Initial Clinical Experience With Novel Directional Low-Dose Rate Brachytherapy for Retroperitoneal Sarcoma.

BACKGROUND: A novel Palladium-103 low-dose rate (LDR) brachytherapy device was developed to provide dose-escalation to the tumor bed after resection while shielding adjacent tissues. This multicenter report describes the initial experience with this device in patients with retroperitoneal sarcoma (RPS). MATERIALS AND METHODS: Patients with recurrent RPS, prior radiotherapy, and/or concern for positive margins were considered. An LDR brachytherapy dose of 20-60 Gy was administered, corresponding to biologically effective dose values of 15-53 Gy and equivalent dose values of 12-43 Gy. RESULTS: Six patients underwent implantation at four institutions. Of these, five had recurrent disease in the retroperitoneum or pelvic sidewall, one had untreated locally advanced leiomyosarcoma, two had prior external beam radiation therapy at the time of initial diagnosis, and four received neoadjuvant external beam radiation therapy plus brachytherapy. The device was easily implanted and conformed to the treatment area. Median follow-up was 16 mo; radiation was delivered to the at-risk margin with minimal irradiation of adjacent structures. No local recurrences at the site of implantation, device migration, or radiation-related toxicities were observed. CONCLUSIONS: The novel LDR directional brachytherapy device successfully delivered a targeted dose escalation to treat RPS high-risk margins. Lack of radiation-related toxicity demonstrates its safety.

Intrafractional prostate motion during external beam radiotherapy monitored by a real-time target localization system.

This paper investigates the clinical significance of real-time monitoring of intrafractional prostate motion during external beam radiotherapy using a commercial 4D localization system. Intrafractional prostate motion was tracked during 8,660 treatment fractions for 236 patients. The following statistics were analyzed: 1) the percentage of fractions in which the prostate shifted 2-7 mm for a certain duration; 2) the proportion of the entire tracking time during which the prostate shifted 2-7mm; and 3) the proportion of each minute in which the shift exceeded 2-7 mm. The ten patients exhibiting maximum intrafractional-motion patterns were analyzed separately. Our results showed that the percentage of fractions in which the prostate shifted by > 2, 3, 5, and 7 mm off the baseline in any direction for > 30 s was 56.8%, 27.2%, 4.6%, and 0.7% for intact prostate and 68.7%, 35.6%, 10.1%, and 1.8% for postprostatectomy patients, respectively. For the ten patients, these percentages were 91.3%, 72.4%, 36.3%, and 6%, respectively. The percentage of tracking time during which the prostate shifted > 2, 3, 5, and 7 mm was 27.8%, 10.7%, 1.6%, and 0.3%, respectively, and it was 56.2%, 33.7%, 11.2%, and 2.1%, respectively, for the ten patients. The percentage of tracking time for a > 3 mm posterior motion was four to five times higher than that in other directions. For treatments completed in 5 min (VMAT) and 10 min (IMRT), the proportion for the prostate to shift by > 3mm was 4% and 12%, respectively. Although intrafractional prostate motion was generally small, caution should be taken for patients who exhibit frequent large intrafractional motion. For those patients, adjustment of patient positioning may be necessary or a larger treatment margin may be used. After the initial alignment, the likelihood of prostate motion increases with time. Therefore, it is favorable to use advanced techniques (e.g., VMAT) that require less delivery time in order to reduce the treatment uncertainty resulting from intrafractional prostate motion.

Synthesis and characterization of a matrix-metalloproteinase responsive silk-elastinlike protein polymer.

Silk-elastinlike protein polymers (SELPs) are recombinant polymers consisting of tandem repeats of silk (GAGAGS) and elastin (GVGVP) units. By modification of the length and composition of these repeats, the properties of SELP hydrogels can be controlled for specific applications including nucleic acid and virus delivery and tissue engineering. Here, the structure of SELPs is further modified to include a sequence that is sensitive to matrix-metalloproteinases (MMPs). MMPs are a ubiquitous family of extracellular matrix-modifying enzymes that are commonly associated with numerous vital processes. Increased levels of MMPs are found at high levels locally in many types of solid tumors. By modifying the SELP backbone with MMP-sensitive peptide sequences, a hydrogel that is degradable by MMPs was produced. The MMP-sensitivity of the polymer was examined by incubation with MMP-2 and MMP-9, which yielded complete cleavage of all full-length polymers by 36 hours and 48 hours, respectively, with no observable effect on unmodified SELP. Hydrogel sensitivity was tested by exposure to MMP-2 or MMP-9 for 2 weeks, during which samples were taken to analyze protein loss from the hydrogel and release of 100 nm fluorescent beads. Following the incubation period, hydrogels were tested in mechanical compression to examine the loss of hydrogel stiffness due to degradation. It was found that MMP-2 and MMP-9 caused 63% and 44% increased protein loss and 65% and 95% increased release from MMP-sensitive hydrogels, while the compressive modulus decreased by 41% and 29%. These results suggest the potential of MMP-responsive SELPs for localized delivery of bioactive agents where MMPs are overexpressed.

