Dependable Guidance by SRS Financials

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Stereotactic radiosurgery SRS Financials is a longtime non-invasive ablative therapy for brain metastases. Early medical trials with SRS proved that tumor Command prices are remarkable to whole brain radiotherapy (WBRT) on your own. Therefore, WBRT additionally SRS was greatly adopted for individuals with a limited variety of Mind metastases (“limited quantity” customarily usually means one-four). Subsequent trials centered on answering whether WBRT upfront was necessary in any respect. Depending on latest randomized controlled trials (RCTs) and meta-analyses evaluating SRS by yourself to SRS moreover WBRT, adjuvant WBRT leads to improved intracranial Handle; nevertheless, for the expense of neurocognitive working and quality of life. These adverse consequences of WBRT may negatively influence on survival in young patients. Based upon the effects of those scientific studies, treatment method has shifted to SRS by itself in sufferers having a restricted number of metastases. In addition, RCTs are assessing the position of SRS by yourself in patients with >four Mind metastases. New developments in SRS include things like fractionated SRS for giant tumors and The mixing of SRS with focused systemic therapies that cross the blood Mind barrier and/or encourage an immune reaction. We current With this critique The existing superior amount proof and rationale supporting SRS given that the conventional of care for clients with confined Mind 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.

Even though the role of neurosurgery were established within the 1990s as a way to attain area Command and prolong survival, it absolutely was reserved for your minority of individuals presenting with only one metastasis and no other disease over and above the brain [4-7]. Continue to lacking was a focal ablative non-invasive therapy that could be used proficiently to the Significantly broader inhabitants of clients with brain metastases. This set the phase for the development of stereotactic radiosurgery (SRS). SRS is actually a concentrated ablative radiation treatment method delivered with sub-millimeter precision on the tumor localized in three-Proportions in one-5 fractions.

The focus of the evaluation will be to summarize the current high stage proof to explain the position of SRS as best management for people presenting with limited Mind metastases. Furthermore, we provide an summary of the emerging applications of SRS since it carries on to evolve into a treatment substitute to WBRT, with the intent To maximise neurcognitive perform and Standard of living (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from the Main tumor mass to form distant colonies by implantation at an ectopic web site, including the Mind [eight-ten]. To take action necessitates CTCs to arrest in the circulation, extravasate with the bloodstream or lymphatics into your Mind, and endure and proliferate [11-13]. The process of metastatic colonization requires a direct conversation of CTCs with endothelial cells and astrocytes from the Mind microenvironment. Such as, CTCs which have arrested inside the capillary bed direct community endothelial cells to remodel the adjacent environment to market tumour mobile progress and invasion [14-sixteen]. Even further, metastatic tumour cells recruit systemic stromal cells, for instance fibroblasts, to aid with early colonization , and co-choose nearby stromal cells, for instance reactive astrocytes and microglia, to market tissue invasion [fifteen, eighteen, 19]. Astrocytes inside the tumour microenvironment could also Enjoy a job in defending tumour cells from chemotherapy-induced cytotoxicity, through a but to become defined mechanism demanding mobile-cell Get in touch with [20, 21]. Tumour cells, by release of migration inhibitory issue, interleukin-eight, and plasminogen activator inhibitor 1, induce astrocyte activation and modify the inflammatory milieu to enhance tumor-mobile proliferation in vitro [22-24]. These molecular processes characterize novel and understudied attainable therapeutic targets with the treatment method of intracranial metastatic ailment.

