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Patients with gynecological, gastrointestinal, or genitourinary malignancy are at elevated risk for developing premature ovarian insufficiency (POI) from the multimodality therapies used to treat their cancers. POI can result in long term decrements to all-cause mortality, bone density, cardiovascular health, sexual health, cognitive health, and body mass. HRT has been demonstrated to reverse these long term sequalae with the goal of restoring estrogen concentrations to physiological levels. Herein, we discuss a practical approach for initiation of HRT as well as challenges to consider., (Copyright © 2024. Published by Elsevier Inc.)

18 F-16α-Fluoroestradiol ( 18 F-FES) is a radiolabeled estrogen analogue positron emission tomography (PET) imaging agent that binds to the estrogen receptor (ER) in the nucleus of ER-expressing cells. Proof-of-concept studies of 18 F-FES demonstrated expected correlation between tumoral 18 F-FES-positivity on PET-imaging and ER+ status assessed on biopsy samples by radioligand binding and immunohistochemistry. After decades of study, 18 F-FES PET/CT gained clinical approval in 2016 in France and 2020 in the United States for use in patients with ER+ metastatic or recurrent breast cancer. ER+ as assessed by 18 F-FES PET/CT has been shown to serve as a biomarker, identifying metastatic breast cancer patients who may respond to endocrine therapy and those who are unlikely to respond. In 2023, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published Appropriate Use Criteria for 18 F-FES PET/CT, identifying four indications in which use of 18 F-FES PET/CT was "appropriate": (1) To assess functional ER status in metastatic lesions unfavorable to biopsy or when biopsy is nondiagnostic, (2) To detect ER status when other imaging tests are equivocal or suspicious, and at (3) initial diagnosis of metastatic disease or (4) progression of metastatic disease, for considering endocrine therapy. This article reviews the foundations of 18 F-FES imaging, including normal distribution, false positives, and false negatives, and describes the most up-to-date clinical uses as well as emerging research in breast cancer and other patient populations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sophia O'Brien reports a relationship with GE that includes: consulting or advisory. Austin Pantel reports a relationship with GE that includes: consulting or advisory. David Mankoff reports a relationship with GE that includes: consulting or advisory. Neil Taunk reports a relationship with Boston Scientific, Point Biopharma, Novartis, GE Healthcare, Varian Medical Systems that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Sophia O'Brien, Austin Pantel, Christine Edmonds, and David Mankoff are supported by a Komen Scholar Grant (Komen SAC231245), (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Institutional radiation safety committees review research studies with radiation exposure. However, ensuring that the potential patient benefit and knowledge gained merit the radiation risks involved often necessitates revisions that inadvertently delay protocol activations. This quality-improvement study analyzed protocols, identified factors associated with approval time by a radiation safety committee, and developed guidelines to expedite reviews without compromising quality. Clinical protocols submitted to the University of Pennsylvania's Radiation Research Safety Committee (RRSC) for review between 2017 and 2021 were studied. Protocol characteristics, review outcome, stipulations, and approval times were summarized. Statistical analysis (Spearman's rho) was used to investigate stipulations and approval time; rank-sum analysis (Kruskal-Wallis or Wilcoxon) was used to determine whether approval time differed by protocol characteristics. One hundred ten (110) protocols were analyzed. Approximately two-thirds of protocols used approved radiopharmaceuticals to aid investigational therapy trials. Twenty-three percent (23%) of protocols received RRSC approval, and 73% had approval withheld with stipulations, which included requests for edits or additional information. Submissions had a median of three stipulations. Median and mean RRSC approval times were 62 and 80.1 d, and 41% of protocols received RRSC approval after IRB approval. RRSC approval time was positively correlated with stipulations (Spearman's rho = 0. 632, p < 0.001). RRSC approval time was longer for studies using investigational new drugs (median 80 d) than approved radiopharmaceuticals (median 57 d, p = 0.05). The review process is lengthy and may benefit from changes, including publishing standardized radiation safety language and commonly required documents and encouraging timely response to stipulations., (Copyright © 2024 Health Physics Society.)

