Dependable Guidance by SRS Financials

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Stereotactic radiosurgery SRS Financials is a longtime non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor Manage charges are outstanding to entire Mind radiotherapy (WBRT) by yourself. Therefore, WBRT in addition SRS was commonly adopted for patients having a minimal variety of Mind metastases (“minimal number” customarily implies 1-4). Subsequent trials focused on answering irrespective of whether WBRT upfront was necessary in any respect. Determined by latest randomized managed trials (RCTs) and meta-analyses evaluating SRS by yourself to SRS in addition WBRT, adjuvant WBRT ends in greater intracranial Regulate; on the other hand, within the expenditure of neurocognitive operating and Standard of living. These adverse consequences of WBRT may also negatively influence on survival in young clients. Determined by the final results of those scientific studies, remedy has shifted to SRS alone in patients which has a minimal variety of metastases. Furthermore, RCTs are evaluating the position of SRS alone in patients with >four brain metastases. New developments in SRS include fractionated SRS for giant tumors and The combination of SRS with targeted systemic therapies that cross the blood Mind barrier and/or stimulate an immune reaction. We current Within this review The existing large level proof and rationale supporting SRS because the conventional of look after sufferers with restricted Mind metastases, and emerging apps of SRS.

Brain metastases are a significant cause of morbidity and mortality in patients with metastatic cancer, with an incidence of up to 65% during the course of illness [1, 2]. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer . Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. The development of brain metastases was viewed as an oncologic terminal event.

As systemic therapies have become more efficacious in patients with metastatic disease, improved survival rates are now being observed. In addition, the patterns of disease progression are shifting such that the incidence of brain metastases is increasing while extra-cranial disease remains controlled. This phenomena is likely a consequence of the central nervous system (CNS) being a sanctuary site from drug penetration. As a result, the management of brain metastases has become a major focus of research, with the intent to improve intra-cerebral control and decrease neurologic deaths.

Although the job of neurosurgery had been founded while in the nineteen nineties as a means to attain neighborhood Manage and prolong survival, it absolutely was reserved for the minority of clients presenting with a single metastasis and no other ailment beyond the brain [four-seven]. Nonetheless missing was a focal ablative non-invasive cure that could be used successfully to your Significantly broader populace of clients with brain metastases. This established the stage for the event of stereotactic radiosurgery (SRS). SRS is a targeted ablative radiation therapy shipped with sub-millimeter precision on the tumor localized in a few-Proportions in 1-5 fractions.

The main focus of this evaluation is usually to summarize The existing higher degree proof to make clear the job of SRS as exceptional management for sufferers presenting with constrained Mind metastases. In addition, we offer an outline of the emerging applications of SRS since it carries on to evolve right into a treatment different to WBRT, with the intent to maximize neurcognitive function and quality of life (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from the Principal tumor mass to sort distant colonies through implantation at an ectopic website, such as the Mind [eight-ten]. To take action necessitates CTCs to arrest throughout the circulation, extravasate within the bloodstream or lymphatics into your Mind, and endure and proliferate [eleven-13]. The process of metastatic colonization requires a immediate conversation of CTCs with endothelial cells and astrocytes during the Mind microenvironment. One example is, CTCs which have arrested inside the capillary bed immediate area endothelial cells to remodel the adjacent environment to market tumour mobile progress and invasion [14-sixteen]. Even further, metastatic tumour cells recruit systemic stromal cells, for instance fibroblasts, to help with early colonization , and co-choose nearby stromal cells, such as reactive astrocytes and microglia, to market tissue invasion [15, eighteen, 19]. Astrocytes in the tumour microenvironment may additionally Perform a job in shielding tumour cells from chemotherapy-induced cytotoxicity, by way of a however to be outlined mechanism demanding cell-mobile Get hold of [20, 21]. Tumour cells, as a result of release of migration inhibitory factor, 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 procedures signify novel and understudied probable therapeutic targets to the therapy of intracranial metastatic sickness.

