Impact of patient positioning uncertainty in noncoplanar intracranial stereotactic radiotherapy.

The aim of this study is to evaluate the patient positioning uncertainty in noncoplanar stereotactic radiosurgery or stereotactic radiotherapy (SRS/SRT) for intracranial lesions with the frameless 6D ExacTrac system. In all, 28 patients treated with SRS/SRT of 70 treatment plans at our institution were evaluated in this study. Two X-ray images with the frameless 6D ExacTrac system were first acquired to correct (XC) and verify (XV) the patient position at a couch angle of 0º. Subsequently, the XC and XV images were also acquired at each planned couch angle for using noncoplanar beams to detect position errors caused by rotating a couch. The translational XC and XV shift values at each couch angle were calculated for each plan. The percentages of the translational XC shift values within 1.0 mm for each planned couch angle for using noncoplanar beams were 77.86%, 72.26%, and 98.47% for the lateral, longitudinal, and vertical directions, respectively. Those within 2.0 mm were 98.22%, 97.96%, and 99.75% for the lateral, longitudinal, and vertical directions, respectively. The maximum absolute values of the translational XC shifts among all planned couch angles for using noncoplanar beams were 2.69, 2.45, and 2.17 mm for the lateral, longitudinal, and vertical directions, respectively. The overall absolute values of the translational XV shifts were less than 1.0 mm for all directions except for one case in the longitudinal direction. The patient position errors were detected after couch rotation for using noncoplanar beams, and they exceeded a planning target volume (PTV) margin of 1.0-2.0 mm used commonly in SRS/SRT treatment. These errors need to be corrected at each planned couch angle, or the PTV margin should be enlarged.

Small-field dosimetry of TrueBeamTM flattened and flattening filter-free beams: A multi-institutional analysis.

PURPOSE: Detector-dependent interinstitutional variations of the beam data may lead to uncertainties of the delivered dose to patients. Here we evaluated the inter-unit variability of the flattened and flattening filter-free (FFF) beam data of multiple TrueBeam (Varian Medical Systems) linear accelerators focusing on the small-field dosimetry. METHODS: The beam data of 6- and 10-MV photon beams with and without flattening filter measured for modeling of an iPLAN treatment planning system (BrainLAB) were collected from 12 institutions - ten HD120 Multileaf Collimator (MLC) and two Millennium120 MLC. Percent-depth dose (PDD), off-center ratio (OCR), and detector output factors (OFdet ) measured with different detectors were evaluated. To investigate the detector-associated effects, we evaluated the inter-unit variations of the OFdet before and after having applied the output correction factors provided by the International Atomic Energy Agency (IAEA) Technical Reports Series no. 483. RESULTS: PDD measured with a field size of 5 × 5 mm2 showed that the data measured using an ionization chamber had variations exceeding 1% from the median values. The maximum difference from median value was 2.87% for 10 MV photon beam. The maximum variations of the penumbra width for OCR with 10 × 10 mm2 field size were 0.97 mm. The OFdet showed large variations exceeding 15% for a field size of 5 × 5 mm2 . When the output correction factors were applied to the OFdet , the variations were greatly reduced. The relative difference of almost all field output factors were within ± 5% from the median field output factors. CONCLUSION: In this study, the inter-unit variability of small-field dosimetry was evaluated for TrueBeam linear accelerators. The variations were large at a field size of 5 × 5 mm2 , and most occurred in a detector-dependent manner.

Impact of detector selections on inter-institutional variability of flattening filter-free beam data for TrueBeam™ linear accelerators.

