Multi-phase failure modes and effects analysis for low dose bilateral whole lung irradiation of COVID-19 positive patients requiring respiratory ventilation.

PURPOSE: To identify high-priority risks in a clinical trial investigating the use of radiation to alleviate COVID-19 pneumonia using a multi-phase failure modes and effects analysis (FMEA). METHODS: A comprehensive FMEA survey of 133 possible causes of failure was developed for the clinical trial workflow (Phase I). The occurrence, severity, and detection risk of each possible cause of failure was scored by three medical physicists. High-risk potential failure modes were identified using the risk priority number (RPN) and severity scores, which were re-scored by 13 participants in radiation oncology (Phase II). Phase II survey scores were evaluated to identify steps requiring possible intervention and examine risk perception patterns. The Phase II participants provided consensus scores as a group. RESULTS: Thirty high-priority failure modes were selected for the Phase II survey. Strong internal consistency was shown in both surveys using Cronbach's alpha (αc ≥ 0.85). The 10 failures with the largest median RPN values concerned SARS-CoV-2 transmission (N = 6), wrong treatment (N = 3), and patient injury (N = 1). The median RPN was larger for COVID-related failures than other failure types, primarily due to the perceived difficulty of failure detection. Group re-scoring retained 8/10 of the highest-priority risk steps that were identified in the Phase II process, and discussion revealed interpretation differences of process steps and risk evaluation. Participants who were directly involved with the trial working group had stronger agreement on severity scores than those who were not. CONCLUSIONS: The high ranking of failures concerning SARS-CoV-2 transmission suggest that these steps may require additional quality management intervention when treating critically ill COVID-19+ patients. The results also suggest that a multi-phase FMEA survey led by a facilitator may be a useful tool for assessing risks in radiation oncology procedures, supporting future efforts to adapt FMEA to clinical procedures.

Assessment of MRI image distortion based on 6 consecutive years of annual QAs and measurements on 14 MRI scanners used for radiation therapy.

PURPOSE: To determine the magnitude of MRI image distortion based on 6 consecutive years of annual quality assurances/measurements on 14 MRI scanners used for radiation therapy and to provide evidence for the inclusion of additional margin for treatment planning. METHODS AND MATERIALS: We used commercial MRI image phantoms to quantitatively study the MRI image distortion over period of 6 years for up to 14 1.5 and 3 T MRI scanners that could potentially be used to provide MRI images for treatment planning. With the phantom images collected from 2016 to 2022, we investigated the MRI image distortion, the dependence of distortion on the distance from the imaging isocenter, and the possible causes of large distortion discovered. RESULTS: MRI image distortion increases with the distance from the imaging isocenter. For a region of interest (ROI) with a radius of 100 mm centered at the isocenter, the mean magnitude of distortion for all MRI scanners is 0.44 ± 0.18 mm $0.44 \pm 0.18\;{\rm{mm}}$ , and the maximum distortion varies from 0.52 to 1.31 mm $0.52\;{\rm{to}}\;1.31\;{\rm{mm}}$ depending on MRI scanners. For an ROI with a radius of 200 mm centered at the isocenter, the mean magnitude of distortion increases to 0.84 ± 0.45 mm $0.84 \pm 0.45\;{\rm{mm}}$ , and the range of the maximum distortion increases to 1.92 - 5.03 mm $1.92 - 5.03\;{\rm{mm}}$ depending on MRI scanners. The distortion could reach 2 mm at 150 mm from the isocenter. CONCLUSION: An additional margin to accommodate image distortion should be considered for treatment planning. Imaging with proper patient alignment to the isocenter is vital to reducing image distortion. We recommend performing image distortion checks annually and after major upgrade on MRI scanners.

Validating kQ =1.0 assumption in TG51 with PTW 30013 farmer chamber for Varian TrueBeam's 2.5 MV imaging beam.

