Reliable Direction by SRS Financials

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Stereotactic radiosurgery SRS Financials is an established non-invasive ablative therapy for brain metastases. Early medical trials with SRS proved that tumor control fees are excellent to whole Mind radiotherapy (WBRT) by itself. Therefore, WBRT additionally SRS was broadly adopted for people having a restricted variety of brain metastases (“confined variety” customarily usually means 1-4). Subsequent trials centered on answering no matter if WBRT upfront was essential in the least. Determined by current randomized managed trials (RCTs) and meta-analyses comparing SRS on your own to SRS moreover WBRT, adjuvant WBRT brings about greater intracranial Management; on the other hand, at the expense of neurocognitive functioning and quality of life. These adverse consequences of WBRT could also negatively impact on survival in youthful patients. Determined by the final results of those research, cure has shifted to SRS by itself in sufferers having a limited number of metastases. On top of that, RCTs are analyzing the purpose of SRS alone in patients with >four Mind metastases. New developments in SRS include fractionated SRS for giant tumors and The combination of SRS with specific systemic therapies that cross the blood Mind barrier and/or stimulate an immune response. We existing On this assessment the current high level proof and rationale supporting SRS as the standard of look after clients with limited brain metastases, and rising purposes of SRS.

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

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

Even though the role of neurosurgery had been founded inside the nineteen nineties as a means to achieve neighborhood Command and extend survival, it was reserved for that minority of patients presenting with an individual metastasis and no other ailment beyond the Mind [4-seven]. Nevertheless lacking was a focal ablative non-invasive remedy that might be used competently to your much broader population of patients with brain metastases. This established the phase for the development of stereotactic radiosurgery (SRS). SRS is often a focused ablative radiation cure delivered with sub-millimeter precision to the tumor localized in a few-Proportions in one-five fractions.

The focus of the overview would be to summarize The existing large amount evidence to make clear the role of SRS as exceptional administration for clients presenting with confined Mind metastases. Furthermore, we provide an summary of the emerging apps of SRS mainly because it carries on to evolve right into a treatment method alternate to WBRT, With all the intent To maximise neurcognitive functionality and quality of life (QOL).

PATHOPHYSIOLOGY OF Mind METASTASES

Circulating tumor cells (CTCs) can disseminate from the Principal tumor mass to kind distant colonies as a result of implantation at an ectopic site, such as the brain [eight-10]. To do so involves CTCs to arrest in the circulation, extravasate from the bloodstream or lymphatics into the brain, and endure and proliferate [eleven-thirteen]. The whole process of metastatic colonization involves a immediate conversation of CTCs with endothelial cells and astrocytes while in the Mind microenvironment. As an example, CTCs which have arrested inside the capillary bed immediate neighborhood endothelial cells to remodel the adjacent atmosphere to market tumour cell advancement and invasion [14-sixteen]. Even further, metastatic tumour cells recruit systemic stromal cells, for instance fibroblasts, to aid with early colonization , and co-choose neighborhood stromal cells, such as reactive astrocytes and microglia, to promote tissue invasion [15, 18, 19]. Astrocytes inside the tumour microenvironment may Perform a role in shielding tumour cells from chemotherapy-induced cytotoxicity, by way of a nonetheless to be defined mechanism demanding mobile-cell Get in touch with [twenty, 21]. Tumour cells, by way of release of migration inhibitory variable, interleukin-eight, and plasminogen activator inhibitor 1, induce astrocyte activation and modify the inflammatory milieu to enhance tumor-mobile proliferation in vitro [22-24]. These molecular procedures stand for novel and understudied feasible therapeutic targets for the treatment of intracranial metastatic condition.

