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Importance: Black patients with endometrial cancer (EC) in the United States have higher mortality than patients of other races with EC. The prevalence of POLE and POLD1 pathogenic alterations in patients of different races with EC are not well studied., Objective: To explore the prevalence of and outcomes associated with POLE and POLD1 alterations in differential racial groups., Design, Setting, and Participants: This retrospective cohort study incorporated the largest available data set of patients with EC, including American Association for Cancer Research Project GENIE (Genomics Evidence Neoplasia Information Exchange; 5087 participants), Memorial Sloan Kettering-Metastatic Events and Tropisms (1315 participants), and the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (517 participants), collected from 2015 to 2023, 2013 to 2021, and 2006 to 2012, respectively. The prevalence of and outcomes associated with POLE or POLD1 alterations in EC were evaluated across self-reported racial groups., Exposure: Patients of different racial groups with EC and with or without POLE or POLD1 alterations., Main Outcomes and Measures: The main outcome was overall survival. Data on demographic characteristics, POLE and POLD1 alteration status, histologic subtype, tumor mutation burden, fraction of genome altered, and microsatellite instability score were collected., Results: A total of 6919 EC cases were studied, of whom 444 (6.4%), 694 (10.0%), and 4869 (70.4%) patients were self-described as Asian, Black, and White, respectively. Within these large data sets, Black patients with EC exhibited a lower weighted average prevalence of pathogenic POLE alterations (0.5% [3 of 590 cases]) compared with Asian (6.1% [26 of 424]) or White (4.6% [204 of 4520]) patients. By contrast, the prevalence of POLD1 pathogenic alterations was 5.0% (21 cases), 3.2% (19 cases), and 5.6% (255 cases) in Asian, Black, and White patients with EC, respectively. Patients with POLD1 alterations had better outcomes regardless of race, histology, and TP53 alteration status. For a total of 241 clinically annotated Black patients with EC, a composite biomarker panel of either POLD1 or POLE alterations identified 7.1% (17 patients) with positive outcomes (1 event at 70 months follow up) in the small sample of available patients., Conclusions and Relevance: In this retrospective clinicopathological study of patients of different racial groups with EC, a composite biomarker panel of either POLD1 or POLE alteration could potentially guide treatment de-escalation, which is especially relevant for Black patients.

Introduction: Treatment for endometrial cancer (EC) is increasingly guided by molecular risk classifications. Here, we aimed at using machine learning (ML) to incorporate clinical and molecular risk factors to optimize risk assessment., Methods: The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (n = 596), Memorial Sloan Kettering-Metastatic Events and Tropisms (n = 1315) and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (n = 4561) datasets were used to identify genetic alterations and clinicopathological features. Software packages including Keras, Pytorch, and Scikit Learn were tested to build artificial neural networks (ANNs) with a binary output as either intra-abdominal metastatic progression ('1') vs. non-metastatic ('0')., Results: Black patients with EC have worse prognosis than White patients, adjusting for TP53 or POLE mutation status. Over 75% of Black patients carry TP53 mutations as compared to approximately 40% of White patients. Older age is associated with an increasing likelihood of TP53 mutation, high risk histology, and distant metastasis. For patients above age 70, 91% of Black and 60% of White EC patients carry TP53 mutations. A ML-based New Unified classifiCATion Score (NU-CATS) that incorporates age, race, histology, mismatch repair status, and TP53 mutation status showed 75% accuracy in prognosticating intra-abdominal progression. A higher NU-CATS is associated with an increasing risk of having positive pelvic or para-aortic lymph nodes and distant metastasis. NU-CATS was shown to outperform Leiden/TransPORTEC model for estimating risk of FIGO Stage I/II disease progression and survival in Black EC patients., Conclusion: The NU-CATS, a ML-based, cost-effective algorithm, incorporates diverse clinicopathologic and molecular variables of EC and yields superior prognostication of the risk of nodal involvement, distant metastasis, disease progression, and overall survival., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest the study presented for publication., (Copyright © 2023. Published by Elsevier Inc.)

Introduction/background: Myeloid sarcoma is a rare extramedullary manifestation of immature myeloid/monocyte cells. Radiotherapy (RT) yields good local control, but data on different fractionation schemes are limited. The goal of this retrospective study was to share our institutional experience and assess volumetric regression with differential fractionation., Materials and Methods: We evaluated patients treated for myeloid sarcoma between 2000 and 2019 and categorized them into Group A (treated with RT) and Group B (no RT). We assessed local control using cumulative incidence function analysis. Post-treatment imaging sequences were analyzed for volumetric calculations., Results: Forty-four patients with 80 lesions were assessed. Twenty-three patients with 52 lesions received RT (Group A), and 6 lesions received a single fraction of RT. There were 2 instances of local progression in Group A and 8 in Group B, with a cumulative incidence function estimate of local progression in Group A of 2.4% at 1 year and 6.9% at 2 years, significantly reduced compared to 29.7% and 35.5% in Group B, respectively (hazard ratio 0.13 [95% confidence interval 0.030.63], P = .011). No lesion treated with a single fraction of RT developed local progression. Volumetric analysis for 19 chronologically followed lesions (including 3 treated with a single fraction) revealed no difference in regression between single or multi-fraction treatment., Conclusion: RT for myeloid sarcoma yields excellent local control and may be as effective in a single fraction as more protracted courses, though this requires validation. For a diagnosis associated with poor survival, a single palliative fraction may be optimal with potential for higher utilization., Competing Interests: Disclosure EGN has nothing to disclose. MKR has nothing to disclose. EDD has nothing to disclose. BBM has nothing to disclose. SS has nothing to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Opinion Statement: Oligometastatic breast cancer, typically defined as the presence of 1-5 metastases, represents an intermediate state between locally advanced and widely metastatic disease. Emerging research suggests that oligometastatic cancer has a unique molecular signature distinct from widely metastatic disease, and that it carries a superior prognosis. Owing to its more limited capacity for widespread progression, oligometastatic disease may benefit from aggressive ablative therapy to known metastases. Options for ablation include surgical excision, radiofrequency ablation, and hypofractionated image-guided radiotherapy (HIGRT). The phase II SABR-COMET trial, which enrolled patients with oligometastatic disease of multiple histologies and randomized them to HIGRT vs. standard of care, found a notable survival advantage in favor of HIGRT. Other data suggest that HIGRT may synergize with immunotherapy by releasing powerful cytokines that increase anti-tumor immune surveillance and by recruiting tumor infiltrating lymphocytes, helping to overcome resistance to therapy. There are many ongoing trials exploring the role of ablative therapy, most notably HIGRT, with or without immunotherapy, for the treatment of oligometastatic breast cancer.We believe that patients with oligometastatic breast cancer should be offered enrollment on prospective clinical trials when possible. Outside the context of a clinical trial, we recommend that select patients with oligometastatic breast cancer be offered treatment with a curative approach, including ablative therapy to all sites of disease if it can be safely accomplished. Currently, selection criteria to consider for ablative therapy include longer disease-free interval from diagnosis to metastasis (>2 years), fewer metastases, and fewer involved organs. Undoubtedly, new data will refine or even upend our understanding of the definition and optimal management of oligometastatic disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in "real-world" clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment., Methods: TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR)., Results: The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%., Conclusion: The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