Objective: Stage IVA patients comprise a small proportion of participants in cervical cancer trials, yet survival outcomes are disproportionately poor. We aim to perform a systematic review evaluating stage IVA cervical cancer., Methods: This systematic review was completed via PRISMA 2020 guidelines using two databases. Inclusion criteria comprised Phase III trials (2004-2024) assessing stage IVA cervical cancer including patients by stage. Searches had MeSH terms: ((cervical cancer) AND (stage IVA) AND (locally advanced)). 761 were articles identified, including books, trials, reviews, and meta-analyses. Of the articles identified, 12 met inclusion criteria., Results: A total of 133 (3.8% of study populations) stage IVA and 818 (40% of study populations) stage III-IVA cervical cancer patients were analyzed. Two studies (stage IVA n = 15; 3.1%) established cisplatin as chemoradiotherapy agent of choice, while one study (stage IVA n = 2; 1%) showed no benefit with cisplatin versus radiotherapy alone. Four studies (stage IVA n = 32; 3.6%; stages IIIB-IVA n = 220; 24%) found no benefit with adjuvant chemotherapy, with one analyzing stage IIIB-IVA patients (progression-free survival (PFS) hazard ratio (HR) = 0.84; 95% confidence interval (CI): 0.57-1.23). Three studies (stage IVA n = 71; 5%) found no benefit adding immunomodulator (stage IVA overall survival HR = 3.48; 95% CI: 0.52-23.29), hypoxic cell sensitizer, or immunotherapy (stage III-IVA PFS HR = 0.71; 95% CI: 0.49-1.03) to chemoradiotherapy. One study (stages III-IVA n = 598; 56%) found benefit adding immunotherapy to chemoradiotherapy (stage III-IVA PFS HR = 0.58; 95% CI: 0.42-0.8). One study (stage IVA n = 13; 3.5%) showed benefit with induction chemotherapy., Conclusion: Trials have not included substantial IVA patients to draw reasonable conclusions. Despite mixed results for immunotherapy, adjuvant chemotherapy, and induction chemotherapy, the exact benefit for stage IVA patients remains unknown. Future clinical trials should include a greater number of stage IVA cervical cancer patients and analyze them individually., Competing Interests: Declaration of competing interest There are no conflicts of interest for this systematic review., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this work was to report the effect of mismatch repair (MMR) status on outcomes of patients with stage I-II endometrioid endometrial adenocarcinoma (EEC) who receive adjuvant radiation therapy., Methods and Materials: This is a multi-institutional retrospective cohort study across 11 institutions in North America. Patients with known MMR status and stage I-II EEC status postsurgical staging were included. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated via the Kaplan-Meier method. Univariable and multivariable analyses were performed via Cox proportional hazard models for RFS and OS. Statistical analyses were conducted using SPSS version 27., Results: In total, 744 patients with a median age at diagnosis of 65 years (IQR, 58-71) were included. Most patients were White (69.4%) and had Federation of Obstetrics and Gynecology 2009 stage I (84%) and Federation of Obstetrics and Gynecology grade 1 to 2 (73%). MMR deficiency was reported in 234 patients (31.5%), whereas 510 patients (68.5%) had preserved MMR. External beam radiation therapy with or without vaginal brachytherapy was delivered to 186 patients (25%), whereas 558 patients (75%) received vaginal brachytherapy alone. At a median follow-up of 43.5 months, the estimated crude OS and RFS rates for the entire cohort were 92.5% and 84%, respectively. MMR status was significantly correlated with RFS. RFS was inferior for MMR deficiency compared with preserved MMR (74.3% vs 88.6%, P < .001). However, no difference in OS was seen (90.8% vs 93.2%, P = .5). On multivariable analysis, MMR deficiency status was associated with worse RFS (hazard ratio, 1.86; P = .001) but not OS., Conclusions: MMR status was independently associated with RFS but not OS in patients with early-stage EEC who were treated with adjuvant radiation therapy. These findings suggest that differential approaches to surveillance and/or treatment based on MMR status could be warranted., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Treatment options for patients with metastatic castration-resistant prostate cancer include use of radioligand therapy with 177Lu-PSMA-617. 177Lu-PSMA-617 is used to target prostate cancer cells selectively by targeting prostate specific membrane antigen (PSMA); however, PSMA is also expressed on lacrimal glands among other tissues. Herein, we report on a case of a Common Terminology Criteria for Adverse Events version 5 grade 3 dry eye event with concomitant blepharitis after administration of 177Lu-PSMA-617. The patient was managed with neomycin-polymyxin-dexamethasone 3.5-10000-0.1 ophthalmic suspension, artificial tears, lubricating ointments, lid scrubs, and oral antihistamines., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Abstract: Radiopharmaceutical therapy has emerged as a promising approach for the treatment of various cancers. The exploration of novel targets such as tumor-specific antigens, overexpressed receptors, and intracellular biomolecules using antibodies, peptides, or small molecules has expanded the scope of radiopharmaceutical therapy, enabling precise and effective cancer treatment for an increasing number of tumor types. Alpha emitters, characterized by their high linear energy transfer and short path length, offer unique advantages in targeted therapy due to their potent cytotoxicity against cancer cells while sparing healthy tissues. This article reviews recent advancements in identifying novel targets for radiopharmaceutical therapy and applications in utilizing α-emitters for targeted treatment., Competing Interests: Conflicts of Interest and Source of Funding: N.K.T. reports consulting fees, research grants, travel expenses, or honoraria from Boston Scientific, Varian Medical Systems, Therapanacea AI, Point BioPharma, and Telix Pharmaceuticals. J.S.L. reports research support from Clarity Pharmaceuticals; has acted as an adviser of Inhibrx, Inc., Alpha-9 Theranostics Inc., Clarity Pharmaceuticals, Earli Inc., Evergreen Theragnostics and Telix Pharmaceuticals; is a coinventor on technologies licensed to Diaprost, Elucida Oncology, Theragnostics, Ltd., CheMatech and Samus Therapeutics LLC; is the cofounder of pHLIP Inc.; and holds equity in Curie Therapeutics Inc., Summit Biomedical Imaging, Telix Pharmaceuticals and Evergreen Theragnostics. F.E.E. reports no conflicts. L.B. reports noncompensated consultancy for AAA-Novartis, Ipsen, Clovis, ITM, IBA, Great Point Partners, PointBiopharma, and RayzeBio and research grant from AAA-Novartis., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To identify the characteristics, indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at an academic medical center., Materials and Methods: A retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010 to 2019. Patients were followed from the start of PBT until death or last follow-up. Acute (3 months) toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0. Imaging response was assessed using the Response Evaluation Criteria in Solid Tumors v1.1. The χ 2 test was used to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with toxicity., Results: Bet299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Median age was 68 years (19-94 years), 58% male. The most common cancer was nonsmall cell lung cancer (27%). Patients were treated for symptom palliation alone (11%), durable control (57%), curative intent (16%), local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received reirradiation. Median treatment time was 32 days (1-189 days). Acute toxicity was noted in 85% of the patients (31% G1, 53% G2, 15% G3). Thirteen patients (4%) experienced chronic toxicity. Breast and hematologic malignancy were associated with palliative intent χ 2 (1, N  = 14) = 17, P  = .013; (χ 2 (1, N  = 14) = 18, P  = .009)., Conclusion: The number of patients treated with PBT at the EOL was low compared to all comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Some patients spent a large portion of their remaining days on treatment. A prognostic indicator may better optimize patient selection for PBT at the EOL., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Neil K Taunk reports a relationship with Varian Medical Systems Inc that includes: consulting or advisory and funding grants. Neil K Taunk reports a relationship with Therapanacea AI that includes: funding grants. Neil K Taunk reports a relationship with Radiological Society of North America that includes: funding grants. Neil K Taunk reports a relationship with POINT Biopharma Global Inc that includes: consulting or advisory. Neil K Taunk reports a relationship with Telix Pharmaceuticals Limited that includes: consulting or advisory. Neil K Taunk reports a relationship with Boston Scientific Corp that includes: consulting or advisory. James M Metz reports a relationship with Varian Medical Systems Inc that includes: speaking and lecture fees. James M Metz reports a relationship with IBA Dosimetry US that includes: speaking and lecture fees. Jeffrey D Bradley reports a relationship with Varian Medical Systems Inc that includes: consulting or advisory. Jeffrey D Bradley reports a relationship with AstraZeneca Pharmaceuticals LP that includes: board membership and consulting or advisory. Jeffrey D Bradley reports a relationship with Mevion Medical Systems that includes: board membership. Jeffrey D Bradley reports a relationship with Genentech that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Opinion Statement: The standard of treatment for node-positive endometrial cancer (FIGO Stage IIIC) in North America has been systemic therapy with or without additional external beam radiation therapy (RT) given as pelvic or extended field RT. However, this treatment paradigm is rapidly evolving with improvements in systemic chemotherapy, the emergence of targeted therapies, and improved molecular characterization of these tumors. The biggest question facing providers regarding management of stage IIIC endometrial cancer at this time is: what is the best management strategy to use with regard to combinations of cytotoxic chemotherapy, immunotherapy, other targeted therapeutics, and radiation that will maximize clinical benefit and minimize toxicities for the best patient outcomes? While clinicians await the results of ongoing clinical trials regarding combined immunotherapy/RT as well as management based on molecular classification, we must make decisions regarding the best treatment combinations for our patients. Based on the available literature, we are offering stage IIIC patients without measurable disease postoperatively both adjuvant chemotherapy and IMRT with carboplatin, paclitaxel, and with or without pembrolizumab/dostarlimab as primary adjuvant therapy. Patients with measurable disease post operatively, high risk histologies, or stage IV disease receive chemoimmunotherapy, and vaginal brachytherapy is added for those with uterine risk factors for vaginal recurrence. In the setting of endometrioid EC recurrence more than 6 months after treatment, patients with pelvic nodal and vaginal recurrence are offered IMRT and brachytherapy without chemotherapy. For measurable recurrence not suitable for pelvic radiation alone, chemoimmunotherapy is preferred as standard of care., (© 2024. The Author(s).)

