Trustworthy Steering by SRS Financials

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Stereotactic radiosurgery SRS Financials is a longtime non-invasive ablative therapy for brain metastases. Early scientific trials with SRS proved that tumor Handle fees are outstanding to total Mind radiotherapy (WBRT) alone. Due to this fact, WBRT in addition SRS was extensively adopted for patients that has a constrained number of Mind metastases (“restricted number” customarily indicates one-four). Subsequent trials focused on answering regardless of whether WBRT upfront was necessary at all. Based on existing randomized controlled trials (RCTs) and meta-analyses evaluating SRS by yourself to SRS in addition WBRT, adjuvant WBRT ends in better intracranial Regulate; on the other hand, with the cost of neurocognitive functioning and Standard of living. These adverse results of WBRT could also negatively influence on survival in youthful patients. Dependant on the final results of these research, procedure has shifted to SRS on your own in people that has a minimal range of metastases. Furthermore, RCTs are analyzing the part of SRS on your own in patients with >4 brain metastases. New developments in SRS involve fractionated SRS for big tumors and The combination of SRS with specific systemic therapies that cross the blood Mind barrier and/or encourage an immune reaction. We existing in this overview The existing substantial degree evidence and rationale supporting SRS since the typical of look after patients with confined brain metastases, and emerging applications of SRS.

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

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

Even though the purpose of neurosurgery were proven within the 1990s as a method to realize nearby control and lengthen survival, it had been reserved for the minority of people presenting with an individual metastasis and no other sickness outside of the brain [four-7]. Nevertheless missing was a focal ablative non-invasive remedy that might be used proficiently to a Considerably broader population of sufferers with Mind metastases. This set the phase for the development of stereotactic radiosurgery (SRS). SRS is a centered ablative radiation therapy sent with sub-millimeter precision to the tumor localized in a few-dimensions in 1-five fractions.

The focus of this critique is always to summarize The existing high level proof to clarify the part of SRS as exceptional management for individuals presenting with minimal Mind metastases. Furthermore, we provide an outline with the rising applications of SRS because it carries on to evolve right into a cure alternate to WBRT, Along with the intent To maximise neurcognitive function and quality of life (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from a Main tumor mass to type distant colonies by means of implantation at an ectopic web-site, including the Mind [eight-ten]. To take action involves CTCs to arrest throughout the circulation, extravasate within the bloodstream or lymphatics into your Mind, and endure and proliferate [11-13]. The process of metastatic colonization requires a direct interaction of CTCs with endothelial cells and astrocytes in the brain microenvironment. By way of example, CTCs that have arrested inside the capillary bed immediate area endothelial cells to remodel the adjacent ecosystem to market tumour cell development and invasion [14-sixteen]. Further more, metastatic tumour cells recruit systemic stromal cells, like fibroblasts, to aid with early colonization , and co-decide neighborhood stromal cells, including reactive astrocytes and microglia, to promote tissue invasion [fifteen, eighteen, 19]. Astrocytes inside the tumour microenvironment might also play a job in safeguarding tumour cells from chemotherapy-induced cytotoxicity, through a however to become described mechanism demanding cell-mobile Make contact with [20, 21]. Tumour cells, by release of migration inhibitory aspect, interleukin-eight, and plasminogen activator inhibitor one, induce astrocyte activation and modify the inflammatory milieu to enhance tumor-mobile proliferation in vitro [22-24]. These molecular processes characterize novel and understudied achievable therapeutic targets with the treatment method of intracranial metastatic disease.

