Stereotactic radiosurgery SRS Financials is an established non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor Regulate rates are excellent to full brain radiotherapy (WBRT) by yourself. Because of this, WBRT plus SRS was extensively adopted for sufferers having a confined range of Mind metastases (“constrained quantity” customarily means one-4). Subsequent trials centered on answering whether or not WBRT upfront was essential in the least. Based upon current randomized controlled trials (RCTs) and meta-analyses comparing SRS on your own to SRS as well as WBRT, adjuvant WBRT brings about better intracranial Handle; however, for the cost of neurocognitive operating and Standard of living. These adverse consequences of WBRT might also negatively impact on survival in younger people. Depending on the outcomes of these studies, procedure has shifted to SRS on your own in sufferers which has a restricted range of metastases. Moreover, RCTs are evaluating the purpose of SRS alone in individuals with >four Mind metastases. New developments in SRS involve fractionated SRS for big tumors and The mixing of SRS with focused systemic therapies that cross the blood Mind barrier and/or promote an immune reaction. We present On this critique The present substantial degree evidence and rationale supporting SRS as being the common of care for people with restricted 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 purpose of neurosurgery had been recognized in the 1990s as a means to obtain nearby Handle and extend survival, it had been reserved to the minority of people presenting with just one metastasis and no other ailment outside of the Mind [4-7]. Even now lacking was a focal ablative non-invasive treatment method that can be utilized proficiently into a Substantially broader populace of patients with brain metastases. This set the stage for the development of stereotactic radiosurgery (SRS). SRS is really a focused ablative radiation remedy shipped with sub-millimeter precision towards the tumor localized in a few-Proportions in 1-five fractions.
The focus of the review would be to summarize the current high degree proof to clarify the role of SRS as ideal management for clients presenting with limited brain metastases. On top of that, we offer an outline on the emerging applications of SRS mainly because it proceeds to evolve into a therapy different to WBRT, with the intent to maximize neurcognitive operate and quality of life (QOL).
PATHOPHYSIOLOGY OF Mind METASTASES
Circulating tumor cells (CTCs) can disseminate from a Key tumor mass to sort distant colonies as a result of implantation at an ectopic web page, such as the Mind [eight-10]. To take action calls for CTCs to arrest throughout the circulation, extravasate from your bloodstream or lymphatics into the Mind, and endure and proliferate [eleven-thirteen]. The whole process of metastatic colonization entails a direct conversation of CTCs with endothelial cells and astrocytes from the Mind microenvironment. Such as, CTCs that have arrested in the capillary bed immediate community endothelial cells to remodel the adjacent atmosphere to market tumour mobile progress and invasion [14-16]. More, metastatic tumour cells recruit systemic stromal cells, including fibroblasts, to aid with early colonization , and co-choose neighborhood stromal cells, for example reactive astrocytes and microglia, to promote tissue invasion [fifteen, eighteen, 19]. Astrocytes throughout the tumour microenvironment might also Enjoy a role in defending tumour cells from chemotherapy-induced cytotoxicity, through a but being described system requiring cell-cell contact [20, 21]. Tumour cells, by release of migration inhibitory aspect, interleukin-8, and plasminogen activator inhibitor one, induce astrocyte activation and modify the inflammatory milieu to enhance tumor-mobile proliferation in vitro [22-24]. These molecular procedures depict novel and understudied doable therapeutic targets for that procedure of intracranial metastatic condition.
