Stereotactic radiosurgery SRS Financials is an established non-invasive ablative therapy for Mind metastases. Early medical trials with SRS proved that tumor Command charges are outstanding to full Mind radiotherapy (WBRT) alone. Due to this fact, WBRT plus SRS was extensively adopted for sufferers that has a limited quantity of brain metastases (“restricted variety” customarily suggests one-four). Subsequent trials focused on answering no matter if WBRT upfront was vital whatsoever. Depending on recent randomized managed trials (RCTs) and meta-analyses comparing SRS alone to SRS moreover WBRT, adjuvant WBRT leads to far better intracranial Command; nonetheless, for the price of neurocognitive functioning and quality of life. These adverse outcomes of WBRT may negatively influence on survival in youthful people. Determined by the outcome of these research, therapy has shifted to SRS on your own in individuals with a restricted number of metastases. On top of that, RCTs are assessing the purpose of SRS by yourself in people with >4 brain metastases. New developments in SRS contain fractionated SRS for big tumors and The combination of SRS with specific systemic therapies that cross the blood Mind barrier and/or encourage an immune reaction. We current in this critique The existing superior level proof and rationale supporting SRS since the conventional of take care of clients with minimal Mind metastases, and rising purposes 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 function of neurosurgery had been founded during the 1990s as a means to accomplish nearby Management and extend survival, it was reserved to the minority of people presenting with a single metastasis and no other disease past the Mind [four-7]. Still missing was a focal ablative non-invasive treatment that might be utilized successfully to the A lot broader populace of patients with brain metastases. This established the phase for the development of stereotactic radiosurgery (SRS). SRS is really a targeted ablative radiation procedure delivered with sub-millimeter precision to the tumor localized in three-Proportions in 1-five fractions.
The focus of the evaluate is always to summarize the current high stage evidence to clarify the job of SRS as best management for sufferers presenting with confined Mind metastases. Moreover, we provide an outline from the rising purposes of SRS since it proceeds to evolve right into a procedure choice to WBRT, While using the intent To optimize neurcognitive purpose and Standard of living (QOL).
PATHOPHYSIOLOGY OF BRAIN METASTASES
Circulating tumor cells (CTCs) can disseminate from a Key tumor mass to type distant colonies through implantation at an ectopic web-site, including the brain [eight-10]. To take action needs CTCs to arrest throughout the circulation, extravasate through the bloodstream or lymphatics into your brain, and survive and proliferate [11-13]. The entire process of metastatic colonization will involve a immediate interaction of CTCs with endothelial cells and astrocytes within the brain microenvironment. As an example, CTCs that have arrested within the capillary mattress direct nearby endothelial cells to remodel the adjacent ecosystem to market tumour mobile progress and invasion [14-16]. Further, metastatic tumour cells recruit systemic stromal cells, such as fibroblasts, to assist with early colonization , and co-decide area stromal cells, including reactive astrocytes and microglia, to advertise tissue invasion [fifteen, eighteen, 19]. Astrocytes in the tumour microenvironment can also Perform a role in preserving tumour cells from chemotherapy-induced cytotoxicity, by way of a still to generally be outlined system necessitating mobile-mobile Speak to [20, 21]. Tumour cells, through release of migration inhibitory element, interleukin-eight, and plasminogen activator inhibitor one, induce astrocyte activation and modify the inflammatory milieu to reinforce tumor-cell proliferation in vitro [22-24]. These molecular processes signify novel and understudied attainable therapeutic targets with the treatment of intracranial metastatic ailment.
