Reliable Assistance by SRS Financials

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Stereotactic radiosurgery SRS Financials is an established non-invasive ablative therapy for Mind metastases. Early scientific trials with SRS proved that tumor Command rates are top-quality to complete brain radiotherapy (WBRT) on your own. Due to this fact, WBRT in addition SRS was broadly adopted for people having a limited quantity of brain metastases (“constrained range” customarily means 1-4). Subsequent trials focused on answering no matter whether WBRT upfront was important in any respect. Depending on present-day randomized controlled trials (RCTs) and meta-analyses evaluating SRS by itself to SRS as well as WBRT, adjuvant WBRT leads to superior intracranial Manage; nevertheless, with the expenditure of neurocognitive performing and Standard of living. These adverse consequences of WBRT might also negatively impact on survival in youthful people. Based upon the outcomes of such reports, cure has shifted to SRS on your own in sufferers that has a confined quantity of metastases. On top of that, RCTs are evaluating the function of SRS alone in individuals with >four Mind metastases. New developments in SRS consist of fractionated SRS for large tumors and the integration of SRS with targeted systemic therapies that cross the blood Mind barrier and/or encourage an immune reaction. We current With this evaluate The existing higher stage evidence and rationale supporting SRS as the regular of care for individuals with confined brain metastases, and emerging 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 position of neurosurgery had been set up inside the 1990s as a method to attain local Manage and extend survival, it absolutely was reserved for that minority of individuals presenting with just one metastasis and no other disease outside of the brain [four-7]. Nonetheless missing was a focal ablative non-invasive treatment method that might be used successfully to some A lot broader inhabitants of individuals with Mind metastases. This set the stage for the event of stereotactic radiosurgery (SRS). SRS is really a centered ablative radiation treatment sent with sub-millimeter precision for the tumor localized in a few-dimensions in one-five fractions.

The focus of this overview is always to summarize The present high stage evidence to clarify the position of SRS as exceptional administration for people presenting with restricted brain metastases. Furthermore, we provide an outline with the emerging programs of SRS because it carries on to evolve right into a treatment choice to WBRT, with the intent To optimize neurcognitive purpose and Standard of living (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from a Main tumor mass to kind distant colonies by implantation at an ectopic web page, including the Mind [eight-ten]. To take action involves CTCs to arrest in the circulation, extravasate from the bloodstream or lymphatics in to the Mind, and survive and proliferate [11-13]. The entire process of metastatic colonization requires a direct interaction of CTCs with endothelial cells and astrocytes inside the Mind microenvironment. For example, CTCs which have arrested in the capillary bed direct community endothelial cells to remodel the adjacent environment to market tumour mobile development and invasion [fourteen-sixteen]. Even further, metastatic tumour cells recruit systemic stromal cells, including fibroblasts, to assist with early colonization , and co-decide regional stromal cells, for instance reactive astrocytes and microglia, to promote tissue invasion [fifteen, 18, 19]. Astrocytes throughout the tumour microenvironment may Engage in a role in protecting tumour cells from chemotherapy-induced cytotoxicity, via a but to be described mechanism demanding mobile-cell Get in touch with [twenty, 21]. Tumour cells, by means of launch of migration inhibitory aspect, interleukin-eight, and plasminogen activator inhibitor 1, induce astrocyte activation and modify the inflammatory milieu to reinforce tumor-cell proliferation in vitro [22-24]. These molecular processes depict novel and understudied feasible therapeutic targets for that therapy of intracranial metastatic sickness.

