TITLE: Gamma Knife Surgery Compared with Linac-Based Radiosurgery Systems in the Treatment of Intracranial Lesions or Tumours and Functional Neurosurgery: A Review of the Precision, Accuracy, Clinical Effectiveness, Cost-Effectiveness, and Guidelines DATE:

11 March 2014

CONTEXT AND POLICY ISSUES Stereotactic radiosurgery (SRS) is a noninvasive treatment for a variety of intracranial lesions.1 Unlike conventional radiation therapy or whole brain radiotherapy, SRS is designed to focus a radiation dose on a predefined target while minimizing the radioactive dose outside of the target.2 The advanced imaging techniques, computed tomography (CT) and magnetic resonance imaging (MRI), have enabled precise, submillimeter targeting of intracranial lesions in three dimensional space using different SRS systems.2-4 As the various modern SRS systems represent a substantial investment, an evidence-based approach to a purchasing decisions serves the interests of patients and healthcare providers. The gamma knife (GK) (Elekta Instruments AB, Stockholm, Sweden) is the most common SRS system used for intracranial radiosurgery and is considered by some to be the gold standard.1,2 The unique features of this SRS system include the use of about 200 convergent sources of radiation and a fixed frame attached to the patient’s head to ensure accuracy. Recent GK models include a non-invasive frame facilitating fractionated SRS.1 Geometric design constraints limit GK SRS systems to treatment of intracranial lesions.2 Focusing therapeutic radiation for SRS can also be accomplished using a linear accelerator (LINAC). LINAC-based SRS systems include CyberKnife (CK) (Accuray, Sunnyvale, CA, USA), Novalis (NTx) (BrainLAB AG, Feldkirchen, Germany), and X-knife (Siemens, Germany).1,2,5 In addition to a single radiation source, LINAC-based SRS systems differ from GK as they are frameless and the radiation source moves instead of the patient.6 An essential aspect of SRS is avoiding radiation toxicity and damage to critical regions of normal tissue. This necessitates accuracy and precision of SRS systems. Dosimetric parameters are calculated by SRS system-specific software and used to plan treatment. Dosimetric parameters include the conformity index (CI), a volume-based measure of Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

prescription dose delivery to the tumour; the gradient index (GI), a measure of the concentration of the radiation in the prescribed target volume; and homogeneity index (HI), a measure of the consistency of the dose within the prescribed target volume.4 These parameters can be used to compare accuracy and precision of different SRS systems.1,4,5,7,8 The purpose of this report is to retrieve and review existing evidence comparing different SRS systems with regard to accuracy and precision, clinical safety and effectiveness, costeffectiveness and to review evidence-based guidelines for particular SRS systems. RESEARCH QUESTIONS 1.

What is the accuracy and precision of Gamma Knife compared with framed and frameless LINAC-based radiosurgery systems used in the treatment of intracranial lesions or tumors and functional neurosurgery?

2.

What is the comparative clinical safety and effectiveness of Gamma Knife and LINACbased radiosurgery systems when used in the treatment of intracranial lesions or tumors and functional neurosurgery?

3.

What is the comparative cost effectiveness of Gamma Knife and LINAC-based radiosurgery systems when used in the treatment of intracranial lesions or tumors and functional neurosurgery?

4.

What are the evidence-based guidelines for Gamma Knife and framed and frameless LINAC-based radiosurgery systems using in the treatment of intracranial lesions or tumors and functional neurosurgery?

KEY FINDINGS Evidence presented in this report is unable to distinguish between Gamma Knife (GK) and LINAC-based stereotactic radiosurgery (SRS) systems with regard to clinical effectiveness, safety and cost-effectiveness. Evidence of statistically significant differences in dosimetric parameters that reflect accuracy and precision was identified. These differences did not exclusively favour GK or LINAC-based SRS systems nor was evidence identified that these differences have clinical relevance. Additionally the literature search methodology in this report found no evidence-based guidelines that were specific to any particular SRS system. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2014, Issue 1), University of York Centre for Reviews and Dissemination (CRD) databases. Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 01, 2009 and February 10, 2014.

