Trusted Guidance by SRS Financials

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Stereotactic radiosurgery SRS Financials is an established non-invasive ablative therapy for brain metastases. Early scientific trials with SRS proved that tumor Handle premiums are outstanding to full brain radiotherapy (WBRT) by yourself. Due to this fact, WBRT furthermore SRS was greatly adopted for individuals that has a limited number of brain metastases (“minimal selection” customarily indicates 1-four). Subsequent trials centered on answering whether WBRT upfront was needed in the least. Dependant on current randomized managed trials (RCTs) and meta-analyses comparing SRS on your own to SRS as well as WBRT, adjuvant WBRT brings about better intracranial Manage; even so, with the price of neurocognitive operating and Standard of living. These adverse results of WBRT can also negatively effect on survival in more youthful sufferers. Determined by the final results of these research, therapy has shifted to SRS by yourself in individuals that has a confined quantity of metastases. Moreover, RCTs are evaluating the function of SRS on your own in individuals with >four Mind metastases. New developments in SRS incorporate fractionated SRS for giant tumors and The mixing of SRS with specific systemic therapies that cross the blood Mind barrier and/or stimulate an immune response. We current Within this evaluation The existing large level proof and rationale supporting SRS given that the normal of look after patients with limited brain metastases, and rising programs of SRS.

Brain metastases are a significant cause of morbidity and mortality in patients with metastatic cancer, with an incidence of up to 65% during the course of illness [1, 2]. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer . Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. The development of brain metastases was viewed as an oncologic terminal event.

As systemic therapies have become more efficacious in patients with metastatic disease, improved survival rates are now being observed. In addition, the patterns of disease progression are shifting such that the incidence of brain metastases is increasing while extra-cranial disease remains controlled. This phenomena is likely a consequence of the central nervous system (CNS) being a sanctuary site from drug penetration. As a result, the management of brain metastases has become a major focus of research, with the intent to improve intra-cerebral control and decrease neurologic deaths.

Although the job of neurosurgery had been set up in the nineties as a way to obtain local Management and extend survival, it absolutely was reserved for your minority of sufferers presenting with only one metastasis and no other disease over and above the Mind [4-7]. Even now lacking was a focal ablative non-invasive cure that might be utilized proficiently to your much broader population of individuals with brain metastases. This set the stage for the development of stereotactic radiosurgery (SRS). SRS is usually a concentrated ablative radiation cure shipped with sub-millimeter precision on the tumor localized in 3-Proportions in one-5 fractions.

The focus of this review is usually to summarize the current large stage proof to make clear the job of SRS as optimal administration for sufferers presenting with minimal Mind metastases. Furthermore, we offer an outline from the rising purposes of SRS as it carries on to evolve right into a treatment different to WBRT, with the intent To maximise neurcognitive perform and quality of life (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from the Main tumor mass to type distant colonies as a result of implantation at an ectopic site, such as the brain [eight-10]. To do so calls for CTCs to arrest inside the circulation, extravasate within the bloodstream or lymphatics into your brain, and endure and proliferate [11-thirteen]. The whole process of metastatic colonization entails a direct interaction of CTCs with endothelial cells and astrocytes from the Mind microenvironment. As an example, CTCs which have arrested in the capillary mattress direct area endothelial cells to remodel the adjacent setting to market tumour cell growth and invasion [14-sixteen]. Additional, metastatic tumour cells recruit systemic stromal cells, such as fibroblasts, to aid with early colonization , and co-decide area stromal cells, such as reactive astrocytes and microglia, to market tissue invasion [fifteen, eighteen, 19]. Astrocytes throughout the tumour microenvironment might also Participate in a job in preserving tumour cells from chemotherapy-induced cytotoxicity, via a yet to be defined mechanism requiring mobile-cell Get hold of [20, 21]. Tumour cells, as a result of release of migration inhibitory variable, interleukin-eight, and plasminogen activator inhibitor one, induce astrocyte activation and modify the inflammatory milieu to boost tumor-cell proliferation in vitro [22-24]. These molecular processes stand for novel and understudied achievable therapeutic targets for the cure of intracranial metastatic disorder.

