Stereotactic radiosurgery SRS Financials is a longtime non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor Regulate costs are top-quality to full Mind radiotherapy (WBRT) by itself. Due to this fact, WBRT furthermore SRS was commonly adopted for clients which has a limited quantity of brain metastases (“constrained range” customarily suggests 1-4). Subsequent trials centered on answering regardless of whether WBRT upfront was needed at all. Based upon latest randomized controlled trials (RCTs) and meta-analyses comparing SRS on your own to SRS plus WBRT, adjuvant WBRT brings about improved intracranial Management; nevertheless, for the cost of neurocognitive operating and quality of life. These adverse consequences of WBRT may additionally negatively influence on survival in young people. Based on the outcomes of those reports, remedy has shifted to SRS by yourself in patients that has a confined number of metastases. Moreover, RCTs are analyzing the function of SRS on your own in people with >4 brain metastases. New developments in SRS involve fractionated SRS for large tumors and The combination of SRS with qualified systemic therapies that cross the blood Mind barrier and/or promote an immune reaction. We current On this evaluation The existing substantial amount proof and rationale supporting SRS as being the normal of look after patients with confined Mind metastases, and emerging applications of SRS.
Brain metastases are a significant cause of morbidity and mortality in patients with metastatic cancer, with an incidence of up to 65% during the course of illness [1, 2]. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer . Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. The development of brain metastases was viewed as an oncologic terminal event.
As systemic therapies have become more efficacious in patients with metastatic disease, improved survival rates are now being observed. In addition, the patterns of disease progression are shifting such that the incidence of brain metastases is increasing while extra-cranial disease remains controlled. This phenomena is likely a consequence of the central nervous system (CNS) being a sanctuary site from drug penetration. As a result, the management of brain metastases has become a major focus of research, with the intent to improve intra-cerebral control and decrease neurologic deaths.
Although the position of neurosurgery had been set up while in the nineties as a method to obtain neighborhood Command and prolong survival, it absolutely was reserved for your minority of patients presenting with a single metastasis and no other condition past the Mind [4-seven]. Nevertheless missing was a focal ablative non-invasive therapy that might be used efficiently to a much broader inhabitants of people with brain metastases. This set the phase for the development of stereotactic radiosurgery (SRS). SRS is often a targeted ablative radiation cure sent with sub-millimeter precision towards the tumor localized in a few-Proportions in one-five fractions.
The focus of the review is always to summarize the current superior amount evidence to explain the job of SRS as optimal administration for clients presenting with limited Mind metastases. Furthermore, we offer an outline with the emerging programs of SRS since it proceeds to evolve into a remedy alternate to WBRT, With all the intent To optimize neurcognitive function and quality of life (QOL).
PATHOPHYSIOLOGY OF Mind METASTASES
Circulating tumor cells (CTCs) can disseminate from the Principal tumor mass to sort distant colonies by implantation at an ectopic web-site, such as the brain [8-ten]. To do so necessitates CTCs to arrest inside the circulation, extravasate through the bloodstream or lymphatics into your Mind, and endure and proliferate [eleven-thirteen]. The whole process of metastatic colonization entails a immediate conversation of CTCs with endothelial cells and astrocytes while in the brain microenvironment. One example is, CTCs which have arrested in the capillary bed direct neighborhood endothelial cells to remodel the adjacent atmosphere to market tumour mobile development and invasion [fourteen-16]. More, metastatic tumour cells recruit systemic stromal cells, which include fibroblasts, to help with early colonization , and co-choose neighborhood stromal cells, such as reactive astrocytes and microglia, to market tissue invasion [fifteen, eighteen, 19]. Astrocytes inside the tumour microenvironment may additionally Participate in a job in safeguarding tumour cells from chemotherapy-induced cytotoxicity, by way of a yet being described system requiring cell-cell Get hold of [twenty, 21]. Tumour cells, through launch of migration inhibitory issue, interleukin-eight, and plasminogen activator inhibitor 1, induce astrocyte activation and modify the inflammatory milieu to reinforce tumor-cell proliferation in vitro [22-24]. These molecular processes signify novel and understudied attainable therapeutic targets for that procedure of intracranial metastatic illness.
