Purpose: Quantification of integral radiation dose delivered during treatment for prostate cancer is lacking. We performed a comparative quantification of dose to nontarget body tissues delivered via 4 common radiation techniques: conventional volumetric modulated arc therapy, stereotactic body radiation therapy, pencil-beam scanning proton therapy, and high-dose-rate brachytherapy. Methods and Materials: Plans for each radiation technique were generated for 10 patients with typical anatomy. For brachytherapy plans, virtual needles were placed to achieve standard dosimetry. Standard planning target volume margins or robustness margins were applied as appropriate. A “normal tissue” structure (entire computed tomography simulation volume minus planning target volume) was generated for integral dose computation. Dose-volume histogram parameters for targets and normal structures were tabulated. Normal tissue integral dose was calculated by multiplying normal tissue volume by mean dose. Results: Normal tissue integral dose was lowest for brachytherapy. Pencil-beam scanning protons, stereotactic body radiation therapy, and brachytherapy resulted in 17%, 57%, and 91% absolute reductions compared with standard volumetric modulated arc therapy, respectively. Mean nontarget tissues receiving 25%, 50%, and 75% of the prescription dose were reduced by 85%, 76%, and 83% for brachytherapy relative to volumetric modulated arc therapy, by 79%, 64%, and 74% relative to stereotactic body radiation therapy, and 73%, 60%, and 81% relative to proton therapy. All reductions observed using brachytherapy were statistically significant. Conclusions: High-dose-rate brachytherapy is an effective technique for reducing dose to nontarget body tissues relative to volumetric modulated arc therapy, stereotactic body radiation therapy, and pencil-beam scanning proton therapy.

Purpose/Objective(s)Randomized clinical trials have validated the efficacy and safety of hypofractionated whole breast irradiation (HWBI) in patients with early-stage breast cancer. Toxicities associated with hypofractionated treatment in patients requiring regional nodal irradiation are less well described, and the utilization of hypofractionation in these patients is uncommon in the United States. We report an interim analysis of acute toxicity of a prospective trial of hypofractionated regional nodal irritation (H-RNI).Materials/MethodsThis is a prospective, single-arm trial at a single institution. Eligible patients comprised those with locally advanced, non-metastatic breast cancer and required adjuvant radiation therapy to the regional lymphatics in addition to the breast or chest wall. Patients were stratified into two groups based on extent of axillary surgery: ≤ 5 lymph nodes (Group 1) and > 5 lymph nodes removed (Group 2). We enrolled 31 patients (23 in Group 1, 8 in Group 2) from 11/2018 to 12/2021. Patients received a dose of 42.56 Gy in 16 fractions to the breast/chest wall and regional lymphatics with a sequential boost of 10-12.5 Gy in 4-5 fractions to the surgical cavity or mastectomy scar. Circumferential arm measurements at 10 cm intervals were taken at baseline and predefined intervals following treatment. The primary endpoint is clinically significant lymphedema, defined as a ≥ 10% difference in ipsilateral arm, forearm, or both, compared to the contralateral side. Additional toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) criteria.ResultsThe median follow up was 19 months and the median age was 59 years. Acute lymphedema and CTCAE toxicities were analyzed in 27 and 31 patients, respectively. One patient (3.2%) in Group 2 met the predetermined criteria for clinically significant lymphedema. One patient experienced symptomatic lymphedema, requiring a compression sleeve. However, her measurements did not meet the threshold for clinically significant lymphedema. The most prevalent Grade 1 toxicities were hyperpigmentation (66.7%), fatigue (66.7%), breast pain (63.3%), and radiation dermatitis (63.3%). The most prevalent Grade 2 toxicities were radiation dermatitis (26.7%) and hyperpigmentation (20%). The incidence of any ≥ Grade 3 toxicity was 6.5% (n=2) related to hyperpigmentation. One patient (3.2%) developed grade 2 pneumonitis. All cosmetic outcomes were rated as good or excellent at 3 months. There were no grade 4 or 5 toxicities.ConclusionOur preliminary data suggest that H-RNI is well tolerated. The rates of acute lymphedema and acute toxicity were very low. A matched comparison with patients treated with conventionally fractionated RNI at our institution is ongoing.