SRS was to begin with an exceedingly useful resource intensive therapy available only at specialized facilities and indicated only for metastatic individuals with a very good daily life expectancy. The obstacle lay in prognosticating people successfully and as a result the Radiation Therapy Oncology Group (RTOG) recursive partitioning Evaluation (RPA) [28, 29] was made. According to the affected person's Karnofsky Efficiency Standing (KPS), age, position of the primary tumor and presence of extracranial sickness, patients ended up grouped into course one, 2 or 3 with corresponding median survivals of 7.one, four.two and a pair of.3 months, respectively. While A serious progress at some time, the RPA is currently deemed overly simplistic as existing oncologic determination earning is much more complicated incorporating molecular, histological, scientific and radiographic disorder properties. You'll find now a lot more sophisticated classification instruments, including the prognosis-precise graded prognostic assessment (DS-GPA). This method presents histology-distinct estimates of survival and can separate, for example, probably the most favorable breast cancer people using an predicted survival of twenty five months (outstanding KPS and luminal B form breast cancer) in the least favorable clients with the anticipated survival of three months (weak KPS and basal-like breast cancer) . Even with advances in prognostication of sufferers with brain metastases, doctors remain mainly struggling to correctly forecast lengthy-phrase survivors. A analyze asking expert doctors to estimate survival of a one hundred fifty people with information about most cancers form, quantity of Mind metastases, neurological presentation, further-cranial ailment standing, KPS, RPA class, prior full-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that a lot more than 45% of predictions were off by in excess of six months and 18% have been off by more than 12 months . Even further advances in prognostic exams including the “liquid biopsy” (a non-invasive blood take a look at which can detect tumor DNA or RNA fragments or CTCs) are wanted and in improvement . These Merge Superior individual and tumor unique genomic data to the equation, so as to attain personalised survival predictions.

Surgical treatment carries on to become a significant therapy selection for patients with constrained brain metastases. It is actually indicated when metastases are large (>three-four cm), or every time a pathologic prognosis is required. Moreover, medical procedures is chosen while in the presence of substantial edema demanding extended significant dose dexamethasone, or to most likely reverse neurological deficits. Normally, The present evidence implies that the efficacy of SRS is ample to accomplish resilient regional Manage which is similar to surgical procedure. Although there isn't any RCTs right comparing The 2, numerous trials happen to be documented comparing SRS to SRS with WBRT (Desk 1), and is particularly A serious concentrate of the evaluation.

HR: hazard ratio, WHO: environment overall health organization, KPS: Karnofsky general performance standing, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery, yr: calendar year, mos: months, NS: not important, NR: not recorded, NA: not relevant, HVLT-R: Hopkins Verbal Understanding Take a look at revised.

People from the observation team had both surgery on your own or SRS on your own. Purposeful end result was not analyzed separately by surgical procedure or SRS alone.

The very first RCTs evaluating SRS mimicked the design on the initial surgical experiments for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These studies confirmed that SRS enhanced community Handle, and also a survival edge in selected individuals with only one Mind metastasis was revealed. These trials ended up prosperous in shifting the paradigm from WBRT alone to WBRT furthermore SRS for individuals presenting with limited Mind metastases and a superb efficiency position.

The subsequent number of clinical trials were intended to respond to if WBRT was in any way important, and in comparison SRS on your own to SRS with adjuvant WBRT. 3 RCTs have been documented in sufferers presenting with around 4 metastases [35-37] along with a forth in abstract type . Aoyama et al. described the primary RCT, randomizing 132 individuals to SRS on your own (sixty five individuals) or WBRT moreover SRS (sixty seven patients). The main endpoint was brain tumor recurrence. Although the 1-12 months regional Command amount was significant with SRS by itself at 73%, extra nearby Manage with adjuvant WBRT at 89%, was noticed. In addition, adjuvant WBRT lowered the rate of distant intra-cranial relapse at 1 12 months from 64% to 42%. Nonetheless, these gains in intra-cranial Regulate did not translate into a benefit with respect to cognition, depending on Mini-Psychological Standing Exam (MMSE), nor survival. What's more, people had increased premiums of necrosis and leukoencephalopathy from the WBRT arm. The trial was Therefore productive in supplying the primary amount 1 proof to clarify the relative affect of SRS on your own versus SRS with WBRT.

