Trusted Direction by SRS Financials

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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 remarkable to whole brain radiotherapy (WBRT) on your own. As a result, WBRT in addition SRS was greatly adopted for patients having a constrained variety of Mind metastases (“minimal selection” customarily indicates 1-four). Subsequent trials focused on answering no matter whether WBRT upfront was important in any respect. Based on recent randomized managed trials (RCTs) and meta-analyses comparing SRS on your own to SRS plus WBRT, adjuvant WBRT leads to superior intracranial Manage; however, on the price of neurocognitive performing and quality of life. These adverse results of WBRT may additionally negatively influence on survival in young patients. Determined by the results of these scientific studies, cure has shifted to SRS by itself in people with a restricted quantity of metastases. Also, RCTs are analyzing the purpose of SRS by itself in clients with >four Mind metastases. New developments in SRS contain fractionated SRS for big tumors and The combination of SRS with focused systemic therapies that cross the blood brain barrier and/or stimulate an immune reaction. We existing With this critique The existing substantial stage evidence and rationale supporting SRS because the standard of look after people with minimal Mind metastases, and emerging applications 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 purpose of neurosurgery had been established during the nineties as a means to obtain regional Management and prolong survival, it absolutely was reserved to the minority of sufferers presenting with a single metastasis and no other disorder past the Mind [4-seven]. However lacking was a focal ablative non-invasive procedure that might be used proficiently to the A great deal broader population of clients with brain metastases. This established the phase for the development of stereotactic radiosurgery (SRS). SRS is usually a targeted ablative radiation cure delivered with sub-millimeter precision on the tumor localized in a few-dimensions in one-five fractions.

The focus of this evaluate is always to summarize The existing superior degree evidence to make clear the job of SRS as optimal management for sufferers presenting with confined Mind metastases. Moreover, we provide an outline on the rising applications of SRS as it carries on to evolve right into a treatment option to WBRT, Together with the intent To maximise neurcognitive purpose and Standard of living (QOL).

PATHOPHYSIOLOGY OF Mind METASTASES

Circulating tumor cells (CTCs) can disseminate from the Key tumor mass to variety distant colonies by means of implantation at an ectopic web site, like the Mind [8-10]. To do so demands CTCs to arrest in the circulation, extravasate from the bloodstream or lymphatics in the Mind, and survive and proliferate [11-13]. The process of metastatic colonization consists of a immediate conversation of CTCs with endothelial cells and astrocytes from the Mind microenvironment. For instance, CTCs that have arrested inside the capillary mattress immediate nearby endothelial cells to remodel the adjacent ecosystem to promote tumour cell growth and invasion [14-sixteen]. Further more, metastatic tumour cells recruit systemic stromal cells, for instance fibroblasts, to help with early colonization , and co-opt local stromal cells, which include reactive astrocytes and microglia, to market tissue invasion [fifteen, eighteen, 19]. Astrocytes in the tumour microenvironment can also Perform a task in protecting tumour cells from chemotherapy-induced cytotoxicity, by way of a however to become described system requiring mobile-mobile Make contact with [twenty, 21]. Tumour cells, through release 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 to the treatment method of intracranial metastatic condition.