SRS was at first an incredibly resource intense therapy available only at specialized centers and indicated just for metastatic individuals with a great lifestyle expectancy. The problem lay in prognosticating patients properly and Because of this the Radiation Therapy Oncology Group (RTOG) recursive partitioning Investigation (RPA) [28, 29] was developed. Determined by the affected person's Karnofsky General performance Status (KPS), age, status of the main tumor and existence of extracranial illness, clients were being grouped into course one, two or three with corresponding median survivals of 7.1, 4.2 and a pair of.three months, respectively. Whilst An important enhancement at time, the RPA is now regarded extremely simplistic as present oncologic decision producing is much more complex incorporating molecular, histological, medical and radiographic sickness properties. There are now much more subtle classification applications, including the analysis-particular graded prognostic evaluation (DS-GPA). This technique presents histology-specific estimates of survival and will independent, as an example, the most favorable breast most cancers sufferers using an expected survival of twenty five months (excellent KPS and luminal B form breast most cancers) in the minimum favorable clients having an expected survival of 3 months (lousy KPS and basal-like breast cancer) . Irrespective of developments in prognostication of individuals with Mind metastases, physicians are still mostly not able to precisely predict extended-term survivors. A study asking expert physicians to estimate survival of a 150 sufferers with information about most cancers type, amount of brain metastases, neurological presentation, excess-cranial condition status, KPS, RPA course, prior whole-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that a lot more than 45% of predictions had been off by in excess of six months and eighteen% ended up off by over twelve months . Additional advancements in prognostic checks such as the “liquid biopsy” (a non-invasive blood take a look at that could detect tumor DNA or RNA fragments or CTCs) are desired As well as in enhancement . These Blend Innovative patient and tumor certain genomic facts to the equation, as a way to accomplish personalised survival predictions.

Surgical procedures continues being a significant treatment choice for clients with limited brain metastases. It really is indicated when metastases are significant (>three-four cm), or when a pathologic analysis is required. Also, surgical procedures is favored from the existence of major edema requiring extended superior dose dexamethasone, or to perhaps reverse neurological deficits. Otherwise, The existing proof indicates which the efficacy of SRS is adequate to attain long lasting neighborhood Management that is certainly comparable to surgical treatment. Although there isn't any RCTs directly evaluating the two, numerous trials are reported evaluating SRS to SRS with WBRT (Desk 1), and is also a major aim of the review.

HR: hazard ratio, WHO: globe overall health organization, KPS: Karnofsky efficiency standing, WBRT: whole Mind radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not sizeable, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Mastering Take a look at revised.

Individuals during the observation team had either surgery by yourself or SRS alone. Practical final result was not analyzed independently by surgical procedures or SRS on your own.

The primary RCTs analyzing SRS mimicked the look on the Original surgical scientific tests for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These studies confirmed that SRS improved nearby Handle, in addition to a survival gain in picked sufferers with an individual Mind metastasis was shown. These trials have been prosperous in shifting the paradigm from WBRT by yourself to WBRT furthermore SRS for patients presenting with limited brain metastases and an excellent functionality status.

Another series of medical trials had been intended to remedy if WBRT was whatsoever necessary, and in contrast SRS alone to SRS with adjuvant WBRT. A few RCTs are actually described in individuals presenting with approximately 4 metastases [35-37] along with a forth in summary sort . Aoyama et al. described the initial RCT, randomizing 132 sufferers to SRS by itself (sixty five sufferers) or WBRT moreover SRS (sixty seven people). The principal endpoint was Mind tumor recurrence. Even though the 1-calendar year nearby Regulate amount was superior with SRS by yourself at 73%, additional local control with adjuvant WBRT at 89%, was noticed. Moreover, adjuvant WBRT decreased the speed of distant intra-cranial relapse at 1 year from sixty four% to 42%. However, these gains in intra-cranial Management didn't translate into an advantage with regard to cognition, determined by Mini-Mental Position Exam (MMSE), nor survival. Furthermore, people experienced greater rates of necrosis and leukoencephalopathy within the WBRT arm. The trial was thus prosperous in providing the main degree 1 evidence to explain the relative influence of SRS by itself compared to SRS with WBRT.