Purpose: Our purpose was to report complications requiring surgical intervention among patients treated with postmastectomy proton radiation therapy (PMPRT) for breast cancer in the setting of breast reconstruction (BR)., Methods and Materials: Patients enrolled on a prospective proton registry who underwent BR with immediate autologous flap, tissue expander (TE), or implant in place during PMPRT (50/50.4 Gy +/- chest wall boost) were eligible. Major reconstruction complication (MRC) was defined as a complication requiring surgical intervention. Absolute reconstruction failure was an MRC requiring surgical removal of BR. A routine revision (RR) was a plastic surgery refining cosmesis of the BR. Kaplan-Meier method was used to assess disease outcomes and MRC. Cox regression was used to assess predictors of MRC., Results: Seventy-three courses of PMPRT were delivered to 68 women with BR between 2013 and 2021. Median follow-up was 42.1 months. Median age was 47 years. Fifty-six (76.7%) courses used pencil beam scanning PMPRT. Of 73 BR, 29 were flaps (39.7%), 30 implants (41.1%), and 14 TE (19.2%) at time of irradiation. There were 20 (27.4%) RR. There were 9 (12.3%) MRC among 5 implants, 2 flaps, and 2 TE, occurring a median of 29 months from PMPRT start. Three-year freedom from MRC was 86.9%. Three (4.1%) of the MRC were absolute reconstruction failure. Complications leading to MRC included capsular contracture in 5, fat necrosis in 2, and infection in 2. On univariable analysis, BR type, boost, proton technique, age, and smoking status were not associated with MRC, whereas higher body mass index trended toward significance (hazard ratio, 1.07; 95% CI, 0.99-1.16; P = .10)., Conclusions: Patients undergoing PMPRT to BR had a 12.3% incidence of major complications leading to surgical intervention, and total loss of BR was rare. MRC rates were similar among reconstruction types. Minor surgery for RR is common in our practice., Competing Interests: Taoran Li reports grant and honoraria for Varian Medical System and consulting for Boston Scientific. Neil K. Taunk reports grants from Varian Medical Systems and Therapanacea, consulting for Boston Scientific and Point Biopharma, honoraria for Boston Scientific, and an advisory board role for Point Biopharma and Varian Medical Systems., (© 2023 The Authors.)