Instead of the normal endpoint of survival or intra-cranial Handle, Chang et al. took a different approach and evaluated neurocognition as the key endpoint. Importantly, the validated Hopkins Verbal Understanding Test-Revised (HVLT-R) assessment tool, was used to evaluate neurocognitive operating as opposed to the MMSE which is not a delicate take a look at for neurocognition . Fifty-eight people have been randomized to SRS by yourself (n = thirty) or WBRT moreover SRS (n = 28). Early stopping principles were invoked at the interim Evaluation, plus the research concluded that SRS by yourself was favored with respect for the probability of neurocognitive decrease at four months submit-procedure. This reward was understood despite the 1 calendar year nearby control and distant Mind Command charges favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial Regulate results were In step with the final results with the Aoyama examine, but what wasn't envisioned was the survival advantage observed within the SRS alone arm. The median survival was 15 months while in the SRS alone arm and 6 months within the SRS with WBRT arm (p = 0.003). This survival consequence triggered the trial to endure substantial scrutiny with lots of arguing the survival benefit for SRS on your own was a result of imbalances among the two arms, as additional sufferers handled with SRS moreover WBRT experienced better excess-cranial (far more liver and adrenal metastases) and intracranial ailment (much larger volume of brain metastases) .

The European Organization for Study and Cure of Cancer (EORTC) also took another strategy with their primary endpoint specializing in useful independence . They used, nevertheless, the more clinically acquainted Environment Wellness Corporation (WHO) general performance standing (PS) scale, and measured time to WHO PS deterioration to over two. This RCT concluded the addition of WBRT did not Increase the median length of purposeful independence (SRS by yourself: 10.0 months vs SRS moreover WBRT: nine.5 months). The secondary end result of QOL, calculated Using the validated EORTC-QLQC30 Resource, was observed to generally be worse in patients who received WBRT in various QOL domains . Importantly, these final results were being noticed Regardless of adjuvant WBRT lessening the 2-12 months area failure price (31% to 19%), distant Mind failure (forty eight% to 33%), and the need for salvage therapies (51% vs. sixteen%). No sizeable differences in survival were being noticed albeit the trial wasn't driven to handle survival.

These 4 trials have set up the job of SRS on your own given that the regular of care in clients having a confined quantity of Mind metastases, but they have not been intended to Examine the effect of WBRT on Over-all survival.

The inclusion criteria across the RCTs evaluating SRS by yourself to SRS moreover WBRT were related (Desk one), nonetheless, the primary endpoints had been fully distinctive, and no demo was intended to Examine overall survival. To higher make clear the outcomes of community control, distant brain Manage and survival, a meta-Examination (MAL) was done by Tsao, Xu and Sahgal in 2012 . They described hazard ratios for community Regulate and distant Mind Management favoring adjuvant WBRT at two.sixty one and a couple of.fifteen, respectively, but ended up not able to mix the survival benefits because of limitations in the way the info were reported. Sahgal et al. then executed an individual patient data (IPD) MAL of the identical RCTs aimed toward evaluating therapy results on survival, and execute sub-group analyses . With regard to In general survival, a treatment method result was observed favoring SRS by itself in people ≤fifty decades. In older clients, no survival downside was noticed with SRS by yourself. With respect to distant brain Manage, a cure influence was also noticed with hazard reductions in the event of recent brain metastases in more mature people addressed with WBRT, but no benefit within the youthful individuals (≤50 many years) handled with WBRT. As envisioned, neighborhood Management was improved with further WBRT in all age groups. The concordance between a survival detriment and lack of reward in distant brain Command Inspite of treatment with WBRT, inside the more youthful people, led the authors to hypothesize that exposure on the acknowledged harms of WBRT (mentioned intimately under) might negatively influence client survival. This hypothesis is provocative, and stays to be validated.

