Practical Radiation OncologyÒ (2023) 13, 183−194

TagedEn
TagedFiur TagedEn

www.practicalradonc.org

Physics Contribution

TagedH1ISRS Technical Guidelines for Stereotactic

Radiosurgery: Treatment of Small Brain
Metastases (≤1 cm in Diameter)TagedEn
TagedPDiana Grishchuk, MSc,a,* Alexis Dimitriadis, PhD,a Arjun Sahgal, MD,b
Antonio De Salles, MD, PhD,c Laura Fariselli, MD,d Rupesh Kotecha, MD,e
Marc Levivier, MD, PhD,f Lijun Ma, PhD,g Bruce E. Pollock, MD,h
Jean Regis, MD,i Jason Sheehan, MD, PhD,j John Suh, MD,k
Shoji Yomo, MD, PhD,l and Ian Paddick, MScaTagedEn
TagedP National Hospital for Neurology and Neurosurgery, London, United Kingdom; bDepartment of Radiation Oncology,
a

Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada; cDepartment of Neurosurgery, University of
California, Los Angeles, California; dRadiotherapy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta Milano, Unita
di Radiotherapia, Milan, Italy; eDepartment of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida,
Miami, Florida; fNeurosurgery Service and Gamma Knife Center, Center Hospitalier Universitaire Vaudois, Lausanne,
Switzerland; gDepartment of Radiation Oncology, University of California San Francisco, San Francisco, California;
h
Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota; iDepartment of Functional Neurosurgery, La
Timone Hospital, Aix-Marseille University, Marseille, France; jDepartment of Neurologic Surgery, University of Virginia,
Charlottesville, Virginia; kDepartment of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio; and lDivision of Radiation
Oncology, Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, JapanTagedEn

Received 2 September 2022; accepted 12 October 2022

TagedEnSources of support: This work had no specific funding. Scientific advisory board member for Novocure, Neutron Therapeutics,
TagedEnDisclosures: Diana Grishchuk: BrainLAB. Dr Sahgal: Advisor/con- and Philips. Ian Paddick: Works as an ad hoc consultant for Elekta; past
sultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), educational seminars with Elekta AB and Zap Surgical; board member
Elekta (Gamma Knife Icon), BrainLAB, and VieCure (medical advisory ISRS, serving as past president. All other authors have no disclosures to
board); board member International Stereotactic Radiosurgery Society declare.
(ISRS); past educational seminars with Elekta AB, Accuray Inc, Varian TagedEnDisclaimer and Adherence: These guidelines should not be consid-
(CNS teaching faculty), BrainLAB, Medtronic Kyphon; research grant ered inclusive of all methods of care or exclusive of other methods or
with Elekta AB; travel accommodations/expenses by Elekta, Varian, care reasonably directed to obtain similar results. The physician must
BrainLAB; belongs to the Elekta MR LINAC Research Consortium, make the ultimate judgment depending on characteristics and circum-
Elekta Spine, Oligometastases and LINAC Based SRS Consortia. Dr Fari- stances of individual patients. Adherence to this guideline will not
selli: ISRS president. Dr Kotecha: Honoraria from Accuray Inc, Elekta ensure successful treatment in every situation. The authors of this guide-
AB, ViewRay Inc, Novocure Inc, Peerview Institute for Medical Educa- line and the International Stereotactic Radiosurgery Society assume no
tion, Elsevier Inc, and Brainlab and institutional research funding from liability for the information, conclusions, and recommendations con-
Medtronic Inc, Blue Earth Diagnostics Ltd, Novocure Inc, GT Medical tained in this report.
Technologies, AstraZeneca, Exelixis, ViewRay Inc, and Brainlab. Dr TagedEn
* Corresponding author: Diana Grishchuk, MSc; E-mail:
Regis: Elekta Instrument Research Grant, secretary of the European [email protected]
Society for Stereotactic and Functional Neurosurgery, secretary of the
World Society for Stereotactic and Functional Neurosurgery. Dr Suh:

https://doi.org/10.1016/j.prro.2022.10.013
1879-8500/Ó 2022 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
TagedEn184 D. Grishchuk et al Practical Radiation Oncology: May/June 2023