This study evaluates the type of detector influencing the inter-institutional variability in flattening filter-free (FFF) beam-specific parameters for TrueBeam™ linear accelerators (Varian Medical Systems,Palo Alto, CA, USA). Twenty-four beam data sets, including the percent depth dose (PDD), off-center ratio (OCR), and output factor (OPF) for modeling within the Eclipse (Varian Medical Systems) treatment planning system, were collected from 19 institutions. Although many institutions collected the data using CC13 (IBA Dosimetry, Schwarzenbruck, Germany) or PTW31010 semiflex (PTW Freiburg, Freiburg, Germany) ionization chambers, some institutions used diode detectors, diamond detectors, and ionization chambers with smaller cavities. The OCR data included penumbra width, full width at half maximum (FWHM), and FFF beam-specific parameters, including unflatness and slope. The data measured by CC13/PTW31010 ionization chambers were compared with those measured by all other detectors. PDD data demonstrated the variations within ±1% at the dose fall-off region deeper than peak depth. The penumbra widths of the OCR measured with the CC13/PTW31010 detectors were significantly larger than those measured with all other detectors (P < 0.05). Especially the EDGE detector (Sun Nuclear Corp., Melbourne, FL, USA) and the microDiamond detectors (model 60019; PTW Freiburg) demonstrated much smaller penumbra values compared to those of the CC13/PTW31010 detectors for the 30 × 30 mm2 field. There was no difference in the FWHM, unflatness, and slope parameters between the values for the CC13/PTW31010 detectors and all other detectors. OPF curves demonstrated small variations, and the relative difference from the mean value of each data point was almost within 1% for all field sizes. Although the penumbra region exhibited detector-dependent variations, all other parameters showed tiny interunit variations regardless of the detector type.

An effective method to reduce the interplay effects between respiratory motion and a uniform scanning proton beam irradiation for liver tumors: A case study.

PURPOSE: For scanning particle beam therapy, interference between scanning patterns and interfield organ motion may result in suboptimal dose within target volume. In this study, we developed a simple offline correction technique for uniform scanning proton beam (USPB) delivery to compensate for the interplay between scanning patterns and respiratory motion and demonstrate the effectiveness of our technique in treating liver cancer. METHODS: The computed tomography (CT) and respiration data of two patients who had received stereotactic body radiotherapy for hepatocellular carcinoma were used. In the simulation, the relative beam weight delivered to each respiratory phase is calculated for each beam layer after treatment of each fraction. Respiratory phases with beam weights higher than 50% of the largest weight are considered "skipped phases" for the next fraction. For the following fraction, the beam trigger is regulated to prevent beam layers from starting irradiation in skipped phases by extending the interval between each layer. To calculate dose-volume histogram (DVH), the dose of the target volume at end-exhale (50% phase) was calculated as the sum of each energy layer, with consideration of displacement due to respiratory motion and relative beam weight delivered per respiratory phase. RESULTS: For a single fraction, D1% , D99% , and V100% were 114%, 88%, and 32%, respectively, when 8 Gy/min of dose rate was simulated. Although these parameters were improved with multiple fractions, dosimetric inhomogeneity without motion management remained even at 30 fractions, with V100% 86.9% at 30 fractions. In contrast, the V100% values with adaptation were 96% and 98% at 20 and 30 fractions, respectively. We developed an offline correction technique for USPB therapy to compensate for the interplay effects between respiratory organ motion and USPB beam delivery. CONCLUSIONS: For liver tumor, this adaptive therapy technique showed significant improvement in dose uniformity even with fewer treatment fractions than normal USPB therapy.

Do the representative beam data for TrueBeam™ linear accelerators represent average data?

If the vendor's representative beam data (RBD) for TrueBeam linear accelerators are to be valid for use in clinical practice, the variations in the beam data used for beam modeling must be small. Although a few studies have reported the variation of the beam data of the TrueBeam machines, the numbers of machines analyzed in those studies were small. In this study, we investigated the variation in the beam data for 21 TrueBeam machines collected from 17 institutions with their agreement. In the exponential regions, the percent depth dose (PDD) values showed very small variation, <1% for all the photon energies analyzed. Similarly, the off-center ratio (OCR) values also showed small variation for all energies. In the field regions, the standard deviations of the values of dose difference (DD) between the data for each machine and the study average were <1% for field sizes ≥100 × 100 mm2 . The maximum distance-to-agreement from the average data was <0.5 mm in the penumbra regions. The output factor (OPF) values also showed very small variation (<1%) for all energies and field sizes. Both the PDD and OCR of the average study data showed good agreement with the vendor's RBD for field sizes ≥100 × 100 mm2 . The OPF of the average study data also showed good agreement with the vendor's RBD for all field sizes. However, although all the institutions used ionization chambers with similar cavity volumes, the 30 × 30 mm2 field size showed large DD variations (≥2%) in OCR in the field regions. We conclude that the intermachine variability of TrueBeam linear accelerators was very small except for small field dosimetry, supporting the validity of the use of the RBD for clinical applications. The use of the vendor's RBD might greatly facilitate the quick installation of a new linear accelerator.