SRS was at first an exceedingly resource intense therapy provided only at specialized facilities and indicated only for metastatic clients with a great life expectancy. The problem lay in prognosticating clients efficiently and Due to this fact the Radiation Therapy Oncology Team (RTOG) recursive partitioning Evaluation (RPA) [28, 29] was designed. Based on the affected person's Karnofsky General performance Status (KPS), age, status of the main tumor and existence of extracranial sickness, individuals had been grouped into course one, two or three with corresponding median survivals of seven.one, four.two and a couple of.3 months, respectively. Although A significant growth at the time, the RPA is currently deemed overly simplistic as latest oncologic conclusion making is much more sophisticated incorporating molecular, histological, clinical and radiographic illness attributes. You can find now much more refined classification resources, such as the analysis-distinct graded prognostic evaluation (DS-GPA). This system provides histology-precise estimates of survival and may separate, for instance, probably the most favorable breast most cancers sufferers with the predicted survival of 25 months (outstanding KPS and luminal B kind breast most cancers) through the least favorable people using an expected survival of three months (inadequate KPS and basal-like breast most cancers) . Even with improvements in prognostication of people with brain metastases, medical professionals are still mostly unable to correctly forecast extended-time period survivors. A research inquiring professional medical professionals to estimate survival of a a hundred and fifty people with information regarding most cancers sort, quantity of brain metastases, neurological presentation, excess-cranial condition standing, KPS, RPA course, prior complete-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that over forty five% of predictions were off by a lot more than six months and 18% have been off by much more than 12 months . Even further advancements in prognostic checks such as the “liquid biopsy” (a non-invasive blood examination which will detect tumor DNA or RNA fragments or CTCs) are desired and in advancement . These Blend Highly developed patient and tumor certain genomic facts into your equation, to be able to accomplish customized survival predictions.

Operation proceeds to be a crucial remedy choice for sufferers with minimal Mind metastases. It can be indicated when metastases are substantial (>three-four cm), or every time a pathologic prognosis is required. Additionally, surgical treatment is chosen in the presence of considerable edema requiring extended superior dose dexamethasone, or to most likely reverse neurological deficits. Usually, The present evidence implies the efficacy of SRS is adequate to achieve durable area Manage that's corresponding to surgical procedures. While there won't be any RCTs straight evaluating The 2, many trials have already been described comparing SRS to SRS with WBRT (Desk 1), which is A significant focus of the evaluation.

HR: hazard ratio, WHO: environment health and fitness Group, KPS: Karnofsky effectiveness status, WBRT: full Mind radiotherapy, SRS: stereotactic radiosurgery, yr: year, mos: months, NS: not major, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Discovering Check revised.

Patients while in the observation team had possibly medical procedures by itself or SRS alone. Functional final result wasn't analyzed individually by operation or SRS alone.

The primary RCTs analyzing SRS mimicked the design in the First surgical studies for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific tests verified that SRS improved community Command, plus a survival edge in chosen people with just one brain metastasis was demonstrated. These trials were being effective in shifting the paradigm from WBRT on your own to WBRT in addition SRS for people presenting with limited brain metastases and a great effectiveness position.

The next series of clinical trials were intended to reply if WBRT was in the least vital, and in contrast SRS alone to SRS with adjuvant WBRT. Three RCTs have already been documented in sufferers presenting with approximately four metastases [35-37] and also a forth in summary sort . Aoyama et al. described the 1st RCT, randomizing 132 clients to SRS alone (65 patients) or WBRT furthermore SRS (67 people). The first endpoint was Mind tumor recurrence. Even though the 1-yr nearby Manage rate was higher with SRS alone at 73%, added local Handle with adjuvant WBRT at 89%, was noticed. Furthermore, adjuvant WBRT reduced the speed of distant intra-cranial relapse at 1 calendar year from sixty four% to 42%. However, these gains in intra-cranial control didn't translate into a bonus with respect to cognition, according to Mini-Psychological Standing Exam (MMSE), nor survival. Also, clients experienced increased charges of necrosis and leukoencephalopathy within the WBRT arm. The demo was Hence effective in furnishing the 1st degree one evidence to explain the relative impression of SRS on your own vs . SRS with WBRT.

