ABSTRACT. In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for ''biologically equivalent dose'', from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be ''triangulated'' to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion ''How Fractionation Really Works''. BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation.

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The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay -these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions.Experiments carried out over the past half century have revealed that neutrinos are found in three states, or flavors, and can transform from one flavor into another. These results indicate that each neutrino flavor state is a mixture of three different nonzero mass states, and to date offer the most compelling evidence for physics beyond the Standard Model. In a single experiment, LBNE will enable a broad exploration of the three-flavor model of neutrino physics with unprecedented detail. Chief among its potential discoveries is that of matter-antimatter asymmetries (through the mechanism of charge-parity violation) in neutrino flavor mixing -a step toward unraveling the mystery of matter generation in the early Universe. Independently, determination of the unknown neutrino mass ordering and precise measurement of neutrino mixing parameters by LBNE may reveal new fundamental symmetries of Nature.Grand Unified Theories, which attempt to describe the unification of the known forces, predict rates for proton decay that cover a range directly accessible with the next generation of large underground detectors such as LBNE's. The experiment's sensitivity to key proton decay channels will offer unique opportunities for the ground-breaking discovery of this phenomenon.Neutrinos emitted in the first few seconds of a core-collapse supernova carry with them the potential for great insight into the evolution of the Universe. LBNE's capability to collect and analyze this high-statistics neutrino signal from a supernova within our galaxy would provide a rare opportunity to peer inside a newly-formed neutron star and potentially witness the birth of a black hole.To achieve its goals, LBNE is conceived around three central components: (1) a new, highintensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a fine-grained near neutrino detector installed just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is ∼1,300 km from the neutrino source at Fermilab -a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions.With its exceptional combi...

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Total body radiation (TBI) has been used for many years as a preconditioning agent before bone marrow transplantation. Many side effects still plague its use. We investigated the planning and delivery of total body irradiation (TBI) and selective total marrow irradiation (TMI) and a reduced radiation dose to sensitive structures using image-guided helical tomotherapy. To assess the feasibility of using helical tomotherapy, (A) we studied variations in pitch, field width, and modulation factor on total body and total marrow helical tomotherapy treatments. We varied these parameters to provide a uniform dose along with a treatment times similar to conventional TBI (15-30 min). (B) We also investigated limited (head, chest, and pelvis) megavoltage CT (MVCT) scanning for the dimensional pretreatment setup verification rather than total body MVCT scanning to shorten the overall treatment time per treatment fraction. (C) We placed thermoluminescent detectors (TLDs) inside a Rando phantom to measure the dose at seven anatomical sites, including the lungs. A simulated TBI treatment showed homogeneous dose coverage (+/-10%) to the whole body. Doses to the sensitive organs were reduced by 35%-70% of the target dose. TLD measurements on Rando showed an accurate dose delivery (+/-7%) to the target and critical organs. In the TMI study, the dose was delivered conformally to the bone marrow only. The TBI and TMI treatment delivery time was reduced (by 50%) by increasing the field width from 2.5 to 5.0 cm in the inferior-superior direction. A limited MVCT reduced the target localization time 60% compared to whole body MVCT. MVCT image-guided helical tomotherapy offers a novel method to deliver a precise, homogeneous radiation dose to the whole body target while reducing the dose significantly to all critical organs. A judicious selection of pitch, modulation factor, and field size is required to produce a homogeneous dose distribution along with an acceptable treatment time. In addition, conformal radiation to the bone marrow appears feasible in an external radiation treatment using image-guided helical tomotherapy.

Total radiation dose is not a reliable measure of biological effect when dose-per-fraction or dose-rate is changed. Large differences in biological effectiveness (per gray) are seen between the 2 Gy doses of external beam radiotherapy and the large boost doses given at high dose-rate from afterloading sources. The effects are profoundly different in rapidly or slowly proliferating tissues, that is for most tumors versus late complications. These differences work the opposite way round for prostate tumors versus late complications compared with most other types of tumor. Using the Linear-Quadratic formula it is aimed to explain these differences, especially for treatments of prostate cancer. The unusually slow growth rate of prostate cancers is associated with their high sensitivity to increased fraction size, so a large number of small fractions, such as 35 or 40 ''daily'' doses of 2 Gy, is not an optimum treatment. Theoretical modeling shows a stronger enhancement of tumor effect than of late complications for larger (and fewer) fractions, in prostate tumors uniquely. Biologically Effective Doses and Normalized Total Doses (in 2 Gy fraction equivalents) are given for prostate tumor, late rectal reactions, and */a new development */acute rectal mucosa. Tables showing the change of fraction-size sensitivity (the alpha/beta ratio) with proliferation rates of tissues lead to the association of slow cell doubling times in prostate tumors with small a/b ratios. Clinical evidence to confirm this biological expectation is reviewed. The a/b ratios of prostate tumors appear to be as low as 1.5 Gy (95% confidence interval 1.3 Á/1.8 Gy), in contrast with the value of about 10 Gy for most other types of tumor. The important point is that a/b0/1.5 Gy appears to be significantly less than the a/b0/3 Gy for late complications in rectal tissues. Such differences are also emerging from recent clinical results. From this important difference stems the superior schedules of, for example, 20 fractions of 3 Gy, or 10 fractions of 4.7 Gy, or 5 fractions of 7 Gy, which can all give tumor results equivalent to 80 Á/90 Gy in 2 Gy fractions, while keeping late complications equivalent to only 72 Gy in 2 Gy fractions. Combination treatments of external beam (EBRT) and brachytherapy boost doses (25F )/2 Gy plus 2)/10 Gy) can give higher biological tumor effects than any EBRT using daily 2 Gy doses, and with acceptable late complications. Monotherapy by brachytherapy for low-risk cancer prostate using two to four fractions in a few days can give even higher biological effects on the tumors.

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