Equivalent Dose In 2Gy Fractions Research Articles

Effect of high-dose radiation therapy on positive margins after breast-conserving surgery for invasive breast cancer.

Positive margins after breast-conserving surgery are associated with poor oncological outcomes and warrant additional surgery. This study aimed to evaluate the effectiveness of high-dose radiation therapy for positive margins by comparing local recurrence between patients with positive and negative margins. We retrospectively evaluated 550 patients treated with adjuvant radiation therapy after breast-conserving surgery for invasive breast cancer between 2013 and 2019. The total equivalent dose in 2Gy fractions (EQD2) to the tumor bed ranged from 65.81 to 66.25Gy for positive margins and 59.31-61.81Gy for negative margins. The differences in local recurrence between the positive and negative margin groups were analyzed. After a median follow-up of 58 months, the crude local recurrence rate was 7.3% in the positive margin group (n=55) and 2.4% in the negative margin group (n=495). Positive margins were associated with higher local recurrence without statistical significance in the entire cohort (p=0.062). Among patients aged <60 years, those with positive margins had a significantly lower 5-year local recurrence-free survival rate than those with negative margins (89.16% vs. 97.57%, respectively; p=0.005). In contrast, there was no significant difference in the 5-year local recurrence-free survival rate between patients with positive and negative margins among those aged ≥60 years (100.00% vs. 94.38%, respectively; p=0.426). In this study, positive margins were not associated with poor local control in older patients after a high-dose boosts. Further prospective studies are needed to verify our findings.

Re-irradiation for recurrent high-grade glioma: an analysis of prognostic factors for survival and predictors of radiation necrosis.

Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for re-irradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009 to 2020 from our institutional database. The primary objective was overall survival (OS). Secondary endpoints included prognostic factors for early death (< 6months after re-RT) and predictors of radiation necrosis (RN). For the 79 patients identified, the median OS after re-RT was 9.9months (95% CI 8.3-11.6). On multivariate analyses, re-resection at progression (HR 0.56, p = 0.027), interval from primary treatment to first progression ≥ 16.3months (HR 0.61, p = 0.034), interval from primary treatment to re-RT ≥ 23.9months (HR 0.35, p < 0.001), and re-RT PTV volume < 112cc (HR 0.27, p < 0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR 12.4, p = 0.034), ≥ 3 prior systemic treatment lines (OR 29.1, p = 0.022), interval to re-RT < 23.9months (OR 9.0, p = 0.039), and re-RT PTV volume ≥ 112cc (OR 17.8, p = 0.003) were more likely to die within 6months of re-RT. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12months. Concurrent bevacizumab use (HR < 0.001, p < 0.001) and cumulative equivalent dose in 2Gy fractions (EQD2, α/β = 2) < 99 Gy2 (HR < 0.001, p < 0.001) were independent protective factors against RN. Re-RT allowed for less corticosteroid dependency. Sixty-six percent of failures after re-RTwere in-field. We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab mitigated the risk of RN.

PO35 Presentation Time: 10:30 AM: Initial Outcomes for Utilization of the Venezia Hybrid High-Dose Rate Brachytherapy Applicator in Definitive Treatment of Locally-Advanced Cervical and Endometrial Cancer

<h3>Purpose</h3> The Venezia gynecological applicator (Elekta) is a hybrid interstitial/intracavitary brachytherapy applicator used to treat cervical cancers. Previous data supporting the use of hybrid brachytherapy comes mainly from the EMBRACE cohort showing increased coverage of the high-risk CTV (HR-CTV) with decreased toxicity. Single-institution data, further supports this technique. We undertook this study to report our initial experience with the Venezia applicator for treatment of locally advanced cervical and endometrial cancers. <h3>Materials/Methods</h3> We retrospectively reviewed 21 patients who received brachytherapy using the Venezia applicator for definitive treatment of cervical or endometrial cancer, treated from June, 2021 to March, 2022. All patients completed chemoradiotherapy followed by brachytherapy boost. For each brachytherapy fraction, patients received sedation and the Venezia applicator was placed. Radiation treatment planning was performed on CT imaging fused to daily MRI, using the Oncentra® treatment planning system. If needles were required for hybrid interstitial brachytherapy, the plan was optimized first without utilizing the needles, to meet constraint to organs at risk (OARs). Subsequently, planning was performed considering the interstitial needles with a focus on optimizing the balance of target coverage and dose to organs at risk. Radiation dose to target volumes and organs at risk were recorded as equivalent dose in 2Gy fractions (EQD2). <h3>Results</h3> Median age was 54 years. Ninety percent of patients were treated for a primary cervical cancer and 10% for primary endometrial cancer. Twenty-nine percent of patients had T1 primary tumor, 48% had a primary T2 tumor and 24% had a primary T3 tumor. The most common histology was squamous cell carcinoma (SCC) in 76% of patients, with adenocarcinoma in 10% and the remaining being undifferentiated or endometrioid. Median follow up was 4.3 months. Thirty-three percent of patients experienced acute toxicity with brachytherapy, all of which were grade 1-2. Twenty-nine percent experienced acute GI toxicity, 10% experienced acute GU toxicity and 10% experienced bleeding. Median brachytherapy dose and fractionation was 28Gy delivered over 4 fractions. Sixty-two percent of patients required hybrid interstitial brachytherapy and the median number of interstitial needles placed was 4. Median volume of the Gross Tumor Volume (GTV) and HR-CTV at first fraction were respectively 5.22cm³(IQR 4.26cm³-10.28cm³) and 27.84cm³(IQR 24.71cm³-40.36cm³⁾. Median HR-CTV D90 and D98 were respectively 85.3Gy(IQR 83.1Gy-88.8Gy) and 76.8Gy (IQR 74.2Gy-79.6Gy). Median GTV D98 was 98.4Gy (IQR 94.3Gy-116.3Gy). Regarding OARs, median D2cc dose to the rectum, sigmoid and bladder were respectively 56.9Gy (IQR 53.7Gy-59.1Gy), 60Gy (IQR 55.9Gy-63.7Gy) and 75.3Gy (IQR 72.3Gy-77.6Gy). Median D1cc dose to the bowel was 50Gy (IQR 46.6Gy-56.8Gy). Median D0.1cc dose to the left and right ureter were respectively 71.8Gy (IQR 62.6Gy-85Gy) and 67.5Gy (IQR 61.6Gy-89.1Gy). <h3>Conclusions</h3> Brachytherapy using the Venezia hybrid applicator was implemented with good dosimetry and sparing of organs at risk. Procedure related complications were mild.