SRS was originally an exceedingly useful resource intensive therapy available only at specialized facilities and indicated just for metastatic sufferers with a good daily life expectancy. The challenge lay in prognosticating sufferers effectively and Therefore the Radiation Therapy Oncology Team (RTOG) recursive partitioning Evaluation (RPA) [28, 29] was formulated. Dependant on the individual's Karnofsky Performance Status (KPS), age, standing of the first tumor and presence of extracranial ailment, people had been grouped into class one, two or three with corresponding median survivals of 7.1, 4.2 and a couple of.three months, respectively. Even though A serious enhancement at the time, the RPA is now regarded extremely simplistic as current oncologic selection generating is considerably more complicated incorporating molecular, histological, clinical and radiographic ailment features. There are now a lot more innovative classification instruments, including the analysis-unique graded prognostic evaluation (DS-GPA). This method provides histology-specific estimates of survival and can separate, for instance, quite possibly the most favorable breast most cancers people having an envisioned survival of 25 months (superb KPS and luminal B sort breast cancer) in the least favorable people having an envisioned survival of three months (inadequate KPS and basal-like breast cancer) . Regardless of advances in prognostication of patients with Mind metastases, doctors are still largely struggling to correctly predict lengthy-time period survivors. A analyze asking professional physicians to estimate survival of the one hundred fifty patients with specifics of most cancers sort, number of Mind metastases, neurological presentation, added-cranial condition status, KPS, RPA course, prior entire-Mind radiotherapy, and synchronous or metachronous presentation, showed that greater than forty five% of predictions have been off by greater than six months and 18% were being off by a lot more than 12 months . Even further improvements in prognostic tests like the “liquid biopsy” (a non-invasive blood exam which can detect tumor DNA or RNA fragments or CTCs) are essential As well as in growth . These Mix Highly developed individual and tumor specific genomic facts to the equation, so that you can obtain individualized survival predictions.

Operation continues to get an important treatment method option for people with limited Mind metastases. It really is indicated when metastases are huge (>three-four cm), or every time a pathologic analysis is required. In addition, surgical treatment is desired within the presence of considerable edema requiring extended high dose dexamethasone, or to possibly reverse neurological deficits. Or else, the current proof suggests which the efficacy of SRS is ample to obtain strong regional control that is certainly comparable to surgical procedure. Despite the fact that there aren't any RCTs right evaluating the two, various trials happen to be noted evaluating SRS to SRS with WBRT (Table 1), and is particularly An important concentrate of the review.

HR: hazard ratio, WHO: world wellness Group, KPS: Karnofsky general performance position, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not significant, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Understanding Check revised.

Clients during the observation team had both surgery by yourself or SRS alone. Functional consequence was not analyzed individually by medical procedures or SRS on your own.

The 1st RCTs evaluating SRS mimicked the design of the First surgical scientific studies for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These reports confirmed that SRS enhanced nearby Command, plus a survival gain in picked clients with only one Mind metastasis was shown. These trials ended up thriving in shifting the paradigm from WBRT on your own to WBRT in addition SRS for clients presenting with minimal brain metastases and a great effectiveness position.

The next series of clinical trials have been intended to response if WBRT was in any respect necessary, and in comparison SRS alone to SRS with adjuvant WBRT. A few RCTs have already been reported in clients presenting with around 4 metastases [35-37] and also a forth in summary form . Aoyama et al. noted the very first RCT, randomizing 132 clients to SRS by itself (sixty five people) or WBRT as well as SRS (sixty seven individuals). The main endpoint was Mind tumor recurrence. Although the one-yr regional Handle rate was substantial with SRS by yourself at seventy three%, further local Regulate with adjuvant WBRT at 89%, was observed. On top of that, adjuvant WBRT reduced the rate of distant intra-cranial relapse at one calendar year from sixty four% to forty two%. However, these gains in intra-cranial Command did not translate into an advantage with respect to cognition, according to Mini-Mental Standing Exam (MMSE), nor survival. Moreover, patients experienced bigger charges of necrosis and leukoencephalopathy within the WBRT arm. The demo was As a result successful in furnishing the primary stage one proof to clarify the relative effect of SRS on your own as opposed to SRS with WBRT.

