife VIM
thalamotomy (n=68; maximum dose 140 Gy, mean follow-up
up is 65 months). The results are comparable to those seen
after bilateral Deep Brain Stimulation. Head and neck tremor
improved in the applied tremor scale from a mean of 3.1 +/- 1.2
preoperatively to 2.2 +/- 1.1 after unilateral Gamma Knife thal-
amotomy and to 1.1 +/- 0.7 after bilateral thalamotomy. Similar,
statistically signifi cant improvements were seen in both voice
and lower jaw tremor. Two patients experienced complications
including speech, balance and gait problem of the total of 136
procedures176.
The functional VIM target in 7T and 3T MRI. From Constantin Tuleasca169
46 46
Imaging and ThalamotomyHigh-resolution susceptibility weighted images at 7Tesla MRI
provided a superior resolution and an improved image contrast
within the central gray matter and allowed visualization of
thalamic subparts to improve anatomic imaging for Gamma
Knife radiosurgery of VIM. The 7T images could be imported
into the Leksell Gamma Plan® software and co-registered with
stereotactic images169. On the other hand it was shown that
susceptibility artifacts in the interfacing areas of paranasal sinus
and skull base can impair the acquisition of detailed images in
the 7.0T5.
VIM target defi nition in 7T MRI. From Constantin Tuleasca169
As an alternative, a novel approach using 3-T multiband DTI
appears to delineate most internal nuclei of the thalamus
based on diff erences in track density and/or diff usion anisot-
ropy at 500-micron resolution. The results appear signifi cant-
ly improved compared to previous diffusion tensor imaging
parcellations of the thalamus170.
Visualisation of thalamic nuclei based on diff erences in track density and/or diff usion anisotropy. From Douglas Kondziolka170
47
Imaging Accuracy The delineation of target is a manual process, influenced by
both experience and image quality. Significant differences and
variability in target identification were demonstrated between
radiosurgical centers emphasizing the importance of under-
standing target definition in stereotactic radiosurgery166.
MRI is the primary imaging modality used for Gamma Knife
radiosurgery, yet inherent distortions with this imaging modal-
ity are well known. Using two dif ferent target phantoms,
image distortion at different points in the clinical target area
were measured for multiple protocols on 57 MR scanners at 45
Gamma Knife sites. The mean and maximum errors for 57 test-
ed MR scanners were 0.76 mm (range 0.40 to 1.58 mm) and 1.27
mm (range 0.78 to 3.78 mm) respectively.
Mean errors measured with a phantom were on average 1.6
times larger than the mean fiducial errors quoted by LGP, while
maximum errors were about the same. The mean and maxi-
mum errors for all CT scanners investigated (n=30) were 0.46
mm (range 0.23 to 0.98 mm) and 0.81mm (range 0.45 to 1.96
mm) respectively167.
It is generally accepted that targets that are located above
the MR fiducial box can be treated. A quantitative evaluation
showed that targets up to 36 mm over the fiducial box are safe-
ly treated, since the effect of not having fiducial is not expected
to alter the MR information by more than ±0.1 mm168.
48
Stereotactic hypofractionation using the Gamma Knife was
applied in pilocytic astrocytoma154, vestibular schwannom-
as125, large meningiomas111, perioptic meningioma112 and for
large brain metastases (>10cc in volume22)177. The results are
discussed in the respective sections.
A technical alternative to the Extend frame was presented that
allows fractionated GKRS using a relocatable frame: four plas-
tic fi ducial screws are mounted in the outer surface of the skull
prior to MRI imaging. For MRI, fi ducial markers are attached on
the fiducial screws, producing a stereotactic image without
merging or co-registration. The fi ducial screws function both
as fi ducial markers and fi xation devices for a stereotactic frame.
After MRI, a relocatable Leksell G frame is attached to the fi du-
cial screws. A feasibility study demonstrated stability and repro-
ducibility177.
Jonathan Knisely reviewed the pros and cons for fractionated
stereotactic radiosurgery and came to the conclusion that there
is still no strong evidence base upon which to recommend frac-
tionated radiosurgery, since there are no class I data comparing
single-fraction radiosurgery to fractionated radiosurgery178.
Fractionation
48
49
Orbital LesionsThe effect of GKRS in 31 children with orbital lesions was
reported (median age 6 years; mean prescription dose 15.9Gy,
median follow-up: 32 months). No further tumor enlargement
was observed after GKRS. 25.8% had an improvement in their
symptoms, and remained stable in 58%, and deteriorated in
16.1%. The most common complication was reversible conjunc-
tival edema usually within 3 months. No other serious acute
adverse eff ects were observed179.
Ophthalmologic Indications: Stenopeic Eye FixationDue to eye ball movement, radiosurgery of intra orbital lesions
typically requires the surgical fi xation of the eye during image
acquisition and dose delivery. Instead of this comparatively
invasive approach, a simple and non invasive fi xation solution
was presented using a plate with a pinhole for each eye. The
plate is fi xed to the anterior posts of the frame. The eye ball is
naturally fi xed when the patient is looking through the pinhole
of the side of the lesion during both MRI and dose delivery. So
far 10 patients with orbital lesions have been treated relying
on this eye fi xation system and the authors stated ”a suffi cient
residual visual acuity”180.
GlaucomaA retrospective series after GKRS in the treatment of secondary
glaucoma compared the 2-year results with the 7-year results in
57 patients. The authors had used four shots using 8 mm colli-
mators to irradiate the ciliary body (prescription dose 20 Gy for
blind eyes and prescription dose 15Gy for partially preserved
vision). The average follow-up up was 82 months. The conclu-
sion was that GKRS can eff ectively achieve reduction of pain,
intraocular pressure and extensive pharmacotherapy in second-
ary glaucoma181.
Ophthalmologic Indications
50
Gamma Knife Hypophysectomy for Cancer PainIn an interesting novel approach 21 patients with cancer pain
were treated with Gamma Knife radiosurgery lesioning of the
anterior lobe of the pituitary gland with 140-180Gy maximum
dose using one shot of the 8 mm collimator. A total of 90.5%
of the patients experienced signifi cant pain reduction without
significant complication except for endocrinological impair-
ment156.
Modern Genetic Approaches to GliomaRobert Darnell, New York, NY182
Robert Darnell’s lab has discovered that neurons have unique
systems for regulating gene expression, but not at the level of
DNA transcription. Rather, these systems regulate RNA metab-
olism via neuron-specifi c RNA binding proteins. Many diff erent
RNA variants, and consequently protein variants, can be gener-
ated by this system. To understand this regulation in the brain,
Robert Darnell’s lab has developed a high throughput genomic
method termed HITS-CLIP to precisely map relevant protein-
RNA interaction sites with single resolution. Relevant systems
that are undergoing current analysis include RNA control and
dysregulation in brain tumors, in chronically stressed brain
in Alzheimer’s disease, and in ischemic brain. Robert Darnell
discussed these studies along with their relevance and appli-
cability to various clinical scenarios and with a focus on genetic
approaches to glioma182.
A Stem-Cell Based Surgical Transplantation Therapy for Parkinson’s DiseaseOle Isacson, Boston, MA183
The experimental field of restorative neurology continues
to advance with implantation of cells or transfer of genes to
treat patients with neurological diseases. Both strategies have
demonstrated their capacity for structural and molecular modi-
fication in the adult brain. However, both approaches have
yet to successfully address the complexities of actual clinical
applicability. New non-pharmacological treatment strategies
involve cell and synaptic renewal or cell replacement in the
living brain to restore the function of neuronal systems, includ-
ing the dopaminergic (DA) system in Parkinson’s disease. The
experimental cell transplantation to patients with Parkinson’s
disease (PD) utilizes dissected pieces of fetal midbrain tissue as
donor cells. Stem cell and progenitor cell biology provide new
opportunities for selection and development of large batches
of specifi c therapeutic cells. This may allow for cell composition
analysis and dosing in order to create a benefit for individual
patients. The biotechnology used for cell and gene therapy for
treatment of neurological disease could eventually become
as advanced as today’s pharmaceutical drug-related design
processes. Current gene therapy phase 1 safety trials for PD
include the delivery of a growth factor (neurturin) and a trans-
mitter enzyme (glutamic acid decarboxylase and aromatic acid
decarboxylase).
Novel Approaches
50
51
Although recent laboratory work has focused on using stem
cells as a starting point for exogenous or endogenous deri-
vation of the optimal DA cells for repair, DA cell therapy using
dissected fetal DA tissue containing neurons has already been
explored in PD patients. Human fetal dopamine ventral mesen-
cephalic neurons have been shown to be functional in clinical
trials in PD patients.
Many new insights from cell biological and molecular stud-
ies provide opportunities to selectively express or suppress
factors relevant to neuroprotection involved in Parkin-
son’s disease. Future gene and cell therapies are likely to
coexist with classic pharmacological therapies because
their use can be tailored to individual patients’ underly-
ing condition. Open-label trials consistently demonstrat-
ed that functional motor deficits associated with Parkin-
son’s disease can be reduced after application of this new
technology, but so far double-blind trials failed to show
evidence of significant benefit in comparison with placebo.
The fi eld was reviewed by Ole Isacson183.
Novel Approaches
52
Focused Ultrasound: The New Frontier? Jessica Foley: Focused Ultrasound Foundation,
Charlottesville, VA USA184
Circa 1950 Lars Leksell invented focused ultrasound as a less
invasive alternative to open surgery for the treatment of move-
ment disorders. However, after treating a number of patients,
he abandoned this technology because it required a craniot-
omy and because there was no imaging technology to enable
effective guidance, monitoring, and control of the treatment. At
that time, there was no option to focus beams of ultrasound on
a target in the brain through the intact skull. Currently, focused
ultrasound is experiencing a renaissance. As a result of advanc-
es in ultrasound transducer design, high-speed computing
technologies and MR imaging, focused ultrasound now has the
potential to treat a variety of intracranial disorders noninvasive-
ly. Indications at various stages of research and development
currently include movement disorders, brain tumors, epilepsy,
neuropathic pain, OCD, thromboembolic and hemorrhagic
stroke. Near-term studies on blood brain barrier opening and
neuromodulation are also planned. The new developments
were reviewed by Jessica Foley184.