As an alternative to the traditional endpoint of survival or intra-cranial Regulate, Chang et al. took a special strategy and evaluated neurocognition as the key endpoint. Importantly, the validated Hopkins Verbal Mastering Test-Revised (HVLT-R) evaluation tool, was utilized to evaluate neurocognitive operating as opposed to the MMSE which is not a delicate test for neurocognition . Fifty-8 people had been randomized to SRS by yourself (n = 30) or WBRT additionally SRS (n = 28). Early halting guidelines ended up invoked at the interim Examination, and the research concluded that SRS by yourself was favored with regard towards the likelihood of neurocognitive drop at 4 months publish-cure. This benefit was recognized Regardless of the one year neighborhood Command and distant brain Handle costs favoring adjuvant WBRT with complete gains of 33% and 27%, respectively. The intracranial control results were In line with the outcome within the Aoyama study, but what was not expected was the survival advantage observed within the SRS on your own arm. The median survival was 15 months while in the SRS by itself arm and six months in the SRS with WBRT arm (p = 0.003). This survival outcome triggered the trial to go through appreciable scrutiny with quite a few arguing which the survival edge for SRS by yourself was a result of imbalances amongst the two arms, as far more clients dealt with with SRS moreover WBRT experienced higher added-cranial (far more liver and adrenal metastases) and intracranial ailment (more substantial quantity of brain metastases) .

The European Business for Study and Therapy of Cancer (EORTC) also took a different approach with their Most important endpoint specializing in useful independence . They utilized, however, the greater clinically acquainted Earth Wellbeing Firm (WHO) general performance standing (PS) scale, and measured some time to WHO PS deterioration to in excess of 2. This RCT concluded that the addition of WBRT didn't improve the median period of useful independence (SRS on your own: 10.0 months vs SRS as well as WBRT: 9.five months). The secondary final result of QOL, calculated With all the validated EORTC-QLQC30 tool, was noticed to become even worse in individuals who been given WBRT in many QOL domains . Importantly, these outcomes were being observed despite adjuvant WBRT lessening the 2-calendar year neighborhood failure rate (31% to 19%), distant brain failure (forty eight% to 33%), and the need for salvage therapies (fifty one% vs. 16%). No significant variances in survival were observed albeit the demo was not driven to deal with survival.

These four trials have recognized the function of SRS by itself because the typical of care in people that has a limited amount of Mind metastases, but they have got not been built to Assess the impression of WBRT on overall survival.

The inclusion standards through the RCTs evaluating SRS alone to SRS in addition WBRT were comparable (Table one), however, the main endpoints ended up wholly various, and no trial was built to evaluate General survival. To better explain the results of nearby Management, distant Mind Command and survival, a meta-analysis (MAL) was carried out by Tsao, Xu and Sahgal in 2012 . They described hazard ratios for area Command and distant brain Handle favoring adjuvant WBRT at 2.sixty one and a pair of.15, respectively, but have been unable to combine the survival outcomes on account of constraints in how the information ended up claimed. Sahgal et al. then executed somebody client facts (IPD) MAL of a similar RCTs targeted at assessing treatment method results on survival, and accomplish sub-team analyses . With respect to All round survival, a remedy impact was observed favoring SRS alone in individuals ≤50 decades. In more mature sufferers, no survival disadvantage was observed with SRS by itself. With respect to distant brain Command, a procedure result was also observed with hazard reductions in the event of new Mind metastases in more mature individuals treated with WBRT, but no gain inside the younger people (≤fifty a long time) treated with WBRT. As anticipated, local Regulate was improved with supplemental WBRT in all age groups. The concordance between a survival detriment and deficiency of advantage in distant Mind Manage Inspite of treatment method with WBRT, within the young patients, led the authors to hypothesize that exposure on the known harms of WBRT (talked over in detail down below) could negatively impact client survival. This hypothesis is provocative, and stays to be validated.

