All radiation types produce δ -rays of about a ≈1 keV or less that can impart MGy doses to 10-nm-size volumes of DNA. These events can produce severe dual double-strand breaks (DDSB) at the periphery of nucleosomes in single events particularly in heterochromatic DNA. These DDSBs are the most common multiply damaged sites, and their probabilities generally determine the biological effectiveness and therapeutic responses. The recent understanding that most normal tissues with intact TP53 genes generally are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA) implies that the well-known universal clinical fractionation window at ≈2 Gy/Fr defines the optimal tolerance level of most organs at risk and not the optimal tumor dose per fraction at least when using intensity-modulated radiation therapy (IMRT). Interestingly, practically all cancer cells are linked to genomic instability in some DNA repair, cell cycle, or growth control genes like TP53 that is affected in more than 50% of all tumors. Unfortunately, this often gives tumor cells a low-dose radiation-resistant (LDRR) phenotype. The fractionation window is due to the low-dose and linear energy transfer (LET) initiation of full DNA repair capability after ≈½ Gy or 18 DSB, and we should use this acquired repair advantage in normal tissues to its full extent up to ≈2.3 Gy where the high-dose apoptosis (HDA) starts to set in. Understanding quantum biological cure implies that light ions should truly have the lowest possible LET in normal tissues to retain the classical fractionation window but have a high LET only in the gross tumor region. Carbon ion therapy substantially benefits from the last ≈10 GyE of the treatment being delivered by low LET (electrons or photons) to minimize normal tissue damage, get a steepest possible dose response, and maximize complication-free cure. Interestingly, this also necessitates the use of the lightest ions with a low LET in normal tissues, allowing quantum biology-optimized molecular radiation therapy with He-Li-B ions, with minimal adverse therapeutic effect in normal tissues and the highest possible apoptosis, senescence, and cell kill in the tumor!

The lightest ions beyond protons, principally helium, lithium, and boron ions, make highly specific molecular Bragg peak radiation therapy of malignant tumors possible with minimal adverse normal tissue reactions. The Bragg peak ionization density is mainly elevated in a few mm wide spot at the end of these ions with substantially increased local apoptosis and senescence induction. Mainly placing Bragg peaks in the gross tumor volume with increased local therapeutic effect and only low ionization density and easily repairable damage in normal tissues. The possible geometrical accuracy of the dose delivery will be ≈1 mm with these ions. Interestingly, high-resolution molecular tumor imaging will then be possible, particularly with 8Boron ions that are our lightest positron emitter allowing immediate accurate PET-CT imaging to delineate the target volume dose delivery. Compared to carbon ions the boron radiation damage to normal tissues in front of and behind the tumor is reduced at the same time as tumor apoptosis and senescence are increased. A mean tumor cure as high as 80% should be possible with Boron ion therapy using new clinical fractionation principles and even more when early tumor detection and malignancy estimation methods are brought into more regular clinical use.