Purpose: The objective of this literature review was to develop International Stereotactic Radiosurgery Society (ISRS) consensus techni-
cal guidelines for the treatment of small, ≤1 cm in maximal diameter, intracranial metastases with stereotactic radiosurgery. Although
different stereotactic radiosurgery technologies are available, most of them have similar treatment workflows and common technical
challenges that are described.
Methods and Materials: A systematic review of the literature published between 2009 and 2020 was performed in Pubmed using the
Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) methodology. The search terms were limited to those
related to radiosurgery of brain metastases and to publications in the English language.
Results: From 484 collected abstract 37 articles were included into the detailed review and bibliographic analysis. An additional 44
papers were identified as relevant from a search of the references. The 81 papers, including additional 7 international guidelines, were
deemed relevant to at least one of five areas that were considered paramount for this report. These areas of technical focus have been
employed to structure these guidelines: imaging specifications, target volume delineation and localization practices, use of margins,
treatment planning techniques, and patient positioning.
Conclusions: This systematic review has demonstrated that Stereotactic Radiosurgery (SRS) for small (1 cm) brain metastases can be
safely performed on both Gamma Knife (GK) and CyberKnife (CK) as well as on modern LINACs, specifically tailored for radiosurgical
procedures, However, considerable expertise and resources are required for a program based on the latest evidence for best practice.
Ó 2022 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

TagedH1IntroductionTagedEn TagedPThe purpose of this systematic review was to develop

ISRS guidelines specific to technical considerations for
SRS to small brain metastases, defined as ≤1 cm in maxi-
TagedPBrain metastases occur in 10% to 40% of all adult
mal diameter.TagedEn
cancers,1 and they are increasing in incidence as
patients with metastatic disease are surviving longer
with the use of novel systemic agents, improved imag-
TagedH1Methods and MaterialsTagedEn
ing techniques, and increased screening of patients at
risk of developing subclinical brain metastases. This
increase has also resulted in a greater proportion of TagedPUsing the Preferred Reporting Items for Systematic
patients with small and multiple metastases, which can Review and Meta-Analyses (PRISMA) methodology, a
result in technical challenges given that most centers systematic review of the literature was performed by
are equipped with modern multileaf collimator (MLC) searching PubMed for articles published between from
image guidance based linear accelerators (LINAC) lim- 2009 and 2020. The search was restricted to English lan-
ited by the uncertainties of small field dosimetry and guage only. A more detailed overview of the search
geometry. In addition to the apparatus used, technical parameters can be found in Supplementary Material E1.TagedEn
challenges in stereotactic radiosurgery (SRS) treat- TagedPA review of the 484 collected abstracts plus their biblio-
ments include imaging, target volume delineation and graphic analysis was performed to screen for additional pub-
localization practices, use of margins, treatment plan- lications, followed by a more detailed review of 37 articles
ning techniques, and patient positioning.TagedEn that were deemed relevant for these guidelines. An addi-
TagedPRecent studies have shown the efficacy of upfront SRS tional 44 articles were identified in the references of the
for the treatment of brain metastases,2,3 with strong evi- papers reviewed or from other sources. There were no stud-
dence supporting the treatment of patients presenting ies that contained duplicated (related to the same patients)
with up to 4 brain metastases4 and increasing evidence clinical data. Well-known international publications and
supporting its use in patients with multiple metastases (at guidelines were added to support some of the statements.TagedEn
least up to 10).5−8 For patients who have received whole- TagedPA survey consisting of 10 questions was developed to
brain radiation therapy (WBRT), SRS is often used to sal- specifically address areas of controversy related to the
vage new or progressive brain metastases, especially in treatment of small brain metastases with SRS. Fourteen
those with radioresistant disease.9 However, the practice members of the ISRS guidelines committee completed the
of upfront WBRT is becoming less common because of survey.TagedEn
the risk of cognitive impairment10 and lack of tumor con-
trol.11 Moreover, in some histologies such as melanoma,
the increasing use of targeted and immune-modifying TagedH1ResultsTagedEn
agents that penetrate into the central nervous system tis-
sues and evidence suggesting WBRT does not reduce the TagedPIn total, 81 articles met the inclusion and exclusion cri-
risk of intracranial relapse12 have led to questioning the teria for this study and review. The details of the PRISMA
use of WBRT altogether unless it is considered as salvage search are shown in Fig 1. Most articles represented single-
therapy when SRS cannot be performed.13TagedEn institution publications (n = 57, 70%), and contributed to
TagedEnP
TagedFiur ractical Radiation Oncology: May/June 2023 ISRS guidelines for small brain metastases 185

Figure 1 Summary of PRISMA search.