SRS was at first a very source intensive therapy supplied only at specialized centers and indicated only for metastatic sufferers with an excellent daily life expectancy. The problem lay in prognosticating individuals properly and Therefore the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) [28, 29] was formulated. Determined by the affected individual's Karnofsky General performance Status (KPS), age, position of the main tumor and presence of extracranial disease, sufferers ended up grouped into class 1, two or three with corresponding median survivals of seven.one, 4.two and 2.3 months, respectively. Though An important improvement at enough time, the RPA is currently regarded extremely simplistic as existing oncologic decision making is a great deal more complicated incorporating molecular, histological, clinical and radiographic ailment properties. You can find now additional advanced classification resources, including the prognosis-particular graded prognostic evaluation (DS-GPA). This system delivers histology-specific estimates of survival and will separate, for instance, probably the most favorable breast most cancers individuals having an expected survival of 25 months (great KPS and luminal B variety breast cancer) in the the very least favorable patients by having an envisioned survival of three months (very poor KPS and basal-like breast cancer) . Inspite of advances in prognostication of patients with brain metastases, medical professionals are still largely not able to properly predict prolonged-expression survivors. A review asking professional doctors to estimate survival of a a hundred and fifty individuals with specifics of cancer style, range of brain metastases, neurological presentation, extra-cranial illness standing, KPS, RPA class, prior full-brain radiotherapy, and synchronous or metachronous presentation, showed that over forty five% of predictions have been off by in excess of 6 months and 18% had been off by a lot more than twelve months . Additional innovations in prognostic checks including the “liquid biopsy” (a non-invasive blood exam that will detect tumor DNA or RNA fragments or CTCs) are wanted As well as in improvement . These Merge State-of-the-art patient and tumor precise genomic details to the equation, as a way to obtain personalised survival predictions.
Surgical treatment carries on for being an important procedure choice for sufferers with restricted brain metastases. It really is indicated when metastases are significant (>three-4 cm), or whenever a pathologic analysis is necessary. Additionally, operation is favored inside the presence of sizeable edema demanding prolonged large dose dexamethasone, or to possibly reverse neurological deficits. Usually, the current proof indicates the efficacy of SRS is enough to accomplish durable regional Management that is similar to surgical procedures. While there are no RCTs immediately comparing the two, numerous trials have been described evaluating SRS to SRS with WBRT (Desk one), and is A significant emphasis of the overview.
HR: hazard ratio, WHO: environment health and fitness Group, KPS: Karnofsky general performance status, WBRT: complete brain radiotherapy, SRS: stereotactic radiosurgery, yr: calendar year, mos: months, NS: not major, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Studying Take a look at revised.
Clients from the observation team experienced possibly surgical treatment on your own or SRS alone. Functional end result was not analyzed independently by surgical procedure or SRS by itself.
The initial RCTs analyzing SRS mimicked the design in the Preliminary surgical scientific studies for Mind metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific studies verified that SRS enhanced community Command, in addition to a survival advantage in chosen patients with only one brain metastasis was demonstrated. These trials ended up productive in shifting the paradigm from WBRT on your own to WBRT furthermore SRS for clients presenting with restricted Mind metastases and a very good overall performance standing.
The next series of medical trials ended up meant to reply if WBRT was in any respect important, and as opposed SRS by yourself to SRS with adjuvant WBRT. Three RCTs are reported in people presenting with as many as 4 metastases [35-37] in addition to a forth in abstract type . Aoyama et al. documented the main RCT, randomizing 132 patients to SRS by yourself (sixty five sufferers) or WBRT additionally SRS (67 patients). The first endpoint was Mind tumor recurrence. Although the 1-year area Manage level was superior with SRS by itself at seventy three%, added area control with adjuvant WBRT at 89%, was observed. On top of that, adjuvant WBRT diminished the rate of distant intra-cranial relapse at 1 yr from 64% to 42%. Even so, these gains in intra-cranial Management didn't translate into a bonus with regard to cognition, based on Mini-Psychological Standing Test (MMSE), nor survival. In addition, clients had larger fees of necrosis and leukoencephalopathy in the WBRT arm. The demo was Hence prosperous in supplying the initial level 1 proof to explain the relative influence of SRS by yourself vs . SRS with WBRT.