SRS was to begin with a very useful resource intensive therapy offered only at specialized facilities and indicated only for metastatic sufferers with a good life expectancy. The problem lay in prognosticating individuals correctly and Because of this the Radiation Therapy Oncology Team (RTOG) recursive partitioning analysis (RPA) [28, 29] was produced. Based upon the affected person's Karnofsky Effectiveness Position (KPS), age, status of the principal tumor and existence of extracranial sickness, patients had been grouped into class 1, two or three with corresponding median survivals of seven.one, four.2 and 2.3 months, respectively. While An important advancement at time, the RPA is currently regarded overly simplistic as recent oncologic final decision making is much more intricate incorporating molecular, histological, medical and radiographic illness attributes. There are actually now extra complex classification applications, including the analysis-distinct graded prognostic assessment (DS-GPA). This method presents histology-precise estimates of survival and will independent, as an example, one of the most favorable breast cancer patients having an envisioned survival of 25 months (excellent KPS and luminal B style breast cancer) in the least favorable clients with the envisioned survival of three months (very poor KPS and basal-like breast cancer) . Inspite of improvements in prognostication of patients with brain metastases, doctors are still mainly unable to correctly predict lengthy-time period survivors. A review inquiring qualified doctors to estimate survival of a 150 people with specifics of cancer type, number of Mind metastases, neurological presentation, further-cranial ailment position, KPS, RPA class, prior entire-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that over 45% of predictions were off by over 6 months and 18% were off by greater than 12 months . More advancements in prognostic checks such as the “liquid biopsy” (a non-invasive blood examination which can detect tumor DNA or RNA fragments or CTCs) are wanted and in improvement . These Blend Innovative affected person and tumor precise genomic facts in to the equation, so that you can realize personalized survival predictions.

Medical procedures proceeds to generally be a very important cure option for patients with limited brain metastases. It's indicated when metastases are big (>3-4 cm), or when a pathologic diagnosis is necessary. Also, operation is most well-liked while in the presence of considerable edema necessitating extended superior dose dexamethasone, or to most likely reverse neurological deficits. Normally, the current evidence implies that the efficacy of SRS is sufficient to accomplish long lasting neighborhood Manage that is corresponding to operation. Despite the fact that there aren't any RCTs directly evaluating the two, various trials are documented comparing SRS to SRS with WBRT (Desk 1), and is particularly a major aim of this review.

HR: hazard ratio, WHO: entire world wellness Corporation, KPS: Karnofsky overall performance position, WBRT: total brain radiotherapy, SRS: stereotactic radiosurgery, yr: calendar year, mos: months, NS: not substantial, NR: not recorded, NA: not relevant, HVLT-R: Hopkins Verbal Learning Test revised.

Sufferers within the observation group experienced either operation by yourself or SRS alone. Purposeful consequence wasn't analyzed separately by medical procedures or SRS by yourself.

The main RCTs assessing SRS mimicked the design from the Original surgical studies for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These research confirmed that SRS improved regional Command, plus a survival gain in selected clients with a single Mind metastasis was proven. These trials ended up effective in shifting the paradigm from WBRT on your own to WBRT moreover SRS for individuals presenting with limited brain metastases and a fantastic performance status.

The next series of medical trials have been meant to solution if WBRT was in the slightest degree vital, and in contrast SRS on your own to SRS with adjuvant WBRT. A few RCTs are already reported in sufferers presenting with as many as four metastases [35-37] plus a forth in abstract type . Aoyama et al. documented the first RCT, randomizing 132 people to SRS by itself (sixty five sufferers) or WBRT as well as SRS (sixty seven sufferers). The principal endpoint was brain tumor recurrence. Even though the one-12 months neighborhood Manage level was superior with SRS by itself at seventy three%, extra nearby Regulate with adjuvant WBRT at 89%, was noticed. Additionally, adjuvant WBRT lowered the rate of distant intra-cranial relapse at one 12 months from 64% to forty two%. Nonetheless, these gains in intra-cranial Manage did not translate into a benefit with regard to cognition, according to Mini-Mental Position Exam (MMSE), nor survival. In addition, people had larger premiums of necrosis and leukoencephalopathy from the WBRT arm. The demo was So successful in delivering the initial level one proof to clarify the relative impact of SRS alone compared to SRS with WBRT.