Rather then the normal endpoint of survival or intra-cranial Manage, Chang et al. took a different method and evaluated neurocognition as the principal endpoint. Importantly, the validated Hopkins Verbal Studying Examination-Revised (HVLT-R) assessment Software, was utilized to measure neurocognitive performing versus the MMSE which isn't a delicate examination for neurocognition . Fifty-8 individuals were being randomized to SRS on your own (n = thirty) or WBRT furthermore SRS (n = 28). Early stopping guidelines were invoked at the interim Examination, plus the examine concluded that SRS alone was favored with respect to your chance of neurocognitive decline at 4 months submit-therapy. This gain was realized Regardless of the 1 calendar year neighborhood Manage and distant Mind Handle charges favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial Handle results have been in keeping with the final results within the Aoyama examine, but what wasn't predicted was the survival gain observed from the SRS by yourself arm. The median survival was 15 months from the SRS by itself arm and 6 months while in the SRS with WBRT arm (p = 0.003). This survival consequence brought on the demo to undertake appreciable scrutiny with lots of arguing that the survival advantage for SRS alone was a result of imbalances among The 2 arms, as additional sufferers handled with SRS furthermore WBRT had greater excess-cranial (more liver and adrenal metastases) and intracranial disease (larger volume of brain metastases) .

The ecu Organization for Investigate and Treatment of Most cancers (EORTC) also took a distinct technique with their Principal endpoint focusing on useful independence . They used, having said that, the more clinically acquainted Entire world Wellbeing Firm (WHO) efficiency status (PS) scale, and measured some time to WHO PS deterioration to much more than two. This RCT concluded the addition of WBRT didn't Increase the median duration of functional independence (SRS by itself: ten.0 months vs SRS plus WBRT: 9.5 months). The secondary result of QOL, measured While using the validated EORTC-QLQC30 Device, was noticed being worse in clients who acquired WBRT in various QOL domains . Importantly, these benefits were observed Irrespective of adjuvant WBRT decreasing the two-calendar year local failure fee (31% to 19%), distant brain failure (forty eight% to 33%), and the need for salvage therapies (fifty one% vs. sixteen%). No important variances in survival have been observed albeit the trial wasn't driven to address survival.

These 4 trials have proven the function of SRS alone given that the standard of treatment in sufferers by using a restricted number of Mind metastases, but they've got not been made to evaluate the effects of WBRT on In general survival.

The inclusion conditions across the RCTs evaluating SRS on your own to SRS in addition WBRT ended up equivalent (Desk one), however, the main endpoints have been wholly various, and no trial was intended to Consider Total survival. To raised clarify the results of regional Command, distant brain Management and survival, a meta-Assessment (MAL) was executed by Tsao, Xu and Sahgal in 2012 . They noted hazard ratios for area Management and distant brain Management favoring adjuvant WBRT at two.61 and a couple of.15, respectively, but were being not able to mix the survival benefits due to limitations in the way the information have been noted. Sahgal et al. then carried out an individual affected person info (IPD) MAL of the identical RCTs aimed toward evaluating procedure results on survival, and perform sub-group analyses . With regard to All round survival, a cure influence was observed favoring SRS by itself in sufferers ≤fifty several years. In more mature patients, no survival downside was noticed with SRS alone. With regard to distant Mind Command, a treatment effect was also noticed with threat reductions in the development of new Mind metastases in older individuals taken care of with WBRT, but no gain during the younger clients (≤50 yrs) treated with WBRT. As anticipated, area control was enhanced with additional WBRT in all age groups. The concordance involving a survival detriment and insufficient benefit in distant Mind Handle Regardless of therapy with WBRT, from the more youthful sufferers, led the authors to hypothesize that exposure on the acknowledged harms of WBRT (mentioned in detail underneath) might negatively impact patient survival. This speculation is provocative, and continues to be to generally be validated.