SRS was originally an exceedingly useful resource intensive therapy presented only at specialised centers and indicated just for metastatic patients with a superb everyday living expectancy. The problem lay in prognosticating people proficiently and as a result the Radiation Therapy Oncology Team (RTOG) recursive partitioning Assessment (RPA) [28, 29] was made. According to the affected individual's Karnofsky General performance Standing (KPS), age, standing of the primary tumor and existence of extracranial disorder, people were grouped into class one, 2 or 3 with corresponding median survivals of 7.one, four.2 and 2.three months, respectively. Though An important growth at the time, the RPA is now regarded overly simplistic as present oncologic final decision making is much more sophisticated incorporating molecular, histological, clinical and radiographic illness traits. You'll find now a lot more advanced classification resources, such as the analysis-precise graded prognostic assessment (DS-GPA). This system provides histology-precise estimates of survival and can separate, for instance, the most favorable breast most cancers patients by having an anticipated survival of 25 months (outstanding KPS and luminal B sort breast most cancers) from your least favorable clients with the envisioned survival of 3 months (bad KPS and basal-like breast most cancers) . Even with advances in prognostication of clients with brain metastases, medical professionals are still mostly unable to properly predict extensive-phrase survivors. A analyze asking qualified doctors to estimate survival of a a hundred and fifty patients with information regarding most cancers type, quantity of brain metastases, neurological presentation, excess-cranial illness position, KPS, RPA class, prior complete-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that over 45% of predictions were being off by in excess of six months and 18% had been off by in excess of 12 months . Even further advancements in prognostic assessments including the “liquid biopsy” (a non-invasive blood test that may detect tumor DNA or RNA fragments or CTCs) are necessary As well as in progress . These Incorporate Highly developed patient and tumor unique genomic details into the equation, so that you can attain personalized survival predictions.
Surgical procedures continues to become a vital therapy selection for sufferers with limited Mind metastases. It is actually indicated when metastases are significant (>three-four cm), or each time a pathologic analysis is needed. Furthermore, surgical treatment is most popular in the existence of important edema demanding extended higher dose dexamethasone, or to most likely reverse neurological deficits. Otherwise, the current evidence indicates which the efficacy of SRS is enough to achieve strong neighborhood Handle that's similar to surgery. While there won't be any RCTs right comparing The 2, several trials happen to be noted evaluating SRS to SRS with WBRT (Desk 1), and it is a major emphasis of the evaluation.
HR: hazard ratio, WHO: globe wellness Business, KPS: Karnofsky efficiency status, WBRT: entire Mind radiotherapy, SRS: stereotactic radiosurgery, yr: yr, mos: months, NS: not sizeable, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Understanding Test revised.
Patients during the observation team had possibly operation by itself or SRS by itself. Practical outcome wasn't analyzed separately by operation or SRS alone.
The first RCTs evaluating SRS mimicked the look in the First surgical scientific studies for Mind metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific tests confirmed that SRS enhanced community Management, and also a survival advantage in chosen people with only one brain metastasis was revealed. These trials were being prosperous in shifting the paradigm from WBRT by itself to WBRT moreover SRS for individuals presenting with confined brain metastases and a great effectiveness status.
Another number of clinical trials have been meant to remedy if WBRT was in the least required, and compared SRS on your own to SRS with adjuvant WBRT. A few RCTs have already been noted in sufferers presenting with up to four metastases [35-37] in addition to a forth in abstract variety . Aoyama et al. documented the initial RCT, randomizing 132 individuals to SRS on your own (65 people) or WBRT furthermore SRS (67 patients). The main endpoint was brain tumor recurrence. Even though the one-calendar year neighborhood Command fee was large with SRS by itself at seventy three%, additional regional Command with adjuvant WBRT at 89%, was observed. Moreover, adjuvant WBRT lessened the speed of distant intra-cranial relapse at 1 12 months from 64% to 42%. However, these gains in intra-cranial control did not translate into a benefit with regard to cognition, based upon Mini-Mental Standing Test (MMSE), nor survival. Furthermore, individuals had increased prices of necrosis and leukoencephalopathy from the WBRT arm. The demo was As a result prosperous in furnishing the main degree one proof to make clear the relative impact of SRS by yourself as opposed to SRS with WBRT.
