Multicellular Spheroids as In Vitro Models of Oxygen Depletion During FLASH Irradiation.

PURPOSE: The differential response of normal and tumor tissues to ultrahigh-dose-rate radiation (FLASH) has raised new hope for treating solid tumors but, to date, the mechanism remains elusive. One leading hypothesis is that FLASH radiochemically depletes oxygen from irradiated tissues faster than it is replenished through diffusion. The purpose of this study was to investigate these effects within hypoxic multicellular tumor spheroids through simulations and experiments. METHODS AND MATERIALS: Physicobiological equations were derived to model (1) the diffusion and metabolism of oxygen within spheroids; (2) its depletion through reactions involving radiation-induced radicals; and (3) the increase in radioresistance of spheroids, modeled according to the classical oxygen enhancement ratio and linear-quadratic response. These predictions were then tested experimentally in A549 spheroids exposed to electron irradiation at conventional (0.075 Gy/s) or FLASH (90 Gy/s) dose rates. Clonogenic survival, cell viability, and spheroid growth were scored postradiation. Clonogenic survival of 2 other cell lines was also investigated. RESULTS: The existence of a hypoxic core in unirradiated tumor spheroids is predicted by simulations and visualized by fluorescence microscopy. Upon FLASH irradiation, this hypoxic core transiently expands, engulfing a large number of well-oxygenated cells. In contrast, oxygen is steadily replenished during slower conventional irradiation. Experimentally, clonogenic survival was around 3-fold higher in FLASH-irradiated spheroids compared with conventional irradiation, but no significant difference was observed for well-oxygenated 2-dimensional cultured cells. This differential survival is consistent with the predictions of the computational model. FLASH irradiation of spheroids resulted in a dose-modifying factor of around 1.3 for doses above 10 Gy. CONCLUSIONS: Tumor spheroids can be used as a model to study FLASH irradiation in vitro. The improved survival of tumor spheroids receiving FLASH radiation confirms that ultrafast radiochemical oxygen depletion and its slow replenishment are critical components of the FLASH effect.

Precision radiotherapy using monochromatic inverse Compton x-ray sources.

PURPOSE: The dosimetric properties of inverse Compton (IC) x-ray sources were investigated to determine their utility for stereotactic radiation therapy. METHODS: Monte Carlo simulations were performed using the egs brachy user code of EGSnrc. Nominal IC source x-ray energies of 80 and 150 keV were considered in this work. Depth-dose and lateral dose profiles in water were calculated, as was dose enhancement in the bone. Further simulations were performed for brain and spine treatment sites. The impact of gold nanoparticle doping was also investigated for the brain treatment site. Analogous dose calculations were performed in a clinical treatment planning system using a clinical 6 MV photon beam model and were compared to the Monte Carlo simulations. RESULTS: Both 80 and 150 keV IC beams were observed to have sharp 80-20 penumbra (i.e., < 0.1 mm) with broad low-dose tails in water. For reference, the calculated penumbra for the 6 MV clinical beam was 3 mm. Maximum dose enhancement factors in bone of 3.1, 1.4, and 1.1 were observed for the 80, 150 keV, and clinical 6 MV beams, respectively. The plan quality for the single brain metastasis case was similar between the IC beams and the 6 MV beam without gold nanoparticles. As the concentration of gold within the target increased, the V12 Gy to the normal brain tissue and D max within the target volume significantly decreased and the conformity significantly improved, which resulted in superior plan quality over the clinical 6 MV beam plan. In the spine cases, the sharp penumbra and enhanced dose to bone of the IC beams produced superior plan quality (i.e., better conformity, normal tissue sparing, and spinal cord sparing) as compared to the clinical 6 MV beam plans. CONCLUSIONS: The findings from this work indicate that inverse Compton x-ray sources are well suited for stereotactic radiotherapy treatments due to their sharp penumbra and dose enhancement around high atomic number materials. Future work includes investigating the properties of intensity-modulated inverse Compton x-ray sources to improve the homogeneity within the target tissue.

External beam radiation therapy with kilovoltage x-rays.