SRS was in the beginning a very resource intensive therapy offered only at specialized facilities and indicated just for metastatic people with a great everyday living expectancy. The problem lay in prognosticating individuals properly and Therefore the Radiation Therapy Oncology Team (RTOG) recursive partitioning Investigation (RPA) [28, 29] was designed. Determined by the patient's Karnofsky Functionality Position (KPS), age, position of the main tumor and existence of extracranial ailment, sufferers were grouped into class 1, 2 or 3 with corresponding median survivals of seven.one, 4.2 and a pair of.3 months, respectively. Whilst A serious advancement at enough time, the RPA is now deemed extremely simplistic as existing oncologic conclusion generating is far more complicated incorporating molecular, histological, scientific and radiographic sickness attributes. You will discover now much more complex classification resources, such as the diagnosis-specific graded prognostic assessment (DS-GPA). This technique presents histology-certain estimates of survival and can individual, as an example, the most favorable breast cancer individuals using an envisioned survival of 25 months (excellent KPS and luminal B form breast most cancers) through the the very least favorable sufferers with the expected survival of three months (very poor KPS and basal-like breast most cancers) . Despite developments in prognostication of people with brain metastases, medical professionals remain mainly not able to precisely forecast lengthy-expression survivors. A analyze asking expert medical professionals to estimate survival of a one hundred fifty people with information about most cancers kind, variety of Mind metastases, neurological presentation, additional-cranial ailment standing, KPS, RPA class, prior entire-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that over forty five% of predictions had been off by more than six months and 18% were being off by in excess of twelve months . More improvements in prognostic exams like the “liquid biopsy” (a non-invasive blood exam that could detect tumor DNA or RNA fragments or CTCs) are required As well as in progress . These combine Sophisticated patient and tumor precise genomic data in the equation, as a way to realize individualized survival predictions.

Surgery proceeds to generally be an essential therapy option for individuals with minimal brain metastases. It can be indicated when metastases are significant (>three-four cm), or each time a pathologic prognosis is required. Moreover, medical procedures is favored while in the presence of significant edema demanding extended high dose dexamethasone, or to probably reverse neurological deficits. Normally, The present evidence indicates which the efficacy of SRS is adequate to attain sturdy regional Manage that may be similar to operation. Although there are no RCTs immediately comparing the two, various trials have been described comparing SRS to SRS with WBRT (Desk one), and is also A significant concentration of this evaluation.

HR: hazard ratio, WHO: entire world health Business, KPS: Karnofsky overall performance status, WBRT: complete brain radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not major, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Mastering Test revised.

Patients inside the observation group experienced either surgical procedure on your own or SRS by itself. Purposeful end result wasn't analyzed separately by surgical treatment or SRS on your own.

The main RCTs evaluating SRS mimicked the look in the Original surgical scientific tests for Mind metastases, and evaluated the addition of SRS to WBRT [33, 34]. These research confirmed that SRS improved nearby Regulate, and a survival gain in picked sufferers with only one brain metastasis was proven. These trials had been effective in shifting the paradigm from WBRT on your own to WBRT in addition SRS for individuals presenting with constrained Mind metastases and a very good performance status.

Another number of medical trials were meant to remedy if WBRT was in any way essential, and in contrast SRS alone to SRS with adjuvant WBRT. Three RCTs are already reported in patients presenting with around 4 metastases [35-37] and also a forth in summary sort . Aoyama et al. documented the very first RCT, randomizing 132 clients to SRS alone (65 people) or WBRT additionally SRS (sixty seven patients). The principal endpoint was brain tumor recurrence. Although the one-calendar year regional control amount was significant with SRS alone at seventy three%, extra community Regulate with adjuvant WBRT at 89%, was observed. Also, adjuvant WBRT reduced the speed of distant intra-cranial relapse at one yr from sixty four% to forty two%. Nevertheless, these gains in intra-cranial Handle didn't translate into a benefit with regard to cognition, according to Mini-Psychological Position Exam (MMSE), nor survival. Also, sufferers experienced higher prices of necrosis and leukoencephalopathy in the WBRT arm. The trial was Hence effective in providing the first level 1 proof to clarify the relative impression of SRS on your own versus SRS with WBRT.