AAPM Report 142 recommends and the State of Ohio requires that the imaging dose be quantified in radiotherapy applications. Using the TG51 dose calibration protocol for MV Imaging dose measurement requires knowledge of the kQ parameter for the beam quality and the ionization chamber type under investigation. The %dd(10)x of the Varian TrueBeam 2.5 MV imaging beam falls outside the range of the available data for the calculation of the kQ value. Due to the similarities of the 2.5 MV imaging beam and the 60 Co beam, we and others made the assumption that kQ = 1.0 in TG51 calculations. In this study, we used the TG21 and TG51 calibration protocols in conjunction to validate that kQ = 1.0 for the 2.5 MV imaging beam using a PTW 30013 farmer chamber. Standard measurements for TG51 absolute dosimetry QA were performed at 100 cm SSD, 10 cm depth, 10 × 10 field size, delivering 100 Monitor Units to a waterproof Farmer Chamber (PTW TN30013) for both 2.5 and 6 MV. Both the TG21 and TG51 formalisms were used to calculate the dose to water per MU at dmax (Dw /MU) for the 6 MV beam. The calculated outputs were 1.0005 and 1.0004 cGy/MU respectively. The TG21 formalism was then used to calculate (Dw /MU) for the 2.5 MV imaging beam. This value was then used in the TG51 formalism to find kQ for the 2.5 MV imaging beam. A kQ value of 1.00 ± 0.01 was calculated for 2.5 MV using this method.

Quality assurance for a six degrees-of-freedom table using a 3D printed phantom.

PURPOSE: To establish a streamlined end-to-end test of a 6 degrees-of-freedom (6DoF) robotic table using a 3D printed phantom for periodic quality assurance. METHODS: A 3D printed phantom was fabricated with translational and rotational offsets and an imbedded central ball-bearing (BB). The phantom underwent each step of the radiation therapy process: CT simulation in a straight orientation, plan generation using the treatment planning software, setup to offset marks at the linac, registration and corrected 6DoF table adjustments via hidden target test, delivery of a Winston-Lutz test to the BB, and verification of table positioning via field and laser lights. The registration values, maximum total displacement of the combined Winston-Lutz fields, and a pass or fail criterion of the laser and field lights were recorded. The quality assurance process for each of the three linacs were performed for the first 30 days. RESULTS: Within a 95% confidence interval, the overall uncertainty values for both translation and rotation were below 1.0 mm and 0.5° for each linac respectively. When combining the registration values and other uncertainties for all three linacs, the average deviations were within 2.0 mm and 1.0° of the designed translation and rotation offsets of the 3D print respectively. For all three linacs, the maximum total deviation for the Winston-Lutz test did not exceed 1.0 mm. Laser and light field verification was within tolerance every day for all three linacs given the latest guidance documentation for table repositioning. CONCLUSION: The 3D printer is capable of accurately fabricating a quality assurance phantom for 6DoF positioning verification. The end-to-end workflow allows for a more efficient test of the 6DoF mechanics while including other important tests needed for routine quality assurance.

Commissioning and comprehensive evaluation of the ArcCHECK cylindrical diode array for VMAT pretreatment delivery QA.

We present commissioning and comprehensive evaluation for ArcCHECK as a QA equipment for volumetric-modulated arc therapy (VMAT), using the 6 MV photon beam with and without the flattening filter, and the SNC patient software (version 6.2). In addition to commissioning involving absolute dose calibration, array calibration, and PMMA density verification, ArcCHECK was evaluated for its response dependency on linac dose rate, instantaneous dose rate, radiation field size, beam angle, and couch insertion. Scatter dose characterization, consistency and symmetry of response, and dosimetry accuracy evaluation for fixed aperture arcs and clinical VMAT patient plans were also investigated. All the evaluation tests were performed with the central plug inserted and the homogeneous PMMA density value. Results of gamma analysis demonstrated an overall agreement between ArcCHECK-measured and TPS-calculated reference doses. The diode based field size dependency was found to be within 0.5% of the reference. The dose rate-based dependency was well within 1% of the TPS reference, and the angular dependency was found to be ± 3% of the reference, as tested for BEV angles, for both beams. Dosimetry of fixed arcs, using both narrow and wide field widths, resulted in clinically acceptable global gamma passing rates on the 3%/3mm level and 10% threshold. Dosimetry of narrow arcs showed an improvement over published literature. The clinical VMAT cases demonstrated high level of dosimetry accuracy in gamma passing rates.

Evaluation of sodium borocaptate (BSH) and boronophenylalanine (BPA) as boron delivery agents for neutron capture therapy (NCT) of cancer: an update and a guide for the future clinical evaluation of new boron delivery agents for NCT.

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. First, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. Second, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. Third, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.

Technical note: Commissioning of a linear accelerator producing ultra-high dose rate electrons.