Purpose/Objective(s)The role of post-mastectomy radiotherapy (PMRT) in patients with pT3 pN0 breast cancer remains controversial. We previously showed a correlation between PMRT and improved overall survival (OS) in pT3N0 patients who do not receive chemotherapy. However, it is unknown whether this correlation extends to patients with low genomic recurrence score (RS). In this analysis, we used the National Cancer Database (NCDB) to investigate the benefit of PMRT in pT3N0 patients with low RS.Materials/MethodsWe performed an analysis of NCDB patients with pT3N0 breast cancer who had low Oncotype DX RS (ORS) (< 25) and did not receive systemic chemotherapy. Patients were matched for baseline patient, tumor, and treatment characteristics using inverse probability of treatment weighting to minimize the impact of potential confounding variables. We stratified patients based on receipt of PMRT and compared OS using Kaplan-Meier estimates. Univariate and doubly-robust multivariable analyses were used to correlate PMRT and various baseline characteristics with OS.ResultsWe identified 444 patients with pT3N0 breast cancer who had undergone mastectomy and had low-risk genomic assay scores who did not receive systemic chemotherapy. After IPTW matching, there were no significant differences in baseline patient characteristics. In the PMRT group, 44% received treatment to the chest-wall only, and 66% patients received chest wall and regional nodal irradiation. PMRT was associated with improved overall survival on both the univariate (HR=0.201; 95% CI=0.05-0.78; p=0.021) and doubly-robust multivariable analyses (HR=0.128; 95% CI=0.02-0.66; p=0.014). Receipt of endocrine therapy was also found to significantly improve overall survival (p=0.02). We attempted to repeat the analysis in patients with RS >25 who received chemotherapy, but we only identified a total of 78 such patients and could not perform a robust analysis.ConclusionThis cohort analysis shows a strong correlation between PMRT and improved OS in pT3N0 patients with low ORS who do not receive chemotherapy. It is possible that with the de-escalation of chemotherapy and axillary surgery in this patient population in the modern era, the benefit of locoregional treatment with radiotherapy is magnified. Our analysis suggests that prospective data are needed before de-escalation of radiotherapy for these patients based on ORS. The role of post-mastectomy radiotherapy (PMRT) in patients with pT3 pN0 breast cancer remains controversial. We previously showed a correlation between PMRT and improved overall survival (OS) in pT3N0 patients who do not receive chemotherapy. However, it is unknown whether this correlation extends to patients with low genomic recurrence score (RS). In this analysis, we used the National Cancer Database (NCDB) to investigate the benefit of PMRT in pT3N0 patients with low RS. We performed an analysis of NCDB patients with pT3N0 breast cancer who had low Oncotype DX RS (ORS) (< 25) and did not receive systemic chemotherapy. Patients were matched for baseline patient, tumor, and treatment characteristics using inverse probability of treatment weighting to minimize the impact of potential confounding variables. We stratified patients based on receipt of PMRT and compared OS using Kaplan-Meier estimates. Univariate and doubly-robust multivariable analyses were used to correlate PMRT and various baseline characteristics with OS. We identified 444 patients with pT3N0 breast cancer who had undergone mastectomy and had low-risk genomic assay scores who did not receive systemic chemotherapy. After IPTW matching, there were no significant differences in baseline patient characteristics. In the PMRT group, 44% received treatment to the chest-wall only, and 66% patients received chest wall and regional nodal irradiation. PMRT was associated with improved overall survival on both the univariate (HR=0.201; 95% CI=0.05-0.78; p=0.021) and doubly-robust multivariable analyses (HR=0.128; 95% CI=0.02-0.66; p=0.014). Receipt of endocrine therapy was also found to significantly improve overall survival (p=0.02). We attempted to repeat the analysis in patients with RS >25 who received chemotherapy, but we only identified a total of 78 such patients and could not perform a robust analysis. This cohort analysis shows a strong correlation between PMRT and improved OS in pT3N0 patients with low ORS who do not receive chemotherapy. It is possible that with the de-escalation of chemotherapy and axillary surgery in this patient population in the modern era, the benefit of locoregional treatment with radiotherapy is magnified. Our analysis suggests that prospective data are needed before de-escalation of radiotherapy for these patients based on ORS.

PURPOSE:External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer. METHODS AND MATERIALS:The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time. RESULTS:In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P = .051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk. CONCLUSIONS:Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection.

