Reliable Steerage 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 Regulate prices are top-quality to whole brain radiotherapy (WBRT) by yourself. As a result, WBRT additionally SRS was commonly adopted for people with a restricted variety of Mind metastases (“minimal selection” customarily suggests one-four). Subsequent trials centered on answering whether or not WBRT upfront was important in any respect. Dependant on existing randomized managed trials (RCTs) and meta-analyses evaluating SRS on your own to SRS as well as WBRT, adjuvant WBRT results in greater intracranial control; on the other hand, in the cost of neurocognitive functioning and Standard of living. These adverse outcomes of WBRT could also negatively effect on survival in young patients. Based upon the outcome of these studies, treatment has shifted to SRS on your own in individuals with a limited range of metastases. On top of that, RCTs are evaluating the purpose of SRS on your own in people with >four brain metastases. New developments in SRS include things like fractionated SRS for large tumors and the integration of SRS with targeted systemic therapies that cross the blood brain barrier and/or stimulate an immune response. We current During this review the current higher degree evidence and rationale supporting SRS given that the regular of care for patients with limited Mind metastases, and rising apps 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 part of neurosurgery were proven inside the nineties as a method to accomplish neighborhood control and lengthen survival, it absolutely was reserved for the minority of patients presenting with a single metastasis and no other disorder past the Mind [4-seven]. Even now lacking was a focal ablative non-invasive procedure that would be applied successfully to a Substantially broader population of clients with brain metastases. This set the phase for the event of stereotactic radiosurgery (SRS). SRS is a focused ablative radiation treatment sent with sub-millimeter precision to the tumor localized in 3-Proportions in 1-five fractions.

The focus of the review will be to summarize the current substantial degree proof to clarify the part of SRS as optimal management for clients presenting with limited brain metastases. In addition, we offer an summary in the emerging apps of SRS mainly because it carries on to evolve right into a procedure option to WBRT, Together with the intent To optimize neurcognitive function and quality of life (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from a Main tumor mass to type distant colonies by implantation at an ectopic web-site, including the Mind [8-ten]. To take action involves CTCs to arrest throughout the circulation, extravasate from the bloodstream or lymphatics in to the brain, and endure and proliferate [eleven-13]. The entire process of metastatic colonization requires a direct interaction of CTCs with endothelial cells and astrocytes in the Mind microenvironment. As an example, CTCs that have arrested within the capillary bed immediate area endothelial cells to remodel the adjacent environment to promote tumour cell progress and invasion [fourteen-sixteen]. More, metastatic tumour cells recruit systemic stromal cells, which include fibroblasts, to assist with early colonization , and co-decide community stromal cells, such as reactive astrocytes and microglia, to promote tissue invasion [fifteen, eighteen, 19]. Astrocytes throughout the tumour microenvironment might also Engage in a task in protecting tumour cells from chemotherapy-induced cytotoxicity, through a but to get described system necessitating mobile-mobile Make contact with [twenty, 21]. Tumour cells, by launch of migration inhibitory variable, interleukin-eight, and plasminogen activator inhibitor one, induce astrocyte activation and modify the inflammatory milieu to improve tumor-mobile proliferation in vitro [22-24]. These molecular procedures represent novel and understudied probable therapeutic targets for that treatment method of intracranial metastatic disease.