SRS was in the beginning an exceptionally resource intensive therapy available only at specialized centers and indicated only for metastatic clients with a fantastic life expectancy. The challenge lay in prognosticating patients properly and Consequently the Radiation Therapy Oncology Group (RTOG) recursive partitioning Assessment (RPA) [28, 29] was produced. Dependant on the individual's Karnofsky General performance Status (KPS), age, standing of the key tumor and existence of extracranial condition, sufferers were grouped into class 1, two or three with corresponding median survivals of seven.one, 4.2 and a pair of.three months, respectively. While An important development at time, the RPA is currently regarded overly simplistic as recent oncologic conclusion earning is far more sophisticated incorporating molecular, histological, medical and radiographic ailment properties. There are actually now more refined classification instruments, like the diagnosis-particular graded prognostic assessment (DS-GPA). This system presents histology-particular estimates of survival and can different, such as, the most favorable breast most cancers clients with the expected survival of twenty five months (exceptional KPS and luminal B form breast cancer) in the the very least favorable clients using an expected survival of three months (very poor KPS and basal-like breast most cancers) . Inspite of improvements in prognostication of patients with Mind metastases, physicians remain mostly unable to correctly predict prolonged-term survivors. A analyze asking expert medical professionals to estimate survival of a one hundred fifty patients with information regarding cancer style, variety of Mind metastases, neurological presentation, added-cranial sickness standing, KPS, RPA course, prior entire-Mind radiotherapy, and synchronous or metachronous presentation, showed that in excess of 45% of predictions have been off by a lot more than six months and 18% ended up off by greater than 12 months . Further more improvements in prognostic assessments including the “liquid biopsy” (a non-invasive blood check which will detect tumor DNA or RNA fragments or CTCs) are needed and in growth . These Incorporate Sophisticated individual and tumor distinct genomic details into the equation, as a way to realize individualized survival predictions.

Medical procedures continues to become a vital cure selection for people with confined Mind metastases. It is indicated when metastases are big (>3-4 cm), or any time a pathologic prognosis is required. Moreover, operation is most well-liked in the existence of sizeable edema demanding extended superior dose dexamethasone, or to likely reverse neurological deficits. If not, the current evidence implies which the efficacy of SRS is ample to obtain strong local Command that may be corresponding to operation. While there won't be any RCTs immediately comparing The 2, many trials are actually described evaluating SRS to SRS with WBRT (Table one), and is also A significant concentrate of this assessment.

HR: hazard ratio, WHO: globe health Group, KPS: Karnofsky overall performance position, WBRT: total Mind radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not major, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Learning Take a look at revised.

Sufferers while in the observation group experienced either surgical procedure alone or SRS by yourself. Functional result was not analyzed independently by surgical treatment or SRS by itself.

The primary RCTs analyzing SRS mimicked the design of your Original surgical scientific tests for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific tests verified that SRS improved local Manage, along with a survival edge in picked individuals with one Mind metastasis was proven. These trials were being productive in shifting the paradigm from WBRT by yourself to WBRT furthermore SRS for sufferers presenting with confined brain metastases and an excellent performance status.

The subsequent number of scientific trials were being meant to answer if WBRT was in any way vital, and in contrast SRS on your own to SRS with adjuvant WBRT. 3 RCTs are reported in individuals presenting with as many as 4 metastases [35-37] plus a forth in summary variety . Aoyama et al. noted the primary RCT, randomizing 132 clients to SRS by itself (sixty five clients) or WBRT as well as SRS (67 clients). The primary endpoint was brain tumor recurrence. Although the 1-year nearby Manage charge was significant with SRS by yourself at seventy three%, more neighborhood Manage with adjuvant WBRT at 89%, was noticed. Additionally, adjuvant WBRT decreased the speed of distant intra-cranial relapse at one calendar year from sixty four% to forty two%. On the other hand, these gains in intra-cranial Manage did not translate into an advantage with regard to cognition, dependant on Mini-Psychological Position Examination (MMSE), nor survival. In addition, sufferers had higher rates of necrosis and leukoencephalopathy in the WBRT arm. The demo was So prosperous in delivering the primary degree one proof to make clear the relative influence of SRS by itself vs . SRS with WBRT.

