Three-dimensional printing in radiation oncology: A systematic review of the literature.

PURPOSE/OBJECTIVES: Three-dimensional (3D) printing is recognized as an effective clinical and educational tool in procedurally intensive specialties. However, it has a nascent role in radiation oncology. The goal of this investigation is to clarify the extent to which 3D printing applications are currently being used in radiation oncology through a systematic review of the literature. MATERIALS/METHODS: A search protocol was defined according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Included articles were evaluated using parameters of interest including: year and country of publication, experimental design, sample size for clinical studies, radiation oncology topic, reported outcomes, and implementation barriers or safety concerns. RESULTS: One hundred and three publications from 2012 to 2019 met inclusion criteria. The most commonly described 3D printing applications included quality assurance phantoms (26%), brachytherapy applicators (20%), bolus (17%), preclinical animal irradiation (10%), compensators (7%), and immobilization devices (5%). Most studies were preclinical feasibility studies (63%), with few clinical investigations such as case reports or series (13%) or cohort studies (11%). The most common applications evaluated within clinical settings included brachytherapy applicators (44%) and bolus (28%). Sample sizes for clinical investigations were small (median 10, range 1-42). A minority of articles described basic or translational research (11%) and workflow or cost evaluation studies (3%). The number of articles increased over time (P < 0.0001). While outcomes were heterogeneous, most studies reported successful implementation of accurate and cost-effective 3D printing methods. CONCLUSIONS: Three-dimensional printing is rapidly growing in radiation oncology and has been implemented effectively in a diverse array of applications. Although the number of 3D printing publications has steadily risen, the majority of current reports are preclinical in nature and the few clinical studies that do exist report on small sample sizes. Further dissemination of ongoing investigations describing the clinical application of developed 3D printing technologies in larger cohorts is warranted.

Developing a MLC modifier program to improve fiducial detection for MV/kV imaging during hypofractionated prostate volumetric modulated arc therapy.

PURPOSE: To develop an Eclipse plug-in (MLC_MODIFIER) that automatically modifies control points to expose fiducials obscured by MLC during VMAT, thereby facilitating tracking using periodic MV/kV imaging. METHOD: Three-dimensional fiducial tracking was performed during VMAT by pairing short-arc (3°) MV digital tomosynthesis (DTS) images to triggered kV images. To evaluate MLC_MODIFIER efficacy, two cohorts of patients were considered. For first 12 patients, plans were manually edited to expose one fiducial marker. Next for 15 patients, plans were modified using MLC_MODIFIER script. MLC_MODIFIER evaluated MLC apertures at appropriate angles for marker visibility. Angles subtended by control points were compressed and low-dose "imaging" control points were inserted and exposed one marker with 1 cm margin. Patient's images were retrospectively reviewed to determine rate of MV registration failures. Failure categories were poor DTS image quality, MLC blockage of fiducials, or unknown reasons. Dosimetric differences in rectum, bladder, and urethra D1 cc, PTV maximum dose, and PTV dose homogeneity (PTV HI) were evaluated. Statistical significance was evaluated using Fisher's exact and Student's t test. RESULT: Overall MV registration failures, failures due to poor image quality, MLC blockage, and unknown reasons were 33% versus 8.9% (P < 0.0001), 8% versus 6.4% (P < 0.05), 13.6% versus 0.1% (P < 0.0001), and 7.6% versus 2.4% (P < 0.0001) for manually edited and MLC_MODIFIER plans, respectively. PTV maximum and HI increased on average from unmodified plans by 2.1% and 0.3% (P < 0.004) and 22.0% and 3.3% (P < 0.004) for manually edited and MLC_MODIFIED plans, respectively. Changes in bladder, rectum, and urethra D1CC were similar for each method and less than 0.7%. CONCLUSION: Increasing fiducial visibility via an automated process comprised of angular compression of control points and insertion of additional "imaging" control points is feasible. Degradation of plan quality is minimal. Fiducial detection and registration success rates are significantly improved compared to manually edited apertures.

Comparison of outcomes for MR-guided versus CT-guided high-dose-rate interstitial brachytherapy in women with locally advanced carcinoma of the cervix.