SRS was initially an exceptionally source intense therapy made available only at specialised centers and indicated only for metastatic patients with a great lifestyle expectancy. The challenge lay in prognosticating patients correctly and Subsequently the Radiation Therapy Oncology Team (RTOG) recursive partitioning Examination (RPA) [28, 29] was created. Based on the client's Karnofsky Effectiveness Standing (KPS), age, status of the primary tumor and existence of extracranial illness, patients were being grouped into class one, 2 or three with corresponding median survivals of seven.1, four.2 and 2.three months, respectively. Despite the fact that a major enhancement at enough time, the RPA is now thought of overly simplistic as present-day oncologic determination creating is considerably more sophisticated incorporating molecular, histological, scientific and radiographic condition characteristics. You will find now extra advanced classification instruments, such as the prognosis-precise graded prognostic assessment (DS-GPA). This system delivers histology-certain estimates of survival and might separate, by way of example, probably the most favorable breast cancer clients having an expected survival of twenty five months (outstanding KPS and luminal B type breast most cancers) in the the very least favorable clients using an predicted survival of 3 months (lousy KPS and basal-like breast cancer) . Despite advancements in prognostication of patients with Mind metastases, physicians are still largely not able to properly predict very long-phrase survivors. A review asking professional doctors to estimate survival of the 150 people with details about most cancers type, variety of Mind metastases, neurological presentation, extra-cranial condition position, KPS, RPA class, prior entire-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that more than 45% of predictions have been off by in excess of 6 months and eighteen% ended up off by more than 12 months . Even more innovations in prognostic tests such as the “liquid biopsy” (a non-invasive blood examination which will detect tumor DNA or RNA fragments or CTCs) are desired As well as in development . These combine Superior individual and tumor precise genomic data into your equation, in order to attain customized survival predictions.

Surgical procedure continues to generally be an important cure option for patients with limited Mind metastases. It can be indicated when metastases are substantial (>three-4 cm), or any time a pathologic analysis is necessary. Additionally, surgical procedure is preferred within the presence of significant edema demanding extended superior dose dexamethasone, or to most likely reverse neurological deficits. Normally, the current proof indicates which the efficacy of SRS is ample to attain strong regional Handle that's comparable to surgical procedures. Despite the fact that there aren't any RCTs directly evaluating the two, several trials have been claimed evaluating SRS to SRS with WBRT (Table one), and is also a major aim of this review.

HR: hazard ratio, WHO: earth wellness organization, KPS: Karnofsky general performance status, WBRT: complete brain radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not substantial, NR: not recorded, NA: not relevant, HVLT-R: Hopkins Verbal Studying Take a look at revised.

Individuals during the observation group experienced either medical procedures alone or SRS on your own. Purposeful end result wasn't analyzed individually by surgical procedures or SRS alone.

The 1st RCTs evaluating SRS mimicked the look with the initial surgical reports for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific tests confirmed that SRS enhanced community Manage, as well as a survival edge in chosen individuals with an individual Mind metastasis was revealed. These trials were thriving in shifting the paradigm from WBRT on your own to WBRT moreover SRS for patients presenting with constrained Mind metastases and a good functionality status.

The next series of scientific trials ended up meant to respond to if WBRT was in any respect required, and when compared SRS by yourself to SRS with adjuvant WBRT. 3 RCTs are actually claimed in people presenting with up to 4 metastases [35-37] along with a forth in abstract type . Aoyama et al. noted the initial RCT, randomizing 132 patients to SRS alone (65 individuals) or WBRT additionally SRS (67 individuals). The main endpoint was brain tumor recurrence. Even though the one-yr neighborhood Management charge was large with SRS alone at seventy three%, more regional Handle with adjuvant WBRT at 89%, was observed. Moreover, adjuvant WBRT decreased the speed of distant intra-cranial relapse at 1 year from sixty four% to 42%. Nevertheless, these gains in intra-cranial Manage didn't translate into a bonus with regard to cognition, dependant on Mini-Psychological Status Test (MMSE), nor survival. Additionally, people experienced greater fees of necrosis and leukoencephalopathy during the WBRT arm. The trial was So effective in delivering the 1st level 1 evidence to make clear the relative influence of SRS on your own compared to SRS with WBRT.