TagedEn
Abbreviation: PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

at least 1 area of the key topics related to the treatment of target(s) to be treated. Magnetic resonance imaging
small brain metastases with SRS, consisting of: imaging (MRI) is a prerequisite for the visualization of small
(n = 20), target volume delineation (n = 8), margins metastases, as it is the only modality that can provide the
(n = 6), and technical issues and geometric accuracy adequate specificity and contrast-to-noise ratio necessary
(n = 33). The greatest proportion of the articles were cen- for consistent contouring. An MRI-only treatment plan-
tered on LINAC-based SRS (n = 21) and mixed-platform ning method can be employed with dose calculation algo-
studies (n = 21), followed by Gamma Knife SRS (Elekta rithms that assume a uniform water-equivalent density.14
AB, Stockholm, Sweden) (n = 20), and lastly CyberKnife Contrast-free computed tomography (CT) imaging is
(Accuray Inc, Sunnyvale, CA) (n = 2). The remaining were necessary to enable a Hounsfield unit to relative electron
related to imaging devices and were equally applicable to density conversion in areas of heterogeneous density for
any SRS platform. Fourteen papers represented technical convolution-based or Monte Carlo calculation
reports, whereas 9 were retrospective reviews describing algorithms.15TagedEn
clinical outcomes (n = 7) or positioning accuracy analyses TagedPClinically relevant MRI sequences must be optimized
(n = 2). Finally, 7 international guidelines from The Ameri- for SRS with focus on reducing artifacts and system- and
can Association of Physicists in Medicine (AAPM), Inter- patient-specific geometric distortion.16 The most com-
national Atomic Energy Agency, and International monly used T1-weighted (T1w) sequences for SRS plan-
Commission on Radiation Units and Measurements ning of brain metastases are Gradient Echo (for example:
(ICRU) were included and evaluated, as they represented Fast Low Angle Shot, Magnetization-Prepared Rapid
substantial bodies of work that have been incorporated Aquisition Gradient Echo, Fast Field Echo, Fast Spoiled
into national codes and regulations.TagedEn Gradient Echo, Gradient Recalled Echo, Brain Volume
TagedPThe survey completion rate was 100%. The list of ques- Imaging and Spin Echo (for example: Spin Echo, Sam-
tions can be found in the Supplementary Materials. The pling Perfection with Application optimised Contrast
survey results are summarized in Table 1 and were rated using different flip angle Evolution). Several studies have
based on the level of agreement: 80% or more (agree or been conducted comparing different T1w sequences for
strongly agree) were ranked as strong consensus, 60% to the detection of brain metastases.17−19,3 Although detect-
79% was ranked as moderate consensus, and less than ability was higher with certain T1w sequences, the differ-
60% was ranked as consensus was not reached. A strong ence did not always reach statistical significance. This,
consensus for only 5 questions was reached while 3 ques- however, changes for scan slice thickness, where fine-cut
tions yielded no consensus, which indicates a high vari- scans (1-2−mm slice thickness) detected a statistically sig-
ability in current practices.TagedEn nificant increase of additional small lesions (<1 cm in
TagedPA brief summary of recommendation by ISRS guide- diameter).20,21 The aforementioned studies demonstrate
lines committee members for each topic discussed is pre- the need for finely tuned sequences for SRS with expert
sented in Table 2.TagedEn input from neuroradiology and MRI physics.TagedEn
TagedPThe improved contrast-to-noise ratio achieved with
higher magnetic strength scanners (eg, 3T) have potential
TagedH1DiscussionTagedEn benefits in the detection of small brain metastases.22 How-
ever, the disadvantage of higher field strengths is
TagedH2ImagingTagedEn increased magnetic susceptibility, which is directly pro-
portional to the static B field. This and other factors can
TagedPTarget volume delineation requires 1 or more reference increase geometric distortion in the image, which can
image sets of the intracranial region that contain the potentially lead to positional errors in targeting. An
TagedEn186 D. Grishchuk et al Practical Radiation Oncology: May/June 2023

TagedEnTable 1 Questionnaire results summary

(Continued)
TagedEnPractical Radiation Oncology: May/June 2023 ISRS guidelines for small brain metastases 187

Abbreviations: CTV = clinical target volume; GTV = gross target volume; MRI = magnetic resonance imaging; PTV = planning target volume;
QA = quality assurance; T1w = T1-weighted.

important consideration is that the relative effect of geo- the responsibility lies with the clinical team to evaluate
metric distortion on treatment plan dosimetry is highly whether these corrected images are clinically appropriate.
dependent on target volume, with smaller targets being Studies investigating correction of MRI geometric
more prone to this effect.23TagedEn distortions24,25 show that this can be a source of large
TagedPSeveral on-board distortion correction methods are errors. Regular quality assurance (QA) should be manda-
available from MRI-scanner manufacturers that can be tory, using an appropriate phantom to ensure that image
applied to the image acquisition. These corrections, how- quality and geometric distortions are within tolerance. It
ever, do not guarantee improvements in distortion, and is important to note that such algorithms do not correct
TagedEn188 D. Grishchuk et al Practical Radiation Oncology: May/June 2023