Measurement comparison and Monte Carlo analysis for volumetric-modulated arc therapy (VMAT) delivery verification using the ArcCHECK dosimetry system.

The objective of this study is to validate the capabilities of a cylindrical diode array system for volumetric-modulated arc therapy (VMAT) treatment quality assurance (QA). The VMAT plans were generated by the Eclipse treatment planning system (TPS) with the analytical anisotropic algorithm (AAA) for dose calculation. An in-house Monte Carlo (MC) code was utilized as a validation tool for the TPS calculations and the ArcCHECK measurements. The megavoltage computed tomography (MVCT) of the ArcCHECK system was adopted for the geometry reconstruction in the TPS and for MC simulations. A 10 × 10 cm2 open field validation was performed for both the 6 and 10 MV photon beams to validate the absolute dose calibration of the ArcCHECK system and also the TPS dose calculations for this system. The impact of the angular dependency on noncoplanar deliveries was investigated with a series of 10 × 10 cm2 fields delivered with couch rotation 0° to 40°. The sensitivity of detecting the translational (1 to 10 mm) and the rotational (1° to 3°) misalignments was tested with a breast VMAT case. Ten VMAT plans (six prostate, H&N, pelvis, liver, and breast) were investigated to evaluate the agreement of the target dose and the peripheral dose among ArcCHECK measurements, and TPS and MC dose calculations. A customized acrylic plug holding an ion chamber was used to measure the dose at the center of the ArcCHECK phantom. Both the entrance and the exit doses measured by the ArcCHECK system with and without the plug agreed with the MC simulation to 1.0%. The TPS dose calculation with a 2.5 mm grid overestimated the exit dose by up to 7.2% when the plug was removed. The agreement between the MC and TPS calculations for the ArcCHECK without the plug improved significantly when a 1 mm dose calculation grid was used in the TPS. The noncoplanar delivery test demonstrated that the angular dependency has limited impact on the gamma passing rate (< 1.2% drop) for the 2%-3% dose and 2mm-3 mm DTA criteria. A 1° rotational misalignment introduces 11.3% (3%/3mm) to 21.3% (1%/1 mm) and 0.2% (3%/3 mm) to 0.8% (1%/1 mm) Gamma passing rate drop for ArcCHECK system and MatriXX system, respectively. Both systems have comparable sensitivity to the AP misalignments. However, a 2 mm RL misalignment introduces gamma passing rate drop ranging from 0.9% (3%/3 mm) to 4.0% (1%/1 mm) and 5.0% (3%/3 mm) to 12.0% (1%/1 mm) for ArcCHECK and MatriXX measurements, respectively. For VMAT plan QA, the gamma analysis passing rates ranged from 96.1% (H&N case) to 99.9% (prostate case), when using the 3%/3 mm DTA criteria for the peripheral dose validation between the TPS and ArcCHCEK measurements. The peripheral dose validation between the MC simulation and ArcCHECK measurements showed at least 97.9% gamma passing rates. The central dose validation also showed an agreement within 2.2% between TPS/MC calculations and ArcCHECK measurements. The worst discrepancy was found in the H&N case, which is the most complex VMAT case. The ArcCHECK system is suitable for VMAT QA evaluation based on the sensitivity to detecting misalignments, the clinical impact of the angular dependency, and the correlation between the dose agreements in the peripheral region and the central region. This work also demonstrated the importance of carrying out a thorough validation of both the TPS and the dosimetry system prior to utilizing it for QA, and the value of having an independent dose calculation tool, such as the MC method, in clinical practice.

2D IMRT QA passing rate dependency on coronal plane.