Purpose: We report the results of a phase 1/2 trial of external beam partial breast radiation using proton therapy., Methods and Materials: Eligible patients included stage 0-IIA breast cancer pTis-T2, N0, and size ≤3 cm. Proton beam radiation was used to deliver 3.85 Gy twice daily to 38.5 Gy. The phase 1 portion determined feasibility based on criteria of successful plan creation, treatment delivery, and acute toxicity grade ≥3 in ≤20% of patients. The phase 2 portion had efficacy goals of acute toxicity grade ≥3 in ≤20% of patients and observing physician-rated cosmesis of excellent or good >85% of patients at 2 years., Results: From April 2013 to March 2015, there were 12 patients enrolled onto the phase 1 portion, and the preplanned analysis of feasibility was met in all 4 required criteria. From July 2015 through December 2019 there were 28 patients with 29 treated breasts (1 bilateral) enrolled onto the phase 2 portion of the trial out of 45 originally planned. The trial was closed to accrual because of the coronavirus pandemic and not reopened. Thirty-eight breasts were treated with double-scattering and 3 pencil-beam scanning protons. The median follow-up of the 40 patients is 5.4 years (range, 2.3-8.6 years). There was 1 local recurrence. There was no grade ≥3 acute or late toxicity. At baseline all patients had physician-rated cosmesis good or excellent but at 2 years was excellent in 56%, good in 19%, and fair in 25%., Conclusions: Proton-accelerated partial breast irradiation delivered with a twice-daily fractionation was feasible and associated with very low acute and long-term toxicity. However, the trial did not meet goals for cosmesis outcomes and was closed prematurely. Future study is needed to determine whether pencil-beam scanning protons or different fractionation could improve these outcomes., Competing Interests: Taoran Li reports a grant and honorarium from Varian Medical Systems, and a consulting fee from Boston Scientific. Neil K. Taunk reports a grant from Varian Medical Systems, as well as a consulting fee and honorarium from Boston Scientific., (© 2023 The Author(s).)

Purpose: Optimal integration of local therapy and systemic immune therapy for patients with mucosal melanoma (MM) is uncertain. We evaluated treatment patterns and outcomes following radiation therapy (RT) in combination with immune checkpoint inhibition (ICI) in MM., Methods and Materials: Thirty-seven patients with localized (n = 32, 87%) or node-positive (n = 5, 14%) MM were treated across 4 institutions with RT to the primary tumor with or without oncologic resection (n = 28, 76%) and ICI from 2012 to 2020. Recurrence rates were estimated using cumulative incidence in the presence of the competing risk of death., Results: Mucosal sites were head/neck (n = 29, 78%), vaginal (n = 7, 19%), and anorectal (n = 1, 3%). Patients received ICI prior to or concurrent with RT (n = 14, 38%), following RT (n = 5, 14%), or at recurrence (n = 18, 49%). The objective response rate for evaluable patients was 31% for ICI as initial treatment (95% CI, 11%-59%) and 19% for ICI at recurrence (95% CI, 4%-46%). Median follow-up was 26 months for living patients; median overall survival (OS) was 54 months (95% CI, 31 months-not reached). Two-year OS was 85%; distant metastasis-free survival 44%. The 2-year cumulative incidence of local recurrence (LR) was 26% (95% CI, 13%-41%). For 9 patients with unresectable disease, 2-year OS was 88% (95% CI, 35%-98%); LR was 25% (95% CI, 3%-58%). For 5 patients with positive nodes at diagnosis, 2-year OS was 100%; LR was 0%., Conclusions: High rates of local control were achieved with RT with or without oncologic resection and ICI for localized and locally advanced MM. In particular, favorable local control was possible even for patients with unresectable or node-positive disease. Although risk of distant failure remains high, patients with MM may benefit from aggressive local therapy including RT in the setting of immunotherapy treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: The COVID-19 pandemic has placed demands and limitations on the delivery of health care. We sought to assess the effect of COVID-19 on the delivery of gynecologic oncologic care from the perspective of practicing radiation oncologists in the United States., Methods and Materials: An anonymous online survey was created and distributed to preidentified radiation oncologists in the United States with clinical expertise in the management of gynecologic patients. The survey consisted of demographic questions followed by directed questions to assess specific patterns of care related to the COVID-19 pandemic., Results: A total of 47 of 96 invited radiation oncologists responded to the survey for a response rate of 49%. Fifty-six percent of respondents reported an increase in locally advanced cervical cancer with no similar increase for endometrial, vulvar, or vaginal patients. Most respondents (66%) reported a pause in surgical management, with a duration of 1 to 3 months being most common (61%). There was a reported increased use of shorter brachytherapy regimens during the pandemic. Most providers (61%) reported caring for at least 1 patient with a positive COVID-19 test. A pause or delay in treatment due to COVID-19 positivity was reported by 45% of respondents, with 55% reporting that patients chose to delay their own care because of COVID-19-related concerns. Total treatment times >8 weeks for patients with cervical cancer were observed by 33% of respondents, but occurred in >25% of patients., Conclusions: Data from this prospectively collected anonymous survey of practice patterns among radiation oncologists reveal that the COVID-19 pandemic resulted in delays initiating care, truncated brachytherapy treatment courses, and a reported increase in locally advanced cervical cancer cases at presentation. These data can be used as a means of self-assessment to ensure appropriate decision making for gynecologic patients during the endemic phase of COVID-19., (© 2023 The Authors.)