In lieu of the traditional endpoint of survival or intra-cranial Management, Chang et al. took a unique tactic and evaluated neurocognition as the primary endpoint. Importantly, the validated Hopkins Verbal Discovering Examination-Revised (HVLT-R) evaluation Resource, was accustomed to measure neurocognitive working rather than the MMSE which isn't a sensitive check for neurocognition . Fifty-8 sufferers have been randomized to SRS by itself (n = thirty) or WBRT furthermore SRS (n = 28). Early halting regulations were invoked at the interim Assessment, as well as the examine concluded that SRS on your own was favored with respect into the chance of neurocognitive drop at 4 months submit-remedy. This reward was understood despite the 1 12 months community control and distant Mind Management prices favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial control results have been in keeping with the outcome in the Aoyama analyze, but what was not anticipated was the survival advantage observed during the SRS on your own arm. The median survival was 15 months during the SRS on your own arm and six months from the SRS with WBRT arm (p = 0.003). This survival outcome caused the trial to undergo appreciable scrutiny with many arguing which the survival benefit for SRS alone was a result of imbalances concerning The 2 arms, as more clients addressed with SRS in addition WBRT experienced higher added-cranial (additional liver and adrenal metastases) and intracranial disorder (greater volume of Mind metastases) .

The ecu Group for Study and Cure of Most cancers (EORTC) also took a special method with their Most important endpoint focusing on practical independence . They used, nonetheless, the more clinically acquainted Earth Overall health Group (WHO) effectiveness position (PS) scale, and measured some time to WHO PS deterioration to in excess of 2. This RCT concluded the addition of WBRT did not improve the median length of purposeful independence (SRS alone: ten.0 months vs SRS plus WBRT: 9.5 months). The secondary outcome of QOL, measured Along with the validated EORTC-QLQC30 tool, was noticed to become worse in individuals who obtained WBRT in various QOL domains . Importantly, these results have been noticed Irrespective of adjuvant WBRT cutting down the 2-yr community failure fee (31% to 19%), distant brain failure (48% to 33%), and the need for salvage therapies (fifty one% vs. 16%). No considerable distinctions in survival have been observed albeit the trial wasn't driven to address survival.

These four trials have established the role of SRS alone as the typical of treatment in people with a confined number of brain metastases, but they have not been designed to Assess the impact of WBRT on General survival.

The inclusion conditions through the RCTs assessing SRS alone to SRS moreover WBRT were being comparable (Table one), nevertheless, the key endpoints were being fully diverse, and no demo was meant to Examine Total survival. To raised make clear the outcomes of local control, distant brain Manage and survival, a meta-Evaluation (MAL) was carried out by Tsao, Xu and Sahgal in 2012 . They noted hazard ratios for local Manage and distant Mind Regulate favoring adjuvant WBRT at 2.61 and 2.15, respectively, but ended up unable to combine the survival benefits as a result of constraints in just how the info have been documented. Sahgal et al. then executed an individual affected person information (IPD) MAL of precisely the same RCTs aimed at evaluating procedure consequences on survival, and carry out sub-group analyses . With regard to overall survival, a cure effect was noticed favoring SRS by itself in patients ≤50 several years. In more mature sufferers, no survival drawback was observed with SRS alone. With regard to distant brain Management, a procedure result was also noticed with hazard reductions in the event of latest brain metastases in older clients taken care of with WBRT, but no reward in the youthful clients (≤fifty a long time) taken care of with WBRT. As anticipated, local Manage was enhanced with additional WBRT in all age teams. The concordance concerning a survival detriment and deficiency of reward in distant brain Regulate Even with remedy with WBRT, during the young sufferers, led the authors to hypothesize that publicity towards the recognised harms of WBRT (talked about intimately under) might negatively impact patient survival. This hypothesis is provocative, and stays to become validated.

By far the most convincing demo style and design to confirm the adverse effects of WBRT is always to randomize patients without having visualized Mind metastases to observation or WBRT. This has been done in reports assessing prophylactic cranial irradiation (PCI) in equally small mobile lung cancer (SCLC) [forty four, 45] and non-compact mobile lung most cancers (NSCLC) [forty six, forty seven]. PCI, not dissimilar towards the addition of WBRT to SRS, is proven to cut back the potential risk of intra-cranial relapse. Nonetheless, this achieve arrives on the expenditure of the detrimental effect on QOL. Such as, significant boosts in tiredness, urge for food loss, nausea and vomiting and leg weak spot ended up observed in patients with intensive stage SCLC at six and twelve weeks publish PCI . Also, in domestically Highly developed NSCLC individuals, a increased decline in HVLT-R measures of quick and delayed remember were observed even nearly 1 12 months submit-PCI . With respect to for a longer time-term adverse effects of WBRT, a devastating consequence may be the development of leukoencephalopathy. In fact, radiation-induced dementia charges have been reported to be as substantial as eleven% in long-term Mind metastases survivors (>12 months) immediately after WBRT , and claimed being bigger in clients dealt with with WBRT and SRS versus SRS alone [35, 50].