OBJECTIVE: The purpose was to compare local control (LC), overall survival (OS) and dose to the organs at risk (OAR) in women with locally advanced cervical cancer treated with MR-guided versus CT-guided interstitial brachytherapy (BT). METHODS: 56 patients (29 MR, 27 CT) were treated with high-dose-rate (HDR) interstitial BT between 2005-2015. The MR patients had been prospectively enrolled on a Phase II clinical trial. Data were analyzed using Kaplan-Meier (K-M) and Cox proportional hazards statistical modeling in JMP® & R®. RESULTS: Median follow-up time was 19.7months (MR group) and 18.4months (CT group). There were no statistically significant differences in patient age at diagnosis, histology, percent with tumor size >4cm, grade, FIGO stage or lymph node involvement between the groups. Patients in the MR group had more lymphovascular involvement compared to patients in the CT group (p<0.01). When evaluating plans generated, there were no statistically significant differences in median cumulative dose to the high-risk clinical target volume or the OAR. 2-year K-M LC rates for MR-based and CT-based treatments were 96% and 87%, respectively (log-rank p=0.65). At 2years, OS was significantly better in the MR-guided cohort (84% vs. 56%, p=0.036). On multivariate analysis, squamous histology was associated with longer OS (HR 0.23, 95% CI 0.07-0.72) in a model with MR BT (HR 0.35, 95% CI 0.08-1.18). There was no difference in toxicities between CT and MR BT. CONCLUSION: In this population of locally advanced cervical-cancer patients, MR-guided HDR BT resulted in estimated 96% 2-year local control and excellent survival and toxicity rates.

Characterizing gradient echo signal decays in gynecologic cancers at 3T using a Gaussian augmentation of the monoexponential (GAME) model.

PURPOSE: To assess whether R2* mapping with a standard Monoexponential (ME) or a Gaussian Augmentation of the Monoexponential (GAME) decay model better characterizes gradient-echo signal decays in gynecological cancers after external beam radiation therapy at 3T, and evaluate implications of modeling for noninvasive identification of intratumoral hypoxia. MATERIALS AND METHODS: Multi-gradient-echo signals were acquired on 25 consecutive patients with gynecologic cancers and three healthy participants during inhalation of different oxygen concentrations at 3T. Data were fitted with both ME and GAME models. Models were compared using F-tests in tumors and muscles in patients, muscles, cervix, and uterus in healthy participants, and across oxygenation levels. RESULTS: GAME significantly improved fitting over ME (P < 0.05): Improvements with GAME covered 34% of tumor regions-of-interest on average, ranging from 6% (of a vaginal tumor) to 68% (of a cervical tumor) in individual tumors. Improvements with GAME were more prominent in areas that would be assumed hypoxic based on ME alone, reaching 90% as ME R2* approached 100 Hz. Gradient echo decay parameters at different oxygenation levels were not significantly different (P = 0.81). CONCLUSION: R2* may prove sensitive to hypoxia; however, inaccurate representations of underlying data may limit the success of quantitative assessments. Although the degree to which R2 or σ values correlate with hypoxia remains unknown, improved characterization with GAME increases the potential for determining any correlates of fit parameters with biomarkers, such as oxygenation status. J. MAGN. RESON. IMAGING 2016;44:1020-1030.

Outcomes with volume-based dose specification in CT-planned high-dose-rate brachytherapy for stage I-II cervical carcinoma: A 10-year institutional experience.

OBJECTIVE: To determine prognostic factors for progression-free survival (PFS) and overall survival (OS) for stage I-II cervical-cancer patients treated using computed-tomography (CT)-planned high-dose-rate (HDR) intracavitary brachytherapy (BT). METHODS: A total of 150 patients were treated for Stage I-II cervical cancer using CT-planned BT between 4/2004 and 10/2014. Of these, 128 were eligible for inclusion. Kaplan-Meier local control (LC), pelvic control (PC), overall survival (OS), and PFS estimates were calculated. RESULTS: After a median follow-up of 30months, the 2-year LC rate was 96%, PFS was 88%, and OS was 88%. Overall, 18 patients (14%) experienced any recurrence (AR), 8 had distant recurrence only and 10 had a combination of local, pelvic, regional, and distant recurrence. No patients had LR only. A prognostic factor for AR was tumor size >4cm (p=0.01). Patients with tumors >4cm were 3.3 times more likely to have AR than those with tumors ≤4cm (hazard ratio [HR]=3.3; 95% confidence interval [CI] 1.28-9.47). Point A was 85% of prescription for tumors < 4 cm and decreased approximately 3% over 5 fractions compared to 90% of prescription for tumors > 4 cm that decreased approximately 4% over 5 fractions. Two patients (2%) experienced grade≥2 late toxicity. There were no acute or late grade≥3 toxicities. CONCLUSION: CT-planned BT resulted in excellent local control and survival. Large tumor size was associated with an increased risk of recurrence outside the radiation field and worse PFS and OS. A volume-optimized plan treated a smaller area than a point A standard plan for patients with Stage I-II cervical cancer that have received chemoradiation. Given the outstanding LC achieved with modern therapy including chemoradiation, HDR, and image-based BT, further efforts to combat spread outside the radiation field with novel therapies are warranted.