Most ionizing radiation produces δ-rays of ≈1 keV that can impart MGy doses to 100 nm3 volumes of DNA. These events can produce severe dual double-strand breaks (DDSBs) on nucleosomes, particularly in dense heterochromatic DNA. This is the most common multiply damaged site, and their probabilities determine the biological effectiveness of different types of radiation. We discuss their frequency, effect on cell survival, DNA repair, and imaging by gold nanoparticle tracers and electron microscopy. This new and valuable nanometer resolution information can be used for determining the optimal tumor cure by maximizing therapeutic effects on tumors and minimizing therapeutic effects on normal tissues. The production of DDSBs makes it important to deliver a rather high dose and LET to the tumor (>2.5 Gy/Fr) and at the same time reach approximately 1.8–2.3 Gy of the lowest possible LET per fraction in TP53 intact normal tissues at risk. Therefore, their intrinsic low-dose hyper-sensitivity (LDHS)-related optimal daily fractionation window is utilized. Before full p53 activation of NHEJ and HR repair at ≈½ Gy, the low-dose apoptosis (LDA) and LDHS minimize normal tissue mutation probabilities. Ion therapy should thus ideally produce the lowest possible LET in normal tissues to avoid elevated DDSBs. Helium to boron ions can achieve this with higher-LET Bragg peaks, producing increased tumor DDSB densities. Interestingly, the highest probability of complication-free cure with boron or heavier ions requires a low LET round-up for the last 10–15 GyE, thereby steepening the dose response and further minimizing normal tissue damage. In conclusion, the new high-resolution DSB and DDSB diagnostic methods, and the new more accurate DNA-repair-based radiation biology, have been combined to increase our understanding of what is clinically important in curative radiation therapy. In fact, we must understand that we already passed the region of optimal LET and need to go back one step rather than forward, with oxygen being contemplated. As seen by the high overkill and severely high LET in the distal tumor and the increased LET to normal tissues (reminding of neutrons or neon ions), it is therefore preferable to use lithium–boron ions or combine carbon with an optimal 10–15 GyE photon, electron, or perhaps even a proton round-up, thus allowing optimized, fractionated, curative, almost complication-free treatments with photons, electrons, and light ions, introducing a real paradigm shift in curative radiation therapy with a potential 5 GyE tumor boost, 25% increase in complication-free cure and apoptotic–senescent Bragg Peak molecular light ion radiation therapy.

The new biological interaction cross-section-based repairable–homologically repairable (RHR) damage formulation for radiation-induced cellular inactivation, repair, misrepair, and apoptosis was applied to optimize radiation therapy. This new formulation implies renewed thinking about biologically optimized radiation therapy, suggesting that most TP53 intact normal tissues are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA). This generates a fractionation window in LDHS normal tissues, indicating that the maximum dose to organs at risk should be ≤2.3 Gy/Fr, preferably of low LET. This calls for biologically optimized treatments using a few high tumor dose-intensity-modulated light ion beams, thereby avoiding secondary cancer risks and generating a real tumor cure without a caspase-3-induced accelerated tumor cell repopulation. Light ions with the lowest possible LET in normal tissues and high LET only in the tumor imply the use of the lightest ions, from lithium to boron. The high microscopic heterogeneity in the tumor will cause local microscopic cold spots; thus, in the last week of curative ion therapy, when there are few remaining viable tumor clonogens randomly spread in the target volume, the patient should preferably receive the last 10 GyE via low LET, ensuring perfect tumor coverage, a high cure probability, and a reduced risk for adverse normal tissue reactions. Interestingly, such an approach would also ensure a steeper rise in tumor cure probability and a higher complication-free cure, as the few remaining clonogens are often fairly well oxygenated, eliminating a shallower tumor response due to inherent ion beam heterogeneity. With the improved fractionation proposal, these approaches may improve the complication-free cure probability by about 10–25% or even more.