Extreme N-methyl-D-aspartate (NMDA) receptor stimulation, similar to the pathophysiology inherent to Parkinson's dementia , continues to be postulated as a person mechanism conveying the adverse neurocognitive effects of WBRT. To be a strategy to mitigate the danger, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a significant randomized placebo controlled demo involving 554 sufferers. At 24 months, sixty four% of people with no memantine and fifty four% with memantine had cognitive operate failure based upon evaluation With all the HVLT-R. Although the Major endpoint didn't arrive at significance due to higher attrition level, there was a solid craze (p = 0.059) supporting memantine therapy. Investigation of secondary endpoints confirmed that memantine considerably extended enough time to cognitive drop and yielded superior benefits for executive operate, processing velocity and delayed recognition at 24 weeks. Eventually, these info demonstrate the majority of sufferers put up with cognitive dysfunction with WBRT, and that pharmacologic strategies to mitigate the danger by focusing on comparable pathways linked to Parkinson's dementia could possibly be worthy of additional investigation.

Further more insight into WBRTs’ mechanism of damage has originate from a current Period two trial analyzing hippocampal avoidance WBRT (HA-WBRT). Complex contemporary radiation technological know-how was applied to limit dose exposure to your hippocampus to not more than 80% of your prescribed 30Gy in ten fractions . This non-randomized phase two demo measured neurocognitive purpose utilizing the HVLT-R, and as opposed results to historic controls handled with typical WBRT from a RTOG trial databases. HA-WBRT resulted in a very seven% decrease while in the necessarily mean relative HVLT-R delayed remember, which was considerably lower as opposed to 30% drop received from historic controls. Whilst this analyze is encouraging with regard to limiting toxicity from WBRT, a randomized trial is required to completely recognize the therapeutic benefit in this technologically complex kind of WBRT.

In 2012, the American Modern society for Therapeutic Radiation Oncology revealed an evidence-dependent guideline that has a number of suggestions on the management of Mind metastases . Given that that time, the proof from clinical trials has manufactured it crystal clear that the preferred up-front radiation treatment method choice for sufferers with confined Mind metastases is SRS alone. In truth, the American Society for Radiation Oncology (ASTRO) has lately produced a definitive advice inside their Choose Correctly campaign and recommend to not routinely add adjuvant WBRT to SRS for minimal Mind metastases . Also, the not too long ago revised Countrywide Thorough Cancer Community (NCCN) tips now aid SRS on your own even further than Individuals individuals with “limited” metastases, and don't specify an higher Restrict for the volume of metastases . The latter is ahead considering; metastasis counting is likely irrelevant and what issues is if not the suitability of your individual for SRS [57-59]. Hence, the onus is now not on people who handle with SRS alone to justify the omission of WBRT; rather it's on those that take care of with WBRT within a SRS acceptable affected individual.

WHAT ABOUT THE Individual WITH Extra Substantial Mind METASTASES?

Previous complex limits in SRS technologies restricted the applying of SRS to clients with only a few Mind metastases. Developments in fastened frame and frameless SRS technologies now let procedure of various metastases in a single session [sixty, sixty one].