Real-time active MR-tracking of metallic stylets in MR-guided radiation therapy.

PURPOSE: To develop an active MR-tracking system to guide placement of metallic devices for radiation therapy. METHODS: An actively tracked metallic stylet for brachytherapy was constructed by adding printed-circuit micro-coils to a commercial stylet. The coil design was optimized by electromagnetic simulation, and has a radio-frequency lobe pattern extending ∼5 mm beyond the strong B0 inhomogeneity region near the metal surface. An MR-tracking sequence with phase-field dithering was used to overcome residual effects of B0 and B1 inhomogeneities caused by the metal, as well as from inductive coupling to surrounding metallic stylets. The tracking system was integrated with a graphical workstation for real-time visualization. The 3 Tesla MRI catheter-insertion procedures were tested in phantoms and ex vivo animal tissue, and then performed in three patients during interstitial brachytherapy. RESULTS: The tracking system provided high-resolution (0.6 × 0.6 × 0.6 mm(3) ) and rapid (16 to 40 frames per second, with three to one phase-field dithering directions) catheter localization in phantoms, animals, and three gynecologic cancer patients. CONCLUSION: This is the first demonstration of active tracking of the shaft of metallic stylet in MR-guided brachytherapy. It holds the promise of assisting physicians to achieve better targeting and improving outcomes in interstitial brachytherapy.

A finite element method for modeling diffusion of alpha-emitting particles in tissue.

BACKGROUND: Diffusing alpha-emitters Radiation Therapy ("DaRT") is a promising new modality for the treatment of solid tumors. Interstitial sources containing 224 Ra are inserted into the tumor, producing alpha particles via the decay of 224 Ra and its daughters. The alpha particles are able to produce a "kill region" of several mm due to the diffusion of the alpha-emitting atoms. The Diffusion-Leakage (D-L) model has been proposed to describe the movement of the alpha-emitters used in DaRT in tumor tissue. PURPOSE: To date, estimating the dose delivered under the D-L model has been accomplished with numerical solutions based on finite difference methods, namely DART1D and DART2D, as well as with asymptotic expressions for the long time limit. The aim of this work is to develop a flexible method of finite elements for solving the D-L model and to validate prior solutions of the D-L model. METHODS: We develop a two-dimensional finite element solution to the D-L model implemented using the FEniCS software library. Our approach solves the variational formulation of the D-L equations on an unstructured mesh of triangular Lagrangian elements. We calculate the local dose in the mid- and axial planes of the source and validate our results against the one- and two-dimensional solutions obtained using the previously proposed numerical scheme, DART1D and DART2D. We use our model to estimate the change in dose in the source midplane as a function of the physical parameters used in the D-L model. RESULTS: The local dose at the end of a 30 day treatment period estimated by our numerical method differs from DART1D and DART2D by less than 1% in the source midplane and less than 3% along the source axis over clinically relevant distances, with the largest discrepancies in high gradient areas where the Finite Element Method (FEM) mesh has a higher element density. We find that within current experimentally estimated ranges for D-L model parameters, the dose in the source midplane at a distance of 2 mm can vary by over a factor of 3. CONCLUSIONS: The 2D finite element model reproduces the calculated dose obtained with DART1D and DART2D under the assumptions D-L model. The variation in predicted dose within current experimental ranges for model parameters suggests the necessity of further studies to better determine their statistical distributions. Finally, the FEM model can be used to calculate dose from DaRT in a variety of realistic 2D geometries beyond the D-L model.

Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2-51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63-87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

Clinical outcomes following 3D image-guided brachytherapy for vaginal recurrence of endometrial cancer.

PURPOSE: To evaluate clinical outcomes for women with recurrent endometrial cancer treated with 3D image-guided brachytherapy METHODS AND MATERIALS: 44 women, of whom 13 had received prior RT, received salvage RT for vaginal recurrence from 9/03 to 8/11. HDR or LDR interstitial brachytherapy was performed under MR or CT guidance in 35 patients (80%); 9 (20%) had CT-guided HDR cylinder brachytherapy. The median cumulative dose in EQD2 was 75.5 Gy. Actuarial estimates of local failure (LF), disease-free (DFS) and overall survival (OS) were calculated by Kaplan-Meier. RESULTS: Histologic subtypes were endometrioid (EAC, 33), papillary serous/clear cell (UPSC/CC, 5) and carcinosarcoma (CS, 6). The 2-year DFS/OS rates were 75%/89% for EAC and 11%/24% for UPSC/CC/CS (both p<0.01). On MVA, high tumor grade was associated with recurrence (HR 3.2 for grade 2, 9.6 for grade 3, p<0.01). The LF rate at 2 years was 4% for patients without versus 39% for those with prior RT (p=0.1). Patients who had prior RT received lower cumulative doses at recurrence (66.5 Gy vs. 74.4 Gy, p<0.01). The 2-year DFS/OS rates with and without prior RT were 26%/55% and 72%/80% (both p=0.1). Four patients (9%) experienced grade 3 late toxicity, including 3 of 13 (23%) in the re-irradiation setting and 1 of 31 (3%) with no prior radiotherapy. DISCUSSION: 3D image-guided brachytherapy results in excellent local control for women with recurrent endometrial cancer, particularly with cumulative EQD2 doses greater than 70 Gy. Successful salvage of vaginal recurrence is related to tumor grade and histologic subtype.

Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer.

OBJECTIVE: To report clinical outcomes following adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) for early-stage uterine papillary serous (UPSC) and clear cell (CC) endometrial cancer. METHODS: A retrospective study of Stage I and II papillary serous and clear cell endometrial cancer treated with post-operative HDR VB between October 2005 and May 2012 was performed. A total of 37 patients were identified, 26 with UPSC, 9 with CC and 2 with mixed UPSC/CC. After total hysterectomy and bilateral salpingo-oophorectomy, VB was administered without external-beam radiation with a dose of 24 Gy in 6 fractions prescribed to the vaginal surface. Chemotherapy was given to 30 patients (75%). RESULTS: The median follow up time was 24.8 months (range, 2.0 to 71.5 months). Four patients relapsed, 2 with UPSC and 2 with CC. The initial site of relapse was concurrent vagina, pelvic/para-aortic nodes and abdominal wall (1), pelvic/para-aortic nodes (1) and para-aortic nodes alone (2). The 2-year vaginal-control rate was 96.8%. The pelvic-control rate including vaginal and nodal relapse was 93.5%. The 2-year disease-free and overall survival rates were 89.3% and 100%, respectively. CONCLUSION: HDR VB as the sole adjuvant treatment modality for early-stage UPSC/CC is associated with a low rate of vaginal relapse and excellent survival outcomes. This novel low-dose regimen for VB is safe and effective.

Clinical Experience and Feasibility of Using 2D-kVimage Online Intervention in the Ultrafractionated Stereotactic Radiation Treatment of Prostate Cancer.