Purpose/objective: The objective of this study was to assess the association between pretreatment p53, hypoxia inducible factor 1a (HIF1a), Ki-67, carbonic anhydrase-9 (CA-9), and glucose transporter 1 (GLUT1) expression in locally advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), local-regional control (LC), and distant metastases-free survival (DMFS)., Patients and Methods: Twenty-eight patients treated definitively and consecutively for cervical cancer with CRT had p53, HIF1a, Ki-67, CA-9, and GLUT1 protein expression assessed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes. Outcomes were stratified by p53 (H-score: <15 vs. ≥15), HIF1a (H-score: <95 vs. ≥95), Ki-67 (labeling index <41% vs. ≥41%), CA-9 (H-score: <15 vs. ≥15), and GLUT1 (H-score: <175 vs. ≥175) expression. OS, PFS, LC, and DMFS rates were calculated using the Kaplan-Meier method, and differences between groups were evaluated by the log-rank test., Results: Notable clinical characteristics of the cohort included median age of 51 years (range: 32 to 74 y), FIGO stage IIB disease (57.2%), clinical node-negative disease (64.3%), squamous cell carcinoma (89.3%), and adenocarcinoma (10.7%). Treatment outcomes included 5-year OS (57.2%), PFS (48.1%), LC (72.1%), and DMFS (62.9%). For HIF1a H-score <95 and ≥95, the 5-year OS (52.0% and 68.4%, P=0.58), PFS (53.0% and 40.9%, P=0.75), LC (71.6% and 68.2%, P=0.92), and DMFS (59.7% and 52.0%, P=0.91) were not significantly different. For Ki-67 labeling index <41% and ≥41%, the 5-year OS (44.9% and 66.6%, P=0.35), PFS (38.9% and 55.4%, P=0.53), LC (57.7% and 85.7%, P=0.22), and DMFS (67.3% and 61.0%, P=0.94) were not significantly different. For CA-9 H-score <15 and ≥15, the 5-year OS (54.4% and 66.7%, P=0.39), PFS (57.3% and 40.0%, P=0.87), LC (70.0% and 70.0%, P=0.95), and DMFS (70.0% and 46.7%, P=0.94) were not significantly different. For GLUT1 H-score <175 and ≥175, the 5-year OS (43.6% and 43.6%, P=0.32), PFS (55.6% and 49.5%, P=0.72), LC (72.9% and 71.5%, P=0.97), and DMFS (62.5% and 59.6%, P=0.76) were not significantly different. For p53, H-score <15 and ≥15, the 5-year OS (62% and 53%), PFS (63% and 30.3%), LC (87.5% and 52%), and DMFS (79.6% and 41.6%)., Conclusions: In this study population, HIF1a, Ki-67, CA-9, and GLUT1 expression did not predict treatment response or outcomes in locally advanced cervical cancer patients treated definitively with CRT. There was a nonstatistically significant trend towards worse outcomes with p53 expression., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The limits of radiation tolerance, which often deter the use of large doses, have been a major challenge to the treatment of bulky primary and metastatic cancers. A novel technique using spatial modulation of megavoltage therapy beams, commonly referred to as spatially fractionated radiation therapy (SFRT) (e.g., GRID radiation therapy), which purposefully maintains a high degree of dose heterogeneity across the treated tumor volume, has shown promise in clinical studies as a method to improve treatment response of advanced, bulky tumors. Compared to conventional uniform-dose radiotherapy, the complexities of megavoltage GRID therapy include its highly heterogeneous dose distribution, very high prescription doses, and the overall lack of experience among physicists and clinicians. Since only a few centers have used GRID radiation therapy in the clinic, wide and effective use of this technique has been hindered. To date, the mechanisms underlying the observed high tumor response and low toxicity are still not well understood. To advance SFRT technology and planning, the Physics Working Group of the Radiosurgery Society (RSS) GRID/Lattice, Microbeam and Flash Radiotherapy Working Groups, was established after an RSS-NCI Workshop. One of the goals of the Physics Working Group was to develop consensus recommendations to standardize dose prescription, treatment planning approach, response modeling and dose reporting in GRID therapy. The objective of this report is to present the results of the Physics Working Group's consensus that includes recommendations on GRID therapy as an SFRT technology, field dosimetric properties, techniques for generating GRID fields, the GRID therapy planning methods, documentation metrics and clinical practice recommendations. Such understanding is essential for clinical patient care, effective comparisons of outcome results, and for the design of rigorous clinical trials in the area of SFRT. The results of well-conducted GRID radiation therapy studies have the potential to advance the clinical management of bulky and advanced tumors by providing improved treatment response, and to further develop our current radiobiology models and parameters of radiation therapy design., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

The purpose of this study was to explore the treatment planning methods of spatially fractionated radiation therapy (SFRT), commonly referred to as GRID therapy, in the treatment of breast cancer patients using multileaf collimator (MLC) in the prone position. A total of 12 patients with either left or right breast cancer were retrospectively chosen. The computed tomography (CT) images taken for the whole breast external beam radiation therapy (WB-EBRT) were used for GRID therapy planning. Each GRID plan was made by using two portals and each portal had two fields with 1-cm aperture size. The dose prescription point was placed at the center of the target volume, and a dose of 20 Gy with 6-MV beams was prescribed. Dose-volume histogram (DVH) curves were generated to evaluate dosimetric properties. A modified linear-quadratic (MLQ) radiobiological response model was used to assess the equivalent uniform doses (EUD) and therapeutic ratios (TRs) of all GRID plans. The DVH curves indicated that these MLC-based GRID therapy plans can deliver heterogeneous dose distribution in the target volume as seen with the conventional cerrobend GRID block. The plans generated by the MLC technique also demonstrated the advantage for accommodating different target shapes, sparing normal structures, and reporting dose metrics to the targets and the organs at risks. All GRID plans showed to have similar dosimetric parameters, implying the plans can be made in a consistent quality regardless of the shape of the target and the size of volume. The mean dose of lung and heart were respectively below 0.6 and 0.7 Gy. When the size of aperture is increased from 1 to 2 cm, the EUD and TR became smaller, but the peak/valley dose ratio (PVDR) became greater. The dosimetric approach of this study was proven to be simple, practical and easy to be implemented in clinic., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: Brachytherapy in the management of cervical cancer is directly linked to improved survival. Unfortunately, we continue to see a decline in its utilization. A recent survey of U.S. residents demonstrated limited caseload as the greatest barrier to achieving independence in brachytherapy practice. To improve residents' brachytherapy skills and confidence in performing brachytherapy independently, a gynecologic brachytherapy simulation course was developed and tested., Methods and Materials: The gynecologic brachytherapy curriculum and simulation modules were developed using a combination of didactic education, self-study, practicums, and patient-centered cases. The simulation modules consisted of 2-h sessions. The first hour occurred within a simulated OR environment, where residents independently performed all aspects of applicator insertion in a cadaver model. The second hour consisted of contouring, dosimetric planning, and treatment evaluation. A brachytherapy training survey developed by the Association of Residents in Radiation Oncology was given before and after the course., Results: The perceived ability to perform brachytherapy independently for a given disease site correlated directly with number of cases performed. Most residents believed that after performing five cases they would be capable of performing additional cases independently (10 of 18). All strongly agreed (8 of 18) or agreed (10 of 18) this to be true after 15 cases. Compared with survey data before the brachytherapy simulation course, trainees felt that their ability to independently perform brachytherapy (p < 0.001) improved., Conclusions: A brachytherapy simulation course can be used to gain further experience in a controlled environment. Our results demonstrate that gynecologic brachytherapy simulation increased trainees' confidence in performing the procedures independently., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Nuclear factor kappa B (NFkB) is a transcription factor shown to confer treatment resistance in tumors. A previous report suggested an association between pretreatment NFkB and poorer outcomes for cervical cancer patients treated with chemoradiation therapy (CRT). We aimed to validate their findings in a larger patient cohort., Materials and Methods: This Institutional Review Board approved study included patients with locally advanced cervical cancer patients treated with CRT. Evaluation of both nuclear and cytoplasmic immunoreactivity for NFkB was scored semiquantitatively by 3 pathologists. Cytoplasmic positivity incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H-score), whereas nuclear positivity was assessed by percentage of positive cells. Outcomes were stratified by NFkB overexpression and tumor characteristics. Overall survival (OS), progression-free survival (PFS), distant metastases-free survival (DMFS), and local regional control (LC) were obtained using Kaplan-Meier and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained using Cox regression for both univariate and multivariate analyses., Results: The mean age was 51 years old and most (78.57%) had locally advanced disease. Five-year OS, PFS, LC, and DMFS in the entire cohort were 57.18% (confidence interval [CI], 34.06%-74.82%), 48.07% (CI, 25.50%-67.52%), 72.11% (CI, 49.96%-85.73%), and 62.85% (CI, 36.33%-80.82%), respectively. There was no significant association between NFkB expression (H-index ≥180) and 3-year and 5-year OS (P-value=0.34), PFS (P-value=0.21), LC (P-value=0.86), or DMFS (P-value=0.18)., Conclusions: Our study demonstrated that cytoplasmic NFkB-p65 expression (H-index ≥180) was associated with a nonstatistically significant trend toward poor clinical outcomes in locally advanced cervical cancer patients treated definitively with CRT.