In lieu of the normal endpoint of survival or intra-cranial Command, Chang et al. took a special approach and evaluated neurocognition as the main endpoint. Importantly, the validated Hopkins Verbal Understanding Take a look at-Revised (HVLT-R) assessment Instrument, was used to measure neurocognitive operating in contrast to the MMSE which is not a sensitive test for neurocognition . Fifty-eight people ended up randomized to SRS by itself (n = 30) or WBRT as well as SRS (n = 28). Early stopping regulations were invoked at the interim Assessment, along with the research concluded that SRS by itself was favored with respect into the probability of neurocognitive decrease at 4 months article-treatment method. This gain was recognized despite the 1 calendar year local Manage and distant Mind Command costs favoring adjuvant WBRT with complete gains of 33% and 27%, respectively. The intracranial Handle results were being In line with the final results in the Aoyama study, but what was not expected was the survival benefit observed within the SRS by yourself arm. The median survival was fifteen months while in the SRS alone arm and 6 months during the SRS with WBRT arm (p = 0.003). This survival final result induced the trial to endure significant scrutiny with several arguing that the survival advantage for SRS by itself was a result of imbalances amongst The 2 arms, as far more people handled with SRS furthermore WBRT had better extra-cranial (additional liver and adrenal metastases) and intracranial illness (much larger volume of brain metastases) .
The eu Organization for Investigation and Procedure of Most cancers (EORTC) also took a unique method with their Most important endpoint focusing on useful independence . They utilized, however, the more clinically common Globe Overall health Business (WHO) efficiency position (PS) scale, and calculated time to WHO PS deterioration to in excess of two. This RCT concluded the addition of WBRT didn't Increase the median period of functional independence (SRS on your own: ten.0 months vs SRS moreover WBRT: 9.5 months). The secondary outcome of QOL, calculated While using the validated EORTC-QLQC30 Software, was observed to get even worse in patients who been given WBRT in several QOL domains . Importantly, these results had been observed Even with adjuvant WBRT minimizing the two-12 months area failure amount (31% to 19%), distant brain failure (forty eight% to 33%), and the need for salvage therapies (51% vs. sixteen%). No considerable discrepancies in survival were being noticed albeit the demo wasn't driven to deal with survival.
These 4 trials have proven the purpose of SRS alone as being the regular of care in individuals that has a confined variety of Mind metastases, but they've got not been meant to evaluate the effect of WBRT on General survival.
The inclusion standards throughout the RCTs evaluating SRS alone to SRS moreover WBRT were comparable (Desk 1), having said that, the main endpoints ended up wholly distinct, and no trial was designed to Appraise General survival. To raised make clear the outcomes of local Command, distant Mind Handle and survival, a meta-Examination (MAL) was executed by Tsao, Xu and Sahgal in 2012 . They reported hazard ratios for community Regulate and distant brain Management favoring adjuvant WBRT at two.61 and 2.fifteen, respectively, but were being not able to combine the survival effects due to limitations in how the data ended up described. Sahgal et al. then performed somebody individual facts (IPD) MAL of exactly the same RCTs aimed toward assessing procedure outcomes on survival, and perform sub-team analyses . With regard to General survival, a treatment result was noticed favoring SRS by itself in sufferers ≤50 several years. In more mature patients, no survival disadvantage was observed with SRS by yourself. With regard to distant Mind control, a cure outcome was also observed with risk reductions in the event of recent Mind metastases in more mature sufferers addressed with WBRT, but no advantage inside the younger patients (≤50 decades) dealt with with WBRT. As expected, area Manage was improved with additional WBRT in all age groups. The concordance amongst a survival detriment and deficiency of benefit in distant brain control Regardless of remedy with WBRT, within the young sufferers, led the authors to hypothesize that publicity to your regarded harms of WBRT (mentioned intimately under) could negatively affect affected individual survival. This speculation is provocative, and continues to be to become validated.