Neuro-Immunology and Therapeutic Radiation Kevin Tracey, Manhasset, NY185
The autonomic nervous system maintains homeostasis through
its sympathetic and parasympathetic divisions. During inflam-
mation, cells of the immune system release cytokines and
other mediators that cause fever, hypotension, and tissue inju-
ry. Although the effect of cytokines on the nervous system has
been known for decades, only recently has it become evident
that the autonomic nervous system, in turn, regulates cytokine
production through neural pathways. Neural circuits regulate
cytokine production to prevent potentially damaging inflam-
mation.
It has previously been shown that efferent vagus nerve signals
inhibit TNF-α production in spleen by a mechanism requir-
ing acetylcholine signaling through the α7 nicotinic acetyl-
choline receptor expressed on cytokine-producing macro-
phages. This mechanism has been termed “the cholinergic
anti-inflammatory pathway”. Nerve fibers in spleen lack the
enzymatic machinery necessary for acetylcholine produc-
tion, but an acetylcholine-producing, memory phenotype
T cell population in mice has been identified that is integral to
the inflammatory reflex. These acetylcholine-producing T cells
are required for inhibition of cytokine production by vagus
nerve stimulation.
Thus, action potentials originating in the vagus nerve regulate
T cells, which in turn produce the neurotransmitter, acetylcho-
line, required to control innate immune responses. This mecha-
nism can conceptually be modified by vagus nerve stimulation,
which so far has been used to treat patients with rheumatoid
arthritis185.
53
Neural circuits can regulate cytokine production. From Kevin Tracey185
During endotoxemia, vagus nerve stimulation specifically
attenuates TNF-α production by spleen macrophages in the
red pulp and the marginal zone. The cholinergic anti-infl amma-
tory pathway regulates TNF-a (alpha) production in discrete
macrophage populations via two serially connected neurons:
one preganglionic, originating in the dorsal motor nucleus of
the vagus nerve, and the second postganglionic, originating
in the celiac-superior mesenteric plexus, and projecting in the
splenic nerve. The modulation of this circuit could potentially
attenuate the outcome in patients with septic shock185.
54
The collateral dose to normal tissues during treatment contin-
ues to be an area of interest, being a hallmark of radiosur-
gery treatment. With a trend towards an increased number
of metastases treated per patient, some Gamma Knife users
are insecure about the dose to the normal brain being within
acceptable limits.
Ian Paddick spoke on brain doses from the treatment of multi-
ple metastases with the Gamma Knife. He compared dose
volume histograms from a GK plan for 28 metastases with
those from WBRT (30Gy in 10 fractions). The Gamma Knife
plan had around an order of magnitude less dose to the whole
head, i.e., about the level of just one fraction of WBRT. This low
dose corroborates a safety that even allows multiple treatment
sessions. In an extreme example, of 114 metastases managed
with Gamma Knife over 5 sessions in 15 months, there was
again a very low whole head dose which was approximately
equivalent to a single fraction of WBRT, once sub-lethal repair
had taken place in between each treatment session.
Lijun Ma backed this up with his latest publication; ‘Variations
in dose interplay across radiosurgical apparatus in treating brain
metastasis’. Ma’s goal was to benchmark Truebeam Flattening
Filter Free (FFF) linac technology with results already published
for Gamma Knife, Cyberknife and Novalis. Gamma Knife was
shown to be overall the most conformal of all the radiosurgery
platforms and also gave up to 74% lower dose to normal brain
tissue. Even when up to three non-coplanar arcs were used
with the Truebeam platform, normal brain doses were still far
higher than those from the Gamma Knife.
PHYSICS AND RADIOBIOLOGYIan Paddick, MS
The 17th meeting of the Leksell Gamma Knife Society had a strong physics presence. Previously relegated to parallel sessions, the
physics sessions were well attended by clinicians which gave them a chance to catch up on a number of current key issues in the
area of Gamma Knife physics.
Brain Doses from the Treatment of Multiple Metastases
54
55
Technological DevelopmentsThe next Gamma Knife model is always an intriguing subject.
A number of excellent presentations were made by physicists
from Elekta’s R&D department, covering topics related to the
development of the next generation Leksell Gamma Knife.
Håkan Nordström talked about cone beam CT (CBCT) image
quality, and the difficulties of the high scatter component
of cone beam CT. Jonas Johansson spoke about the poten-
tial increases in skin dose from mask fi xation, which although
signifi cant, were still less than skin doses calculated by Leksell
GammaPlan. The complexity of various issues related to the
new Gamma Knife development were appreciated by the
attendees. The detail of work carried out by the Elekta R&D
team reassured us that every aspect of the development has
been considered and thoroughly investigated.
Ian Paddick reminded us that even small changes to the radio-
surgery platform can enhance the delivered treatment, in
an historical review of how planning parameters (coverage,
selectivity, conformity, gradient index and beam on time) have
improved with each successive version of the Gamma Knife
over the last 15 years. Interestingly, he also showed that recent
enhancements to GammaPlan have contributed equally signifi -
cant improvements to treatment plan quality, when compared
with hardware developments.
56
Accuracy of Co-RegistrationThe co-registration tool in Leksell GammaPlan is loved by many,
but still eyed with suspicion by some, as it is very difficult to
quantify the accuracy of the process. Co-registration in Gamma-
Plan is a simple but powerful tool that can be used in a number
of ways. For example: co-registration of 3T MRI to stereotactic
CT on the day of treatment gives a treating team the flexibil-
ity to obtain images of superior quality, using 16 or even 32
channel head coils, that are not compatible with the Leksell
frame. The freedom to allow pre-planning in an unpressurised
environment is also appreciated by some. However, there have
been concerns regarding the accuracy of this process. Some
novel presentations at the meeting have reassured sceptics of
many concerns and suggested that co-registration to CT may
be as accurate as a dedicated stereotactic MRI scan.
Francisco Li presented his work on co-registration accuracy in
thalamotomy treatments, where the highest degree of accu-
racy is required. He found that co-registration of 3T MRI to CT
gave lower errors than using 3T alone. Average deviation was
less than 1mm. Using DTI to demonstrate the internal capsule
helped further to define a consistent target. It may be that the
additional confidence in the target outline gained by better
3T scanning outweighs the uncertainty in the co-registration
process.
Håkan Nordström spoke about the co-registration algorithm,
in connection with the next generation Leksell Gamma Knife
project. During this project, an additional refinement step was
added in the co-registration process, and a calculation of an
estimated mean target registration error (TRE) was devised,
giving an estimation of the accuracy of the process. For regis-
tration of MRI to CT, typical TREs were less than 0.1mm. This
compelling work suggested that co-registration with CT can be
very good indeed.
Target OutliningIs target outlining a source of inaccuracy in our treatments?
Helena Sandström updated us on her excellent work, looking
at the consistency in target outlining between 12 centers. Each
center was asked to outline and plan 6 different targets. Even
for a target as simple as a vestibular schwannoma, the common
volume, agreed by all 12 centers, was just 50% of the aggre-
gate volume drawn by at least one center. The inconsistency of
target definition reminded us that this is still the least accurate
process in the whole of radiosurgery.
Outside of the presentations, on a related matter, the Organ
At Risk (OAR) Standardization Working Group, led by Caro-
line Chung, met and found common ground with the aim of
producing a consensus document of contouring recommen-
dations to improve consistency of outlining and hence the
quality of prospective data collection to help establish radiosur-
gery-specific dose constraints.
57
RadiobiologyAnother major area of uncertainty is in the Biologically Effective
Dose of treatment. This is proportional to the dose prescribed if
the treatment is given at the same dose rate, but the dose rate
is known to vary. Until recently, studies have only explored the
effect of the reference dose rate of the machine with clinical
effect. It is not surprising that this has shown no relationship.
We often plan similar targets to the same dose, with resulting
treatment times that vary by a greater range than the refer-
ence dose rate will ever do. Furthermore, each voxel ‘sees’ a
dose rate that varies dramatically during treatment, depending
on its proximity to every isocenter which makes up the overall
treatment. John Hopewell showed the world’s first Biologically
Effective Dose Volume Histograms (BEDVHs) of dosimetrically
similar Gamma Knife treatment plans for vestibular schwanno-
ma. This showed that the BED varied by up to 15% between
plans prescribed to the same dose.
Viewing this in another way, while one plan had 100% coverage
of a BED referenced to its prescription dose, the other plan had
only 65% coverage of this same BED (3 isocenters vs 13 isocen-
ters , Model B), despite both plans being prescribed to the same
dose. Furthermore, due to the efficiency of treatment delivery,
Perfexion treatments had about a further 15% increase in BED
when compared with similar plans treated with the Model B.
One may ask why does a certain dose control a lesion in one
patient, but not another? Granted, a range in inherent biologi-
cal sensitivity is to be expected, but the answer to this question
has never been quite clear.
A physicist is obsessed with ensuring consistent treatments. In
terms of absolute dose, we have now nailed this down to just
two or three percent, but new areas have opened up (target
outlining, BED), showing us huge variations in the effective
treatment we are giving. This gives a fantastic opportunity build
on the work we have done and to address these variations, to
give more consistent and better treatments to our patients.
58
NEW AND ONGOING STUDIESReport of the North American Gamma Knife ConsortiumAjay Niranjan: University of Pittsburgh - Pittsburgh, PA USA186
The North American Gamma Knife Consortium (NAGKC) was formed in 2008 in order to facilitate both retrospective and prospective
clinical trials of radiosurgery performed with the same delivery platform. The consortium has published retrospective clinical trials related
to cluster headache, glomus tumors, chordoma, and non-functioning pituitary tumors. Completed retrospective clinical trials related to
chondrosarcoma and hemangioblastomas were submitted. Trials in accrual include posterior fossa meningiomas, repeat AVM radiosur-
gery, meningioma edema, and pineal region tumors. Prospective clinical trials include NAGKC 12-01 (outcomes for more than five brain
metastases using a neurocognitive and tumor control endpoints, PI Igor Barani, UCSF) and NAGKC 12-02 (malignant glioma, radiosurgery
plus bevacizumab, a phase II clinical trial, PI Ajay Niranjan, UPMC) funded by a combination of external and internal sources.