Purpose/Objective(s)Accelerated partial breast irradiation (APBI) can reduce treatment time and spare normal breast tissue. Techniques for APBI include applicator-based, external beam radiotherapy (EBRT), intra-operative radiotherapy (IORT), and interstitial implant-based. Data comparing these various APBI modalities and associated outcomes are lacking in the literature. We conducted a single-institution retrospective analysis of patients treated with APBI to compare treatment techniques and report outcomes.Materials/MethodsPatients treated with APBI between 1990 and 2019 were included. Baseline patient characteristics, clinical and pathological features, treatment details, and clinical outcomes were retrospectively reviewed using a single-institution database. Outcomes were updated through August 2020. Statistical methods included Kruskal-Wallis test, Fisher's exact test, chi-square test of independence, and Kaplan-Meier analysis.ResultsA total of 926 APBI cases were analyzed, a majority of which were invasive ductal carcinoma (50.6%). Comparing applicator-based to EBRT, IORT, and implant-based, there was no difference in overall survival, freedom from local recurrence, or freedom from mastectomy (Table 1). 5-, 10-, and 25-year cumulative incidence of ipsilateral breast tumor recurrence (IBTR) was 1.5% (0.87-2.5%), 3.3% (2.3-4.7%), and 5.2% (3.9-6.7%), with no difference between treatment techniques. The median follow-up time was 121.6 months (66-165.7 months). Cosmesis was good/excellent in 91%, 84%, and 93%, for applicator, EBRT, and interstitial techniques, respectively. Late toxicities assessed included pigmentary changes, telangiectasias, induration/fibrosis, and fat necrosis. The majority of late toxicities were none or Grade 1, with less than 10% of patients experiencing Grade 2 or greater toxicity.ConclusionWith our 30-year single-institution APBI experience using various treatment techniques, long term outcomes of both disease control and local morbidity demonstrate that the various APBI techniques are equally effective for suitable early-stage breast cancer patients. As evolving radiotherapy paradigms incorporate more shortened time-course treatments, these results affirm that APBI remains a viable alternative for such favorable patients.

Purpose: In this study, we investigate linac volumetric-modulated arc therapy (VMAT) planning strategies for bilateral hip prostheses prostate patients with respect to plan quality and deliverability, while limiting entrance dose to the prostheses. Methods: Three VMAT plans were retrospectively created for 20 patients: (1) partial arcs (PA), (2) 2 full arcs optimized with 500 cGy max prostheses dose (MD), and (3) 2 full arcs optimized with max dose-volume histogram (DVH) constraint of 500 cGy to 10% prostheses volume (MDVH). PA techniques contained 6 PA with beam angles that avoid entering each prosthesis. For each patient, other than prostheses constraints, the same Pinnacle VMAT optimization objectives were used. Plans were normalized with PTV D95% = 79.2 Gy prescription dose. Organ-at-risk DVH metrics, monitor units (MUs), conformality, gradient, and homogeneity indices were evaluated for each plan. Mean entrance prosthesis dose was determined in Pinnacle by converting each arc into static beams and utilizing only control points traversing each prosthesis. Plan deliverability was evaluated with SunNuclear ArcCheck measurements (gamma criteria 3%/2 mm) on an Elekta machine. Results: MD and MDVH had similar dosimetric quality, both improved DVH metrics for rectum and bladder compared to PA. Plan complexities among all plans were similar (average MUs: 441-518). Conformality, homogeneity, and gradient indices were significantly improved in MD and MDVH versus PA (P < .001). Gamma pass rates for MD (99.0 ± 1.2%) and MDVH (99.2 ± 0.99%) were comparable. A significant difference over PA was observed (96.8 ± 1.6%, P < .001). Field-by-field analysis demonstrated 12/20 PA plans resulted in fields with pass rates <95% versus 1/20 plans for MD and none for MDVH. Cumulative mean entrance doses to each prosthesis were 62.9 ± 17.7 cGy for MD plans and 83.4 ± 27.5 cGy for MDVH plans. Conclusion: MD and MDVH plans had improved dosimetric quality and deliverability over PA plans with minimal entrance doses (∼1% of prescription) to each prosthesis and are an improved alternative for bilateral prostheses prostate patients.

Background: Using a prospectively collected institutional database, we compared rectal toxicity following high dose rate (HDR) brachytherapy as monotherapy relative to dose-escalated external beam radiotherapy (EBRT) for patients with localized prostate cancer. Methods: 2683 patients treated with HDR or EBRT between 1994 and 2017 were included. HDR fractionation was 38 Gy/4 fractions (n = 321), 24 Gy/2 (n = 96), or 27 Gy/2 (n = 128). EBRT patients received a median dose of 75.6 Gy in 1.8 Gy fractions [range 70.2-82.8 Gy], using either 3D conformal or intensity modulated radiotherapy (IMRT). EBRT patients underwent 3D image guidance via an off-line adaptive process. Results: Median follow-up was 7.5 years (7.4 years for EBRT and 7.9 years for HDR). 545 patients (20.3%) received HDR brachytherapy and 2138 (79.7%) EBRT. 69.1% of EBRT patients received IMRT. Compared to EBRT, HDR was associated with decreased rates of acute grade >= 2 diarrhea (0.7% vs. 4.5%, p < 0.001), rectal pain/tenesmus (0.6% vs. 7.9%, p < 0.001), and rectal bleeding (0% vs. 1.6%, p = 0.001). Rates of chronic grade >= 2 rectal bleeding (1.3% vs. 8.7%, p < 0.001) and radiation proctitis (0.9% vs. 3.3%, p = 0.001) favored HDR over EBRT. Rates of any chronic rectal toxicity grade >= 2 were 2.4% vs. 10.5% (p < 0.001) for HDR versus EBRT, respectively. In those treated with IMRT, acute and chronic rates of any grade >= 2 GI toxicity were significantly reduced but remained significantly greater than those treated with HDR. Conclusions: In appropriately selected patients with localized prostate cancer undergoing radiation therapy, HDR brachytherapy as monotherapy is an effective strategy for reducing rectal toxicity. (C) 2020 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 147 (2020) 123-129