One of the most convincing trial layout to confirm the adverse consequences of WBRT is usually to randomize individuals without visualized brain metastases to observation or WBRT. This continues to be finished in experiments evaluating prophylactic cranial irradiation (PCI) in both equally smaller cell lung most cancers (SCLC) [forty four, forty five] and non-smaller cell lung cancer (NSCLC) [forty six, 47]. PCI, not dissimilar to the addition of WBRT to SRS, is shown to cut back the potential risk of intra-cranial relapse. Nevertheless, this attain arrives at the price of the damaging effect on QOL. For instance, significant improves in exhaustion, urge for food decline, nausea and vomiting and leg weak point were noticed in individuals with in depth phase SCLC at six and twelve weeks article PCI . Furthermore, in domestically advanced NSCLC clients, a better decrease in HVLT-R measures of quick and delayed remember had been noticed even nearly 1 calendar year article-PCI . With respect to longer-term adverse consequences of WBRT, a devastating consequence is often the development of leukoencephalopathy. In fact, radiation-induced dementia premiums are already noted to be as higher as eleven% in extensive-expression brain metastases survivors (>12 months) soon after WBRT , and documented to generally be greater in people handled with WBRT and SRS versus SRS by itself [35, 50].
Extreme N-methyl-D-aspartate (NMDA) receptor stimulation, much like the pathophysiology inherent to Parkinson's dementia , has become postulated as one mechanism explaining the adverse neurocognitive outcomes of WBRT. For a strategy to mitigate the risk, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a substantial randomized placebo controlled demo involving 554 clients. At 24 months, 64% of patients with out memantine and 54% with memantine experienced cognitive operate failure based upon assessment While using the HVLT-R. Even though the Most important endpoint did not get to significance because of the significant attrition amount, there was a robust pattern (p = 0.059) supporting memantine procedure. Assessment of secondary endpoints showed that memantine drastically prolonged enough time to cognitive decline and yielded outstanding results for government functionality, processing speed and delayed recognition at 24 months. Ultimately, these facts show nearly all of individuals go through cognitive dysfunction with WBRT, and that pharmacologic methods to mitigate the danger by focusing on similar pathways involved in Parkinson's dementia may be worthy of more investigation.
Further more insight into WBRTs’ system of harm has originate from a recent Section two trial evaluating hippocampal avoidance WBRT (HA-WBRT). Subtle present day radiation technology was applied to limit dose exposure to your hippocampus to not more than eighty% of the prescribed 30Gy in 10 fractions . This non-randomized section 2 demo calculated neurocognitive operate utilizing the HVLT-R, and when compared outcomes to historic controls addressed with conventional WBRT from the RTOG trial databases. HA-WBRT resulted within a seven% drop in the imply relative HVLT-R delayed recall, which was appreciably reduce compared to the 30% decline attained from historic controls. Even though this study is encouraging with regard to limiting toxicity from WBRT, a randomized trial is required to completely fully grasp the therapeutic value During this technologically complicated kind of WBRT.
In 2012, the American Society for Therapeutic Radiation Oncology released an evidence-primarily based guideline that has a series of tips on the administration of brain metastases . Because that time, the evidence from medical trials has designed it very clear that the popular up-entrance radiation cure choice for patients with minimal brain metastases is SRS by itself. In fact, the American Culture for Radiation Oncology (ASTRO) has recently built a definitive recommendation of their Pick out Correctly campaign and endorse to not routinely add adjuvant WBRT to SRS for minimal Mind metastases . Moreover, the a short while ago revised Countrywide Detailed Cancer Network (NCCN) suggestions now assist SRS by itself even beyond All those clients with “limited” metastases, and don't specify an upper Restrict for the quantity of metastases . The latter is forward wondering; metastasis counting is probably going irrelevant and what matters is otherwise the suitability of your affected person for SRS [fifty seven-59]. Therefore, the onus is not on those that treat with SRS by yourself to justify the omission of WBRT; instead it's on individuals that treat with WBRT inside a SRS suitable patient.
How about THE Individual WITH Far more EXTENSIVE BRAIN METASTASES?
Previous complex limits in SRS technological know-how limited the applying of SRS to sufferers with only a few Mind metastases. Developments in mounted body and frameless SRS systems now allow cure of diverse metastases in one session [60, sixty one].