The recent interaction cross-section-based formulation for radiation-induced direct cellular inactivation, mild and severe sublethal damage, DNA-repair and cell survival have been developed to accurately describe cellular repair, misrepair and apoptosis in TP53 wild-type and mutant cells. The principal idea of this new non-homologous repairable-homologous repairable (RHR) damage formulation is to separately describe the mild damage that can be rapidly handled by the most basic repair processes including the non-homologous end joining (NHEJ), and more complex damage requiring longer repair times and high-fidelity homologous recombination (HR) repair. Taking the interaction between these two key mammalian DNA repair processes more accurately into account has significantly improved the method as indicated in the original publication. Based on the principal mechanisms of 7 repair and 8 misrepair processes presently derived, it has been possible to quite accurately describe the probability that some of these repair processes when unsuccessful can induce cellular apoptosis with increasing doses of γrays, boron ions and PRIMA-1. Interestingly, for all LETs studied (≈0.3-160 eV/nm) the increase in apoptosis saturates when the cell survival reaches about 10% and the fraction of un-hit cells is well below the 1% level. It is shown that most of the early cell kill for low-to-medium LETs are due to apoptosis since the cell survival as well as the non-apoptotic cells agree very well at low doses and other death processes dominate beyond D > 1 Gy. The low-dose apoptosis is due to the fact that the full activation of the checkpoint kinases ATM and Chk2 requires >8 and >18 DSBs per cell to phosphorylate p53 at serine 15 and 20. Therefore, DNA repair is not fully activated until well after 1/2 Gy, and the cellular response may be apoptotic by default before the low-dose hyper sensitivity (LDHS) is replaced by an increased radiation tolerance as the DNA repair processes get maximal efficiency. In effect, simultaneously explaining the LDHS and inverse dose rate phenomena. The partial contributions by the eight newly derived misrepair processes was determined so they together accurately described the experimental apoptosis induction data for γ rays and boron ions. Through these partial misrepair contributions it was possible to predict the apoptotic response based solely on carefully analyzed cell survival data, demonstrating the usefulness of an accurate DNA repair-based cell survival approach. The peak relative biological effectiveness (RBE) of the boron ions was 3.5 at 160 eV/nm whereas the analogous peak relative apoptotic effectiveness (RAE) was 3.4 but at 40 eV/nm indicating the clinical value of the lower LET light ions (15 ≤ LET ≤ 55 eV/nm, 2 ≤ Z ≤5) in therapeutic applications to maximize tumor apoptosis and senescence. The new survival expressions were also applied on mouse embryonic fibroblasts with key knocked-out repair genes, showing a good agreement between the principal non-homologous and homologous repair terms and also a reasonable prediction of the associated apoptotic induction. Finally, the formulation was used to estimate the increase in DNA repair and apoptotic response in combination with the mutant p53 reactivating compound PRIMA-1 and γ rays, indicating a 10-2 times increase in apoptosis with 5 µM of the compound reaching apoptosis levels not far from peak apoptosis boron ions in a TP53 mutant cell line. To utilize PRIMA-1 induced apoptosis and cellular sensitization for reactive oxygen species (ROS), concomitant biologically optimized radiation therapy is proposed to maximize the complication free tumor cure for the multitude of TP53 mutant tumors seen in the clinic. The experimental data also indicated the clinically very important high-absorbed dose ROS effect of PRIMA-1.

This work provides a description of a new interaction, cross-section-based model for radiation-induced cellular inactivation, sublethal damage, DNA repair and cell survival, with the ability to more accurately elucidate different radiation-response phenomena. The principal goal of this work is to describe the damage-induction cross sections, as well as repair and survival, as Poisson processes with two main types of damage: mild damage that can be rapidly handled by the most basic repair processes; and more complex damage requiring longer repair times and the high-fidelity homologous recombination (HR) repair process to ensure accuracy and safety in the survival. This work is unique in its use of Poisson statistics to quantify the main repairable cell compartments that are exposed to simple and more complex sublethal hits, the cross section of which determines what is homologically and non-homologically repairable. The new method is applied to central radiation damage and survival data, such as in vitro cellular repair and survival with key DNA repair genes knocked out, low-dose hypersensitivity (LDHS), change in survival over the cell cycle, and variation with linear energy transfer (LET) for densely ionizing ions, all results supporting our basic assumptions. Among the results, it was shown that less than 1% of the simple DSBs are lethal at approximately 2 Gy and below for sparsely ionizing radiations, but their δ-electron track ends of between 1.5 and 0.5 keV can deliver 0.5 MGy to a few hundred nm3 volumes, mainly due to multiple scatter detours and multiple secondary electrons. They can cause dual double-strand breaks (DSBs) on the periphery of nucleosomes that are the most common multiply damaged sites, with an average of 1–2 δ-electron track ends per cell nucleus at 2 Gy. LDHS is most likely due to the normal lack of fast, efficient repair of sublethal damage below approximately 0.5 Gy, and requires largely intact key DNA repair genes to achieve significant repair recovery at higher doses. The new repair model describes this phenomenon quite accurately. Cells with key non-homologous end joining (NHEJ) genes knocked-out, lose LDHS but provoke HR repair, and cells with HR genes knocked out may lose some LDHS, but provoke NHEJ repair. The DNA duplication during the S phase results in a direct doubling as well of the total and sublethal hit cross sections. For the lowest LET carbon ions, NHEJ is reduced to where it is almost eliminated at maximum relative biological effectiveness (RBE), while HR is induced more than by X rays, due to complex damage and misrepair of DSBs produced by numerous δ electrons. The use of a lower LET such as electrons or photons during the final week of radiation treatment may potentially maximize complication-free cure. Optimally-designed weekly fractionation schedules are proposed to maximize the DNA repair potential in normal tissues. Additionally, the optimal therapeutic ion species, LET, apoptosis and permanent growth arrest/senescence window is identified with helium, lithium and boron ions and LETs at approximately 15–55 eV/nm, to maximize these quantities in the tumor and minimize them in the normal tissues, resulting in a very high probability of complication-free cure.

