Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas.

High-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood-brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456-69. ©2017 AACR.

Experimental characterization of the dosimetric properties of a newly designed I-Seed model AgX100 ¹²5I interstitial brachytherapy source.

PURPOSE: To measure the dosimetric properties of the Model AgX100 ¹²5I source for interstitial brachytherapy. METHODS AND MATERIALS: The photon energy spectrum emitted by the AgX100 source was measured using a high-resolution germanium spectrometer customized for low-energy brachytherapy source spectrometry. The dose distribution around the source was measured using the 1×1×1 mm³ lithium fluoride thermoluminescent dosimeters in water-equivalent solid phantoms. The dosimetric parameters needed for dose calculation using the American Association of Physicists in Medicine Task Group No. 43 (TG-43) formalism were determined and compared with the results of a Monte Carlo simulation by an independent research group and with the TG-43 consensus values of the well-established model 6711 source. RESULTS: It was found that (1) the photon energy spectrum emitted by the AgX100 source was nearly identical to that emitted by the model 6711, (2) the dose-rate constant determined by the photon spectrometry technique (0.957±0.037 cGy·h⁻¹·U⁻¹) and by the thermoluminescent dosimeter technique (0.995±0.066 cGy·h⁻¹·U⁻¹) was within 1.5% of the corresponding values determined for the model 6711 source, and (3) the radial dose function and the anisotropy function of the AgX100 source were also found to be similar to the consensus data established for the model 6711 source in the TG-43 update report. CONCLUSIONS: A comprehensive dosimetric characterization has been carried out for the model AgX100 ¹²5I source. The American Association of Physicists in Medicine TG-43 dosimetry parameters for this source has been determined from the experimental data.

Impact of source-production revision on the dose-rate constant of 131Cs interstitial brachytherapy sources.

PURPOSE: Since its introduction in 2004, the model CS-1 Rev.1 131Cs source has been used in many radiation therapy clinics for prostate brachytherapy. In 2006, this source model underwent a Rev.2 production revision. The aim of this work was to investigate the dosimetric influences of the Rev.2 production revision using high-resolution photon spectrometry. METHODS: Three CS-1 Rev.1 and three CS-1 Rev.2 131Cs sources were used in this study. The relative photon energy spectrum emitted by each source in the transverse bisector of the source was measured using a high-resolution germanium detector designed for low-energy photon spectrometry. Based on the measured photon energy spectrum and the radioactivity distribution in the source, the dose-rate constant (lamda) of each source was determined. The effects of the Rev.2 production revision were quantified by comparing the emitted photon energy spectra and the lamda values determined for the sources manufactured before and after the production revision. RESULTS: The relative photon energy spectrum originating from the principal emissions of 131Cs was found to be nearly identical before and after the Rev.2 revision. However, the portion of the spectrum originating from the production of fluorescent x rays in niobium, a trace element present in the source construction materials, was found to differ significantly between the Rev.1 and Rev.2 sources. The peak intensity of the Nb Kalpha and Nb Kbeta fluorescent x rays from the Rev.2 source was approximately 35% of that from the Rev.1 source. Consequently, the nominal lamda value of the Rev.2 source was found to be greater than that determined for the Rev.1 source by approximately 0.7% +/- 0.5%. CONCLUSIONS: A significant reduction (65%) in relative niobium fluorescent x-ray yield was observed in the Rev.2 131Cs sources. The impact of this reduction on the dose-rate constant was found to be small, with a relative difference of less than 1%. This study demonstrates that photon spectrometry can be used as a sensitive and convenient tool for monitoring and for quantifying the dosimetric effects of brachytherapy source-production revisions. Because production revision can change both the geometry and the atomic composition of brachytherapy sources, its dosimetric impact should be carefully monitored and evaluated for each production revision.

A photon spectrometric dose-rate constant determination for the Advantage Pd-103 brachytherapy source.

PURPOSE: Although several dosimetric characterizations using Monte Carlo simulation and thermoluminescent dosimetry (TLD) have been reported for the new Advantage Pd-103 source (IsoAid, LLC, Port Richey, FL), no AAPM consensus value has been established for the dosimetric parameters of the source. The aim of this work was to perform an additional dose-rate constant (lamda) determination using a recently established photon spectrometry technique (PST) that is independent of the published TLD and Monte Carlo techniques. METHODS: Three Model IAPD-103A Advantage Pd-103 sources were used in this study. The relative photon energy spectrum emitted by each source along the transverse axis was measured using a high-resolution germanium spectrometer designed for low-energy photons. For each source, the dose-rate constant was determined from its emitted energy spectrum. The PST-determined dose-rate constant (PST lamda) was then compared to those determined by TLD (TLD lamda) and Monte Carlo (MC lamda) techniques. A likely consensus lamda value was estimated as the arithmetic mean of the average lamda values determined by each of three different techniques. RESULTS: The average PST lamda value for the three Advantage sources was found to be (0.676 +.- 0.026) cGyh(-1) U(-1). Intersource variation in PST lamda was less than 0.01%. The PST lamda was within 2% of the reported MC lamda values determined by PTRAN, EGSnrc, and MCNP5 codes. It was 3.4% lower than the reported TLD lamda. A likely consensus lamda value was estimated to be (0.688 +/- 0.026) cGyh(-1) U(-1), similar to the AAPM consensus values recommended currently for the Theragenics (Buford, GA) Model 200 (0.686 +/- 0.033) cGyh(-1) U(-1), the NASI (Chatsworth, CA) Model MED3633 (0.688 +/- 0.033) cGyh(-1) U(-1), and the Best Medical (Springfield, VA) Model 2335 (0.685 +/- 0.033) cGyh(-1) U(-1) 103Pd sources. CONCLUSIONS: An independent lamda determination has been performed for the Advantage Pd-103 source. The PST lamda obtained in this work provides additional information needed for establishing a more accurate consensus lamda value for the Advantage Pd-103 source.

