Spatial‐temporal modulation in radiation therapy

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