SRS was in the beginning an incredibly source intensive therapy supplied only at specialised centers and indicated only for metastatic patients with a great daily life expectancy. The problem lay in prognosticating people proficiently and Due to this fact the Radiation Therapy Oncology Team (RTOG) recursive partitioning Evaluation (RPA) [28, 29] was made. Determined by the individual's Karnofsky General performance Standing (KPS), age, position of the key tumor and existence of extracranial condition, clients were grouped into class one, 2 or three with corresponding median survivals of 7.1, 4.2 and a pair of.three months, respectively. Though A serious enhancement at time, the RPA is currently thought of extremely simplistic as latest oncologic selection producing is much more complex incorporating molecular, histological, scientific and radiographic illness traits. You'll find now far more complex classification applications, such as the diagnosis-unique graded prognostic evaluation (DS-GPA). This system supplies histology-certain estimates of survival and might independent, as an example, by far the most favorable breast most cancers sufferers with the envisioned survival of twenty five months (superb KPS and luminal B variety breast most cancers) with the minimum favorable individuals with the envisioned survival of three months (very poor KPS and basal-like breast cancer) . Inspite of advances in prognostication of sufferers with Mind metastases, doctors are still mostly struggling to correctly forecast extensive-expression survivors. A examine asking specialist medical professionals to estimate survival of a a hundred and fifty patients with specifics of most cancers variety, quantity of brain metastases, neurological presentation, added-cranial ailment status, KPS, RPA class, prior whole-Mind radiotherapy, and synchronous or metachronous presentation, showed that over forty five% of predictions ended up off by a lot more than 6 months and eighteen% had been off by more than twelve months . More advances in prognostic tests such as the “liquid biopsy” (a non-invasive blood test that can detect tumor DNA or RNA fragments or CTCs) are wanted and in enhancement . These Incorporate Sophisticated patient and tumor precise genomic info in the equation, so that you can obtain individualized survival predictions.
Surgical procedure proceeds to become a very important remedy selection for clients with confined Mind metastases. It is actually indicated when metastases are huge (>three-4 cm), or whenever a pathologic diagnosis is necessary. Additionally, surgical treatment is desired while in the existence of major edema requiring extended superior dose dexamethasone, or to possibly reverse neurological deficits. Or else, the current evidence implies the efficacy of SRS is ample to obtain strong regional Command that is definitely similar to operation. Whilst there aren't any RCTs right comparing The 2, various trials happen to be described comparing SRS to SRS with WBRT (Desk one), and is a major concentrate of this evaluation.
HR: hazard ratio, WHO: planet overall health Firm, KPS: Karnofsky effectiveness position, WBRT: entire brain radiotherapy, SRS: stereotactic radiosurgery, yr: year, mos: months, NS: not substantial, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Learning Test revised.
People during the observation team had either surgical treatment by yourself or SRS by itself. Useful final result wasn't analyzed separately by surgical procedures or SRS by itself.
The 1st RCTs analyzing SRS mimicked the look with the initial surgical experiments for Mind metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific studies confirmed that SRS enhanced nearby control, and also a survival edge in selected people with an individual brain metastasis was proven. These trials were being prosperous in shifting the paradigm from WBRT on your own to WBRT moreover SRS for sufferers presenting with limited Mind metastases and a great performance standing.
The next number of scientific trials have been meant to reply if WBRT was in the slightest degree needed, and compared SRS by yourself to SRS with adjuvant WBRT. Three RCTs are noted in people presenting with as much as 4 metastases [35-37] along with a forth in summary type . Aoyama et al. described the primary RCT, randomizing 132 people to SRS by itself (sixty five people) or WBRT plus SRS (sixty seven patients). The main endpoint was brain tumor recurrence. Even though the one-12 months community Handle fee was superior with SRS by itself at 73%, supplemental local Manage with adjuvant WBRT at 89%, was observed. Moreover, adjuvant WBRT lessened the speed of distant intra-cranial relapse at one yr from 64% to 42%. On the other hand, these gains in intra-cranial Command did not translate into a benefit with regard to cognition, according to Mini-Mental Status Exam (MMSE), nor survival. In addition, individuals experienced increased prices of necrosis and leukoencephalopathy from the WBRT arm. The trial was thus productive in delivering the initial stage one evidence to make clear the relative impression of SRS by itself as opposed to SRS with WBRT.