In lieu of the normal endpoint of survival or intra-cranial control, Chang et al. took another approach and evaluated neurocognition as the main endpoint. Importantly, the validated Hopkins Verbal Finding out Check-Revised (HVLT-R) assessment Instrument, was accustomed to measure neurocognitive working in contrast to the MMSE which isn't a delicate examination for neurocognition . Fifty-8 patients had been randomized to SRS by yourself (n = 30) or WBRT furthermore SRS (n = 28). Early halting guidelines were being invoked in the interim Investigation, and also the study concluded that SRS on your own was favored with regard towards the likelihood of neurocognitive decline at 4 months put up-cure. This reward was recognized despite the 1 year area Regulate and distant Mind Regulate costs favoring adjuvant WBRT with complete gains of 33% and 27%, respectively. The intracranial control outcomes had been In step with the final results within the Aoyama study, but what was not anticipated was the survival advantage observed while in the SRS by yourself arm. The median survival was fifteen months while in the SRS by yourself arm and six months from the SRS with WBRT arm (p = 0.003). This survival consequence prompted the demo to undertake sizeable scrutiny with many arguing which the survival advantage for SRS alone was a results of imbalances between the two arms, as additional clients 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 a distinct method with their primary endpoint focusing on practical independence . They utilized, however, the greater clinically common Entire world Overall health Firm (WHO) functionality status (PS) scale, and measured some time to WHO PS deterioration to much more than 2. This RCT concluded that the addition of WBRT didn't Enhance the median duration of useful independence (SRS on your own: ten.0 months vs SRS moreover WBRT: nine.5 months). The secondary outcome of QOL, measured with the validated EORTC-QLQC30 Instrument, was noticed to become even worse in people who been given WBRT in several QOL domains . Importantly, these success were noticed Regardless of adjuvant WBRT decreasing the 2-year local failure price (31% to 19%), distant Mind failure (forty eight% to 33%), and the need for salvage therapies (51% vs. 16%). No significant variances in survival ended up noticed albeit the demo wasn't powered to address survival.

These four trials have founded the part of SRS on your own given that the normal of care in sufferers which has a limited number of Mind metastases, but they have not been designed to Assess the effect of WBRT on Over-all survival.

The inclusion criteria over the RCTs evaluating SRS alone to SRS as well as WBRT were being equivalent (Desk 1), even so, the principal endpoints ended up completely diverse, and no trial was built to Examine In general survival. To higher make clear the outcomes of neighborhood Handle, distant brain Handle and survival, a meta-Examination (MAL) was carried out by Tsao, Xu and Sahgal in 2012 . They documented hazard ratios for neighborhood Handle and distant brain Handle favoring adjuvant WBRT at 2.sixty one and a pair of.fifteen, respectively, but had been not able to mix the survival final results resulting from constraints in the way in which the data were being documented. Sahgal et al. then performed someone individual information (IPD) MAL of the same RCTs directed at assessing treatment outcomes on survival, and perform sub-team analyses . With regard to All round survival, a treatment influence was noticed favoring SRS by yourself in clients ≤fifty years. In more mature clients, no survival downside was observed with SRS by yourself. With regard to distant brain control, a cure outcome was also noticed with hazard reductions in the development of latest brain metastases in older sufferers taken care of with WBRT, but no reward from the young people (≤fifty years) treated with WBRT. As envisioned, local control was enhanced with supplemental WBRT in all age teams. The concordance involving a survival detriment and deficiency of reward in distant brain Handle Even with cure with WBRT, during the younger patients, led the authors to hypothesize that exposure for the acknowledged harms of WBRT (mentioned in detail underneath) may perhaps negatively impression patient survival. This hypothesis is provocative, and remains to become validated.

By far the most convincing trial style and design to substantiate the adverse effects of WBRT is always to randomize people with no visualized brain metastases to observation or WBRT. This has actually been carried out in reports analyzing prophylactic cranial irradiation (PCI) in both of those little cell lung most cancers (SCLC) [forty four, 45] and non-little cell lung cancer (NSCLC) [46, 47]. PCI, not dissimilar on the addition of WBRT to SRS, is revealed to cut back the chance of intra-cranial relapse. Nevertheless, this attain comes in the cost of the negative effect on QOL. By way of example, sizeable improves in fatigue, appetite loss, nausea and vomiting and leg weakness were observed in individuals with substantial stage SCLC at 6 and twelve weeks publish PCI . Furthermore, in regionally advanced NSCLC individuals, a better decrease in HVLT-R actions of quick and delayed remember ended up noticed even approximately 1 yr submit-PCI . With respect to for a longer time-phrase adverse results of WBRT, a devastating consequence might be the development of leukoencephalopathy. Without a doubt, radiation-induced dementia costs are already claimed being as substantial as 11% in lengthy-term Mind metastases survivors (>twelve months) right after WBRT , and noted for being greater in people taken care of with WBRT and SRS versus SRS alone [35, fifty].