TagedEnTable 2 Summary of recommendations

Imaging  Recent MR imaging (≤7 days from treatment) is a prerequisite for contouring.TagedEn
 Fine-cut MR scans should be acquired (≤1.5-mm slice thickness).TagedEn
 A scan time delay of between 10 and 15 minutes should be applied after contrast injection.TagedEn
 MR sequences should be optimized for SRS to reduce artifacts and geometric distortion. Regular MRI
QA is mandatory to monitor geometric distortion as a potential source of error.TagedEn
 CT scans, if used for planning, should be equal to or thinner than MR slice thickness.TagedEn

Contouring  All targets and OARs should be contoured to quantitatively assess tumor coverage constraints and
OAR tolerance levels.TagedEn
 Margins are associated with an increased dose to normal tissue and need to be carefully considered
according to the SRS platform.TagedEn

Patient treatment  Sub-millimeter geometric accuracy must be achieved during treatment. To comply with this
requirement the choice of immobilization device and in-room imaging should be made based on the
achievable accuracy of patient positioning and target localization. Patient immobilization and
localization techniques are critical in this regard.TagedEn
 Lower energy beams may reduce dose to normal tissue.TagedEn

Dosimetry  Dosimetric accuracy within 5% must be achieved.TagedEn

 Recommendations regarding dosimetrical measurements for small fields have been published by IAEA
and AAPM.TagedEn

Abbreviations: AAPM = The American Association of Physicists in Medicine; CT = computed tomography; IAEA = International Atomic Energy
Agency; MR = magnetic resonance; OAR = organ at risk; QA = quality assurance; SRS = stereotactic radiosurgery.

for patient-specific distortions and steps must be taken to safety. Equally important is the timing of the scan after
prevent or reduce these effects. This is particularly impor- contrast injection. Delayed MRI may increase the num-
tant when planning is solely based on MR images. Core- ber, volume size, and conspicuity of metastatic lesions.30
gistration of MRI and CT is 1 common method used to A time delay between 10 and 15 minutes is recommended
reduce distortion. However, coregistration accuracy for optimal tumor definition; however, this has not been
should be tested before clinical use.TagedEn universally adopted in clinical practice.TagedEn
TagedPFor LINAC-, CyberKnife, and Gamma Knife Icon based TagedPThe significant growth rate of brain metastases necessi-
treatments, CT scans (cone beam CT for Gamma Knife tates recent imaging from treatment planning to SRS deliv-
Icon) can be used as the reference study for treatment plan- ery. In a retrospective study of 151 brain metastases, the
ning and patient positioning. MRI scans serve as the sec- 12-month local freedom from progression after SRS was
ondary image data sets for volume definition. MRI and CT 95% versus 56% when MRI images used for contouring
images are then fused, and the quality of coregistration were <14 and ≥14 days from SRS delivery, respectively.31
depends on a variety of factors, including image quality In a more recent study, 531 lesions were evaluated on 2
and spatial resolution. The precision of head localization MRI scans with median interscan time interval of 8 days
during image-guided positioning also depends on image and demonstrated a median tumor volume growth of 20%
acquisition settings and, for example, can be improved by a for this period.32 The danger of a target changing size and/
factor of 2 when the slice thickness is reduced from 3.0 to or shape or the appearance of new lesions between the
1.5 mm.26 At present, a CT slice thickness on the order of acquisition of planning images and delivery of treatment
1 mm is widely used for SRS treatments to provide suffi- should not be ignored. This is particularly important in the
cient fusion and setup accuracy.TagedEn treatment of melanoma and renal cell cancers where intra-
TagedPThe choice of gadolinium-based contrast agent may tumoural bleeding can often occur spontaneously.33TagedEn
also be a significant factor in the MRI visualization of
small metastatic disease.27 There is also evidence suggest-
ing that a double or even triple dose of contrast agent is TagedH2Target delineationTagedEn
beneficial.28 However, the potential of renal toxicity and
long-term gadolinium retention in the brain should be TagedPThe gross tumor volume is a volume defined by ICRU
considered to balance the risk versus benefit of improved 91 as “very likely to be tumor.”34 In the case of small met-
target visualization.29 The use of the more stable type III astatic lesions, these tend to be spherical or ellipsoid and
gadolinium-based contrast agents should also improve are most commonly delineated from MRI scans. The
TagedEnPractical Radiation Oncology: May/June 2023 ISRS guidelines for small brain metastases 189