Ongoing Studies: NAGKC 12-01 Randomized controlled study of outcomes in patients with five or more brain metastases update: a study of cognition in patients with 5+ MetastasesPI Igor J. Barani, M.D
NAGKC 12-02: Multicenter Phase II Study of Border Zone Stereotactic Radiosurgery with Bevacizumab in Patients with Recurrent or Progressive Glioblastoma MultiformePI Ajay Niranjan MBA Hideyuki Kano MD, PhD Edward Monaco III,
MD, PhD John C Flickinger MD, L. Dade Lunsford MD
STUDY TYPE: InterventionalSTUDY DESIGN: Single-arm, one-stage phase II trialALLOCATION: Non-RandomizedENDPOINT CLASSIFICATION: Safety/Efficacy StudyMASKING: Open Label Primary Purpose: Treatment Patient NUMbErS: 40INDICATION: Recurrent or Progressive GBMHYPOTHESIS: ‘Border zone’ of GBM is defined as MRI volume of enhance-ment plus up to 2 cm of the surrounding T2 volume. This represents the volume of tumor infiltrated white matter and is the route of GBM spread.
HYPOTHESES:1. GBM is a “local” disease2. Failure to eradicate tumor cells in the migration path- ways (the “border zone”) leads to tumor progression.3. Survival will improve if SRS target volume includes the “border zone”4. Bevacizumab, a monoclonal antibody to VEGF, has been approved for GBM.5. SRS + BVZ will be an effective strategy for GBM (BVZ will maximize the effects of radiation in the treated volume and potentially reduce radiation toxicity in the adjacent brain)
NAGKC 13-01 Radiosurgery or Open Surgery for Epilepsy (ROSE)• Phase3trialcomparingtemporallobectomywith radiosurgery – 14 U.S. sites, 2 India, 2 U.K.• Randomizedcomparisonof234cases• Largenumberrequiredtoshow“non-inferiority”• Sixyearswithprimaryaimseizure-freedominthird follow-up year• Radiosurgeryrequiresanaverageof1yearforinitialresponse• Definitionofseizure-freeis12consecutivemonthswith no seizures
58
59
PrOCEDUrE• Afteratreatmentplanisdeveloped,itwillbetransferred electronically to UCSF for review and approval.• Amygdala,anterior2cmofthehippocampus,parahip- pocampal gyrus will be included in the radiosurgical target (volume to range from 5.5-7.5).• Patientswillreceive24Gytothe50%isodoselineusingan unlimited number of isocenters (likely to range from six to 30).• Brainstem/ON10Gy/8Gy
Target volume for Gamma Knife treatment of Mesial Temporal lobe Epilepsy. From Nicholas M. Barbaro187
59
French Prospective Trial in ProgressGamma Knife Subthalamotomy for Parkinson’s Disease: A Prospective Trial.PI Jean Régis, Tatiana Witjas, Romain Carron, Jean Philippe Azulay
• StereotacticthermocoagulationoftheSTNmayinduce signifi cant and long-lasting results (Alvarez et al. 2005 & 2009).• Intranuclearlesionisassociatedwithnooronlymild dyskinesia (Guridi & Obeso, Brain 2001)
UPDATE: 1st inclusion: 14 February 2011END OF THE INCLUSIONS: 31 December 20131ST TrEATMENT: 15 February 2011NUMbEr OF PATIENTS INCLUDED DECEMbEr 31, 2013: 14 (initial goal 20 patients) NUMbEr OF PATIENT UNDEr FU: 11AT THIS DATE:• 4patientsgotGK1+GK2at12months• 1patientgotGK2at15monthsfromGK1• 2patientsstillwaitingforGK2at18&21months from the fi rst GK• 1patient,completingisFUwithonlyonesidetreated.
Japanese Leksell Gamma Knife (JLGK) Study GroupJLGK1101 Retrospective study of symptomatic cavernous angioma.PI: Yoshihisa Kida (submitting)
334 cases from 23 facilities.
JLGK1201 Retrospective study of central neurocytoma.PI: Kazuiro Yamanaka (submitting)
36 cases from 23 facilities.CUMULATIVE LOCAL CONTrOL: 95%/5 years, 86%/10 years.CUMULATIVE PrOGrESSION-FrEE rATES (INCL DISTANT LESIONS): 88%/5 years, 64%/10 years.Neither pre-SRS clinical factors nor radiosurgical parameters were shown to correlate to progression-free survival. Symptomatic tumor hemorrhage and adverse radiation eff ect occurred in one patient each.
JLGK1302 Retrospective study of jugular foramen schwannomas.PI: Toshinori Hasegawa (recruiting cases)
117 cases from 17 facilities.
JLGK1303 Retrospective study of craniopharyngioma.PI: Tatsuhiko Tsugawa (analyzing data)
286 cases from 15 facilities.
JLGK1401 Retrospective study of brain metastases PI: Masaaki Yamamoto (recruiting cases)
74 cases from 18 facilities as of May 06, 2014.
60
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24. Ghare A, Khan, O.H, Kilian A., Mansouri, A.S. , Zadeh, G.: Toronto Western Hospital- University Health Network - Toronto, Canada. PREDICTORS OF TREATMENT RESPONSE OF CYSTIC BRAIN METASTASIS TO GAMMA KNIFE RADIOSURGERY 2014.
25. K. Ranh Voong: MD Anderson Cancer Center - Houston TU. BRAINSTEM METASTASES GAMMA KNIFE STEREOTACTIC RADIOSURGERY IN THE TREATMENT OF BRAINSTEM METASTASES 2014.
26. Halloran E Peterson: Gamma Knife of Spokane - Spokane WU. GAMMA KNIFE TREATMENT OF BRAINSTEM METASTASES2014.
27. Rupesh Kotecha: Cleveland Clinic Foundation - Cleveland OU. CALVARI-AL AND SKULL BASE METASTASES: EXPANDING THE CLINICAL UTILITY OF GAMMA KNIFE RADIOSURGERY 2014.
28. Masaaki Yamamoto: Katsuta Hospital Mito GammaHouse - Hitachi-naka J. SURGICAL REMOVAL PLUS SRS FOR BRAIN METASTASES: POST-OPERATIVE VS PRE-OPERATIVE TREATMENT 2014.
29. Vladimir Avkshtol: William Beaumount Hospital - Royal Oak MU. SURGI-CAL RESECTION AND THE RISK OF MENINGEAL RECURRENCE IN PATIENTS TREATED WITH GAMMA KNIFE2014.
30. Jason Chan: Brown University - Providence RU. TREATMENT OF BRAIN METASTASES WITH SURGERY FOLLOWED BY RADIOSURGERY VERSUS RADIOSURGERY ALONE 2014.
31. John Y.K. Lee MUoP, Dept of Radiation Oncology - Philadelphia, PA USA. PATTERNS OF INTRACRANIAL CONTROL AFTER STEREOTACTIC RADIOSUR-GERY TO THE RESECTION CAVITY 2014.
32. Christian Iorio-Morin: University of Sherbrooke - Sherbrooke QC. ADJU-VANT GAMMA-KNIFE RADIOSURGERY TO THE TUMOR BED OF RESECTED METASTASES: A SERIES OF 130 PATIENTS 2014.
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35. Patrick Hanssens, Tilburg Gamma Knife center, the Netherlands. THREE OR MORE BRAIN METASTASES - GAMMA KNIFE SURGERY OR WHOLE BRAIN RADIATION THERAPY? 2014.
36. Paul Sperduto: Gamma Knife Center UoM-M, MN USA. THE GRADED PROGNOSTIC ASSESSMENT: A TOOL TO ESTIMATE SURVIVAL FOR PATIENTS WITH BRAIN METASTASES2014.
37. Toru Serizawa: Tokyo Gamma Unit Cetner TNC-T, Japan. VALIDITY OF DS-GPA FOR BREAST CANCER BRAIN METASTASES TREATED WITH GAMMA KNIFE RADIOSURGERY 2014.
38. Osamu Nagano: Chiba Cardiovascuar Ceter Gamma Knife House - Ichihara J. VALIDITY TEST OF GRADING SYSTEMS PREVIOUSLY REPORTED IN BRAIN METASTASES PATIENTS2014.
39. Daniel Devriendt: Gamma Knife of Brussels - Brussels B. BRAIN METAS-TASES AND LGK RADIOSURGERY: 10 YEARS FOLLOW-UP UP COMPARING RPA, SIR, BSBM AND GPA SYSTEMS 2014.
40. Masaaki Yamamoto: Katsuta Hospital Mito GammaHouse - Hitachi-naka J. VALIDITY OF RECENTLY-PROPOSED PROGNOSTIC GRADING INDICES FOR BRAIN MET PATIENTS UNDERGOING RE-SRS 2014.
41. Toru Serizawa: Tokyo Gamma Unit Cetner TNC-T, Japan. NEW GRADING SYSTEM PREDICTING NEUROLOGICAL OUTCOMES FOR BRAIN METASTA-SIS: MODIFIED BSBM2014.
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43. Andrew Hanna: University of Maryland Medical Center Department - Balti-more MU. PREDICTORS OF STEROID USE AFTER GAMMA KNIFE RADIOSUR-GERY FOR BRAIN METASTASES 2014.
44. Pierre Martin: Yale New Haven Hospital - New Haven CU. SYSTEMIC TREATMENT AND RADIATION NECROSIS FOLLOWING GAMMA KNIFE RADIOSURGERY IN THE TREATMENT OF BRAIN METASTASES2014.
46. Cheng-chia Lee: Taipei Veteran General Hospital - Taipei T. APPLICATION OF DIFFUSION- WEIGHTED MAGNETIC RESONANCE IMAGING TO PREDICT THE INTRACRANIAL METASTATIC TUMOR RESPONSE TO GAMMA KNIFE RADIOSURGERY2014.
47. In-Young Kim: Chonnam National University Hwasun Hospital - Hwasun K. USEFULNESS OF [11C]METHIONINE PET-CT IN DIFFERENTIAL DIAGNOSIS BETWEEN TUMOR RECURRENCE AND RADIATION NECROSIS2014.
48. Kazutaka Yatsushiro: Fujimoto General Hospital - Miyakonojo City J. 11C-METHIONINE AND 18F-FDG PET, AND T1/T2 MISMATCH FOR DIFFER-ENTIAL DIAGNOSIS OF RADIATION INJURY 2014.
49. Tang Xuqun: Department of Neurosurgery - Shanghai C. BEVACIZUM-AB AS A TREATMENT OPTION FOR GAMMA KNIFE RADIATION-INDUCED CEREBRAL NECROSIS IN 10 PATIENTS 2014.