Eight different data sets, covering the whole human genome are compared with regard to their genomic distribution. A close correlation between cytological detected chiasma and MLH1 immunofluorescence sites with the recombination density distribution from the HapMap project was found. Sites with a high probability of chromatid breakage after exposure to low and high ionization density radiations are often located inside common and rare Fragile Sites (FSs) indicating that the common Radiation-Induced Breakpoint sites (RIBs) may be a new kind of more local fragility. Furthermore, Oncogenes and other cancer-related genes are commonly located in regions with an increased probability of rearrangements during genomic recombination, or in regions with high probability of copy number changes, possibly since these processes may be involved in oncogene activation and cancer induction. An increased CpG density is linked to regions of high gene density to secure high fidelity reproduction and survival. To minimize cancer induction these genes are often located in regions of decreased recombination density and/or higher than average CpG density. Interestingly, copy number changes occur predominantly at common RIBs and/or FSs at least for breast cancers with poor prognosis and they decrease weakly but significantly in regions with increasing recombination density and CpG density. It is compelling that all these datasets are influenced by the cells handling of double strand breaks and more generally DNA damage on its genome. In fact, the DNA repair genes are systematically avoiding regions with a high recombination density. This may be a consequence of natural selection, as they need to be intact to accurately handle repairable DNA lesions.

In this work, we compared the genomic distribution of common radiation-induced chromosomal breaks to eight different data sets covering the whole human genome. Sites with a high probability of chromatid breakage after exposure to low and high ionization density radiations were often located inside common and rare fragile sites, indicating that they may be a new and more local type of DNA repair-related fragility. Breaks in specific chromosome bands after acute exposure to oil and benzene also showed strong correlation with these sites and fragile sites. In addition, close correlation was found with cytologically detected chiasma and MLH1 immunofluorescence sites and with the HapMap recombination density distributions. Also, of interest, copy number changes occurred predominantly at radiation-induced breaks and fragile sites, at least for breast cancers with poor prognosis, and they decreased weakly but significantly in regions with increasing recombination and CpG density. An increased CpG density is linked to regions of high gene density to secure high-fidelity reproduction and survival. To minimize cancer induction, cancer-related genes are often located in regions of decreased recombination density and/or higher-than-average CpG density. It is compelling that all these data sets were influenced by the cells' handling of double-strand breaks and, more generally, DNA damage on its genome. In fact, the DNA repair genes systematically avoid regions with a high recombination density, as they need to be intact to accurately handle repairable DNA lesions.