As opposed to the normal endpoint of survival or intra-cranial Regulate, Chang et al. took a special method and evaluated neurocognition as the principal endpoint. Importantly, the validated Hopkins Verbal Learning Take a look at-Revised (HVLT-R) assessment Software, was accustomed to measure neurocognitive performing in contrast to the MMSE which is not a sensitive take a look at for neurocognition . Fifty-8 people have been randomized to SRS by itself (n = 30) or WBRT as well as SRS (n = 28). Early halting rules ended up invoked in the interim Investigation, and also the examine concluded that SRS on your own was favored with regard to the chance of neurocognitive decline at 4 months article-treatment. This gain was understood Regardless of the one year regional Regulate and distant Mind Manage costs favoring adjuvant WBRT with complete gains of 33% and 27%, respectively. The intracranial Command outcomes have been In line with the final results within the Aoyama study, but what was not anticipated was the survival edge observed within the SRS on your own arm. The median survival was fifteen months from the SRS alone arm and 6 months within the SRS with WBRT arm (p = 0.003). This survival final result brought about the demo to undergo sizeable scrutiny with lots of arguing which the survival benefit for SRS by yourself was a result of imbalances concerning The 2 arms, as much more clients handled with SRS moreover WBRT experienced larger more-cranial (additional liver and adrenal metastases) and intracranial condition (more substantial volume of brain metastases) .
The ecu Corporation for Study and Remedy of Cancer (EORTC) also took a different strategy with their Main endpoint concentrating on functional independence . They utilized, on the other hand, the more clinically familiar World Overall health Business (WHO) general performance position (PS) scale, and calculated time to WHO PS deterioration to much more than two. This RCT concluded which the addition of WBRT didn't Enhance the median period of purposeful independence (SRS by yourself: 10.0 months vs SRS moreover WBRT: 9.five months). The secondary final result of QOL, calculated Along with the validated EORTC-QLQC30 Resource, was observed to get even worse in clients who acquired WBRT in various QOL domains . Importantly, these benefits had been noticed Inspite of adjuvant WBRT decreasing the 2-calendar year nearby failure price (31% to 19%), distant Mind failure (48% to 33%), and the necessity for salvage therapies (fifty one% vs. sixteen%). No important differences in survival have been observed albeit the trial wasn't run to handle survival.
These 4 trials have proven the role of SRS by yourself as the conventional of treatment in sufferers with a restricted quantity of Mind metastases, but they have got not been created to Consider the influence of WBRT on overall survival.
The inclusion conditions throughout the RCTs analyzing SRS by itself to SRS in addition WBRT ended up identical (Table 1), on the other hand, the first endpoints had been entirely various, and no trial was meant to evaluate Total survival. To raised explain the outcomes of regional Handle, distant Mind Handle and survival, a meta-Examination (MAL) was performed by Tsao, Xu and Sahgal in 2012 . They reported hazard ratios for neighborhood Regulate and distant Mind Management favoring adjuvant WBRT at 2.sixty one and 2.fifteen, respectively, but ended up not able to mix the survival effects as a result of restrictions in the way the information were being documented. Sahgal et al. then performed somebody client info (IPD) MAL of the same RCTs geared toward assessing procedure results on survival, and accomplish sub-group analyses . With regard to In general survival, a procedure impact was noticed favoring SRS alone in sufferers ≤50 years. In more mature patients, no survival downside was observed with SRS by yourself. With respect to distant Mind Command, a treatment method result was also observed with hazard reductions in the event of recent brain metastases in more mature people dealt with with WBRT, but no benefit while in the more youthful sufferers (≤50 years) treated with WBRT. As envisioned, neighborhood Management was improved with more WBRT in all age groups. The concordance between a survival detriment and not enough benefit in distant Mind Handle Regardless of remedy with WBRT, in the more youthful individuals, led the authors to hypothesize that publicity on the acknowledged harms of WBRT (discussed in detail down below) could negatively effect patient survival. This hypothesis is provocative, and remains being validated.