BACKGROUND: Ultra-high dose rate radiation (UHDR) is being explored by researchers in promise of advancing radiation therapy treatments. PURPOSE: This work presents the commissioning of Varian's Flash Extension for research (FLEX) conversion of a Clinac to deliver UHDR electrons. METHODS: A Varian Clinac iX with the FLEX conversion was commissioned for non-clinical research use with 16 MeV UHDR (16H) energy. This involved addition of new hardware, optimizing the electron gun voltages, radiofrequency (RF) power, and steering coils in order to maximize the accelerated electron beam current, sending the beam through custom scattering foils to produce the UHDR with 16H beam. Profiles and percent depth dose (PDD) measurements for 16H were obtained using radiochromic film in a custom vertical film holder and were compared to 16 MeV conventional electrons (16C). Dose rate and dose per pulse (DPP) were calculated from measured dose in film. Linearity and stability were assessed using an Advanced Markus ionization chamber. RESULTS: Energies for 16H and 16C had similar beam quality based on PDD measurements. Measurements at the head of the machine (61.3 cm SSD) with jaws set to 10×10 cm2 showed the FWHM of the profile as 7.2 cm, with 3.4 Gy as the maximum DPP and instantaneous dose rate of 8.1E5 Gy/s. Measurements at 100 cm SSD with 10 cm standard cone showed the full width at half max (FWHM) of the profile as 10.5 cm, 1.08 Gy as the maximum DPP and instantaneous dose rate of 2.E5 Gy/s. Machine output with number of pulses was linear (R = 1) from 1 to 99 delivered pulses. Output stability was measured within ±1% within the same session and within ±2% for daily variations. CONCLUSIONS: The FLEX conversion of the Clinac is able to generate UHDR electron beams which are reproducible with beam properties similar to clinically used electrons at 16 MeV. Having a platform which can quickly transition between UHDR and conventional modes (<1 min) can be advantageous for future research applications.

Blinding of Residency Applications in Medical Physics: Promises and Pitfalls.

Purpose: The feasibility of blinding applications for a medical physics residency program has yet to be demonstrated in the literature. We explore the application of an automated approach with human review and intervention to blind applications during the annual medical physics residency review cycle. Methods and Materials: Applications were blinded using an automated process and used for the first phase of residency review in the program. We retrospectively compared self-reported demographic and gender data with blinded and nonblinded cohorts from 2 sequential years of review from a medical physics residency program. Demographic data were analyzed comparing applicants with candidates selected to move to the next phase of the review process. Interrater agreement was also evaluated from the applicant reviewers. Results: We show the feasibility of blinding applications for a medical physics residency program. We observed no more than a 3% difference between the gender selection within the first phase of application review but greater differences when examining race and ethnicity between the 2 methods. The greatest difference was shown to be between Asian and White candidates, where there are statistical differences in the scores in the rubric categories of essay and overall impression. Conclusions: We suggest that each training program critically evaluate its selection criteria for potential sources of bias within the review process. We recommend further critical investigation of processes to promote equity and inclusion to ensure the methods and outcomes are aligned with the mission of the program. Finally, we recommend that the common application provide an option for blinding applications at the source so this can be an option to facilitate efforts for evaluating unconscious bias in the review process.

Comparison of Gonadal Toxicity of Single-Fraction Ultra-High Dose Rate and Conventional Radiation in Mice.

Purpose: Increasing evidence suggests that ultra-high-dose-rate (UHDR) radiation could result in similar tumor control as conventional (CONV) radiation therapy (RT) while reducing toxicity to surrounding healthy tissues. Considering that radiation toxicity to gonadal tissues can cause hormone disturbances and infertility in young patients with cancer, the purpose of this study was to assess the possible role of UHDR-RT in reducing toxicity to healthy gonads in mice compared with CONV-RT. Methods and Materials: Radiation was delivered to the abdomen or pelvis of female (8 or 16 Gy) and male (5 Gy) C57BL/6J mice, respectively, at conventional (∼0.4 Gy/s) or ultrahigh (>100 Gy/s) dose rates using an IntraOp Mobetron linear accelerator. Organ weights along with histopathology and immunostaining of irradiated gonads were used to compare toxicity between radiation modalities. Results: CONV-RT and UHDR-RT induced a similar decrease in uterine weights at both studied doses (∼50% of controls), which indicated similarly reduced ovarian follicular activity. Histologically, ovaries of CONV- and UHDR-irradiated mice exhibited a comparable lack of follicles. Weights of CONV- and UHDR-irradiated testes were reduced to ∼30% of controls, and the percentage of degenerate seminiferous tubules was also similar between radiation modalities (∼80% above controls). Pairwise comparisons of all quantitative data indicated statistical significance between irradiated (CONV or UHDR) and control groups (from P ≤ .01 to P ≤ .0001) but not between radiation modalities. Conclusions: The data presented here suggest that the short-term effects of UHDR-RT on the mouse gonads are comparable to those of CONV-RT.