PURPOSE: This study reports clinical experience and feasibility of using a 2-dimensional (2D)-kV image system with online intervention in the ultrafractionated stereotactic body radiation treatment (UF-SBRT) of prostate cancer. METHODS AND MATERIALS: Fifteen patients with prostate cancer who had a low- to intermediate-risk marker implanted received UF-SBRT with online 2D-kV image tracking and a manual beam interruption strategy with a 2-mm motion threshold. A total of 180 kV paired setup images and 1272 intrabeam 2D-kV images were analyzed to evaluate the setup deviation and intratreatment target deviation. Correlation of expected treatment interruptions with a set of parameters (eg, image and treatment time; direction of deviation) was performed (Spearman test). A subset of the data from 22 fractions was re-evaluated to check the differences in analysis results between using the planning position and using the pretreatment setup position as a reference. Margins based on the derived system and random errors were calculated to evaluate the feasibility of the workflow in ensuring prostate coverage during treatment. RESULTS: Mean target motion in 3D propagated from 1.0 mm (setup at 0 minutes) to 2.0 mm (beam on at 7 minutes) to 2.4 mm (end at 13.5 minutes). Out of 75 fractions, 50 were found to require beam interruption. Interruption had a strong correlation with prostate motion along the longitudinal direction and had moderate correlation with prostate motion along the vertical direction and the prostate's treatment starting position along vertical and longitudinal directions. Using the pretreatment position as a reference for intrabeam monitoring, the magnitude of motion deviation from the reference position was reduced by 0.3 mm at a vertical direction and 0.4 mm at lateral and longitudinal directions. The calculated 3D margin to ensure target coverage was 3.7 mm, 4.6 mm, and 5.0 mm in lateral, vertical, and longitudinal directions, respectively. CONCLUSIONS: Prostate motion propagated over time. It is feasible to use a 2D-kV online intrabeam monitoring system with a proper intervention scheme to perform UF-SBRT for prostate cancer.

Feasibility and Safety of Diffusing Alpha-Emitter Radiation Therapy for Recurrent or Unresectable Skin Cancers.

Importance: Patients with recurrent or unresectable skin cancers have limited treatment options. Diffusing alpha-emitter radiation therapy (DaRT), a novel solid tumor management strategy using alpha-particle interstitial brachytherapy, may address this challenge. Objective: To evaluate the feasibility and safety of using DaRT to manage recurrent or unresectable skin cancers. Design, Setting, and Participants: This prospective cohort study of patients who received a 2-week to 3-week treatment course and were followed up for 24 weeks after treatment during 2021 and 2022 at 2 sites in the US. Patients with malignant skin tumors or soft tissue tumors were recruited if they had limited treatment options for tumors recurrent after prior surgery or external beam radiotherapy or unresectable tumors. Intervention: Patients underwent DaRT to deliver a physical dose of 10 Gy (equivalent weighted dose of 200 CGE) to the tumor. Main Outcomes and Measures: Feasibility of the DaRT procedure was evaluated based on the ability of investigators to successfully deliver radiation to the tumor. Patients were followed up for adverse events (AEs) for 24 weeks and for tumor response by physicians' physical examination and imaging 12 weeks after device removal. Results: This study included 10 participants with recurrent or unresectable skin cancer (median [IQR] age, 72 [68-75] years; 6 males [60%]; 4 females [40%]). Six patients (60%) had recurrent disease, and 4 (40%) had tumors that were deemed unresectable. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. Median (range) tumor volume before treatment was 2.1 cm3 (0.65-12.65 cm3). The mean (SD) prescription dose coverage of the gross tumor volume was 91% (2.8%) with all tumors having coverage of 85% or more. No device-related grade 3 AEs were noted. Common AEs were grade 1 to 2 erythema, edema, and pruritus. At 12 weeks following treatment, there was a 100% complete response rate. Nine of 10 complete responses (90%) were confirmed by CT imaging. Conclusions and Relevance: This cohort study suggests the feasibility and preliminary safety of DaRT in the management of recurrent or unresectable skin cancers. The favorable safety profile and high response rates are promising. A US trial for marketing approval based on this pilot study is under way. Trial Registration: ClinicalTrials.gov Identifier: NCT04377360.

HDR prostate brachytherapy plan robustness and its effect on in-vivo source tracking error thresholds: A multi-institutional study.