Intensity modulated radiation therapy (IMRT) delivery involves a complex series of beam angles and multileaf collimator (MLC) arrangements, requiring quality assurance to be performed to validate delivery before treatment. The purpose of this work is to investigate the effect of dose gradient on quality assurance (QA) passing rate. Many (n = 40) IMRT plans were delivered and measured using a 2D planar array of ion chambers; additionally, eleven plans were measured at several coronal planes. For each measurement, dose gradient was assessed using a number of metrics and passing rate assessed at both 3%/3 mm and 3%/2 mm criteria. The passing rates of the various IMRT plans were shown to be generally correlated to gradient, with an average distance correlation of 0.54 ± 0.04 for the lateral dose gradient. The passing rate for an individual plan was shown to vary with coronal slice, though the correlation to dose gradient was not predictable. Even though the passing rate was strongly related to dose gradient for many of the plans, the signs of the correlations were not always negative, as hypothesized. The coronal plane at which QA is performed affects passing rate, though dose gradient may not easily be used to predict slices at which passing rate is higher.

A new target localization method for image-guided radiation therapy of prostate cancer.

In imaged-guided radiation therapy (IGRT), target localization is usually done with rigid-body registration based on anatomy matching. Problems arise when the target volume can only be matched partially due to inter-fractional organ motion and deformation, resulting in deteriorated target coverage and critical structure sparing. A new target localization method is investigated in which the treatment target volume is aligned with the prescription isodose surface. Our study included 15 prostate patients previously treated with intensity-modulated radiation therapy (IMRT). Patient setup and target localization were performed using a CT-on-rails system before and after the IMRT treatment. IMRT plans were generated on the original simulation CTs (15) and the same MUs and leaf sequences were used to compute the dose distributions on post-treatment CTs (98) with the isocenter adjustments based on either anatomical structure matching or prescription isodose surface alignment. When patients were aligned with the traditional anatomy matching method, the dose to 95% of the CTV, D95, received 74.0 - 77.6 Gy and the minimum CTV dose, Dmin, was 61.9 - 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 35.7% of the treatment fractions. When patients were aligned using the new localization method, the dose to 95% of the CTV, D95, received 74.0 - 78.2 Gy and the minimum CTV dose, Dmin, was 68.4 - 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 17.3% of the treatment fractions. Traditional IGRT target localization based on anatomy matching is effective for population-based PTV margins but not ideal for those patients with large inter-fractional prostate rotation/deformation due to large rectal and bladder volume variation. The new method using the prescription isodose surface to align the target volume could improve the target coverage and rectal sparing for these patients, which can be implemented clinically to improve target dose delivery accuracy.

Long-Term Results of a Phase 3 Randomized Prospective Trial of Erectile Tissue-Sparing Intensity-Modulated Radiation Therapy for Men With Clinically Localized Prostate Cancer.

PURPOSE: The objective of this study was to determine whether limiting the doses delivered to the penile bulb (PB) and corporal bodies with intensity modulated radiation therapy (IMRT) preserves erectile function compared with standard IMRT in men with prostate cancer. METHODS AND MATERIALS: A total of 117 patients with low- to intermediate-risk, clinical T1a-T2c prostate adenocarcinoma were enrolled in a single-institution, prospective, single-blind, phase 3 randomized trial. All received definitive IMRT to 74 to 80 Gy in 37 to 40 fractions and standard IMRT (s-IMRT) or erectile tissue-sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the penile bulb and corporal bodies to ≤15 Gy and ≤7 Gy, respectively. Erectile potency was assessed with components of the International Index of Erectile Function and phosphodiesterase type 5 inhibitor (PDE5) medication records. RESULTS: Sixty-two patients received ETS-IMRT, and 54 received s-IMRT; 1 patient did not receive radiation therapy. Before treatment, all patients reported erectile potency. No patients received androgen deprivation therapy. In the intention-to-treat analysis, treatment arms did not differ in potency preservation at 24 months (37.1% ETS-IMRT vs 31.5% s-IMRT, P = .53). Of 85 evaluable patients with International Index of Erectile Function and PDE5 medication follow-up, erectile potency was seen in 47.9% of patients in the ETS-IMRT arm and 46.0% of patients in the s-IMRT arm (P = .86). PDE5 inhibitors were initiated in 41.7% of ETS-IMRT patients and 35.1% of s-IMRT patients (P = .54). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (5-year 91.8% vs 90.7%, respectively, P = .77), with a median follow-up of 7.4 years. There were no differences in acute or late gastrointestinal or genitourinary toxicity. An unplanned per-protocol analysis demonstrated no differences in potency preservation or secondary endpoints between patients who exceeded erectile tissue-sparing constraints and those who met constraints, although power was limited by attrition and unplanned dosimetric crossover. CONCLUSIONS: ETS-IMRT that strictly limits dose to the penile bulb and corporal bodies is safe and feasible. Use of this planning technique did not show an effect on potency preservation outcomes at 2 years, though power to detect a difference was limited.