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Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for the final article selection, according to selection criteria presented in Table 1. Table 1: Selection Criteria Population Patients of all ages demonstrating intracranial lesions or tumours or requiring neurosurgery for neurological disorders. Intervention Gamma Knife Surgery Comparator

Framed and frameless LINAC-based radiosurgery systems

Outcomes

Clinical benefit and harm Clinical Effectiveness Cost-Effectiveness Accuracy and Precision Guidelines Health Technology Assessments (HTA)/ Systematic review (SR)/Meta-analysis (MA); Randomized controlled trials (RCTs); Nonrandomized studies; and Guidelines

Study Designs

Exclusion Criteria Studies were excluded if they did not meet the selection criteria, were duplicates or included in a selected SR, MA or HTA, or were published prior to 2011. Critical Appraisal of Individual Studies The quality of the included MA was analyzed using the assessment of multiple systematic reviews tool (AMSTAR).9 The quality of the included studies was evaluated using the Downs and Black checklist.10 Instead of assigning numerical scores for each included study, the strengths and limitations were described narratively and tabulated. SUMMARY OF EVIDENCE Quantity of Research Available The literature search strategy identified 186 articles and 23 additional articles were identified by searching the grey literature. Following screening of titles and available abstracts 16 full text articles were retrieved. One MA, one cost comparison and four retrospective comparative studies (RCS) met the selection criteria (Table 1) upon review. The 33 studies excluded from this report consisted 13 studies and guidelines that did not examine the specific interventions of interest, five examined an irrelevant intervention, two examined an irrelevant comparator, four were published outside the specified date limits, and nine were review articles and communications. The selection procedure for the literature included in this review is described in a PRISMA flowchart (Appendix 1).

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The four retrospective studies all address the question of accuracy and precision of the interventions and comparators.4,5,7,8 The question of safety and effectiveness is addressed in the included MA.11 No studies more recent than the included 2011 MA were identified that examined clinical outcomes of treatment using the different SRS systems of interest. The included cost comparison partially addresses the question regarding cost-effectiveness.12 No guidelines were identified specific to the intervention or comparator. Guidelines were identified that are generally relevant to SRS and may be of interest outside of the stated research questions, therefore the included in the reference section is a selection of these additional references.13-16 Summary of Study Characteristics Study characteristics of the included retrospective comparative studies (RCSs) are tabulated in Appendix 2. Study design A total of six studies, consisting of one MA,11 one economic study12 and four RCSs,4,5,7,8 were identified as meeting the selection criteria. The RCSs used patient imaging data to plan treatment with the different SRS systems and reported the resulting dosimetric parameters. Population The populations examined in the included studies were patients with metastatic brain lesions,4,5,8 arteriovenous malformation (AVM),5,8 acoustic neuromas (AN),5,7 benign tumours,5 primary cranial malignancy,5 meningioma,5,12 pituitary adenoma,5 and glomus jugulare tumours.11 The included MA exclusively examined patients with glomus jugulare tumours, analyzing data from 335 patients, 278 of which received GK SRS while the remaining 57 patients received an unspecified LINAC-based SRS.11 The MA included 10 of 19 studies with a mean or median follow-up time of greater than 36 months. The economic analysis exclusively examined 59 benign meningioma patients treated in The Netherlands.12 Three included RCSs examined twelve metastatic lesions in a single patient,8 10 patients with AVM and five patients with ANs,7 and 15 patients with 26 brain metastases.4 Another identified RCS examined treatment plans, based on imaging data and dosimetric indices, for 14 X-knife patients consisting of seven AN, three single metastases, one meningioma, one pituitary adenoma and two benign tumours, and plans for 20 GK patients consisting of seven AN, four pituitary adenomas, four meningioma, two AVM and three benign tumours. Interventions and comparators All included studies examined the use of GKS as compared to LINAC-based radiosurgery. The included MA examined 14 studies that used GKS and 5 studies that used unspecified LINACbased radiosurgery or CK.11