Reducing organ at risk (OAR) dose to as low as reasonably achievable (ALARA), without sacrificing planning target volume (PTV) coverage, is a tenet of radiation therapy planning. Indeed, a wide array of techniques and technology have been developed in this regard. We sought to evaluate the impact of a simple 90-degree collimator rotation on OAR dose. Rotating the collimator 90 degrees results in the "X" jaws being closer to the patient, resulting in reduced head scatter. Sixty patients were selected for this study and were planned using an inverse-planned 3D conformal technique. Plans were compared with and without the additional collimator rotation by evaluating PTV coverage and dose to critical structures. Dosimetric data was evaluated for normality, and medians were compared using the Wilcoxon Signed Rank test. Effect size was evaluated per Cohen's classification. All statistical analyses were performed using RStudio. Collimator rotation resulted in a statistically significant reduction in the median dose maximum (Dmax) (7.4 vs. 6.9 Gy, P < 0.001) and mean heart (1 vs. 0.77 Gy, P < 0.001) dose. The median percent reduction in mean heart dose was 22.7% (IQR 8.9%, Range 4.6-46.5%). Likewise, there was a statistically significant reduction in the median dose maximum (Dmax) (4.6 vs. 4.4 Gy, P < 0.001) and mean left anterior descending artery (LAD) dose (2.4 vs. 2.2 Gy, P < 0.001). Additionally, collimator rotation resulted in a statistically significant reduction in the mean lung (4.4 vs 4.1 Gy, P < 0.001) dose, without affecting the volume of PTV receiving 95% (99.2 vs. 99%, P = 0.1) or 90% (100 vs. 100%, P = 0.43) prescription dose. Rotating the collimator in certain linear accelerators with can reduce scatter contribution and reduce OAR dose without sacrificing PTV coverage. This simple modification in treatment planning results in clinically significant reductions in dose to multiple organs at risk.

Purpose: To update outcome and toxicity results of a prospective trial of 19-Gy single-fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer. Methods and Materials: Patients were treated on a prospective study of single-fraction HDR brachytherapy. All patients had low- or intermediate-risk prostate cancer. Patients with prostate volumes >50 cm(3), taking alpha-blockers for urinary symptoms, or with baseline American Urologic Association symptom scores >12 were ineligible. Patients underwent transrectal ultrasound-guided interstitial implant of the prostate followed by single-fraction HDR brachytherapy to a prescription dose of 19 Gy. Results: Sixty-eight patients were enrolled with a median follow-up of 3.9 years. Median age was 62 years. Median gland volume at the time of treatment was 35 cm(3), 92.6% of patients had T1 disease, 63.2% had a Gleason score of 6, and median pretreatment prostate-specific antigen was 5.0 ng/mL. Chronic grade 2 genitourinary toxicity was 14.7%. No grade 3 urinary toxicity occurred. A single patient experienced grade 2+ rectal toxicity (grade 3 diarrhea) that was transient and resolved with medical management. The 5-year estimated disease-free survival was 77.2% with no significant difference between low- and intermediate-risk patients. A single patient developed distant metastases during the follow-up period. Biopsy-proven local failure at 5 years was 18.8%, occurring at a median interval of 4.0 years posttreatment. No deaths occurred during follow-up. Conclusions: With extended follow-up, toxicity rates after single-fraction 19-Gy HDR brachytherapy remain low. Higher-than-expected rates of biochemical and local failure, however, raise concerns regarding the adequacy of this dose. Additional investigation to define the optimal single-fraction HDR brachytherapy dose is warranted, and single-fraction treatment currently should not be offered outside the context of a clinical trial. (C) 2019 Elsevier Inc. All rights reserved.