PURPOSE: The purpose of this study was to examine the effect of departmental planning techniques on appropriate in-vivo source tracking error thresholds for high dose rate (HDR) prostate brachytherapy (BT) treatments, and to determine if a single in-vivo source tracking error threshold would be appropriate for the same patient anatomy. METHODS: The prostate, rectum, and urethra were contoured on a single patient transrectal ultrasound (TRUS) dataset. Anonymized DICOM files were disseminated to 16 departments who created an HDR prostate BT treatment plan on the dataset with a prescription dose of 15 Gy in a single fraction. Departments were asked to follow their own local treatment planning guidelines. Source positioning errors were then simulated in the 16 treatment plans and the effect on dose-volume histogram (DVH) indices calculated. Change in DVH indices were used to determine appropriate in-vivo source tracking error thresholds. Plans were considered to require intervention if the following DVH conditions occurred: prostate V100% < 90%, urethra D0.1cc > 118%, and rectumtt Dmax > 80%. RESULTS: There was wide variation in appropriate in-vivo source tracking error thresholds among the 16 participating departments, ranging from 1 to 6 mm. Appropriate in-vivo source tracking error thresholds were also found to depend on the direction of the source positioning error and the endpoint. A robustness parameter was derived, and found to correlate with the sensitivity of plans to source positioning errors. CONCLUSIONS: A single HDR prostate BT in-vivo source tracking error threshold cannot be applied across multiple departments, even for the same patient anatomy. The burden on in-vivo source tracking devices may be eased through improving HDR prostate BT plan robustness during the plan optimisation phase.

Protocol for the measurement of the absorbed dose rate to water for a planar 32P beta emitting brachytherapy source: A multi-institutional validation.

PURPOSE: This is a multi-institutional report on inter-observer and inter-instrument variation in the calibration of the absorbed dose rate for a planar 32P beta emitting brachytherapy source. Measurement accuracy is essential since the dose profile is steep and the source is used for the treatment of tumors that are located in close proximity to healthy nervous system structures. METHODS AND MATERIALS: An RIC-100 32P source was calibrated by three institutions using their own equipment and following their standard procedures. The first institution calibrated the source with an electron diode and EBT3 film. The second institution used an electron diode. The third institution used HD810 film. Additionally, each institution was asked to calibrate the source using an electron diode and procedure that was shared among all institutions and shipped along with the radiation source. The dose rate was reported in units of cGy*min-1 at a water equivalent depth of 1 mm. RESULTS: Close agreement was observed in the measurements from different users and equipment. The variation across all diode detectors and institutions had a standard deviation of 1.8% and maximum difference of 4.6%. The observed variation among two different diode systems used within the same institution had a mean difference of 1.6% and a maximum variation of 1.8%. The variations among film and diode systems used within the same institution had a mean difference of 2.9% and a maximum variation of 4.3% CONCLUSIONS: The absorbed dose rate measurement protocol of the planar beta-emitting 32P source permits consistent dosimetry across three institutions and five different electron diode and radiochromic film systems. The methodologies presented herein should enable measurement consistency among other clinical users, which will help ensure high quality patient treatments and outcomes analysis.

Early outcomes of high-dose-rate brachytherapy combined with ultra-hypofractionated radiation in higher-risk prostate cancer.

PURPOSE: This study evaluated outcomes associated with a high-dose-rate (HDR) brachytherapy boost combined with stereotactic body radiation therapy (SBRT) for patients with higher-risk localized prostate cancer. MATERIALS AND METHODS: We identified 101 patients with National Comprehensive Cancer Network high-risk, unfavorable intermediate-risk, or favorable intermediate-risk with probable extra-prostatic extension treated with HDR brachytherapy (15 Gy x 1 fraction) followed by SBRT (5 Gy x 5 daily fractions to the prostate and/or seminal vesicles and/or pelvic lymph nodes). Androgen deprivation therapy was used in 55.4% of all patients (90% of high-risk, 33% of intermediate-risk). Toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and International Prostate Symptom Scores were prospectively documented at each followup visit. Biochemical relapse was defined as PSA nadir +2ng/mL. RESULTS: The median follow-up time after SBRT was 24.1 months. No grade ≥3 toxicities were observed. The incidence of acute and late grade 2 gastrointestinal toxicities was both 0.99%. Acute and late grade 2 genitourinary (GU) toxicities were observed in 5.9% and 9.9%, respectively. Median time to a grade 2 GU toxicity was 6 months with a 14% 2-year actuarial rate of grade 2 GU toxicity. Median International Prostate Symptom Scores at 24 months was not significantly different than baseline (6 vs. 5; p = 0.24). Inclusion of pelvic lymph nodes and absence of a rectal spacer were significantly associated with more frequent grade ≥1 GU toxicity, but not grade ≥2 GU or gastrointestinal toxicity. The 2-year biochemical relapse free survival was 97%. CONCLUSIONS: HDR brachytherapy combined with SBRT was associated with a favorable early toxicity profile and encouraging cancer control outcomes.

