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• W4308116166 abstract "In his treaty Physics and Philosophy, the renowned physicist Sir James Jeans started with the following opening statement:1 “Science usually advances by a succession of small steps, through a fog in which even the most keen-sighted explorer can seldom see more than a few paces ahead. Occasionally the fog lifts, an eminence is gained, and a wider stretch of territory can be surveyed – sometimes with startling results.” Jeans, as he crafted that statement, had in mind the development of modern physics in the early 1900s. Built upon the foundation of Newtonian and Maxwellian theories, the physics community was looking for a new path in physics to resolve the critical challenges of certain anomalies revealed in a collection of experiments. As if a blessing from the sky, the younger generation of physicists were able to strike major breakthroughs by following the leads revealed in effects – that were “tiny and subtle”, sometimes even considered “non-essential” – by some of the established authorities of the day. However, in science, often when the fog has lifted, the new insights are not always captured or recognized immediately. An example that comes to mind is the perihelion orbit of the planet Mercury, described as a tiny “anomalous” effect when it was first recognized in 1859, but then, it would take the insight of an Einstein to point out its significance half a century later, with his revolutionary new theory of gravity. As we examine the history of medicine, specific to the development of radiation therapy (RT), it appears that as a scientific community we have come to a cross-road, similar to the Rubicon traversed by classical physics in the early part of last century. In a general sense, the critical-target theory of traditional radiobiology has been, to a great degree, guiding the field of RT since its inception. With the concepts of the 4Rs being established to form its biological backbone, RT has firmly established itself as one of the indispensable pillars of cancer treatment management – with both hyper- and hypo-fractionation strategies being the gold standards of clinical practice. Historically, technical advances in RT have centered on the improvement of dose distribution – in terms of conformity to the targets – while minimizing normal tissue exposure, and the delivery's accuracy and efficiency of treatments. The impressive success and advances in modern RT are, however, accompanied by the frustrations of RT's limitations in the apparent confinement to local control, and in the further reduction of normal tissue toxicities. To overcome these limitations, we have been seeking signs and indications that might point to new directions for radically improving the therapeutic ratio, where this pursuit has become the “Holy Grail” of research initiatives in radiation oncology. In the absence of other presented groundbreaking opportunities, there emerged three unconventional spatial-temporal modulation (STM) irradiation techniques that have shown signs of some new, yet subtle, therapeutic effects. These three techniques are: spatially fractionated radiotherapy (SFRT), microbeam radiotherapy (MRT), and FLASH RT. From the physical perspective, these techniques are unconventional in the sense that the radiation deliveries are carried out via new ways of spatial and temporal modulations that differ from the established conventions. Remarkably, the origins of these three techniques can all be traced back to the first half of the last century, with SFRT being a direct, but non-mainstream, application in RT, whereas MRT and FLASH RT debuted in laboratory settings, quietly announcing their “anomalous” effects. SFRT, in its early form of GRID therapy, was proposed and implemented by Kohler and his peers over 100 years ago.2 What was initially intended as a technique to spare the skin when treating large tumors with kV X-rays has, in turn, set in motion a new dynamic, which, most likely, was not anticipated by its early developers. With SFRT, there have been “anomalous” effects, although not consistently observable, however, persistently present, and “odd” enough to keep the early and subsequent practitioners and investigators up at night. These effects were “anomalous” against the background of mainstream “establishment” conditions in radiobiology, in the sense that the observed clinical outcomes, when manifested, would notably surpass the theoretical predictions – namely, beyond the traditionally expected effects of partial irradiation; so much so that GRID therapy never vanished from the RT community. Within a relatively small collection of RT centers, the practice of SFRT continued, using modern MV Linacs with new apparatuses – MV GRID Blocks or MLCs – or even particle beams to deliver GRID, as well as the more recently developed – 3D LATTICE radiation therapy – for patients with bulky tumors.3-7 From the perspectives of physics and dosimetry, the highly heterogeneous peak-to-valley dose distribution of SFRT presents a radical departure from the uniform, or homogeneous, dose-volume coverage of traditional/conventional RT, and accordingly, the irradiated target volume was said to be spatially fractionated.3 Notwithstanding, the anomalous effects remained largely anomalous. The hallmark of our non-trivial understanding of SFRT is the denotation of “bystander” and “abscopal” to those anomalous effects.8 More specifically, the underlying biological principles behind the bystander/abscopal effects that have shown to manifest under STM RT alone or combined synergistically with other therapeutic modalities are not yet well understood. To date, modern radiobiology has offered a number of probable mechanisms, including the following notable three that have been under active investigation: (1) radiation-mediated antitumor immunity9, 10; (2) radiation-triggered cytokine/chemokine mediated apoptosis11; and (3) radiation-induced ceramide-mediated ischemia/reperfusion injury.12 However, the results of the basic research have not yet been robustly translatable in a manner that can offer a clear guide to clinical practice. It is acknowledged that the use of SFRT techniques has not been without controversy. The