As an alternative to the standard endpoint of survival or intra-cranial control, Chang et al. took another tactic and evaluated neurocognition as the principal endpoint. Importantly, the validated Hopkins Verbal Understanding Test-Revised (HVLT-R) evaluation Device, was used to evaluate neurocognitive working instead of the MMSE which isn't a sensitive check for neurocognition . Fifty-8 patients were randomized to SRS by itself (n = 30) or WBRT moreover SRS (n = 28). Early stopping rules ended up invoked on the interim Assessment, plus the research concluded that SRS by yourself was favored with respect to your probability of neurocognitive drop at 4 months put up-treatment method. This benefit was recognized Regardless of the 1 12 months neighborhood Command and distant brain Command charges favoring adjuvant WBRT with complete gains of 33% and 27%, respectively. The intracranial Handle results were In line with the effects from your Aoyama review, but what was not anticipated was the survival edge noticed inside the SRS by itself arm. The median survival was 15 months inside the SRS by itself arm and 6 months inside the SRS with WBRT arm (p = 0.003). This survival result caused the trial to bear substantial scrutiny with many arguing that the survival benefit for SRS by yourself was a results of imbalances in between the two arms, as much more clients addressed with SRS furthermore WBRT had increased more-cranial (more liver and adrenal metastases) and intracranial ailment (larger sized quantity of Mind metastases) .

The European Organization for Analysis and Treatment method of Most cancers (EORTC) also took another approach with their Main endpoint concentrating on practical independence . They used, having said that, the greater clinically common Environment Health and fitness Organization (WHO) overall performance status (PS) scale, and measured the time to WHO PS deterioration to greater than 2. This RCT concluded that the addition of WBRT didn't Increase the median period of useful independence (SRS on your own: 10.0 months vs SRS furthermore WBRT: 9.five months). The secondary final result of QOL, calculated While using the validated EORTC-QLQC30 Resource, was noticed to get worse in individuals who obtained WBRT in several QOL domains . Importantly, these results have been noticed In spite of adjuvant WBRT decreasing the two-12 months regional failure charge (31% to 19%), distant brain failure (forty eight% to 33%), and the necessity for salvage therapies (fifty one% vs. 16%). No considerable variations in survival were noticed albeit the trial wasn't driven to address survival.

These 4 trials have proven the function of SRS by itself since the normal of care in sufferers using a confined quantity of brain metastases, but they may have not been intended to Assess the effect of WBRT on overall survival.

The inclusion standards across the RCTs analyzing SRS alone to SRS as well as WBRT were related (Table one), nonetheless, the first endpoints have been completely unique, and no trial was intended to evaluate Total survival. To higher clarify the results of local Management, distant Mind Manage and survival, a meta-Investigation (MAL) was performed by Tsao, Xu and Sahgal in 2012 . They described hazard ratios for local Handle and distant Mind Manage favoring adjuvant WBRT at two.sixty one and a couple of.15, respectively, but ended up not able to combine the survival final results as a consequence of restrictions in how the info had been documented. Sahgal et al. then executed somebody affected person knowledge (IPD) MAL of a similar RCTs aimed at evaluating remedy outcomes on survival, and accomplish sub-team analyses . With regard to Over-all survival, a procedure effect was observed favoring SRS on your own in patients ≤fifty decades. In more mature patients, no survival disadvantage was observed with SRS alone. With respect to distant brain Manage, a remedy influence was also noticed with chance reductions in the development of new brain metastases in more mature patients treated with WBRT, but no benefit within the younger people (≤50 many years) handled with WBRT. As predicted, regional Management was improved with supplemental WBRT in all age teams. The concordance involving a survival detriment and deficiency of reward in distant brain Manage Regardless of treatment with WBRT, in the young people, led the authors to hypothesize that publicity on the identified harms of WBRT (mentioned in detail underneath) could negatively influence affected person survival. This speculation is provocative, and continues to be for being validated.