Convection enhanced delivery of carboplatin in combination with radiotherapy for the treatment of brain tumors.

The purpose of this study was to further evaluate the therapeutic efficacy of convection enhanced delivery (CED) of carboplatin in combination with radiotherapy for treatment of the F98 rat glioma. Tumor cells were implanted stereotactically into the brains of syngeneic Fischer rats, and 13 or 17 d. later carboplatin (20 µg/10 µl) was administered by either CED over 30 min or by Alzet osmotic pumps (0.5 µg/µl/h for 168 h.) beginning at 7 d after tumor implantation. Rats were irradiated with a 15 Gy fractionated dose (5 Gy × 3) of 6 MV photons to the whole brain beginning on the day after drug administration. Other groups of rats received either carboplatin or X-irradiation alone. The tumor carboplatin concentration following CED of 20 µg in 10 µl was 10.4 µg/g, which was equal to that observed following i.v. administration of 100 mg/kg b.w. Rats bearing small tumors, treated with carboplatin and X-irradiation, had a mean survival time (MST) of 83.4 d following CED and 111.8 d following pump delivery with 40% of the latter surviving >180 d (i.e. cured) compared to 55.2 d for CED and 77.2 d. for pump delivery of carboplatin alone and 31.8 d and 24.2 d, respectively, for X-irradiated and untreated controls. There was no microscopic evidence of residual tumor in the brains of all long-term survivors. Not surprisingly, rats with large tumors had much shorter MSTs. Only modest increases in MSTs were observed in animals that received either oral administration or CED of temozolomide plus X-irradiation (23.2 d and 29.3 d) compared to X-irradiation alone. The present survival data, and those previously reported by us, are among the best ever obtained with the F98 glioma model. Initially, they could provide a platform for a Phase I clinical trial to evaluate the safety and potential therapeutic efficacy of CED of carboplatin in patients with recurrent glioblastomas, and ultimately a Phase II trial of carboplatin in combination with radiation therapy.

Accelerators, Gantries, Magnets and Imaging Systems for Particle Beam Therapy: Recent Status and Prospects for Improvement.

The paper begins by emphasizing the clinical and commercial importance of proton or other charged particle such as carbon ion therapy, refers to the manufacturers of such systems of which more than 120 are installed or under construction worldwide by April 2021. A general review of charged particle therapy systems refers to six manufacturers and provides in tabular form some details of systems installed in the US, Europe, Asia, and elsewhere. In a description of the principles of particle beam therapy a comparison is made of the properties of photons (x-rays) versus protons and protons versus carbon ions. A brief discussion of accelerators in general is followed by descriptions of cyclotrons (including the isosynchronous cyclotron and the synchrocyclotron) and synchrotrons. An interesting case study describes the evolution of a normal-conducting 220 ton cyclotron into an iron-free synchrocyclotron weighing only 5 tons. The general principles of beam handling and gantry design are described. Subsequent sections describe gantry magnets in detail - normal conducting gantry magnets, superconducting gantry magnets for proton- and carbon therapy. Mention is made of a novel CERN-designed superconducting toroidal gantry for hadron therapy, GaToroid. This device, operating under steady state current and magnetic field, is able to deliver a beam at discrete angles over a range of treatment energies. Also considered are low temperature superconducting (LTS) and high temperature superconducting (HTS) magnet windings, and the choice of REBCO conductors for cryogen-free carbon-ion gantries. Finally, the paper mentions an important "Prospect for Improvement", viz: the introduction of MRI image guidance. A well-known property of the particle beam as it passes through tissue is its energy dependent absorption that rises to a pronounced peak (the Bragg peak) at the end of its range. In order to take advantage of this effect the exact targeting of the tumor and positioning of the patient should be guided by imaging visualization using X-ray, CT, and hopefully advanced MRI. Unlike MRI-guided photon therapy the direct interaction of the magnetic field with the charged particle beam presents a huge challenge such that MRI image-guided proton/particle therapy has not yet been available in clinical practice. Modeling studies have been undertaken on the general topic of beam-line/magnetic field interaction using, for example, the software GEANT4 (GEometry And Tracking) a platform for simulating the passage of charged particles through matter using a Monte Carlo method.