50. JW Welsh et al. - Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol. 2013;31: 895-902.
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55. Manmeet Ahluwalia C, OH. TARGETED CHEMOTHERAPY AND RADIOSUR-GERY FOR THE TREATMENT OF BRAIN METASTASES: TARGETED THERAPY AND RADIOSURGERY2014.
56. Jung-Il Lee: Dept. of Neurosurgery SMC, Sun - Seoul, South Korea. CLIN-ICAL OUTCOME OF METASTASTIC BRAIN TUMOR FROM NSCLC-SINGLE INSTITUE EXPERIENCE OF 817 PATIENTS2014.
57. Greg Bowden: UWO - London OC. GAMMA KNIFE RADIOSURGERY FOR THE MANAGEMENT OF CEREBRAL METASTASES FROM NON-SMALL CELL LUNG CANCER2014.
58. Jin Wook Kim: Neurosurgery SNUH-S, South Korea. RADIOSURGERY FOR BRAIN METASTASIS FROM NSCLC: TUMOR CONTROL & FAILURE PATTERN ACCORDING TO SUBTYPES2014.
59. Serizawa T, Ono J, Iichi T, et al. Gamma knife radiosurgery for metastat-ic brain tumors from lung cancer: a comparison between small cell and non-small cell carcinoma. Journal of neurosurgery. 2002;97: 484-488.
60. Wegner RE, Olson AC, Kondziolka D, Niranjan A, Lundsford LD, Flickinger JC. Stereotactic Radiosurgery for Patients With Brain Metastases From Small Cell Lung Cancer. International journal of radiation oncology, biol-ogy, physics. 2011.
61. Shoji Yomo: Aizawa Hospital - Matsumoto J. UPFRONT STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM SMALL CELL LUNG CANCER 2014.
62. Takuya Kawabe: Kyoto Prefectural University of Medicine - Kyoto J. GAMMA KNIFE RADIOSURGERY FOR BRAIN METASTASES FROM PULMO-NARY LARGE CELL NEUROENDOCRINE CARCINOMA 2014.
63. Hung-Chuan Pan: Department of Neurosurgery Taichung Veterans Gener - Taichung T. INCREASED SURVIVAL WITH GAMMA KNIFE RADIOSURGERY AND IRESSA FOR LUNG CANCER BRAIN METASTASIS PATIENT 2014.
64. Dong Gyu Kim: Neurosurgery SNUH-S, South Korea. MANAGEMENT OF BRAIN METASTASIS FROM NSCLC: COMBINATION OF GKS AND EGFR TKI 2014.
65. Paul Sperduto: Gamma Knife Center UoM-M, MN USA. RTOG 0320: PHASE III TRIAL OF WBRT + SRS +/- CHEMOTHERAPY IN PATIENTS WITH BRAIN METASTASES 2014.
66. Pavel Ivanov: International institute of biological systems - Saint-Peters-burg R. ANALYSIS OF OUTCOMES AFTER GAMMA KNIFE RADIOSURGERY FOR PATIENTS WITH MELANOMA BRAIN METASTASIS2014.
67. Satoshi Suzuki: Steel Memorrial Yawata Hospital - Kitakyushu J. FACTORS AFFECTING LOCAL TUMOR CONTROL IN GKRS FOR METASTATIC BRAIN TUMORS FROM BREAST CANCER2014.
68. Sung Kwon Kim: Neurosurgery SNUH-S, South Korea. RADIOSURGERY FOR BRAIN METASTASES FROM COLORECTAL CANCER2014.
69. Mikhail Chernov: Faculty of Advanced Techno-Surgery; Tokyo Women’s Medical University - Tokyo J. OUTCOME AFTER GAMMA KNIFE SURGERY FOR INTRACRANIAL METASTASES OF COLORECTAL CARCINOMA 2014.
70. Do Hoon Kwon: Asan Medical Center - Seoul K. GAMMA KNIFE RADIOSUR-GERY FOR BRAIN METASTASIS FROM HEPATOMA2014.
71. Greg Bowden: UWO - London OC. GAMMA KNIFE RADIOSURGERY FOR MANAGEMENT OF CEREBRAL METASTASES FROM ESOPHAGEAL CARCI-NOMA2014.
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72. Qingsheng Xu: Department of Neurosurgery tFAH-H, China. GAMMA KNIFE SURGERY FOR BRAIN METASTASES FROM HEPATOCELLULAR CARCI-NOMA2014.
73. Likhacheva AO. COST MINIMIZATION STUDY OF LINAC-BASED AND GAMMA KNIFE RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES USING HOSPITAL COST DATA.2014.
74. Matthew Hall: City of Hope National Medical Center - Duarte CU. COST-EF-FECTIVENESS OF GAMMA KNIFE SRS WITH AND WITHOUT WBRT FOR NEWLY DIAGNOSED BRAIN METASTASES2014.
75. Roman Liscak: Na Homolce Hospital - Prague C. LEKSELL GAMMA KNIFE RADIOSURGERY OF THE GLOMUS TUMOR LONG TERM RESULTS 2014.
76. Nguyen Thanh Binh: Cho Ray Hospital - Ho Chi Minh V. GAMMA KNIFE RADIOSURGERY OF ARTERIOVENOUS MALFORMATIONS: SUMMARY OF EXPERIENCE IN 401 CASES FOLLOWED2014.
77. Antonella del Vecchio: San Raffaele Scientific Institute - Milan I. ARTE-RO-VENOUS MALFORMATION OCCLUSION AFTER GAMMA KNIFE TREAT-MENT: PREDICTIVE PARAMETERS 2014.
78. Zdravko Heinrich: Gamma Knife Centre Zagreb Dept. of Neurosurgery - Zagreb C. GAMMA KNIFE RADIOSURGERY IN TREATMENT OF BRAIN ARTE-RIOVENOUS MALFORMATIONS 2014.
79. Greg Bowden: UWO - London OC. STEREOTACTIC RADIOSURGERY FOR ARTERIOVENOUS MALFORMATIONS OF THE POSTGENICULATE VISUAL PATHWAY 2014.
80. Greg Bowden: UWO - London OC. STEREOTACTIC RADIOSURGERY FOR ARTERIOVENOUS MALFORMATIONS WITHIN OR ADJACENT TO THE VENTRICLES 2014.
81. Won Hee Lee: Inje University Com-S, Korea. TREATMENT EFFECT OF GAMMA KNIFE RADIOSURGERY FOR ARTERIOVENOUS MALFORMATION ASSOCIATED WITH ANEURYSM2014.
82. JP Mohr , MK Parides, et al. - Medical management with or without inter-ventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383: 614-621.
83. Gary Steinberg S, CA. MANAGEMENT OF AVMs WITH COMBINED EMBOLI-ZATION, RADIOSURGERY AND MICROSURGERY 2014.
84. Shunya Hanakita: The University of Tokyo Hospital - Tokyo J. RADIOSUR-GERY FOR UNRUPTURED CEREBRAL ARTERIOVENOUS MALFORMATIONS 2014.
85. Mooseong Kim: Inje University Busan Paik Hospital - Busan SK. EMBOLIZA-TION WTH GAMMAKNIFE SURGERY OFGIANT INTRACRANIAL ARTERIOVE-NOUS MALFORMATIONS 2014.
86. Michele Longhi: AOUI Verona - DPT Neurosurgery - Verona I. LGK FOR PEDIATRIC AND ADOLESCENT CAVMS: RESULTS ON 100 CASES FOLLOWED UP FOR AT LEAST 36 MONTHS2014.
87. Zachary Seymour: UCSF - San Francisco CU. VOLUME-STAGED RADIO-SURGERY FOR LARGE ARTERIOVENOUS MALFORMATIONS: AN EVOLVING PARADIGM 2014.
88. Michele Longhi: AOUI Verona - Verona I. STAGED DOSE RADIOSURGERY VS. STAGED VOLUME IN TREATMENT OF LARGE CEREBRAL AVMS. PRELIMI-NARY RESULTS. 2014.
89. Michele Longhi: AOUI Verona - DPT Neurosurgery - Verona I. LGK FOR PEDIATRIC AND ADOLESCENT CAVMS: RESULTS ON 100 CASES FOLLOWED UP FOR AT LEAST 36 MONTHS 2014.
90. Shunya Hanakita: The University of Tokyo Hospital - Tokyo J. STEREOTAC-TIC RADIOSURGERY FOR ARTERIOVENOUS MALFORMATIONS IN CHILDREN (<15YEARS OLD) 2014.
91. Daniel Tonetti: University of Pittsburgh Department of Neurologica - Pittsburgh PU. HEMORRHAGE FROM AVMS DURING PREGNANCY IN THE LATENCY INTERVAL AFTER STEREOTACTIC RADIOSURGERY 2014.
92. Chun-Po Yen: University of Virginia - Charlottesville VU. RADIATION-IN-DUCED IMAGING CHANGES FOLLOWING GAMMA KNIFE SURGERY FOR CEREBRAL AVMS2014.
93. Hideyuki Kano: University of Pittsburgh - Pittsburgh PU. THE RISK OF SYMPTOMATIC ADVERSE RADIATION EFFECTS AFTER STEREOTACTIC RADIOSURGERY FOR ARTERIOVENOUS 2014.
94. Takashi Shuto: Yokohama Rosai Hospital - Yokohama J. PATHOLOGICAL STUDY OF CYST FORMATION AFTER GAMMA KNIFE SURGERY FOR ARTE-RIOVENOUS MALFORMATION2014.
95. Kondziolka D, Lunsford LD, Kestle JR. The natural history of cerebral cavernous malformations. Journal of neurosurgery. 1995;83: 820-824.
96. Hasegawa T, McInerney J, Kondziolka D, Lee JY, Flickinger JC, Lunsford LD. Long-term results after stereotactic radiosurgery for patients with cavern-ous malformations. Neurosurgery. 2002;50: 1190-1197; discussion 1197-1198.
97. Nagy G, Razak A, Rowe JG, et al. Stereotactic radiosurgery for deep-seated cavernous malformations: a move toward more active, early intervention. Clinical article. Journal of neurosurgery. 2010;113: 691-699.
98. Yoshihisa Kida: Kamiiida Daiichi Hospital - Nagoya J. NATURAL HISTORY OF SYMPTOMATIC CAVERNOUS MALFORMATIONS AND RESULTS OF SURGERY2014.
99. Yoshihisa Kida: Kamiiida Daiichi Hospital - Nagoya J. RADIOSURGERY FOR SYMPTOMATIC CAVERNOUS MALFORMATIONS. JOINT RETROSPECTIVE STUDY IN JAPAN 2014.