Objective: To characterize long-term toxicity and disease outcomes with whole pelvis (WP) pencil beam scanning proton radiation therapy (PBS PRT) for gynecologic malignancies., Methods: We reviewed 23 patients treated from 2013 to 2019 with WP PBS PRT for endometrial, cervical, and vaginal cancer. We report acute and late Grade (G)2+ toxicities, graded by Common Terminology Criteria for Adverse Events, Version 5. Disease outcomes were assessed by Kaplan-Meier method., Results: Median age was 59 years. Median follow up was 4.8 years. 12 (52.2%) had uterine cancer, 10 (43.5%) cervical, 1 (4.3%) vaginal. 20 (86.9%) were treated post-hysterectomy. 22 (95.7%) received chemotherapy, 12 concurrently (52.2%). The median PBS PRT dose was 50.4GyRBE (range, 45-62.5). 8 (34.8% had para-aortic/extended fields. 10 (43.5%) received brachytherapy boost. Median follow up was 4.8 years. 5-year actuarial local control was 95.2%, regional control 90.9%, distant control 74.7%, both disease control and progression-free survival 71.2%. Overall survival was 91.3%. In the acute period, 2 patients (8.7%) had G2 genitourinary (GU) toxicity, 6 (26.1%) had gastrointestinal (GI) G2-3 toxicity, 17 (73.9%) had G2-4 hematologic (H) toxicity. In the late period, 3 (13.0%) had G2 GU toxicity, 1 (4.3%) had G2 GI toxicity, 2 (8.7%) had G2-3H toxicity. The mean small bowel V15Gy was 213.4 cc. Mean large bowel V15 Gy was 131.9 cc., Conclusions: WP PBS PRT for gynecologic malignancies delivers favorable locoregional control. Rates of GU and GI toxicity are low. Acute hematologic toxicity was most common, which may be related to the large proportion of patients receiving chemotherapy., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Delays in starting potentially curative treatment for locally-advanced cervical cancer (LACC) decrease survival. Reasons for these delays are poorly understood. We conducted a retrospective chart review examining disparities in time from diagnosis of LACC to first clinic visit and to initiation of treatment based on insurance status within a single health system. We analyzed time to treatment using multivariate regression, adjusted for race, age, and insurance status. 25% of patients had Medicaid and 53% had private insurance. Having Medicaid was associated with delayed time from diagnosis to seeing a radiation oncologist (Mean 76.9 v. 31.3 days, p = 0.03). However, time from first radiation oncology visit to starting radiation was not delayed (Mean 22.6 v. 22.2 days, p = 0.67). Patients with locally-advanced cervical cancer and Medicaid had over double the time from pathologic diagnosis of cervical cancer to seeing radiation oncology; insurance disparities were not observed in treatment start after seeing radiation oncology. Improved referral and navigation processes for patients with Medicaid are needed to improve timely receipt of radiation and potentially improve survival., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)

Purpose: Positron emission tomography (PET)/computed tomography (CT) has become a critical tool in clinical oncology with an expanding role in guiding radiation treatment planning. As its application and availability grows, it is increasingly important for practicing radiation oncologists to have a comprehensive understanding of how molecular imaging can be incorporated into radiation planning and recognize its potential limitations and pitfalls. The purpose of this article is to review the major approved positron-emitting radiopharmaceuticals clinically being used today along with the methods used for their integration into radiation therapy including methods of image registration, target delineation, and emerging PET-guided protocols such as biologically-guided radiation therapy and PET-adaptive therapy., Methods and Materials: A review approach was utilized using collective information from a broad review of the existing scientific literature sourced from PubMed search with relevant keywords and input from a multidisciplinary team of experts in medical physics, radiation treatment planning, nuclear medicine, and radiation therapy., Results: A number of radiotracers imaging various targets and metabolic pathways of cancer are now commercially available. PET/CT data can be incorporated into radiation treatment planning through cognitive fusion, rigid registration, deformable registration, or PET/CT simulation techniques. PET imaging provides a number of benefits to radiation planning including improved identification and delineation of the radiation targets from normal tissue, potential automation of target delineation, reduction of intra- and inter-observer variability, and identification of tumor subvolumes at high risk for treatment failure which may benefit from dose intensification or adaptive protocols. However, PET/CT imaging has a number of technical and biologic limitations that must be understood when guiding radiation treatment., Conclusion: For PET guided radiation planning to be successful, collaboration between radiation oncologists, nuclear medicine physicians, and medical physics is essential, as well as the development and adherence to strict PET-radiation planning protocols. When performed properly, PET-based radiation planning can reduce treatment volumes, reduce treatment variability, improve patient and target selection, and potentially enhance the therapeutic ratio accessing precision medicine in radiation therapy., (© 2023 The Authors.)

Objective: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma., Materials and Methods: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27., Results: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients., Conclusions: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

For decades, the distant progression of breast cancer has been the purview of systemic therapy alone or with low to moderate-dose radiation therapy intended for the palliation of symptomatic metastases. However, for decades there have been anecdotes of long-term disease-free survival with more aggressive local treatment of one or more metastases. The hypothesis of oligometastases is that the treatment of a clinically limited number of distant metastases can change the natural history of stage IV breast cancer. The advance in the technology of stereotactic body radiation (SBRT) has made it more possible to offer a non-invasive, yet potentially disease-modifying, metastases-directed ablative treatment in place of surgery or a palliative radiation regimen. Although there are promising local control and survival outcomes in phase I/II trials, there is still a lack of phase III evidence of ablative SBRT results showing any change in the natural history of metastatic breast cancer. Limited oligometastases may call for an ablative approach with SBRT when definitive long-term local control is needed for the best palliation against symptomatic progression in challenging locations. Some oligometastases that have progression on a certain systemic regimen, while others remain stable or in remission, may also be treated with SBRT in the hopes of prolonging the use of that regimen. Whether SBRT should represent the standard management for stage IV breast cancer of a limited number or of limited progression requires confirmation by phase III data. This review will discuss the data from key clinical trials as it applies to decision making in typical clinical cases considered for potentially ablative SBRT for oligometastases or oligoprogression.