Quite possibly the most convincing trial layout to substantiate the adverse outcomes of WBRT will be to randomize sufferers without visualized Mind metastases to observation or WBRT. This continues to be performed in reports assessing prophylactic cranial irradiation (PCI) in equally modest mobile lung cancer (SCLC) [forty four, forty five] and non-smaller cell lung cancer (NSCLC) [46, forty seven]. PCI, not dissimilar to the addition of WBRT to SRS, has been proven to lower the risk of intra-cranial relapse. However, this acquire will come on the price of the detrimental effect on QOL. By way of example, sizeable improves in fatigue, appetite decline, nausea and vomiting and leg weakness have been noticed in patients with comprehensive stage SCLC at 6 and 12 weeks article PCI . Moreover, in regionally Superior NSCLC patients, a higher decline in HVLT-R measures of quick and delayed recall were noticed even as much as one yr submit-PCI . With respect to for a longer time-expression adverse outcomes of WBRT, a devastating consequence is often the development of leukoencephalopathy. Without a doubt, radiation-induced dementia charges are already described to get as substantial as 11% in very long-phrase brain metastases survivors (>12 months) after WBRT , and reported to become larger in people addressed with WBRT and SRS in contrast to SRS by yourself [35, 50].

Too much N-methyl-D-aspartate (NMDA) receptor stimulation, much like the pathophysiology inherent to Parkinson's dementia , has become postulated as a single mechanism outlining the adverse neurocognitive results of WBRT. Like a technique to mitigate the danger, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a substantial randomized placebo managed demo involving 554 people. At 24 weeks, sixty four% of clients devoid of memantine and fifty four% with memantine experienced cognitive function failure according to assessment With all the HVLT-R. Although the Major endpoint did not arrive at importance due to the substantial attrition level, there was a solid development (p = 0.059) supporting memantine cure. Investigation of secondary endpoints confirmed that memantine drastically prolonged time to cognitive drop and yielded exceptional benefits for government perform, processing velocity and delayed recognition at 24 months. Eventually, these info demonstrate virtually all individuals put up with cognitive dysfunction with WBRT, Which pharmacologic techniques to mitigate the risk by concentrating on equivalent pathways involved in Parkinson's dementia may be deserving of more investigation.

Additional Perception into WBRTs’ mechanism of injury has come from a current Phase two trial evaluating hippocampal avoidance WBRT (HA-WBRT). Refined modern day radiation technologies was placed on limit dose publicity for the hippocampus to no more than eighty% of the prescribed 30Gy in 10 fractions . This non-randomized period two trial calculated neurocognitive perform using the HVLT-R, and compared outcomes to historic controls addressed with typical WBRT from a RTOG demo databases. HA-WBRT resulted within a seven% decline from the indicate relative HVLT-R delayed remember, which was substantially lessen when compared to the 30% decline acquired from historic controls. Though this review is encouraging regarding restricting toxicity from WBRT, a randomized demo is needed to totally comprehend the therapeutic worth During this technologically intricate type of WBRT.

In 2012, the American Modern society for Therapeutic Radiation Oncology published an evidence-based mostly guideline with a series of suggestions over the administration of brain metastases . Considering the fact that that time, the evidence from medical trials has made it distinct that the preferred up-front radiation cure selection for people with restricted brain metastases is SRS on your own. In truth, the American Modern society for Radiation Oncology (ASTRO) has a short while ago made a definitive recommendation in their Select Wisely campaign and suggest to not routinely add adjuvant WBRT to SRS for limited brain metastases . Furthermore, the just lately revised National Thorough Most cancers Community (NCCN) suggestions now aid SRS by itself even further than Those people people with “confined” metastases, and don't specify an higher limit for the number of metastases . The latter is forward thinking; metastasis counting is probably going irrelevant and what issues is normally the suitability of your individual for SRS [57-fifty nine]. Thus, the onus is no longer on people who take care of with SRS alone to justify the omission of WBRT; somewhat it is on individuals who treat with WBRT within a SRS suited client.

WHAT ABOUT THE PATIENT WITH Extra Intensive BRAIN METASTASES?

Previous specialized limitations in SRS technological know-how limited the application of SRS to clients with only a few Mind metastases. Breakthroughs in fixed frame and frameless SRS technologies now permit therapy of various metastases in one session [60, 61].