The first key prospective examine evaluating SRS by yourself for a number of brain metastases was noted in 2014 . Somewhere around 1200 patients with one-10 SRS eligible metastases ended up handled with SRS by yourself utilizing Gamma Knife engineering (Elekta AB, Stockholm, Sweden). The Assessment was broken down according to the 455 clients with one metastases, 531 clients with two to four metastases and 208 with 5 to ten metastases. Survival, distant brain relapse, and native Handle costs weren't appreciably unique in patients with five to 10 metastases vs . 2 to four metastases. These results are of main significance since they challenge the dogma that patients with a lot more than four metastases is not going to take advantage of SRS by itself as a result of shortened survival and will inevitably fall short somewhere else while in the brain. Hence, this trial offers evidence to assistance SRS by yourself in superior KPS people with around ten metastases, offered the individual tumor volume is no more than 10 mL and < 3 cm in longest diameter, and the full cumulative volume of all tumors within the Mind is ≤fifteen mL. Several randomized trials are at the moment evaluating WBRT by yourself compared to SRS by yourself in very similar clients, and in growth is a trial evaluating SRS by yourself versus WBRT as well as SRS Improve in individuals with ten to 20 metastases.

Specific THERAPIES IN COMBINATION WITH BRAIN RADIATION

Compared to common chemotherapy, many qualified agents have greater penetration with the blood-Mind barrier and generate response from the Mind. Extraordinary improvements in ailment control are increasingly being observed even for histologies like melanoma that were Earlier viewed as not only radioresistant but chemoresistant. Table two [63-seventy five] summarizes picked medical trials analyzing the efficacy of specific therapies alone or together with radiation therapy inside the cure of brain metastases. Despite the fact that, with focused therapies alone some amazing reaction charges are observed, development-free of charge-survival (PFS) fees are frequently brief (< eight months). These outcomes are certainly not too dissimilar from what is attained with WBRT alone [33, fifty three]. The exception is in EGFR mutant non-tiny mobile lung cancers taken care of with a tyrosine kinase inhibitor. In the review by Wu et al. by way of example, the median PFS was >fifteen months in EGFR mutant tumours dealt with with erlotinib.

Table two. Summary of picked trials of focused therapy by itself or in combination with brain radiation to the remedy of Mind metastases.

PFS: development free of charge survival, nPFS: neurologic progression free of charge survival, OS: General survival, NSCLC: non-compact mobile lung cancer, EGFR: epidermal advancement factor receptor, WBRT: entire Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not substantial, NR: not recorded, NA: not applicable

Couple of trials have blended focused therapies with radiation, and these are also summarized in Desk two. While, randomized evidence remains to be missing, There may be suggestion from retrospective knowledge that the combination may well result in enhanced results. From the retrospective analysis of the prospective cohort of individuals handled with SRS for melanoma Mind metastases, the group that gained ipilimumab had a appreciably for a longer period median survival (21.three vs 4.9 months) . Nonetheless, warning has to be exercised as concurrent focused therapy and radiation treatment method might not be as innocuous as previously imagined. The RCT analyzing SRS with WBRT alone, versus together with erlotinib or temozlomide, noted drastically bigger Grade 3 to 5 toxicity fees in the combination arm; additional importantly, survival was even worse although it didn't attain statistical significance . A substantial limitation of this study was the focused therapy wasn't biomarker-pushed and may partially account with the very poor survival observed. Caution also needs to be taken as There's proof that Mind metastases and primary tumors might harbor unique genetic alterations. In one examine of 86 matched brain metastases and primary tumors, clinically informative alterations in 53% of brain metastases weren't detected in the first tumor .

The rising evidence indicates that specific therapies will Enjoy an important role in the remedy of Mind metastases. We postulate that Even though qualified agents might not be efficient in managing gross condition from the Mind, They might be helpful in taking care of micro-metastatic ailment while in the brain. Consequently, a reasonable strategy may very well be to mix targeted therapies with SRS by itself, conquering the limitation of SRS in addressing micrometastatic condition during the Mind and resulting in fewer distant brain failures. Another couple of years will yield exciting information as there are a number of trials in development using this strategy.