clinical target volume is a volume encompassing the gross delivery, a PTV margin is not always applied for SRS treat-
tumor volume as an area likely to contain tumor to ensure ment, in particular, for rigid-frame based treatment.TagedEn
that any microscopic spread is treated. A clinical target TagedPIn a study investigating target volume and margin
volume margin is not usually applied in the treatment of growth calculation using different TPS systems,43 volume
metastases with SRS, although there is evidence that infil- calculations varied by as much as 10%. The addition of
tration into normal brain is present for some metastatic margins (of the same nominal size) to small structures
lesions.35 However, the partial volume effect, where an yielded differences up to 40%, resulting in substantially
individual voxel appears bright because of the presence of inconsistent total volumes. The authors concluded that
enhancing tumor in only part of its volume, serves to these are relatively small variations compared with inter-
increase the apparent volume of the enhancing target. observer discrepancies. However, the addition or omis-
This can be as much as 1 pixel in radius, which can in sion of a margin remains the biggest and most
effect add or subtract an unintended margin to the tar- controversial variable in the treatment of small metastases
get.36 This will depend on the resolution of the image, with SRS. By way of illustration, the volume of a 0.8-cm
and a voxel size of ≤1 mm3 will limit this effect.TagedEn diameter sphere is 0.268 cc, whereas the volume after the
TagedPIt has been previously argued that target delineation is addition of a 1-mm margin is 0.524 cc, which effectively
the “weakest link” in SRS.37,38 This is related to biases doubles the volume. Assuming the same prescription
from inter- and intraobserver variations,39 variability in dose is used for both targets, the dose to normal brain will
treatment planning system (TPS) volume calculation,40 increase significantly and, in turn, the risk of radiation
and the inconsistent addition/absence of margins. Meth- necrosis will increase as well. This is particularly impor-
ods range from automatic segmentation to manual delin- tant when large numbers of lesions in proximity to each
eation to targets not being contoured at all despite the other are treated in the same session as a result of dose-
ICRU recommendation that contouring is a standard of interplay effects. In a theoretical study, Ma et al40 used
good practice.34TagedEn Flickinger’s symptomatic radiation necrosis incidence
TagedPA recent study investigated interobserver contouring model to examine the effect of adding various margins in
variations at 22 SRS centers using a range of benchmark- Gamma Knife SRS, from 0.5 to 3 mm. Risks increased
ing targets.41 The case with multiple small metastatic tar- between 6% and 25% depending on the margin and size
gets showed the largest interobserver variations. Although of the target. However, in this study, only 1 of 15 of the
some of these variations are related to image fusion inac- lesions studied were less than 1-cm diameter. Fortunately,
curacies and TPS volume calculation methods, the the risk of radionecrosis is relatively low when treating
authors state that these are also associated with “differen- lesions 1 cm in diameter.44 In a retrospective study of
ces in clinician training, ethos, and accuracy” (p. 20). It 2200 treatments performed on a Gamma Knife unit,
was shown that variations decreased with larger target Sneed et al45 reported a 1-year probability of adverse radi-
volumes, which is in agreement with another published ation effects of 1% or less when treating lesions up to
study.38 Therefore, it is important to recognize that inter- 1 cm in diameter with a dose of ≤20 Gy without a margin.
observer contouring variations are expected to be exacer- Because the baseline risk for these small targets is low in
bated for metastatic lesions significantly smaller than the model as expected, any substantial increase obtained
1 cm in diameter.TagedEn in the relative risk may not significantly affect the absolute
risk for the treatment of these small lesions.TagedEn
TagedPA retrospective clinical study of 93 metastases, treated
TagedH2MarginsTagedEn with or without a 2-mm PTV margin using LINAC-based
SRS, revealed a 7.1% and 19.6% risk of severe parenchy-
TagedPA planning target volume (PTV) is created by adding a mal complications, respectively, with no effect on local
margin to account for possible geometric inaccuracies of control.46 In a prospective randomized trial, 80 metastases
the treatment delivery. It is therefore important to assess in 49 patients were randomized to a 1- or 3-mm PTV
patient set-up uncertainties, on-board imaging accuracy, margin and treated with LINAC-based SRS. No difference
movement during treatment, and physical accuracy of the in local control between the 2 groups was observed; how-
isocenter when considering the margin to be used.34 Equip- ever, an increased incidence in radionecrosis was observed
ment limits, including the magnitude of potential geomet- in the 3-mm cohort.47 Although in theory the lack of a
ric errors and baseline parameters for a QA program, PTV margin, combined with given random errors in
should be characterized during commissioning.42 Routine treatment delivery, may suggest a lack of tumor coverage
end-to-end (E2E) QA tests and, if necessary, pretreatment and greater risk of treatment failure, it may be that the
plan verification should be performed to ensure that the penumbral dose results in sufficient control of microme-
prescription dose can be delivered accurately and to the tastatic spread to compensate. Immunologic reactions
right spatial location. However, although all treatment may also have additive positive effects influencing local
techniques are associated with some level of uncertainty in control, and this remains an area of research.48TagedEn
TagedEn190 D. Grishchuk et al Practical Radiation Oncology: May/June 2023