Rather than the standard endpoint of survival or intra-cranial control, Chang et al. took a distinct method and evaluated neurocognition as the key endpoint. Importantly, the validated Hopkins Verbal Mastering Examination-Revised (HVLT-R) evaluation tool, was accustomed to evaluate neurocognitive working versus the MMSE which is not a delicate test for neurocognition . Fifty-eight clients were being randomized to SRS alone (n = thirty) or WBRT moreover SRS (n = 28). Early stopping regulations were invoked with the interim Assessment, as well as the review concluded that SRS alone was favored with respect to your chance of neurocognitive decline at 4 months article-remedy. This gain was realized despite the 1 yr area Command and distant Mind Command fees favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial Manage results have been In step with the effects with the Aoyama research, but what was not predicted was the survival benefit noticed in the SRS on your own arm. The median survival was fifteen months from the SRS on your own arm and 6 months while in the SRS with WBRT arm (p = 0.003). This survival outcome brought on the trial to undertake appreciable scrutiny with several arguing which the survival edge for SRS alone was a results of imbalances among The 2 arms, as a lot more clients addressed with SRS plus WBRT experienced increased further-cranial (far more liver and adrenal metastases) and intracranial ailment (much larger quantity of brain metastases) .

The European Organization for Investigate and Procedure of Cancer (EORTC) also took a unique method with their Principal endpoint focusing on purposeful independence . They utilized, nevertheless, the greater clinically acquainted Planet Well being Organization (WHO) performance position (PS) scale, and measured time to WHO PS deterioration to in excess of 2. This RCT concluded the addition of WBRT did not improve the median period of practical independence (SRS on your own: 10.0 months vs SRS in addition WBRT: nine.five months). The secondary end result of QOL, measured with the validated EORTC-QLQC30 Resource, was observed being worse in sufferers who acquired WBRT in several QOL domains . Importantly, these effects have been noticed Even with adjuvant WBRT cutting down the two-12 months local failure rate (31% to 19%), distant Mind failure (48% to 33%), and the necessity for salvage therapies (fifty one% vs. 16%). No major variances in survival have been observed albeit the demo was not driven to deal with survival.

These four trials have recognized the function of SRS by yourself since the regular of treatment in sufferers that has a limited amount of Mind metastases, but they have got not been made to Consider the impression of WBRT on All round survival.

The inclusion standards through the RCTs evaluating SRS on your own to SRS in addition WBRT were being equivalent (Desk one), however, the key endpoints have been fully different, and no trial was intended to Examine overall survival. To higher make clear the results of area control, distant Mind Handle and survival, a meta-analysis (MAL) was executed by Tsao, Xu and Sahgal in 2012 . They noted hazard ratios for area Management and distant brain Handle favoring adjuvant WBRT at 2.sixty one and a couple of.fifteen, respectively, but have been not able to combine the survival effects resulting from limitations in the way the information had been noted. Sahgal et al. then carried out somebody affected individual info (IPD) MAL of exactly the same RCTs geared toward evaluating procedure outcomes on survival, and complete sub-group analyses . With respect to Over-all survival, a treatment result was observed favoring SRS on your own in clients ≤fifty years. In older clients, no survival drawback was noticed with SRS by yourself. With respect to distant brain Management, a procedure result was also noticed with possibility reductions in the development of latest Mind metastases in more mature clients addressed with WBRT, but no profit in the younger people (≤50 many years) dealt with with WBRT. As anticipated, area Regulate was improved with extra WBRT in all age teams. The concordance involving a survival detriment and insufficient advantage in distant Mind Manage Even with cure with WBRT, inside the more youthful clients, led the authors to hypothesize that publicity to the regarded harms of WBRT (reviewed in detail beneath) may possibly negatively impression affected person survival. This hypothesis is provocative, and stays to generally be validated.

Probably the most convincing demo design to substantiate the adverse outcomes of WBRT would be to randomize clients with no visualized brain metastases to observation or WBRT. This has long been completed in scientific studies assessing prophylactic cranial irradiation (PCI) in both equally modest mobile lung most cancers (SCLC) [44, forty five] and non-smaller cell lung most cancers (NSCLC) [forty six, forty seven]. PCI, not dissimilar into the addition of WBRT to SRS, is revealed to reduce the chance of intra-cranial relapse. Even so, this attain comes within the cost of the destructive effect on QOL. By way of example, important will increase in fatigue, urge for food reduction, nausea and vomiting and leg weak point were noticed in clients with substantial stage SCLC at six and 12 months article PCI . Additionally, in locally Highly developed NSCLC people, a increased decline in HVLT-R actions of instant and delayed remember have been observed even as many as 1 12 months write-up-PCI . With respect to for a longer time-expression adverse results of WBRT, a devastating consequence could be the development of leukoencephalopathy. Indeed, radiation-induced dementia prices have already been noted to be as significant as 11% in extended-expression brain metastases survivors (>12 months) after WBRT , and claimed being larger in sufferers dealt with with WBRT and SRS as opposed to SRS on your own [35, 50].