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The cost-effectiveness study compared GKS to unspecified LINAC-based radiosurgery and microsurgery.12 Annual total cost differences between GK and LINAC- based SRS systems were also reported. The RCSs contain more information than the other included studies on the specific SRS systems used and on the specific planning methodology. While all RCSs examine the Leksell GK, the models identified and planning software used differ. One RCSs compares GK to CK,4 one RCS compares GK to X-knife5 while two RCSs compare GK to CK and NTx systems.7,8 These dosimetry studies examine the result of planning software on the accuracy and precision of SRS treatment scenarios and therefore the software is an essential component of the specific intervention and comparator. All of the studies describe the planning method used for the different SRS systems, none of which were identical.4,5,7,8 One study compared different planning approaches for the same SRS system, NTx.7 The intervention and comparator details of the included RCSs are tabulated in Appendix 2. Outcomes The MA, Guss et al. (2011), primarily examined tumour control and clinical control outcomes. Tumour control was defined as unchanged or reduced tumour volume after radiosurgery as assessed by imaging. Clinical control was defined as unchanged or improved clinical status after treatment. Documented complications and toxicities were also tabulated for each of the studies included in the MA.11 The cost-effectiveness study reported on the direct and indirect costs of both initial treatment and one year follow-up costs. Unit costs in the analysis included direct costs associated with diagnostic procedures (medical imaging and laboratory services), consumables (medications and disposables), inpatient stay, labor (including neurosurgeons, anesthesiologists, radiation oncologists, residents, physicists, radiation technicians, operation assistants, and nurses) and indirect costs such as overheads (general expenses, administration and registration, energy, maintenance, insurance, and personnel costs of nonpatient services such as management and administration) and capital (depreciation of buildings and inventory, and interest). Follow-up costs included visits to healthcare providers (including the general practitioner, medical specialist, physiotherapist, social worker, and company physician), medical imaging services, inpatient stay, medications, and medical aids (such as wheelchairs, rolling walkers, and walking canes).12 Dosimetry indices were used for comparison of the different SRS treatment plans in the included RCSs. The CI4,5,7 and/or variations of this parameter including Radiation Therapy Oncology Group conformity index (RTOG CI),4, new conformity index (nCI)4, and Paddick’s conformity index (PCI),5,8 were reported in the included RCSs. A volume based gradient index (GI) is reported in two of the four RCSs4,7, one RCS reports a related parameter ᵞ,5 while the remaining RCS plots normal brain isodose volumes that reflect this parameter.8 Two RCSs additionally report a homogeneity index (HI)4,5 while one reports a related parameter, dose heterogeneity (DH), as well as treatment time.7 A technical summary of CI, GI and homogeneity index (HI) is available in Appendix 1 of the included RCS, Sio et al., 2014.4 One report examines the effect of multiple targets on PCI and on normal brain isodose volumes using the different radiosurgical systems.8 Two of the studies examined different types of intracranial targets,5,7 one of these reported separate dosimetric indices for the different targets.7

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Summary of Critical Appraisal Critical appraisal of the included literature is tabulated in Appendix 3. The single MA identified that examined differences in clinical outcomes for GK vs LINAC-based SRS was published in 2011. The analysis provides a description for a comprehensive literature search without any specific mention of any grey literature sources. While the MA included a description of exclusion criteria, a list of studies that were excluded was not provided. Details provided from included studies was limited to average dose, modality, number of patients, and length of follow-up. The quality of the included studies was not assessed. Data from the included studies was tabulated but the methods of extracting data from the studies was not described. Publication bias was examined in funnel plots and the degree of combinability of the included studies was also assessed. A statement declaring no conflicts of interest was provided. The primary focus was not a comparison of GK with LINAC-based radiosurgical systems but instead was an examination of the effectiveness of any radiosurgical treatment modality on glomus jugulare tumours. However, the results from GK and LINAC-based approaches were also examined separately allowing the authors some conclusions relevant to this review.11 The identified cost-analysis study was not a true cost-effectiveness study as it did not measure costs against any clinical outcome. Conducted in The Netherlands using data from 2007, this study may also have limited relevance to a current Canadian healthcare setting. The analysis is from a healthcare provider’s prospective and did not include productivity costs, however unit costs included were comprehensive and relevant to a Canadian setting, though differences in costs such as labour and medications may be significant. Data in this study was from a small sample of patients, however the characteristics of the included patients were tabulated and the inclusion criteria for patients was well described. Additionally one-way sensitivity analyses were carried out to determine the uncertainty of the obtained cost estimates. This study examined both direct and indirect costs and included preoperative evaluation and follow-up costs. The authors report funding received from a manufacturer of one of the SRS systems representing a potential conflict of interest.12 The retrospective studies examining accuracy and precision of different SRS systems do not examine relationships between the dosimetric indices and clinical outcomes.4,5,7,8 These studies often calculated related dosimetric indices describing a similar parameter but do not report any relevance to previous clinical findings.4,5,7,8 All of the studies acknowledged this limitation however only one study explicitly stated additional related limitations.4 As the dosimetric parameters are calculated prior to treatment, three of these studies evaluated parameters in the same patients, eliminating a source of variation for comparing the accuracy and precision of the different SRS systems.4,7,8 One of these studies examined only one patient with multiple targets however this study also examined the effect of target number on dosimetric parameters.8 Two of these studies stated the authors had no conflict of interest,5,7 one study disclosed industry support,8 and one study did not have any conflict of interest statement.4 One study tabulated patient demographic characteristics4, the remaining studies only described patients in terms of diagnosis, target volumes and target numbers.5,7,8 The statistical significance of differences in dosimetric parameters was calculated in three studies,4,5,7 while the study that examined multiple targets in one patient did not calculate statistical significance.8 Summary of Findings Findings of the included studies in this review are tabulated in Appendix 4.