Prospective dual-surrogate validation study of periodic imaging during treatment for accurately monitoring intrafraction motion of prostate cancer patients.

BACKGROUND AND PURPOSE: The goal of this prospective study is to validate the use of periodic imaging during treatment with a fiducial marker detection algorithm using radiofrequency transponders for prostate cancer patients undergoing treatment for radiation therapy. MATERIALS AND METHODS: Ten male patients were enrolled in this study and treated for prostate cancer with implanted electromagnetic monitoring beacons. We evaluated the accuracy and limitations of Intrafraction Motion Review (IMR) by comparing the known locations of the beacons using the electromagnetic monitoring system to the position data reported from IMR images. RESULTS: A total of 4054 images were taken during treatment. The difference in vector magnitude of the two methods is centered around zero (mean: 0.03 cm, SD: 0.16 cm) and Lin's Concordance Correlation Coefficient (CCC) is 0.99 (95% CI: 0.98, 1) overall. The Euclidean distance between the two methods was close to zero (median: 0.09 cm, IQR: 0.06, 0.14 cm). The difference in distance between any two markers was centered around zero (mean: 0.01 cm, SD: 0.12 cm) and Lin's CCC is 0.97 (95% CI: 0.96, 0.98) overall. CONCLUSION: The accuracy of the algorithm for detected markers within the 2D images is comparable to electromagnetic monitoring for fiducial identification when detected. IMR could provide an alternate solution for patients with contraindications of use of an electromagnetic monitoring system and a cost effective alternative to the acquisition of an additional system for patient monitoring, but does not provide data for pre-treatment set-up verification and real-time 3D positioning during treatment.

A framework for automated and streamlined kV cone beam computed tomography image quality assurance: a multi-institutional study.

The purpose of this study was to develop and evaluate a framework to support automated standardized testing and analysis of Cone Beam Computed Tomography (CBCT) image quality QA across multiple institutions. A survey was conducted among the participating institutions to understand the variability of the CBCT QA practices. A commercial, automated software platform was validated by seven institutions participating in a consortium dedicated to automated quality assurance. The CBCT image analysis framework was used to compare periodic QA results among 23 linear accelerators (linacs) from seven institutions. The CBCT image quality metrics (geometric distortion, spatial resolution, contrast, HU constancy, uniformity and noise) data are plotted as a function of means with the upper and lower control limits compared to the linac acceptance criteria and AAPM recommendations. For example, mean geometric distortion and HU constancy metrics were found to be 0.13 mm (TG142 recommendation: ≤2 mm) and 13.4 respectively (manufacturer acceptance specification: ≤±50).Image upload and analysis process was fully automated using a MATLAB-based platform. This analysis enabled a quantitative, longitudinal assessment of the performance of quality metrics which were also compared across 23 linacs. For key CBCT parameters such as uniformity, contrast, and HU constancy, all seven institutions used stricter goals than what would be recommended based on the analysis of the upper and lower control limits. These institutional goals were also found to be stricter than that found in AAPM published guidance. This work provides a reference that could be used to machine-specific optimized tolerance of CBCT image maintenance via control charts to monitor performance we well as the sensitivity of different tests in support of a broader quality assurance program. To ensure the daily image quality needed for patient care, the optimized statistical QA metrics recommended to using along with risk-based QA.

Comparison of real-time intraoperative ultrasound-based dosimetry with postoperative computed tomography-based dosimetry for prostate brachytherapy.