Essentially the most convincing trial structure to confirm the adverse results of WBRT is usually to randomize sufferers without any visualized Mind metastases to observation or WBRT. This has long been done in scientific studies evaluating prophylactic cranial irradiation (PCI) in the two small cell lung most cancers (SCLC) [44, 45] and non-modest mobile lung cancer (NSCLC) [forty six, 47]. PCI, not dissimilar into the addition of WBRT to SRS, has been proven to lessen the potential risk of intra-cranial relapse. Having said that, this achieve will come on the expenditure of the unfavorable effect on QOL. For instance, major increases in fatigue, urge for food loss, nausea and vomiting and leg weak point were being observed in people with considerable phase SCLC at six and twelve weeks publish PCI . On top of that, in regionally Highly developed NSCLC patients, a increased decrease in HVLT-R actions of quick and delayed recall were noticed even approximately 1 12 months article-PCI . With regard to lengthier-expression adverse outcomes of WBRT, a devastating consequence may be the development of leukoencephalopathy. Indeed, radiation-induced dementia fees are reported to generally be as substantial as 11% in extended-time period Mind metastases survivors (>12 months) after WBRT , and documented to become increased in people treated with WBRT and SRS rather than SRS by yourself [35, 50].

Excessive N-methyl-D-aspartate (NMDA) receptor stimulation, similar to the pathophysiology inherent to Parkinson's dementia , has long been postulated as 1 system explaining the adverse neurocognitive consequences of WBRT. Being a technique to mitigate the risk, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a large randomized placebo managed demo involving 554 clients. At 24 months, sixty four% of individuals devoid of memantine and fifty four% with memantine experienced cognitive perform failure based on evaluation with the HVLT-R. Although the Most important endpoint didn't reach significance as a result of significant attrition fee, there was a strong trend (p = 0.059) supporting memantine procedure. Examination of secondary endpoints confirmed that memantine significantly extended enough time to cognitive decline and yielded outstanding benefits for government perform, processing pace and delayed recognition at 24 months. Ultimately, these data display nearly all of people put up with cognitive dysfunction with WBRT, and that pharmacologic strategies to mitigate the danger by concentrating on equivalent pathways associated with Parkinson's dementia can be deserving of additional investigation.

Even more Perception into WBRTs’ system of damage has come from a modern Period two demo evaluating hippocampal avoidance WBRT (HA-WBRT). Sophisticated modern day radiation technological know-how was applied to limit dose publicity into the hippocampus to not more than eighty% of the prescribed 30Gy in ten fractions . This non-randomized period two demo measured neurocognitive functionality using the HVLT-R, and in comparison results to historic controls handled with traditional WBRT from the RTOG demo database. HA-WBRT resulted in a very seven% decline inside the suggest relative HVLT-R delayed recall, which was drastically decreased when compared to the thirty% drop attained from historic controls. While this analyze is encouraging in terms of restricting toxicity from WBRT, a randomized demo is needed to totally understand the therapeutic benefit in this technologically complex method of WBRT.

In 2012, the American Modern society for Therapeutic Radiation Oncology released an evidence-primarily based guideline having a series of tips over the administration of brain metastases . Given that that time, the proof from medical trials has produced it clear that the popular up-front radiation therapy option for clients with minimal brain metastases is SRS alone. In actual fact, the American Culture for Radiation Oncology (ASTRO) has not too long ago created a definitive recommendation of their Pick out Correctly campaign and recommend to not routinely insert adjuvant WBRT to SRS for constrained brain metastases . Moreover, the a short while ago revised Nationwide Comprehensive Most cancers Network (NCCN) suggestions now support SRS by itself even past People individuals with “restricted” metastases, and do not specify an higher limit for the volume of metastases . The latter is forward considering; metastasis counting is probably going irrelevant and what issues is if not the suitability from the individual for SRS [fifty seven-fifty nine]. Therefore, the onus is no more on those that take care of with SRS by itself to justify the omission of WBRT; relatively it truly is on people who deal with with WBRT inside of a SRS ideal affected individual.

WHAT ABOUT THE Affected individual WITH Additional Considerable Mind METASTASES?

Previous complex limitations in SRS engineering restricted the appliance of SRS to clients with only a few Mind metastases. Improvements in mounted frame and frameless SRS technologies now allow for procedure of various metastases in an individual session [60, 61].