As opposed to the traditional endpoint of survival or intra-cranial Regulate, Chang et al. took a special approach and evaluated neurocognition as the key endpoint. Importantly, the validated Hopkins Verbal Studying Take a look at-Revised (HVLT-R) assessment Resource, was used to measure neurocognitive operating instead of the MMSE which isn't a delicate check for neurocognition . Fifty-8 patients have been randomized to SRS alone (n = 30) or WBRT additionally SRS (n = 28). Early halting policies were being invoked on the interim analysis, and the research concluded that SRS by yourself was favored with respect for the chance of neurocognitive drop at 4 months post-remedy. This profit was realized despite the 1 yr area Manage and distant brain Management prices favoring adjuvant WBRT with complete gains of 33% and 27%, respectively. The intracranial Handle outcomes ended up Consistent with the effects from your Aoyama examine, but what was not predicted was the survival edge noticed from the SRS by itself arm. The median survival was fifteen months during the SRS alone arm and 6 months in the SRS with WBRT arm (p = 0.003). This survival end result induced the trial to go through considerable scrutiny with numerous arguing that the survival advantage for SRS by yourself was a result of imbalances amongst The 2 arms, as far more sufferers dealt with with SRS as well as WBRT experienced increased further-cranial (far more liver and adrenal metastases) and intracranial ailment (more substantial volume of brain metastases) .

The ecu Corporation for Investigate and Procedure of Most cancers (EORTC) also took another technique with their primary endpoint specializing in purposeful independence . They utilized, nonetheless, the more clinically common Earth Overall health Business (WHO) overall performance status (PS) scale, and calculated some time to WHO PS deterioration to much more than two. This RCT concluded which the addition of WBRT didn't improve the median period of practical independence (SRS on your own: 10.0 months vs SRS moreover WBRT: nine.5 months). The secondary result of QOL, measured with the validated EORTC-QLQC30 Software, was observed to generally be even worse in people who received WBRT in several QOL domains . Importantly, these effects had been noticed In spite of adjuvant WBRT decreasing the two-calendar year local failure rate (31% to 19%), distant brain failure (forty eight% to 33%), and the need for salvage therapies (fifty one% vs. sixteen%). No considerable differences in survival have been noticed albeit the trial was not run to address survival.

These four trials have recognized the function of SRS by yourself as the common of treatment in individuals having a minimal range of Mind metastases, but they have not been built to evaluate the affect of WBRT on overall survival.

The inclusion conditions through the RCTs assessing SRS by itself to SRS plus WBRT had been very similar (Desk one), nevertheless, the key endpoints had been fully unique, and no demo was built to Consider General survival. To better make clear the results of area control, distant brain Manage and survival, a meta-Investigation (MAL) was done by Tsao, Xu and Sahgal in 2012 . They described hazard ratios for community Command and distant Mind Handle favoring adjuvant WBRT at two.sixty one and a couple of.fifteen, respectively, but were being not able to mix the survival success as a consequence of restrictions in the way the information have been claimed. Sahgal et al. then executed someone patient knowledge (IPD) MAL of exactly the same RCTs aimed toward evaluating treatment consequences on survival, and conduct sub-group analyses . With regard to All round survival, a cure effect was noticed favoring SRS alone in individuals ≤50 decades. In more mature sufferers, no survival disadvantage was noticed with SRS by itself. With respect to distant Mind Handle, a treatment method result was also observed with threat reductions in the development of latest brain metastases in more mature patients treated with WBRT, but no profit in the young sufferers (≤50 decades) treated with WBRT. As anticipated, community Management was enhanced with extra WBRT in all age groups. The concordance amongst a survival detriment and not enough advantage in distant Mind Command Even with cure with WBRT, during the young clients, led the authors to hypothesize that publicity on the regarded harms of WBRT (reviewed intimately underneath) may possibly negatively influence client survival. This hypothesis is provocative, and stays to become validated.

Essentially the most convincing trial structure to verify the adverse outcomes of WBRT is to randomize people without having visualized Mind metastases to observation or WBRT. This has long been done in experiments assessing prophylactic cranial irradiation (PCI) in equally smaller mobile lung cancer (SCLC) [44, forty five] and non-little cell lung cancer (NSCLC) [forty six, 47]. PCI, not dissimilar towards the addition of WBRT to SRS, has actually been proven to lessen the risk of intra-cranial relapse. Nonetheless, this achieve will come within the expense of the destructive effect on QOL. As an example, important boosts in exhaustion, appetite loss, nausea and vomiting and leg weakness had been observed in sufferers with considerable stage SCLC at six and twelve months put up PCI . On top of that, in locally Sophisticated NSCLC sufferers, a increased decrease in HVLT-R actions of fast and delayed recall have been noticed even approximately 1 yr submit-PCI . With respect to lengthier-phrase adverse results of WBRT, a devastating consequence is usually the development of leukoencephalopathy. Certainly, radiation-induced dementia prices are already claimed being as high as 11% in lengthy-term brain metastases survivors (>12 months) soon after WBRT , and documented to become increased in clients taken care of with WBRT and SRS rather than SRS alone [35, fifty].