Dosimetric effect of rotational setup errors in stereotactic radiosurgery with HyperArc for single and multiple brain metastases.

PURPOSE: In stereotactic radiosurgery (SRS) with single-isocentric treatments for brain metastases, rotational setup errors may cause considerable dosimetric effects. We assessed the dosimetric effects on HyperArc plans for single and multiple metastases. METHODS: For 29 patients (1-8 brain metastases), HyperArc plans with a prescription dose of 20-24 Gy for a dose that covers 95% (D95% ) of the planning target volume (PTV) were retrospectively generated (Ref-plan). Subsequently, the computed tomography (CT) used for the Ref-plan and cone-beam CT acquired during treatments (Rot-CT) were registered. The HyperArc plans involving rotational setup errors (Rot-plan) were generated by re-calculating doses based on the Rot-CT. The dosimetric parameters between the two plans were compared. RESULTS: The dosimetric parameters [D99% , D95% , D1% , homogeneity index, and conformity index (CI)] for the single-metastasis cases were comparable (P > 0.05), whereas the D95% for each PTV of the Rot-plan decreased 10.8% on average, and the CI of the Rot-plan was also significantly lower than that of the Ref-plan (Ref-plan vs Rot-plan, 0.93 ± 0.02 vs 0.75 ± 0.14, P < 0.01) for the multiple-metastases cases. In addition, for the multiple-metastases cases, the Rot-plan resulted in significantly higher V10Gy (P = 0.01), V12Gy (P = 0.02), V14Gy (P = 0.02), and V16Gy (P < 0.01) than those in the Ref-plan. CONCLUSION: The rotational setup errors for multiple brain metastases cases caused non-negligible underdosage for PTV and significant increases of V10Gy to V16Gy in SRS with HyperArc.

Feasibility of virtual starshot analysis providing submillimeter radiation isocenter accuracy: A long-term multi-institutional analysis.

PURPOSE: We developed a technique to calculate the offset between room lasers and the radiation isocenter using a digital Winston-Lutz (WL) test with a starshot technique. We have performed isocenter localization quality assurance (QA) with submillimeter accuracy for a long period. Here we evaluated the feasibility and accuracy of this virtual starshot (VS) analysis for isocenter localization QA. METHODS: A 6-MV photon beam with a square multileaf collimator field was used to irradiate a WL sphere positioned at the intersection of the room lasers. Images were acquired using an electronic portal imaging device. A four-field WL test was performed, and the path of each beam was calculated from the offset between the beam and sphere. Virtual starshot analysis was used to analyze the radiation isocenter, which calculates the center of the beam paths by using a least-squares method, similar to the starshot analysis. Then, eight coplanar and 12 noncoplanar beams were irradiated to evaluate isocenter localization accuracy. RESULTS: Several VS analyses, using different WL spheres, were performed at three institutions, and the calculated accuracies were within 0.1 mm at all institutions. Long-term analysis showed that the isocenter localization accuracy was appropriately managed with three-dimensional accuracy within ± 0.5 mm for 90 months after the first laser adjustments. The offset between each beam and the room laser was within 0.6 mm and within 1.0 mm for eight coplanar and 12 noncoplanar beams, respectively, for 90 months. Cone-beam computed tomography images, acquired after verification beams, showed that the offset between the radiation isocenter and the imaging center was within 0.66 mm for 90 months. The isocenter localization accuracy within 1 mm was kept for long period at other four institutions. CONCLUSIONS: Long-term analysis showed the feasibility of VS analysis for isocenter localization QA, including room laser re-alignment, noncoplanar irradiation verification, and image guidance accuracy.

Salvage high-dose-rate interstitial brachytherapy for locally recurrent rectal cancer: long-term follow-up results.