TagedH2Technical issuesTagedEn (»1 cc), the potential for harm exists, so it is essential for
doses of this magnitude to be delivered with a high degree
TagedPSRS planning and treatment techniques are platform of geometric and dosimetric accuracy.59 A geometric miss
dependent. Although traditional intracranial SRS treat- can damage functional brain tissue and/or undertreat the
ment platforms used multi-isocenter or individualized disease, risking tumor recurrence. As discussed by
target planning techniques, treatment planning has Schmitt et al,52 there are numerous publications and
changed significantly with technological evolution. One guidelines advising on tolerance levels for an SRS-stereo-
recent solution allows for single isocenter, noncoplanar tactic body radiation therapy QA program. A challenge
volumetric modulated arc therapy for the treatment of for the clinical team is to establish practical but meaning-
multiple brain metastases.49,50 A list of conditions pro- ful tolerance levels for QA results. The authors’ consensus
posed for efficient treatment includes an MLC of 5-mm is that a geometric tolerance ≤1 mm in system-specific
width or less, on-board imaging combined with a E2E tests should be adhered to for treatment of small
6degrees-of-freedom (6-DoF) robotic couch to correct metastases. However, because of the finite volume irradi-
translational and rotation errors, and the possibility to ated, dosimetric uncertainties may be acceptable in spe-
verify patient position at different couch angles for nonco- cific clinical scenarios. Readers should refer to the AAPM
planar arcs. A 2.5-mm wide MLC might be beneficial for Task Group Report 142 (TG142),60 TG198,61 and
smaller targets, irregular shaped lesions, or those located TG17862 reports to reference how to assess such uncer-
next to organs-at-risk,51 but this is balanced by a number tainties.TagedEn
of new challenges that include small field dosimetry, TagedPPatient positioning and target localization during treat-
beam modeling in the TPS, MLC calibration accuracy, ment are essential to ensure accurate dose delivery. His-
and so forth. Judgment on the superiority of 2.5- versus torically, patients were immobilized using a rigid frame
5-mm MLC cannot be made based solely on the MLC attached to the patient’s skull and then fixed to the treat-
width parameter. This is also complicated by vendor var- ment machine. Isocenters were mechanically secured
iations in the recommended technical implementation of using the machine and/or frame coordinate system with-
smaller leaves. There is a debate in the literature compar- out any in-room image guidance (IG). Although this is
ing SRS plan qualities depending on leaf width,52−56 and still considered the gold standard in SRS, as it ensures
the only definitive conclusion we can derive is that an sub-millimeter target localization accuracy, it has a num-
MLC width of no more than 5 mm is a prerequisite for ber of limitations that include potential frame distortion
SRS treatments.TagedEn and slippage,63 patient discomfort, potential cranial com-
TagedPAlthough the majority of intracranial SRS treatments plications when fixing the frame near a craniotomy site,
are delivered with energies between 60Co and 6 MV, the inability to perform fractionated SRS without multiple
advent of flattering filter free (FFF) treatments has frame applications, and mandatory clinician involvement
enabled energies up to 10 MV FFF to be used. A 10 MV during frame fixation. As IG is now standard on modern
FFF beam can offer a higher dose rate but is also associ- LINAC platforms and more recent Gamma Knife units,
ated with a wider penumbra because of the increased lat- in-room imaging guidance can be useful for secondary
eral scattering of secondary electrons. This effect is verifications immediately before the treatment delivery.TagedEn
aggravated for small fields that increase the proportion of TagedPIn an attempt to allow fractioned treatments to become
energy scattered outside of the primary photon beam. less invasive and more patient friendly, frameless posi-
Laoui et al57 studied a series of 93 lesions in 35 patients tioning devices such as bite-block systems and thermo-
planned with 6 and 10 MV FFF photon beams. The vol- plastic masks have been introduced. These devices
ume of normal brain irradiated, as defined by the volume removed the need to treat the same day and for a clinician
within 50% of the prescription isodose line, was 11% to be involved in preparation. The use of a noninvasive
lower for the 6 MV FFF beams. This suggests that the 12- immobilization system requires in-room IG, for example,
Gy volume and the associated risk of radionecrosis may stereoscopic x-rays or on-board cone beam CT with volu-
be greater with increasing FFF beam energy.TagedEn metric image coregistration capability or both. For
LINAC-based and CyberKnife radiosurgery, IG is nor-
mally accompanied by robotic 6-DoF positional correc-
TagedH2Geometric accuracyTagedEn tion, which accounts for both translational and rotational
offsets. This system reduces a potential loss of target cov-
TagedPIn 1 study, for lesions ≤2 cm in diameter, a prescrip- erage due to targeting errors.64 A 6-DoF couch is espe-
tion dose of 24 Gy was associated with greater local con- cially important for mono-isocentric multiple-target SRS
trol and less than a 10% risk of radionecrosis.58 The dose and has been correlated to clinical outcome.65 E2E tests
used in clinical practice for lesions 1 cm in diameter have demonstrated that for a single-isocentric noncopla-
ranges from 18 to 25 Gy,2 with further reductions for nar arc technique, with cone beam CT and a 6-DoF
metastases within or near eloquent regions of the brain. couch, spatial uncertainty is within 1 mm for targets
Even though only a small volume receives this high dose located within 4 cm of the isocenter and increases to
TagedEnPractical Radiation Oncology: May/June 2023 ISRS guidelines for small brain metastases 191