Dose rate dependence of the relative biological effectiveness of 103Pd for continuous low dose rate irradiation of BA1112 rhabdomyosarcoma cells in vitro relative to acute exposures.

PURPOSE: To measure the relative biological effectiveness (RBE) of continuous low dose rate irradiation (CLDRI) using 103Pd sources relative to acute high dose rate irradiations (AHDRI) from a 250 kVp x-ray beam and an x-ray beam having an equivalent mono-energetic photon energy equal to the average energy of the 103Pd source for BA1112 rhabdomyosarcoma cells. MATERIALS AND METHODS: A customized 103Pd irradiator was built to provide CLDRI using 103Pd at different dose rates relevant to clinical interstitial brachytherapy to BA1112 rhabdomyosarcoma cells growing in exponential phase in culture. A special x-ray beam that simulates the photon energies emitted by the 103Pd source was also developed to provide acute high dose rate irradiation at those energies. Cell survival curves from different irradiation conditions were measured. The RBE with respect to AHDRI using standard 250 kVp x-rays was determined from the doses required to achieve a cell surviving faction of 0.01. RESULTS: For acute irradiation, the RBE of the x-rays simulating (103)Pd was 1.24 relative to 250 kVp x-rays. A profound dose rate effect was observed at low dose rates in the range of 6.8 - 14.4 cGy/h that are typical of permanent interstitial brachytherapy. At cell-surviving fraction of 0.01, the RBE of CLDRI at 6.8 and 14.4 cGy/h using 103Pd sources was reduced by a factor of 3 and 2, respectively, relative to the acute exposure. This observation is in good agreement with recent in vivo tumor cure studies performed on BA1112 tumor. CONCLUSION: The relative biological effectiveness of the photons emitted by 103Pd depends on both the linear energy transfer (LET) of the low energy photons and the dose rate of the irradiation. The higher LET of 103Pd photons is biologically more effective in killing BA1112 tumor cells compared to conventional 250 kVp x-rays when both are delivered at the same dose rate. But the gain in RBE that results from the higher LET can be quickly negated by the reduced dose rate of the irradiation.

Relative biological effectiveness of 103Pd and 125I photons for continuous low-dose-rate irradiation of Chinese hamster cells.

Monolayers of Chinese hamster lung cells (CCL-16) in a polystyrene phantom were irradiated in vitro by 103Pd and 125I sources at dose rates of 6 to 72 cGy/h. Cell survival curves for acute high-dose-rate irradiation (over 30 Gy/h) were also measured using nearly monoenergetic X-ray beams which were designed to simulate the mean energies of photons emitted by 125I and 103Pd and also using a clinical 250 kVp X-ray beam. A profound dose-rate effect is observed over the dose-rate range of 6 to 20 cGy/h. An inverse dose-rate effect was observed for both radionuclides, with its onset occurring at a dose rate of about 20-30 cGy/h. The average RBE of 103Pd relative to 125I was determined to be 1.45 +/- 0.07, 1.41 +/- 0.07, 0.70 +/- 0.07 and 1.49 +/- 0.07 at dose rates of 6.9, 12.6, 19.0 and 26.7 cGy/h, respectively. Because 103Pd implants are generally prescribed at a higher initial dose rate (21 cGy/h) than the corresponding 125I implants (7 cGy/h), the effects of both dose rate and photon energy on biological response must be considered together. For the CCL-16 cells, the RBE of 103Pd at 19.0 cGy/h relative to that of 125I at 6.9 cGy/h was estimated to be 2.3 +/- 0.5.

Development of a rat solid tumor model for continuous low-dose-rate irradiation studies using 125I and 103Pd sources.

PURPOSE: To develop an experimental technique for studying the radiobiology of continuous low-dose-rate irradiation (CLDRI) using clinical brachytherapy sources emitting low energy photons for a rat solid tumor model. METHODS AND MATERIALS: BA1112 tumors were grown between the ears of 14-week-old male WAG/Rij rats by interdermal inoculation. A radioactive source afterloading system, which consists of a lightweight helmet sutured to the rat and a nine-source polystyrene applicator, was fabricated for in vivo tumor irradiation by (125)I and (103)Pd brachytherapy sources. This system has a 12 x 12 mm opening in the center to accommodate the tumor and its growth during irradiation (the diameter of a typical BA1112 tumor was about 6 mm when radiation was applied). The spatial locations of the nine sources were optimized to produce an as uniform as possible three-dimensional dose distribution to the central portion of the applicator for both the (125)I and (103)Pd sources. Absolute dose delivered by the applicator was verified by point dose measurements using calibrated TLD in a polystyrene phantom that mimics the scattering environment of the tumor on the rat. RESULTS: The feasibility of tumor cure experiments using the experimental technique presented in this work was demonstrated. The technique was used to study the influence of initial dose rate on the in vivo tumor cure probability of BA1112 tumors irradiated by (125)I and (103)Pd sources at dose rates varying from 8-20 cGy/h. The technique was also used for studying the in vitro tumor cell survival following in vivo CLDRI irradiation of the tumor. CONCLUSION: An experimental technique using an in vivo tumor model has been developed for studying the radiobiological effects of continuous low-dose-rate irradiations using (125)I sources alone, (103)Pd sources alone, or a mixture of (125)I and (103)Pd sources.