Rather then the normal endpoint of survival or intra-cranial Management, Chang et al. took another approach and evaluated neurocognition as the principal endpoint. Importantly, the validated Hopkins Verbal Finding out Take a look at-Revised (HVLT-R) assessment Resource, was accustomed to evaluate neurocognitive working instead of the MMSE which isn't a delicate examination for neurocognition . Fifty-eight sufferers were randomized to SRS on your own (n = 30) or WBRT plus SRS (n = 28). Early stopping guidelines had been invoked at the interim Examination, as well as the analyze concluded that SRS by itself was favored with regard to your chance of neurocognitive decrease at 4 months submit-treatment method. This profit was recognized despite the 1 12 months regional control and distant Mind Handle prices favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial Management results have been In step with the outcome from your Aoyama research, but what wasn't anticipated was the survival advantage observed from the SRS on your own arm. The median survival was fifteen months within the SRS by itself arm and 6 months within the SRS with WBRT arm (p = 0.003). This survival end result brought about the trial to undergo sizeable scrutiny with lots of arguing which the survival benefit for SRS on your own was a result of imbalances concerning the two arms, as additional patients dealt with with SRS plus WBRT had larger excess-cranial (a lot more liver and adrenal metastases) and intracranial sickness (greater quantity of Mind metastases) .
The ecu Business for Exploration and Treatment of Cancer (EORTC) also took a unique method with their Principal endpoint concentrating on functional independence . They utilized, on the other hand, the more clinically common Globe Wellbeing Firm (WHO) functionality standing (PS) scale, and calculated the time to WHO PS deterioration to in excess of 2. This RCT concluded the addition of WBRT didn't Increase the median duration of purposeful independence (SRS alone: ten.0 months vs SRS moreover WBRT: nine.five months). The secondary consequence of QOL, measured While using the validated EORTC-QLQC30 Software, was observed to generally be even worse in sufferers who acquired WBRT in many QOL domains . Importantly, these success were noticed Regardless of adjuvant WBRT lowering the two-12 months community failure level (31% to 19%), distant brain failure (48% to 33%), and the necessity for salvage therapies (fifty one% vs. 16%). No substantial variations in survival were being noticed albeit the demo was not driven to deal with survival.
These 4 trials have proven the purpose of SRS by yourself as the typical of treatment in clients which has a confined number of Mind metastases, but they've not been intended to evaluate the impression of WBRT on In general survival.
The inclusion criteria through the RCTs analyzing SRS alone to SRS moreover WBRT ended up comparable (Desk one), on the other hand, the primary endpoints ended up entirely various, and no demo was meant to evaluate All round survival. To better clarify the results of area Command, distant brain Command and survival, a meta-Investigation (MAL) was carried out by Tsao, Xu and Sahgal in 2012 . They described hazard ratios for nearby Handle and distant Mind Manage favoring adjuvant WBRT at 2.61 and a couple of.fifteen, respectively, but were not able to mix the survival outcomes resulting from restrictions in the best way the information had been claimed. Sahgal et al. then performed a person patient facts (IPD) MAL of the identical RCTs targeted at analyzing therapy consequences on survival, and execute sub-group analyses . With regard to All round survival, a treatment method influence was noticed favoring SRS alone in individuals ≤fifty decades. In more mature patients, no survival disadvantage was observed with SRS by yourself. With regard to distant Mind Manage, a remedy outcome was also noticed with possibility reductions in the event of latest Mind metastases in older sufferers treated with WBRT, but no advantage from the youthful patients (≤fifty a long time) addressed with WBRT. As anticipated, local Command was improved with more WBRT in all age groups. The concordance among a survival detriment and lack of gain in distant brain control Even with procedure with WBRT, within the younger patients, led the authors to hypothesize that exposure on the recognized harms of WBRT (discussed in detail below) may negatively affect affected individual survival. This speculation is provocative, and continues to be to get validated.