Abnormal N-methyl-D-aspartate (NMDA) receptor stimulation, just like the pathophysiology inherent to Parkinson's dementia , has been postulated as a single mechanism detailing the adverse neurocognitive effects of WBRT. To be a strategy to mitigate the chance, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a big randomized placebo managed demo involving 554 individuals. At 24 months, sixty four% of clients without the need of memantine and 54% with memantine had cognitive perform failure based upon assessment Together with the HVLT-R. Although the Principal endpoint didn't get to importance due to substantial attrition rate, there was a robust trend (p = 0.059) supporting memantine procedure. Evaluation of secondary endpoints confirmed that memantine substantially prolonged enough time to cognitive decrease and yielded excellent results for govt purpose, processing velocity and delayed recognition at 24 weeks. In the long run, these information display the majority of clients go through cognitive dysfunction with WBRT, and that pharmacologic strategies to mitigate the risk by targeting comparable pathways involved with Parkinson's dementia may very well be worthy of more investigation.

Additional insight into WBRTs’ mechanism of damage has come from a the latest Section 2 trial assessing hippocampal avoidance WBRT (HA-WBRT). Complex modern-day radiation technologies was placed on limit dose exposure to your hippocampus to not more than eighty% of the prescribed 30Gy in 10 fractions . This non-randomized phase two demo measured neurocognitive perform utilizing the HVLT-R, and when compared outcomes to historic controls treated with regular WBRT from the RTOG trial database. HA-WBRT resulted in a very seven% decline inside the necessarily mean relative HVLT-R delayed recall, which was drastically lower when compared to the thirty% drop received from historic controls. Although this review is encouraging with regard to restricting toxicity from WBRT, a randomized trial is needed to totally fully grasp the therapeutic benefit During this technologically elaborate type of WBRT.

In 2012, the American Modern society for Therapeutic Radiation Oncology published an proof-dependent guideline using a number of suggestions to the administration of brain metastases . Since that time, the evidence from medical trials has built it apparent that the preferred up-front radiation cure choice for sufferers with restricted Mind metastases is SRS by itself. In truth, the American Culture for Radiation Oncology (ASTRO) has lately made a definitive suggestion in their Opt for Correctly campaign and propose to not routinely add adjuvant WBRT to SRS for restricted Mind metastases . Additionally, the lately revised Countrywide Extensive Most cancers Network (NCCN) suggestions now assistance SRS by yourself even beyond All those sufferers with “confined” metastases, and do not specify an upper Restrict for the amount of metastases . The latter is ahead pondering; metastasis counting is probably going irrelevant and what issues is or else the suitability on the patient for SRS [57-fifty nine]. For that reason, the onus is now not on those that treat with SRS by yourself to justify the omission of WBRT; alternatively it's on those who handle with WBRT inside a SRS ideal individual.

How about THE Affected person WITH Far more Considerable BRAIN METASTASES?

Preceding technical restrictions in SRS technological innovation limited the applying of SRS to patients with only some Mind metastases. Developments in fastened body and frameless SRS technologies now permit remedy of various metastases in an individual session [sixty, sixty one].