Randomized clinical trials support the use of hypofractionated whole breast irradiation (H-WBI) in select patients with early stage breast cancer following breast conserving surgery. Patients who received chemotherapy (CHT) are not well represented on these trials. This study investigates whether receiving CHT prior to WBI is associated with increased toxicity or worse cosmetic outcomes. We identified 7,014 women in a state-wide radiation oncology quality consortium database who received WBI with a surgical cavity boost between 11/2011 and 8/2018. Toxicity data were available for 6,870 patients. Significant acute toxicity was defined as patient-reported moderate/severe breast pain (≥4/10), physician-reported CTCAE ≥grade 2 breast pain, or the development of moist desquamation between 7 days prior to and 42 days following the completion of radiotherapy. We determined rates of physician-reported fair/poor cosmetic outcome per the Harvard criteria in 2,012 patients who had ≥1 year of follow-up. Rates of significant acute toxicity and fair/poor cosmetic outcome were compared among patients receiving conventionally fractionated treatment (C-WBI) or H-WBI. Multivariable modeling, adjusting for age, race, BMI, breast volume, separation along the central axis, comorbidity index, smoking status, radiation planning technique, breast D50, triple negative breast cancer, pTis disease, treatment at an academic institution, and receipt of CHT, were used to quantify the strength of association, given as an odds ratio [95%CI], between patient or treatment related factors and clinical endpoints. C-WBI and H-WBI most commonly comprised 45-50.4 Gy in 25-28 fractions and 40-42.72 Gy in 15-16 fractions, respectively. A boost of 10-16 Gy in 5-8 fractions and 10 in 4 fractions was most common for C-WBI and H-WBI, respectively. CHT was administered prior to radiation therapy in 1266 (35%) of the 3,628 patients who received C-WBI and in 558 (17%) of the 3,242 patients who received H-WBI. Crude rates of significant acute toxicity were 43% and 40% for patients receiving CHT followed by C-WBI and C-WBI without CHT, respectively, and 29% and 27% for patients receiving CHT followed by H-WBI and H-WBI without CHT, respectively. CHT was not associated with worse acute toxicity for patients receiving C-WBI (OR=0.94 [0.79-1.12], p=0.50) or H-WBI (OR=0.79 [0.63-1.00], p=0.054). CHT was not associated with increased rates of fair/poor cosmetic outcomes at 1 year (OR=1.21 [0.82-1.78], p=0.33), independent of fractionation. In this large, multi-center cohort, rates of significant acute toxicity and fair/poor cosmetic outcomes were not worse in patients receiving chemotherapy prior to whole breast irradiation, compared to patients who did not receive chemotherapy, regardless of fraction size.

Background and purpose: Recent retrospective studies suggest improved overall survival (OS) with breast conserving therapy (BCT), including breast conserving surgery and adjuvant whole breast radiotherapy, compared to mastectomy in the modern era. The patient subset most likely to benefit from BCT remains unclear, and the role of Oncotype DX Recurrence Score (RS) in this context is unknown. We compared BCT to mastectomy in early-stage, node-negative breast cancer. We further explored outcomes after stratification by RS and age. Materials and methods: We performed a matched-cohort analysis of National Cancer Database (NCDB) patients with pT1-2, pN0, cM0 breast cancer treated between 2006 and 2014 with BCT or mastectomy. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights. Results: We identified 144,263 eligible patients treated with BCT and 87,379 patients treated with mastectomy. After IPTW-matching, OS was higher with BCT compared to mastectomy: 5-year OS of 94.4% vs. 91.8% (P < 0.001) and 7-year OS of 90% vs. 85.2% (P < 0.001). Doubly robust multivariable analysis showed an association between BCT and improved OS (HR 0.66, 95% CI, 0.64-0.69, P < 0.001). In a subset analysis, BCT was associated with improved OS in patients with RS >25, but not patients with RS <= 25. When stratified by age, only patients >50 years had improved OS with BCT. Conclusion: BCT is associated with improved OS compared to mastectomy in women with early-stage, node-negative breast cancer. The improvement in OS with BCT appears to be most pronounced in patients with high RS and >50 years of age. Prospective validation of these findings is required. (C) 2019 Elsevier B.V. All rights reserved.