PURPOSE: To evaluate whether real-time intraoperative ultrasound (US)-based dosimetry can replace conventional postoperative computed tomography (CT)-based dosimetry in prostate brachytherapy. METHODS AND MATERIALS: Between December 2001 and November 2002, 82 patients underwent (103)Pd prostate brachytherapy. An interplant treatment planning system was used for real-time intraoperative transrectal US-guided treatment planning. The dose distribution was updated according to the estimated seed position to obtain the dose-volume histograms. Postoperative CT-based dosimetry was performed a few hours later using the Theraplan-Plus treatment planning system. The dosimetric parameters obtained from the two imaging modalities were compared. RESULTS: The results of this study revealed correlations between the US- and CT-based dosimetry. However, large variations were found in the implant-quality parameters of the two modalities, including the doses covering 100%, 90%, and 80% of the prostate volume and prostate volumes covered by 100%, 150%, and 200% of the prescription dose. The mean relative difference was 38% and 16% for doses covering 100% and 90% of the prostate volume and 10% and 21% for prostate volumes covered by 100% and 150% of the prescription dose, respectively. The CT-based volume covered by 200% of the prescription dose was about 30% greater than the US-based one. Compared with CT-based dosimetry, US-based dosimetry significantly underestimated the dose to normal organs, especially for the rectum. The average US-based maximal dose and volume covered by 100% of the prescription dose for the rectum was 72 Gy and 0.01 cm(3), respectively, much lower than the 159 Gy and 0.65 cm(3) obtained using CT-based dosimetry. CONCLUSION: Although dosimetry using intraoperative US-based planning provides preliminary real-time information, it does not accurately reflect the postoperative CT-based dosimetry. Until studies have determined whether US-based dosimetry or postoperative CT-based dosimetry can better predict patient outcomes, the American Brachytherapy Society recommendation of CT-based postimplant dosimetry should remain the standard of care.

Hypofractionation regimens for stereotactic radiotherapy for large brain tumors.

PURPOSE: To investigate equivalent regimens for hypofractionated stereotactic radiotherapy (HSRT) for brain tumor treatment and to provide dose-escalation guidance to maximize the tumor control within the normal brain tolerance. METHODS AND MATERIALS: The linear-quadratic model, including the effect of nonuniform dose distributions, was used to evaluate the HSRT regimens. The alpha/beta ratio was estimated using the Gammaknife stereotactic radiosurgery (GKSRS) and whole-brain radiotherapy experience for large brain tumors. The HSRT regimens were derived using two methods: (1) an equivalent tumor control approach, which matches the whole-brain radiotherapy experience for many fractions and merges it with the GKSRS data for few fractions; and (2) a normal-tissue tolerance approach, which takes advantages of the dose conformity and fractionation of HSRT to approach the maximal dose tolerance of the normal brain. RESULTS: A plausible alpha/beta ratio of 12 Gy for brain tumor and a volume parameter n of 0.23 for normal brain were derived from the GKSRS and whole-brain radiotherapy data. The HSRT prescription regimens for the isoeffect of tumor irradiation were calculated. The normal-brain equivalent uniform dose decreased as the number of fractions increased, because of the advantage of fractionation. The regimens for potential dose escalation of HSRT within the limits of normal-brain tolerance were derived. CONCLUSIONS: The designed hypofractionated regimens could be used as a preliminary guide for HSRT dose prescription for large brain tumors to mimic the GKSRS experience and for dose escalation trials. Clinical studies are necessary to further tune the model parameters and validate these regimens.

Fractionated grid therapy in treating cervical cancers: conventional fractionation or hypofractionation?

PURPOSE: To evaluate the conventionally fractionated and hypofractionated grid therapy in debulking cervical cancers using the linear quadratic (LQ) model. METHODS AND MATERIALS: A Monte Carlo technique was used to calculate the dose distribution of a commercially available grid in a 6-MV photon beam. The LQ model was used to evaluate the therapeutic outcome of both the conventionally fractionated (2 Gy/fraction) and hypofractionated (15 Gy/fraction) grid therapy regimens to debulk cervical cancers with different LQ parameters. The equivalent open-field dose (EOD) to the cancer cells and therapeutic ratio (TR) were defined by comparing grid therapy with the open debulking field. The clinical outcomes from 114 patients were used to verify our theoretical model. RESULTS: The cervical cancer and normal tissue cell survival statistics for grid therapy in two regimens were calculated. The EODs and TRs were derived. The EOD was only a fraction of the prescribed dose. The TR was dependent on the prescribed dose and the LQ parameters of both the tumor and normal tissue cells. The grid therapy favors the acutely responding tumors inside radiosensitive normal tissues. Theoretical model predictions were consistent with the clinical outcomes. CONCLUSIONS: Grid therapy provided a pronounced therapeutic advantage in both the hypofractionated and conventionally fractionated regimens compared with that seen with single fraction, open debulking field regimens, but the true therapeutic advantage exists only in the hypofractionated grid therapy. The clinical outcomes and our study indicated that a course of open-field radiotherapy is necessary to control tumor growth fully after a grid therapy.