Abnormal N-methyl-D-aspartate (NMDA) receptor stimulation, similar to the pathophysiology inherent to Parkinson's dementia , has long been postulated as one system conveying the adverse neurocognitive consequences of WBRT. As a technique to mitigate the risk, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a substantial randomized placebo managed trial involving 554 people. At 24 months, 64% of sufferers with no memantine and 54% with memantine experienced cognitive function failure determined by assessment Using the HVLT-R. Although the primary endpoint didn't arrive at significance due to the higher attrition fee, there was a solid trend (p = 0.059) supporting memantine cure. Examination of secondary endpoints confirmed that memantine drastically prolonged the time to cognitive decrease and yielded exceptional outcomes for government operate, processing pace and delayed recognition at 24 weeks. Finally, these details show nearly all of people suffer cognitive dysfunction with WBRT, and that pharmacologic strategies to mitigate the chance by targeting similar pathways linked to Parkinson's dementia could possibly be deserving of additional investigation.

Even more insight into WBRTs’ system of harm has originate from a new Section 2 trial analyzing hippocampal avoidance WBRT (HA-WBRT). Subtle fashionable radiation technology was placed on limit dose exposure to the hippocampus to not more than 80% from the prescribed 30Gy in 10 fractions . This non-randomized section two trial measured neurocognitive functionality utilizing the HVLT-R, and in comparison outcomes to historic controls treated with common WBRT from the RTOG trial database. HA-WBRT resulted inside of a 7% decline in the necessarily mean relative HVLT-R delayed remember, which was drastically reduce than the thirty% decrease acquired from historic controls. Though this study is encouraging with regard to limiting toxicity from WBRT, a randomized trial is necessary to fully have an understanding of the therapeutic price Within this technologically complex kind of WBRT.

In 2012, the American Society for Therapeutic Radiation Oncology revealed an evidence-centered guideline by using a number of suggestions over the management of Mind metastases . Because that point, the proof from clinical trials has manufactured it apparent that the preferred up-entrance radiation treatment method option for sufferers with confined brain metastases is SRS by itself. Actually, the American Culture for Radiation Oncology (ASTRO) has recently created a definitive advice within their Decide on Sensibly campaign and advocate not to routinely include adjuvant WBRT to SRS for minimal Mind metastases . In addition, the a short while ago revised Nationwide Complete Cancer Community (NCCN) tips now assist SRS by itself even beyond Individuals clients with “limited” metastases, and do not specify an upper limit for the amount of metastases . The latter is forward contemplating; metastasis counting is likely irrelevant and what issues is otherwise the suitability of the affected person for SRS [fifty seven-fifty nine]. Hence, the onus is no more on individuals who deal with with SRS alone to justify the omission of WBRT; alternatively it is actually on people that handle with WBRT inside a SRS suitable affected individual.

WHAT ABOUT THE PATIENT WITH Extra Intensive BRAIN METASTASES?

Former technical constraints in SRS technological innovation restricted the appliance of SRS to patients with just a few brain metastases. Progress in mounted frame and frameless SRS systems now allow procedure of various metastases in a single session [60, 61].