BACKGROUND: We retrospectively examined outcomes of salvage high-dose-rate interstitial brachytherapy (HDR-ISBT) for locally recurrent rectal cancer (LRRC). METHODS: Nine patients with LRRC were treated with salvage HDR-ISBT. Their median age was 63 years. The median maximum diameter of LRRC was 40 mm (range 20-80 mm). Adenocarcinomas were histologically confirmed in all cases. The prescribed dose was 30 Gy/5 fractions/3 days to 50 Gy/10 fractions/6 days in the combined external-beam radiotherapy group (four patients) and 54 Gy/9 fractions/5 days to 60 Gy/10 fractions/6 days in the monotherapeutic group (five patients). Median follow-up time was 90 months (range 6-221 months). RESULTS: Local control at final follow-up was achieved in five of nine patients. Of these five patients, one experienced a locally re-recurrent tumor in the vaginal wall 33 months after treatment and received re-HDR-ISBT as re-salvage treatment. The 8-year overall survival, local control, and progression-free survival rates were 56, 44, and 33 %, respectively. Based on the Common Terminology Criteria for Adverse Events ver. 4.03, the following Grade 3 adverse events were observed in three patients (≥3 months): Grade 3 skin ulceration in one patient who showed tumor invasion of the skin and whose V100 was 400 cc; Grade 3 vaginal perforation in one patient whose tumor had invaded the vaginal wall; and Grade 3 vagina-to-bladder fistula in one patient whose tumor received re-irradiation. Late adverse events above Grade 3 were not observed. CONCLUSIONS: Long-term follow-up results revealed that salvage HDR-ISBT is a promising treatment for LRRC with tolerable toxicity.

Intra- and intervariability in beam data commissioning among water phantom scanning systems.

Accurate beam data acquisition during commissioning is essential for modeling the treatment planning system and dose calculation in radiotherapy. Although currently several commercial scanning systems are available, there is no report that compared the differences among the systems because most institutions do not acquire several scanning systems due to the high cost, storage space, and infrequent usage. In this report, we demonstrate the intra- and intervariability of beam profiles measured with four commercial scanning systems. During a recent educational and training workshop, four different vendors of beam scanning water phantoms were invited to demonstrate the operation and data collection of their systems. Systems were set up utilizing vendor-recommended protocols and were operated with a senior physicist, who was assigned as an instructor along with vendor. During the training sessions, each group was asked to measure beam parameters, and the intravariability in percent depth dose (PDD). At the end of the day, the profile of one linear accelerator was measured with each system to evaluate intervariability. Relatively very small (SD < 0.12%) intervariability in PDD was observed among four systems at a region deeper than peak (1.5 cm). All systems showed almost identical profiles. At the area within 80% of radiation field, the average, and maximum differences were within ± 0.35% and 0.80%, respectively, compared to arbitrarily chosen IBA system as reference. In the penumbrae region, the distance to agreement (DTA) of the region where dose difference exceed ± 1% was less than 1 mm. Repeated PDD measurement showed small intravariability with SD < 0.5%, although large SD was observed in the buildup region. All four water phantom scanning systems demonstrated adequate accuracy for beam data collection (i.e., within 1% of dose difference or 1 mm of DTA among each other). It is concluded that every system is capable of acquiring accurate beam. Thus the selection of a water scanning system should be based on institutional comfort, personal preference of software and hardware, and financial consideration.

Gemstone spectral imaging: determination of CT to ED conversion curves for radiotherapy treatment planning.

The monochromatic images acquired by Gemstone spectral imaging (GSI) mode on the GE CT750 HD theoretically determines the computed tomography (CT) number more accurately than that of conventional scanner. Using the former, the CT number is calculated from (synthesized) monoenergetic X-ray data. We reasoned that the monochromatic image might be applied to radiotherapy treatment planning (RTP) to calculate dose distribution more accurately. Our goal here was to provide CT to electron density (ED) conversion curves with monochromatic images for RTP. Therefore, we assessed the reproducibility of CT numbers, an important factor on quality assurance, over short and long time periods for different substances at varying energy. CT number difference between measured and theoretical value was investigated. The scanner provided sufficient reproducibility of CT numbers for dose calculation over short and long time periods. The CT numbers of monochromatic images produced by this scanner had reasonable values for dose calculation. The CT to ED conversion curve becomes linear with respect to the relationship between CT numbers and EDs as the energy increases. We conclude that monochromatic imaging from a fast switching system can be applied for the dose calculation, keeping Hounsfield units (HU) stability.