Purpose: Compared with conventional external-beam radiation therapy (cEBRT) for patients with breast cancer (BC) and prostate cancer (PC), shorter radiation regimens may be associated with lower treatment noncompletion rates. We assess disparities in receipt of shorter radiation regimens and treatment noncompletion for BC and PC., Patients and Methods: The 2004-2017 National Cancer Database was queried for adjuvant cEBRT or hypofractionated EBRT (hEBRT) for nonmetastatic BC; and definitive cEBRT, moderate hypofractionation (mEBRT), or stereotactic body radiotherapy (SBRT) for localized PC. Multivariable logistic regression identified factors associated with treatment noncompletion and receipt of shorter regimens., Findings: We identified 170,386 men with PC (median age [interquartile range], 70 [64-75] years; Black, 17.5%; White, 82.5%) and 306,846 women with BC (61 [52-69] years; Black, 12.3%; White, 87.7%). Among patients who received cEBRT for PC, Black men had higher treatment noncompletion rates compared with White (14.1% v 13.0%; odds ratio [95% CI] 1.07 [1.03 to 1.12]; P < .001). In contrast, treatment noncompletion was not disparate with SBRT (Black 1.6% v White 1.3%; 1.20 [0.72 to 2.00], P = .49) or mEBRT (Black 9.0% v White 7.1%; 1.05 [0.72 to 1.54], P = .79). From 2004 to 2017, SBRT (0.07% to 11.8%; 1.32 [1.31 to 1.33]) and mEBRT (0.35% to 9.1%; 1.27 [1.25 to 1.28]) increased (both P < .001); however, Black men were consistently less likely to receive SBRT (7.4% v White, 8.3%; 0.84 [0.79 to 0.89], P < .001). Among women with BC, there were no racial differences in treatment noncompletion; however, hEBRT was associated with lower treatment noncompletion rates (1.0% v cEBRT 2.3%; 0.39 [0.35 to 0.44], P < .001). Although hEBRT for BC increased (0.8% to 35.6%) between 2004 and 2017, Black women were less likely to receive hEBRT (10.4% v 15.3%; 0.78 [0.75 to 0.81], P < .001)., Interpretation: Black patients were consistently less likely to receive hypofractionated radiation for PC or BC, despite evidence suggesting that shorter regimens may lower rates of treatment noncompletion with similar oncologic outcomes.

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma., Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT., Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2)., Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study., (© 2022 The Authors.)

Introduction: Proton radiation therapy (PBT) may reduce cardiac doses in breast cancer treatment. Limited availability of proton facilities could require significant travel distances. This study assessed factors associated with travel distances for breast PBT., Materials and Methods: Patients receiving breast PBT at the University of Pennsylvania from 2010 to 2021 were identified. Demographic, cancer, and treatment characteristics were summarized. Straight-line travel distances from the department to patients' addresses were calculated using BatchGeo. Median and mean travel distances were reported. Given non-normality of distribution of travel distances, Wilcoxon rank sum or Kruskal-Wallis test was used to determine whether travel distances differed by race, clinical trial participation, disease laterality, recurrence, and prior radiation., Results: Of 1 male and 284 female patients, 67.8% were White and 21.7% Black. Median travel distance was 13.5 miles with interquartile range of 6.1 to 24.8 miles, and mean travel distance was 13.5 miles with standard deviation of 261.4 miles. 81.1% of patients traveled less than 30 and 6.0% more than 100 miles. Black patients' travel distances were significantly shorter than White patients' and non-Black or non-White patients' travel distances (median = 4.5, 16.5, and 11.3 miles, respectively; P < .0001). Patients not on clinical trials traveled more those on clinical trials (median = 14.7 and 10.2 miles, respectively; P = .032). There was no difference found between travel distances of patients with left-sided versus right-sided versus bilateral disease ( P = .175), with versus without recurrent disease ( P = .057), or with versus without prior radiation ( P = .23)., Conclusion: This study described travel distances and demographic and clinicopathologic characteristics of patients receiving breast PBT at the University of Pennsylvania. Black patients traveled less than White and non-Black or non-White patients and comprised a small portion of the cohort, suggesting barriers to travel and PBT. Patients did not travel further to receive PBT for left-sided or recurrent disease., Competing Interests: Conflicts of Interest: The authors have no relevant conflicts of interest to disclose., (©Copyright 2022 The Author(s).)