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The MA examining the clinical effectiveness of SRS reported the percentage of tumour control and clinical control of glomus jugulare tumours in SRS treated patients. Data on patients treated with GK or LINAC/CK were analyzed separately and both SRS systems demonstrated high success rates of tumour control and clinical control that were statistically indistinguishable. The authors conclude that “either modality is suitable for the management of glomus jugulare tumours.” (pp. 500)11 The MA was the only identified study that contained safety information. The authors were not confident in the consistency of adverse event reporting and long-term effect reporting of the examined studies to make any statistical statements regarding the safety of the SRS systems. Studies included in the MA reported adverse events such as transient lowgrade nausea, vertigo, hearing loss, mucositis, facial palsy and others. The authors also made no statements regarding adverse events or safety considerations unique to GK or LINAC-based radiosurgery systems.11 The cost-analysis study found that microsurgical methods of treating meningioma patients costs over three times as much as GK or LINAC-based SRS. When comparing GK with LINAC-based SRS the study found that initial GK SRS costs are almost 30% higher, largely due to higher associated equipment costs. Equipment was valued using replacement and maintenance costs with an anticipated life expectancy of 10 years. The initial equipment cost for GK was estimated at €3 000 000 while LINAC-based SRS equipment was estimated at €2 500 000. Annual total cost differences between GK and LINAC- based SRS systems were not statistically significant when evaluated using equipment costs per treatment. As the clinical outcomes of this small patient sample were not examined, this study does not reflect the relative cost-effectiveness of GK and LINAC-based SRS.12 All four RCS reports have data suggesting GK has superior GI4,5,7,8 while CK,4,7,8 NTx7 or Xknife5 have more homogenous treatment plans. With regard to conformity indices, one study suggested GK had superior plans to CK and NTx,8 one study demonstrated a statistically significant superiority of GK compared to X-knife5 and two studies found no statistically significant CI difference between GK and CK.4,7 One study examined treatment plans for NTx using DCA forward planning that were statistically significantly superior to GK in conformity and treatment time.7 This study also demonstrated a statistically significant improvement in GI by using different treatment plan methodology on the same NTx system.7 An increase in the number of target lesions did increase the volume of normal brain receiving a peripheral dose but did not degrade the dose conformity of GK, CK or NTx systems.8 These reports did not present any evidence for the relative clinical importance of any of the parameters or findings.4,5,7,8 Limitations No consensus in the evidence identified in this review suggested advantages in clinical superiority, safety or cost-effectiveness of any specific SRS system. The clinically relevant data exclusively examined glomus jugular tumours which may not be representative of other intracranial lesions.11 No data was identified on the relative safety or rates of adverse events of different SRS systems. The cost-analysis study did not examine the effect of clinical outcomes and therefore may not be representative of the total costs associated with GK or LINAC-based radiosurgical treatment.12 While some consensus was reached in the studies examining the dosimetric parameters of GK and LINAC-based radiosurgical systems it was not suggested that these parameters have any established clinical relevance. No guidelines specific to a particular SRS system or evidence–based recommendations on which SRS system to use in any particular clinical situation were identified.4,5,7,8

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CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Evidence in this review was unable to distinguish between the clinical effectiveness of GK and LINAC/CK, although both exhibited high rates of tumour and clinical control. GK had higher initial equipment costs than LINAC-based SRS, however the annual costs, evaluated as equipment costs per treatment, had no statistically significant difference. Consensus was identified in studies that examined accuracy and precision and suggested GK treatment plans had superior GI while LINAC-based SRS treatment plans had superior HI. The cost-analysis and accuracy and precision studies identified in this review were not associated with any clinical outcomes which limits the conclusions that can be drawn regarding patient outcomes associated with SRS and the cost-effectiveness of these approaches. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

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REFERENCES 1.