Evaluating suggested stricter gamma criteria for linac-based patient-specific delivery QA in the conventional and SBRT environments.

PURPOSE: To evaluate AAPM TG-218 recommended tolerances for IMRT QA for conventional and SBRT delivery. METHODS: QA analysis was repeated for 150 IMRT/VMAT patients with varying gamma criteria. True composite delivery was utilized, corrected for detector and output variation. Universal tolerance (TLuniv) and action limits (ALuniv) were compared with statistical process control (SPC) TLSPC and ALSPC values. Analysis was repeated as a function of plan complexity for 250 non-stereotactic body radiotherapy (SBRT) VMAT patients at 3%/2mm and a threshold of 10% and for 75 SBRT VMAT patients at 2%/2 mm and a threshold of 50% with results plotted as a function of PTV volume. Regions of failure were dose-scaled on the planning CT data sets based on delivery results. RESULTS: The IMRT/VMAT TLSPC and ALSPC for gamma criteria of 3%/3 mm were 96.5% and 95.6% and for 3%/2 mm were 91.2% and 89.2%, respectively. Correlation with plan complexity for conventional fractionation VMAT was "low" for all sites with pelvis having the highest r value at -0.35. The equivalent SBRT PTV diameter ranged from 2.0 cm to 5.6 cm. Negative low correlation was found for 38 of 75 VMAT cases below ALuniv. CONCLUSIONS: The ALuniv and ALSPC are similar for 3%/2 mm. However, our 5% failure rate for ALuniv, may result in treatment start delays approximately 2 times/month, given 40 new cases/month. VMAT QA failure at stricter criteria did not correlate strongly with plan complexity. Site-specific action limits vary less than 3% from the average. SBRT QA results do not strongly correlate with target size over the range studied.

Dosimetric evaluation of image-guided radiation therapy for prostate cancer.

The aim of this study was to investigate the dosimetric accuracy of imaged-guided radiation therapy for prostate patients using the in-room computed tomography (CT) target localization technique. A Siemens CT-on-rails system was used for patient setup and target localization for intensity-modulated radiation therapy (IMRT) of prostate cancer. Fifteen previously treated prostate patients were included in this retrospective study. CT-on-Rails scans were performed before and after the IMRT treatment under local IRB approval. A total of 15 original simulation CT scans and 98 post-treatment CT scans were contoured by the same oncologist to delineate the prostate target, bladder, and rectum. IMRT plans were generated on the original simulation CTs and the same MUs and leaf sequences were used to compute the dose distributions using post-treatment CTs. Varian Velocity deformable registration was used for the summation of the fractional doses and the cumulative doses were compared with the planned doses. For the 15 patients investigated, the mean isocenter shift was up to 4.0 mm in the left-right direction, 5.9 mm in the anterior-posterior direction and 5.6 mm in the superior-inferior direction due to interfractional organ motion. The mean rectal volume varied from 0.6 to 1.73 times and the mean bladder volume varied from 0.59 to 3.65 times between simulation and the end of treatment. The prescription dose to 95% of the PTV, Dp, was set to 76 Gy for all treatment plans. The dose to 95% of the clinical treatment volume (CTV), D95, was 74.0 to 77.6 Gy and the minimum CTV dose, Dmin, was 61.0 to 71.6 Gy, respectively, in the cumulative dose distributions. Detailed analyses showed that 7.1% of the treatment fractions had cold spots (< 85% of Dp) in the peripheral CTV, leading to Dmin < 64 Gy in the cumulative dose distributions for 4 patients. The rectal dose-volume constraints were violated in 35.7% of the treatment fractions while the bladder dose was much improved in 82.7% of the treatment fractions. The current IGRT procedure for patient setup and target localization using rigid-body registration based on contour/anatomy matching is effective for population-based PTV margins. For a small group of patients, specific PTV margins and/or real-time target monitoring/tracking will be necessary due to significant prostate deformation/rotation caused by inter- and intrafractional bladder and rectal volume variation.

Practical Clinical Implementation of the Special Physics Consultation Process in the Re-irradiation Environment.