A new era in cancer radiation therapy has been gradually emerging during the last decade with the rapid development of many new and powerful methods for plan­ ning treatment and for optimizing the delivery of radiation doses. This process parallels in many respects the rapid devel­ opment in medical imaging technology that took place during the last 20 years, where computed tomography (CT), mag­ netic resonance imaging (MRI), and single photon and positron emission computed tomography (PET and SPECT) soon matured as universal diagnostic tools for clinical use. However, the parallels between the therapeutic and diagnostic developments are more profound than one might think at first sight. Both the diagnostic and the therapeu­ tic technologies allow a true three-dimen­ sional approach to be followed along the entire therapeutic chain, from diagnostic imaging to the delivery of the therapeutic effect by accurately shaped radiation beams incident on a tumour. But there are also deeper parallels between the two areas because the mathematical methods used in tomographic image reconstruction are similar to those adopted in some of the new methods for optimizing radiation therapy. This is seen most clearly in the analogy between the non-uniform dose delivery required by most of these meth­ ods and the back projection of filtered transmission or emission profiles used in image reconstruction algorithms [1, 2]. Owing to the existence of nuclide uptake, a distribution of photon attenua­ tion properties, or a proton density distri­ bution for SPECT, CT or MRI, respectively, these imaging techniques have the advan­ tage that there exists a true solution to the reconstruction problem, at least if all

With the lightest ions beyond protons, i.e., Helium, Lithium and Beryllium ions, highly specific Molecular Bragg peak radiation therapy of malignant tumors is possible with minimal adverse normal tissue reactions elsewhere in the body.The Bragg peak ionization density is only elevated in a few mm wide spot at the end of the ion range with resultant increased local apoptosis and senescence.By only placing Bragg peaks in the tumor, an increased local therapeutic effect is obtained with only low ionization density and easily repairable damage in surrounding normal tissues.A geometrical accuracy in dose delivery of about 1 mm is possible with these ions, and high-resolution molecular tumor imaging is then needed to accurately delineate the target volume.It is proposed that ultra-sensitivity whole body PET cameras should be built to achieve mm resolution in the whole target region.With about 1 m axial field of view an almost 50-fold increased sensitivity and a reduced imaging time down to a few minutes should be in reach.To get sub mm resolution with whole body spectroscopic MR, about 15 Tesla to 20 Tesla is needed and will significantly increase the resolution with tumor specific metabolite imaging from the 10 mm to 15 mm available today.In the future, it should also be possible to achieve a resolution as high as 10 µm with Stereoscopic Phase Contrast X-ray imaging, or to reduce the dose and imaging time by using 2 projections instead of 400 to get 3D images, thanks to the significantly increased contrast in each projection.When these new methods are brought into clinical use together with light ion therapy a mean tumor cure as high as 80% should be possible, and even more if the new early tumor detection and malignancy estimation methods are brought into more regular clinical use.

In the present study we develop a new technique for the production of clean quasi-monochromatic 11C positron emitter beams for accurate radiation therapy and PET–CT dose delivery imaging and treatment verification. The 11C ion beam is produced by projectile fragmentation using a primary 12C ion beam. The practical elimination of the energy spread of the secondary 11C fragments and other beam contaminating fragments is described. Monte Carlo calculation with the SHIELD-HIT10+ code and analytical methods for the transport of the ions in matter are used in the analysis. Production yields, as well as energy, velocity and magnetic rigidity distributions of the fragments generated in a cylindrical target are scored as a function of the depth within 1cm thick slices for an optimal target consisting of a fixed 20cm section of liquid hydrogen followed by a variable thickness section of polyethylene. The wide energy and magnetic rigidity spread of the 11C ion beam can be reduced to values around 1% by using a variable monochromatizing wedge-shaped degrader in the beam line. Finally, magnetic rigidity and particle species selection, as well as discrimination of the particle velocity through a combined Time of Flight and Radio Frequency-driven Velocity filter purify the beam from similar magnetic rigidity contaminating fragments (mainly 7Be and 3He fragments). A beam purity of about 99% is expected by the combined method.