Purpose: Lymphedema after regional nodal irradiation is a severe complication that could be minimized without significantly compromising nodal coverage if the anatomic region(s) associated with lymphedema were better defined. This study sought to correlate dose-volume relationships within subregions of the axilla with lymphedema outcomes to generate treatment planning guidelines for reducing lymphedema risk., Methods and Materials: Women with stage II-III breast cancer who underwent breast surgery with axillary assessment and regional nodal irradiation were identified. Nodal targets were prospectively contoured per Radiation Therapy Oncology Group guidelines for field design. The axilla was divided into 8 distinct subregions that were retrospectively contoured. Lymphedema outcomes were assessed by arm circumferences. Multivariate Cox proportional hazards regression assessed patient, surgical, and dosimetric predictors of lymphedema outcomes., Results: Treatment planning computed tomography scans for 265 women treated between 2013 and 2017 were identified. Median post-radiation therapy follow-up was 3 years (interquartile range [IQR], 1.9-3.6). Dose to the axillary-lateral thoracic vessel juncture (ALTJ; superior to level I) was most associated with lymphedema risk (maximally selected rank statistic = 6.3, P < .001). The optimal metric was ALTJ minimum dose (D min ) <38.6 Gy (3-year lymphedema rate 5.7% vs 37.4%, P <.001), although multiple parameters relating to sparing of the ALTJ were highly correlated. Multivariate analysis confirmed ALTJ D min <38.6 Gy (hazard ratio [HR], 0.13; P < .001), body mass index (HR, 1.06/unit; P = .002), and number of lymph nodes removed (HR, 1.08/node; P < .001) as significant predictors. Women with ALTJ D min <38.6 Gy maintained median V 45Gy of 99% in the supraclavicular (IQR, 94-100%), 100% in level III (IQR, 97%-100%), 98% in level II (IQR, 86%-100%), and 91% in level I (IQR, 75%-98%) nodal basins., Conclusions: Anatomic studies suggest the ALTJ region is typically traversed by arm lymphatics and appears to be an organ at risk in breast radiation therapy. Ideally, avoidance of the ALTJ may be feasible while simultaneously encompassing breast-draining nodal basins. Confirmation of this finding in future prospective studies is needed., (Copyright © 2019. Published by Elsevier Inc.)