Too much N-methyl-D-aspartate (NMDA) receptor stimulation, just like the pathophysiology inherent to Parkinson's dementia , is postulated as 1 system detailing the adverse neurocognitive effects of WBRT. Being a technique to mitigate the risk, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a big randomized placebo controlled demo involving 554 patients. At 24 weeks, 64% of clients without the need of memantine and 54% with memantine had cognitive operate failure dependant on assessment Using the HVLT-R. Although the Principal endpoint did not attain significance mainly because of the large attrition level, there was a robust development (p = 0.059) supporting memantine remedy. Assessment of secondary endpoints confirmed that memantine appreciably prolonged time to cognitive drop and yielded outstanding effects for executive purpose, processing velocity and delayed recognition at 24 weeks. In the end, these knowledge show virtually all people endure cognitive dysfunction with WBRT, and that pharmacologic tactics to mitigate the danger by targeting very similar pathways associated with Parkinson's dementia can be deserving of additional investigation.

Even more Perception into WBRTs’ system of injury has originate from a current Phase two demo evaluating hippocampal avoidance WBRT (HA-WBRT). Subtle present day radiation technological know-how was applied to limit dose exposure to your hippocampus to not more than eighty% of the prescribed 30Gy in ten fractions . This non-randomized phase 2 trial measured neurocognitive perform using the HVLT-R, and in comparison results to historic controls dealt with with common WBRT from the RTOG demo databases. HA-WBRT resulted inside of a seven% drop during the mean relative HVLT-R delayed remember, which was noticeably lower than the thirty% decline attained from historic controls. Though this review is encouraging with regards to limiting toxicity from WBRT, a randomized trial is needed to fully realize the therapeutic price Within this technologically elaborate kind of WBRT.

In 2012, the American Culture for Therapeutic Radiation Oncology posted an proof-centered guideline by using a series of recommendations to the administration of Mind metastases . Since that point, the proof from medical trials has manufactured it apparent that the popular up-front radiation procedure selection for sufferers with restricted Mind metastases is SRS alone. In truth, the American Modern society for Radiation Oncology (ASTRO) has not long ago designed a definitive suggestion within their Select Properly marketing campaign and recommend not to routinely add adjuvant WBRT to SRS for constrained Mind metastases . Also, the lately revised Nationwide Thorough Cancer Network (NCCN) suggestions now assist SRS alone even beyond All those patients with “limited” metastases, and don't specify an higher Restrict for the volume of metastases . The latter is ahead contemplating; metastasis counting is probably going irrelevant and what issues is normally the suitability in the affected individual for SRS [57-59]. Consequently, the onus is now not on those who treat with SRS by itself to justify the omission of WBRT; rather it's on individuals who handle with WBRT within a SRS acceptable affected individual.

How about THE Individual WITH Extra In depth BRAIN METASTASES?

Previous complex constraints in SRS technologies restricted the applying of SRS to sufferers with only some brain metastases. Advancements in fixed body and frameless SRS technologies now make it possible for therapy of various metastases in one session [60, sixty one].