Objectives: Evaluate whether the addition of external beam radiation (EBRT) to adjuvant chemotherapy with or without vaginal brachytherapy is associated with better survival for patients with stage IIIC endometrioid endometrial carcinoma., Materials and Methods: Patients diagnosed between 2010 and 2015 with apparent early-stage endometrioid adenocarcinoma, without a history of another tumor, who underwent hysterectomy with lymphadenectomy and had positive lymph nodes were identified in the National Cancer Database. Those who received adjuvant chemotherapy (defined as receipt of treatment within 6 mo from surgery) and had at least 1 month of follow-up were selected for further analysis. Overall survival was compared between patients who did and did not receive EBRT within 6 months from surgery with the log-rank test. A Cox model was also constructed to control for confounders., Results: A total of 3116 patients were identified; 1458 (46.8%) received chemotherapy without and 1658 (53.2%) with EBRT. Pathologic characteristics (tumor grade, size, endocervical, and lymph-vascular invasion) were comparable between the two groups. Patients who received external beam radiation had better survival compared with those who did not, P =0.001; 5-year overall survival rates were 83.1% and 77.9%, respectively. After controlling for patient age, race, presence of comorbidities, insurance status, tumor size, grade and endocervical invasion, and the presence of lymph-vascular invasion, the addition of EBRT was associated with a survival benefit (HR: 0.75, 95% CI: 0.62, 0.91)., Conclusions: For patients with endometrioid adenocarcinoma metastatic to the lymph nodes, addition of external beam radiation to adjuvant chemotherapy may be associated with a survival benefit., Competing Interests: R.L.G.: medical monitor for CAPRI trial by Astra Zeneca. A.F.H.: GSK research fund, GSK advisory board, honoraria for Axess ovarian cancer lecture. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We aimed to evaluate the utilization and impact of surgical para-aortic lymph node staging on the survival of patients with locally advanced stage cervical carcinoma receiving definitive chemoradiation., Methods: We identified patients in the National Cancer Database diagnosed between January 2010 and December 2015 with locally advanced (FIGO 2009 stage IB2-IVA) cervical carcinoma who did not undergo hysterectomy, received primary chemoradiation and had at least 1 month of follow-up. Two groups of patients were formed based on the assessment method of para-aortic lymph node status - radiologic assessment only versus surgical lymphadenectomy. Overall survival was compared with the log-rank test after Kaplan-Meier curves were generated. A Cox model was constructed to control for a priori selected confounders., Results: We identified a total of 3540 patients who met the inclusion criteria. Para-aortic staging was performed in 333 (9.4%) patients. These patients were younger (median age 46 vs 52 years, p<0.001), less likely to have co-morbidities (8.7% vs 15.6%, p<0.001), more likely to have private insurance (48.9% vs 37.8%, p<0.001) and receive brachytherapy (76.9% vs 70.9%, p=0.022). The rate of para-aortic lymphadenectomy was comparable between patients with stage IB2-II and III-IVA disease (9.4% for both groups, p=0.98). Patients who underwent para-aortic lymphadenectomy were also more likely to have lymph nodes categorized as positive compared with those who had imaging only (27.3% vs 13.2%, p<0.001). There was no difference in overall survival between patients who underwent radiologic only or surgical para-aortic lymph node assessment (p=0.80 from log-rank test); 4 year overall survival rates were 62.9% and 63%. After controlling for confounders, performance of para-aortic lymphadenectomy was not associated with a survival benefit (HR 1.07, 95% CIs: 0.88 to 1.31)., Conclusions: In a large cohort of patients with locally advanced stage cervical carcinoma, para-aortic lymphadenectomy was rarely performed and not associated with a survival benefit., Competing Interests: Competing interests: None related to this study RL: medical monitor for CAPRI trial by Astra ZenecaAH: GSK research fund, GSK advisory board, Honoraria: Axess ovarian cancer lecture., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To present recommendations for the use of imaging for evaluation and procedural guidance of brachytherapy for cervical cancer patients., Methods: An expert panel comprised of members of the Society of Abdominal Radiology Uterine and Ovarian Cancer Disease Focused Panel and the American Brachytherapy Society jointly assessed the existing literature and provide data-driven guidance on imaging protocol development, interpretation, and reporting., Results: Image-guidance during applicator implantation reduces rates of uterine perforation by the tandem. Postimplant images may be acquired with radiography, computed tomography (CT), or magnetic resonance imaging (MRI), and CT or MRI are preferred due to a decrease in severe complications. Pre-brachytherapy T2-weighted MRI may be used as a reference for contouring the high-risk clinical target volume (HR-CTV) when CT is used for treatment planning. Reference CT and MRI protocols are provided for reference., Conclusions: Image-guided brachytherapy in locally advanced cervical cancer is essential for optimal patient management. Various imaging modalities, including orthogonal radiographs, ultrasound, computed tomography, and magnetic resonance imaging, remain integral to the successful execution of image-guided brachytherapy., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation., Materials and Methods: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling., Results: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31)., Conclusion: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations., Competing Interests: James M. MetzConsulting or Advisory Role: Varian Medical Systems, IBAResearch Funding: Varian Medical Systems (Inst) Arun GoelEmployment: Flatiron Health (I), Capsule (I)Stock and Other Ownership Interests: Amgen (I), Pfizer (I), Moderna Therapeutics (I), Gilead Sciences (I) Neil K. TaunkHonoraria: Sensus HealthcareConsulting or Advisory Role: Boston Scientific, Indemolecule LLC John N. LukensResearch Funding: Merck (Inst) Abigail T. BermanEmployment: CVS HealthHonoraria: Varian Medical Systems, ImedexConsulting or Advisory Role: AstraZenecaResearch Funding: Merck (Inst)Travel, Accommodations, Expenses: Varian Medical SystemsOpen Payments Link: https://openpaymentsdata.cms.gov/physician/939528 Andrzej P. WojcieszynskiConsulting or Advisory Role: Gerson Lehrman GroupResearch Funding: Philips HealthcareNo other potential conflicts of interest were reported.

Background: Nurse-led education can improve patient satisfaction, and telemedicine has increased patient access during the COVID-19 pandemic., Objectives: The aim of this article was to investigate how nursing telemedicine educational visits influence patient satisfaction., Methods: Patients receiving standard of care in-person education for breast cancer radiation therapy (RT) between January 2019 and June 2019 comprised the preintervention cohort. After July 2019, patients received the same information virtually and represented the postintervention cohort. Press Ganey surveys were used to evaluate patient satisfaction, t tests were performed to differentiate satisfaction scores, and f tests were calculated to determine differences in the variances of response., Findings: Patient satisfaction increased in the postintervention cohort for what to expect during RT, how to manage side effects, and nurses' attentiveness to patient questions and worries. There was decreased variance in patient satisfaction in the postintervention group for quality of care received from nurses and caring manner of nurses.