PURPOSE: The purpose of this work is to present a practical, structured process allowing for consistent, safe radiation therapy delivery in the re-treatment environment. METHODS AND MATERIALS: A process for reirradiation is described with documentation in the form of a special physics consultation. Data acquisition associated with previous treatment is described from highest to lowest quality. Methods are presented for conversion to equieffective dose, as well as our departmental assumptions for tissue repair. The generation of organ-at-risk available physical dose for use in treatment planning is discussed. Results using our methods are compared with published values after conversion to biologically effective dose. Utilization of pulsed-low-dose-rate delivery is described, and data for reirradiation using these methods over the previous 5 years are presented. RESULTS: Between 2015 and 2019, the number of patients in our department requiring equieffective dose calculation has doubled. We have developed guidelines for estimation of sublethal damage repair as a function of time between treatment courses ranging from 0% for <6 months to 50% for >1 year. These guidelines were developed based on available spinal cord data because we found that 84% of organs at risk involved nerve-like tissues. The average percent repair used increased from 32% to 37% over this time period. When comparing the results obtained using our methods with published values, 99% of patients had a cumulative biologically effective dose below the limits established for acceptable myelopathy rates. Pulsed-low-dose-rate use over this period tripled with an average prescription dose of 49 Gy. CONCLUSIONS: The methods described result in safe, effective treatment in the reirradiation setting. Further correlation with patient outcomes and side effects is warranted.

Silk-elastin-like hydrogel improves the safety of adenovirus-mediated gene-directed enzyme-prodrug therapy.

Recombinant silk-elastin-like protein polymers (SELPs) are well-known for their highly tunable properties on both the molecular and macroscopic hydrogel levels. One specific structure of these polymers, SELP-815K, has been investigated as an injectable controlled delivery system for the treatment of head and neck cancer via a gene-directed enzyme prodrug therapy (GDEPT) approach. Due to its pore size and gelation properties in vivo, SELP restricts the distribution and controls the release of therapeutic viruses for up to one month. It has been shown that SELP-mediated delivery significantly improves therapeutic outcome of the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system in xenograft models of human head and neck cancer. However little is known about potential benefits of this approach with regard to toxicity in the presence of a fully intact immune system. The studies presented here were designed to assess the change in toxicity of the SELP-mediated viral delivery compared to free viral injection in a non-tumor-bearing immune competent mouse model. Toxicity was assessed at 1, 2, 4, and 12 weeks via body weight monitoring, complete blood count (CBC), and blood chemistry. It was found that in the acute and subacute phases (weeks 1-4) there is significant toxicity in groups combining the virus and the prodrug, and matrix-mediated gene delivery with SELP demonstrates a reduction in toxicity from the 2 week time point through the 4 week time point. At the end of the subchronic phase (12 weeks), signs of toxicity had subsided in both groups. Based on these results, recombinant SELPs offer a significant reduction in toxicity of virus-mediated GDEPT treatment compared to free virus injection in the acute and subacute phases.

Uncertainties in IMRT dosimetry.

PURPOSE: The purpose of this study is to investigate some characteristics of the beam delivery system and their effects on the dose distribution of intensity-modulated radiation therapy (IMRT) and the results of patient-specific IMRT quality assurance (QA). These characteristics include the accelerator source distribution and multileaf collimator (MLC) geometry. METHODS: Monte Carlo dose calculations based on intensity maps that were built from the actual deliverable IMRT leaf sequences with and without considering the characteristics of the beam delivery system were performed in this study using in-house Monte Carlo software. The effect of the resolution of the intensity maps on the dose distribution was investigated first. The mean dose of the treatment target and the voxel doses in the high dose region of seven IMRT plans generated by different treatment planning systems for Varian 21EX and Siemens Primus linear accelerators were used for comparison and evaluation. RESULTS: The results show that a 0.2 x 0.2 mm2 or smaller pixel size is needed for the intensity maps for accurate IMRT dose calculation. The extrafocal source, MLC leaf thickness, leakage, tongue-and-groove structure, and the effective leaf offset can affect the mean dose by up to 1.5%, 4.5%, 5.6%, 5.3%, and 7.8%, respectively, when these factors are considered separately. They also cause significant uncertainties to the voxel dose with standard deviations up to 2.5%, 0.7%, 2.1%, 1.3%, and 5%, respectively. The overall effect on the mean dose is up to 8% and the standard deviation of the voxel dose uncertainty is up to 6.4% when all the effects are included. The maximum standard deviation is reduced to 4.6% if the voxel size of the dose calculation matrix is increased from 0.04 to 0.3 cm3 to make it comparable with the sensitive volume of the ionization chamber used for IMRT QA measurements. CONCLUSIONS: It can be concluded that the characteristics of the beam delivery system are the major contributors to the uncertainty of measurement-based IMRT QA because most of them are not fully considered in the currently available treatment planning systems.