Levivier M, Gevaert T, Negretti L. Gamma Knife, CyberKnife, TomoTherapy: gadgets or useful tools? Curr Opin Neurol. 2011 Dec;24(6):616-25.

2.

Chung HT, Kim DG. Modern radiosurgery equipment for treating brain metastases. Prog Neurol Surg. 2012;25:236-47.

3.

Descovich M, Sneed PK, Barbaro NM, McDermott MW, Chuang CF, Barani IJ, et al. A dosimetric comparison between Gamma Knife and CyberKnife treatment plans for trigeminal neuralgia. J Neurosurg. 2010 Dec;113 Suppl:199-206.

4.

Sio TT, Jang S, Lee SW, Curran B, Pyakuryal AP, Sternick ES. Comparing Gamma Knife and CyberKnife in patients with brain metastases. J Appl Clin Med Phys. 2014;15(1):4095.

5.

Semwal MK, Singh S, Sarin A, Bhatnagar S, Pathak HC. Comparative clinical dosimetry with X-knife and gamma knife. Phys Med. 2012 Jul;28(3):269-72.

6.

Wowra B, Muacevic A, Tonn JC. CyberKnife radiosurgery for brain metastases. Prog Neurol Surg. 2012;25:201-9.

7.

Gevaert T, Levivier M, Lacornerie T, Verellen D, Engels B, Reynaert N, et al. Dosimetric comparison of different treatment modalities for stereotactic radiosurgery of arteriovenous malformations and acoustic neuromas. Radiother Oncol. 2013 Feb;106(2):192-7.

8.

Ma L, Petti P, Wang B, Descovich M, Chuang C, Barani IJ, et al. Apparatus dependence of normal brain tissue dose in stereotactic radiosurgery for multiple brain metastases. J Neurosurg. 2011 Jun;114(6):1580-4.

9.

Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2014 Feb 4];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

10.

Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2014 Feb 11];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf

11.

Guss ZD, Batra S, Limb CJ, Li G, Sughrue ME, Redmond K, et al. Radiosurgery of glomus jugulare tumors: a meta-analysis. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e497-e502.

12.

Tan SS, van PE, Nijdam WM, Hanssens P, Beute GN, Nowak PJ, et al. A microcosting study of microsurgery, LINAC radiosurgery, and gamma knife radiosurgery in meningioma patients. J Neurooncol [Internet]. 2011 Jan [cited 2014 Feb 13];101(2):237-

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45. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996536/pdf/11060_2010_Article_243.pdf 13.

Niranjan A, Kano H, Lunsford LD. Gamma knife radiosurgery for brain vascular malformations. Prog Neurol Surg. 2013;27:130-40.

14.

Ammirati M, Cobbs CS, Linskey ME, Paleologos NA, Ryken TC, Burri SH, et al. The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol [Internet]. 2010 Jan [cited 2014 Feb 13];96(1):85-96. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808530/pdf/11060_2009_Article_55.pdf

15.

Linskey ME, Andrews DW, Asher AL, Burri SH, Kondziolka D, Robinson PD, et al. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010 Jan;96(1):45-68. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808519

16.

Tsao MN, Rades D, Wirth A, Lo SS, Danielson BL, Gaspar LE, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol. 2012 Jul;2(3):210-25. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808749

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List of Abbreviations APS AMSTAR AN AVM AVR CI nCI CK COI CT DCA DH DTS ᵞ GI50 GI25 GK Gy HDMLC HI MA IMRT LGK LINAC MRI NTx PCI RTOG CI SD SRS Tt

automatic positioning system assessment of multiple systematic reviews tool acoustic neuromas arteriovenous malformations average volume ratio conformity index new conformity index cyberknife conflict of interest computed tomography dynamic arc heterogeneity index dynamic tracking software gradient index gradient index (using volume enclosed by 50% prescribed dose) gradient index (using volume enclosed by 25% prescribed dose) gamma knife gray high-definition-multileaf-collimator homogeneity index meta-analysis intensity modulated radiotherapy Leksell gamma knife linear accelerator magnetic resonance imaging Novalis Tx system Paddick’s conformity index Radiation Therapy Oncology Group conformity index standard deviation stereotactic radiosurgery treatment time

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APPENDIX 1: Selection of Included Studies 186 citations identified from electronic literature search and screened 170 citations excluded