Interstitial brachytherapy (IBT) is often utilized to treat women with bulky endometrial or cervical cancers not amendable to intracavitary treatments. A modern trend in IBT is the utilization of magnetic resonance imaging (MRI) with a high dose rate (HDR) afterloader for conformal 3D image-based treatments. The challenging part of this procedure is to properly complete many sequenced and co-related physics preparations. We presented the physics preparations and clinical workflow required for implementing MRI-based HDR IBT (MRI-HDR-IBT) of gynecologic cancer patients in a high-volume brachytherapy center. The present document is designed to focus on the clinical steps required from a physicist's standpoint. Those steps include: (a) testing IBT equipment with MRI scanner, (b) preparation of templates and catheters, (c) preparation of MRI line markers, (d) acquisition, importation and registration of MRI images, (e) development of treatment plans and (f) treatment evaluation and documentation. The checklists of imaging acquisition, registration and plan development are also presented. Based on the TG-100 recommendations, a workflow chart, a fault tree analysis and an error-solution table listing the speculated errors and solutions of each step are provided. Our workflow and practice indicated the MRI-HDR-IBT is achievable in most radiation oncology clinics if the following equipment is available: MRI scanner, CT (computed tomography) scanner, MRI/CT compatible templates and applicators, MRI line markers, HDR afterloader and a brachytherapy treatment planning system capable of utilizing MRI images. The OR/procedure room availability and anesthesiology support are also important. The techniques and approaches adopted from the GEC-ESTRO (Groupe Européen de Curiethérapie - European Society for Therapeutic Radiology and Oncology) recommendations and other publications are proven to be feasible. The MRI-HDR-IBT program can be developed over time and progressively validated through clinical experience, this document is expected to serve as a reference workflow guideline for implementing and performing the procedure., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: Regional nodal irradiation for women with breast cancer is known to be an important risk factor for the development of upper extremity lymphedema, but tools to accurately predict lymphedema risks for individual patients are lacking. This study sought to develop and validate a nomogram to predict lymphedema risk after axillary surgery and radiation therapy in women with breast cancer., Methods and Materials: Data from 1832 women accrued on the MA.20 trial between March 2000 and February 2007 were used to create a prognostic model with National Cancer Institute Common Toxicity Criteria Version 2.0 grade 2 or higher lymphedema as the primary endpoint. Multivariable logistic regression estimated model performance. External validation was performed on data from a single large academic cancer center (N = 785)., Results: In the MA.20 trial cohort, 3 risk factors were predictive of lymphedema risk: body mass index (adjusted odds ratio, 1.05 per unit body mass index; 95% confidence interval [CI], 1.03-1.08, P < .001), extent of axillary surgery (adjusted odds radio for 8-11 lymph nodes removed, 3.28 [95% CI, 1.53-7.89] P = .004; 12-15 lymph nodes, 4.04 [95% CI, 1.76-10.26] P = .002; ≥16 nodes, 5.08 [95% CI, 2.26-12.70] P < .001), and extent of nodal irradiation (adjusted odds radio for limited, 1.66 [95% CI, 1.08-2.56] P = .02; for extensive, 2.31 [95% CI, 1.28-4.10] P = .004). A nomogram was created from these data that predicted lymphedema risk with reasonable accuracy confirmed by both internal (concordance index, 0.69; 95% CI, 0.64-0.74) and external validation (concordance index, 0.71; 95% CI, 0.66-0.76)., Conclusions: The nomogram created from the MA.20 randomized trial data using clinical information may be useful for lymphedema screening and risk stratification for therapeutic intervention trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The patterns of failure and long-term outcomes of patients with relapsed or refractory classical Hodgkin lymphoma treated with total lymphoid irradiation (TLI) and high-dose chemotherapy followed by autologous stem cell transplantation (aSCT) are reported., Methods and Materials: Patients with biopsy-proven primary refractory or relapsed classical Hodgkin lymphoma who received salvage chemotherapy and accelerated hyperfractionated TLI before high-dose chemotherapy and aSCT were included. Patterns of failure were delineated after fusing pretransplant planning computed tomography to the scan reporting the first failure. Survival rates were computed using the Kaplan-Meier method. Multivariate analysis using proportional hazards regression was done to determine prognostic factors for overall survival (OS) and progression-free survival (PFS)., Results: Between 1993 and 2016, 89 patients underwent salvage treatments. Twenty patients failed at a median of 6.1 months after aSCT. Posttreatment scans were available for 16 patients who failed in a combined 43 different sites, 11 of which were extranodal. Patients failed at multiple sites, mostly within radiation fields. The 5-, 10-, and 15-year OS rates were 72.8%, 68.0%, and 58.3%; PFS rates were 73.3%, 68.5%, and 58.7%; event-free survival rates were 72.3%, 67.5%, and 57.8% respectively. The 5- and 10- year actuarial local control rates were both 77.6%. Complete response (CR) to salvage chemotherapy was associated with statistically significant improvements in OS and PFS. Eight patients developed secondary malignancies; 5 were hematologic and 3 were solid tumors., Conclusions: Most failures were within the irradiated volume, which reflects the treatment-resistant disease biology. As part of a conditioning regimen, TLI yields good survival outcomes, particularly in patients achieving CR before transplant. However, need for RT in this setting should be assessed and new strategies should be developed to combat the treatment-resistant biology, especially in patients with less than CR after salvage chemotherapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The optimal adjuvant management of women with FIGO Stage III-IVA endometrial cancer (EC) is unclear. While recent prospective data suggest that treatment with pelvic radiotherapy (RT) prior to chemotherapy (CT) is not associated with a survival benefit compared to CT alone, no prospective randomized trial has included a treatment arm in which CT is given before RT., Methods: An observational cohort study was performed on women with FIGO Stage III-IVA Type 1 (grade 1-2, endometrioid) EC who underwent hysterectomy and received multi-agent CT and/or RT from 2004 to 2014 at Commission on Cancer-accredited hospitals. Multivariable parametric accelerated failure time models were performed to estimate the association of sequence of adjuvant CT and RT with overall survival (OS) using propensity score-adjusted matched cohorts., Results: Of 5795 women identified, 1260 (21.7%) received RT only, 2465 (42.5%) received CT only, 593 (9.7%) received RT before CT, and 1506 (26.0%) received RT after CT. Women who received RT after CT experienced significantly longer 5-year OS than women who received RT before CT (5-year OS: 80.1% vs 73.3%; time-ratio (TR) = 1.37, 95% CI = 1.18-1.58, P < 0.001), CT only (68.9%; TR = 1.33, 95% CI = 1.19-1.48, P < 0.001), or RT only (64.5%, TR = 1.50, 95% CI = 1.32-1.70, P < 0.001)., Conclusions: For women with advanced EC, treatment with multi-agent CT followed by RT is associated with longer OS compared with treatment with RT followed by CT or either treatment alone. These hypothesis-generating data support inclusion in future prospective trials of regimens in which multi-agent CT starts prior to RT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: Inguinal lymph node involvement is considered the most important prognostic risk factor for survival in vulvar cancer. However, controversy exists concerning the optimal adjuvant therapy for node-positive disease. This study sought to identify the optimal adjuvant therapy for each subset of women with node-positive disease., Material and Methods: The National Cancer Database (NCDB) was queried to identify women with inguinal node positive vulvar cancer. Survival analysis was performed using log-rank test, the Kaplan-Meier estimates, and Cox proportional hazards to both clarify prognosis and identify the benefit of each treatment modality in individual subsets of women., Results: A total of 2779 women with inguinal node positive vulvar cancer were identified. On multivariate Cox model hazard ratio, radiotherapy yielded a survival advantage for women with one positive node (HR 0.81, p = 0.027) and two or more positive nodes (HR = 0.59, p < 0.001). The addition of chemotherapy to radiotherapy yielded an incremental improvement in survival for women with 2 or more positive nodes (HR = 0.79, p = 0.022) but not women with 1 positive node (HR = 0.93, p = 0.605)., Conclusions: All patients with node positive disease benefited from radiotherapy. By contrast, only those with 2 or more positive nodes benefited from the addition of chemotherapy to radiotherapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The occurrence of upper extremity lymphedema after regional nodal irradiation (RNI) for breast cancer treatment varies significantly based on patient and treatment factors. The relationship between the radiation therapy (RT) field design and lymphedema risk is not well-characterized. The present study sought to correlate the variations in RT field design with lymphedema outcomes., Methods and Materials: Women with stage II-IV breast cancer receiving RNI after breast surgery that included sentinel lymph node biopsy or axillary dissection were identified. Their arm circumference was measured before RT and at each follow-up visit to assess for lymphedema. Nodal RT fields were defined using a trifurcated system. Group 1 excluded the upper level I and II axilla, defined by the lateral border of the nodal field encompassing less than one-third of the humeral head. Group 2 included the upper level I and II axilla, defined by the lateral border of the nodal field encompassing more than one-third of the humoral head treated with an anterior oblique beam. Group 3 included the upper level I and II axilla the same as for group 2 but with parallel-opposed beams delivering a significant dose to the musculature posterior to the axilla., Results: From 1999 to 2013, 526 women received RNI. The median post-RT follow-up was 5.5 years. For the 492 women meeting the inclusion criteria, the cumulative incidence of lymphedema was 23.5% at 2 years and 31.8% at 5 years. On univariate analysis, the patients in group 1 had a lower 5-year lymphedema rate (7.7%) than those in group 2 (37.1%) and group 3 (36.7%; P < .0001). On multivariate analysis, inclusion of the upper level I and II axilla (groups 2 and 3) remained significantly associated with increased lymphedema risk., Conclusions: Variations in the RT field design significantly affect the development of lymphedema after RNI. In particular, the upper level I and II axilla appear to be important regions for lymphedema risk after axillary dissection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been questioned given advances in systemic therapy. The 21-gene recurrence score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT. Experimental Design: An observational cohort study was performed on women with T1-2 N1 estrogen receptor-positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the surveillance, epidemiology, and end results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts. Results: In both the NCDB ( N = 7,332) and SEER ( N = 3,087) cohorts, there was a significant interaction of RS and PMRT with OS ( P = 0.009 and P = 0.03, respectively). PMRT was associated with longer OS in women with a low RS [NCDB: time ratio (TR) = 1.70; 95% CI (confidence interval), 1.30-2.22; P < 0.001; SEER: TR = 1.85; 95% CI, 1.33-2.57; P < 0.001], but not in women with an intermediate RS (NCDB: TR = 0.89; 95% CI, 0.69-1.14; P = 0.35; SEER: TR = 0.84; 95% CI, 0.62-1.14; P = 0.26), or a high RS (NCDB: TR = 1.10; 95% CI, 0.91-1.34; P = 0.33; SEER: TR = 0.79; 95% CI, 0.50-1.23; P = 0.28). Conclusions: Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at the lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS. Clin Cancer Res; 24(16); 3878-87. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Importance: Circulating tumor cells (CTCs) represent the liquid component of solid tumors and are a surrogate marker for residual cancer burden. Although CTC status is prognostic of recurrence and death in breast cancer, its role in guiding clinical management remains unknown., Objective: To determine whether CTC status is predictive of radiotherapeutic benefit in early-stage breast cancer., Design, Setting, and Participants: The cohort studies in the present analysis included patients with stages pT1 to pT2 and pN0 to pN1 breast cancer and known CTC status from the National Cancer Database (NCDB) and the multicenter phase 3 SUCCESS clinical trial. Multivariable parametric accelerated failure time models were used to evaluate the association of CTC status and radiotherapy (RT) with survival outcomes. Data were collected from January 1, 2004, through December 31, 2014, from the NCDB cohort. The SUCCESS trial collected data from September 1, 2005, through September 30, 2013. The analyses were completed from November 1, 2016, through December 17, 2017., Exposure: Adjuvant RT., Main Outcomes and Measures: Overall survival (OS), local recurrence-free survival (LRFS), and disease-free survival (DFS)., Results: A total of 1697 patients from the NCDB (16 men [0.9%] and 1681 women [99.1%]; median age, 63 years; interquartile range, 53-71 years) and 1516 patients from the SUCCESS clinical trial (median age, 52 years; interquartile range, 45-60 years) were identified. Circulating tumor cells were detected in 399 patients (23.5%) in the NCDB cohort and 294 (19.4%) in the SUCCESS cohort. The association of RT with survival was dependent on CTC status within the NCDB cohort (4-year OS, 94.9% for CTC-positive RT vs 88.0% for CTC-positive non-RT vs 93.9% for CTC-negative RT vs 93.4% for CTC-negative non-RT groups; P < .001) and 5-year DFS within the SUCCESS cohort (88.0% for CTC-positive RT vs 75.2% for CTC-positive non-RT vs 92.3% for CTC-negative RT vs 88.3% for CTC-negative non-RT; P = .04). In the NCDB cohort, RT was associated with longer OS in patients with CTCs (time ratio [TR], 2.04; 95% CI, 1.55-2.67; P < .001), but not in patients without CTCs (TR, 0.80; 95% CI, 0.52-1.25; P = .33). In the SUCCESS cohort, CTC-positive patients treated with RT exhibited longer LRFS (TR, 2.73; 95% CI, 1.62-4.80; P < .001), DFS (TR, 3.03; 95% CI, 2.22-4.13; P < .001), and OS (TR, 1.83; 95% CI, 1.23-2.72; P = .003). Among patients from both cohorts who underwent breast-conserving surgery, RT was associated with longer OS in patients with CTCs (TR, 4.37; 95% CI, 2.71-7.05; P < .001) but not in patients without CTCs (TR, 0.87; 95% CI, 0.47-1.62; P = .77). Radiotherapy was not associated with OS after mastectomy in CTC-positive or CTC-negative patients., Conclusions and Relevance: Treatment with RT was associated with longer LRFS, DFS, and OS in patients with early-stage breast cancer and detectable CTCs. These results are hypothesis generating; a prospective trial evaluating CTC-based management for RT after breast-conserving surgery in women with early-stage breast cancer is warranted.