2 mm beyond this distance.65 Therefore, for mono-iso- localization, and treatment. Geometric and dosimetric
centric techniques, SRS targeting accuracy decreases with differences between the planning system and the delivered
increasing distance from the isocenter, and the residual dose are then measured and analyzed.TagedEn
rotational uncertainties remain the primary concern.TagedEn TagedPExternal dosimetry audits before clinical implementa-
TagedPThermoplastic masks are not a new concept in radiation tion have an important role in ensuring a safe SRS clinical
therapy, and are the most common immobilization devices service. A United Kingdom audit assessed dosimetry
used in the treatment of brain and head and neck patients. accuracy achieved in 30 centers across the country.59 Var-
However, their suitability for single fraction SRS is contro- iations between calculated and delivered doses for differ-
versial. Ohtakara et al66 compared positioning accuracy ent platforms revealed significant outliers and highlighted
and stability between a dedicated SRS mask system (Brain- the need for standardization of practice. Because the need
Lab, Munich, Germany) and a general thermoplastic mask for external audits was recognized by the study it led to
system used for conventional radiation therapy using Exac- the establishment of an external SRS audit program in the
Trac (BrainLab) on-board imaging. The dedicated mask United Kingdom.TagedEn
did not have any benefit in initial setup, but post-treatment
imaging showed a median vector displacement of 0.38 mm
TagedH2LimitationsTagedEn
with a maximal translation residual error of 1 mm for the
BrainLab mask versus a 0.74 mm median vector displace-
ment with a maximum residual error of 2 mm for the con- TagedPThe most important steps of the SRS workflow, with
ventional mask. The study concluded that dedicated masks regards to the treatment of small brain metastases, are
should always be used for treating small targets to mini- covered by these guidelines. However, the topics of SRS
mize intrafraction movement.TagedEn service commissioning, QA program development, treat-
TagedPProlonged treatment, which is associated with a greater ment planning, and delivery techniques that have plat-
risk of position shifts and patient stability during mask- form-specific challenges are outside the scope of this
based treatment, is another consideration. If there is no paper. National and international dosimetric protocols
real-time monitoring nor adjustments of patient position, and technical guidelines should be used to help set up
time delays between imaging and beam-on delivery commissioning and QA programs.70,71 One example of
should be as short as possible and preferably under 5 the latest international document, International Atomic
minutes to minimize potential targeting errors. For longer Energy Agency TRS 483, discusses in depth the challenges
time delays, reverification of the patient’s position should associated with small-field dosimetry in external beam
be considered.67 Optical surface IGRT is a viable solution radiation therapy.TagedEn
for intrafraction motion tracking. It uses an open-face TagedPClinical complications may not manifest themselves
mask and allows monitoring of intrafraction movements over a single SRS session, but with longer survival and
via patient facial topography in real time with an infrared additional SRS treatments (in particular as salvage to the
camera, reducing the need for additional x-rays68 while same lesion), we should remain concerned about the
improving patient comfort and feelings of claustrophobia. cumulative dose delivered to the normal brain. This is a
Pham et al69 reported that the clinical outcome of SRS complex problem, especially where multiple lesions are
treatment with surface IGRT was comparable with con- treated over multiple sessions with uneven time gaps in
ventional frame-based and frameless SRS for brain metas- between. Such concerns are becoming clinically relevant
tases, but the volume range of lesions as well as the off- and warrant further investigation.TagedEn
center distance of these lesions was not specified in the
study. The integration of x-ray imaging and surface IG is
evolving in this technology.TagedEn TagedH1ConclusionsTagedEn
TagedPThe options available for immobilization and localiza-
tion will depend on the equipment used for treatment. TagedPWe have described the main technological considera-
Table 3 shows the reported results for immobilization and tions when administering SRS treatments to patients with
on-board imaging combinations. Although there are small (≤1 cm) brain metastases. Traditionally, small
many commercially available immobilization devices, the metastases were treated with SRS only in specialized
level of accuracy required to treat targets less than 1 cm departments using Gamma Knife, cone-based LINAC sys-
limits options. Before clinical implementation of an SRS tems, and later CyberKnife. At present, there is evidence
service, E2E testing, such as that recommended by the to show that small metastases can be safely treated with
AAPM task group, must be implemented to validate the modern LINACs that are appropriately adapted and care-
entire treatment process.42 An E2E test aims to reveal fully verified for radiosurgical procedures. This provides
problems at any point along the treatment workflow. For an opportunity for treatments at more centers, which is
such a test, a head phantom encompassing detectors or beneficial for global patient care. However, establishing
radiochromic film goes through the entire SRS treatment an SRS program should be undertaken with caution as
chain including imaging, contouring, planning, target considerable expertise and resources are required.TagedEn
TagedEn192 D. Grishchuk et al Practical Radiation Oncology: May/June 2023