5 Background: We present a large retrospective analysis comparing rectal toxicity following high dose rate (HDR) brachytherapy as monotherapy relative to dose-escalated external beam radiotherapy (EBRT) for patients with localized prostate cancer. Methods: 2683 patients treated with HDR or EBRT between 1994 and 2017 were included. 545 (20.3%) received HDR and 2138 (79.7%) EBRT. HDR fractionation was 38 Gy/4 fractions (n=321), 24 Gy/2 (n=96), or 27 Gy/2 (n=128). EBRT patients received a median dose of 75.6 Gy in 1.8 Gy fractions [range 70.2-82.8 Gy], using either 3D conformal or intensity modulated radiotherapy (IMRT). All EBRT patients underwent 3D image guidance via an off-line adaptive process. Treatment was directed to prostate only (n=780) or prostate and seminal vesicles (n=1351). No nodal therapy was given. Target volume for HDR patients included the prostate with no expansion. Acute and chronic gastrointestinal (GI) toxicity was defined as occurring ≤ 6 and > 6 months, respectively, after radiotherapy and was graded per CTCAE version 3.0. Toxicity variables were analyzed with χ2 test. Results: Median follow-up was 7.5 years (7.4 years for EBRT and 7.9 years for HDR). 69.1% of EBRT patients received IMRT with the remainder treated using 3D conformal technique. Compared to EBRT, HDR was associated with decreased rates of acute grade ≥ 2 diarrhea (0.7% vs. 4.5%, p < 0.001), rectal pain/tenesmus (0.6% vs. 7.9%, p < 0.001), and rectal bleeding (0% vs. 1.6%, p=0.001). Rates of chronic grade ≥ 2 rectal bleeding (1.3% vs. 8.7%, p < 0.001) and radiation proctitis (0.9% vs. 3.3%, p=0.001) favored HDR over EBRT. Rates of any chronic rectal toxicity grade ≥ 2 were 2.4% vs. 10.5% (p < 0.001) for HDR vs. EBRT, respectively. For the 1478 EBRT patients treated with IMRT, acute and chronic rates of any grade ≥ 2GI toxicity were 4.2% and 5.6%, respectively, compared to 1.5% (p=0.002) and 2.4% (p=0.002), respectively, for HDR patients. Conclusions: In appropriately selected patients with localized prostate cancer undergoing definitive radiation therapy, HDR brachytherapy as monotherapy is an effective strategy for reducing acute and chronic rectal toxicity.

Patients with pT3N0 breast cancer following mastectomy and axillary staging constitute a heterogeneous population with outcomes dependent on underlying tumor biology and treatment received. We analyzed the NCDB to compare overall survival (OS) rates of patients with pT3N0 disease treated with mastectomy with or without post-mastectomy radiation therapy (PMRT). Patients with pT3N0 breast cancer (2004-2014) were included in this NCDB retrospective cohort analysis. Patients receiving neoadjuvant chemotherapy were excluded. Propensity scores were generated using logistic regression. Inverse probability of treatment weighting (IPTW) was utilized to account for confounding variables. Univariate and subset analyses were performed using the IPTW-weighted Kaplan-Meier method. Multivariate modeling was performed using the Cox proportional hazards model, with a double robust model reported utilizing IPTW. Hazard ratios are reported with 95% confidence intervals. We identified 4,285 patients with pT3N0 disease treated with mastectomy, of which 43% also received PMRT. Following IPTW, all baseline factors were similar. Univariate analysis revealed an OS advantage with PMRT compared to mastectomy alone (HR: 0.43 [0.37-0.49], 5-year estimate - 82.0% vs. 74.8%, p = 0.0002). Doubly robust weighted cox modeling demonstrated a persistent benefit of PMRT over mastectomy alone, with a HR of 0.804 (0.704-0.918). Subset IPTW analysis revealed a benefit of PMRT if patients received hormonal therapy (HR: 0.64 [0.51-0.79]), but the benefit was not statistically significant in those receiving chemotherapy (HR: 0.85 [0.67-1.1]). While patients with right-sided disease benefited from PMRT (HR: 0.74 [0.6-0.9]), those with left-sided disease did not show a benefit with PMRT (HR: 0.89 [0.74-1.06]). We identified an overall survival benefit for PMRT among a recent cohort of patients with pT3N0 breast cancer; this benefit persisted on univariate, multivariate, and IPTW analyses. There may be subsets of patients with pT3N0 disease that receive a limited benefit from PMRT, including those who receive adjuvant chemotherapy. Longer follow-up and information regarding cause-specific mortality would help confirm the lack of benefit of PMRT in patients with left-sided disease. Potential differences in outcome may be due to radiation-induced cardiac toxicity in this cohort, an outcome that is not able to be assessed with the NCDB. Future studies are needed to properly identify who benefits most from PMRT to minimize treatment-related toxicity which may have a significant impact on overall survival.

The NRG B-39/0413 phase III trial reported that post lumpectomy PBI was not statistically equivalent to WBI, but with an absolute difference for in-breast recurrence at 10 years (y) < 1% it may be a reasonable option for many breast cancer patients (pts). The cosmetic outcome of PBI compared to WBI could be an important determinant for radiation (RT) method selection.