Optimization of Fluence Map for CyberKnife Raster Scanning Intensity Modulated Radiotherapy.

BACKGROUND/AIM: Stereotactic body radiotherapy for prostate cancer using CyberKnife with circular cone requires a long treatment time. Raster scanning intensity modulated radiotherapy (RS-IMRT) has a potential of improving treatment efficacy, introducing shorter treatment time, better target dose uniformity, and lower organ at risk (OAR) dose. The purpose of the study was to develop a fluence optimization system for RS-IMRT. PATIENTS AND METHODS: RS-IMRT plans were created for five prostate cancer patients treated with the Novalis system and parameters were compared to the Novalis treatment plans. From 80 nodes available for the CyberKnife, twelve nodes were arbitrarily selected. On the beam's eye view of each beam, a 100×100 matrix of optimization points was created at the target center plane. The beam fluence map was optimized using the attraction-repulsion model (ARM). The beam fluence maps were converted to the scanning sequence using the ARM and a final dose calculation was performed. RESULTS: For planning target volume (PTV), RS-IMRT plans showed higher dose covering 2% of the volume (D2%) and lower D98% compared to the Novalis plans. However, the homogeneity was within our Institutional clinical protocol. The RS-IMRT plans showed significantly lower OAR dose parameters including bladder volume receiving 100% of prescribed dose (V100%) and dose delivered to 5 cm3 of rectum (D5 cc). CONCLUSION: We developed a fluence optimization system for RS-IMRT that performs the entire RS-IMRT treatment planning process, including scanning sequence optimization and final dose calculation. The RS-IMRT was capable of generating clinically acceptable plans.

Evaluation of Lung and Liver Tumor Dose Coverage Treated With the CyberKnife Synchrony System With Consideration of Measured Tracking Errors.

BACKGROUND/AIM: Lung and liver tumor dose coverage was evaluated for the CyberKnife synchrony respiratory tracking system (SRTS) with consideration of the motion tracking accuracy measured for motion patterns of individual patients. PATIENTS AND METHODS: Seven treatment plans of six cases treated with the SRTS were evaluated. The motion phantom was moved with the motion data derived from the treatment log files. A laser emitted from the linac head to the moving phantom block was recorded with a webcam, and the tracking accuracy was evaluated. The dose volume histogram (DVH) of planning target volume (PTV) and gross tumor volume (GTV) were calculated by a pencil beam algorithm with shifting the beams with Gaussian random numbers mimicking the measured tracking errors. RESULTS: The tracking errors measured with the motion phantom in the lateral direction were within ±2 mm for 90% of beam-on time. The tracking errors in the longitudinal direction were within ±3.0 mm and ±1.1 mm for 90% and 50% of beam-on time, respectively. Although one case showed a decrease in the dose covering 95% of PTV (D95%) by 1.8%, the change in the dose covering 99% of GTV (D99%) was within 1%. CONCLUSION: This study evaluated the motion tracking errors of the SRTS by a motion phantom moved with the patients' respiration signal, and the impact of the tracking errors on the target coverage was calculated. Even for respiratory patterns with large maximum tracking errors, sufficient GTV coverage is achievable if the beam is accurately delivered for high percentage of beam-on time.

Inverse planning optimization with lead block effectively suppresses dose to the mandible in high-dose-rate brachytherapy for tongue cancer.