16 potentially relevant articles retrieved for scrutiny (full text, if available)

23 potentially relevant reports retrieved from other sources (grey literature, hand search)

39 potentially relevant reports

33 reports excluded: -irrelevant intervention (5) -irrelevant comparator (2) -published outside date limits (4) -not specific intervention (13) -other (review articles, editorials)(9)

6 reports included in review

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Appendix 2: Summary of Study Characteristics of Included Retrospective Comparative Studies Study Design Patient Intervention Comparator Dosimetric Characteristics, Parameters Sample Size Sio et al., 20144 RCS 15 patients with Leksell Gamma CyberKnife using RTOG_CI, CI, 26 brain Knife C using MultiPlan DTS nCI, HI, GI50, metastases Leksell 3.0 (Accuray) GI25 and AVR GammaPlan 8.3 (Elekta) Gevaert et al., 20137 RCS 10 AVM, 5 AN Leksell Gamma Novalis Tx Maximum Dose, patients Knife Perfexion system PCI, DH, GI, (Elekta) using (BrainLAB) using treatment time forward planning DCA with forward planning and IMRT using inverse planning CyberKnife (Accuray) using inverse planning Semwal et al., 20125 RCS X-Knife: 14 patients consisting of 7 AN, 3 single metastases, 1 meningioma, 1 pituitary adenoma, 2 benign tumours Gamma Knife: 20 patients consisting of 7 AN, 4 pituitary adenomas, 4 meningioma, 2 AVM and 3 benign tumours Ma et al., 20118 RCS 1 patient with 12 metastatic lesions

Leksell Gamma Knife model 4C using APS Gamma Plan 4C release 5.34 (Elekta)

X-knife (Radionics) with LINAC model Primus (Siemens) using X-knife RT (Radionics)

PCI, ᵞ, HI

Leksell Gamma Knife using Gamma Plan (Elekta)

CyberKnife using MultiPlan (Accuray)

Graph of PCI, Plots of normal brain isodose volumes variance with target number and SRS system

Novalis using iPlan (BrainLAB)

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APS=automatic positioning system; AN=acoustic neuromas; AVM= arteriovenous malformations; AVR= average volume ratio; CI= conformity index; nCI= new conformity index; DCA=dynamic arc; DH= heterogeneity index; DTS = Dynamic Tracking Software; ᵞ= gradient index; GI50= gradient index (using volume enclosed by 50% prescribed dose); GI25= gradient index (using volume enclosed by 25% prescribed dose); HI= homogeneity index; IMRT=intensity modulated radiotherapy; LINAC= linear accelerator; PCI= Paddick’s conformity index; RCS=retrospective comparative study; RTOG CI= Radiation Therapy Oncology Group conformity index; SRS = Stereotactic Radiosurgery

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Appendix 3: Summary of Critical Appraisal of Included Studies Strengths Systematic Review Guss et al., 201111 • systematic comprehensive literature search • exclusion criteria defined • bias quantified • degree of combinability of included studies assessed • included studies tabulated • COI statement

Cost-Effectiveness Study Tan et al., 201112 • purpose of study explicitly stated • well defined patient inclusion criteria • tabulated patient characteristics • intervention and comparator justified • direct and indirect costs listed • preoperative evaluation and follow-up costs included • one-way sensitivity analyses carried out Retrospective Comparative Studies Sio et al., 20144 • cohorts perfectly matched (same patients) • introduction to dosimetric concepts and indices • limitations discussed • patient characteristics tabulated Gevaert et al., 20137 • cohorts perfectly matched (same patients) • evaluated indices for AVMs and ANs independently • treatment time examined as an outcome • Novalis Tx examined using different planning approaches • COI statement Semwal et al., 20125 • COI statement • results tabulated and graphed for individual patients

Limitations

• characteristics of included studies not provided • no mention of searching grey literature sources • quality of included studies not assessed • data extraction methods not described • list of excluded studies not provided • comparison of SRS systems was not primary purpose

• economic context of study not described • not a true cost-effectiveness study (did not weigh costs of meningioma treatment against clinical outcome measures) • small sample of patients • COI – industry funding • conducted in The Netherlands – may have limited applicability to a Canadian healthcare setting

• results not correlated with clinical outcome • choice of dosimetric indices evaluated not based on clinical relevance • no COI statement

• results not correlated with clinical outcome • choice of dosimetric indices evaluated not based on clinical relevance • not all dosimetric parameter differences of interest were evaluated for statistical significance