The very first main potential analyze evaluating SRS alone for several brain metastases was claimed in 2014 . Approximately 1200 clients with 1-10 SRS qualified metastases have been treated with SRS on your own utilizing Gamma Knife technological innovation (Elekta AB, Stockholm, Sweden). The analysis was broken down according to the 455 sufferers with one metastases, 531 individuals with two to four metastases and 208 with five to ten metastases. Survival, distant Mind relapse, and local Regulate charges were not significantly diverse in sufferers with 5 to ten metastases compared to 2 to 4 metastases. These final results are of big significance as they challenge the dogma that patients with over four metastases will not reap the benefits of SRS alone as a consequence of shortened survival and can inevitably are unsuccessful in other places in the Mind. Therefore, this trial offers proof to support SRS by yourself in great KPS sufferers with as many as 10 metastases, furnished the person tumor quantity is not more than 10 mL and < 3 cm in longest diameter, and the total cumulative quantity of all tumors within the Mind is ≤fifteen mL. Numerous randomized trials are presently analyzing WBRT by itself compared to SRS by itself in very similar people, and in development can be a trial evaluating SRS by yourself as opposed to WBRT as well as SRS Increase in individuals with ten to twenty metastases.

Specific THERAPIES IN COMBINATION WITH BRAIN RADIATION

As compared to conventional chemotherapy, several targeted brokers have larger penetration through the blood-brain barrier and generate reaction from the brain. Extraordinary improvements in disorder Command are now being noticed even for histologies such as melanoma that were Formerly viewed as don't just radioresistant but chemoresistant. Desk 2 [sixty three-seventy five] summarizes selected medical trials evaluating the efficacy of specific therapies on your own or together with radiation therapy from the treatment method of brain metastases. Though, with focused therapies by yourself some impressive response premiums are noticed, progression-free-survival (PFS) charges are frequently quick (< 8 months). These success will not be much too dissimilar from what has long been reached with WBRT by itself [33, 53]. The exception is in EGFR mutant non-little mobile lung cancers handled by using a tyrosine kinase inhibitor. During the study by Wu et al. by way of example, the median PFS was >15 months in EGFR mutant tumours dealt with with erlotinib.

Desk 2. Summary of selected trials of targeted therapy on your own or together with brain radiation for your remedy of brain metastases.

PFS: development free survival, nPFS: neurologic progression no cost survival, OS: Total survival, NSCLC: non-smaller cell lung most cancers, EGFR: epidermal development aspect receptor, WBRT: full Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not considerable, NR: not recorded, NA: not relevant

Few trials have blended targeted therapies with radiation, and these are also summarized in Desk two. Although, randomized proof remains to be missing, there is recommendation from retrospective information that The mix may perhaps result in improved outcomes. Within the retrospective Examination of the prospective cohort of patients handled with SRS for melanoma brain metastases, the team that received ipilimumab experienced a drastically lengthier median survival (21.three vs 4.nine months) . Nevertheless, warning should be exercised as concurrent focused therapy and radiation procedure will not be as innocuous as previously considered. The RCT assessing SRS with WBRT by yourself, compared to together with erlotinib or temozlomide, noted considerably increased Quality 3 to 5 toxicity costs in the combination arm; extra importantly, survival was even worse although it did not achieve statistical importance . A major limitation of this study was which the focused therapy wasn't biomarker-pushed and could partially account to the weak survival observed. Caution also really should be taken as There may be evidence that Mind metastases and primary tumors might harbor unique genetic alterations. In one examine of 86 matched Mind metastases and first tumors, clinically informative alterations in 53% of Mind metastases were not detected in the key tumor .

The rising evidence implies that targeted therapies will Perform an important position within the treatment method of Mind metastases. We postulate that Whilst qualified agents may not be productive in managing gross condition during the Mind, They could be effective in handling micro-metastatic condition while in the Mind. For that reason, a reasonable tactic may be to mix specific therapies with SRS by yourself, beating the limitation of SRS in addressing micrometastatic disease from the Mind and resulting in much less distant brain failures. Another several years will yield fascinating data as There are a selection of trials in progress employing this technique.