Evaluation of Repeated Lung Stereotactic Body Radiotherapy Using a Radiotherapy Dose Accumulation Routine

<h3>Purpose/Objective(s)</h3> Repeated lung SBRT has been used for recurrent or metachronous non-small-cell lung cancer. Comprehensive evaluation of cumulative dose is essential for safe reirradiation to minimize the risk of pneumonitis and esophageal toxicity. We evaluated an in-house script named RADAR (Radiotherapy Dose Accumulation Routine) designed to provide accurate dose assessment that accounts for registration uncertainties, and improve the efficiency of clinical workflow. <h3>Materials/Methods</h3> In this pilot study, we analyzed a cohort of 20 patients who underwent 2-5 courses of repeated lung SBRT. Lung volume changed 8±8% between courses. Planning CT images from earlier treatment courses were registered onto the final course in two steps: first, a rigid registration based on alignment of spine and rib cage, then a deformable image registration (DIR) using a ‘demons' algorithm in a planning system. The resulting deformable vector fields were used by RADAR to transform voxels for automated dose accumulation. User can choose to output either physical dose or equivalent dose in 2Gy fractions (EQD2, α/β=3) with a discount factor (Paradis, ARO 2019). RADAR provides three approaches for dose accumulation: 1) direct sum that outputs voxel level dose summation; 2) unrestricted search that incorporates DIR uncertainty by conservatively assigning the maximum dose within a search radius (3mm) to the voxel of interest for dose accumulation; 3) restricted search, which performs the same dose accumulation as in 2) but imposes structure label matching in the search radius, therefore including only voxels within the same structure. Accumulated dose distribution was written back to the planning system for evaluation. We extracted mean lung dose (MLD) and esophagus D5cc (EsoD5cc) with respect to various accumulation approaches for comparison. <h3>Results</h3> MLD and EsoD5cc were significantly higher when accounting for DIR uncertainties (<i>p</i><0.001 two-tailed t-test). MLD has less uncertainty than EsoD5cc due to its averaging nature. For radiotherapy with >2 courses, RADAR considerably shortened the processing time by auto-accumulating dose from multiple courses simultaneously, as opposed to the cumbersome manual approach of creating plan sums iteratively. Typical time for dose accumulation and evaluation using RADAR is < 10 mins. <h3>Conclusion</h3> RADAR is a convenient and efficient tool to calculate and evaluate cumulative dose for lung reirradiation cases. It identifies higher OAR doses due to dose accumulation uncertainties, for example coming from the registration. Our study provides initial data to establish clinical guidance for design and optimization of repeated lung SBRT.

Extracting Organ-Specific Radiobiological Model Parameters of Abdominal Organs from Clinical Outcome Data for Biological Radiation Treatment Planning

<h3>Purpose/Objective(s)</h3> It is desirable to consider organ-specific treatment response in a variety of biological radiotherapy (RT) planning scenarios, e.g., adaptive RT with varying daily dose, reirradiation, multi-modality RT, varying fractionation. This study aims to extract organ-specific radiobiological model parameters for selected abdominal organs and to demonstrate their applications in determining OAR dose constraints using biologically effective dose (BED) and equivalent dose in 2Gy fractions (EQD2). <h3>Materials/Methods</h3> Available clinical studies from the literature reporting dose volume constraints for abdominal organs, e.g., duodenum, stomach, small bowel, and rectum, along with the compiled data in available sources such as TG101, QUANTEC, HyTEC, national and institutional trial protocols were analyzed. The data ranging from conventional fractionation RT (CFRT) to stereotactic body RT (SBRT) were analyzed to determine the maximum point doses (MPD) corresponding to no more than 5% grade ≥ 3 toxicity. The endpoints were selected according to toxicity scales (e.g., CTCAE (v3 or v4), RTOG). Iso-effect fittings (e.g., MPD vs. fractional dose) on the data collected for each organ were performed using both the linear quadratic (LQ) and the linear-quadratic-linear (LQL) models to extract the organ-specific radiobiological parameters. The dose constraint MPD in terms of BED and EQD2 for each OAR was calculated using the obtained organ-specific parameters. The use of the obtained MPD constraints was demonstrated in reirradiation planning. <h3>Results</h3> More than 50 studies were screened to find an average of 10 to 20 relevant studies for each OAR. The LQL and LQ models fit the clinical data from CFRT to SBRT reasonably well, although the LQL model showed a better fit compared to the LQ model. The table below shows the obtained LQ and LQL model parameters and the MPD constraints in terms of BED and EQD2 for selected abdominal organs, where χ²/df is the reduced chi-square. Using the data in the table, the MPD in the small bowel for a vaginal tumor case re-irradiated with 4 × 5Gy after one year from the initial RT of 10 × 3Gy was estimated as 50.2 Gy EQD2, below the constraint of 53.1 Gy. <h3>Conclusion</h3> We developed a robust method to successfully extract abdominal organ-specific radiobiological parameters from clinical data. These parameters can be used to convert OAR dose constraints from different RT fractionations/techniques for biologically optimized RT planning.