Likelihood of unacceptable normal tissue doses in breast cancer patients undergoing regional nodal irradiation in routine clinical practice.

PURPOSE: As indications for regional nodal irradiation (RNI) for breast cancer have expanded, so too has scrutiny over potential late toxicity from radiotherapy. This emphasizes the need for careful radiation treatment planning to maximize the therapeutic ratio. We sought to evaluate how often unacceptable doses (UDs) to organs at risk (OARs) occur and the associated factors for patients receiving RNI in daily practice. METHODS AND MATERIALS: Treatment records of patients who received RNI from February 2012 to May 2015 were studied. The NSABP B51/RTOG 1304 clinical dose-volume constraints for targets/OARs receiving RNI were used as the benchmark. Dose-volume histograms were analyzed for the rate of ≥1 UD delivered to the following organs: heart, mean >5 Gy; ipsilateral lung, V20 >35%, V10 >60%, V5 >70%; contralateral lung (CL), V5 >15%; and contralateral breast, V4.1 >5%. Logistic regression was used to test the association between UDs to OAR and key variables. RESULTS: Two hundred three consecutive cases received RNI (105 left, 98 right), to the chest wall in 171 (84%) and to the internal mammary nodes in 170 (84%); 77.4% of cases met all OAR constraints. The most common OAR UDs were delivered to the contralateral breast (n = 32, 15.7%) and ipsilateral lung V5 (n = 22, 10.8%). On multivariate analysis, use of intensity modulated radiation therapy (odds ratio [OR], 64.7; 95% confidence interval, 20.8-201.5; P < .001) and use of nodal boost (OR, 5.5; 95% confidence interval, 1.1-27.1; P = .04), but not internal mammary node irradiation (OR, 2.7; P = .35) or reconstruction (OR, 0.62; P = .33), were independently associated with higher OAR UD rate. For 3-dimensional conformal radiation therapy plans, 7.9% had OAR UDs. CONCLUSION: The OAR UD rate with 3-dimensional conformal radiation therapy ± deep inspiration breath-hold in routine clinical practice is low and not independently associated with internal mammary node irradiation or reconstruction presence. Women treated with intensity modulated radiation therapy had a significantly higher overall OAR UD rate, and clinicians should be aware of this as they initiate RNI treatment planning.

Effect of edema, relative biological effectiveness, and dose heterogeneity on prostate brachytherapy.

Many factors influence response in low-dose-rate (LDR) brachytherapy of prostate cancer. Among them, edema, relative biological effectiveness (RBE), and dose heterogeneity have not been fully modeled previously. In this work, the generalized linear-quadratic (LQ) model, extended to account for the effects of edema, RBE, and dose heterogeneity, was used to assess these factors and their combination effect. Published clinical data have shown that prostate edema after seed implant has a magnitude (ratio of post- to preimplant volume) of 1.3-2.0 and resolves exponentially with a half-life of 4-25 days over the duration of the implant dose delivery. Based on these parameters and a representative dose-volume histogram (DVH), we investigated the influence of edema on the implant dose distribution. The LQ parameters (alpha=0.15 Gy(-1) and alpha/beta=3.1 Gy) determined in earlier studies were used to calculate the equivalent uniform dose in 2 Gy fractions (EUD2) with respect to three effects: edema, RBE, and dose heterogeneity for 125I and 103Pd implants. The EUD2 analysis shows a negative effect of edema and dose heterogeneity on tumor cell killing because the prostate edema degrades the dose coverage to tumor target. For the representative DVH, the V100 (volume covered by 100% of prescription dose) decreases from 93% to 91% and 86%, and the D90 (dose covering 90% of target volume) decrease from 107% to 102% and 94% of prescription dose for 125I and 103Pd implants, respectively. Conversely, the RBE effect of LDR brachytherapy [versus external-beam radiotherapy (EBRT) and high-dose-rate (HDR) brachytherapy] enhances dose effect on tumor cell kill. In order to balance the negative effects of edema and dose heterogeneity, the RBE of prostate brachytherapy was determined to be approximately 1.2-1.4 for 125I and 1.3-1.6 for 103Pd implants. These RBE values are consistent with the RBE data published in the literature. These results may explain why in earlier modeling studies, when the effects of edema, dose heterogeneity, and RBE were all ignored simultaneously, prostate LDR brachytherapy was reported to show an overall similar dose effect as EBRT and HDR brachytherapy, which are independent of edema and RBE effects and have a better dose coverage.