The main major future review analyzing SRS alone for various Mind metastases was described in 2014 . Somewhere around 1200 individuals with 1-10 SRS eligible metastases ended up taken care of with SRS on your own making use of Gamma Knife technologies (Elekta AB, Stockholm, Sweden). The Evaluation was damaged down in accordance with the 455 sufferers with one metastases, 531 patients with 2 to 4 metastases and 208 with 5 to ten metastases. Survival, distant Mind relapse, and native Command prices weren't appreciably diverse in clients with 5 to 10 metastases as opposed to two to 4 metastases. These results are of important significance since they problem the dogma that people with over four metastases will not likely take pleasure in SRS by yourself because of shortened survival and may inevitably fail in other places within the Mind. For that reason, this trial supplies evidence to help SRS by yourself in good KPS patients with as much as 10 metastases, provided the person tumor quantity is not more than ten mL and < 3 cm in longest diameter, and the entire cumulative quantity of all tumors during the Mind is ≤fifteen mL. Several randomized trials are at present evaluating WBRT alone versus SRS alone in similar clients, and in improvement is really a demo analyzing SRS by itself as opposed to WBRT plus SRS Raise in clients with 10 to twenty metastases.
Focused THERAPIES Together WITH BRAIN RADIATION
In comparison with traditional chemotherapy, various focused brokers have higher penetration with the blood-Mind barrier and generate response in the brain. Dramatic enhancements in sickness Manage are now being noticed even for histologies which include melanoma that were Earlier regarded as don't just radioresistant but chemoresistant. Desk two [63-75] summarizes chosen clinical trials analyzing the efficacy of targeted therapies on your own or together with radiation therapy within the cure of Mind metastases. Whilst, with focused therapies by yourself some impressive response prices are noticed, development-free-survival (PFS) charges are often quick (< 8 months). These benefits are not as well dissimilar from what has become reached with WBRT by yourself [33, fifty three]. The exception is in EGFR mutant non-smaller mobile lung cancers treated having a tyrosine kinase inhibitor. In the study by Wu et al. such as, the median PFS was >15 months in EGFR mutant tumours taken care of with erlotinib.
Table two. Summary of selected trials of targeted therapy by itself or in combination with brain radiation to the remedy of brain metastases.
PFS: development free of charge survival, nPFS: neurologic development totally free survival, OS: overall survival, NSCLC: non-compact cell lung most cancers, EGFR: epidermal expansion element receptor, WBRT: full Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: months, NS: not considerable, NR: not recorded, NA: not relevant
Several trials have blended targeted therapies with radiation, and these are definitely also summarized in Table 2. Even though, randomized evidence remains lacking, There may be suggestion from retrospective knowledge that The mixture may perhaps result in enhanced results. In the retrospective analysis of a possible cohort of clients handled with SRS for melanoma Mind metastases, the group that gained ipilimumab had a considerably more time median survival (21.three vs 4.9 months) . On the other hand, warning needs to be exercised as concurrent qualified therapy and radiation cure may not be as innocuous as previously believed. The RCT evaluating SRS with WBRT on your own, compared to in combination with erlotinib or temozlomide, reported significantly better Grade three to 5 toxicity rates in the combination arm; more importantly, survival was even worse although it didn't attain statistical significance . A big limitation of this examine was that the targeted therapy was not biomarker-pushed and could in part account with the poor survival noticed. Warning also should be taken as You can find evidence that brain metastases and first tumors may well harbor unique genetic alterations. In one analyze of 86 matched Mind metastases and primary tumors, clinically insightful alterations in fifty three% of brain metastases were not detected in the primary tumor .
The rising evidence implies that focused therapies will play an important job during the procedure of brain metastases. We postulate that Even though specific agents will not be powerful in managing gross condition within the brain, They might be helpful in handling micro-metastatic sickness inside the Mind. Therefore, a rational strategy may be to mix qualified therapies with SRS by itself, beating the limitation of SRS in addressing micrometastatic ailment within the brain and bringing about much less distant Mind failures. The following number of years will generate remarkable knowledge as There are a selection of trials in progress employing this strategy.