Improvements IN SRS - INDICATIONS AND Apps

As tumors get much larger, SRS dosing is counter-intuitively reduced with regard to tumor Management, to maintain basic safety to the conventional brain tissue; or else, the potential risk of radiation necrosis will become prohibitive . Therefore, tumors greater than four cm have generally been excluded from single fraction SRS. In the event the tumors are non-operable, then these people have been handled with WBRT In spite of its weak community control. The appearance of non-invasive head immobilization products, on-board graphic-steering systems and State-of-the-art radiation delivery program has result in the apply of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, 78]. Essentially by fractionating, the safety profile with regard to the normal Mind tissue toxicity is improved, and the total tumor dose could be escalated this sort of that doses like 24Gy in three fractions and thirty-40Gy in five fractions are actually commonplace. A person exciting retrospective sequence claimed higher prices of Management and lessen prices of toxicities with hypofractionated SRT (36Gy in 6 fractions) when compared to solitary fraction SRS . Nevertheless, this practice is still in its infancy and we've been in need of a RCT to determine whether one portion SRS must be reserved just for smaller metastases (e.g. 1-two centimeters), as the data recommend even worse regional Manage for much larger tumors [80, 81]. Determine one is undoubtedly an illustration of the efficacy of hypofractionated SRT in a sizable tumor. This client would have usually been excluded from solitary portion SRS and addressed with WBRT upfront (additionally or minus a SRS Raise), or operated upon.

A. MRI of 3.6cm ideal cerebellar metastases from lung cancer. B. Extremely conformal remedy prepare Using the 100% (eco-friendly line) and eighty% (blue line) isodose strains wrapping tightly throughout the gross tumour (pink colorwash), and setting up target volume (orange colorwash). The brainstem (blue colorwash) is spared from large dose. (B) MRI 2 months article completion of radiation (30Gy in 5 fractions). C. Total resolution in the tumour at one calendar year.

In publish-operative sufferers, the practice of routinely dealing with with WBRT is also starting to be outdated. There exists growing utilization of SRS for the article-operative surgical cavity as a way to spare individuals from your adverse consequences of WBRT and to further improve neighborhood Manage [eighty two-ninety three]. Within the Sunnybrook Odette Cancer Centre, We have now adopted hypofractionated SRT as our normal of treatment, delivering 30-35Gy in five fractions to your write-up-operative tumor bed . Fractionation has the benefit of minimizing the adverse effects to the conventional tissues, on condition that the targets tend to be significant and irregularly formed. Our Preliminary outcomes have revealed one year nearby Management charges of ∼80% in individuals which have either recurred and re-operated upon immediately after previous WBRT, or in clients without any prior record of WBRT and operated on. There is an ongoing review analyzing write-up-surgical cavity single fraction SRS alone as opposed to WBRT and could be a practice-defining analyze .

Over the past many many years, medical trials have informed us about the suitable administration of patients with Mind metastases. To begin with, SRS was thought of an adjunct to WBRT in selected patients presenting having a confined number of brain metastases. Nonetheless, the function of WBRT has considering the fact that been questioned as We've got figured out of its prospective to adversely have an effect on QOL and neurocognition. Because of this, SRS by yourself has emerged as the current standard of care with Stage one proof to help its practice. Current exploration is focused on the analysis of broader apps of SRS to several clinical circumstances which were ordinarily regarded as complete indications for WBRT. One example is, SRS by yourself is at this time currently being evaluated while in the procedure of 5 or even more brain metastases, and in write-up-operative clients. A different era of trials is additionally emerging investigating the influence of specific therapies concurrent with SRS.

Scientific trials in clients with Mind metastases are a major challenge as summarized with the recent stories from your Reaction Assessment in Neuro-Oncology (RANO) Mind metastases team [95, 96]. They advocate for trial design and response evaluation that trials be tumor or biomarker particular, that assessment be according to distinction-Increased MRI, that baseline and recurring neurocognitive and QOL screening be executed with validated and sensitive instruments, that stratification be determined by added-cranial ailment standing, Which acceptable timing be considered with regards to endpoint tests. In the long run, the oncology Neighborhood has identified that the event of brain metastases is no longer the terminal oncologic function from the past.

CONFLICTS OF Curiosity, Monetary DISCLOSURES

Dr. Arjun Sahgal has been given honorarium from former educational seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also obtained analysis grants from Elekta AB, normally there isn't any conflicts of curiosity to reveal.

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