By far the most convincing trial design to substantiate the adverse outcomes of WBRT should be to randomize sufferers with no visualized brain metastases to observation or WBRT. This has actually been accomplished in scientific studies evaluating prophylactic cranial irradiation (PCI) in equally smaller mobile lung cancer (SCLC) [44, forty five] and non-little cell lung most cancers (NSCLC) [46, 47]. PCI, not dissimilar on the addition of WBRT to SRS, has long been demonstrated to cut back the potential risk of intra-cranial relapse. Nevertheless, this get will come within the cost of the adverse effect on QOL. One example is, important improves in exhaustion, urge for food loss, nausea and vomiting and leg weak point have been noticed in individuals with considerable stage SCLC at 6 and 12 months put up PCI . Moreover, in regionally Sophisticated NSCLC individuals, a larger drop in HVLT-R measures of quick and delayed remember ended up noticed even up to 1 calendar year write-up-PCI . With regard to for a longer time-time period adverse results of WBRT, a devastating consequence is usually the event of leukoencephalopathy. Without a doubt, radiation-induced dementia rates are actually reported being as substantial as eleven% in long-expression Mind metastases survivors (>12 months) soon after WBRT , and claimed to generally be greater in patients dealt with with WBRT and SRS rather than SRS on your own [35, fifty].
Abnormal N-methyl-D-aspartate (NMDA) receptor stimulation, just like the pathophysiology inherent to Parkinson's dementia , is postulated as one particular mechanism explaining the adverse neurocognitive effects of WBRT. As being a strategy to mitigate the chance, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a significant randomized placebo controlled trial involving 554 people. At 24 months, sixty four% of clients with out memantine and fifty four% with memantine experienced cognitive functionality failure depending on evaluation with the HVLT-R. Even though the Major endpoint did not attain importance a result of the significant attrition charge, there was a strong pattern (p = 0.059) supporting memantine procedure. Analysis of secondary endpoints confirmed that memantine drastically prolonged enough time to cognitive drop and yielded outstanding final results for executive operate, processing velocity and delayed recognition at 24 months. In the long run, these information clearly show many patients put up with cognitive dysfunction with WBRT, and that pharmacologic approaches to mitigate the chance by focusing on identical pathways associated with Parkinson's dementia may be deserving of even further investigation.
Even further Perception into WBRTs’ system of damage has come from a new Phase 2 demo analyzing hippocampal avoidance WBRT (HA-WBRT). Sophisticated modern radiation technology was applied to limit dose publicity to your hippocampus to not more than eighty% on the prescribed 30Gy in ten fractions . This non-randomized period 2 demo calculated neurocognitive functionality utilizing the HVLT-R, and compared results to historic controls taken care of with traditional WBRT from a RTOG demo database. HA-WBRT resulted within a seven% decline within the indicate relative HVLT-R delayed recall, which was considerably decrease than the 30% decrease obtained from historic controls. Whilst this research is encouraging with regard to restricting toxicity from WBRT, a randomized trial is required to completely realize the therapeutic worth In this particular technologically complicated form of WBRT.
In 2012, the American Society for Therapeutic Radiation Oncology posted an proof-based guideline having a series of recommendations on the administration of brain metastases . Because that time, the evidence from medical trials has created it clear that the popular up-front radiation remedy selection for patients with limited brain metastases is SRS on your own. In actual fact, the American Society for Radiation Oncology (ASTRO) has recently designed a definitive recommendation inside their Pick out Wisely campaign and suggest to not routinely insert adjuvant WBRT to SRS for limited brain metastases . Furthermore, the recently revised National In depth Most cancers Community (NCCN) suggestions now assist SRS by yourself even past Those people patients with “restricted” metastases, and don't specify an higher Restrict for the amount of metastases . The latter is forward wondering; metastasis counting is probably going irrelevant and what issues is usually the suitability of the affected person for SRS [57-59]. Therefore, the onus is not on those that handle with SRS on your own to justify the omission of WBRT; relatively it can be on those who handle with WBRT in a very SRS ideal individual.
How about THE Individual WITH Far more In depth BRAIN METASTASES?
Earlier technical restrictions in SRS technology restricted the appliance of SRS to people with only a few Mind metastases. Advancements in preset body and frameless SRS systems now enable treatment method of various metastases in an individual session [sixty, sixty one].