By far the most convincing trial layout to substantiate the adverse results of WBRT should be to randomize individuals without having visualized brain metastases to observation or WBRT. This has become done in scientific studies evaluating prophylactic cranial irradiation (PCI) in both tiny mobile lung most cancers (SCLC) [44, 45] and non-compact cell lung cancer (NSCLC) [46, forty seven]. PCI, not dissimilar to your addition of WBRT to SRS, has been proven to lessen the chance of intra-cranial relapse. Having said that, this acquire comes with the expenditure of a destructive impact on QOL. For instance, considerable will increase in tiredness, urge for food reduction, nausea and vomiting and leg weak point have been noticed in clients with extensive stage SCLC at six and 12 months post PCI . In addition, in regionally Innovative NSCLC sufferers, a increased decline in HVLT-R measures of instant and delayed recall had been observed even around 1 12 months write-up-PCI . With regard to extended-time period adverse outcomes of WBRT, a devastating consequence is often the development of leukoencephalopathy. In truth, radiation-induced dementia premiums are actually claimed being as significant as 11% in prolonged-expression brain metastases survivors (>12 months) soon after WBRT , and described to get better in patients treated with WBRT and SRS in contrast 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 outlining the adverse neurocognitive results of WBRT. As a technique to mitigate the danger, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a sizable randomized placebo controlled trial involving 554 individuals. At 24 weeks, 64% of people with out memantine and fifty four% with memantine experienced cognitive purpose failure based on evaluation Together with the HVLT-R. Even though the primary endpoint didn't arrive at significance because of the significant attrition charge, there was a solid pattern (p = 0.059) supporting memantine treatment. Examination of secondary endpoints showed that memantine drastically extended time to cognitive decrease and yielded exceptional success for executive operate, processing velocity and delayed recognition at 24 months. In the end, these knowledge show virtually all people endure cognitive dysfunction with WBRT, and that pharmacologic tactics to mitigate the chance by targeting equivalent pathways involved with Parkinson's dementia may very well be worthy of more investigation.

Additional insight into WBRTs’ mechanism of harm has originate from a the latest Section 2 demo analyzing hippocampal avoidance WBRT (HA-WBRT). Innovative modern day radiation technological innovation was applied to Restrict dose publicity for the hippocampus to no more than eighty% on the prescribed 30Gy in 10 fractions . This non-randomized section two trial measured neurocognitive functionality using the HVLT-R, and compared outcomes to historic controls taken care of with standard WBRT from the RTOG trial databases. HA-WBRT resulted in a very 7% decline during the indicate relative HVLT-R delayed recall, which was significantly decreased as opposed to 30% decrease obtained from historic controls. Whilst this examine is encouraging when it comes to restricting toxicity from WBRT, a randomized trial is necessary to completely have an understanding of the therapeutic value On this technologically elaborate form of WBRT.

In 2012, the American Culture for Therapeutic Radiation Oncology released an proof-dependent guideline that has a number of recommendations around the management of Mind metastases . Considering the fact that that time, the evidence from medical trials has designed it apparent that the preferred up-entrance radiation treatment option for clients with confined brain metastases is SRS alone. In reality, the American Society for Radiation Oncology (ASTRO) has just lately designed a definitive advice inside their Opt for Correctly marketing campaign and propose not to routinely increase adjuvant WBRT to SRS for confined Mind metastases . Moreover, the recently revised Countrywide Comprehensive Most cancers Community (NCCN) suggestions now assist SRS on your own even past All those sufferers with “limited” metastases, and do not specify an higher limit for the volume of metastases . The latter is ahead imagining; metastasis counting is probably going irrelevant and what issues is normally the suitability in the affected person for SRS [57-fifty nine]. Thus, the onus is no longer on individuals that address with SRS on your own to justify the omission of WBRT; alternatively it truly is on individuals that treat with WBRT in the SRS suitable affected person.

How about THE Affected individual WITH Much more Substantial BRAIN METASTASES?

Former specialized constraints in SRS know-how limited the application of SRS to individuals with just a few brain metastases. Improvements in preset body and frameless SRS systems now allow treatment method of numerous metastases in an individual session [sixty, sixty one].