We aimed to better quantify the impact of a postexcision preirradiation mammogram (PPM), first by identifying factors associated with abnormal results and then incorporating these findings into a nomogram. Beginning February 2011, our institution made a practice change to obtain a PPM on all patients with any calcifications identified. A total of 530 patients underwent a PPM. Suspicious abnormalities were reported in 61 patients (11.5%), with the PPM leading to a change in management in 47 instances (8.9%). A nomogram was created based on patient and tumor characteristics to identify patients most likely to have an abnormal PPM., (© 2017 Wiley Periodicals, Inc.)

Purpose: The current standard of care for women diagnosed with early stage breast cancer is breast-conserving surgery (BCS) followed by external beam radiation therapy, commonly delivered over 3-6 weeks. As an alternative, select patients can undergo intra-operative radiation therapy (IORT) at the time of BCT. This technique delivers a single fraction of radiation at the time of surgery, enabling patients to undergo both surgery and radiation in a single session. Our current study analyzed the value of incorporating breast MRI into the routine work-up of patients deemed eligible for IORT, to quantify the impact on patient eligibility and requirement for additional work-up., Materials and Methods: We retrospectively identified patients treated by a single surgeon who were eligible for IORT based on institutional eligibility criteria which included: women age ≥55, grades 1-2, size <3 cm, estrogen receptor (ER) positive, Her-2 neu non-amplified and low/intermediate Ki-67, unifocal invasive ductal/mixed histology carcinomas. All patients must have undergone a physical exam and bilateral diagnostic mammography with ultrasound. From this population, we identified all patients who had undergone bilateral breast MRI as part of pre-operative evaluation., Results: A total of 215 women were identified who met all eligibility criteria. MRI detected additional abnormalities in the breast in 89 patients (41%). Sixty-eight women underwent additional biopsies, with a total of 117 separate lesions biopsied. Of these, pathology was benign in 61 (52.1%), atypical ductal hyperplasia (ADH) in 21 (18%), ductal carcinoma in-situ (DCIS) in 17 (14.5%) and invasive disease in 18 (15.4%). Six patients had MRI-detected abnormalities in the contralateral breast only, with biopsies identifying invasive disease (3), DCIS (1) and benign (2) findings. MRI showed abnormalities in both breasts in 6 patients and 18 additional lesions were biopsied which reveled invasive carcinoma (6), DCIS (7), ADH (3) and benign findings (2). Fifteen patients had either multifocal/multicentric disease or index lesion >3 cm on MRI and were deemed ineligible for IORT. Based on either MRI size or biopsy results, management was ultimately changed for 27 patients (12.5%). Extramammary findings were observed in 17 patients and 11 of these patients underwent further imaging studies all of which returned negative results., Conclusion: Preoperative bilateral breast MRI is a valuable tool in the proper selection of patients best suited for IORT. Even in highly selected, favorable risk patients, MRI detected additional lesions that changed surgical and radiation therapy recommendations in 12.5% of patients. However, the cost/benefit ratio needs to be taken into consideration given the high frequency of benign biopsies and additional radiological work-up., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: NRG Oncology RTOG 9704 was the first adjuvant trial to validate the prognostic value of postresection CA19-9 levels for survival in patients with pancreatic carcinoma. The data resulting from this study also provide information about predictors of recurrence that may be used to tailor individualized management in this disease setting. This secondary analysis assessed the prognostic value of postresection CA19-9 and surgical margin status (SMS) in predicting patterns of disease recurrence., Methods and Materials: This multicenter cooperative trial included participants who were enrolled as patients at oncology treatment sites in the United States and Canada. The study included 451 patients analyzable for SMS, of whom 385 were eligible for postresection CA19-9 analysis. Postresection CA19-9 was analyzed at cut points of 90, 180, and continuously. Patterns of disease recurrence included local/regional recurrence (LRR) and distant failure (DF). Multivariable analyses included treatment, tumor size, and nodal status. To adjust for multiple comparisons, a P value of ≤ .01 was considered statistically significant and > .01 to ≤ .05 to be a trend., Results: For CA19-9, 132 (34%) patients were Lewis antigen-negative (no CA19-9 expression), 200 (52%) had levels <90, and 220 (57%) had levels <180. A total of 188 patients (42%) had negative margins, 152 (34%) positive, and 111 (25%) unknown. On univariate analysis, CA19-9 cut at 90 was associated with increases in LRR (trend) and DF. Results were similar at the 180 cut point. SMS was not associated with an increase in LRR on univariate or multivariate analyses. On multivariable analysis, CA19-9 ≥ 90 was associated with increased LRR and DF. Results were similar at the 180 cut point., Conclusions: In this prospective evaluation, postresection CA19-9 was a significant predictor of both LRR and DF, whereas SMS was not. These findings support consideration of adjuvant radiation therapy dose intensification in patients with elevated postresection CA19-9.