Quantifying clinical severity of physics errors in high-dose rate prostate brachytherapy using simulations.

PURPOSE: To quantitatively evaluate through automated simulations the clinical significance of potential high-dose rate (HDR) prostate brachytherapy (HDRPB) physics errors selected from our internal failure-modes and effect analysis (FMEA). METHODS AND MATERIALS: A list of failure modes was compiled and scored independently by 8 brachytherapy physicists on a one-to-ten scale for severity (S), occurrence (O), and detectability (D), with risk priority number (RPN) = SxOxD. Variability of RPNs across observers (standard deviation/average) was calculated. Six idealized HDRPB plans were generated, and error simulations were performed: single (N = 1722) and systematic (N = 126) catheter shifts (craniocaudal; -1cm:1 cm); single catheter digitization errors (tip and connector needle-tips displaced independently in random directions; 0.1 cm:0.5 cm; N = 44,318); and swaps (two catheters swapped during digitization or connection; N = 528). The deviations due to each error in prostate D90%, urethra D20%, and rectum D1cm3 were analyzed using two thresholds: 5-20% (possible clinical impact) and >20% (potentially reportable events). RESULTS: Twenty-nine relevant failure modes were described. Overall, RPNs ranged from 6 to 108 (average ± 1 standard deviation, 46 ± 23), with responder variability ranging from 19% to 184% (average 75% ± 30%). Potentially reportable events were observed in the simulations for systematic shifts >0.4 cm for prostate and digitization errors >0.3 cm for the urethra and >0.4 cm for rectum. Possible clinical impact was observed for catheter swaps (all organs), systematic shifts >0.2 cm for prostate and >0.4 cm for rectum, and digitization errors >0.2 cm for prostate and >0.1 cm for urethra and rectum. CONCLUSIONS: A high variability in RPN scores was observed. Systematic simulations can provide insight in the severity scoring of multiple failure modes, supplementing typical FMEA approaches.

Low-Dose-Rate Brachytherapy Combined With Ultrahypofractionated Radiation Therapy for Clinically Localized, Intermediate-Risk Prostate Cancer: Results From a Prospective Trial.

PURPOSE: To report early toxicity and tumor control outcomes of Pd-103 brachytherapy with ultrahypofractionated stereotactic radiation therapy (RT) for intermediate-risk prostate cancer. METHODS AND MATERIALS: This prospective trial included 40 patients with intermediate-risk prostate cancer who underwent low-dose-rate (Pd-103) brachytherapy (prescription dose, 100 Gy), followed 1 month later with ultrahypofractionated stereotactic RT (25 Gy in 5 fractions) to the prostate and seminal vesicles. The primary endpoint was the rate of grade 2+ genitourinary toxicity at 12 months using Common Terminology Criteria for Adverse Events v 4.0. Secondary endpoints included patient-reported quality-of-life metrics (International Prostate Scoring System [IPSS], International Index of Erectile Function, and Expanded Prostate Cancer Index Composite-bowel). Biochemical failure was defined as prostate-specific antigen nadir +2 ng/mL. Posttreatment biopsies were performed at between 24 and 36 months; median follow-up was 36 months. RESULTS: The rate of grade 2 urinary toxicity at 12 months was 25% with no grade 3 urinary toxicity noted. Mean IPSS at baseline and 12 and 24 months was 5, 10, and 6.2, respectively. Mean change in IPSS from baseline at 12 months was +5.5 (interquartile range, 1-9.75) and +1.05 (interquartile range, -3 to 3.25) at 24 months. Grade 2 bowel toxicity was 5% at 12 months with no grade 3 bowel toxicity noted. Mean Expanded Prostate Cancer Index Composite-bowel domain scores at baseline and 12 months were 92.8 and 90.3, respectively. Of patients who were potent (International Index of Erectile Function ≥21) at baseline, 75% remained potent at 12 months. Of 40 patients, 28 underwent posttreatment prostate biopsy (PPB), which was negative (n = 20) or demonstrated severe treatment effect (n = 8). No patient had a positive PPB or developed biochemical failure during the follow-up period. One patient without a PPB developed osseous metastases at 18 months posttreatment in the absence of biochemical failure. CONCLUSION: Low-dose-rate brachytherapy in combination with ultrahypofractionated stereotactic RT was safe and effective for intermediate-risk prostate cancer in early results of this trial.