• results not correlated with clinical outcome • choice of dosimetric indices evaluated not based on clinical relevance • different patient groups in each treatment • not all dosimetric parameter differences of interest were evaluated for statistical significance

Ma et al., 20118

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Strengths • cohorts perfectly matched (same patient) • examined the effects of having multiple targets

Limitations • results not correlated with clinical outcome • choice of dosimetric indices evaluated not based on clinical relevance • only one patient – no data for statistical analysis • COI – industry funding

COI= conflict of interest

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Appendix 4: Summary of Findings Main Study Findings Systematic Review Guss et al., 201111 Tumour control GK: 97% (95% CI, 94-99%) LINAC/CK: 97% (95% CI, 92-100%) Clinical control GK: 94% (95% CI, 91-97%) LINAC/CK: 97% (95% CI, 92-100%)

Author’s Conclusions

Clinical Effectiveness “The high success rates in tumor and clinical control in both the GK and the LINAC/CK studies for >300 patients suggest that either modality is suitable for the management of glomus jugulare tumors.” (pp. 500) “…a longer period of follow-up is needed to detect the onset of secondary malignancies.” (pp. 501) Adverse Events “A wide variance in the manner and detail of reporting acute complications and long-term sequelae across the 19 studies prevented statistical analysis of these features.”(pp. 499)

Cost-Analysis Study Tan et al., 201112 Equipment Capital cost GK: €3 000 000 CK: €2 500 000 Treatment costs GK: €963/treatment CK: €701/treatment Includes maintenance, treatment of 550 patients/year and assumes an equipment lifespan of 10 years.

The majority of the difference between the initial treatment costs of GK and LINAC were due to equipment costs. “Accounting for 40% of total treatment costs, equipment was a relatively important cost driver in gamma knife radiosurgery.” (pp. 241)

Initial treatment costs Diagnostics, consumables, inpatient stay, labour, equipment, and overheads GK: €2 412 LINAC: €1 547

“Annual total costs of LINAC and gamma knife radiosurgery were not significantly different (P = 0.096).” (pp. 243)

Follow-up costs Labour, imaging services, inpatient stay, medication and medical aids GK: €1 553 LINAC: €1 514

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Main Study Findings Retrospective Comparative Studies Sio et al., 20144 GK: prescribed to 40-50% isodose line CK: prescribed to 77-92% isodose line GK vs CK median ± SD Minimum Dose 18.2 ± 3.4 vs 17.6 ± 2.4 Gy, p = 0.395 Mean Dose 29.6 ± 5.1 vs 20.6 ± 2.8 Gy, p < 0.00001 Maximum Dose 40.3 ± 6.5 vs 22.7 ± 3.3 Gy, p < 0.00001 HI 2.22 ± 0.19 vs 1.18 ± 0.06, p < 0.00001 GK vs CK, with range RTOG_CI 1.76 (1.12 – 4.14) vs 1.53 (1.16–2.12), p = 0.0220 CI 1.76 (1.15–4.14) vs. 1.55 (1.18–2.21), p = 0.050 nCI 1.76 (1.59–4.14) vs. 1.57 (1.20–2.30), p = 0.082 GI50 2.91 (2.48–3.67) vs. 4.90 (3.42–11.68), p < 0.00001 GI25 6.58 (4.18–10.20) vs. 14.85 (8.80–48.37), p < 0.00001 AVR Tabulated results show a statistically significant sharper dose falloff favouring GK. Gevaert et al., 20137 GK: prescribed to 50% isodose line CK: prescribed to 80% isodose line NTx: prescribed to 80% isodose line for both planning methods Table 2: Mean Indices for SRS systems GK NTx DCA NTx IMRT CK Max 33.93±7.59 21.31±4.58 21.39±4.88 21.16±4.61 Dose (Gy) PCI 0.77±0.04a 0.66±0.04a 0.68±0.04 0.77±0.06 HI 0.84±0.05 0.30±0.03 0.18±0.05 0.22±0.02 GI 2.59±0.10b 3.16±0.55b,c 3.94±0.92c 3.48±0.47 Tt 68.1±27.5d 16.8±2.2d 21.7±3.4 28.4±8.1 (min) a-d are reported as statistically significant differences (p < 0.01)