Brain and Brainstem Necrosis after Re-Irradiation for Recurrent Childhood Central Nervous System (CNS) Tumors: A Report from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Task Force

<h3>Purpose/Objective(s)</h3> Re-irradiation is increasingly used in children, adolescents and young adults (AYA) with recurrent CNS tumors. The PENTEC re-irradiation task force reports the results on the risk of symptomatic necrosis following cranial re-irradiation, and its dependence on cumulative dose. <h3>Materials/Methods</h3> A systematic literature search for peer-reviewed articles 1975 to 2021 identified 1183 studies on re-irradiation and 92 studies on re-irradiation for recurrent CNS tumors. Studies on predominantly adult populations and re-irradiation for secondary neoplasms were excluded (n=49). Data from the remaining 43 studies were captured. 17 studies (n=449), reporting brain and brainstem necrosis were used for analysis. While all studies mentioned techniques and range of doses used for re-irradiation, they lacked details on significant dose-volume metrics (e.g., percentage of re-irradiation treatment volume overlapping with primary radiotherapy, mean and maximum cumulative equivalent dose in 2Gy fractions, with alpha-beta ratio=2 (EQD2/2) to organs at risk) necessary for a dose-response modelling. We, therefore, estimated the incidence of necrosis with an exact 95% confidence interval (CI) and provided a qualitative description of the data. <h3>Results</h3> Treated cancers included ependymoma (n=279;7 studies), medulloblastoma (n=98; 6 studies), any CNS tumors (n=62: 3 studies) and supratentorial high-grade gliomas (n=10: 1 study). The median interval between initial and re-irradiation was 2.3 years (range 1.2-4.75). The median cumulative EQD2/2 prescription dose was 103.8 Gy (range 79.7-141.3). Among 449 children/AYA treated with re-irradiation, 22 (4.9%, 95% CI 3.1-7.3%) developed brain necrosis and 14 (3.1%, 95% CI 1.7-5.2%) brainstem necrosis. The median cumulative prescription EQD2/2 was 111.4 Gy (range 79.7-141.3) for development of any necrosis, 107.7 Gy (range 79.7-141.3) for brain necrosis and 112.1 Gy (range 100.2-117) for brainstem necrosis. In 6 studies (n=176) of conventionally fractionated (≤2 Gy per fractions) re-irradiation, 7 patients developed brain necrosis (3.9%) and 4 brainstem necrosis (1.7). In the 5 studies (n=160) of hypofractionated (4-24 Gy per fraction) re-irradiation, 9 patients developed brain necrosis (5.6%) and 10 brainstem necrosis (6.9%). Though there were more necroses in the hypofractionated group, it was not statistically significant (Fisher's exact test 2-tailed p value=0.4664). The remaining six studies (n=113) used a range of fraction size (1.8-24 Gy). No studies reported cumulative dosing for individual organs at risk. <h3>Conclusion</h3> Existing literature suggests that in children and AYA with recurrent brain tumors, re-irradiation results in less than 5-7% incidence of brain/brainstem necrosis with conventional prescription doses after a median follow-up of 2.3 years. A uniform approach for reporting dosimetric endpoints is recommended to derive a robust predictive model of late toxicities following re-irradiation.

Trastuzumab emtansine increases the risk of stereotactic radiosurgery-induced radionecrosis in HER2 + breast cancer.

In this study, we investigate factors associated with radionecrosis (RN) in HER2 + (human epidermal growth factor receptor 2) patients with brain metastases (BrM) treated with stereotactic radiosurgery (SRS). Patients with HER2 + breast cancer BrM treated with SRS (2010-2020) were identified from an institutional database. The incidence of RN was determined per treated BrM according to serial imaging and/or histology. Factors associated with RN such as age, RT dose, BrM volume, and initiation of Trastuzumab Emtansine (T-DM1) were investigated with univariate and multivariable analyses (MVA). 67 HER2 + patients with 223 BrM were identified. 21 patients (31.3%) were treated with T-DM1 post-SRS, including 14 patients (20.9%) who received T-DM1 within 12months of SRS. The median follow-up was 15.6 (interquartile range (IQR) 5.4-35.3) months. The overall probability of RN post-SRS was 21.6% (95% confidence interval (CI) 2.7-10.7), and the 1 and 2year risk was 6.7% (95% CI 2.7-10.7) and 15.2% (95% CI 9.2-21.3). MVA identified T-DM1 treatment post-SRS (hazard ratio (HR) 2.5, 95% CI 1.2-5.3, p = 0.02) and equivalent dose in 2Gy fractions (EQD2) > 90 Gy2 (HR 2.4, 95% CI 1.1-5.1, p = 0.02) as predictors of RN. Patients treated with T-DM1 and SRS had a 29.9% (95% CI 15.3-44.6%) probability of RN, with a 25.2% (95% CI 12.8-37.6%) risk at 1- and 2years post-T-DM1. The majority of RN were symptomatic (71%), with a median time to RN of 4.8months. T-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

Estimating Cumulative Radiation Dose to Organs at Risk for Glioblastoma Multiforme Cases via a Radiotherapy Dose Accumulation Routine