Kilovoltage (kV) x-rays are most commonly used for diagnostic imaging due to their sensitivity to tissue composition. In radiation therapy (RT), due to their fast attenuation, kV x-rays are typically only used for superficial irradiation of skin cancer and for intra-operative RT (IORT). Recently, however, a number of kV RT techniques have emerged. In this review article, we provide a brief overview of the use of kV x-rays for RT. Various kV x-ray source technologies suitable for RT, such as conventional x-ray tubes as well as novel x-ray sources, are first described. This x-ray source section is then followed by a section on their implementation in terms of clinical, veterinary and preclinical applications. Specifically, IORT, superficial RT and dose enhancement with iodine and gold nanoparticles, as well as microbeam RT and FLASH RT are discussed in this context. Then, a number of kV x-ray RT applications in modeling and proof-of-principle stages, such as breast external beam RT with rotational sources, kilovoltage arc therapy and the BriXS Compton pulsed x-ray sources, are reviewed. Finally, some clinical and economic considerations for the development of kV RT techniques are discussed.

Inverse optimization of low-cost kilovoltage x-ray arc therapy plans.

PURPOSE: The objective of this work was to investigate the benefits of using inverse optimization treatment planning for kilovoltage arc therapy (KVAT) and to assess the dosimetric limitations of KVAT. METHODS: Monte Carlo (MC) calculated, inversely optimized KVAT plans of spherical, idealized breast, lung, and prostate lesions were calculated using the EGSnrc/BEAMnrc and DOSXYZnrc MC codes. The dose delivered with the KVAT system, which generates 200-225 kV photon beamlets, was calculated and inversely optimized using an optimization framework developed at McGill University. KVAT dose distributions were compared with inversely optimized and MC generated megavoltage (MV) volumetric modulated arc therapy (VMAT) plans as a reference. Prescription doses delivered to 95% of the planning target volume (PTV) were 38.5 (10 fractions), 60 (30 fractions) and 73.8 (41 fractions) Gy for the breast, lung and prostate patients, respectively. Dose distributions, dose volume histograms, and PTV homogeneity indices were used to evaluate KVAT and VMAT plans based on RTOG protocols. RESULTS: All organ-at-risk (OAR) doses were within prescribed dose limits for KVAT and VMAT plans. Generally, KVAT plans delivered higher doses to OARs. For example, due to the lower energy of KVAT, 50% of the rib volume received 12.9 Gy from KVAT while only receiving 2.5 Gy from VMAT. OAR doses were especially high for the KVAT prostate plan due to the presence of large volumes of bony anatomy, which illustrates a limitation of the KVAT system. The KVAT treatment times per fraction for the breast, lung and prostate patients were 2.8, 2.6 and 5.5 min, respectively. CONCLUSIONS: The inversely optimized KVAT plans presented in this work have demonstrated the ability of our novel low-cost, kilovoltage x-ray therapy system to safely treat deep-seated spherical lesions in breast and lung patients while meeting RTOG dose constraints on OARs.

Monte Carlo simulations of a kilovoltage external beam radiotherapy system on phantoms and breast patients.