Essentially the most convincing trial style and design to verify the adverse effects of WBRT should be to randomize sufferers with no visualized Mind metastases to observation or WBRT. This is completed in studies assessing prophylactic cranial irradiation (PCI) in each small mobile lung cancer (SCLC) [44, forty five] and non-little mobile lung cancer (NSCLC) [46, forty seven]. PCI, not dissimilar to your addition of WBRT to SRS, has long been demonstrated to reduce the chance of intra-cranial relapse. Nevertheless, this attain arrives at the price of the adverse impact on QOL. By way of example, substantial boosts in fatigue, appetite decline, nausea and vomiting and leg weakness were being observed in sufferers with extensive stage SCLC at six and twelve weeks put up PCI . Furthermore, in locally State-of-the-art NSCLC patients, a increased drop in HVLT-R measures of quick and delayed remember have been noticed even as much as one calendar year put up-PCI . With regard to longer-phrase adverse outcomes of WBRT, a devastating consequence is usually the development of leukoencephalopathy. Without a doubt, radiation-induced dementia fees happen to be documented being as superior as 11% in prolonged-term Mind metastases survivors (>twelve months) just after WBRT , and reported to become increased in sufferers dealt with with WBRT and SRS versus SRS by itself [35, 50].

Abnormal N-methyl-D-aspartate (NMDA) receptor stimulation, comparable to the pathophysiology inherent to Parkinson's dementia , is postulated as a person mechanism detailing 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 controlled trial involving 554 individuals. At 24 weeks, 64% of people without memantine and fifty four% with memantine experienced cognitive function failure determined by evaluation Together with the HVLT-R. Although the Major endpoint did not reach importance due to significant attrition fee, there was a powerful pattern (p = 0.059) supporting memantine therapy. Analysis of secondary endpoints confirmed that memantine appreciably prolonged the time to cognitive drop and yielded remarkable benefits for government perform, processing velocity and delayed recognition at 24 weeks. Eventually, these info present nearly all people go through cognitive dysfunction with WBRT, and that pharmacologic approaches to mitigate the risk by concentrating on related pathways associated with Parkinson's dementia may be deserving of additional investigation.

Further insight into WBRTs’ system of harm has come from a modern Phase two trial assessing hippocampal avoidance WBRT (HA-WBRT). Sophisticated modern-day radiation technological know-how was placed on Restrict dose exposure to your hippocampus to no more than eighty% of the prescribed 30Gy in ten fractions . This non-randomized phase 2 demo measured neurocognitive operate using the HVLT-R, and when compared results to historic controls taken care of with common WBRT from the RTOG demo database. HA-WBRT resulted inside of a 7% drop within the necessarily mean relative HVLT-R delayed recall, which was substantially lessen as opposed to thirty% decline received from historic controls. Although this examine is encouraging concerning limiting toxicity from WBRT, a randomized trial is needed to totally realize the therapeutic value On this technologically elaborate type of WBRT.

In 2012, the American Culture for Therapeutic Radiation Oncology released an proof-based guideline using a number of tips around the management of brain metastases . Due to the fact that point, the proof from scientific trials has made it distinct that the preferred up-front radiation remedy selection for individuals with restricted Mind metastases is SRS by itself. In reality, the American Culture for Radiation Oncology (ASTRO) has just lately designed a definitive advice of their Choose Wisely campaign and suggest to not routinely include adjuvant WBRT to SRS for confined brain metastases . Additionally, the just lately revised Nationwide Extensive Cancer Network (NCCN) tips now aid SRS by itself even outside of All those clients with “constrained” metastases, and do not specify an upper Restrict for the volume of metastases . The latter is ahead pondering; metastasis counting is likely irrelevant and what issues is usually the suitability of your client for SRS [57-59]. Hence, the onus is no longer on people who deal with with SRS alone to justify the omission of WBRT; rather it is on individuals that take care of with WBRT within a SRS ideal client.

WHAT ABOUT THE Affected person WITH Extra Considerable BRAIN METASTASES?

Prior technological restrictions in SRS technologies restricted the application of SRS to clients with only a few Mind metastases. Improvements in set body and frameless SRS technologies now let treatment method of numerous metastases in one session [60, 61].