The very first important possible analyze assessing SRS by itself for a number of Mind metastases was documented in 2014 . Approximately 1200 sufferers with one-10 SRS suitable metastases have been addressed with SRS by itself making use of Gamma Knife technologies (Elekta AB, Stockholm, Sweden). The Examination was damaged down according to the 455 patients with one metastases, 531 sufferers with 2 to 4 metastases and 208 with five to ten metastases. Survival, distant Mind relapse, and local Handle charges were not significantly distinct in clients with five to ten metastases as opposed to two to four metastases. These effects are of major importance since they challenge the dogma that individuals with more than 4 metastases will never benefit from SRS on your own on account of shortened survival and can inevitably are unsuccessful elsewhere from the brain. As a result, this trial supplies proof to support SRS by yourself in very good KPS people with around 10 metastases, presented the person tumor volume is no more than 10 mL and < three cm in longest diameter, and the overall cumulative quantity of all tumors during the Mind is ≤15 mL. Numerous randomized trials are now analyzing WBRT alone versus SRS alone in similar clients, As well as in development is a demo evaluating SRS alone vs . WBRT in addition SRS Increase in clients with ten to twenty metastases.
Specific THERAPIES Together WITH BRAIN RADIATION
When compared to regular chemotherapy, various qualified brokers have bigger penetration in the blood-Mind barrier and yield response in the Mind. Dramatic enhancements in ailment Regulate are now being observed even for histologies such as melanoma that were Formerly considered not merely radioresistant but chemoresistant. Table two [63-seventy five] summarizes picked clinical trials analyzing the efficacy of qualified therapies on your own or in combination with radiation therapy from the procedure of brain metastases. Whilst, with focused therapies by yourself some extraordinary reaction fees are noticed, progression-totally free-survival (PFS) fees are usually quick (< eight months). These results are usually not too dissimilar from what has been accomplished with WBRT by itself [33, 53]. The exception is in EGFR mutant non-compact cell lung cancers handled which has a tyrosine kinase inhibitor. While in the analyze by Wu et al. as an example, the median PFS was >fifteen months in EGFR mutant tumours addressed with erlotinib.
Desk 2. Summary of selected trials of targeted therapy by itself or together with Mind radiation with the treatment of Mind metastases.
PFS: progression free of charge survival, nPFS: neurologic progression free survival, OS: overall survival, NSCLC: non-tiny cell lung most cancers, EGFR: epidermal development element receptor, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: months, NS: not major, NR: not recorded, NA: not relevant
Several trials have put together specific therapies with radiation, and these are also summarized in Table 2. Despite the fact that, randomized evidence remains to be missing, There is certainly recommendation from retrospective data that The mixture might bring on enhanced results. Within the retrospective Investigation of the prospective cohort of people treated with SRS for melanoma Mind metastases, the team that obtained ipilimumab had a appreciably longer median survival (21.three vs four.nine months) . On the other hand, caution has to be exercised as concurrent focused therapy and radiation treatment method is probably not as innocuous as Beforehand assumed. The RCT analyzing SRS with WBRT by yourself, versus in combination with erlotinib or temozlomide, noted considerably bigger Grade three to five toxicity charges in the combination arm; extra importantly, survival was even worse although it did not reach statistical significance . A big limitation of this review was that the specific therapy was not biomarker-driven and may partially account to the weak survival noticed. Caution also must be taken as You can find evidence that Mind metastases and primary tumors may harbor unique genetic alterations. In a single review of 86 matched brain metastases and first tumors, clinically informative alterations in 53% of brain metastases were not detected in the primary tumor .
The emerging evidence implies that targeted therapies will Enjoy a significant role while in the treatment of brain metastases. We postulate that Even though targeted agents will not be efficient in managing gross disorder within the brain, They might be effective in taking care of micro-metastatic disease in the brain. For that reason, a logical method might be to combine targeted therapies with SRS alone, beating the limitation of SRS in addressing micrometastatic condition while in the brain and resulting in much less distant Mind failures. The subsequent several years will produce fascinating data as There are a selection of trials in development using this technique.