Novel intraoperative radiotherapy utilizing prefabricated custom three-dimensionally printed high-dose-rate applicators.

BACKGROUND: Intraoperative radiotherapy (IORT) is an effective strategy for the delivery of high doses of radiotherapy to a residual tumor or resection cavity with relative sparing of nearby healthy tissues. This strategy is an important component of the multimodality management of pediatric soft tissue sarcomas, particularly in cases where patients have received prior courses of external beam radiotherapy. PURPOSE: Tumor beds with significant topographic irregularity remain a therapeutic challenge because existing IORT technologies are typically most reliable with flat surfaces. To address this limitation, we have developed a novel strategy to create custom, prefabricated high-dose-rate (HDR)-IORT applicators designed to match the shape of an anticipated surgical cavity. METHODS AND MATERIALS: Silastic applicators are constructed using three-dimensional (3D) printing and are derived from volumetric segmentation of preoperative imaging. RESULTS: HDR preplanning with the applicators improves dosimetric accuracy and minimizes incremental operative time. In this report, we describe the fabrication process for the 3D-printed applicators and detail our experience utilizing this strategy in two pediatric patients who underwent HDR-IORT as part of complex base of skull sarcoma resections. CONCLUSIONS: Early experience suggests that usage of the custom applicators is feasible, versatile for a variety of clinical situations, and enables the uniform delivery of high superficial doses of radiotherapy to irregularly shaped surgical cavities.

Placement of an absorbable rectal hydrogel spacer in patients undergoing low-dose-rate brachytherapy with palladium-103.

PURPOSE: Rates of rectal toxicity after low-dose-rate (LDR) brachytherapy for prostate cancer are dependent on rectal dose, which is associated with rectal distance from prostate and implanted seeds. Placement of a hydrogel spacer between the prostate and rectum has proven to reduce the volume of the rectum exposed to higher radiation dose levels in the setting of external beam radiotherapy. We present our findings with placing a rectal hydrogel spacer in patients following LDR brachytherapy, and we further assess the impact of this placement on dosimetry and acute rectal toxicity. METHODS AND MATERIALS: Between January 2016 and April 2017, 74 patients had placement of a hydrogel spacer, immediately following a Pd-103 seed-implant procedure. Brachytherapy was delivered as follows: as a monotherapy to 26 (35%) patients; as part of planned combination therapy with external beam radiotherapy to 40 (54%) patients; or as a salvage monotherapy to eight (11%) patients. Postoperative MRI was used to assess separation achieved with rectal spacer. Acute toxicity was assessed retrospectively using Radiation Oncology Therapy Group radiation toxicity grading system. Rectal dosimetry was compared with a consecutive cohort of 136 patients treated with seed implantation at our institution without a spacer, using a 2-tailed paired Student's t test (p < 0.05 for statistical significance). RESULTS: On average, 11.2-mm (SD 3.3) separation was achieved between the prostate and the rectum. The resultant mean rectal volume receiving 100% of prescribed dose (V100%), dose to 1 cc of rectum (D1cc), and dose to 2 cc of rectum (D2cc) were 0 (SD 0.05 cc), 25.3% (SD 12.7), and 20.5% (SD 9.9), respectively. All rectal dosimetric parameters improved significantly for the cohort with spacer placement as compared with the nonspacer cohort. Mean prostate volume, prostate V100 and dose to 90% of gland (D90) were 29.3 cc (SD 12.4), 94.0% (SD 3.81), and 112.4% (SD 12.0), respectively. Urethral D20, D5cc, and D1cc were 122.0% (SD 17.27), 133.8% (SD 22.8), and 144.0% (SD 25.4), respectively. After completing all treatments, at the time of first the followup, 7 patients reported acute rectal toxicity-6 experiencing Grade 1 rectal discomfort and 1 (with preexisting hemorrhoids) experiencing Grade 1 bleeding. CONCLUSIONS: Injection of rectal spacer is feasible in the post-LDR brachytherapy setting and reduces dose to the rectum with minimal toxicity. Prostate and urethral dosimetries do not appear to be affected by the placement of a spacer. Further studies with long-term followup are warranted to assess the impact on reduction of late rectal toxicity.