In 2018 ASTRO published an update to the 2011 evidence-based guideline for the use of hypofractionated whole breast irradiation (HF-WBI), increasing the patient populations for whom expert consensus supports the use of HF-WBI. While individualized decision making is encouraged, this updated guideline has been expanded to support HF-WBI for patients <50 years, receipt of chemotherapy, larger separation distance, and a diagnosis of DCIS. For some of these indications, however, only moderate data exist. Thus, we now assess patient and physician reported toxicity data in a large prospective registry for populations not well represented on the trials and in whom there is less experience with this approach. Prospective data were evaluated from 2,083 patients receiving HF-WBI plus boost, treated between 1/1/2016 – 8/31/2018 at 24 academic and community centers participating in a statewide consortium. A composite toxicity endpoint was defined as occurrence of self-reported (4-10 modified brief pain inventory) or physician-assessed moderate or severe breast pain (CTCAE v. 4.0 grade 2-3) when patient report absent, and/or physician-assessed presence of moist desquamation. Logistic regression models were constructed isolating the effect of specific criteria from the 2011 HF-WBI guidelines, specifically age <50 years, separation distance >25cm, chemotherapy use, and DCIS. This was further adjusted for patient BMI, breast volume, race, comorbidity, smoking status, and IMRT. Mean age was 62 years, mean separation was 22cm. Twenty-two percent of patients were treated for DCIS with the remaining 78% treated for invasive cancer; 17% of patients received chemotherapy. Of the 2,083 patients, 376 patients had more than one 2011 guideline discordance (for ex. <50 years with chemotherapy), therefore 1707 patients were included in this analysis. On multivariable analysis, patients age < 50 years were estimated to be 82% more likely to experience toxicity than older patients (OR=1.82, 95% CI: 1.11-2.97, p=0.02). While unadjusted difference on univariate analysis showed increased toxicity with separation > 25 cm, multivariable analysis revealed no significant difference in toxicity for separation > 25 cm(p=0.25), DCIS (p=0.6753), or treatment following chemotherapy p=0.10). Young breast cancer patients may be at increased risk of acute toxicity compared with other patients when receiving HF-WBI. Additional work is needed to determine why patients <50 years, who were notably underrepresented in the prospective trials establishing the safety and efficacy of HF-WBI, may experience increased breast pain and dermatitis. Work is underway in our group to determine if this same increased risk is appreciated for patients <50 years receiving conventionally fractionated radiotherapy.

Both definitive radiation therapy (RT) ±androgen deprivation therapy (ADT) and radical prostatectomy (RP) + adjuvant RT±ADT are considered standard of care treatment regimens for patients with high risk prostate cancer. The ideal modality to treat this patient population and achieve disease control while also limiting treatment related toxicity remains debated. In this study, we utilized a retrospective matched pair analysis to compare survival and overall disease control outcomes relative to primary treatment modality. 1436 pts with National Comprehensive Cancer Network defined high risk prostate cancer diagnosed between August 1992 and October 2016 at a single institution were analyzed. All those eligible were treated with RP + adjuvant RT ±ADT (n=774) or definitive RT alone ±ADT (n=660), which consisted of either high dose rate (HDR) brachytherapy boost together with pelvic external beam RT (EBRT) or dose-escalated, adaptive radiation therapy (ART). A 1:1 matched pair analysis was completed, which paired 196 pts based on three poor prognostic characteristics: pre-treatment prostate-specific antigen (PSA) ≥ 20, Gleason score ≥ 8, and clinical T stage ≥T2c. There were 98 pts in both the RT and RP cohorts for this analysis. The average age of the RT and RP groups were 66.4 years and 66.7 years respectively. The median follow-up for those treated with RP was 13.6 years, while those treated with RT was 8.96 years. 21 (21.4%) treated with RP had ≥ T2c disease, while 37 (37.7%) treated with RT had ≥T2c disease. 40.8% in both the RP and RT cohorts had Gleason score ≥ 8. 37.8% of pts had a pre-treatment PSA ≥ 20 in both the RP and RT cohorts. 5 pts (5.1%) in both the RP and RT cohorts received ADT. 37 (37.7%) in the RT cohort were treated with HDR combined with EBRT, while 61 (62.2%) of the RT cohort were treated with ART. There was no statistical difference between pts treated with RT and those treated with RP for overall survival (p =0.21), cause specific survival (p=0.28), or distant disease control (p=0.88). RT was statistically superior compared to RP in regard to locoregional control (p=0.015). When analyzing the two modalities of RT used to treat high risk prostate cancer in this patient cohort compared to RP, both ART and HDR were statistically superior compared to RP in regard to locoregional disease control (p=0.049). Based on this retrospective matched pair analysis of 196 pts with high risk prostate cancer, the addition of radical prostatectomy to locoregional RT did not improve survival or locoregional disease control rates. Neither approach was associated with improved long-term survival, and locoregional disease control was superior in pts treated with definitive RT.

PURPOSE:To report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG. METHODS AND MATERIALS:Patients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method. RESULTS:One hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA >10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3 gastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points. CONCLUSIONS:Combined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

Prior reports investigating single fraction HDR brachytherapy at a dose of 19 Gy have suggested favorable toxicity profiles, albeit with a higher-than-expected incidence of biochemical and local treatment failures. We report here the initial toxicity Results of a prospective trial investigating an escalated single fraction HDR brachytherapy dose to 21 Gy for men with low-intermediate risk prostate cancer.