100. Josa Frischer: Medical University Vienna - Vienna A. EVALUATION OF TREATMENT OPTIONS FOR BRAINSTEM CAVERNOUS MALFORMATIONS: A SINGLE CENTRE EXPERIENCE2014.
101. Antonio Santacroce: Dept. of Neurosurgery and Radiation Oncology Hein-rich Heine Universität - Düsseldorf G. RADIOSURGERY FOR BENIGN INTRA-CRANIAL MENINGIOMAS OUTCOMES FROM A EUROPEAN MULTICENTRE STUDY2014.
107. Hyun Ho Jung: Yonsei University CoM-S, South Korea. PROGNOSIS AND RISK FACTOR OF PERITUMORAL EDEMA AFTER GKS FOR 778 INCIDENTAL MENINGIOMA2014.
108. Gelareh Zadeh: University Health Network - Toronto OC. PREDICTORS OF MENINGIOMA RESPONSE TO STEREOTACTIC RADIOSURGERY AND POST-OPERATIVE COMPLICATIONS 2014.
109. Vincent Bulthuis: Department of Neurosurgery MM-M, Netherlands. GAMMA KNIFE RADIOSURGERY FOR INTRACRANIAL MENINGIOMAS: DO WE NEED TO TREAT THE DURAL TAIL? 2014.
110. Bodo Lippitz: Bupa Cromwell Hospital - London U. 10-YEAR FOLLOW-UP AFTER GAMMA KNIFE RADIOSURGERY OF MENINGIOMA 2014.
111. Shin Jung: Chonnam Chonnam National University Hwasun Hospital - Hwasun K. FRACTIONATED GAMMA KNIFE RADIOSURGERY FOR ALTERNA-TIVE TREATMENT CHOICE OF SURGICALLY HIGH RISK MENINGIOMA 2014.
112. Alberto Franzin: IRCCS San Raffaele - Milan I. MULTISESSION GAMMA KNIFE RADIOSURGERY FOR PERIOPTIC MENINGIOMAS2014.
113. I Yang, Sughrue Me Fau - Han SJ, Han Sj Fau - Fang S, et al. - Facial nerve preservation after vestibular schwannoma Gamma Knife radiosurgery. J Neurooncol. 2009;93: 41-48.
114. I Yang, Sughrue Me Fau - Han SJ, Han Sj Fau - Aranda D, et al. - A compre-hensive analysis of hearing preservation after radiosurgery for vestibular schwannoma. J Neurosurg. 2010;112: 851-859.
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115. E Myrseth, Moller P, Pedersen P-H, Lund-Johansen M Vestibular schwan-noma: surgery or gamma knife radiosurgery? A prospective, nonrandom-ized study. Neurosurgery. 2009;64: 654-661.
116. Pietro Mortini: San Raffaele Scientific Institute - Milano I. GAMMA KNIFE RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS: CLINICAL RESULTS IN A LARGE SERIES. 2014.
117. Hidefumi Jokura: Jiro Suzuki Memorial Gamma House FS-O, Japan. HOW LONG DO WE HAVE TO FOLLOW THE PATIENTS AFTER GAMMA KNIFE RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS? 2014.
118. Alberto Franzin: IRCCS San Raffaele - Milan I. GAMMA KNIFE TREATMENT FOR LARGE VESTIBULAR SCHWANNOMAS: CLINICAL AND RADIOLOGICAL OUTCOME 2014.
119. Shinya Watanabe: Katsuta Hospital Mito Gammahouse - Hitachinaka-shi J. LONG-TERM FOLLOW-UP OF SRS FOR VESTIBULAR SCHWANNOMAS: FACTORS INFLUENCING HEARING PRESERVATION 2014.
120. Cheng-Siu Chang: Chang Bin Show Chwan Memorial Hospital - Chang-hua County T. IMPACT OF RADIATION DOSE ON OUTCOME IN ACOUSTIC NEUROMA TREATED WITH GAMMA KNIFE SURGERY2014.
121. Jeffrey Jacob: Mayo Clinic - Rochester MU. SIGNIFICANCE OF COCHLEAR DOSE IN THE RADIOSURGICAL TREATMENT OF VESTIBULAR SCHWANNO-MA 2014.
122. Constantin Tuleasca: Lausanne University Hospital/ University of Lausan - Lausanne S. SHOULD KOOS I VESTIBULAR SCHWANNOMAS BE TREATED EARLY WITH GAMMA KNIFE SURGERY? 2014.
123. Motohiro Hayashi: Department of Neurosurgery; Tokyo Women’s Medical University - Tokyo J. HEARING PRESERVATION AFTER ROBOTIC GAMMA KNIFE MICRORADIOSURGERY FOR VIII NERVE SCHWANNOMAS 2014.
124. Yoshio Arai: University of Pittsburgh - Pittsburgh PU. RELATIONSHIP AMONG TUMOR LOCATION, VOLUME, AND HEARING STATUS WITH UNILATERAL ACOUSTIC NEUROMA 2014.
125. Ester Kim: Swedish Radiosurgery Center - Seattle WU. A COMPARISON OF SINGLE AND MULTI-FRACTION RADIOSURGERY OUTCOMES IN THE TREAT-MENT OF ACOUSTIC NEUROMA 2014.
126. Mercy George: Lausanne University Hospital/ University of Lausan - Laus-anne S. COMBINED APPROACHES IN LARGE VESTIBULAR SCHWANNOMAS: A SERIES OF 16 CONSECUTIVE CASES2014.
127. Yoshiyasu Iwai: Department of Neurosurgery OCGH-O, Japan. HEAR-ING PRESERVATION AFTER PLANNED PARTIAL SURGICAL RESECTION FOLLOWED BY GAMMA KNIFE RADIOSURGERY 2014.
128. Shibin Sun: Gamma Knife Center BNI-B, China. LONG TERM FOLLOW-UP STUDIES OF GAMMA KNIFE SURGERY FOR NEUROFIBROMATOSIS TYPE 2 2014.
129. Wu Han Feng: Shanghai Gamma Hospital - Shanghai C. STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS CAUSED BY NEUROFI-BROMATOSIS TYPE II: A SINGLE- CENTER EXPERIENCE2014.
130. J R, Radatz M Fau - Kemeny A, A K. - Radiosurgery for type II neurofibro-matosis. Prog Neurol Surg. 2008;21: 176-182.
131. Michael Torrens: Hygeia Hospital - Athens G. MALIGNANT TRANSFORMA-TION IN VESTIBULAR SCHWANNOMA - CASE REPORT, LITERATURE SEARCH AND DEBATE. 2014.
132. Kazuhiro Yamanaka: Department of Neurosurgery OCU-O, Japan. TREAT-MENT RESULTS OF GAMMA KNIFE RADIOSURGERY FOR CENTRAL NEURO-CYTOMA: REPORT OF A JAPANESE MULTI-INSTITUTIONAL CO-OPERATIVE STUDY (JLGK1201)2014.
133. Ayaka Sasaki: Tokyo Women’s Medical University - Tokyo J. GAMMA KNIFE RADIOSURGERY FOR FACIAL SCHWANNOMA AND THE RESULT2014.
134. Toshinori Hasegawa: Neurosurgery - Komaki J. LONG-TERM RESULTS FOR TRIGEMINAL SCHWANNOMAS TREATED WITH GAMMA KNIFE SURGERY 2014.
135. Sheehan JP, Starke R, Mathieu D, Young B, Sneed P, Chiang V, Lee J, Kano H, Park KJ, Niranjan A, Kondziolka D, Barnett G, Rush S, Golfinos J, Lunsford LD: Gamma Knife Radiosurgery for the Management of Nonfunctioning Pitu-itary Adenomas: A Multicenter Study. Journal of Neurosurgery 119(2):446-456, 2013.
136. Piero Picozzi: Ospedale San Raffaele IRCCS - Milano I. PATTERNS OF PITU-ITARY ADENOMAS PROGRESSION AFTER FAILED RADIOSURGERY 2014.
137. Mohammad ali Bitaraf: PhD candidate in nutritional sciences - Tehran I. REPEATED TRANSSPHENOIDAL SURGERY OR GAMMA KNIFE IN RECUR-RENT CUSHING DISEASE AFTER TSS SURGERY 2014.
138. Junchao Liang: Guangzhou General Hospital of Guangzhou Command - Guangzhou C. LONG-TERM OUTCOMES AFTER GAMMA KNIFE RADIOSUR-GERY FOR PITUITARY MICROADENOMAS 2014.
139. Amr El-Shehaby: Gamma Knife Center Cairo - Cairo E. BIOCHEMICAL REMISSION DETERMINANTS AFTER GAMMA KNIFE RADIOSURGERY FOR FUNCTIONING PITUITARY ADENOMAS 2014.
140. Mooseong Kim: Inje University Busan Paik Hospital - Busan SK. GAMMAK-NIFE SURGERY FOR PITUITARY MICROPROLACTINOMA2014.
141. Bruce Pollock: Mayo Clinic - Rochester MU. DOSE-VOLUME ANALY¬SIS OF RADIATION- INDUCED OPTIC NEUROPATHY IN PITUITARY ADENOMA RADIOSURGERY 2014.
142. Huai-che Yang: Taipei Veterans General Hospital - Taipei T. LONG TERM FOLLOW-UP IN GAMMA KNIFE TREATMENT FOR CRANIOPHARYNGIOMA 2014.
143. Tatsuya Kobayashi: Nagoya Radiosurgery Center NKH-N, Japan, Japan. GAMMA KNIFE RADIOSURGERY FOR CRANIOPHARYNGIOMARESULTS AND TOPICS OF 27 CASES TREATED AT NRC2014.
144. Christopher Duma: Brain And Spine Surgeons Of Orange County - Newport Beach CU. UP- FRONT “LEADING EDGE”C GAMMA KNIFE RADIO-SURGERY FOR NEWLYDIAGNOSED GBM: A 15-YEAR FOLLOW-UP 2014.
145. Lin Yiguang: Gamma Knife Center DoN, Tianjin Medical University 2nd Hospital - Tianjin, China. THE ULTRA SHORT-TERM EFFECT OF LOW-DOSE GAMMA KNIFE RADIATION ON INVASIVE PROPERTIES OF GLIOMA CELLS 2014.