Estimating Cumulative Radiation Dose to Organs at Risk for Glioblastoma Multiforme Cases via a Radiotherapy Dose Accumulation Routine

Improving GI Toxicity Models Through Deep Learning-Based Segmentation and Biomechanical Model-Based Dose Accumulation

<h3>Purpose/Objective(s)</h3> Current GI toxicity models are limited by the uncertainty in the estimated delivered dose used to develop the models. The purpose of this study is to assess the benefit of harnessing deep learning and biomechanical models to improve the understanding of the dose-toxicity relationship. <h3>Materials/Methods</h3> Retrospective dose accumulation was conducted on 75 patients with primary and metastatic liver cancer treated with external beam radiotherapy guided by daily CT-on-rails (CTOR), based on a novel deformable image registration (DIR) approach that applies biomechanical model-based and intensity-based DIR inside and outside the liver, respectively. The liver was auto-segmented on all images using a clinically validated 2D deep learning model. On a sub-cohort, the combination of stomach and duodenum region of interest (GI ROI) was auto-contoured using a 3D UNet model trained independently on 102 patients. These contours were compared to physician-drawn contours on CTOR, using Dice similarity coefficient (DSC), mean distance to agreement (DTA), Hausdorff distance (HD), and planned dose metrics. Intra-observer variability was evaluated. Doses were converted to equivalent dose in 2Gy fractions (EQD2) for analysis (α/β = 3.5). Differences between planned and delivered dose were calculated, as well as GI ROI daily dose variation. Toxicity probability was calculated based on previously developed accumulated dose normal tissue complication probability (NTCP) models for duodenum and stomach. <h3>Results</h3> Average (SD) DSC, DTA, and HD between the deep learning model and physician-drawn GI ROI were 0.9 (0.1), 0.2 (0.1) cm, and 2.4 (2.2) cm; intra-observer values were 0.9 (0.0), 0.1 (0.0) cm, and 2.3 (0.8) cm, <i>P</i> > 0.1. Average differences in volume (SD), D50 (SD), and D1 (SD) between the AI model and physician-drawn contours were 25.0 (36.7) cc, 0.6 (1.1) Gy, and 0.5 (0.2) Gy; intra-observer values were 7.1 (4.5) cc, 0.2 (0.3) Gy and 0.3 (0.3) Gy, <i>P</i> > 0.1. Average planned and accumulated D1 (EQD2) to the GI ROI were 28.1 Gy and 26.6 Gy, respectively. These distributions were significantly different (<i>P</i> < 0.01), with differences ranging from 0.2 Gy to 2.9 Gy. Daily D1 to the GI ROI varied by up to 47% (average 25%). For 38% of patients, relative differences in NTCP based on planned and accumulated dose were greater than 50%. Compared to planned dose, 63% of the patients had lower NTCP with accumulated dose, and 13% had higher NTCP. <h3>Conclusion</h3> Variability between AI-based and physician-drawn stomach and duodenum segmentation was equivalent to intra-observer variability. Accumulated dose showed statistically significant differences from planned dose for the stomach and duodenum leading to meaningful differences in NTCP. The daily variability in the maximum dose varied by an average of +/- 25%, demonstrating the potential to optimize daily fractionation based on anatomical configuration of the day.

Effective Pain Control With Very Low Dose Palliative Radiation Therapy for Patients With Multiple Myeloma With Uncomplicated Osseous Lesions

Background: Osteolytic lesions are present in 75% of patients with multiple myeloma (MM) and frequently require palliation with radiation therapy (RT). Prior case series of patients with MM with bone pain undergoing palliative RT suggests doses ≥12 Gy (equivalent dose in 2Gy fractions, EQD2) provide excellent bone pain relief. However, recent advances in care and novel biologic agents have significantly improved overall survival and quality of life for patients with MM. We hypothesized that lower-dose RT (LDRT, EQD2 <12 Gy) offers an effective alternative to higher-dose RT (HDRT, EQD2 ≥12 Gy) for palliation of painful, uncomplicated MM bone lesions. Methods: We retrospectively identified patients with MM treated with RT for uncomplicated, painful bone lesions and stratified by EQD2 ≥/< 12 Gy. Clinical pain response (CPR) rates, acute and late toxicity, pain response duration, and retreatment rates between LDRT and HDRT groups were analyzed. Results: Thirty-five patients with 70 treated lesions were included: 24 patients (48 lesions) treated with HDRT and 11 patients (22 lesions) with LDRT. Median follow-up was 14 and 16.89 months for HDRT and LDRT, respectively. The median dose of HDRT treatment was 20 Gy versus 4 Gy in the LDRT group. The CPR rate was 98% for HDRT and 95% for LDRT. There was no significant difference in any-grade acute toxicity between the HDRT and LDRT cohorts (24.5% vs 9.1%, Χ2P = .20). Pain recurred in 10% of lesions (12% HDRT vs 9.5% LDRT). Median duration of pain response did not significantly differ between cohorts (P = .91). Five lesions were retreated, 2 (9.5%) in the LDRT cohort, and 3 (6.3%) in the HDRT cohort. Conclusion: In this study, LDRT effectively palliated painful, uncomplicated MM bony lesions with acceptable CPR and duration of palliation. These data support prospective comparisons of LDRT versus HDRT for palliation of painful, uncomplicated MM bony lesions.