Biologically Optimized Radiation Therapy, pp. 157-294 (2014) No Access4: Development of High Quality Beams for Uniform and Intensity-Modulated Radiation TherapyAnders Brahme, Roger Svensson and Bo NilssonAnders Brahme, Roger Svensson and Bo Nilssonhttps://doi.org/10.1142/9789814277761_0004Cited by:0 PreviousNext AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsRecommend to Library ShareShare onFacebookTwitterLinked InRedditEmail Abstract: The following sections are included: Toward Advanced Dose Delivery Techniques Development of Radiation Sources for External Beam Treatments Traditional Uniform Beam Dose Delivery Treatment Head Design for Broad Photon and Electron Beams Electron Beams Fundamentals of electron beams design Electron beam quality parameters Electron beam flattening Electron beam collimation Scanned beams Photon Beams Bremsstrahlung production Elementary bremsstrahlung pencil beam production Effective source and penumbra Beam-flattening filter Secondary photons Secondary electrons Air Filters Collimators Surface dose beam profiles Total contamination Scanned beams Photon beam quality parameters Intensity-modulated Beams Modern Advanced Dose Delivery Techniques Pencil beam therapy Fan beam therapy Scan beam therapy Dynamic Multileaf Collimation MLC development Dynamic multileaf collimation Equation of motion during dynamic multileaf collimation Narrow Scanned Photon and Electron Beams Introduction Treatment head design for scanned beams Compact treatment head design Scanned bremsstrahlung beams Purging magnet and electron collector design Purging magnet design for full range target Purging magnet design for transmission target technology Design and magnetic field simulation in OPERA 3D Electron collector Collector material MLC as electron collector Verification and safety issues Clinical characterization of scanned photon beams Lateral beam properties Penumbra and effective source size Collimator design for scanned beams Influence of the collimator leaf width on treatment outcome Fast and efficient MLC Optimization of the leaf thickness and edge shape Clinical Possibilities Using High-energy Photon Pencil Beam Scanning Ultrafast IMRT using Scanned Beams Combined with Multileaf Collimation Treatment Outcome with Bremsstrahlung Beams Uniform Beam Optimization Pencil Beam Optimization without Multileaf Collimation Scanned Beam Optimization with a Static Collimator Setting Scanned Beam Optimization with a Number of Collimator Segments Uniform beams Scanned beams Compact High-energy Treatment Units based on Electron Recirculation Gantry-mounted Racetrack Magnet Alignment and Beam Transport in a Gantry-mounted Racetrack Accelerator Shifts in Position of Beam Optics, Quadrupoles Misalignment Contribution from the Earth's Magnetic Field Modeling Gantry-mounted Racetrack Gantry Deformation Inaccuracy in Isocentric Rotation due to Deformations 3D Photon Beam Dose Delivery Monitoring by PET-CT Imaging In Vivo Dose Delivery Verification Using Photonuclear Reactions Phantom Studies Dose Delivery Verification by PET-CT Imaging of Photonuclear Reactions during High-energy Photon Therapy Bibliography FiguresReferencesRelatedDetails Biologically Optimized Radiation TherapyMetrics History PDF download

Heterogeneous tumors may have a wide spectrum of radiation sensitivities due to factors like their clonal distribution and degree of genetic instability and gradients of oxygen and nutrients. Recent studies demonstrate that the radiation response of heterogeneous tumors can be well described by a single effective clonogen compartment when the dose–response relation is of main interest. When a correct description of the clonogenic survival is important at both low and high doses, a description based on one sensitive and one resistant clonogen compartment will generally be necessary and sufficient. Such a description is valuable, for example, when in vivo positron emission tomography-CT data are acquired early in the treatment to predict the required curative radiation dose. Methods are given for derivation of the sensitive and resistant cell compartments based on clinically observed dose–response relations and degrees of hypoxia. Principal characteristics of heterogeneous tumors are derived, such as the dose D t describing the transition zone between sensitive and resistant cell predomination, where the maximum change in slope of the cell survival curve occurs. Since the effective compartments are based on the whole spectrum of radiation resistance, they will take both extreme and intermediate values into account, thus providing an accurate description of radiation response over the entire range of clinically relevant doses.