The primary significant potential research analyzing SRS by yourself for multiple Mind metastases was claimed in 2014 . Roughly 1200 individuals with 1-10 SRS suitable metastases were being handled with SRS alone applying Gamma Knife technological innovation (Elekta AB, Stockholm, Sweden). The Evaluation was damaged down based on the 455 patients with one metastases, 531 individuals with two to four metastases and 208 with five to ten metastases. Survival, distant brain relapse, and native Management costs weren't considerably distinct in clients with 5 to ten metastases compared to two to four metastases. These benefits are of significant importance as they problem the dogma that clients with a lot more than four metastases will likely not reap the benefits of SRS by yourself due to shortened survival and can inevitably fail in other places while in the brain. Thus, this trial supplies evidence to guidance SRS by itself in good KPS individuals with as much as 10 metastases, offered the individual tumor quantity is no more than ten mL and < three cm in longest diameter, and the entire cumulative quantity of all tumors from the brain is ≤fifteen mL. A number of randomized trials are currently assessing WBRT alone as opposed to SRS alone in very similar sufferers, As well as in growth is actually a trial analyzing SRS alone compared to WBRT moreover SRS Improve in people with ten to 20 metastases.

Qualified THERAPIES IN COMBINATION WITH BRAIN RADIATION

In comparison with common chemotherapy, numerous specific brokers have greater penetration with the blood-brain barrier and produce reaction within the brain. Spectacular advancements in condition Management are being observed even for histologies which include melanoma that were previously viewed as don't just radioresistant but chemoresistant. Table 2 [63-seventy five] summarizes picked scientific trials analyzing the efficacy of targeted therapies alone or in combination with radiation therapy inside the treatment method of Mind metastases. Though, with specific therapies by itself some remarkable response charges are observed, development-absolutely free-survival (PFS) premiums usually are short (< 8 months). These final results aren't much too dissimilar from what has been achieved with WBRT alone [33, fifty three]. The exception is in EGFR mutant non-small mobile lung cancers treated with a tyrosine kinase inhibitor. From the review by Wu et al. for instance, the median PFS was >15 months in EGFR mutant tumours treated with erlotinib.

Desk two. Summary of chosen trials of specific therapy by itself or in combination with brain radiation to the treatment method of Mind metastases.

PFS: progression free of charge survival, nPFS: neurologic progression totally free survival, OS: Total survival, NSCLC: non-tiny cell lung most cancers, EGFR: epidermal expansion issue receptor, WBRT: complete Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not important, NR: not recorded, NA: not relevant

Number of trials have mixed qualified therapies with radiation, and they're also summarized in Table two. Although, randomized proof is still missing, There exists suggestion from retrospective data that the combination may perhaps bring on enhanced results. Within the retrospective Examination of the potential cohort of people dealt with with SRS for melanoma Mind metastases, the team that obtained ipilimumab had a appreciably lengthier median survival (21.three vs four.nine months) . Even so, caution should be exercised as concurrent qualified therapy and radiation treatment method might not be as innocuous as Earlier considered. The RCT assessing SRS with WBRT on your own, vs . in combination with erlotinib or temozlomide, reported considerably increased Grade three to 5 toxicity costs in The mixture arm; far more importantly, survival was even worse even though it didn't attain statistical importance . A major limitation of the examine was the specific therapy wasn't biomarker-pushed and may partly account for that very poor survival noticed. Warning also must be taken as There may be evidence that brain metastases and first tumors could harbor distinct genetic alterations. In one review of 86 matched Mind metastases and first tumors, clinically informative alterations in 53% of brain metastases were not detected in the principal tumor .

The rising proof suggests that focused therapies will Enjoy a big part from the treatment method of Mind metastases. We postulate that While targeted agents will not be efficient in managing gross condition in the brain, They could be successful in taking care of micro-metastatic disease within the brain. Consequently, a logical technique can be to mix specific therapies with SRS on your own, overcoming the limitation of SRS in addressing micrometastatic disease within the Mind and leading to much less distant Mind failures. Another number of years will generate interesting knowledge as there are a number of trials in progress utilizing this approach.