Pelvic Reirradiation Utilizing Pulsed Low-dose Rate Radiation Therapy.

Pulsed low-dose rate radiation therapy has been shown to reduce normal tissue damage while decreasing DNA damage repair in tumor cells. In a cohort of patients treated with palliative or definitive pelvic reirradiation using pulsed low-dose rate radiation therapy, we observed substantial local control and low rates of toxicity.

Ten-Year Update of a Randomized, Prospective Trial of Conventional Fractionated Versus Moderate Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: The previously published single institution randomized prospective trial failed to show superiority in the 5-year biochemical and/or clinical disease failure (BCDF) rate with moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) versus conventionally fractionated IMRT (C-IMRT). We now present 10-year disease outcomes using updated risk groups and definitions of biochemical failure. METHODS: Men with protocol-defined intermediate- and high-risk prostate adenocarcinoma were randomly assigned to receive C-IMRT (76 Gy in 38 fractions) or H-IMRT (70.2 Gy in 26 fractions). Men with high-risk disease were all prescribed 24 months of androgen deprivation therapy (ADT) and had lymph node irradiation. Men with intermediate risk were prescribed 4 months of ADT at the discretion of the treating physician. The primary endpoint was cumulative incidence of BCDF. We compared disease outcomes and overall mortality by treatment arm, with sensitivity analyses for National Comprehensive Cancer Network (NCCN) risk group adjustment. RESULTS: Overall, 303 assessable men were randomly assigned to C-IMRT or H-IMRT. The median follow-up was 122.9 months. Per updated NCCN risk classification, there were 28 patients (9.2%) with low-risk, 189 (62.4%) with intermediate-risk, and 86 (28.4%) with high-risk prostate cancer. The arms were equally balanced for clinicopathologic factors, except that there were more black patients in the C-IMRT arm (17.8% v 7.3%; P = .02). There was no difference in ADT use (P = .56). The 10-year cumulative incidence of BCDF was 25.9% in the C-IMRT arm and was 30.6% in the H-IMRT arm (hazard ratio, 1.31; 95% CI, 0.82 to 2.11). The two arms also had similar cumulative 10-year rates of biochemical failure, prostate cancer-specific mortality, and overall mortality; however, the 10-year cumulative incidence of distant metastases was higher in the H-IMRT arm (rate difference, 7.8%; 95% CI, 0.7% to 15.1%). CONCLUSION: H-IMRT failed to demonstrate superiority compared with C-IMRT in long-term disease outcomes.

Local Control and Toxicity of External Beam Reirradiation With a Pulsed Low-dose-rate Technique.

PURPOSE: To evaluate the efficacy and toxicity of external beam reirradiation using a pulsed low-dose-rate (PLDR) technique. METHODS AND MATERIALS: We evaluated patients treated with PLDR reirradiation from 2009 to 2016 at a single institution. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0, and local control was assessed using the Response Evaluation Criteria In Solid Tumors, version 1.1. On univariate analysis (UVA), the χ2 and Fisher exact tests were used to assess the toxicity outcomes. Competing risk analysis using cumulative incidence function estimates were used to assess local progression. RESULTS: A total of 39 patients were treated to 41 disease sites with PLDR reirradiation. These patients had a median follow-up time of 8.8 months (range 0.5-64.7). The targets were the thorax, abdomen, and pelvis, including 36 symptomatic sites. The median interval from the first radiation course and reirradiation was 26.2 months; the median dose of the first and second course of radiation was 50.4 Gy and 50 Gy, respectively. Five patients (13%) received concurrent systemic therapy. Of the 39 patients, 9 (23%) developed grade ≥2 acute toxicity, most commonly radiation dermatitis (5 of 9). None developed grade ≥4 acute or subacute toxicity. The only grade ≥2 late toxicity was late skin toxicity in 1 patient. On UVA, toxicity was not significantly associated with the dose of the first course of radiation or reirradiation, the interval to reirradiation, or the reirradiation site. Of the 41 disease sites treated with PLDR reirradiation, 32 had pre- and post-PLDR scans to evaluate for local control. The local progression rate was 16.5% at 6 months and 23.8% at 12 months and was not associated with the dose of reirradiation, the reirradiation site, or concurrent systemic therapy on UVA. Of the 36 symptomatic disease sites, 25 sites (69%) achieved a symptomatic response after PLDR, including 6 (17%) with complete symptomatic relief. CONCLUSION: Reirradiation with PLDR is effective and well-tolerated. The risk of late toxicity and the durability of local control were limited by the relatively short follow-up duration in the present cohort.