Characterization of combined intracavitary/interstitial brachytherapy including oblique needles in locally advanced cervix cancer

To characterize and report on dosimetric outcomes of image guided adaptive brachytherapy (IGABT) using intracavitary and interstitial (IC/IS) applicators including oblique needles (O-needles) in locally advanced cervical cancer (LACC). Twenty LACC patients treated with radio-chemotherapy and offered IC/IS-IGABT including O-needles were analyzed. An in-house 3D-printed vaginal template was used to steer the needles parallel and obliquely in relation to the tandem, supplemented with free-hand needles if needed. Implant characteristics and loading patterns were analyzed. Using the equivalent dose in 2Gy-fractions (EQD2) concept, cumulative (EBRT+BT) V85, V75, V60Gy, targets/OARs doses and high dose volumes (150%, 200% and 300% (100% = 85 Gy EQD210)) were evaluated. Median(range) tumor width at diagnosis was 5.5(3.6; 7.5)cm; CTVHR volume was 45(23; 136)cm3 with maximum distance from tandem to CTVHR border of 3.4(2.5; 4.8)cm. T-stage distribution was IIB/III/IVA in 6(30%)/9(45%)/5(25%) of patients. At BT, 13(65%) patients had distal parametrial/pelvic wall infiltration. Median(range) number of needles per patient was 11(8-18). Average distribution of intrauterine, vaginal and interstitial dwell times were 31%, 25% and 44%, respectively. Median(range) dwell-time per dwell position was 11(2-127)% of average point-A based standard loading. Median V85Gy/V150%/V200%/V300% were 85(38; 171)/41(21; 93)/22(12; 41)/7(4; 19) cm3; CTVHR D90% was 93(83; 97)Gy EQD210; bladder/rectum/sigmoid/bowel D2cm3 were 78(64; 104)/65(52; 76)/59(53; 69)/61(47; 76)Gy EQD23. The use of O-needles in patients with large and/or unfavorable tumors resulted in excellent target coverage and OARs sparing. Intrauterine and vaginal loadings were reduced compared to standard loading and almost half of the loading was shifted into IS needles. This was achieved with gentle loading in the majority of dwell positions.

Safety and feasibility of implantable, uni-directional planar low-dose rate (LDR) brachytherapy in borderline resectable pancreatic adenocarcinoma

Presenter: Herman Peters MD | VCU Health Background: The treatment of borderline resectable pancreatic adenocarcinoma continues to evolve as promising evidence toward neoadjuvant chemoradiation strategies emerge. These strategies, ultimately, aim to facilitate a R0 resection for patients whose radiographic staging characteristics place them at risk for positive margins. Despite reported R0 rates after neoadjuvant chemoradiation ranging from 70-98%, those patients with positive margins or patients not eligible for surgery after neoadjuvant treatment (40-60%) have significantly decreased survival. A novel technique for delivering radiation therapy to the area at risk for margin positivity at the time of surgery, while eliminating the pitfalls and constraints for a post-operative external beam RT (EBRT) boost could expand surgical candidacy and offer survival benefits to patients with positive margins. This study details our experience with a surgically implantable, uni-directional LDR brachytherapy sheet as a boost to targeted anatomy in patients with pancreatic adenocarcinoma after neoadjuvant chemoradiation. Methods: Patients with a diagnosis of borderline resectable pancreatic adenocarcinoma who underwent neoadjuvant chemoradiation (2017-2019) and had concern for positive margins based on imaging were eligible for treatment with the implantable LDR sheet at the time of surgery. CivaSheet® (CivaTech Oncology) is an FDA-cleared product consisting of a matrix of Pd-103 radioisotopes on a bio-absorbable membrane with a gold shield providing unidirectional radiation exposure. Dose is prescribed to 5mm depth and in this study was between 38-45Gy equivalent dose in 2Gy fractions. Intra-operatively, the sheet is cut to size for the area of concern, plus a 1cm margin, and secured in place with absorbable suture and/or fibrin glue by the surgical oncologist. Outcomes evaluated included procedural time, time to implant the device, procedural complications related to sheet placement, length of hospital stay, post-operative complications, and survival. Results: From March 2017 to December 2018, 7 patients received LDR sheets. Median age was 63.7 (range 51-75) and 5 patients were female. At initial diagnosis, all 7 patients had borderline resectable disease. All patients received neoadjuvant chemotherapy with 4 to 6 cycles of FOLFINIROX followed by concurrent chemoradiation to a dose of 50.4 Gy in 28 fractions prior to surgery and sheet placement. Surgical procedures included 4 pancreaticoduodenectomy (PD) and 3 distal pancreatectomy (DP). 2 PD required venous reconstruction and 1 DP required arterial reconstruction. Mean procedure time was 6hr 51min out of which sheet placement added an average of 15min. Mean hospital stay was 6.1 days. There were no post-operative complications attributable to the sheet placement. Median follow up is 13 months (range 6-25 months). One patient died with local & distant recurrence at 13 months & one patient is alive with local recurrence at 22 months. 5 patients are alive with no evidence of disease. Conclusion: This is the first study to report the safety and feasibility of an implantable, uni-directional, LDR brachytherapy sheet in patients with borderline resectable pancreatic adenocarcinoma. This novel treatment strategy can be implanted safely and efficiently with potential to improve rates of local control & survival.