PURPOSE: In this study, we developed in-house software to evaluate the effect of the lead block (LB)-inserted spacer on the mandibular dose in interstitial brachytherapy (ISBT) for tongue cancer. In addition, an inverse planning algorithm for LB attenuation was developed, and its performance in mandibular dose reduction was evaluated. METHODS: Treatment plans of 30 patients with tongue cancer treated with ISBT were evaluated. The prescribed dose was 54 Gy/9 fractions. An in-house software was developed to calculate the dose distribution based on the American Association of Physicists in Medicine (AAPM) Task Group No.43 (TG-43) formalism. The mandibular dose was calculated with consideration of the LB attenuation. The attenuation coefficient of the lead was computed using the PHITS Monte Carlo simulation. The software further optimized the treatment plans using an attraction-repulsion model (ARM) to account for the LB attenuation. RESULTS: Compared to the calculation in water, the D2 cc of the mandible changed by - 2.4 ± 2.3 Gy (range, - 8.6 to - 0.1 Gy) when the LB attenuation was considered. The ARM optimization with consideration of the LB resulted in a - 2.4 ± 2.4 Gy (range, - 8.2 to 0.0 Gy) change in mandibular D2 cc. CONCLUSIONS: This study enabled the evaluation of the dose distribution with consideration of the LB attenuation. The ARM optimization with lead attenuation further reduced the mandibular dose.

Dosimetric Evaluation of CyberKnife Synchrony System for Liver Tumors With Respiratory Phase Shifts.

BACKGROUND/AIM: This study evaluated the effects of the respiratory phase shifts between liver tumor and chest wall motions on the dose distribution for the CyberKnife Synchrony respiratory tracking system (SRTS). PATIENTS AND METHODS: Eight patients who received stereotactic body radiotherapy for hepatocellular carcinoma or liver metastases were analyzed. Three-dimensional (3D) motion of the implanted fiducial markers and vertical motion of the sternal bone were derived from the four-dimensional computed tomography (4D-CT) images acquired with a 320-row area detector CT. For each patient, Gaussian random numbers were generated for the standard deviation of the tracking error calculated from the phase shift and a literature. For each voxel of the target, the dose delivered from each beam was calculated 100 times with the random 3D offsets representing the tracking error. RESULTS: The median respiratory phase shifts were 6.0% and 4.6% for the anterior-posterior (AP) and superior-inferior (SI) directions, respectively. The median motion tracking errors influenced by respiratory phase shifts were 1.21 mm and 0.96 mm for the AP and SI directions, respectively. The change in the dose covering 90% of the target (D90%) was within 1.1% when median phase shifts were considered. When evaluating the 90th percentile of the phase shifts, the D90% decreased up to 6.6%. CONCLUSION: We have developed a technique to estimate the impact of the respiratory phase shifts on the dose distribution of a liver tumor treated with the SRTS. The calculation of the respiratory phase shifts from the area-detector 4D-CT will be valuable to improve the tracking accuracy of the SRTS.

Pseudo low-energy monochromatic imaging of head and neck cancers: Deep learning image reconstruction with dual-energy CT.

PURPOSE: Low-energy virtual monochromatic images (VMIs) derived from dual-energy computed tomography (DECT) systems improve lesion conspicuity of head and neck cancer over single-energy CT (SECT). However, DECT systems are installed in a limited number of facilities; thus, only a few facilities benefit from VMIs. In this work, we present a deep learning (DL) architecture suitable for generating pseudo low-energy VMIs of head and neck cancers for facilities that employ SECT imaging. METHODS: We retrospectively analyzed 115 patients with head and neck cancers who underwent contrast enhanced DECT. VMIs at 70 and 50 keV were used as the input and ground truth (GT), respectively. We divided them into two datasets: for DL (104 patients) and for inference with SECT (11 patients). We compared four DL architectures: U-Net, DenseNet-based, and two ResNet-based models. Pseudo VMIs at 50 keV (pVMI50keV) were compared with the GT in terms of the mean absolute error (MAE) of Hounsfield unit (HU) values, peak signal-to-noise ratio (PSNR), and structural similarity (SSIM). The HU values for tumors, vessels, parotid glands, muscle, fat, and bone were evaluated. pVMI50keV were generated from actual SECT images and the HU values were evaluated. RESULTS: U-Net produced the lowest MAE (13.32 ± 2.20 HU) and highest PSNR (47.03 ± 2.33 dB) and SSIM (0.9965 ± 0.0009), with statistically significant differences (P < 0.001). The HU evaluation showed good agreement between the GT and U-Net. U-Net produced the smallest absolute HU difference for the tumor, at < 5.0 HU. CONCLUSION: Quantitative comparisons of physical parameters demonstrated that the proposed U-Net could generate high accuracy pVMI50keV in a shorter time compared with the established DL architectures. Although further evaluation on diagnostic accuracy is required, our method can help obtain low-energy VMI from SECT images without DECT systems.