INNOVATIONS IN SRS - INDICATIONS AND APPLICATIONS

As tumors get larger sized, SRS dosing is counter-intuitively reduced with respect to tumor control, to take care of basic safety to the normal Mind tissue; normally, the chance of radiation necrosis turns into prohibitive . Consequently, tumors greater than four cm have normally been excluded from single portion SRS. When the tumors are non-operable, then these patients are actually dealt with with WBRT In spite of its poor local control. The advent of non-invasive head immobilization gadgets, on-board graphic-assistance systems and State-of-the-art radiation shipping and delivery software has bring on the apply of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, 78]. In essence by fractionating, the safety profile with respect to the traditional brain tissue toxicity is enhanced, and the total tumor dose is usually escalated these kinds of that doses like 24Gy in three fractions and 30-40Gy in 5 fractions at the moment are not unusual. Just one fascinating retrospective sequence noted better costs of Regulate and decrease fees of toxicities with hypofractionated SRT (36Gy in 6 fractions) when compared with single fraction SRS . On the other hand, this practice remains to be in its infancy and we're wanting a RCT to ascertain whether or not single portion SRS ought to be reserved only for smaller metastases (e.g. one-2 centimeters), as the information advise even worse local Manage for much larger tumors [eighty, eighty one]. Determine one is an example of the efficacy of hypofractionated SRT in a big tumor. This client would've if not been excluded from single portion SRS and dealt with with WBRT upfront (moreover or minus a SRS Increase), or operated upon.

A. MRI of 3.6cm proper cerebellar metastases from lung cancer. B. Extremely conformal therapy program Together with the a hundred% (inexperienced line) and eighty% (blue line) isodose traces wrapping tightly across the gross tumour (red colorwash), and organizing concentrate on volume (orange colorwash). The brainstem (blue colorwash) is spared from higher dose. (B) MRI 2 months publish completion of radiation (30Gy in 5 fractions). C. Total resolution from the tumour at 1 year.

In post-operative clients, the practice of routinely treating with WBRT is also becoming out-of-date. There may be rising use of SRS to the post-operative surgical cavity as a method to spare people in the adverse results of WBRT and to improve area Regulate [82-93]. On the Sunnybrook Odette Cancer Centre, We now have adopted hypofractionated SRT as our regular of treatment, providing 30-35Gy in 5 fractions for the publish-operative tumor mattress . Fractionation has the advantage of minimizing the adverse effects to the conventional tissues, on condition that the targets are usually massive and irregularly shaped. Our Preliminary outcomes have proven one calendar year community Manage costs of ∼eighty% in clients that have possibly recurred and re-operated upon just after previous WBRT, or in individuals without prior history of WBRT and operated upon. You can find an ongoing analyze analyzing post-surgical cavity one portion SRS by yourself compared to WBRT and could be a practice-defining examine .

In the last numerous many years, medical trials have informed us about the right management of sufferers with Mind metastases. At first, SRS was regarded an adjunct to WBRT in chosen clients presenting with a constrained range of Mind metastases. Nonetheless, the job of WBRT has given that been questioned as We have now learned of its possible to adversely influence QOL and neurocognition. Subsequently, SRS alone has emerged as the current normal of care with Degree one evidence to support its follow. Latest investigate is centered on the analysis of broader purposes of SRS to several clinical circumstances that were historically deemed complete indications for WBRT. For instance, SRS on your own is at present being evaluated within the remedy of five or maybe more Mind metastases, and in publish-operative sufferers. A whole new period of trials is also emerging investigating the influence of targeted therapies concurrent with SRS.

Scientific trials in clients with brain metastases are a major obstacle as summarized by the modern reports from the Reaction Evaluation in Neuro-Oncology (RANO) brain metastases group [95, ninety six]. They suggest for demo design and style and response evaluation that trials be tumor or biomarker certain, that evaluation be dependant on distinction-enhanced MRI, that baseline and recurring neurocognitive and QOL screening be performed with validated and delicate instruments, that stratification be dependant on further-cranial condition status, and that suitable timing be regarded as with regards to endpoint tests. Finally, the oncology Neighborhood has recognized that the event of brain metastases is now not the terminal oncologic occasion of the earlier.

CONFLICTS OF Curiosity, Monetary DISCLOSURES

Dr. Arjun Sahgal has obtained honorarium from prior educational seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also acquired investigation grants from Elekta AB, otherwise there won't be any conflicts of interest to reveal.

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