The primary significant future research analyzing SRS alone for many brain metastases was described in 2014 . Roughly 1200 clients with 1-ten SRS eligible metastases have been treated with SRS on your own using Gamma Knife know-how (Elekta AB, Stockholm, Sweden). The Examination was damaged down based on the 455 individuals with one metastases, 531 people with 2 to four metastases and 208 with five to 10 metastases. Survival, distant brain relapse, and native Command fees weren't appreciably unique in individuals with five to 10 metastases compared to 2 to 4 metastases. These final results are of main significance as they problem the dogma that patients with greater than 4 metastases will never get pleasure from SRS on your own as a consequence of shortened survival and can inevitably fall short elsewhere during the brain. Consequently, this demo supplies evidence to aid SRS by yourself in excellent KPS patients with as many as 10 metastases, provided the person tumor volume is not more than 10 mL and < three cm in longest diameter, and the entire cumulative quantity of all tumors inside the Mind is ≤15 mL. A number of randomized trials are now evaluating WBRT by yourself versus SRS by itself in identical sufferers, and in improvement is a demo evaluating SRS by yourself versus WBRT as well as SRS Increase in clients with ten to 20 metastases.

TARGETED THERAPIES IN COMBINATION WITH Mind RADIATION

In comparison with common chemotherapy, numerous qualified agents have bigger penetration with the blood-Mind barrier and yield response within the brain. Spectacular advancements in illness Management are increasingly being observed even for histologies including melanoma which were Beforehand considered not just radioresistant but chemoresistant. Table 2 [sixty three-seventy five] summarizes picked scientific trials evaluating the efficacy of focused therapies by yourself or together with radiation therapy within the treatment method of Mind metastases. Even though, with focused therapies alone some outstanding response charges are noticed, development-cost-free-survival (PFS) rates are often quick (< 8 months). These benefits are certainly not much too dissimilar from what has long been achieved with WBRT by itself [33, fifty three]. The exception is in EGFR mutant non-compact mobile lung cancers addressed with a tyrosine kinase inhibitor. In the study by Wu et al. for instance, the median PFS was >15 months in EGFR mutant tumours treated with erlotinib.

Table two. Summary of chosen trials of specific therapy by itself or together with Mind radiation for your remedy of brain metastases.

PFS: development absolutely free survival, nPFS: neurologic development free of charge survival, OS: General survival, NSCLC: non-small mobile lung most cancers, EGFR: epidermal progress variable receptor, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: months, NS: not substantial, NR: not recorded, NA: not applicable

Couple trials have merged focused therapies with radiation, and they're also summarized in Table two. Whilst, randomized evidence remains missing, You can find recommendation from retrospective info that the combination may perhaps cause enhanced results. During the retrospective analysis of the possible cohort of individuals taken care of with SRS for melanoma Mind metastases, the group that been given ipilimumab had a noticeably more time median survival (21.3 vs four.9 months) . Nevertheless, caution really should be exercised as concurrent focused therapy and radiation therapy will not be as innocuous as Beforehand believed. The RCT evaluating SRS with WBRT alone, compared to together with erlotinib or temozlomide, described considerably larger Quality three to 5 toxicity fees in The mixture arm; additional importantly, survival was even worse even though it didn't get to statistical importance . A big limitation of the analyze was which the qualified therapy wasn't biomarker-driven and will partly account for that lousy survival noticed. Caution also has to be taken as There exists evidence that Mind metastases and first tumors may well harbor distinctive genetic alterations. In one analyze of 86 matched brain metastases and primary tumors, clinically enlightening alterations in 53% of brain metastases were not detected in the main tumor .

The emerging evidence indicates that qualified therapies will Engage in a significant function within the remedy of Mind metastases. We postulate that Despite the fact that focused agents will not be efficient in managing gross illness from the Mind, they may be successful in taking care of micro-metastatic disease within the brain. Therefore, a rational technique may be to combine specific therapies with SRS by itself, conquering the limitation of SRS in addressing micrometastatic disease while in the brain and leading to much less distant brain failures. The following several years will generate thrilling knowledge as There are a variety of trials in development using this approach.