Gamma Knife Surgery Compared with Linac-Based Radiosurgery Systems

Author’s Conclusions

“We concluded that in patients with brain metastases, CK and GK resulted in dosimetrically comparable plans that were nearly equivalent in several metrics, including target coverage and minimum dose within the target. Compared to GK, CK produced more homogenous plans with significantly lower mean and maximum doses, and achieved more conformal plans by RTOG_CI criteria. By GI and AVR analyses, GK plans had sharper peripheral dose falloff in most cases.” (pp. 14)

“Our study showed that the introduction of new LINACbased technologies (HDMLC, intensity-modulation) has reduced the gap between Gamma Knife technology and LINAC-based ones, in terms of dose planning. Although taking into account that the essence of SRS is to highly conform the lesion (high CI) while minimizing low dose irradiation of the adjacent healthy structures (low GI), we can conclude that the redesigned treatment unit LGK-PFX is the system which will better comply

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Main Study Findings Separate results for AVM and AN tabulated in study. No statistical differences in dosimetric parameters found between these two lesion types. Semwal et al., 20125 GK: usually prescribed to 50% isodose line X-knife: usually prescribed to 85-90%% isodose line GK vs X-knife median ± SD PCI 0.664 ± 0.048 vs 0.501 ± 0.240, p < 0.001 ᵞ1 1.703 ± 0.247 vs 2.251 ± 0.450, p < 0.001 ᵞ2 1.559 ± 0.099 vs 1.800 ± 0.327, p = 0.018 ᵞ3 1.536 ± 0.058 vs 1.515 ± 0.131, p = 0.580 HI 1.8 - 2.2 vs 1.0 - 1.2

Ma et al., 20118 GK: prescribed to 61 ± 11% isodose line CK: prescribed to 78 ± 5% isodose line NTx: prescribed to 71 ± 3% isodose line Author’s interpretations of data presented in a graph and two scatter plots CI vs SRS system and target number: “…the Perfexion plans were consistently superior to those of CyberKnife or Novalis. No obvious degradation in dose conformity for any platform was noticed with increasing number of targets.” (pp.1581) Normalized non-target volumes vs dose received: With increasing number of targets: “…there is a notable but nonlinear trend of increase in the volume of normal brain tissue receiving a peripheral dose of 4–20 Gy” (pp. 1581)

Author’s Conclusions with all the planning objectives.” (pp. 196)

“…in cases where higher dose at tumour core is desirable, LGK offers advantage. The sharper dose fall-off in the vicinity of the target and the better dose conformity in LGK can help reduce peripheral high dose volume and thus decrease the probability of radiation necrosis incidences.” (pp. 272) “…it can be said that the vastly superior dose homogeneity in X-knife as compared to LGK may provide potential advantage to the former in the treatment of tumours where an organ at risk (OAR) traverses the target volume.” (pp.272) “Our findings indicate that caution should be used in considering the peripheral normal brain dose when performing multitarget SRS. Future studies of different treatment scenarios such as varying the total target volume and number of targets, as well as those designed to further improve planning techniques, are needed. Studies of the cause of SRS systemdependent dose-volume histogram differences are needed to resolve the relative contributions of hardware design and treatment planning algorithms.” (pp 1583)

With different SRS system: “The Gamma Knife Perfexion plans result in much smaller normal brain volumes receiving any particular dose as

Gamma Knife Surgery Compared with Linac-Based Radiosurgery Systems

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Main Study Findings Author’s Conclusions compared with the CyberKnife and Novalis plans. The discrepancy was typically on the order of a factor of 2–3 favoring Gamma Knife Perfexion for all the cases.” (pp. 1581) APS=automatic positioning system; AN=acoustic neuromas; AVM= arteriovenous malformations; AVR= average volume ratio; CI= conformity index; nCI= new conformity index; CK= CyberKnife; DCA=dynamic arc; DH= heterogeneity index; ᵞ= gradient index; GI50= gradient index (using volume enclosed by 50% prescribed dose); GI25= gradient index (using volume enclosed by 25% prescribed dose); GK= gamma knife; Gy= gray; HDMLC= high-definitionmultileaf-collimator; HI= homogeneity index; IMRT=intensity modulated radiotherapy; LGK= Leksell gamma knife; LINAC= linear accelerator; NTx= Novalis Tx system; PCI= Paddick’s conformity index; RTOG CI= Radiation Therapy Oncology Group conformity index; SD= standard deviation; Tt= treatment time

Gamma Knife Surgery Compared with Linac-Based Radiosurgery Systems

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