146. Brigitte Gatterbauer: Medical University Vienna - Vienna A. GAMMA KNIFE RADIOSURGERY IN RECURRENT GLIOBLASTOMA 2014.
147. Laurence Masson-Cote: Center Hospitalier Universitaire de Sherbrooke - Sherbrooke QC. GAMMA KNIFE RADIOSURGERY FOR RECURRENT GLIO-BLASTOMA MULTIFORME: A SINGLE INSTITUTION EXPERIENCE2014.
148. Ernest Dodoo: Karolinska University Hospital - Stockholm S. SALVAGE THERAPY FOR HIGH GRADE GLIOMA UTILIZING DELAYED GAMMA KNIFE SURGERY 2014.
149. Erik Larson: Gamma Knife of Spokane - Spokane WU. EVALUATING THE CLINICAL OUTCOMES OF SIXTY-THREE PATIENTS TREATED WITH GAMMA KNIFE AS SALVAGE THERAPY FOR RECURRENT GLIOBLASTOMA MULTI-FORME 2014.
150. Frederick A Zeiler: Section of Neurosurgery UoM-W, MB Canada. GAMMA KNIFE RADIOSURGERY FOR HIGH GRADE GLIAL NEOPLASMS: A CANADIAN EXPERIENCE 2014.
151. Bodo Lippitz: Bupa Cromwell Hospital - London U. 10-YEAR FOLLOW-UP AFTER GAMMA KNIFE RADIOSURGERY OF PILOCYTIC ASTROCYTOMA 2014.
152. Khaled Abdel Karim: Gamma Knife Center Cairo - Cairo E. GAMMA KNIFE RADIOSURGERY FOR LOW-GRADE GLIOMAS 2014.
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153. Valery Kostjuchenko: Neurosurgery Business Center - Moscow R. STEREO-TACTIC RADIATION THERAPY AND RADIOSURGERY FOR BRAIN PILOCYTIC ASTROCYTOMAS 2014.
154. Roman Liscak: Na Homolce Hospital - Prague 5 C. LEKSELL GAMMA KNIFE TREATMENT FOR PILOCYTIC ASTROCYTOMAS – LONG TERM RESULTS 2014.
155. D Kondziolka, Zorro O, Lobato-Polo J, Kano H, Flannery TJ, Flickinger JC, Lunsford LD. Gamma Knife stereotactic radiosurgery for idiopathic trigeminal neuralgia. Journal of neurosurgery. 2010;112: 758-765.
156. Motohiro Hayashi: Department of Neurosurgery; Tokyo Women’s Medical University - Tokyo J. CLINICAL RESULTS AND HYPOTESIS OF NEUROMOD-ULATION IN GAMMA KNIFE SURGERY FOR THE INTRACTABLE PAIN 2014.
157. Constantin Tuleasca: Lausanne University Hospital/ University of Lausan - Lausanne S. GAMMA KNIFE SURGERY AFTER PREVIOUS MICROVASCULAR DECOMPRESSION: A SERIES OF 45 CASES 2014.
158. Yi-Chieh Hung: Chi-Mei Foundation Hospital - Tainan T. THE ANALYSIS OF CLINICAL RESULTS IN DIFFERENT TARGET LOCATIONS FOR TRIGEMINAL NEURALGIA2014.
159. Dusan Urgosik: Na Homolce Hospital - Prague C. MRI VOLUMETRY OF THE TRIGEMINAL NERVE: RELATIONSHIP TO GAMMA KNIFE SURGERY IN TRIGEMINAL NEURALGIA2014.
160. William Miele: Tufts Medical Center - Boston MU. DOES TRIGEMINAL NERVE ANATOMY ON TREATMENT PLANNING MRI PREDICT CLINICAL TRIGEMINAL NEURALGIA?2014.
161. John W Hopewell WTM, Christer Lindquist , Håkan Nordström, Jonas Gårding. THE ROLE OF THE CONCEPT OF BIOLOGICALLY EFFECTIVE DOSE (BED) IN TREATMENT PLANNING IN RADIOSURGERY 2014.
162. Constantin Tuleasca: Lausanne University Hospital/ University of Lausanne - Lausanne S. DOES EXTREME DOSE RATE INFLUENCE OUTCOME IN TRIGEMINAL NEURALGIA TREATED WITH GAMMA KNIFE SURGERY?2014.
163. Anna Lee: Emory Saint Joseph’s Hospital - Atlanta GU. REPEAT GAMMA KNIFE FOR RECURRENT TRIGEMINAL NEURALGIA2014.
164. Constantin Tuleasca: Lausanne University Hospital/ University of Lausanne - Lausanne S. LONG- TERM SAFETY-EFFICACY OF GAMMA KNIFE SURGERY FOR MULTIPLE SCLEROSIS RELATED TRIGEMINAL NEURALGIA 2014.
165. Roberto Martinez Alvarez: Radiosurgery Unit Ruber International Hospital - Madrid S. GLOSSOPHARYNGEAL NEURALGIA AND RADIOSURGERY 2014.
166. Helena Sandström: Karolinska Institute and Radiumhemmets research fu - Solna S, Sweden. PROSPECTIVE STUDY OF VARIABILITY IN TARGET DELIN-EATION FOR FIVE TARGETS COMMONLY TREATED WITH LGK 2014.
167. Paddick I. IMAGING SYSTEMS QUALITY ASSURANCE 2014.
168. Hamza Benmakhlouf: Karolinska University Hospital - Stockholm S. TREATING OUTSIDE THE BOX 2014.
169. Constantin Tuleasca: Lausanne University Hospital/ University of Lausan - Lausanne S. ULTRA- HIGH FIELD (7 T) MRI FOR GAMMA KNIFE SURGERY TARGETING OF THE VIM: A PILOT 2014.
170. Douglas Kondziolka: NYU Langone Medical Center - New York NU. TRACK DENSITY MRI TO PARCELLATE THALAMIC NUCLEI FOR GAMMA KNIFE THERAPY 2014.
171. VA Jourdain, G Schechtmann. - Health economics and surgical treatment for Parkinson’s disease in a world perspective: results from an internation-al survey. Stereotact Funct Neurosurg. 2014;92: 71-79.
172. Takaomi Taira T, Japan. ABLATION: ‘QUO VADIS’ 2014.
173. Romain Carron: La Timone University Hospital - Marseille F. GK THALAM-OTOMY FOR TREMOR. BLINDED ANALYSIS OF OUTCOME AND NEURO-IM-AGING AT ONE-YEAR FOLLOW-UP. 2014.
174. Sebastian M. Dzierzecki: Centrum Gamma Knife Warsaw - Warsaw P. GAMMA KNIFE THALAMOTOMY FOR ESSENTIAL TREMOR AND PARKIN-SON DISEASE 2014.
175. Dheerendra Prasad: Roswell Park Cancer Institute - Buff alo NU. GAMMA KNIFE THALAMOTOMY FOR ESSENTIAL TREMOR 2014.
176. Jesse Lee: Los Robles Hospital Gamma Knife Center - Thousand Oaks CU. EFFECT OF BILATERAL GAMMA KNIFE THALAMOTOMY ON AXIAL TREMOR 2014.
177. Elfar Úlfarsson: Landspitali University Hospital - Reykjavík I. HYPOFRAC-TIONATED GAMMA KNIFE RADIOSURGERY (HGKRS) FOR LARGE TUMORS AND ELOQUENT REGIONS2014.
178. Jonathan Knisely M, NY. FRACTIONATED RADIOSURGERY - WHEN? WHERE? WHY? - WHAT IS THE CURRENT EVIDENCE? 2014.
179. Guokai Wang: The Second Hospital Of Tianjin Medical University - Tian-jin C. GAMMA KNIFE RADIOSURGERY FOR CHILDREN WITH ORBITAL LESIONS2014.
180. Antoine Dorenlot: AP-HM - Marseille F. STENOPEIC EYE FIXATION FOR GAMMA KNIFE SURGERY TARGETING OPHTHALMOLOGIC LOCALIZATION 2014.
181. Ladislav Novacek: Dept. of Ophthalmology of 1st Faculty of Med. of t - Prague 6 C. THE TREATMENT OF SEC. GLAUCOMA WITH THE USE OF LGK AND A COMPARISON OF SHORT AND MID-TERM RESULTS 2014.
182. Robert Darnell NY, NY. MODERN GENETIC APPROACHES TO GLIOMA2014.
183. Ole Isacson B, MA A Stem Cell-Based Surgical Transplantation Therapy for Parkinson’s Disease2014.
184. Jessica Foley: Focused Ultrasound Foundation - Charlottesville VU. FOCUSED ULTRASOUND: THE NEW FRONTIER?2014.
185. Kevin Tracey M, NY. NEURO-IMMUNOLOGY AND THERAPEUTIC RADIA-TION2014.
186. L. Dade Lunsford: University of Pittsburgh - Pittsburgh PU. REPORT OF THE NORTH AMERICAN GAMMA KNIFE CONSORTIUM2014.
187. Nicholas M. Barbaro I, IN. Radiosurgery or Open Surgery for Epilepsy, 2014.
64
65
INDICATIONS TREATED 1968 TO 2013
68%-100% of sites reporting
Leksell Gamma Knife
66
Treatments by Indication Category
thous.
0
200
400
600
800
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
7.0 11.3 16.7 26.7 40.4 58.1 78.5 100.5 125.2 152.4 180.8214.0
252.5298.7
347.6401.2
451.1504.0
553.4610.3
674.3740.2
809.9
Cumulative Number of Patients Treated by Indication Category
Indication CategoryVascular DisordersOcular DisordersMalignant TumorsFunctional DisordersBenign Tumors
thous.
0
20
40
60
80
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
7.04.3 5.4
9.913.7
17.720.4 22.0
24.7 27.2 28.433.2
38.5
46.248.9
53.649.8
52.949.4
56.8
64.0 65.969.7
Number of Patients Treated by Indication Category
Indication CategoryVascular DisordersOcular DisordersMalignant TumorsFunctional DisordersBenign Tumors
0%
20%
40%
60%
80%
100%
19911992
19931994
19951996
19971998
19992000
20012002
20032004
20052006
20072008
20092010
20112012
2013
13%
33%
51%
27%
31%
40%
33%
38%
27%
34%
42%
22%
34%
42%
19%
36%
41%
18%
38%
39%
16%
40%
37%
14%
8%
42%
35%
13%
9%
45%
34%
12%
8%
48%
31%
11%
9%
46%
33%
11%
9%
49%
32%
10%
9%
46%
33%
11%
9%
45%
35%
11%
8%
46%
35%
11%
8%
47%
35%
10%
8%
46%
35%
10%
8%
45%
38%
10%
7%
43%
39%
11%
7%
44%
39%
10%
43%
39%
10%
7%
43%
39%
10%
7%
Relative Distribution of Indications Per Year
100% 100% 100% 91% 100% 100% 99% 97% 97% 88% 88% 91% 93% 91% 89% 91% 82% 82% 68% 73% 80% 83% 94%1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013Participation %
Leksell Gamma KnifeIndications Treated 1968 to 2013
67
Benign Tumors Treated
thous.