Precision Radiation Therapy for Metastatic Spinal Cord Compression: Final Results of the PRE-MODE Trial

To investigate precision radiation therapy for metastatic spinal cord compression and compare it to conventional radiation therapy. In a multicenter phase 2 study, 40 patients received 5 Gy × 5 fractions of precision radiation therapy (38 volume modulated arc therapy, 2 intensity modulated radiation therapy) for metastatic spinal cord compression and were evaluated for local progression-free survival (LPFS), motor function, ambulatory status, sensory function, sphincter dysfunction, pain, distress, overall survival (OS), and toxicity. Maximum spinal cord dose was 101.5% (myelopathy risk, <0.03%) of the prescription dose. Patients were compared with a historical control group conventionally irradiated with 4 Gy × 5 fractions (propensity score analysis). The equivalent dose in 2Gy-fractions of 5 Gy × 5 fractions is similar to 3 Gy × 10 fractions, which results in better LPFS than 4 Gy × 5 fractions. It was assumed that 5 Gy × 5 fractions is also superior to 4 Gy × 5 fractions for LPFS. (ClinicalTrials.gov-identifier: NCT03070431) RESULTS: Six-month rates of LPFS and OS were 95.0% and 42.6%, respectively. Improvement of motor function occurred in 24 patients (60%). Thirty-three patients (82.5%) were ambulatory after radiation therapy. Eight of 16 patients (50.0%) with sensory deficits improved. Pain and distress relief were reported by 61.9% and 54.2% of patients 1 month after radiation therapy. Grade 3 toxicities occurred in 1 patient and grade 2 toxicities in another 3 patients. Of the control group, 664 patients qualified for the propensity score analysis; 5 Gy × 5 fractions was significantly superior to 4 Gy × 5 fractions with regard to LPFS (P = .026) but not motor function (P= .51) or OS (P = .82). Precision radiation therapy with 5 Gy × 5 fractions was well tolerated and effective and appeared superior to 4 Gy × 5 fractions in terms of LPFS. The retrospective nature of the historic control group, which might have led to a hidden selection bias, needs to be considered when interpreting the results.

Radiotherapy for metastatic spinal cord compression with increased radiation doses (RAMSES-01): a prospective multicenter study

BackgroundPatients with metastatic spinal cord compression (MSCC) and favorable survival prognoses can benefit from radiation doses greater than 30Gy in 10 fractions in terms of improved local progression-free survival (LPFS) and overall survival (OS).Methods/designThis prospective study mainly investigates LPFS after precision radiotherapy (volumetric modulated arc therapy or stereotactic body radiotherapy) with 18 × 2.33Gy in 3.5 weeks. LPFS is defined as freedom from progression of motor deficits during radiotherapy and an in-field recurrence of MSCC following radiotherapy. The maximum relative dose allowed to the spinal cord is 101.5% of the prescribed dose, resulting in an equivalent dose in 2Gy-fractions (EQD2) for radiation myelopathy is 45.5Gy, which is below the tolerance dose of 50Gy according to the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC). The EQD2 of this regimen for tumor cell kill is 43.1Gy, which is 33% higher than for 30Gy in 10 fractions (EQD2 = 32.5Gy). Primary endpoint is LPFS at 12 months after radiotherapy. Secondary endpoints include the effect of 18 × 2.33Gy on motor function, ambulatory status, sensory function, sphincter dysfunction, LPFS at other follow-up times, overall survival, pain relief, relief of distress and toxicity. Follow-up visits for all endpoints will be performed directly and at 1, 3, 6, 9 and 12 months after radiotherapy. A total of 65 patients are required for the prospective part of the study. These patients will be compared to a historical control group of at least 235 patients receiving conventional radiotherapy with 10x3Gy in 2 weeks.DiscussionIf precision radiotherapy with 18 × 2.33Gy results in significantly better LPFS than 10x3Gy of conventional radiotherapy, this regimen should be strongly considered for patients with MSCC and favorable survival prognoses.Trial registrationClinicaltrials.gov NCT04043156. Registered 30-07-2019.

Acute and Late Genitourinary Toxicity Among Patients Receiving Vaginal High Dose Rate Interstitial Brachytherapy

High dose rate (HDR) interstitial brachytherapy (ISBT) is an effective modality to deliver highly conformal doses of radiation for treatment of malignancies centered within the vagina. The aim of this study was to evaluate urethral dose and its correlation to the incidence of genitourinary complications among patients undergoing vaginal ISBT. 39 patients treated with ISBT between January 2017 and April 2018 were retrospectively reviewed after REB approval. Clinical characteristics were collected from their electronic medical records and CTCAE was used to grade toxicity. ISBT dosimetric information was collected through review of individual treatment plans as generated in a treatment planning system. Urethral contours were retrospectively added to the structure sets using a 1 cm diameter brush and dose to 0.1cc (D0.1cc), D0.2cc and D0.5cc of urethra were obtained. Then, the total (ISBT +/- EBRT) equivalent dose in 2Gy fractions (EQD2) received by HRCTV (Gy10) and OARs (Gy3) were calculated. Numerical counts (%) and medians (Inter-Quartile-Range) were used to characterize the data. Fisher’s exact and the Mann-Whitney-Wilcox tests were used as appropriate to determine statistical significance. The median age and follow-up was 66 years (57-73) and 9.3 months (6.4-15.3). 21 (54%) patients had endometrial, 13 (33%) had vaginal, 4 (10%) had vulvar primaries and one (3%) had metastasis from the rectum. 30 (77%) patients received external beam radiation prior to ISBT. 17 (44%) underwent a single brachytherapy insertion and 22 (56%) received two. A median of 4 (3-6) ISBT fractions were delivered to each patient and a median of 15 needles (13-17) were used. Median total EQD2 were 55.4 (46.4-72.5), 52.3 (46.0-67.1), 50.9 (45.6-62.5) Gy for Urethral D0.1cc, D0.2cc and D0.5cc respectively. Median bladder D2cc was 65.5 (46.2-75.1). 16 of 39 (41%) patients experienced any acute and 8 of 30 (27%) any late GU toxicity (9 patients did not have follow-up >6 months). 4 (10%) had grade 2 and 0 (0%) had grade 3+ acute GU toxicity. 1 (3%) patient had grade 2 and 1 (3%) had grade 3 late GU toxicity. Median urethral D0.1cc, D0.2cc and D0.5cc were 73 Gy (51.7-93.8) and 50.5 Gy (45.2-63.7; p=0.009), 69.2 Gy (48.9-87.4) and 49.6 Gy (42.7-58.4; p=0.011) and 62.9 Gy (47.9-79.6) and 48.6 Gy (39.2-55.7; p=0.015), respectively in patients with or without any CTCAE GU toxicity. Additionally, 7 (44%) patients with and 1 (4%) without genitourinary toxicity had bladder intrusion (p=0.004). There was no significant difference in urethral dosimetry between patients experiencing and not experiencing late toxicity. Urethral dose appears to predict acute genitourinary toxicity in ISBT of vaginal tumors. Further study with an expanded cohort and longer follow-up is warranted.