The first big prospective review evaluating SRS on your own for various brain metastases was claimed in 2014 . About 1200 patients with one-ten SRS eligible metastases ended up handled with SRS by yourself using Gamma Knife technological innovation (Elekta AB, Stockholm, Sweden). The Examination was broken down based on the 455 people with 1 metastases, 531 clients with 2 to four metastases and 208 with 5 to 10 metastases. Survival, distant Mind relapse, and native Handle fees were not drastically distinctive in individuals with 5 to 10 metastases vs . two to four metastases. These outcomes are of key importance since they challenge the dogma that sufferers with in excess of four metastases will not take advantage of SRS by yourself as a consequence of shortened survival and will inevitably are unsuccessful elsewhere during the brain. Hence, this demo offers evidence to help SRS by yourself in superior KPS patients with as much as 10 metastases, supplied the individual tumor volume is no more than ten mL and < three cm in longest diameter, and the total cumulative volume of all tumors in the brain is ≤15 mL. A number of randomized trials are at present assessing WBRT by itself versus SRS on your own in equivalent sufferers, and in improvement is really a trial analyzing SRS by yourself as opposed to WBRT in addition SRS Improve in clients with 10 to 20 metastases.

TARGETED THERAPIES Together WITH Mind RADIATION

In comparison with standard chemotherapy, a number of targeted brokers have increased penetration throughout the blood-brain barrier and generate response within the Mind. Dramatic advancements in disorder Handle are being noticed even for histologies for instance melanoma that were previously viewed as not merely radioresistant but chemoresistant. Table two [63-seventy five] summarizes chosen clinical trials analyzing the efficacy of specific therapies on your own or together with radiation therapy inside the treatment of Mind metastases. Even though, with qualified therapies on your own some impressive reaction prices are noticed, progression-totally free-survival (PFS) premiums are generally short (< 8 months). These results are certainly not as well dissimilar from what has long been attained with WBRT by itself [33, 53]. The exception is in EGFR mutant non-smaller cell lung cancers dealt with having a tyrosine kinase inhibitor. From the study by Wu et al. one example is, the median PFS was >15 months in EGFR mutant tumours taken care of with erlotinib.

Desk 2. Summary of chosen trials of qualified therapy on your own or together with brain radiation to the treatment of brain metastases.

PFS: progression cost-free survival, nPFS: neurologic progression free of charge survival, OS: Over-all survival, NSCLC: non-small cell lung cancer, EGFR: epidermal advancement aspect receptor, WBRT: complete Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: months, NS: not significant, NR: not recorded, NA: not applicable

Number of trials have put together targeted therapies with radiation, and they're also summarized in Desk two. While, randomized proof is still lacking, There exists suggestion from retrospective info that The mixture may well produce enhanced results. During the retrospective Examination of the prospective cohort of individuals handled with SRS for melanoma brain metastases, the group that obtained ipilimumab had a drastically extended median survival (21.three vs four.nine months) . On the other hand, warning ought to be exercised as concurrent specific therapy and radiation cure will not be as innocuous as Earlier considered. The RCT assessing SRS with WBRT on your own, as opposed to in combination with erlotinib or temozlomide, noted considerably higher Grade three to five toxicity charges in The mixture arm; far more importantly, survival was worse even though it did not attain statistical significance . A significant limitation of the review was the focused therapy was not biomarker-pushed and should partly account for your bad survival noticed. Warning also should be taken as There is certainly evidence that Mind metastases and primary tumors might harbor distinctive genetic alterations. In a single examine of 86 matched Mind metastases and first tumors, clinically useful alterations in 53% of Mind metastases were not detected in the primary tumor .

The rising evidence implies that specific therapies will Perform an important position inside the treatment of Mind metastases. We postulate that Even though qualified agents may not be productive in controlling gross sickness while in the brain, They might be efficient in running micro-metastatic ailment in the brain. Therefore, a reasonable approach could possibly be to combine specific therapies with SRS by itself, conquering the limitation of SRS in addressing micrometastatic sickness inside the Mind and leading to less distant Mind failures. The subsequent several years will produce thrilling details as there are a number of trials in progress utilizing this technique.