INNOVATIONS IN SRS - INDICATIONS AND Purposes
As tumors get larger, SRS dosing is counter-intuitively decreased with respect to tumor Command, to take care of basic safety to the conventional Mind tissue; in any other case, the risk of radiation necrosis gets prohibitive . Due to this fact, tumors better than four cm have normally been excluded from single fraction SRS. If the tumors are non-operable, then these sufferers happen to be treated with WBRT Inspite of its very poor local control. The arrival of non-invasive head immobilization devices, on-board picture-steerage units and advanced radiation shipping and delivery software has bring about the practice of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, 78]. Fundamentally by fractionating, the security profile with regard to the conventional brain tissue toxicity is improved, and the entire tumor dose could be escalated these that doses like 24Gy in three fractions and thirty-40Gy in five fractions are actually common. A single exciting retrospective sequence documented greater charges of Handle and decrease charges of toxicities with hypofractionated SRT (36Gy in six fractions) when compared with solitary fraction SRS . However, this apply remains to be in its infancy and we are looking for a RCT to find out whether or not one portion SRS needs to be reserved only for compact metastases (e.g. 1-two centimeters), as the information recommend even worse neighborhood Handle for larger tumors [eighty, 81]. Figure one is definitely an illustration of the efficacy of hypofractionated SRT in a big tumor. This client might have or else been excluded from single portion SRS and treated with WBRT upfront (as well as or minus a SRS Increase), or operated on.
A. MRI of 3.6cm right cerebellar metastases from lung cancer. B. Highly conformal treatment program With all the a hundred% (eco-friendly line) and 80% (blue line) isodose strains wrapping tightly around the gross tumour (pink colorwash), and organizing concentrate on volume (orange colorwash). The brainstem (blue colorwash) is spared from superior dose. (B) MRI 2 months submit completion of radiation (30Gy in 5 fractions). C. Total resolution with the tumour at one 12 months.
In write-up-operative patients, the practice of routinely treating with WBRT is additionally getting out-of-date. There is growing use of SRS to the post-operative surgical cavity as a method to spare sufferers through the adverse effects of WBRT and to further improve regional Management [82-ninety three]. Within the Sunnybrook Odette Most cancers Middle, We've got adopted hypofractionated SRT as our standard of treatment, delivering thirty-35Gy in 5 fractions to the write-up-operative tumor mattress . Fractionation has the advantage of reducing the adverse outcomes to the normal tissues, provided that the targets tend to be significant and irregularly shaped. Our initial effects have proven one yr local Command costs of ∼80% in clients that have possibly recurred and re-operated on right after former WBRT, or in individuals without prior record of WBRT and operated upon. There may be an ongoing study assessing write-up-surgical cavity solitary fraction SRS on your own vs . WBRT and may be a apply-defining review .
In the last several decades, clinical trials have informed us about the suitable management of people with brain metastases. At first, SRS was thought of an adjunct to WBRT in chosen people presenting having a constrained amount of brain metastases. However, the role of WBRT has considering that been questioned as We now have uncovered of its probable to adversely have an affect on QOL and neurocognition. Therefore, SRS on your own has emerged as The existing conventional of treatment with Degree 1 proof to guidance its observe. Present-day investigate is focused on the analysis of broader purposes of SRS to various scientific circumstances which were ordinarily deemed complete indications for WBRT. Such as, SRS on your own is currently staying evaluated inside the treatment of 5 or maybe more brain metastases, and in write-up-operative individuals. A different era of trials is also emerging investigating the effects of targeted therapies concurrent with SRS.
Medical trials in individuals with brain metastases are A significant obstacle as summarized because of the the latest experiences through the Response Evaluation in Neuro-Oncology (RANO) brain metastases team [95, ninety six]. They propose for trial design and reaction assessment that trials be tumor or biomarker specific, that evaluation be according to distinction-Increased MRI, that baseline and recurring neurocognitive and QOL tests be executed with validated and sensitive instruments, that stratification be dependant on more-cranial disease standing, and that acceptable timing be deemed with regard to endpoint tests. Ultimately, the oncology Group has identified that the development of Mind metastases is not the terminal oncologic occasion of the previous.
CONFLICTS OF Desire, Fiscal DISCLOSURES
Dr. Arjun Sahgal has obtained honorarium from previous academic seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also obtained research grants from Elekta AB, or else there are no conflicts of curiosity to reveal.