0
50
100
150
200
250
300
350
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
2.3 3.7 5.7 9.9 15.7 22.9 30.9 39.1 47.9 57.1 66.077.0
89.4104.7
121.9140.8
158.2176.8
195.5217.8
242.5268.2
295.6
Benign Tumors - Cumulative Number of Patients Treated Per Year
Benign Tumors
thous.
0
5
10
15
20
25
30
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
2.3 1.4 2.04.2
5.87.2 8.0 8.2 8.7 9.2 8.9
11.012.4
15.317.2
18.917.4
18.6 18.6
22.324.7 25.7
27.3
Benign Tumors - Number of Patients Treated Per Year
Benign Tumors
38%
26%
20%
16%
Benign Tumors - Cumulative Number of Patients Treated by Indication
Indication (thous.)Meningioma 112.7 thous.Vestibular Schwannoma 77.7 thous.Pituitary Adenoma 59.2 thous.Other Indications 45.9 thous.
Leksell Gamma KnifeIndications Treated 1968 to 2013
67
68
Functional Disorders Treated
thous.
0
10
20
30
40
50
60
70
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.2 0.2 0.3 0.5 1.0 1.8 3.1 4.9 7.09.3
12.014.8
18.122.3
26.530.7
34.438.7
42.245.9
50.154.7
60.0
Functional Disorders - Cumulative Number of Patients Treated Per Year
Functional Disorders
thous.
0
1
2
3
4
5
6
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.2 0.1 0.1 0.20.5
0.81.3
1.82.2 2.3
2.7 2.8
3.3
4.2 4.1 4.23.7
4.3
3.53.7
4.24.6
5.2
Functional Disorders - Number of Patients Treated Per Year
Functional Disorders
87%
5%3%
5%
Functional Disorders - Cumulative Number of Patients Treated by Indication
Indication (thous.)Trigeminal Neuralgia 52.1 thous.Epilepsy 2.8 thous.Parkinson's Disease 1.9 thous.Other Indications 3.0 thous.
Leksell Gamma KnifeIndications Treated 1968 to 2013
69
Malignant Tumors Treated
thous.
0
100
200
300
400
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.9 2.1 3.9 7.2 11.9 18.4 26.1 34.9 45.4 57.771.2
86.6105.3
126.6148.7
173.4196.7
221.3243.3
267.7295.9
324.5354.5
Malignant Tumors - Cumulative Number of Patients Treated Per Year
Malignant Tumors
thous.
0
5
10
15
20
25
30
35
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.9 1.2 1.83.3
4.76.4
7.7 8.810.5
12.313.5
15.4
18.721.3 22.1
24.723.3
24.622.0
24.4
28.2 28.630.0
Malignant Tumors - Number of Patients Treated Per Year
Malignant Tumors
86%
9%
3% 1%
Malignant Tumors - Cumulative Number of Patients Treated by Indication
Indication (thous.)Metastatic Tumor 305.6 thous.Malignant Glial Tumor (gr... 33.6 thous.Other Malignant Tumor 12.1 thous.Other Indications 3.3 thous.
Leksell Gamma KnifeIndications Treated 1968 to 2013
69
70
Ocular Disorders Treated
thous.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.0 0.0 0.1 0.1 0.2 0.3 0.3 0.4 0.50.7 0.7
0.91.0
1.31.5
1.61.8
2.02.2
2.42.6
2.83.1
Ocular Disorders - Cumulative Number of Patients Treated Per Year
Ocular Disorders
thous.
0.00
0.05
0.10
0.15
0.20
0.25
0.30
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.0 0.00.0
0.0
0.10.1 0.1
0.1 0.1
0.1
0.1
0.1
0.2
0.20.2
0.20.2 0.2
0.3
0.2
0.2
0.2 0.2
Ocular Disorders - Number of Patients Treated Per Year
Ocular Disorders
79%
10%
10%
Ocular Disorders - Cumulative Number of Patients Treated by Indication
Indication (thous.)Uveal Melanoma 2.4 thous.Glaucoma 0.3 thous.Other Ocular Disorder 0.3 thous.
Leksell Gamma KnifeIndications Treated 1968 to 2013
71
Vascular Disorders Treated
thous.
0
20
40
60
80
100
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
3.6 5.3 6.7 8.9 11.5 14.7 18.1 21.2 24.5 27.7 30.934.7
38.643.8
49.154.7
59.965.2
70.276.4
83.189.9
96.8
Vascular Disorders - Cumulative Number of Patients Treated Per Year
Vascular Disorders
thous.
0
2
4
6
8
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
3.6
1.7 1.5
2.12.6
3.2 3.3 3.1 3.3 3.2 3.23.8 3.9
5.2 5.25.6
5.2 5.3 5.0
6.26.7 6.8 6.9
Vascular Disorders - Number of Patients Treated Per Year
Vascular Disorders
84%
9%
6% 1%
Vascular Disorders - Cumulative Number of Patients Treated by Indication
Indication (thous.)AVM 81.6 thous.Cavernous Angiomas 8.7 thous.Other Vascular Disorder 5.7 thous.Aneurysms 0.7 thous.
Leksell Gamma KnifeIndications Treated 1968 to 2013
71
72
19 12 72 9 1 2 115
65 20 44 16 5 150
437 290 102 172 33 6 1,040
866 475 398 203 14 7 1,963
3,610 3,357 3,189 1,536 327 51 12,070
11,417 11,189 6,522 3,703 681 99 33,611
42,119 84,347 130,749 46,757 828 786 305,586
58,533 99,690 141,032 52,424 1,900 956 354,535
26 13 4 2 45
22 8 16 3 49
39 8 23 2 1 73
506 465 421 392 34 9 1,827
1,275 446 455 408 103 18 2,705
746 888 95 992 237 46 3,004
1,022 679 666 629 87 21 3,104
1,452 794 560 608 69 6 3,489
3,359 402 381 508 258 35 4,943
2,161 1,096 807 810 125 16 5,015
2,670 585 1,432 894 242 32 5,855
4,304 968 626 1,173 406 51 7,528
4,109 1,653 866 1,386 244 48 8,306
34,226 7,875 4,890 10,168 1,734 336 59,229
18,058 17,585 12,497 26,815 2,186 547 77,688
35,168 25,608 15,459 31,408 4,350 710 112,703
109,143 59,073 39,155 76,234 10,080 1,878 295,563
227 71 38 4 2 342
210 93 20 24 1 1 349
3,302 580 857 774 210 10 5,733
5,841 425 408 1,692 292 85 8,743
26,316 14,768 13,467 23,851 1,792 1,441 81,635
35,896 15,937 14,752 26,379 2,299 1,539 96,802
1 1
2 2 4
2 2 1 1 6
1 6 2 9
5 4 9 5 8 31
21 2 5 9 37
4 3 43 1 3 54
80 1 2 1 84
106 71 53 10 240
1 250 25 4 280
119 330 113 185 5 1 753
319 890 172 137 4 9 1,531
672 515 338 375 18 30 1,948
2,284 116 49 337 34 4 2,824
7,677 31,041 4,115 8,590 536 190 52,149
11,292 33,232 4,797 9,762 608 260 59,951
157 28 5 104 7 16 317
47 3 266 2 318
130 82 93 2,067 13 34 2,419
334 113 98 2,437 20 52 3,054
215,198 208,045 199,834 167,236 14,907 4,685 809,905
MalignantTumors
Benign Tumors
VascularDisorders
FunctionalDisorders
Ocular Disorders
Total
Medulloblastoma
Ependymoma
Chondrosarcoma
Nasopharyngeal Carcinoma
Other Malignant Tumor
Malignant Glial Tumor (grade III and IV)
Metastatic Tumor
Total
Hemangioma
Neurocytoma
Jugular Foramen Schwannoma
Hemangiopericytoma
Chordoma
Glomus Tumor
Hemangioblastoma
Other Schwannoma
Pineal Region Tumor
Trigeminal Schwannoma
Craniopharyngioma
Benign Glial Tumors (Grade I and II)
Other Benign Tumor
Pituitary Adenoma
Vestibular Schwannoma
Meningioma
Total
Dural Arteriovenous Fistula
Aneurysm
Other Vascular Disorder
Cavernous Angiomas
AVM
Total
Depression
Cluster Headache
Other Movement Disorders
Other Pain Disorders
Other Behavioral Disorders
Other Epilepsy
Hypothalamic Hamartoma
Mesial Temporal Lobe Epilepsy
OCD
Essential Tremor
Intractable Pain
Other Functional Disorder
Parkinson's Disease
Epilepsy
Trigeminal Neuralgia
Total
Other Ocular Disorder
Glaucoma
Uveal Melanoma
Total
Asia excl.Japan
NorthAmerica
Japan EuropeMiddle East
& AfricaLatin
AmericaTotalIndication Category Indication
Treatments by Indication and Region
0%
50%
100%
Asia exc
l. Japan
North A
meric
a
Japan
Europe
Middle East
&Af
Latin
Am
erica
27%
51%
17%
48%
28%
16%
71%
20%
31%
46%
16%
68%
15%
20%
40%
33%
Indication Category Distribution by Region
Indication Category
Ocular DisordersFunctional DisordersVascular DisordersBenign TumorsMalignant Tumors
Leksell Gamma KnifeIndications Treated 1968 to 2013
Accumulated Treatments by Region and Indication
73
4,362 8,511 9,200 5,070 185 88 27,416
346 367 310 273 96 12 1,404
14 6 6 6 2 1 35
43 25 7 12 5 2 94
280 218 142 116 53 7 816
19 12 72 9 1 2 115
65 20 44 16 5 150
5,129 9,159 9,737 5,530 358 117 30,030
1,937 1,300 663 2,955 385 95 7,335
4,047 1,845 1,050 4,068 645 154 11,809
2,294 478 188 850 276 68 4,154
174 19 68 71 36 4 372
63 35 39 54 20 1 212
84 19 21 25 18 2 169
189 98 45 90 20 3 445
418 78 84 149 39 4 772
189 80 6 113 47 11 446
40 23 30 37 6 136
318 38 33 221 64 8 682
174 50 78 68 5 1 376
150 22 10 45 39 4 270
39 8 23 2 1 73
22 8 16 3 49
26 13 4 2 45
10,164 4,114 2,315 8,789 1,605 358 27,345
7 1 8
149 12 47 42 7 2 259
761 32 18 384 53 34 1,282
1,954 699 515 1,602 294 118 5,182
132 38 22 2 1 195
3,003 781 580 2,051 356 155 6,926
4 4 12 3 23
968 2,370 143 952 120 67 4,620
12 8 2 109 4 8 143