Background: The internal mammary (IM) lymph node chain, along with the axillary nodal basin, is a first-echelon breast lymphatic draining site. A growing body of evidence supports irradiation of this region in node-positive breast cancer. This study evaluated the effectiveness of radiotherapy in treating magnetic resonance imaging (MRI)-detected abnormal IM lymph nodes in newly-diagnosed non-metastatic breast cancer., Methods: A structured query was performed on an electronic institutional database to identify women with radiographic evidence of abnormal IM node(s) on breast MRI from 2005 to 2013. Manual review narrowed inclusion to patients with a primary diagnosis of non-metastatic breast cancer with abnormal IM node(s) based on pathologic size criteria and/or abnormal enhancement., Results: Of the 7070 women who underwent pre-treatment MRI, 19 (0.3%) were identified on imaging to have a total of 25 abnormal pre-treatment IM lymph nodes, of which 96% were located in the first two intercostal spaces and 4% in the third space. A majority of the primary tumors were high-grade (94.7%) and hormone-receptor negative (73.7%), while 47.4% overexpressed HER-2/neu receptor. Axillary nodal disease was present in 89.5% of patients, while one patient had supraclavicular involvement. At a median follow-up of 38 months, 31.6% of patients had developed metastatic disease and 21.1% had died from their disease. Of the patients who received IM coverage, none had progressive disease within the IM lymph node chain., Conclusions: Radiologic evidence of pre-treatment abnormal IM chain lymph nodes was associated with advanced stage, high grade, and negative estrogen receptor status. The majority of positive lymph nodes were located within the first two intercostal spaces, while none were below the third. Radiation of the IM chain in combination with modern systemic therapy was effective in achieving locoregional control without surgical resection in this cohort of patients.

Purpose: This study aimed to assess the association between pretreatment c-Met overexpression in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), distant metastases (DM) control, and local-regional control (LC)., Patients and Methods: This Institutional Review Board-approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of cytoplasmic immunoreactivity for c-Met was performed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes, and incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H score). Treatment outcomes were reviewed and reported. Outcomes were stratified by c-Met overexpression and tumor characteristics. OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained via Cox regression for both univariate and multivariate analyses., Results: The 5-year OS, PFS, LC, and DC were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Ten (35.7%) and 18 patients (64.3%) had c-Met H index >30 and<30, respectively. c-Met overexpression was significantly associated with worse 3- and 5-year OS (P=0.003), PFS (P=0.002), LC (P=0.01), and DC (P=0.0003). Patients with c-Met overexpression had a hazard ratio of 6.297, 5.782, 6.28, and 18.173 for the risks of death, disease progression, local recurrence, and DM, respectively., Conclusion: c-Met overexpression could be a potential predictive marker and therapeutic target for local-regional advanced cervical cancer patients treated definitively with CRT.

It is postulated that the outcomes in treating breast cancer with intraoperative radiotherapy (IORT) would be affected by the residual cancer cell distribution within the tumor bed. The three-dimensional (3D) radiation doses of Intrabeam TM (IB) IORT with a 4-cm spherical applicator at the energy of 50 and 40 kV were calculated. The modified linear quadratic model (MLQ) was used to estimate the radiobiological responses of the cancer cells and interspersed normal tissues with various radiosensitivities. By comparing the average survival fraction of normal tissues in IB-IORT and uniform dose treatment for the same level of cancer cell killing, the therapeutic ratios (TRs) were derived. The equivalent uniform dose (EUD) was found to increase with the prescription dose and decrease with the cancer cell infiltrating distance. For 50 kV beam at the 20 Gy prescription dose, the EUDs are 18.03, 16.49 and 13.56, 11. 29, and 9.28 Gy respectively, for 1.5, 3.0, 6.0, 9, and 15.0 mm of the cancer cell infiltrating distance into surrounding tissue. The dose rate of 50 kV is at least 1.87× higher than that of 40 kV beam. The EUDs of 50 kV beam are up to 15% higher than that of the 40 kV beam. The TR increases with the prescription dose, but decreases with the distance of cancer cell infiltration distance. Average TRs of 50 kV beam are up to 30% larger than that of 40 kV beam. In conclusion, IB-IORT can provide a possible therapeutic advantage on sparing more normal tissue compared with the External Beam IORT (EB-IORT) for shallowly populated unicentric breast lesion. Our data suggest that IB-IORT dose size should be adjusted based on the individual patient's cancer cell infiltrating distance for delivering an effective dose, one dose-fits-all regimen may have undertreated some patients with large cancer infiltrating distance., (© 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Objective: The aim of this study was to evaluate outcomes after breast-conserving surgery (BCS) and intraoperative radiotherapy (IORT), and to identify risk factors associated with complications., Materials/methods: We evaluated patients with early-stage breast cancer treated from January 1, 2011 to January 31, 2014 with BCS and IORT at a single institution. The presence of breast cancer recurrences, complications, or fat necrosis were assessed at subsequent follow-up visits using physical examination and breast imaging., Results: Overall, 113 patients, of whom three were undergoing bilateral treatments, were identified. The median length of time for IORT was 29 min and 36 s (range 15:50-59:00). Fifteen patients received additional external beam radiotherapy (EBRT), and the median follow-up was 40.3 months (range 1.6-58.3) for all patients. To date, one biopsy-proven ipsilateral recurrence has been noted (0.9%), for which the patient elected to undergo a mastectomy. Nine patients were found to have wound complications (7.7%) and two had fat necrosis (1.7%) on follow-up. Of all the evaluated risk factors, only applicator size (p < 0.01) had a statistically significant association with an increase in complications., Conclusions: With a short follow-up, IORT appears to be a safe treatment modality for a select group of patients, leading to a reasonable increase in operating room time and complication rates following BCS. The utilization of larger applicators at the time of IORT was associated with an increase in wound complications and fat necrosis.