Improvements IN SRS - INDICATIONS AND Purposes

As tumors get larger sized, SRS dosing is counter-intuitively lowered with regard to tumor control, to keep up protection to the normal brain tissue; in any other case, the potential risk of radiation necrosis gets prohibitive . Because of this, tumors bigger than four cm have typically been excluded from solitary portion SRS. If your tumors are non-operable, then these clients are dealt with with WBRT despite its weak local Management. The advent of non-invasive head immobilization units, on-board graphic-steerage units and State-of-the-art radiation shipping software package has cause the observe of hypofractionated frameless stereotactic radiotherapy (SRT) [60, seventy eight]. Fundamentally by fractionating, the security profile with regard to the normal brain tissue toxicity is improved, and the full tumor dose can be escalated these kinds of that doses like 24Gy in three fractions and thirty-40Gy in 5 fractions are now common. One particular attention-grabbing retrospective collection reported larger premiums of Management and reduce prices of toxicities with hypofractionated SRT (36Gy in 6 fractions) as compared to one portion SRS . Having said that, this apply continues to be in its infancy and we're needing a RCT to find out whether single fraction SRS need to be reserved just for modest metastases (e.g. 1-2 centimeters), as the info suggest worse nearby Regulate for larger sized tumors [eighty, 81]. Determine 1 is undoubtedly an illustration of the efficacy of hypofractionated SRT in a substantial tumor. This client would've or else been excluded from one fraction SRS and addressed with WBRT upfront (as well as or minus a SRS Raise), or operated on.

A. MRI of three.6cm appropriate cerebellar metastases from lung cancer. B. Extremely conformal treatment method program Using the a hundred% (green line) and 80% (blue line) isodose traces wrapping tightly across the gross tumour (purple colorwash), and preparing goal volume (orange colorwash). The brainstem (blue colorwash) is spared from high dose. (B) MRI 2 months put up completion of radiation (30Gy in 5 fractions). C. Complete resolution in the tumour at 1 yr.

In publish-operative clients, the practice of routinely dealing with with WBRT is usually getting outdated. There exists growing utilization of SRS on the article-operative surgical cavity as a way to spare sufferers from your adverse consequences of WBRT and to further improve area Manage [eighty two-93]. For the Sunnybrook Odette Most cancers Centre, We've adopted hypofractionated SRT as our standard of treatment, delivering thirty-35Gy in five fractions to your publish-operative tumor mattress . Fractionation has the benefit of minimizing the adverse outcomes to the traditional tissues, on condition that the targets are generally big and irregularly shaped. Our First benefits have shown one calendar year neighborhood Management fees of ∼80% in individuals who definitely have either recurred and re-operated upon soon after earlier WBRT, or in sufferers without having prior background of WBRT and operated upon. There is certainly an ongoing review analyzing publish-surgical cavity solitary portion SRS alone as opposed to WBRT and could be a exercise-defining research .

Over the past various many years, scientific trials have educated us about the appropriate management of individuals with brain metastases. Originally, SRS was viewed as an adjunct to WBRT in picked patients presenting having a restricted quantity of brain metastases. Nonetheless, the role of WBRT has given that been questioned as We now have uncovered of its likely to adversely have an impact on QOL and neurocognition. Due to this fact, SRS on your own has emerged as the current conventional of treatment with Degree one evidence to support its observe. Recent analysis is centered on the evaluation of broader purposes of SRS to many scientific scenarios which were usually regarded as absolute indications for WBRT. For example, SRS on your own is currently currently being evaluated within the cure of five or more brain metastases, and in write-up-operative individuals. A whole new period of trials can also be emerging investigating the impression of qualified therapies concurrent with SRS.

Clinical trials in individuals with brain metastases are An important challenge as summarized through the modern stories from the Reaction Evaluation in Neuro-Oncology (RANO) Mind metastases team [95, 96]. They advise for trial design and style and response assessment that trials be tumor or biomarker certain, that assessment be depending on contrast-Improved MRI, that baseline and repeated neurocognitive and QOL testing be performed with validated and sensitive devices, that stratification be according to additional-cranial illness position, Which proper timing be deemed with regard to endpoint tests. Finally, the oncology Local community has recognized that the event of Mind metastases is not the terminal oncologic occasion of the previous.

CONFLICTS OF Curiosity, Monetary DISCLOSURES

Dr. Arjun Sahgal has been given honorarium from past educational seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also been given exploration grants from Elekta AB, normally there are no conflicts of fascination to disclose.

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