Starting from basic phase space physics, the transport of particles in six-dimensional coordinates and velocity, or energy and direction space are described based on the equation of continuity. The different steps in the development of the Vlasov, Liouville, and Boltzmann equations are described along with some of their main applications. Special attention is given to the generalized Fermi–Eyges solution of the Fokker–Planck approximation of the Boltzmann equation owing to its importance in describing the physics of narrow elementary pencil beams of charged particles. The solution is applicable to both electrons and ions taking into account all major interactions from energy loss and attenuation to small-angle multiple Columb scattering. In the last section, many of these transport results are applied to make dosimetry accurate such as in Fano’s theorem and for obtaining a consistent and coherent definition of an effective reference volume concept allowing the accurate definition and separation of the effective point of measurement from the fluence perturbation factor at the same time as the application of traditional stopping-power ratio tabulations. Many of the fluence perturbation factors are derived based on the generalized Fermi–Eyges solution of the Boltzmann equation.

Biologically Optimized Radiation Therapy, pp. 499-648 (2014) No Access8: Physical, Biological, and Clinical Background for the Development of Biologically Optimized Light Ion TherapyAnders Brahme and Hans SvenssonAnders Brahme and Hans Svenssonhttps://doi.org/10.1142/9789814277761_0008Cited by:1 PreviousNext AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsRecommend to Library ShareShare onFacebookTwitterLinked InRedditEmail Abstract: The following sections are included: Introduction Present Use of Radiation Therapy for Malignant Tumors Cancer Statistics Radiation Therapy Treatment Strategy Therapeutic Properties of Light Ion Beams High Dose to the Tumor and Low dose to Healthy Normal Tissues Small Cell Cycle Variation and Generally No Dose Rate Effect on Cell Survival High RBE in the Tumor and Low RBE in the Normal Tissues Low Dependence on the Tumor Oxygenation Status Simultaneously Low OER and High Dose, LET, and RBE in the Tumor Efficient Analytical Description of the Biological Effectiveness of Light Ions at Low and High Doses and LETs Cell survival curve LET dependence of the inactivation cross-section Relative biological effectiveness Oxygen enhancement ratio Repairable and conditionally repairable damage model LET dependence of a, b, and c LET dependence of apoptosis induction High Apoptotic Cell Kill in the Tumor but not in Normal Tissue Relation between the RCR, the Linear, and LQ Models Fewer Microscopic Cold Spots and Higher Microscopic Uniformity of the Energy Deposition at Intermediate LETs Selection of Optimal Treatment Technique and Particle Species Selection of Optimal Radiation Quality and LET Verification of the Position of the High Dose Volume using PET or PET-CT Imaging Summary of the Clinical Value of Different Light Ions Species Clinical Indications Radiation-resistant and Hypoxic Tumors Targets Located Close to Organs at Risk Tumors of Complex Local Spread Estimation of the Potential Number of Patients Important Areas of Research and Development with Light Ions Molecular Genetics to Individualize Cancer Treatment Improved Diagnostic Imaging by PET-CT and Real-time PET Accurate Patient Fixation and Registration of Organ and Tumor Movements Radiation Physics: Macro and Microscopic Dose Delivery, Nano and Microdosimetry, LET, and Secondary Electron Spectra Radiation Biology: OER, RBE, Apoptosis, Senescence, and DRRs Physical and Biological Treatment Optimization Development of Comprehensive Cancer Centers Development of Advanced Biologically Optimized Radiation Therapy Patient Recruitment, Equipment, and Building Design Patient Recruitment and Treatment Capacity Conventional Radiotherapy and Biologically Optimized IMRT Connection to Conventional Radiotherapy Number of Patients Development of a Second-generation Ultra-compact Treatment System for Biologically Optimized Light Ion Therapy at the New Karolinska Beam Delivery System, Treatment Rooms, and Gantries Accelerators Financial Aspects Capital Expenditure Cost per Patient for Different Types of Cancer Treatments Conclusion Bibliography FiguresReferencesRelatedDetailsCited By 1A DNA Repair-Based Model of Cell Survival with Important Clinical ConsequencesAnders Brahme1 Sep 2020 | Radiation Research, Vol. 194, No. 3 Biologically Optimized Radiation TherapyMetrics History PDF download