TagedEnTable
3 Collation of data from the literature for the accuracy of different platform/positioning/immobilization
combinations
Immobilization
device Device characteristics
Gamma Knife IGRT: CBCT (starting from Icon model)
Leksell G Patient positioning accuracy: (0.44 § 0.19) mm (mean § SD) − film measurements inside phantom72
frame (0.48 § 0.23) mm (mean § SD) - film measurements inside phantom73
Positioning tracking: No
Intrafraction motion: Translation: X (0.05 § 0.04) mm Y (0.03 § 0.02) mm Z (0.08 § 0.07) mm
Rotation: X (0.03 § 0.03)° Y (0.07 § 0.07)° Z (0.07 § 0.13)° (ref. 74)
Values relate to: Difference between patient’s pre- and post-treatment CBCT
LINAC frame IGRT: Orthogonal x-rays, CBCT
Patient positioning accuracy: (1.0 § 0.5) mm - orthogonal x-rays (ExacTrac) patient measurements63
Positioning tracking: No
Intrafraction motion: (0.40 § 0.3) mm - ExacTrac patient measurements63
(0.30 § 0.21) mm - ExacTrac patient measurements75
Values relate to: ExacTrac patient measurements
Gamma Knife IGRT: CBCT
SRS mask Patient positioning accuracy: (0.5 § 0.6) mm76
Positioning tracking: HDMM system (tracking accuracy 0.15 mm)76
Intrafraction motion: (0.62 § 0.25) mm after correction based on pre-treatment CBCT77
Values relate to: Observed movements during treatment based on HDMM marker position (used a
displacement HDMM threshold of 1.5 mm)
Actina PinPoint IGRT: CBCT + 6-DoF robotic couch (HexaPod)
bite-block Patient positioning accuracy: 6-DoF robotic couch positioning accuracy § 0.3 mm and § 0.2° (ref. 76)
system Positioning tracking: Alarm if vacuum is lost75
Intrafraction motion: (0.45 § 0.33) mm − difference between pre- and posttreatment patient’s CBCT75
Brainlab mask IGRT: Orthogonal x-rays + 6-DoF robotic couch
Patient positioning accuracy: (0.7 § 0.3) mm − hidden target test63
Positioning tracking: Infrared optical-tracking system for couch
Intrafraction motion: (0.35 § 0.21) mm − patient’s pre- and posttreatment x-ray78
(0.7 § 0.5) mm − patient’s pre- and post-treatment x-ray63
CyberKnife mask IGRT: Orthogonal x-rays + 6-joint robotic treatment couch (RoboCouch, Accuray, Inc)79
Positioning tracking: Repeated x-ray image acquisitions at a user-defined frequency (typically every 30-60 s)
Intrafraction motion: Translation: X (0.27 § 0.61) mm Y (0.24 § 0.62) mm Z (0.14 § 0.24) mm
Rotation: X (0.13 § 0.21)° Y (0.18 § 0.25)° Z (0.28 § 0.44)° (ref. 80)
Based on patient measurements during treatment with 6D-skull tracking
SGRT open masks IGRT: CBCT
Patient positioning accuracy: Not published
Positioning tracking: Tracking 1D accuracy 0.1 § 0.1 mm81
Abbreviations: 6-DoF = 6 degrees of freedom; CBCT = cone beam computed tomography; HDMM = height definition motion management;
IGRT = image guided radiation therapy; LINAC = linear accelerator; SD = standard deviation; SGRT = surface IGRT; SRS = stereotactic
radiosurgery.

TagedH1Supplementary materialsTagedEn TagedP 2. Lippitz B, Lindquist C, Paddick I, Peterson D, O’Neill K, Beaney R.

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