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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 [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Mar 11.

Cover of 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

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 [Internet].

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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).

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.1316

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 LINAC-based radiosurgery or CK.11

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 targets7.

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.

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 low-grade 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 X-knife5 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

Copyright © 2014 Canadian Agency for Drugs and Technologies in Health.

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.

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Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

Bookshelf ID: NBK268762

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