Clinical Outcomes of Reirradiation in IDH-Mutant Astrocytomas and 1p/19q Codeleted Oligodendrogliomas

Recent data has demonstrated that IDH-mutant gliomas (IMGs) have a favorable prognosis as compared to IDH wild type gliomas. While primary fractionated radiation therapy (RT) is part of standard of care for IMGs, clinical outcomes and optimal technique of reirradiation for relapsed IMGs after primary RT are not well defined. This study aims to analyze the clinical outcomes and toxicity of reirradiation for recurrent IMGs. Recurrent IMG patients including IDH-mutant astrocytomas and 1p/19q codeleted oligodendrogliomas who received reirradiation at our institution were retrospectively reviewed. Reirradiation techniques included stereotactic radiosurgery (SRS) or external beam RT (EBRT). Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated from start of reirradiation and compared using Kaplan-Meier analysis. Biologically equivalent dose in 2Gy fractions (EQD2) for brain were estimated for each course of RT using the linear-quadratic model and α/β of 3. Radiation necrosis (RN) was evaluated based on all available clinical, radiographic and pathological data. From 2001-2017, 23 recurrent IMGs were reirradiated (74% oligodendrogliomas, 26% astrocytomas). All tumors were initially diagnosed as grade II (65%) or III (35%) before primary RT. In 21 patients who had surgery for relapsed disease, 62% had increased tumor grade. Median follow up after reirradiation was 20 months (range 1 - 105). Median time between RT courses was 13.2 years (0.4 – 26.2). Fifteen patients (65%) were treated with EBRT (53% Intensity-modulated RT, 47% proton therapy); 8 patients (35%) were treated with SRS (87% single-fraction, 13% multi-fraction). Median EQD2 of reirradiation was 51.8 Gy (25.2 – 92), and cumulative EQD2 of combined RT courses was 102.5 Gy (85 – 148). Sixteen (70%) patients received concurrent or adjuvant chemotherapy.For the entire cohort, 2-year LC was 79%, 2-year PFS was 58%, and 2-year OS was 65%. LC, PFS, and OS were not significantly different between oligodendrogliomas and astrocytomas (all P > 0.05). Two-year LC for EBRT and SRS were 80% for both groups (P= 0.35), and 2-year PFS for EBRT and SRS were 60% and 57%, respectively (P=0.60). Radiation necrosis occurred in 5 patients (22%). Reirradiation appears to show promising activity for radiation-relapsed IMGs with moderate risk of RN. Future investigation with longer follow-up and larger cohort is warranted.

Hippocampal sparing in stereotactic radiotherapy for brain metastases: To contour or not contour the hippocampus?

PurposeThe aim of our study was to evaluate hippocampal irradiation in patients treated with fractionated stereotactic brain radiotherapy. Patients and methodsRetrospective hippocampal dosimetric analysis performed on 22 patients with one to four brain metastases treated with fractionated stereotactic radiotherapy using volumetric intensity-modulated arc therapy. Original plans did not include hippocampus as avoidance structure in optimization criteria; hippocampus was retrospectively delineated on magnetic resonance coregistered with planning CT and using as reference the RTOG 0933 atlas. Hippocampus was defined both as a single and as pair organ. Constraints analysed were: Dmax<16Gy, D40%<7.3Gy, D100%=Dmin<9Gy. Assuming a α/β ratio of 2Gy, biologically equivalent dose in 2Gy fractions was calculated. Hippocampal-sparing plans were developed in cases where hippocampal constraints were not respected in the original plan. ResultsAmong constraints analysed Dmax and D40% have been exceeded in ten out of 22 cases. The constraints were not respected in patients with more than one metastatic lesion and in three patients with only one lesion. Considering all exceeded constraints values in non-hippocampal sparing plans, the 50% of them was respected after replanning. No significant differences were found among conformity and homogeneity index between non-hippocampal sparing and hippocampal sparing plans. ConclusionVolumetric intensity-modulated arc therapy hippocampal sparing plans significantly decreases dose to hippocampus assuring an equal target coverage and organs at risk avoiding.