By far the most convincing demo design to confirm the adverse outcomes of WBRT should be to randomize clients without any visualized brain metastases to observation or WBRT. This continues to be done in reports assessing prophylactic cranial irradiation (PCI) in both of those tiny cell lung most cancers (SCLC) [44, forty five] and non-tiny mobile lung most cancers (NSCLC) [forty six, 47]. PCI, not dissimilar to your addition of WBRT to SRS, is proven to scale back the chance of intra-cranial relapse. Nonetheless, this gain will come on the price of a damaging impact on QOL. For example, considerable improves in fatigue, hunger reduction, nausea and vomiting and leg weakness ended up noticed in clients with comprehensive stage SCLC at 6 and twelve months put up PCI . In addition, in domestically Sophisticated NSCLC people, a better drop in HVLT-R actions of instant and delayed remember had been noticed even nearly 1 year submit-PCI . With respect to lengthier-expression adverse consequences of WBRT, a devastating consequence could be the development of leukoencephalopathy. Without a doubt, radiation-induced dementia fees are already described to get as high as 11% in lengthy-time period Mind metastases survivors (>12 months) soon after WBRT , and claimed to become larger in sufferers treated with WBRT and SRS as opposed to SRS on your own [35, fifty].
Extreme N-methyl-D-aspartate (NMDA) receptor stimulation, comparable to the pathophysiology inherent to Parkinson's dementia , has been postulated as one particular system detailing the adverse neurocognitive consequences of WBRT. For a technique to mitigate the risk, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a considerable randomized placebo managed trial involving 554 clients. At 24 weeks, sixty four% of people without the need of memantine and 54% with memantine had cognitive purpose failure dependant on evaluation With all the HVLT-R. Even though the primary endpoint didn't achieve importance due to superior attrition level, there was a powerful development (p = 0.059) supporting memantine remedy. Assessment of secondary endpoints showed that memantine noticeably prolonged enough time to cognitive decline and yielded excellent results for executive perform, processing speed and delayed recognition at 24 months. In the end, these facts show virtually all people undergo cognitive dysfunction with WBRT, Which pharmacologic strategies to mitigate the danger by concentrating on identical pathways associated with Parkinson's dementia can be worthy of additional investigation.
More insight into WBRTs’ mechanism of damage has come from a modern Section 2 demo evaluating hippocampal avoidance WBRT (HA-WBRT). Sophisticated modern day radiation technological know-how was placed on limit dose exposure to your hippocampus to no more than 80% on the prescribed 30Gy in ten fractions . This non-randomized stage two demo calculated neurocognitive operate using the HVLT-R, and in comparison outcomes to historic controls dealt with with regular WBRT from the RTOG demo databases. HA-WBRT resulted in a very seven% decrease while in the indicate relative HVLT-R delayed recall, which was appreciably decreased than the thirty% decrease acquired from historic controls. Though this research is encouraging with regards to limiting toxicity from WBRT, a randomized demo is necessary to completely recognize the therapeutic worth Within this technologically intricate method of WBRT.
In 2012, the American Culture for Therapeutic Radiation Oncology published an evidence-primarily based guideline by using a number of suggestions around the administration of brain metastases . Given that that point, the evidence from scientific trials has manufactured it very clear that the popular up-entrance radiation remedy selection for clients with constrained brain metastases is SRS by itself. The truth is, the American Society for Radiation Oncology (ASTRO) has a short while ago designed a definitive advice inside their Select Correctly campaign and propose to not routinely add adjuvant WBRT to SRS for minimal brain metastases . What's more, the just lately revised National Detailed Cancer Network (NCCN) tips now help SRS by yourself even beyond People patients with “minimal” metastases, and do not specify an upper limit for the quantity of metastases . The latter is forward wondering; metastasis counting is probably going irrelevant and what matters is normally the suitability from the individual for SRS [fifty seven-59]. As a result, the onus is now not on those that deal with with SRS by yourself to justify the omission of WBRT; alternatively it's on people that treat with WBRT within a SRS acceptable affected person.
How about THE Client WITH Extra In depth BRAIN METASTASES?
Preceding specialized limits in SRS technologies restricted the appliance of SRS to clients with only some brain metastases. Improvements in fastened body and frameless SRS systems now make it possible for procedure of diverse metastases in only one session [60, sixty one].