PURPOSE:The recently published ASCENDE-RT randomized clinical trial demonstrated improved biochemical control, albeit with increased toxicity, for a prostate boost with brachytherapy versus external beam radiation therapy alone in patients with intermediate-high risk prostate cancer. In this study, we investigated the cost-effectiveness of these two modalities in the treatment of intermediate-high risk prostate cancer. METHODS AND MATERIALS:A multistate Markov model was created to model a patient with intermediate-high risk prostate cancer. The two treatment options modeled were (1) 23 fractions of intensity-modulated radiation therapy (IMRT) and two fractions of high-dose-rate prostate brachytherapy (brachytherapy boost) and (2) 44 fractions of IMRT (IMRT alone). Each patient received 1 year of hormone therapy, per the ASCENDE-RT protocol. Model assumptions, including clinical outcomes, toxicity, and utilities were derived from the medical literature. Costs of radiation therapy were estimated using Medicare reimbursement data. RESULTS:The estimated expected lifetime cost of brachytherapy boost was $68,696, compared to $114,944 for IMRT alone. Brachytherapy boost significantly lowered expected lifetime treatment costs because it decreased the incidence of metastatic castration-resistant prostate cancer, cutting the use of expensive targeted therapy for metastatic castration-resistant prostate cancer. Brachytherapy boost had an expected quality-adjusted life years of 10.8 years, compared to 9.3 years for IMRT alone. One-way sensitivity analyses of our results found brachytherapy boost to be cost-effective over a wide range of cost, utility, and cancer progression rate assumptions. CONCLUSIONS:IMRT with high-dose-rate brachytherapy boost is a cost-effective treatment for intermediate-high risk prostate cancer compared to IMRT alone.

2011 ASTRO consensus guidelines suggest appropriateness criteria for the use of hypofractionated whole breast irradiation (H-WBI) based on subsets of patients well represented on randomized trials that compared H-WBI with conventionally fractionated regimens. These subsets included patients ≥50 years of age, patients with pT1-2/pN0 disease, patients whose radiation treatment plans maintained dose heterogeneity within ∼7%, and patients who did not receive adjuvant systemic chemotherapy (CHT). We explored the impact of CHT on the toxicity and cosmetic outcomes of women with early stage breast cancer receiving H-WBI following breast conserving surgery. In this institutional review board-approved study, we reviewed 292 consecutive patients who received H-WBI (42.56 Gy/16 fractions) with a surgical cavity boost (10-10.64 Gy/4 fractions) and had information regarding the use of CHT. Forty-nine patients (17%) out of the entire cohort received CHT. Acute (occurring within 6 weeks of H-WBI) and chronic (occurring 6 weeks after H-WBI) toxicities were assessed using the Common Terminology Criteria for Adverse Events v3; cosmetic score was determined using the Harvard scale. We performed a matched-pair analysis of patients with available toxicity data, using the following criteria: age (±5 years), breast size (±150 cc), and personal history of smoking (Y/N), diabetes (Y/N), and hypertension (Y/N). We compared clinical endpoints between 25 patients who did not receive CHT and 25 matched patients who received CHT. The no CHT and CHT groups were balanced with respect to mean follow up time (1.8 and 1.4 years, respectively, p=0.08), pathological nodal stage, receipt of hormonal therapy, and boost dose, in addition to all match criteria. As expected, compared to the no CHT group, the CHT group had higher T stage (32%/48%/16% vs. 4%/76%/20% with pDCIS/pT1/pT2, respectively, p=0.02) and more patients who received Herceptin (0% vs. 28%, p=0.01). There were similar rates of grade 2 or greater acute toxicities, including dermatitis (0% vs 0%), hyperpigmentation (20% vs 24%, p=0.73), breast pain (4% vs 12%, p=0.3), and edema (4% vs 8%, p=0.6) and a similar rate of an excellent/good early cosmetic outcome (100% vs. 92%, p=0.16). There were also similar rates of grade 2 or higher chronic toxicities, including dermatitis (0% vs. 0%), hyperpigmentation (0% vs 0%), breast pain (0% vs. 6%, p=0.33), edema (0% vs. 7%, p=0.31), fibrosis (0% vs 0%), and telangiectasia (0% vs 0%) and a similar rate of an excellent/good late cosmetic outcome (100% vs. 88%, p=0.16). H-WBI appears to be well tolerated, even in patients receiving systemic chemotherapy. A larger cohort may detect subtle differences in the rates of toxicities and good/excellent cosmetic outcomes when comparing patients who receive CHT to those who do not. Further studies confirming the safety of H-WBI in patients who receive CHT is warranted.