Moving Second Courses of Radiotherapy Forward

Generally, re-irradiation (Re-RT) is offered to patients with glioma recurrences with macroscopic lesions. Results are discussed controversially, and some centers postulate limited benefit of Re-RT. Re-RT is generally offered to tumors up to 4 cm in diameter. Re-resection is also discussed controversially; however, recent studies have shown significant benefit. To combine proactive re-resection and early Re-RT in patients with recurrent glioma. We included 108 patients treated between 2002 and 2016 for recurrent glioma. All patients underwent surgical resection for recurrence; Re-RT was applied with a median dose of 37.5 Gy (range 25 Gy-57Gy/equivalent dose in 2Gy fractions [EQD2]) with high-precision techniques. All patients were followed prospectively in an interdisciplinary follow-up program. Median follow-up after Re-RT was 7 mo. Median survival after surgery and Re-RT was 12 mo (range 1-102 mo). Complete resection had a significant impact on the outcome (P=.03). The strongest predictors of outcome were MGMT-promotor methylation and Karnofsky Performance Score and time interval between primary and second RT. Proactive resection of tumor recurrences combined with early Re-RT conveys into promising outcome in recurrent glioma. Complete resection and early Re-RT lead to improved survival. Thus, moving Re-RT to an earlier timepoint during the treatment of recurrent glioma, eg after complete macroscopic removal of the tumor, may be crucial for treatment optimization. Using advanced RT techniques, side effects are low. Currently, this concept is evaluated in the GLIOCAVE/NOA 17 trial.

Direct dose correlation of MRI morphologic alterations of healthy liver tissue after robotic liver SBRT.

For assessing healthy liver reactions after robotic SBRT (stereotactic body radiotherapy), we investigated early morphologic alterations on MRI (magnetic resonance imaging) with respect to patient and treatment plan parameters. MRI data at 6-17weeks post-treatment from 22patients with 42liver metastases were analyzed retrospectively. Median prescription dose was 40 Gydelivered in 3-5fractions. T2- and T1-weighted MRI were registered to the treatment plan. Absolute doses were converted to EQD2 (Equivalent dose in 2Gy fractions) with α/β-ratios of 2and 3 Gy for healthy, and 8 Gy for modelling pre-damaged liver tissue. Sharply defined, centroid-shaped morphologic alterations were observed outside the high-dose volume surrounding the GTV. On T2-w MRI, hyperintensity at EQD2 isodoses of 113.3 ± 66.1 Gy2, 97.5 ± 54.7 Gy3, and 66.5 ± 32.0 Gy8 significantly depended on PTV dimension (p = 0.02) and healthy liver EQD2 (p = 0.05). On T1-w non-contrast MRI, hypointensity at EQD2 isodoses of 113.3 ± 49.3 Gy2, 97.4 ± 41.0 Gy3, and 65.7 ± 24.2 Gy8 significantly depended on prior chemotherapy (p = 0.01) and total liver volume (p = 0.05). On T1-w gadolinium-contrast delayed MRI, hypointensity at EQD2 isodoses of 90.6 ± 42.5 Gy2, 79.3 ± 35.3 Gy3, and 56.6 ± 20.9 Gy8 significantly depended on total (p = 0.04) and healthy (p = 0.01) liver EQD2. Early post-treatment changes in healthy liver tissue after robotic SBRT could spatially be correlated to respective isodoses. Median nominal doses of 10.1-11.3 Gy per fraction (EQD2 79-97 Gy3) induce characteristic morphologic alterations surrounding the lesions, potentially allowing for dosimetric in-vivo accuracy assessments. Comparison to other techniques and investigations of the short- and long-term clinical impact require further research.

High Rate of Late Toxicity in Patients Treated with MRI-Guided HDR Brachytherapy for Locally Advanced Cervix Cancer: The Importance of Smoking Cessation

Magnetic resonance imaging (MRI)-guided high-dose-rate (HDR) brachytherapy for locally advanced cervical cancer is used to improve target coverage and limit dose to critical structures. Here we evaluate disease control and toxicity rates utilizing this technique. This is a retrospective review of patients with FIGO stage I-IV cervical cancer who underwent MRI -guided HDR tandem and ring (T&R) brachytherapy between January 2010 and January 2015 at a single institution. All patients received pelvic external beam radiotherapy (EBRT) to a median dose of 45 Gy followed by T&R HDR brachytherapy. All patients received an MRI with at least the first brachytherapy insertion (CT was performed for non-MRI insertions) and completed at least 4 fractions of brachytherapy. Gross tumor volume, high-risk clinical target volume (HR-CTV), and organs at risk were all contoured according to GEC-ESTRO guidelines. Forty-three patients underwent 214 HDR T&R brachytherapy insertions between 2010 and 2015. The mean age was 50 years (range: 29-74). Sixty-three percent of patients were smokers. Histopathology was predominantly squamous cell carcinoma (79%). Average tumor size was 5.5cm, and 56% were FIGO stage IIB. Fifty-one percent had positive lymph nodes at diagnosis. Median total (EBRT + brachytherapy) equivalent dose in 2Gy fractions (EQD2) to 90% of the HR-CTV was 79.97Gy, and median total EQD2 dose to Point A was 77.04Gy. Median follow up was 48 months. At 5 years, the local control rate was 98%, the regional control rate was 84%, the freedom from distant metastases rate was 90%, the disease-free survival rate was 73%, the cause-specific survival rate was 78%, and the overall survival rate was 57%. Late grade 3 and higher toxicities were experienced in 14% of patients, and 28% experienced a late grade 2 or higher toxicity. We evaluated the risk of developing a late grade 2 or higher bladder, vaginal, sigmoid or rectal complication based on the total dose to 2cc of each of these structures being greater than or less than the median dose to these structures and found no correlation. The 5 year rate of developing a grade 2 or higher late toxicity was 11% for non-smokers, compared with 60% for smokers (p=0.0035). With a median follow up of 4 years, this study demonstrates excellent local control. However, late toxicity continues to be clinically significant, even with MRI guidance and volume based dosimetry, and smoking is a significant predictive factor for late toxicity. This data supports using aggressive smoking cessation strategies in patients receiving radiotherapy for cervix cancer.