tardiness with which SFRT came to be widely accepted reflects this reality. Nevertheless, following the “subtle anomalous effects” in the technique, the practitioners from the “small community” of SFRT pressed on and continued to accumulate clinical data. Furthermore, various forms of heterogeneous irradiation techniques also started to emerge, such as PATHY – PArtial Tumor irradiation targeting the HYpoxic tumor segment – which aims to augment tumor cell-killing by structural immunomodulation.13 Collectively, the rapidly rising interest in SFRT in recent years has revealed new elements, calling for accelerated investigations. Not too long after the early application of GRID, from a laboratory totally unrelated to RT, the FLASH effect on bacteria was discovered and reported by Dewey and Boag in 195914; and the effects on mouse intestine were subsequently reported in 1971.15 However, little work was carried out toward oncological applications until 2014, when the use of FLASH as a RT modality was proposed by Favaudon et al. based on the non-trivial “anomalous” effect, suggesting that at FLASH dose rate levels (≥40 Gy/s), normal tissues suffer less radiation injury than tumor tissue, and therein could potentially lead to a greater therapeutic ratio.16 The effects of dose rates (from 1 to 20 Gy/min) have not been playing roles of any significance in the history of conventional RT. As new and advanced instrumentation is now making the FLASH dose rate potentially feasible for clinical use, we are currently witnessing an accelerated pace of translating FLASH RT into clinical settings.17 Although the investigation of biological mechanisms and pre-clinical studies continue to be a high priority, several selective clinical applications toward systemic trials have been cautiously carried out. The results are not yet conclusive, but encouraging. Motivated by alternative lines of technical innovation, a quite different form of spatially fractionated radiation has been under investigation in a number of laboratories. Microbeam is a radiation beam composed of multi-slices of radiation fields, where the width and separation are in the micrometer range. Typically, the dose rates of these thin radiation slices are several magnitudes higher than that of conventional broad beams. When applied to tissues, although the integrated dose is in the normal range, the tissues through which the micron-thin radiation slices pass would receive an ultra-high dose, whereas the tissues that fall between slices receive a comparatively negligible dose. In microbeam irradiation, not only is the irradiated tissue spatially fractionated (GRID in micro-scale), but also the dose rate of the micrometer beam slices is drastically increased, reaching the level of FLASH RT. The unconventional biological effect under microbeam irradiation was first reported by Zeman et al. in 1961.18 Although the implication clearly favored tumor control over normal tissue toxicity, its clinical application for RT was not proposed until 1983 by Larson.19 Subsequent development of MRT had been slow until the recent decades, when a steadily intensified interest in this technical advancement has become evident through the markedly increased rate of publications on the topic.20 No patient has been treated by MRT so far, but after decades of earnest basic research and preclinical studies, the anticipation of final clinical translation is mounting. Although SFRT, in the forms of GRID and LATTICE, have been venturing further along into clinical practice than MRT and FLASH RT, all three STM techniques share the same non-conclusive nature of evidence from the perspectives of both fundamental biological mechanisms and clinical data. The “fog” has not quite lifted enough for us to see the whole picture and to subsequently harvest the “subtle effects”. This is undoubtedly the main cause of the controversy. This controversy should not be overly simplified by dividing the camps into optimists and skeptics. Although both the foundation of basic scientific principles and the clinical evidence supported by the collection of systemic data are vitally important, it is acknowledged that the clinical practice of RT, historically, has been known to have taken “leaps of faith” when venturing into, and through, murky waters. As the late Jack Folwer once said, “Had we waited for the conclusive data from radiobiology, RT would still have not started.” After decades of slow gestation on the “subtle effects”, STM in all its forms, including the three specific techniques briefed herein and other emerging variations, such as Split-Course SBRT21 and PULSAR,22 that deviate from the traditional spatial and temporal configurations of RT deliveries, has appeared to bring us to a new front. The recognition of SMT's dynamic potential, while acknowledging its uncertainties, brought clinicians and researchers together, and the converged efforts and enthusiasm have led to the first multidisciplinary international workshop on GRID/LATTICE, FLASH, and Microbeam in 2018, organized by Dr. Mansoor Ahmed of the National Cancer Institute of NIH(USA), in collaboration with the Radiosurgery Society.23 Then the clinical, biology, and physics Working Groups were subsequently formed, with the goal to advance this field through more cohesive collaboration. Does STM hold the key to unlocking further powers of RT, such as expanding RT from being a local control “rifle” to becoming a systematic “drug”, or radically improving the therapeutic ratio through FLASH RT and MRT? As we all look to the future, let us be reminded of the words of the esteemed physicist, Clifford Martin Will, who in 1979, when discussing whether Einstein's Theory of General Relativity would survive, when only two early experimental verifications (subtle effects) were conclusive at the time, wrote,24 that the proposition, “… is a matter of speculation for some, pious hope for some, and supreme confidence for others.” Xiaodong Wu is the primary invertor of US Patent No. 8,395,131: Method of 3D Lattice Radiotherapy" @default.
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• W4308116166 title "Spatial‐temporal modulation in radiation therapy" @default.
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