A multi-institutional phase 2 trial of prostate stereotactic body radiation therapy (SBRT) using continuous real-time evaluation of prostate motion with patient-reported quality of life.

PURPOSE: The use of stereotactic body radiation therapy (SBRT) for prostate cancer has been reported predominantly from single institutional studies, although concerns for broader adoption exist. METHODS AND MATERIALS: From 2011 through 2013, 66 men were accrued to a phase 2 trial at 5 centers. SBRT consisted of 5 fractions of 7.4 Gy to a total dose of 37 Gy using conventional linear accelerators. Electromagnetic transponders were used for motion management. Health-related quality of life (HRQOL) was evaluated via the Expanded Prostate Cancer Index Composite 26 questionnaire. Acute and late toxicities were collected according to Common Terminology Criteria for Adverse Events, version 4.0. Linear mixed modeling was performed to assess changes in HRQOL over time. RESULTS: Median follow-up was 36 months. All men had low- or intermediate-risk disease. There have been 0 biochemical recurrences. No grade 3 urinary or bowel toxicity was reported. Twenty-three percent of patients had acute grade 2 urinary toxicity, with 9% late grade 2 urinary toxicity. Four percent and 5% experienced acute or late grade 2+ bowel toxicity, respectively. Urinary bother and bowel HRQOL transiently decreased during the first 6 to 12 months post-SBRT, and then returned to baseline. In men with good erectile function at baseline, sexual HRQOL declined during the first 6 months and stabilized thereafter. On linear mixed modeling, the strongest predictor of sustained bowel and sexual HRQOL was baseline HRQOL. CONCLUSIONS: In this multi-institutional phase 2 clinical trial using continuous real-time evaluation of prostate motion, prostate SBRT has excellent intermediate-term tumor control with mild and expected treatment-related side effects.

ASTRO's 2007 core physics curriculum for radiation oncology residents.

In 2004, the American Society for Therapeutic Radiology and Oncology (ASTRO) published a curriculum for physics education. The document described a 54-hour course. In 2006, the committee reconvened to update the curriculum. The committee is composed of physicists and physicians from various residency program teaching institutions. Simultaneously, members have associations with the American Association of Physicists in Medicine, ASTRO, Association of Residents in Radiation Oncology, American Board of Radiology, and American College of Radiology. Representatives from the latter two organizations are key to provide feedback between the examining organizations and ASTRO. Subjects are based on Accreditation Council for Graduate Medical Education requirements (particles and hyperthermia), whereas the majority of subjects and appropriated hours/subject were developed by consensus. The new curriculum is 55 hours, containing new subjects, redistribution of subjects with updates, and reorganization of core topics. For each subject, learning objectives are provided, and for each lecture hour, a detailed outline of material to be covered is provided. Some changes include a decrease in basic radiologic physics, addition of informatics as a subject, increase in intensity-modulated radiotherapy, and migration of some brachytherapy hours to radiopharmaceuticals. The new curriculum was approved by the ASTRO board in late 2006. It is hoped that physicists will adopt the curriculum for structuring their didactic teaching program, and simultaneously, the American Board of Radiology, for its written examination. The American College of Radiology uses the ASTRO curriculum for their training examination topics. In addition to the curriculum, the committee added suggested references, a glossary, and a condensed version of lectures for a Postgraduate Year 2 resident physics orientation. To ensure continued commitment to a current and relevant curriculum, subject matter will be updated again in 2 years.

Magnetic resonance-based treatment planning for prostate intensity-modulated radiotherapy: creation of digitally reconstructed radiographs.