The initial main possible study analyzing SRS by itself for multiple brain metastases was documented in 2014 . Around 1200 individuals with 1-10 SRS suitable metastases have been addressed with SRS alone making use of Gamma Knife technological innovation (Elekta AB, Stockholm, Sweden). The Investigation was damaged down in accordance with the 455 patients with one metastases, 531 sufferers with 2 to 4 metastases and 208 with 5 to 10 metastases. Survival, distant brain relapse, and local Management fees were not drastically different in individuals with 5 to ten metastases as opposed to two to four metastases. These outcomes are of key importance since they obstacle the dogma that individuals with a lot more than four metastases will likely not gain from SRS by itself due to shortened survival and will inevitably fall short elsewhere inside the brain. For that reason, this demo presents proof to aid SRS by itself in good KPS individuals with around 10 metastases, supplied the individual tumor volume is no more than ten mL and < three cm in longest diameter, and the overall cumulative quantity of all tumors from the Mind is ≤fifteen mL. Various randomized trials are now analyzing WBRT by yourself as opposed to SRS on your own in related clients, As well as in growth is often a demo analyzing SRS by yourself compared to WBRT in addition SRS Enhance in individuals with 10 to twenty metastases.

Specific THERAPIES IN COMBINATION WITH Mind RADIATION

Compared to regular chemotherapy, many focused brokers have better penetration throughout the blood-brain barrier and generate response within the Mind. Remarkable improvements in sickness Regulate are now being noticed even for histologies for instance melanoma that were Beforehand thought of not merely radioresistant but chemoresistant. Table two [63-seventy five] summarizes selected medical trials evaluating the efficacy of qualified therapies on your own or together with radiation therapy inside the treatment of Mind metastases. While, with focused therapies by itself some amazing response costs are noticed, progression-free of charge-survival (PFS) fees usually are brief (< eight months). These results will not be as well dissimilar from what has actually been accomplished with WBRT by yourself [33, fifty three]. The exception is in EGFR mutant non-tiny mobile lung cancers handled that has a tyrosine kinase inhibitor. From the research by Wu et al. one example is, the median PFS was >fifteen months in EGFR mutant tumours handled with erlotinib.

Table 2. Summary of picked trials of qualified therapy alone or in combination with Mind radiation with the therapy of brain metastases.

PFS: progression no cost survival, nPFS: neurologic progression totally free survival, OS: Total survival, NSCLC: non-compact mobile lung most cancers, EGFR: epidermal growth aspect receptor, WBRT: total Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: months, NS: not considerable, NR: not recorded, NA: not applicable

Several trials have combined targeted therapies with radiation, and these are typically also summarized in Desk 2. Despite the fact that, randomized proof is still missing, There is certainly recommendation from retrospective facts that The mix may bring about improved outcomes. Inside the retrospective Examination of the possible cohort of sufferers dealt with with SRS for melanoma Mind metastases, the team that received ipilimumab had a drastically more time median survival (21.three vs 4.9 months) . Having said that, warning really should be exercised as concurrent qualified therapy and radiation treatment might not be as innocuous as Earlier assumed. The RCT assessing SRS with WBRT by itself, versus together with erlotinib or temozlomide, claimed substantially larger Grade 3 to 5 toxicity charges in the combination arm; a lot more importantly, survival was worse even though it didn't attain statistical importance . An important limitation of the research was that the targeted therapy wasn't biomarker-driven and may partially account for that poor survival noticed. Caution also must be taken as There is certainly proof that brain metastases and primary tumors may well harbor distinct genetic alterations. In a single research of 86 matched Mind metastases and first tumors, clinically useful alterations in 53% of brain metastases were not detected in the primary tumor .

The rising evidence implies that specific therapies will Perform an important part in the cure of Mind metastases. We postulate that Whilst qualified brokers may not be productive in controlling gross ailment within the Mind, they may be productive in handling micro-metastatic disorder inside the Mind. For that reason, a logical strategy may be to mix qualified therapies with SRS on your own, conquering the limitation of SRS in addressing micrometastatic condition during the brain and resulting in much less distant Mind failures. The next couple of years will produce exciting info as There are a variety of trials in development utilizing this technique.