The very first main potential research evaluating SRS by itself for multiple Mind metastases was reported in 2014 . Roughly 1200 individuals with one-10 SRS qualified metastases had been handled with SRS alone making use of Gamma Knife technological innovation (Elekta AB, Stockholm, Sweden). The Examination was broken down according to the 455 patients with one metastases, 531 people with two to four metastases and 208 with 5 to 10 metastases. Survival, distant Mind relapse, and native Regulate charges were not appreciably diverse in individuals with five to 10 metastases vs . two to four metastases. These effects are of big significance as they obstacle the dogma that clients with a lot more than 4 metastases will not benefit from SRS on your own because of shortened survival and may inevitably fall short elsewhere inside the Mind. Thus, this trial delivers proof to guidance SRS on your own in great KPS people with around 10 metastases, provided the person tumor quantity is no more than ten mL and < three cm in longest diameter, and the whole cumulative volume of all tumors while in the brain is ≤15 mL. A number of randomized trials are at this time evaluating WBRT by yourself versus SRS on your own in very similar individuals, As well as in enhancement is actually a demo evaluating SRS on your own vs . WBRT additionally SRS Raise in people with ten to 20 metastases.
Focused THERAPIES Together WITH Mind RADIATION
When compared with regular chemotherapy, a number of focused brokers have bigger penetration through the blood-brain barrier and produce reaction in the brain. Remarkable enhancements in ailment Command are being observed even for histologies for example melanoma that were Earlier thought of not merely radioresistant but chemoresistant. Desk 2 [sixty three-75] summarizes chosen medical trials analyzing the efficacy of qualified therapies by itself or together with radiation therapy while in the procedure of Mind metastases. While, with qualified therapies by itself some outstanding reaction premiums are noticed, development-absolutely free-survival (PFS) premiums tend to be brief (< 8 months). These final results will not be far too dissimilar from what has long been obtained with WBRT by yourself [33, 53]. The exception is in EGFR mutant non-tiny mobile lung cancers addressed by using a tyrosine kinase inhibitor. While in the research by Wu et al. as an example, the median PFS was >15 months in EGFR mutant tumours treated with erlotinib.
Desk two. Summary of chosen trials of targeted therapy by itself or in combination with brain radiation with the procedure of Mind metastases.
PFS: progression no cost survival, nPFS: neurologic development cost-free survival, OS: Total survival, NSCLC: non-tiny cell lung most cancers, EGFR: epidermal progress aspect receptor, WBRT: full Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: months, NS: not significant, NR: not recorded, NA: not applicable
Couple of trials have combined qualified therapies with radiation, and these are typically also summarized in Table two. While, randomized evidence is still missing, There's suggestion from retrospective knowledge that the combination might produce enhanced results. While in the retrospective Assessment of a potential cohort of people taken care of with SRS for melanoma Mind metastases, the team that obtained ipilimumab experienced a substantially for a longer period median survival (21.three vs 4.9 months) . However, caution should be exercised as concurrent targeted therapy and radiation treatment method is probably not as innocuous as Formerly assumed. The RCT evaluating SRS with WBRT alone, as opposed to together with erlotinib or temozlomide, described noticeably higher Quality 3 to five toxicity rates in The mixture arm; far more importantly, survival was even worse even though it didn't achieve statistical importance . An important limitation of the examine was which the targeted therapy wasn't biomarker-driven and could partially account for the very poor survival noticed. Warning also must be taken as There exists proof that Mind metastases and primary tumors could harbor unique genetic alterations. In a single analyze of 86 matched brain metastases and primary tumors, clinically insightful alterations in 53% of brain metastases were not detected in the main tumor .
The rising proof indicates that specific therapies will Enjoy an important part inside the treatment of brain metastases. We postulate that Even though focused agents might not be powerful in controlling gross illness within the Mind, They could be effective in running micro-metastatic disease within the brain. Consequently, a logical approach can be to combine specific therapies with SRS alone, conquering the limitation of SRS in addressing micrometastatic sickness in the Mind and resulting in much less distant Mind failures. The next few years will produce interesting data as There are a selection of trials in progress employing this approach.