Purpose: The purpose of this article is to report the long-term rate and timing of complications associated with postmastectomy radiation therapy (PMRT) following immediate breast reconstruction in a large patient population., Methods and Materials: We identified and reviewed the charts of all patients with stages I through IIIC breast cancer who underwent mastectomy with immediate reconstruction followed by subsequent radiation therapy between November 1997 and May 2010. We aimed to assess the rate of major complications, defined as events requiring a separate and distinct procedure. Statistical analysis between variables was evaluated using Fisher exact test and Pearson χ 2 Elder et al. (2005) test., Results: In total, 134 patients met inclusion criteria for having adequate long-term follow-up and documentation. The median follow-up for all patients was 77.4 months (range, 6-185 months). The overall major complication rate was found to be 44%. Nine patients (6.7%) experienced complications for which a secondary procedure could not be performed to retain a reconstructed breast. The average time between initiation of PMRT and the first major complication was 13.5 months, with 68.3% of first major complications occurring within 1 year of PMRT initiation and 81.7% within 2 years. The difference in incidence of major complications for patients undergoing immediate tissue expander/implant reconstruction followed by PMRT was not statistically different when compared with that for patients with immediate autologous tissue reconstruction followed by PMRT (47.3% vs 30.4%, P = .168)., Conclusions: The risk of first major complications and reconstruction loss in patients undergoing PMRT on immediately reconstructed breasts is greatest within 1 year of beginning radiation therapy and decreases significantly with time. Immediate autologous tissue reconstruction followed by PMRT can be performed with reasonable complication rates., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Randomized controlled trials have consistently shown that the use of postoperative radiotherapy (RT) for stage I endometrial cancer leads to a reduction in the incidence of pelvic recurrences without a corresponding reduction in overall mortality. It was hypothesized that a reduction in mortality associated with the receipt of RT could be identified in a large data set with greater statistical power., Methods: Women with surgically staged IA or IB endometrial adenocarcinoma who were treated with total hysterectomy between 2003 and 2011 were identified in the National Cancer Data Base. Chi-square tests and multivariate logistic regression were performed to analyze factors associated with the treatment type. A survival analysis was performed with log-rank testing, Cox proportional hazards regression, and Kaplan-Meier estimates., Results: A total of 44,309 eligible women were identified (33,380 at stage IA and 10,929 at stage IB): 88.4% of the women with stage IA tumors and 51.6% of the women with stage IB tumors received no RT. Older age, comorbid disease, a higher histologic grade, and a larger tumor size were independently associated with an increase in mortality. The receipt of vaginal brachytherapy (VB) was independently associated with a reduction in mortality for both stage IA disease (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.67-0.97) and stage IB disease (HR, 0.62; 95% CI, 0.51-0.74)., Conclusions: Analyses of this large database support the utility of postoperative VB for many women with stage I endometrial cancer. Unfortunately, RT appears to be underused in this population. Greater adherence to consensus guidelines may lead to improved outcomes. Cancer 2016;122:3724-31. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Purpose: To determine the factors that correlate with cylinder size in vaginal brachytherapy (VB) after hysterectomy for endometrial carcinoma., Methods and Materials: Patients treated for endometrial cancer from January 1, 2003 to December 31, 2013 were reviewed from a single institution. Patients included underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by high-dose-rate VB with or without external beam pelvic radiotherapy (EBRT). According to institutional guidelines, the vaginal cylinder size selected was the largest diameter cylinder the patient could comfortably accommodate. Patient, tumor, and treatment factors were recorded and compared with cylinder size., Results: Three hundred eighty-one eligible patients were identified, including 121 patients treated with pelvic radiotherapy (RT) before VB and 260 treated with VB alone. On univariate analysis, weight (p = 0.0004), body mass index (BMI) (p = 0.001), and receipt of pelvic RT (p ≤ 0.0001) were the only statistically significant factors correlated with vaginal cylinder size. On multivariate analysis, receipt of EBRT retained significance after adjusting for weight or BMI. In patients receiving VB alone, median cylinder size was 3 cm; after pelvic RT, it was 2.5 cm., Conclusions: Higher weight and BMI correlated with accommodation of larger cylinder size. Accounting for this, the receipt of EBRT before VB was associated with smaller cylinder size. Dosimetric data show that larger cylinder size provides superior dose distribution. Although historically the VB boost follows EBRT, reversal of this order may be preferred., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America., Methods: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed., Results: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated., Conclusions: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

Purpose: To review and report the long-term treatment-induced adverse events (AEs) and outcomes of concomitant chemoradiotherapy boosted by low-dose-rate (LDR) conventional brachytherapy (BT) planning in patients with locoregionally advanced cervical cancer., Patients and Methods: After obtaining institutional review board approval, we reviewed the records of patients with stage IB1 to IVA, intact cervical cancer who were treated at our institution between 1983 and 2009. Eligible patients underwent definitive radiotherapy with external-beam radiation concomitant with cisplatin-based chemotherapy and boosted by LDR BT. Patient, tumor, and treatment characteristics; treatment-induced AEs, namely, gastrointestinal and genitourinary toxicities, as well as treatment outcomes; locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were reviewed and reported., Results: The study included 129 eligible cervical cancer patients; the median age was 46 years (mean, 47 ± 11 y; range, 28 to 81 y), consisting of stages I, II, III, and IV (29.5%, 48.1%, 17.8%, and 4.6%, respectively). The median follow-up was 37 months (mean, 58 ± 59 mo; range, 3 to 275 mo). The 3-year OS, PFS, LRC, and DC were 75.9%, 71.6%, 84.7%, and 80.2%, respectively. The 5-year OS, PFS, LRC, and DC were 70.7%, 68.7%, 84.7%, and 78.3%, respectively. The 10-year OS, PFS, LRC, and DC were 68.7%, 62.3%, 82.5%, and 73.2%, respectively. Gastrointestinal and genitourinary grade 3 and 4 acute AEs were reported in 3.9% and 0%, and chronic grade 3 and 4 AEs were reported in 20.9% and 12.4% of all patients, respectively., Conclusions: Definitive chemoradiotherapy followed by conventional LDR BT boost is effective, feasible, and tolerable treatment modality for cervical cancer. A comparison with MRI image-guided BT shows comparable treatment outcomes with superior OS in favor of LDR BT but inferior LC with a relatively worse toxicity profile.

Purpose: To evaluate high-dose-rate (HDR) vaginal cuff brachytherapy (VCBT) in the treatment of endometrial cancer in a cylindrical target volume with either a varied or a constant cancer cell distributions using the linear quadratic (LQ) model., Methods: A Monte Carlo (MC) technique was used to calculate the 3D dose distribution of HDR VCBT over a variety of cylinder diameters and treatment lengths. A treatment planning system (TPS) was used to make plans for the various cylinder diameters, treatment lengths, and prescriptions using the clinical protocol. The dwell times obtained from the TPS were fed into MC. The LQ model was used to evaluate the therapeutic outcome of two brachytherapy regimens prescribed either at 0.5 cm depth (5.5 Gy × 4 fractions) or at the vaginal mucosal surface (8.8 Gy × 4 fractions) for the treatment of endometrial cancer. An experimentally determined endometrial cancer cell distribution, which showed a varied and resembled a half-Gaussian distribution, was used in radiobiology modeling. The equivalent uniform dose (EUD) to cancer cells was calculated for each treatment scenario. The therapeutic ratio (TR) was defined by comparing VCBT with a uniform dose radiotherapy plan in term of normal cell survival at the same level of cancer cell killing. Calculations of clinical impact were run twice assuming two different types of cancer cell density distributions in the cylindrical target volume: (1) a half-Gaussian or (2) a uniform distribution., Results: EUDs were weakly dependent on cylinder size, treatment length, and the prescription depth, but strongly dependent on the cancer cell distribution. TRs were strongly dependent on the cylinder size, treatment length, types of the cancer cell distributions, and the sensitivity of normal tissue. With a half-Gaussian distribution of cancer cells which populated at the vaginal mucosa the most, the EUDs were between 6.9 Gy × 4 and 7.8 Gy × 4, the TRs were in the range from (5.0)(4) to (13.4)(4) for the radiosensitive normal tissue depending on the cylinder size, treatment lengths, prescription depth, and dose as well. However, for a uniform cancer cell distribution, the EUDs were between 6.3 Gy × 4 and 7.1 Gy × 4, and the TRs were found to be between (1.4)(4) and (1.7)(4). For the uniformly interspersed cancer and radio-resistant normal cells, the TRs were less than 1. The two VCBT prescription regimens were found to be equivalent in terms of EUDs and TRs., Conclusions: HDR VCBT strongly favors cylindrical target volume with the cancer cell distribution following its dosimetric trend. Assuming a half-Gaussian distribution of cancer cells, the HDR VCBT provides a considerable radiobiological advantage over the external beam radiotherapy (EBRT) in terms of sparing more normal tissues while maintaining the same level of cancer cell killing. But for the uniform cancer cell distribution and radio-resistant normal tissue, the radiobiology outcome of the HDR VCBT does not show an advantage over the EBRT. This study strongly suggests that radiation therapy design should consider the cancer cell distribution inside the target volume in addition to the shape of target.