Poly (ADP-ribose) polymerase inhibitors sensitize cancer cells to hypofractionated radiotherapy through altered selection of DNA double-strand break repair pathways.

PURPOSE: Poly (ADP-ribose) polymerase inhibitors (PARPi) are known to induce radiosensitization. However, the exact mechanisms of radiosensitization remain unclear. We previously reported that PARPi may have a unique radiosensitizing effect to enhance ß-components of the linear-quadratic model. The aim of this study was to evaluate PARPi in combination with high-dose-per-fraction radiotherapy and to elucidate the underlying mechanisms of its radiosensitization. MATERIALS AND METHODS: Radiosensitizing effects of PARPi PJ34, olaparib, and veliparib were measured using a colony-forming assay in the human cancer cell lines, HCT116, NCI-H460, and HT29. Six different radiation dose fractionation schedules were examined by tumor regrowth assay using three-dimensional multicellular spheroids of HCT116, NCI-H460, SW620, and HCT15. The mechanisms of radiosensitization were analyzed by measuring DNA double-strand breaks (DSB), DNA damage responses, chromosomal translocations, cellular senescence, and cell cycle analysis. RESULTS: Olaparib and PJ34 were found to show radiosensitization preferentially at higher radiation doses per fraction. Similar results were obtained using a mouse model bearing human tumor xenografts. A kinetic analysis of DNA damage responses and repairs showed that olaparib and PJ34 reduced the homologous recombination activity. However, a neutral comet assay showed that PJ34 treatment did not affect the physical rejoining of DNA-DSBs induced by ionizing radiation. Cell cycle analysis revealed that olaparib and PJ34 strikingly increased G1 tetraploid cells following irradiation, leading to premature senescence. The C-banding analysis of metaphase spreads showed that olaparib and PJ34 significantly increased ionizing radiation-induced dicentric chromosomes. The data suggests that PARPi olaparib and PJ34 altered the choice of DNA-DSB repair pathways rather than reducing the total amount of DNA-DSB repair, which resulted in increased repair errors. Increased quadratic misrepair was one of the mechanisms of PARP-mediated radiosensitization, preferentially at the higher dose range compared to the lower dose range. CONCLUSION: PARPi may be a promising candidate to combine with stereotactic hypofractionated radiotherapy, aiming at high-dose region-directed radiosensitization.

Long-term Outcomes of Radiation Therapy for Prostate Cancer in Elderly Patients Aged ≥75 Years.

BACKGROUND/AIM: This study aimed to evaluate the treatment outcomes of radiation therapy (RT) for localized prostate cancer in elderly patients aged ≥75 years. PATIENTS AND METHODS: We retrospectively investigated data of patients aged ≥75 years with prostate cancer who underwent intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) with doses of 70-78 Gy in 35-39 fractions between September 2008 and June 2016. Overall survival (OS), recurrence-free (RF) rates, and occurrence rates of toxicities were calculated. RESULTS: Eighty-eight patients were enrolled in the study. Nineteen patients died, and nine patients reported PSA failure within the follow-up period. The median follow-up time was 83.5 months. The median age was 77 years. In the cohort, 6 were low-risk, 36 were intermediaterisk, and 46 were high-risk patients. The 5-/7-year OS and RF rates were 87.9%/80.2% and 93.5%/89.1%, respectively. By risk, the 5-/7-year RF rates were 100%/80% in the low-, 100%/100% in the intermediate-, and 87.6%/82.7% in the high-risk groups, respectively. The cumulative incidence rates of Grade ≥3 genitourinary and gastrointestinal toxicities were 1.3% and 3.5% at 5 years and 3.3% and 3.5% at 7 years, respectively. CONCLUSION: IMRT and VMAT are effective treatment options for elderly patients with prostate cancer and in a good general condition.