The main significant future research assessing SRS by itself for various Mind metastases was claimed in 2014 . Roughly 1200 sufferers with one-ten SRS suitable metastases were addressed with SRS by itself working with Gamma Knife know-how (Elekta AB, Stockholm, Sweden). The Examination was damaged down according to the 455 patients with one metastases, 531 individuals with two to four metastases and 208 with 5 to 10 metastases. Survival, distant Mind relapse, and native control rates weren't significantly diverse in people with five to ten metastases as opposed to 2 to 4 metastases. These outcomes are of important importance because they challenge the dogma that individuals with more than 4 metastases is not going to benefit from SRS by itself resulting from shortened survival and can inevitably fail in other places while in the brain. Hence, this trial supplies evidence to support SRS by yourself in excellent KPS patients with as many as 10 metastases, delivered the person tumor quantity is no more than 10 mL and < 3 cm in longest diameter, and the total cumulative quantity of all tumors inside the Mind is ≤15 mL. Various randomized trials are presently evaluating WBRT alone as opposed to SRS by itself in related people, and in growth is a trial assessing SRS on your own vs . WBRT plus SRS Enhance in sufferers with 10 to 20 metastases.

Specific THERAPIES Together WITH BRAIN RADIATION

When compared with regular chemotherapy, a number of focused brokers have higher penetration throughout the blood-Mind barrier and generate response in the brain. Dramatic enhancements in condition Manage are now being observed even for histologies including melanoma that were Earlier viewed as not merely radioresistant but chemoresistant. Table two [63-seventy five] summarizes chosen scientific trials analyzing the efficacy of specific therapies on your own or together with radiation therapy in the treatment of Mind metastases. While, with focused therapies on your own some outstanding reaction fees are observed, progression-cost-free-survival (PFS) premiums are usually brief (< 8 months). These final results will not be far too dissimilar from what has been achieved with WBRT alone [33, 53]. The exception is in EGFR mutant non-smaller mobile lung cancers dealt with which has a tyrosine kinase inhibitor. During the analyze by Wu et al. for example, the median PFS was >fifteen months in EGFR mutant tumours addressed with erlotinib.

Desk 2. Summary of picked trials of specific therapy by yourself or together with brain radiation for your remedy of Mind metastases.

PFS: progression cost-free survival, nPFS: neurologic progression free of charge survival, OS: Total survival, NSCLC: non-compact mobile lung most cancers, EGFR: epidermal development component receptor, WBRT: whole Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not substantial, NR: not recorded, NA: not applicable

Several trials have merged focused therapies with radiation, and these are generally also summarized in Table two. Whilst, randomized proof remains missing, There's recommendation from retrospective details that The mixture may bring on enhanced outcomes. From the retrospective Investigation of a potential cohort of clients addressed with SRS for melanoma Mind metastases, the team that acquired ipilimumab had a appreciably extended median survival (21.3 vs four.9 months) . On the other hand, caution really should be exercised as concurrent focused therapy and radiation procedure might not be as innocuous as Formerly assumed. The RCT evaluating SRS with WBRT by itself, compared to in combination with erlotinib or temozlomide, claimed noticeably better Grade three to 5 toxicity fees in the combination arm; extra importantly, survival was even worse although it didn't achieve statistical importance . An important limitation of this examine was which the specific therapy was not biomarker-driven and should in part account for your inadequate survival noticed. Warning also has to be taken as there is evidence that Mind metastases and first tumors might harbor distinct genetic alterations. In a single review of 86 matched brain metastases and primary tumors, clinically useful alterations in 53% of brain metastases weren't detected in the first tumor .

The emerging proof suggests that focused therapies will Engage in a big purpose in the remedy of Mind metastases. We postulate that Whilst qualified brokers is probably not effective in controlling gross illness in the Mind, They could be productive in running micro-metastatic disorder in the brain. For that reason, a reasonable technique could be to combine focused therapies with SRS by itself, conquering the limitation of SRS in addressing micrometastatic disorder within the Mind and leading to much less distant Mind failures. Another number of years will yield thrilling data as There are a variety of trials in development using this strategy.