16 6 4 2 28
1 165 18 4 188
3 4 9 5 8 29
2 2 4
1 6 2 9
2 2 1 1 6
80 1 2 1 84
4 3 43 1 3 54
21 2 5 9 37
1 1
1,113 2,572 155 1,155 138 93 5,226
1 1 2
9 3 10 139 6 167
17 6 7 5 2 37
27 9 10 147 5 8 206
19,436 16,635 12,797 17,672 2,462 731 69,733
MalignantTumors
Benign Tumors
VascularDisorders
FunctionalDisorders
Ocular Disorders
Total
Metastatic Tumor
Malignant Glial Tumor (grade III and IV)
Chondrosarcoma
Nasopharyngeal Carcinoma
Other Malignant Tumor
Medulloblastoma
Ependymoma
Total
Vestibular Schwannoma
Meningioma
Pituitary Adenoma
Craniopharyngioma
Hemangioblastoma
Chordoma
Trigeminal Schwannoma
Other Benign Tumor
Glomus Tumor
Hemangiopericytoma
Benign Glial Tumors (Grade I and II)
Other Schwannoma
Pineal Region Tumor
Jugular Foramen Schwannoma
Neurocytoma
Hemangioma
Total
Aneurysm
Other Vascular Disorder
Cavernous Angiomas
AVM
Dural Arteriovenous Fistula
Total
Intractable Pain
Trigeminal Neuralgia
Parkinson's Disease
OCD
Essential Tremor
Other Behavioral Disorders
Cluster Headache
Other Pain Disorders
Other Movement Disorders
Mesial Temporal Lobe Epilepsy
Hypothalamic Hamartoma
Other Epilepsy
Depression
Total
Glaucoma
Uveal Melanoma
Other Ocular Disorder
Total
Asia excl.Japan
NorthAmerica
Japan EuropeMiddle East
& AfricaLatin
AmericaTotalIndication Category Indication
Treatments 2013 by Region
Leksell Gamma KnifeIndications Treated 1968 to 2013
0
100
200
300
400
500
Asia exc
l. Jap
an
North Am
erica
Japan
Euro
pe
Middle East
& Afri
ca
Latin
America
439 19,309
146
15,317
24213,299
45916,081
193
1,159108
755
Average Treatments by Site and Region 2013
Average Treatments per SiteTotal Number of Treatments
(2013 Average Treatments per Site: 261)
73
74
thous.
0
50
100
150
200
250
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.2 0.5 1.2 4.7 10.6 17.7 25.4 32.6 39.1 45.1 49.457.5 65.0
76.588.4
102.1114.4
127.1139.5
157.6176.5
195.8215.2
Asia excl. Japan - Cumulative Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersVascular DisordersMalignant TumorsBenign Tumors
0
5,000
10,000
15,000
20,000
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
174
325
748
3,43
6 5,95
1
7,09
0
7,63
7
7,20
2
6,54
5
5,98
5
4,33
1
8,05
4
7,56
1
11,4
96
11,8
55 13,7
12
12,3
21
12,7
07
12,4
00
18,0
61
18,8
62
19,3
09
19,4
36
Asia excl. Japan - Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersVascular DisordersMalignant TumorsBenign Tumors
51%
27%
17%
5% 0%
Asia excl. Japan - Cumulative Number of Patients Treated by Indication
Indication Category (thous.)Benign Tumors 109.1 thous.Malignant Tumors 58.5 thous.Vascular Disord... 35.9 thous.Functional Disor... 11.3 thous.Other Indications 0.3 thous.
Treatments by Region - Asia excl. Japan
Leksell Gamma KnifeIndications Treated 1968 to 2013
75
thous.
0
50
100
150
200
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
3.0 4.2 5.8 8.2 11.0 14.4 17.7 21.3 25.4 30.2 35.4 41.248.1
55.864.6
74.584.7
95.3107.4
119.3133.5
149.6
167.2
Europe - Cumulative Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersVascular DisordersMalignant TumorsBenign Tumors
0
5,000
10,000
15,000
20,000
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
2,97
5
1,25
4
1,57
9
2,34
2
2,87
7
3,35
4
3,36
7
3,56
5
4,09
1
4,80
7
5,21
4
5,79
8
6,84
1
7,78
6
8,79
1
9,87
1
10,1
57
10,6
73
12,0
57
11,8
77 14,2
07 16,0
81 17,6
72
Europe - Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersVascular DisordersMalignant TumorsBenign Tumors
46%
31%
16%
6% 1%
Europe - Cumulative Number of Patients Treated by Indication
Indication Category (thous.)Benign Tumors 76.2 thous.Malignant Tumors 52.4 thous.Vascular Disorders 26.4 thous.Functional Disord... 9.8 thous.Other Indications 2.4 thous.
Treatments by Region - Europe
Leksell Gamma KnifeIndications Treated 1968 to 2013
75
76
thous.
0
50
100
150
200
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.6 1.7 3.1 4.7 6.7 10.1 14.6 20.1 27.135.1
44.053.3
65.178.0
92.0107.1
120.8134.5
146.9160.2
173.7187.0
199.8
Japan - Cumulative Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersVascular DisordersBenign TumorsMalignant Tumors
0
5,000
10,000
15,000
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
621
-11,
102
1,33
8
-11,
678
1,92
5
3,41
6
4,50
6
5,49
6
7,01
9
7,96
8
8,89
8
9,36
9 11,7
40
12,9
01
14,0
54
15,0
91
13,7
04
13,7
04
12,3
69
13,3
23
13,5
18
13,2
99
12,7
97
Japan - Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersVascular DisordersBenign TumorsMalignant Tumors
71%
20%
7%2%
Japan - Cumulative Number of Patients Treated by Indication
Indication Category (thous.)Malignant Tumors 141.0 thous.Benign Tumors 39.2 thous.Vascular Disord... 14.8 thous.Other Indications 4.9 thous.
Treatments by Region - Japan
Leksell Gamma KnifeIndications Treated 1968 to 2013
77
thous.
0
1
2
3
4
5
1991 1992 1993 1994 1995 1996 1998 2000 2003 2004 2005 2006 2007 2009 2010 2011 2012 2013
0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 1.1 1.21.4
1.62.0
2.6
3.2
3.9
4.7
Latin America - Cumulative Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersMalignant TumorsVascular DisordersBenign Tumors
0
200
400
600
800
1991 1992 1993 1994 1995 1996 1998 2000 2003 2004 2005 2006 2007 2009 2010 2011 2012 2013
609
63 72 55 44 24 39
81 61
107
105 16
5 197
354
664
559
755
731
Latin America - Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersMalignant TumorsVascular Disorders
609 Benign Tumors
40%
33%
20%
6% 1%
Latin America - Cumulative Number of Patients Treated by Indication
Indication Category (thous.)Benign Tumors 1.9 thous.Vascular Disorders 1.5 thous.Malignant Tumors 1.0 thous.Functional Disorders 0.3 thous.Other Indications 0.1 thous.
Treatments by Region - Latin America
Leksell Gamma KnifeIndications Treated 1968 to 2013
77
78
thous.
0
5
10
15
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0.1 0.1 0.2 0.3 0.3 0.3 0.6 0.81.5
2.23.1
4.15.3
7.3
9.1
11.312.4
14.9
Middle East & Africa - Cumulative Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersMalignant TumorsVascular DisordersBenign Tumors
0
500
1,000
1,500
2,000
2,500
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
75 58 67 58 17 79
219
260
692
722 89
2
954
1,23
0
2,01
3
1,71
8
2,23
2
1,15
9
2,46
2
Middle East & Africa - Number of Patients Treated Per Year
Indication CategoryOcular DisordersFunctional DisordersMalignant TumorsVascular DisordersBenign Tumors
68%
15%
13%
4% 0%
Middle East & Africa - Cumulative Number of Patients Treated by Indication
Indication Category (thous.)Benign Tumors 10.1 thous.Vascular Disorders 2.3 thous.Malignant Tumors 1.9 thous.Functional Disord... 0.6 thous.Other Indications 0.0 thous.
Treatments by Region - Middle East & Africa
Leksell Gamma KnifeIndications Treated 1968 to 2013
79
thous.
0
50
100
150
200
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
2.6 4.2 5.9 8.3 11.2 14.9 19.8 25.4 32.540.8
50.660.4
72.585.6
99.0112.9
125.4140.1
150.3161.5
176.1191.4
208.0
North America - Cumulative Number of Patients Treated Per Year
Indication CategoryOcular DisordersVascular DisordersFunctional DisordersBenign TumorsMalignant Tumors
0
5,000
10,000
15,000
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
2,59
9
1,58
3
1,70
0
2,42
2
2,93
0
3,70
7
4,82
7
5,66
3
7,02
4
8,32
4 9,84
0
9,77
5 12,0
65
13,1
88
13,3
89
13,8
93
12,4
95 14,6
32
10,2
53
11,1
66
14,6
18
15,3
17
16,6
35
North America - Number of Patients Treated Per Year
Indication CategoryOcular DisordersVascular DisordersFunctional DisordersBenign TumorsMalignant Tumors
48%
28%
16%
8% 0%
North America - Cumulative Number of Patients Treated by Indication
Indication Category (thous.)Malignant Tumors 99.7 thous.Benign Tumors 59.1 thous.Functional Disord... 33.2 thous.Vascular Disorders 15.9 thous.Other Indications 0.1 thous.
Treatments by Region - North America
Leksell Gamma KnifeIndications Treated 1968 to 2013
79