To accurately describe the radiation response over a wide dose and ionization density range, binomial and Poisson statistics have been combined with the recently developed potentially repairable–conditionally repairable (RCR) damage-response model. The combination is shown to have several advantages for the accurate description of the cell survival response at both low and very high doses and linear energy transfers (LETs), especially when compared with the classical linear–quadratic cell survival model. Interestingly, the potentially and conditionally repairable damage types also may be linked to the two major radiation damage repair pathways of eukaryotic cells, namely, nonhomologous end-joining and homologous recombination. In addition, the RCR model describes the interaction of low- and high-LET damage in different dose fractions more accurately than any other known model. This is of considerable importance when describing the response of tumors and normal tissues during pencil-beam scanning with light-ion beams where low- and high-LET dose fractions from the plateau and the Bragg peak can interact synergistically when being delivered quasisimultaneously. In conclusion, considering the unique biological properties of light-ion beams (compared to conventional low-LET beams), such as their increased effect on hypoxic tumors, their microdosimetric energy deposition heterogeneity, and their pencil-beam energy deposition kernels, the largest clinical advantages are obtained with medium-LET beams (≈ 20–50 eV nm− 1). This applies even for radiation-resistant tumors, at least when the goal is to maximize tumor cure with minimal adverse reactions in normal tissues.

Biologically Optimized Radiation Therapy, pp. 17-86 (2014) No Access2: Fundamentals of Clinical Radiation BiologyAnders Brahme, Panayiotis Mavroidis and Bengt K. LindAnders Brahme, Panayiotis Mavroidis and Bengt K. Lindhttps://doi.org/10.1142/9789814277761_0002Cited by:1 PreviousNext AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsRecommend to Library ShareShare onFacebookTwitterLinked InRedditEmail Abstract: The following sections are included: Introduction Growth Control, Cell Cycle Regulation, and Damage Surveillance and Repair Molecular Biology of Radiation Sensitivity in Tumors and Normal Tissues Radiation Quality and Radiation Effects Physical and Chemical Effects of Radiation Quality Radiobiological Effects of Radiation Quality From Cell Survival Curves to Dose–Response Relations for Organized Tissues Cell Survival Models Relationship between the RCR Cell Survival Model and the Classical Models Radiation Biology of Functional Tumor Cells Mixed Radiation Qualities Dose–Response Relation Binomial and Poisson models Volume Effects Relative seriality model Parallel architecture model Gaussian distribution model Weibull distribution model Dose–Response Relation for Hypoxic and Generally Heterogeneous Tissues Radiation response with spatially varying dose, clonogen density, and radiation resistance Radiation response with a microscopic distribution of radiation resistance and uniform dose Influence of Fractionation on the Dose–Response Relation Generalization of the Normalized Dose–Response Gradient to Nonuniform Dose Delivery and Complex Tissues Uniform dose delivery Nonuniform dose delivery γ Value for multiple target volumes and normal tissues Derivation of Dose–Response Relations from Clinical Data Tumors Normal Tissues Statistical Analysis Glossary of Terms Radiobiological and Physical Terms Bibliography FiguresReferencesRelatedDetailsCited By 1Fundamentals of Physically and Biologically Based Radiation Therapy OptimizationA. Brahme and J. Löf1 Jan 2014 Biologically Optimized Radiation TherapyMetrics History PDF download