The initial key possible analyze analyzing SRS on your own for a number of Mind metastases was documented in 2014 . Somewhere around 1200 clients with one-ten SRS qualified metastases ended up dealt with with SRS by yourself working with Gamma Knife technological know-how (Elekta AB, Stockholm, Sweden). The analysis was damaged down in accordance with the 455 people with one metastases, 531 clients with 2 to 4 metastases and 208 with five to ten metastases. Survival, distant Mind relapse, and native Management premiums weren't drastically diverse in patients with five to ten metastases as opposed to 2 to 4 metastases. These success are of big importance because they problem the dogma that sufferers with over four metastases will not likely get pleasure from SRS by yourself on account of shortened survival and will inevitably are unsuccessful somewhere else within the Mind. For that reason, this trial presents proof to help SRS alone in good KPS clients with around 10 metastases, presented the individual tumor quantity is no more than ten mL and < 3 cm in longest diameter, and the total cumulative quantity of all tumors within the Mind is ≤15 mL. Several randomized trials are now evaluating WBRT by itself compared to SRS by itself in equivalent people, and in development is often a trial analyzing SRS on your own as opposed to WBRT furthermore SRS Improve in patients with 10 to twenty metastases.

Specific THERAPIES Together WITH BRAIN RADIATION

When compared to standard chemotherapy, numerous qualified agents have increased penetration in the blood-brain barrier and produce reaction from the Mind. Extraordinary advancements in sickness control are increasingly being observed even for histologies like melanoma that were Beforehand thought of don't just radioresistant but chemoresistant. Desk two [63-75] summarizes selected clinical trials evaluating the efficacy of targeted therapies alone or together with radiation therapy in the remedy of brain metastases. While, with specific therapies alone some impressive reaction premiums are noticed, progression-free of charge-survival (PFS) prices are often brief (< eight months). These success aren't as well dissimilar from what continues to be achieved with WBRT by itself [33, 53]. The exception is in EGFR mutant non-little cell lung cancers handled with a tyrosine kinase inhibitor. Within the review by Wu et al. by way of example, the median PFS was >fifteen months in EGFR mutant tumours handled with erlotinib.

Table two. Summary of picked trials of focused therapy by yourself or in combination with brain radiation for the remedy of brain metastases.

PFS: progression no cost survival, nPFS: neurologic development free of charge survival, OS: overall survival, NSCLC: non-smaller cell lung most cancers, EGFR: epidermal progress aspect receptor, WBRT: full brain radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: months, NS: not substantial, NR: not recorded, NA: not relevant

Handful of trials have combined specific therapies with radiation, and they're also summarized in Table 2. Whilst, randomized evidence remains lacking, there is suggestion from retrospective facts that the combination may well bring on improved outcomes. From the retrospective Investigation of the prospective cohort of patients handled with SRS for melanoma Mind metastases, the team that received ipilimumab experienced a considerably for a longer period median survival (21.3 vs four.nine months) . Nevertheless, caution has to be exercised as concurrent qualified therapy and radiation treatment method may not be as innocuous as Earlier believed. The RCT evaluating SRS with WBRT on your own, compared to together with erlotinib or temozlomide, documented noticeably higher Quality three to 5 toxicity fees in the combination arm; a lot more importantly, survival was worse even though it didn't arrive at statistical importance . A significant limitation of this analyze was that the focused therapy wasn't biomarker-pushed and may in part account for that bad survival noticed. Warning also must be taken as There may be proof that brain metastases and primary tumors could harbor distinctive genetic alterations. In a single examine of 86 matched brain metastases and primary tumors, clinically useful alterations in 53% of brain metastases were not detected in the principal tumor .

The emerging proof implies that targeted therapies will Enjoy a big position from the cure of Mind metastases. We postulate that although qualified brokers will not be powerful in controlling gross illness within the brain, They could be productive in taking care of micro-metastatic disease inside the brain. Hence, a reasonable strategy could possibly be to combine qualified therapies with SRS by yourself, overcoming the limitation of SRS in addressing micrometastatic sickness from the brain and leading to much less distant brain failures. The following several years will produce interesting info as there are a number of trials in progress employing this system.