PURPOSE: To determine the most suitable lesion size and depth for radiotherapy treatments with a prototype kilovoltage x-ray arc therapy (KVAT) system through Monte Carlo simulations of the dose delivered to lesion, dose homogeneity, and lesion-to-skin ratio. METHODS: Monte Carlo simulations were used to calculate dose distributions generated by a novel low-energy kilovoltage x-ray system to a variety of clinically relevant lesion sizes and depths in phantoms and for hypothetical partial breast irradiations of patients in supine and prone positions. The treatments by 200 kV KVAT system were modeled for four sizes of tumor (1-4 cm diameter) at three depths (superficial, middle, and deep) in two sizes of cylindrical water phantoms (16.2-cm and 32.2-cm diameter). In addition, treatments of 3-cm and 4-cm diameter lesions were modeled for two breast patients in prone and supine positions. Dose distributions were calculated using the EGSnrc/DOSXYZnrc code package. Phantom study metrics included lesion-to-skin ratio, dose delivered to isocenter (cGy/min), dose homogeneity, dose profiles, and cumulative dose volume histograms. Lesion-to-skin ratio, lesion-to-rib ratio, dose profiles, and cumulative dose volume histograms were used to evaluate simulated breast patient treatments. Supine breast irradiations were compared to 6-MV VMAT plans. The criterion applied to evaluate the dose distributions was derived from NSABP-B39/RTOG 0413 for accelerated partial breast irradiation. Skin dose was limited to a maximum of 250 cGy for a prescribed lesion dose of 385 cGy per fraction (with the whole treatment being delivered in 10 fractions). This produced the minimum lesion-to-skin dose ratio of 1.5 that served as the main guideline, along with other metrics, for evaluation of future clinical viability of treatments. RESULTS: Phantom dose distributions in the centrally located lesions treated with 360-degree KVAT were found to be superior to dose distributions in off-center lesions with the exception of isocenter dose, which was highest for lesions located closer to the phantom surface. Dose metrics were more favorable for smaller lesions, suggesting that KVAT might be most suitable for treatment of lesions of 1-2 cm in diameter down to depths of 8.1 cm along with 3 cm lesions at depths from 3 cm to 8.1 cm. In addition, treatments of 4-cm lesions were found to be acceptable down to the depths of 4.1 cm (in the 16.2-cm phantom) and 8.1 cm (in the 32.2-cm phantom). At depths from 8.1-cm to 16.1-cm, treatments of 1-cm to 4-cm lesions are possible at the cost of decreased dose rate. KVAT breast treatments in the supine patient position demonstrated that increasing the arc angle and decreasing lesion size improved lesion-to-skin ratio and lesion-to-rib ratio. Supine breast data indicate that 3-cm lesions are treatable at a minimum depth of 3 cm. The 6-MV VMAT plan resulted in lower doses to the ipsilateral lung and the body, but a higher heart dose compared to the KVAT plans. Dose distributions for the prone breast phantoms were superior to the supine cases due to the increased treatment angle of 360-degrees. CONCLUSIONS: Although nonoptimized KVAT dose distributions presented here were of inferior quality to VMAT plans, this work has demonstrated the feasibility of delivering low-energy kilovoltage x-rays to lesions up to 4 cm in diameter to depths of 8.1 cm while sparing surrounding tissue.

Effect of J coupling on 1.3-ppm lipid methylene signal acquired with localised proton MRS at 3 T.

The purpose of this work was to investigate the effect of J-coupling interactions on the quantification and T2 determination of 1.3-ppm lipid methylene protons at 3 T. The response of the 1.3-ppm protons of hexanoic, heptanoic, octanoic, linoleic and oleic acid was measured as a function of point-resolved spectroscopy (PRESS) and stimulated echo acquisition mode (STEAM) TE. In addition, a narrow-bandwidth refocusing PRESS sequence designed to rewind J-coupling evolution of the 1.3-ppm protons was applied to the five fatty acids, to corn oil and to tibial bone marrow of six healthy volunteers. Peak areas were plotted as a function of TE, and data were fitted to monoexponentially decaying functions to determine Mo (the extrapolated area for TE = 0 ms) and T2 values. In phantoms, rewinding J-coupling evolution resulted in 198%, 64%, 44%, 20% and 15% higher T2 values for heptanoic, octanoic, linoleic and oleic acid, and corn oil, respectively, compared with those obtained with standard PRESS. The narrow-bandwidth PRESS sequence also resulted in significant changes in Mo , namely -77%, -22%, 28%, 23% and 28% for heptanoic, octanoic, linoleic and oleic acid, and corn oil, respectively. T2 values obtained with STEAM were closer to the values measured with narrow-bandwidth PRESS. On average, in tibial bone marrow (six volunteers) rewinding J-coupling evolution resulted in 21% ± 3% and 9 % ± 1% higher Mo and T2 values, respectively. This work demonstrates that the consequence of neglecting to consider scalar coupling effects on the quantification of 1.3-ppm lipid methylene protons and their T2 values is not negligible. The linoleic and oleic acid T2 results indicate that T2 measures of lipids with standard MRS techniques are dependent on lipid composition.