INNOVATIONS IN SRS - INDICATIONS AND Purposes
As tumors get much larger, SRS dosing is counter-intuitively reduced with respect to tumor control, to maintain protection to the traditional brain tissue; in any other case, the risk of radiation necrosis results in being prohibitive . Due to this fact, tumors increased than 4 cm have commonly been excluded from single portion SRS. Should the tumors are non-operable, then these patients have been taken care of with WBRT Regardless of its poor nearby control. The appearance of non-invasive head immobilization equipment, on-board picture-guidance devices and Sophisticated radiation supply software has cause the observe of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, seventy eight]. Effectively by fractionating, the safety profile with respect to the conventional Mind tissue toxicity is improved, and the whole tumor dose is often escalated this kind of that doses like 24Gy in three fractions and thirty-40Gy in 5 fractions at the moment are commonplace. A person intriguing retrospective series noted bigger rates of Handle and reduced premiums of toxicities with hypofractionated SRT (36Gy in 6 fractions) when compared to one fraction SRS . Even so, this observe is still in its infancy and we're wanting a RCT to ascertain whether or not single fraction SRS must be reserved just for small metastases (e.g. 1-2 centimeters), as the data suggest worse community control for bigger tumors [80, eighty one]. Figure 1 is really an illustration of the efficacy of hypofractionated SRT in a large tumor. This patient would have in any other case been excluded from solitary portion SRS and dealt with with WBRT upfront (furthermore or minus a SRS Increase), or operated upon.
A. MRI of three.6cm right cerebellar metastases from lung cancer. B. Extremely conformal therapy plan While using the a hundred% (environmentally friendly line) and eighty% (blue line) isodose strains wrapping tightly around the gross tumour (red colorwash), and planning target quantity (orange colorwash). The brainstem (blue colorwash) is spared from substantial dose. (B) MRI 2 months write-up completion of radiation (30Gy in five fractions). C. Total resolution from the tumour at 1 calendar year.
In article-operative clients, the apply of routinely treating with WBRT can be starting to be outdated. There is certainly escalating usage of SRS on the put up-operative surgical cavity as a way to spare clients from your adverse consequences of WBRT and to boost neighborhood control [eighty two-ninety three]. For the Sunnybrook Odette Cancer Centre, We have now adopted hypofractionated SRT as our regular of treatment, providing 30-35Gy in five fractions towards the put up-operative tumor bed . Fractionation has the advantage of reducing the adverse effects to the traditional tissues, provided that the targets tend to be massive and irregularly shaped. Our initial effects have proven one 12 months nearby Regulate costs of ∼80% in sufferers who have both recurred and re-operated upon soon after past WBRT, or in sufferers without having prior background of WBRT and operated on. There is an ongoing study analyzing publish-surgical cavity solitary portion SRS on your own vs . WBRT and may be a apply-defining review .
In the last a number of a long time, scientific trials have educated us about the appropriate management of clients with Mind metastases. In the beginning, SRS was regarded as an adjunct to WBRT in picked individuals presenting by using a confined number of Mind metastases. Nevertheless, the position of WBRT has considering the fact that been questioned as We've realized of its prospective to adversely have an affect on QOL and neurocognition. Therefore, SRS alone has emerged as the current normal of treatment with Stage one evidence to support its apply. Recent investigate is centered on the analysis of broader apps of SRS to various scientific cases that were usually viewed as complete indications for WBRT. Such as, SRS by itself is presently becoming evaluated inside the therapy of five or more brain metastases, As well as in put up-operative clients. A fresh period of trials is likewise emerging investigating the effect of qualified therapies concurrent with SRS.
Clinical trials in clients with Mind metastases are A serious challenge as summarized because of the new experiences with the Reaction Evaluation in Neuro-Oncology (RANO) Mind metastases team [ninety five, 96]. They endorse for trial design and reaction assessment that trials be tumor or biomarker precise, that assessment be depending on distinction-enhanced MRI, that baseline and recurring neurocognitive and QOL testing be done with validated and sensitive devices, that stratification be depending on additional-cranial sickness standing, and that correct timing be regarded as with regard to endpoint tests. Ultimately, the oncology Group has acknowledged that the development of brain metastases is now not the terminal oncologic function of the earlier.
CONFLICTS OF Curiosity, FINANCIAL DISCLOSURES
Dr. Arjun Sahgal has gained honorarium from past academic seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also been given investigation grants from Elekta AB, otherwise there won't be any conflicts of interest to disclose.