Improvements IN SRS - INDICATIONS AND APPLICATIONS

As tumors get greater, SRS dosing is counter-intuitively decreased with regard to tumor Manage, to take care of security to the conventional Mind tissue; in any other case, the chance of radiation necrosis becomes prohibitive . Due to this fact, tumors better than 4 cm have ordinarily been excluded from solitary fraction SRS. In case the tumors are non-operable, then these clients happen to be treated with WBRT Irrespective of its inadequate regional Handle. The advent of non-invasive head immobilization equipment, on-board picture-direction systems and Sophisticated radiation supply software package has lead to the apply of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, 78]. Essentially by fractionating, the protection profile with regard to the normal brain tissue toxicity is enhanced, and the entire tumor dose can be escalated these that doses like 24Gy in 3 fractions and thirty-40Gy in five fractions are now common. 1 appealing retrospective collection noted better rates of Handle and decrease premiums of toxicities with hypofractionated SRT (36Gy in six fractions) in comparison with solitary fraction SRS . Having said that, this practice remains in its infancy and we are needing a RCT to ascertain if single fraction SRS should be reserved only for modest metastases (e.g. one-two centimeters), as the info suggest worse community control for greater tumors [eighty, eighty one]. Determine one is an example of the efficacy of hypofractionated SRT in a sizable tumor. This affected person might have normally been excluded from one portion SRS and taken care of with WBRT upfront (plus or minus a SRS boost), or operated upon.

A. MRI of 3.6cm right cerebellar metastases from lung cancer. B. Highly conformal therapy strategy Together with the one hundred% (inexperienced line) and 80% (blue line) isodose lines wrapping tightly around the gross tumour (red colorwash), and planning goal quantity (orange colorwash). The brainstem (blue colorwash) is spared from large dose. (B) MRI 2 months submit completion of radiation (30Gy in five fractions). C. Complete resolution of the tumour at one 12 months.

In put up-operative sufferers, the follow of routinely managing with WBRT is usually becoming out-of-date. There exists escalating usage of SRS to your post-operative surgical cavity as a method to spare sufferers from your adverse effects of WBRT and to further improve regional Handle [82-ninety three]. With the Sunnybrook Odette Cancer Centre, Now we have adopted hypofractionated SRT as our regular of care, providing thirty-35Gy in 5 fractions to the article-operative tumor bed . Fractionation has the advantage of minimizing the adverse effects to the conventional tissues, given that the targets are typically huge and irregularly formed. Our First outcomes have revealed one calendar year nearby Command premiums of ∼80% in individuals which have either recurred and re-operated on right after former WBRT, or in sufferers without having prior background of WBRT and operated on. There's an ongoing review analyzing put up-surgical cavity single fraction SRS on your own versus WBRT and could be a practice-defining review .

Over the past many many years, medical trials have knowledgeable us about the right management of individuals with Mind metastases. In the beginning, SRS was deemed an adjunct to WBRT in chosen people presenting having a constrained range of Mind metastases. Nevertheless, the position of WBRT has considering the fact that been questioned as We have now realized of its probable to adversely impact QOL and neurocognition. Due to this fact, SRS by itself has emerged as The existing standard of care with Degree 1 proof to guidance its observe. Present analysis is focused on the evaluation of broader programs of SRS to many scientific predicaments which were customarily thought of complete indications for WBRT. For example, SRS by itself is currently remaining evaluated during the treatment of five or maybe more Mind metastases, and in post-operative patients. A new period of trials is likewise rising investigating the affect of focused therapies concurrent with SRS.

Clinical trials in individuals with Mind metastases are A serious challenge as summarized by the recent experiences within the Reaction Assessment in Neuro-Oncology (RANO) brain metastases team [95, 96]. They endorse for demo design and style and response evaluation that trials be tumor or biomarker certain, that assessment be based on distinction-Improved MRI, that baseline and recurring neurocognitive and QOL tests be done with validated and sensitive devices, that stratification be determined by additional-cranial illness position, and that appropriate timing be viewed as regarding endpoint tests. In the long run, the oncology Neighborhood has regarded that the development of brain metastases is no more the terminal oncologic occasion of your previous.

CONFLICTS OF INTEREST, Money DISCLOSURES

Dr. Arjun Sahgal has acquired honorarium from former 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.

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