Improvements IN SRS - INDICATIONS AND Programs

As tumors get more substantial, SRS dosing is counter-intuitively reduced with respect to tumor Regulate, to keep up basic safety to the traditional brain tissue; in any other case, the risk of radiation necrosis results in being prohibitive . As a result, tumors higher than four cm have commonly been excluded from solitary fraction SRS. When the tumors are non-operable, then these people have already been addressed with WBRT despite its lousy area Regulate. The appearance of non-invasive head immobilization gadgets, on-board image-advice units and advanced radiation supply program has bring about the practice of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, seventy eight]. Basically by fractionating, the safety profile with regard to the normal Mind tissue toxicity is enhanced, and the total tumor dose is usually escalated these types of that doses like 24Gy in 3 fractions and 30-40Gy in five fractions are actually not unusual. A single interesting retrospective collection noted better prices of Manage and lower fees of toxicities with hypofractionated SRT (36Gy in six fractions) as compared with single fraction SRS . Having said that, this observe continues to be in its infancy and we are wanting a RCT to determine whether single portion SRS needs to be reserved only for modest metastases (e.g. one-two centimeters), as the data suggest worse nearby control for bigger tumors [80, 81]. Determine 1 is really an example of the efficacy of hypofractionated SRT in a significant tumor. This individual would've if not been excluded from single fraction SRS and dealt with with WBRT upfront (additionally or minus a SRS Increase), or operated on.

A. MRI of 3.6cm suitable cerebellar metastases from lung cancer. B. Highly conformal procedure approach with the a hundred% (eco-friendly line) and 80% (blue line) isodose traces wrapping tightly throughout the gross tumour (purple colorwash), and organizing focus on quantity (orange colorwash). The brainstem (blue colorwash) is spared from higher dose. (B) MRI 2 months publish completion of radiation (30Gy in five fractions). C. Finish resolution in the tumour at 1 12 months.

In post-operative clients, the practice of routinely dealing with with WBRT can also be getting to be out-of-date. There is certainly increasing usage of SRS towards the publish-operative surgical cavity as a method to spare clients in the adverse consequences of WBRT and to enhance regional Command [82-93]. At the Sunnybrook Odette Most cancers Heart, We've adopted hypofractionated SRT as our standard of treatment, providing thirty-35Gy in 5 fractions on the article-operative tumor bed . Fractionation has the benefit of minimizing the adverse outcomes to the normal tissues, provided that the targets are typically substantial and irregularly shaped. Our initial effects have proven one 12 months community Manage charges of ∼eighty% in patients that have both recurred and re-operated upon immediately after preceding WBRT, or in people with no prior historical past of WBRT and operated upon. There exists an ongoing analyze evaluating put up-surgical cavity solitary portion SRS alone compared to WBRT and could be a apply-defining examine .

Over the past a number of a long time, medical trials have educated us about the appropriate management of sufferers with brain metastases. To begin with, SRS was regarded as an adjunct to WBRT in picked patients presenting using a confined quantity of brain metastases. Even so, the part of WBRT has considering the fact that been questioned as We've got figured out of its probable to adversely have an affect on QOL and neurocognition. Subsequently, SRS alone has emerged as The existing conventional of treatment with Stage one evidence to help its exercise. Present exploration is centered on the evaluation of broader applications of SRS to several clinical situations which were ordinarily viewed as absolute indications for WBRT. By way of example, SRS by itself is at present getting evaluated in the therapy of five or maybe more brain metastases, As well as in article-operative sufferers. A fresh era of trials is usually rising investigating the effect of qualified therapies concurrent with SRS.

Medical trials in individuals with Mind metastases are A significant challenge as summarized because of the modern reviews within the Response Evaluation in Neuro-Oncology (RANO) Mind metastases group [95, 96]. They endorse for demo layout and response assessment that trials be tumor or biomarker specific, that evaluation be based on distinction-enhanced MRI, that baseline and repeated neurocognitive and QOL tests be carried out with validated and delicate instruments, that stratification be based upon additional-cranial disorder status, Which suitable timing be viewed as with regard to endpoint screening. Ultimately, the oncology Neighborhood has regarded that the development of brain metastases is now not the terminal oncologic occasion of your past.

CONFLICTS OF Fascination, FINANCIAL DISCLOSURES

Dr. Arjun Sahgal has acquired honorarium from former educational seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also gained research grants from Elekta AB, in any other case there won't be any conflicts of interest to disclose.

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