Deep inspiration breath hold (DIBH) is an effective technique to reduce cardiac and pulmonary dose during breast radiotherapy (RT). However, as a result of expense and the technical challenges of program implementation, DIBH has not been widely adopted in clinical practice. This report describes a program for DIBH this is relatively inexpensive to implement and has little impact on patient throughput. Multiple redundant mechanisms are incorporated to assure accurate and safe delivery of RT during DIBH. Laser alignment verifies that chest wall excursion is reliably reproduced and maintained during treatment. Chest wall excursion is also monitored independently using an infrared camera trained on a reflective marker on the chest wall. This system automatically triggers "beam off" in the event of movement of the target beyond pre-determined thresholds. Finally, physician review of cine imaging obtained during treatment provides an off-line verification of accurate RT delivery. The approach described herein lowers the investment necessary for implementation of DIBH and may facilitate broader adoption of this valuable technique., (Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Objectives: The objective of this study was to compare outcomes for patients with cervical cancer treated with radiation concurrently with cisplatin, cisplatin/5-fluorouracil (5-FU), or without chemotherapy., Materials and Methods: We reviewed the records of eligible patients with locoregionally confined, stage IB1 through IVA, intact cervical cancer who were treated at Northwestern Memorial Hospital. All patients underwent definitive radiotherapy with combined external beam radiation-the majority with extended-field (62%)-and received low-dose rate brachytherapy., Results: A total of 236 patients were included: 99 had no concurrent chemotherapy, 95 were treated with concurrent cisplatin, and 42 were treated with cisplatin/5-FU. For all patients treated with or without chemotherapy, overall survival at 5 and 10 years was 64% and 59%, respectively. Patients treated with chemotherapy had a superior recurrence-free survival rate of 69% at 5 years versus 49% in patients who did not receive chemotherapy (P=0.09). Twenty-six percent of patients treated with cisplatin alone, 31% of patients treated with cisplatin/5-FU, and 45% of patients who did not receive chemotherapy experienced a disease recurrence. Adenosquamous histology conferred a higher rate of recurrence as compared with adenocarcinoma and squamous cell histologies (54% vs. 34%, respectively; P=0.05)., Conclusions: Cisplatin-based concurrent chemoradiotherapy showed a trend toward improved recurrence-free survival survival in the definitive treatment of nonmetastatic cervical cancer. The addition of 5-FU to cisplatin did not appear to significantly impact survival or recurrence-free survival. Adenosquamous histology was associated with a higher risk of recurrence as compared with other histologic subtypes.

Purpose: The optimal dosimetric parameters and planning techniques for high-dose-rate vaginal brachytherapy (HDR-VB) are unclear. Our aim was to evaluate the utility of bladder and rectal dosimetry for patients receiving HDR-VB for postoperative treatment of endometrial carcinoma., Material and Methods: Patients with endometrial cancer who underwent postoperative HDR-VB from January 1, 2004 through December 31, 2010 were included. All patients underwent primary surgery consisting of total hysterectomy and bilateral salpingo-oophrectomy (TH-BSO) with or without lymph node dissection and were treated with HDR-VB without pelvic external beam radiotherapy (EBRT) or chemotherapy. Demographic, pathologic, dosimetric and clinical data were collected., Results: One hundred patients were identified with the majority of patients receiving HDR-VB in 700 cGy × 3 fractions (45%) or 550 cGy x 4 fractions (53%). No plan was altered based on bladder dosimetry at the time of planning. The rate of acute urinary reactions (< 90 days from beginning of RT) grades 1 and 2 were 14% and 2%, respectively. The rate of late urinary reactions (> 90 days after RT) grades 1 and 2 were 7% and 3%, respectively. Dose to the bladder point did not correlate with urinary toxicity. No rectal toxicity was reported by patients receiving HDR-VB., Conclusions: In the setting of HDR-VB without EBRT, the measured dose to the bladder point does not predict urinary toxicity and is very unlikely to indicate the need to change the treatment plan. The treatment of endometrial carcinoma utilizing HDR-VB alone is associated with very low rates of high-grade acute or late bladder toxicity.

To more accurately and precisely delineate a tumor in a 3D PET image, we proposed a novel, semi-automatic, two-stage method by utilizing an adaptive region-growing algorithm and a dual-front active contour model. First, a rough region of interest (ROI) is manually drawn by a radiation oncologist that encloses a tumor. The voxel having the highest intensity in the ROI is chosen as a seed point. An adaptive region growing algorithm successively appends to the seed point all neighboring voxels whose intensities > = T of the mean of the current region. When T varies from 100% to 0%, a sharp volume increase, indicating the transition from the tumor to the background, always occurs at a certain T value. A preliminary tumor boundary is determined just before the sharp volume increase, which is found to be slightly outside of the known tumor in all tested phantoms. A novel dual-front active contour model utilizing region-based information is then applied to refine the preliminary boundary automatically. We tested the two-stage method on six spheres (0.5-20 ml) in a cylindrical container under different source to background ratios. Comparisons between the two-stage method and an iterative threshold method demonstrate its higher detection accuracy for small tumors (less than 6 ml). One patient study was tested and evaluated by two experienced radiation oncologists. The study illustrated that this two-stage method has several advantages. First, it does not require any threshold-volume curves, which are different and must be calibrated for each scanner and image reconstruction method. Second, it does not use any iso-threshold lines as contours. Third, the final result is reproducible and is independent of the manual rough ROIs. Fourth, this method is an adaptive algorithm that can process different images automatically.

Purpose: To quantify the amount of free-breathing motion measured using Four-dimensional (4D) CT scans of mediastinal and hilar lymph nodes and to compare this motion to the primary lung tumor motion., Methods and Materials: Twenty patients with primary lung cancer, radiographically positive lymph nodes, and prior 4D CT scans were retrospectively analyzed. The 4D CT data sets were divided into four respiratory phases, and the primary tumor and radiographically positive nodes were contoured. Geometric and volumetric analysis was performed to analyze the motion of the primary tumors and the lymph nodes., Results: The mean lymph node motion was 2.6 mm in the mediolateral direction, 2.5 mm in the anterior-posterior direction, and 5.2 mm in the cranial-caudal direction with a maximum of 14.4 mm. All lymph nodes were found to move inferiorly during inspiration, with 12.5% of nodes moving more than 1 cm. Lymph nodes located below the carina showed significantly more motion than those above the carina (p = 0.01). In comparing the primary tumor motion to the lymph node motion, no correlation was identified., Conclusions: Four-dimensional CT scans can be used to measure the motion of the primary lung tumor and pathologic lymph nodes encountered during the respiratory cycle. Both the primary lung tumor and the lymph node must to be examined to assess their individual degree of motion. This study demonstrates the need for individualized plans to assess the heterogeneous motion encountered in both primary lung tumors and among lymph node stations.