INNOVATIONS IN SRS - INDICATIONS AND Apps

As tumors get much larger, SRS dosing is counter-intuitively reduced with respect to tumor control, to take care of basic safety to the normal Mind tissue; usually, the chance of radiation necrosis results in being prohibitive . As a result, tumors larger than 4 cm have typically been excluded from one portion SRS. Should the tumors are non-operable, then these patients have already been handled with WBRT Irrespective of its very poor area Manage. The arrival of non-invasive head immobilization equipment, on-board image-advice units and Superior radiation supply computer software has bring on the exercise of hypofractionated frameless stereotactic radiotherapy (SRT) [60, seventy eight]. Fundamentally by fractionating, the safety profile with regard to the conventional Mind tissue toxicity is improved, and the overall tumor dose can be escalated these kinds of that doses like 24Gy in three fractions and 30-40Gy in 5 fractions at the moment are not unusual. One particular fascinating retrospective series reported increased fees of Manage and decreased premiums of toxicities with hypofractionated SRT (36Gy in six fractions) as compared with one portion SRS . Nevertheless, this follow remains to be in its infancy and we are in need of a RCT to determine whether solitary portion SRS should be reserved only for tiny metastases (e.g. 1-2 centimeters), as the information advise even worse nearby control for greater tumors [eighty, 81]. Figure one is surely an illustration of the efficacy of hypofractionated SRT in a considerable tumor. This affected individual would've if not been excluded from solitary portion SRS and taken care of with WBRT upfront (in addition or minus a SRS Improve), or operated upon.

A. MRI of 3.6cm appropriate cerebellar metastases from lung cancer. B. Very conformal cure program Together with the one hundred% (eco-friendly line) and 80% (blue line) isodose lines wrapping tightly around the gross tumour (red colorwash), and planning target volume (orange colorwash). The brainstem (blue colorwash) is spared from high dose. (B) MRI 2 months write-up completion of radiation (30Gy in five fractions). C. Full resolution from the tumour at one calendar year.

In write-up-operative clients, the follow of routinely dealing with with WBRT is additionally turning into out-of-date. There may be rising use of SRS to the write-up-operative surgical cavity as a way to spare individuals from the adverse consequences of WBRT and to enhance nearby Command [eighty two-93]. For the Sunnybrook Odette Cancer Center, We have now adopted hypofractionated SRT as our normal of treatment, providing thirty-35Gy in 5 fractions to the submit-operative tumor bed . Fractionation has the benefit of minimizing the adverse outcomes to the normal tissues, given that the targets are generally huge and irregularly formed. Our initial success have proven one 12 months nearby Manage fees of ∼80% in people who may have either recurred and re-operated upon immediately after prior WBRT, or in clients with no prior heritage of WBRT and operated on. There exists an ongoing analyze assessing write-up-surgical cavity single portion SRS alone compared to WBRT and could be a practice-defining examine .

In the last several a long time, scientific trials have informed us about the appropriate administration of clients with Mind metastases. In the beginning, SRS was viewed as an adjunct to WBRT in chosen clients presenting which has a restricted variety of Mind metastases. Having said that, the function of WBRT has due to the fact been questioned as Now we have discovered of its prospective to adversely influence QOL and neurocognition. Subsequently, SRS alone has emerged as the current regular of treatment with Level 1 proof to support its practice. Present investigation is centered on the analysis of broader purposes of SRS to quite a few scientific cases which were usually viewed as complete indications for WBRT. One example is, SRS by yourself is at the moment staying evaluated from the treatment of five or even more Mind metastases, and in post-operative sufferers. A fresh era of trials is additionally emerging investigating the effects of qualified therapies concurrent with SRS.

Medical trials in individuals with Mind metastases are A serious challenge as summarized by the the latest stories from your Response Evaluation in Neuro-Oncology (RANO) brain metastases team [95, ninety six]. They suggest for trial design and response evaluation that trials be tumor or biomarker distinct, that assessment be dependant on contrast-enhanced MRI, that baseline and recurring neurocognitive and QOL testing be executed with validated and sensitive devices, that stratification be determined by added-cranial disease position, and that acceptable timing be regarded as with regards to endpoint screening. Eventually, the oncology community has identified that the development of brain metastases is now not the terminal oncologic celebration from the earlier.

CONFLICTS OF Curiosity, FINANCIAL DISCLOSURES

Dr. Arjun Sahgal has gained honorarium from prior academic seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also received exploration grants from Elekta AB, or else there isn't any conflicts of interest to reveal.

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