INNOVATIONS IN SRS - INDICATIONS AND Purposes

As tumors get greater, SRS dosing is counter-intuitively reduced with regard to tumor control, to take care of safety to the conventional Mind tissue; if not, the chance of radiation necrosis will become prohibitive . As a result, tumors better than four cm have ordinarily been excluded from one fraction SRS. In case the tumors are non-operable, then these people happen to be taken care of with WBRT In spite of its very poor area Manage. The advent of non-invasive head immobilization devices, on-board impression-steerage methods and Superior radiation shipping program has lead to the practice of hypofractionated frameless stereotactic radiotherapy (SRT) [60, 78]. Basically by fractionating, the safety profile with respect to the normal Mind tissue toxicity is improved, and the total tumor dose could be escalated these kinds of that doses like 24Gy in 3 fractions and 30-40Gy in 5 fractions are now not unusual. 1 intriguing retrospective sequence noted greater charges of Handle and decrease charges of toxicities with hypofractionated SRT (36Gy in 6 fractions) in comparison with single fraction SRS . However, this follow remains in its infancy and we have been looking for a RCT to find out if single fraction SRS must be reserved only for little metastases (e.g. one-two centimeters), as the information recommend even worse community Management for greater tumors [80, eighty one]. Figure 1 is an illustration of the efficacy of hypofractionated SRT in a considerable tumor. This individual would have if not been excluded from solitary portion SRS and dealt with with WBRT upfront (additionally or minus a SRS Increase), or operated on.

A. MRI of 3.6cm right cerebellar metastases from lung most cancers. B. Extremely conformal treatment prepare Using the a hundred% (eco-friendly line) and eighty% (blue line) isodose lines wrapping tightly within the gross tumour (purple colorwash), and preparing concentrate on quantity (orange colorwash). The brainstem (blue colorwash) is spared from substantial dose. (B) MRI 2 months put up completion of radiation (30Gy in five fractions). C. Full resolution of the tumour at one year.

In article-operative individuals, the observe of routinely treating with WBRT is usually turning out to be out-of-date. There's raising use of SRS on the write-up-operative surgical cavity as a way to spare clients from the adverse results of WBRT and to boost community Management [eighty two-93]. On the Sunnybrook Odette Most cancers Center, We now have adopted hypofractionated SRT as our conventional of care, delivering 30-35Gy in five fractions to the submit-operative tumor mattress . Fractionation has the benefit of reducing the adverse effects to the conventional tissues, provided that the targets are generally big and irregularly shaped. Our Preliminary final results have demonstrated one calendar year local Handle premiums of ∼eighty% in people who've either recurred and re-operated upon right after preceding WBRT, or in people without having prior history of WBRT and operated on. There's an ongoing research analyzing write-up-surgical cavity one portion SRS by itself versus WBRT and could be a practice-defining study .

Over the past a number of decades, clinical trials have informed us about the right administration of clients with Mind metastases. To begin with, SRS was viewed as an adjunct to WBRT in chosen clients presenting by using a constrained variety of Mind metastases. However, the role of WBRT has because been questioned as We've learned of its potential to adversely influence QOL and neurocognition. Therefore, SRS on your own has emerged as the current conventional of care with Level one proof to help its practice. Current investigation is centered on the evaluation of broader purposes of SRS to quite a few medical circumstances which were ordinarily deemed absolute indications for WBRT. Such as, SRS by yourself is at present being evaluated from the treatment method of 5 or even more Mind metastases, and in write-up-operative clients. A fresh era of trials can also be rising investigating the influence of qualified therapies concurrent with SRS.

Clinical trials in people with brain metastases are An important challenge as summarized via the latest reports through the Response Assessment in Neuro-Oncology (RANO) Mind metastases group [ninety five, 96]. They advise for demo style and reaction evaluation that trials be tumor or biomarker precise, that assessment be based upon contrast-Improved MRI, that baseline and recurring neurocognitive and QOL testing be done with validated and delicate instruments, that stratification be according to more-cranial illness position, and that proper timing be regarded as with regards to endpoint testing. Eventually, the oncology Group has recognized that the development of brain metastases is no more the terminal oncologic party from the previous.

CONFLICTS OF Fascination, Economical DISCLOSURES

Dr. Arjun Sahgal has obtained honorarium from earlier instructional seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also received analysis grants from Elekta AB, normally there isn't any conflicts of desire to reveal.

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