INNOVATIONS IN SRS - INDICATIONS AND Apps

As tumors get larger sized, SRS dosing is counter-intuitively lowered with respect to tumor Management, to keep up protection to the traditional Mind tissue; or else, the risk of radiation necrosis gets prohibitive . Subsequently, tumors greater than 4 cm have usually been excluded from single fraction SRS. In the event the tumors are non-operable, then these clients are actually treated with WBRT In spite of its inadequate community Regulate. The appearance of non-invasive head immobilization equipment, on-board graphic-guidance systems and advanced radiation delivery software program has bring about the apply of hypofractionated frameless stereotactic radiotherapy (SRT) [60, 78]. Essentially by fractionating, the security profile with regard to the conventional brain tissue toxicity is improved, and the total tumor dose is usually escalated these types of that doses like 24Gy in three fractions and 30-40Gy in 5 fractions at the moment are common. A single intriguing retrospective series reported bigger fees of Regulate and decrease costs of toxicities with hypofractionated SRT (36Gy in 6 fractions) when compared with one portion SRS . Even so, this apply remains in its infancy and we have been needing a RCT to ascertain whether one portion SRS needs to be reserved just for modest metastases (e.g. 1-two centimeters), as the data counsel worse local Command for more substantial tumors [80, 81]. Determine 1 is an example of the efficacy of hypofractionated SRT in a large tumor. This client would've normally been excluded from single fraction SRS and treated with WBRT upfront (in addition or minus a SRS boost), or operated upon.

A. MRI of 3.6cm appropriate cerebellar metastases from lung cancer. B. Hugely conformal treatment system Using the one hundred% (green line) and 80% (blue line) isodose traces wrapping tightly within the gross tumour (crimson colorwash), and scheduling target volume (orange colorwash). The brainstem (blue colorwash) is spared from superior dose. (B) MRI 2 months put up completion of radiation (30Gy in five fractions). C. Total resolution on the tumour at one year.

In put up-operative clients, the exercise of routinely managing with WBRT is also turning into outdated. There may be increasing use of SRS on the article-operative surgical cavity as a method to spare patients from your adverse outcomes of WBRT and to further improve local Manage [82-93]. On the Sunnybrook Odette Cancer Middle, We now have adopted hypofractionated SRT as our typical of treatment, offering thirty-35Gy in five fractions to your article-operative tumor mattress . Fractionation has the benefit of minimizing the adverse outcomes to the traditional tissues, on condition that the targets are typically massive and irregularly formed. Our Original outcomes have demonstrated 1 calendar year neighborhood control fees of ∼80% in patients who've both recurred and re-operated on soon after previous WBRT, or in sufferers with no prior record of WBRT and operated upon. There's an ongoing research evaluating publish-surgical cavity single portion SRS by yourself compared to WBRT and may be a apply-defining study .

In the last various a long time, clinical trials have educated us about the suitable management of sufferers with brain metastases. Initially, SRS was considered an adjunct to WBRT in chosen individuals presenting having a limited amount of brain metastases. Even so, the function of WBRT has since been questioned as We have now acquired of its possible to adversely have an impact on QOL and neurocognition. As a result, SRS by yourself has emerged as The existing regular of care with Stage one evidence to guidance its follow. Present-day research is focused on the evaluation of broader programs of SRS to quite a few clinical scenarios that were usually considered absolute indications for WBRT. For instance, SRS by yourself is now becoming evaluated while in the treatment method of five or maybe more Mind metastases, As well as in put up-operative clients. A completely new period of trials is likewise rising investigating the impression of qualified therapies concurrent with SRS.

Medical trials in sufferers with brain metastases are a major obstacle as summarized via the new studies through the Response Evaluation in Neuro-Oncology (RANO) brain metastases team [ninety five, 96]. They suggest for demo layout and response assessment that trials be tumor or biomarker specific, that evaluation be according to distinction-enhanced MRI, that baseline and repeated neurocognitive and QOL tests be carried out with validated and delicate devices, that stratification be determined by additional-cranial sickness status, Which ideal timing be deemed with regards to endpoint testing. Eventually, the oncology Group has recognized that the development of Mind metastases is now not the terminal oncologic occasion with the earlier.

CONFLICTS OF INTEREST, Money DISCLOSURES

Dr. Arjun Sahgal has received honorarium from preceding instructional seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also received analysis grants from Elekta AB, if not there are no conflicts of curiosity to disclose.

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