COVID-19 vaccine-induced Recurrence of the Radiation Recall Phenomenon in the Laryngeal Mucosa Due to a VEGF Inhibitor.

Purpose: The radiation recall phenomenon (RRP) is a rare and unexpected late complication of radiation therapy (RT). Although predominantly in the skin, RRP of the upper respiratory tract has also been reported. In general, RRP is caused by anticancer agents, and the COVID-19 vaccine has also been reported to cause RRP in recent years. Methods and Materials: A 50-year-old woman who had received RT around the larynx 3 years prior and was receiving a docetaxel + ramucirumab (RAM) regimen experienced recurrent sore throat. The administration of RAM was discontinued after a gastroscopic examination revealed mucosal bleeding from around the larynx, which was thought to be RRP caused by RAM, a vascular endothelial growth factor inhibitor. Results: After the remission of the RRP, the patient received a COVID-19 vaccine (Pfizer-BioNTech). Five days later, the appearance of cough and recurrence of sore throat worsened with time, and marked stridor was observed. The patient was admitted, and steroid pulse therapy was administered for 3 days starting on day 18 after vaccination. On day 50 after vaccination, edema of the vocal cords improved. Conclusions: When administering COVID-19 vaccines, considering that these vaccines may cause RRP is important, because RRP can be fatal in patients with a history of RT in the laryngeal region and treated with vascular endothelial growth factor inhibitors.

Development of raster scanning IMRT using a robotic radiosurgery system.

Treatment time with the CyberKnife frameless radiosurgery system is prolonged due to the motion of the robotic arm. We have developed a novel scanning irradiation method to reduce treatment time. We generated treatment plans mimicking eight-field intensity-modulated radiotherapy (IMRT) plans generated for the Novalis radiosurgery system. 2D dose planes were generated with multiple static beam spots collimated by a fixed circular cone. The weights of the uniformly distributed beam spots in each dose plane were optimized using the attraction-repulsion model. The beam spots were converted to the scanning speed to generate the raster scanning plan. To shorten treatment time, we also developed a hybrid scanning method which combines static beams with larger cone sizes and the raster scanning method. Differences between the Novalis and the scanning plan's dose planes were evaluated with the criterion of a 5% dose difference. The mean passing rates of three cases were > 85% for cone sizes ≤ 12.5 mm. Although the total monitor units (MU) increased for smaller cone sizes in an inverse-square manner, the hybrid scanning method greatly reduced the total MU, while maintaining dose distributions comparable to those with the Novalis plan. The estimated treatment time of the hybrid scanning with a 12.5 mm cone size was on average 22% shorter than that of the sequential plans. This technique will be useful in allowing the CyberKnife with conventional circular cones to achieve excellent dose distribution with a shortened treatment time.

Correction of lateral response artifacts from flatbed scanners for dual-channel radiochromic film dosimetry.

In this study, we evaluated the inter-unit variability of the lateral response artifact for multiple flatbed scanners, focusing on the dual-channel method, and investigated the correction method of the lateral non-uniformity. Four scanners with A3+ paper-size and five scanners with A4 paper-size were evaluated. To generate the dose-response curves, small pieces of the Gafchromic EBT3 and EBT-XD films were irradiated, and five of the pieces were repeatedly scanned by moving them on the scanner to evaluate the lateral non-uniformity. To calculate the dose distribution accounting for the lateral non-uniformity, linear functions of the correction factor, representing the difference between the pixel values at offset position and the scanner midline, were calculated for red and blue color channels at each lateral position. Large variations of the lateral non-uniformity among the scanners were observed, even for the same model of scanner. For high dose, red color showed pixel value profiles similar to symmetric curves, whereas the profiles for low dose were asymmetric. The peak positions changed with dose. With correction of the lateral non-uniformity, the dose profiles of the pyramidal dose distribution measured at various scanner positions and that calculated with a treatment planning system showed almost identical profile shapes at all high-, middle- and low-dose levels. The dual-channel method used in this study showed almost identical dose profiles measured with all A3+ and A4 paper-size scanners at any positions when the corrections were applied for each color channel.