PURPOSE: To develop a technique to create magnetic resonance (MR)-based digitally reconstructed radiographs (DRR) for initial patient setup for routine clinical applications of MR-based treatment planning for prostate intensity-modulated radiotherapy. METHODS AND MATERIALS: Twenty prostate cancer patients' computed tomography (CT) and MR images were used for the study. Computed tomography and MR images were fused. The pelvic bony structures, including femoral heads, pubic rami, ischium, and ischial tuberosity, that are relevant for routine clinical patient setup were manually contoured on axial MR images. The contoured bony structures were then assigned a bulk density of 2.0 g/cm(3). The MR-based DRRs were generated. The accuracy of the MR-based DDRs was quantitatively evaluated by comparing MR-based DRRs with CT-based DRRs for these patients. For each patient, eight measuring points on both coronal and sagittal DRRs were used for quantitative evaluation. RESULTS: The maximum difference in the mean values of these measurement points was 1.3 +/- 1.6 mm, and the maximum difference in absolute positions was within 3 mm for the 20 patients investigated. CONCLUSIONS: Magnetic resonance-based DRRs are comparable to CT-based DRRs for prostate intensity-modulated radiotherapy and can be used for patient treatment setup when MR-based treatment planning is applied clinically.

Long-Term Patient-Reported Outcomes From a Phase 3 Randomized Prospective Trial of Conventional Versus Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: To assess the long-term quality of life (QoL) outcomes from a phase 3 trial comparing 2 modes of intensity modulated radiation therapy (IMRT): conventional IMRT (CIMRT) versus hypofractionated IMRT (HIMRT) in patients with localized prostate cancer. METHODS AND MATERIALS: Between 2002 and 2006, 303 men with low-risk to high-risk prostate cancer were randomized to 76 Gy in 38 fractions (CIMRT) versus 70.2 Gy in 26 fractions (HIMRT). QoL was compared by use of the Expanded Prostate Cancer Index Composite (EPIC), the International Prostate Symptom Score (IPSS), and EuroQoL (EQ5D) questionnaires. The primary outcome of the QoL analysis was a minimum clinically important difference defined as a 0.5 standard deviation change from baseline for each respective QoL parameter. Treatment effects were evaluated with the use of logistic mixed effects regression models. RESULTS: A total of 286, 299, and 218 patients had baseline EPIC, IPSS, or EQ5D data available and were included in the analysis. Overall, there was no statistically significant difference between the 2 treatment arms in terms of EPIC, IPSS, or EQ5D scores over time, although there was a trend toward lower EPIC urinary incontinence scores in the HIMRT arm. More patients in the HIMRT arm had a lower EPIC urinary incontinence score relative to baseline versus patients in the CIMRT arm with long-term follow-up. On multivariable analysis, there was no association between radiation fractionation scheme and any QoL parameter. When other clinical factors were examined, lymph node radiation was associated with worse EPIC hormonal scores versus patients receiving no lymph node radiation. In general, QoL outcomes were generally stable over time, with the exception of EPIC hormonal and EQ5D scores. CONCLUSIONS: In this randomized prospective study, there were stable QoL changes in patients receiving HIMRT or CIMRT. Our results add to the growing body of literature suggesting that HIMRT may be an acceptable treatment modality in clinically localized prostate cancer.

Impact of pelvic nodal irradiation with intensity-modulated radiotherapy on treatment of prostate cancer.

PURPOSE: The aim of this study was to evaluate the feasibility of treating the pelvic lymphatic regions during prostate intensity-modulated radiotherapy (IMRT) with respect to our routine acceptance criteria. METHODS AND MATERIALS: A series of 10 previously treated prostate patients were randomly selected and the pelvic lymphatic regions delineated on the fused magnetic resonance/computed tomography data sets. A targeting progression was formed from the prostate and proximal seminal vesicles only to the inclusion of all pelvic lymphatic regions and presacral region resulting in 5 planning scenarios of increasing geometric difficulty. IMRT plans were generated for each stage for two accelerator manufacturers. Dose volume histogram data were analyzed with respect to dose to the planning target volumes, rectum, bladder, bowel, and normal tissue. Analysis was performed for the number of segments required, monitor units, "hot spots," and treatment time. RESULTS: Both rectal endpoints were met for all targets. Bladder endpoints were not met and the bowel endpoint was met in 40% of cases with the inclusion of the extended and presacral lymphatics. A significant difference was found in the number of segments and monitor units with targeting progression and between accelerators, with the smaller beamlets yielding poorer results. Treatment times between the 2 linacs did not exhibit a clinically significant difference when compared. CONCLUSIONS: Many issues should be considered with pelvic lymphatic irradiation during IMRT delivery for prostate cancer including dose per fraction, normal structure dose/volume limits, planning target volumes generation, localization, treatment time, and increased radiation leakage. We would suggest that, at a minimum, the endpoints used in this work be evaluated before beginning IMRT pelvic nodal irradiation.