Dual Nucleosomal Double-Strand Breaks Are the Key Effectors of Curative Radiation Therapy

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

Physical, Biological, and Clinical Merits of High Energy Boron Ions for Radiation Therapy

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

Dose escalation to high-risk sub-volumes based on non-invasive imaging of hypoxia and glycolytic activity in canine solid tumors:a feasibility study

INTRODUCTION: Glycolytic activity and hypoxia are associated with poor prognosis and radiation resistance. Including both the tumor uptake of 2-deoxy-2-[(18) F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer copper(II)diacetyl-bis(N(4))-methylsemithio-carbazone (Cu-ATSM) in targeted therapy planning may therefore lead to improved tumor control. In this study we analyzed the overlap between sub-volumes of FDG and hypoxia assessed by the uptake of (64)Cu-ATSM in canine solid tumors, and evaluated the possibilities for dose redistribution within the gross tumor volume (GTV). MATERIALS AND METHODS: Positron emission tomography/computed tomography (PET/CT) scans of five spontaneous canine solid tumors were included. FDG-PET/CT was obtained at day 1, (64)Cu-ATSM at day 2 and 3 (3 and 24 h pi.). GTV was delineated and CT images were co-registered. Sub-volumes for 3 h and 24 h (64)Cu-ATSM (Cu3 and Cu24) were defined by a threshold based method. FDG sub-volumes were delineated at 40% (FDG40) and 50% (FDG50) of SUV(max). The size of sub-volumes, intersection and biological target volume (BTV) were measured in a treatment planning software. By varying the average dose prescription to the tumor from 66 to 85 Gy, the possible dose boost (D( B )) was calculated for the three scenarios that the optimal target for the boost was one, the union or the intersection of the FDG and (64)Cu-ATSM sub-volumes. RESULTS: The potential boost volumes represented a fairly large fraction of the total GTV: Cu3 49.8% (26.8-72.5%), Cu24 28.1% (2.4-54.3%), FDG40 45.2% (10.1-75.2%), and FDG50 32.5% (2.6-68.1%). A BTV including the union (∪) of Cu3 and FDG would involve boosting to a larger fraction of the GTV, in the case of Cu3∪FDG40 63.5% (51.8-83.8) and Cu3∪FDG50 48.1% (43.7-80.8). The union allowed only a very limited D( B ) whereas the intersection allowed a substantial dose escalation. CONCLUSIONS: FDG and (64)Cu-ATSM sub-volumes were only partly overlapping, suggesting that the tracers offer complementing information on tumor physiology. Targeting the combined PET positive volume (BTV) for dose escalation within the GTV results in a limited D( B ). This suggests a more refined dose redistribution based on a weighted combination of the PET tracers in order to obtain an improved tumor control

Fast IMRT with narrow high energy scanned photon beams

Purpose: Since the first publications on intensity modulated radiation therapy (IMRT) in the early 1980s almost all efforts have been focused on fairly time consuming dynamic or segmental multileaf collimation. With narrow fast scanned photon beams, the flexibility and accuracy in beam shaping increases, not least in combination with fast penumbra trimming multileaf collimators. Previously, experiments have been performed with full range targets, generating a broad bremsstrahlung beam, in combination with multileaf collimators or material compensators. In the present publication, the first measurements with fast narrow high energy (50 MV) scanned photon beams are presented indicating an interesting performance increase even though some of the hardware used were suboptimal. Methods: Inverse therapy planning was used to calculate optimal scanning patterns to generate dose distributions with interesting properties for fast IMRT. To fully utilize the dose distributional advantages with scanned beams, it is necessary to use narrow high energy beams from a thin bremsstrahlung target and a powerful purging magnet capable of deflecting the transmitted electron beam away from the generated photons onto a dedicated electron collector. During the present measurements the scanning system, purging magnet, and electron collimator in the treatment head of the MM50 racetrack accelerator was used with 3-6 mm thick bremsstrahlung targets of beryllium. The dose distributions were measured with diodes in water and with EDR2 film in PMMA. Monte Carlo simulations with GEANT4 were used to study the influence of the electrons transmitted through the target on the photon pencil beam kernel. Results: The full width at half-maximum (FWHM) of the scanned photon beam was 34 mm measured at isocenter, below 9.5 cm of water, 1 m from the 3 mm Be bremsstrahlung target. To generate a homogeneous dose distribution in a 10 x 10 cm(2) field, the authors used a spot matrix of 100 equal intensity beam spots resulting in a uniformity of collimated 80%-20% penumbra of 9 mm at a primary electron energy of 50 MeV. For the more complex cardioid shaped dose distribution, they used 270 spots, which at a pulse repetition frequency of 200 Hz is completed every 1.36 s. Conclusions: The present measurements indicate that the use of narrow scanned photon beams is a flexible and fast method to deliver advanced intensity modulated beams. Fast scanned photon IMRT should, therefore, be a very interesting modality in the delivery of biologically optimized radiation therapy with the possibility for in vivo treatment verification with PET-CT imaging.authorCount :5Affiliation for 4 of the authors of the Stockholm University: Department of Medical Radiation Physics, Karolinska Institutet and Stockholm Universit

Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions.

Light-ion radiation therapy against hypoxic tumors is highly curative due to reduced dependence on the presence of oxygen in the tumor at elevated linear energy transfer (LET) towards the Bragg peak. Clinical ion beams using spread-out Bragg peak (SOBP) are characterized by a wide spectrum of LET values. Accurate treatment optimization requires a method that can account for influence of the variation in response for a broad range of tumor hypoxia, absorbed doses and LETs. This paper presents a parameterization of the Repairable Conditionally-Repairable (RCR) cell survival model that can describe the survival of oxic and hypoxic cells over a wide range of LET values, and investigates the relationship between hypoxic radiation resistance and LET. The biological response model was tested by fitting cell survival data under oxic and anoxic conditions for V79 cells irradiated with LETs within the range of 30-500 keV/um. The model provides good agreement with experimental cell survival data for the range of LET investigated, confirming the robustness of the parameterization method. This new version of the RCR model is suitable for describing the biological response of mixed populations of oxic and hypoxic cells and at the same time taking into account the distribution of doses and LETs in the incident beam and its variation with depth in tissue. The model offers a versatile tool for the selection of LET and dose required in the optimization of the therapeutic effect, without severely affecting normal tissue in realistic tumors presenting highly heterogeneous oxic and hypoxic regions