INNOVATIONS IN SRS - INDICATIONS AND Programs
As tumors get greater, SRS dosing is counter-intuitively lowered with regard to tumor control, to take care of basic safety to the normal Mind tissue; in any other case, the risk of radiation necrosis results in being prohibitive . Subsequently, tumors bigger than 4 cm have normally been excluded from one fraction SRS. If your tumors are non-operable, then these individuals have been addressed with WBRT Irrespective of its poor community control. The arrival of non-invasive head immobilization equipment, on-board impression-direction programs and Sophisticated radiation supply software package has bring on the practice of hypofractionated frameless stereotactic radiotherapy (SRT) [60, 78]. Basically by fractionating, the protection profile with respect to the conventional Mind tissue toxicity is improved, and the entire tumor dose is usually escalated this sort of that doses like 24Gy in 3 fractions and 30-40Gy in five fractions are now not unusual. A single appealing retrospective sequence documented larger costs of Regulate and decrease charges of toxicities with hypofractionated SRT (36Gy in six fractions) when compared with single fraction SRS . Even so, this exercise remains to be in its infancy and we're in need of a RCT to determine whether one portion SRS must be reserved just for tiny metastases (e.g. 1-two centimeters), as the information suggest even worse nearby Command for larger sized tumors [80, 81]. Determine 1 is definitely an illustration of the efficacy of hypofractionated SRT in a substantial tumor. This patient might have normally been excluded from single portion SRS and taken care of with WBRT upfront (in addition or minus a SRS Enhance), or operated upon.
A. MRI of three.6cm proper cerebellar metastases from lung cancer. B. Remarkably conformal therapy prepare While using the a hundred% (eco-friendly line) and 80% (blue line) isodose traces wrapping tightly around the gross tumour (purple colorwash), and arranging target volume (orange colorwash). The brainstem (blue colorwash) is spared from large dose. (B) MRI 2 months write-up completion of radiation (30Gy in five fractions). C. Comprehensive resolution in the tumour at 1 calendar year.
In post-operative individuals, the exercise of routinely dealing with with WBRT is additionally becoming out-of-date. There may be rising use of SRS to your publish-operative surgical cavity as a way to spare people in the adverse results of WBRT and to enhance nearby Regulate [82-93]. At the Sunnybrook Odette Cancer Centre, Now we have adopted hypofractionated SRT as our standard of treatment, offering 30-35Gy in 5 fractions to the put up-operative tumor bed . Fractionation has the benefit of minimizing the adverse consequences to the normal tissues, provided that the targets are usually large and irregularly formed. Our initial benefits have demonstrated 1 year regional Command costs of ∼eighty% in sufferers who may have possibly recurred and re-operated on soon after prior WBRT, or in people without any prior heritage of WBRT and operated on. There is certainly an ongoing analyze assessing write-up-surgical cavity one portion SRS alone compared to WBRT and could be a practice-defining study .
In the last various a long time, medical trials have knowledgeable us about the suitable administration of people with brain metastases. At first, SRS was regarded an adjunct to WBRT in picked sufferers presenting using a limited range of brain metastases. Nonetheless, the purpose of WBRT has since been questioned as we have acquired of its probable to adversely have an effect on QOL and neurocognition. As a result, SRS on your own has emerged as The existing common of care with Stage one evidence to assistance its observe. Latest investigation is centered on the analysis of broader programs of SRS to quite a few medical situations that were typically deemed complete indications for WBRT. For instance, SRS by yourself is currently getting evaluated from the treatment method of five or maybe more brain metastases, and in article-operative clients. A completely new era of trials is additionally rising investigating the affect of focused therapies concurrent with SRS.
Medical trials in people with Mind metastases are A serious obstacle as summarized through the the latest stories within the Reaction Assessment in Neuro-Oncology (RANO) Mind metastases team [ninety five, 96]. They advise for trial layout and reaction assessment that trials be tumor or biomarker distinct, that assessment be based on contrast-Increased MRI, that baseline and repeated neurocognitive and QOL tests be done with validated and delicate instruments, that stratification be depending on additional-cranial sickness standing, Which correct timing be regarded as with regards to endpoint screening. Finally, the oncology Neighborhood has identified that the event of Mind metastases is now not the terminal oncologic party on the previous.
CONFLICTS OF Curiosity, Economical DISCLOSURES
Dr. Arjun Sahgal has been given honorarium from prior educational seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also been given investigation grants from Elekta AB, or else there won't be any conflicts of interest to disclose.