Purpose: To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC)., Methods and Materials: A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes., Results: A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79)., Conclusions: Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Introduction: Cyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition., Methods: We conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging., Results: Thirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8-40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months., Conclusions: The use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: National guidelines specify against immediate breast reconstruction (IBR) among inflammatory breast cancer (IBC) patients. However, limited data exist regarding this practice. We report practice patterns and oncologic outcomes among nonmetastatic IBC patients receiving trimodality therapy, with or without IBR., Methods: Using the National Cancer Database, we identified nonmetastatic IBC patients treated with trimodality therapy from 2004 to 2016. Primary outcome was overall survival (OS), assessed on unadjusted analysis using Kaplan-Meier estimates and on adjusted analysis using multivariable Cox proportional hazards and inverse probability weighting (IPW) models. OS analysis was also conducted with propensity score matched (PSM) cohorts. Secondary outcomes included IBR utilization rates, time to postmastectomy radiotherapy (PMRT), and surgical outcomes., Results: 6589 women were included, including 5954 (90.4%) non-reconstructed and 635 (9.6%) IBR. Among IBR recipients, 250 (39.4%) underwent autologous reconstruction, 171 (26.9%) underwent implant-based reconstruction, and 214 (33.7%) unspecified. IBR utilization increased from 6.3% to 10.1% from 2004 to 2016 at a 4% average annual growth rate (P < 0.001). Median follow-up was 43 and 45 months for IBR and non-reconstructed patients, respectively (P = 0.29). On Cox multivariable analysis, IBR was associated with improved OS (HR 0.63, 95% CI 0.44-0.90, P = 0.01), but this association was not significant on IPW analysis (P = 0.06). In PSM cohorts, this association remained significant (HR 0.60, 95% CI 0.40-0.92, P = 0.02). Margin status, time to PMRT, 30-day readmission, and 30-/90-day mortality did not differ between groups (all P > 0.05)., Conclusion: Although not endorsed by national guidelines, IBR is increasing among IBC patients; however, more granular data are needed to determine oncologic safety., (© 2021. Society of Surgical Oncology.)

Purpose: Hybrid intracavitary and interstitial (IC/IS) applicators improve dose distribution compared to traditional IC applicators in cervical high-dose-rate (HDR) brachytherapy. There is a learning curve to these applicators, and initial standard needle insertion patterns have not been well-established. In this study, we quantified dosimetric benefits of IC/IS applicators, and offer practical initial interstitial needle-selection, insertion depths, and dwell position recommendations., Material and Methods: Fifteen patients previously treated with a tandem and ring IC applicator and magnetic resonance (MR)-guidance were re-planned at first fraction using a digital template of Vienna-style interstitial needles. IC/IS plans maintained identical high-risk clinical target volume (HR-CTV) D 90% while reducing dose to organs at risk (OARs). To assess the validity of planning using virtual needles, virtual needle templates were overlaid on twelve clinical IC/IS plans, and the displacements between 40 physical and virtual needles were measured at 3 cm depth., Results: The median HR-CTV volume in the present study was 19.6 cc (range, 6.6-60.5 cc). HR-CTV D 90% was maintained in all re-plans. Median bladder D 2cc decreased from 5.4 Gy per fraction to 4.8 Gy ( p = 0.003); median rectum D 2cc decreased from 2.4 Gy per fraction to 2.0 Gy ( p = 0.007). We suggest that a standard loading pattern should include needles in lateral channels 4, 5, and 9, 10 inserted 3 cm deep, with dwell times < 20% of the combined tandem and ring dwells. The mean displacement between planned and physical needles was 1.8 mm. All needles but three deviated less than 3.3 mm, demonstrating the validity of re-planning with virtual needles., Conclusions: Hybrid IC/IS applicators maintain excellent D 90% coverage while improving dose to OARs compared to IC-only applicators, even in non-bulky HR-CTVs. We offer practical recommendations for needle selection, insertion depth, and relative weighting for Vienna-style applicators in small HR-CTVs. These results support previous publications, offering practical recommendations for users of Vienna-style hybrid applicators., Competing Interests: NKT reports advisory board fee from the Varian Medical Systems and consulting from the Boston Scientific. Institutional review board approval was required and granted., (Copyright © 2021 Termedia.)

Purpose: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes., Methods and Materials: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method., Results: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P < .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P < .0001., Conclusions: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Intracavitary brachytherapy is critical in treatment of cervical cancer with the highest rates of local control and survival. Only about 50% of graduating residents express confidence to develop a brachytherapy practice with caseload as the greatest barrier. We hypothesize that virtual reality (VR)-based intracavitary brachytherapy simulation will improve resident confidence, engagement, and proficiency., Methods: We created a VR training video of an intracavitary brachytherapy case performed by a board-certified gynecologic radiation oncologist and medical physicist. Residents performed a timed intracavitary procedure on a pelvic simulator before and after viewing the VR simulation module on a commercially available VR headset while five objective measures of implant quality were recorded. The residents completed a pre- and postsimulation questionnaire assessing self-confidence, procedural knowledge, and perceived usefulness of the session., Results: There were 14 residents, including five postgraduate year (PGY)-2, three PGY-3, four PGY-4, and two PGY-5, who participated in the VR curriculum. There were improvements in resident confidence (1.43-3.36), and subjective technical skill in assembly (1.57-3.50) and insertion (1.64-3.21) after the simulation. Average time of implant decreased from 5:51 to 3:34 (p = 0.0016). Median technical proficiencies increased from 4/5 to 5/5. Overall, the residents found VR to be a useful learning tool and indicated increased willingness to perform the procedure again., Conclusions: VR intracavitary brachytherapy simulation improves residents' self-confidence, subjective and objective technical skills, and willingness to perform brachytherapy. Furthermore, VR is an immersive, engaging, time-efficient, inexpensive, and enjoyable tool that promotes residents interest in brachytherapy., (Copyright © 2021 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Local-regional recurrence (LRR) of breast cancer after prior adjuvant radiation (RT) can present a clinical challenge. Proton therapy is recommended by the American Society for Radiation Oncology in cases where reirrradiation is needed; however, data are limited. We present the toxicity and outcomes after reirradiation for local-regional recurrence of breast cancer with proton therapy., Methods and Materials: A single-institution retrospective review identified patients with the following criteria: LRR of breast cancer, prior photon radiation to the same region, proton beam reirradiation, and definitive intent. Surgery or systemic therapy at the time of recurrence was used when indicated. The log-rank test was used to compare Kaplan-Meier survival estimates. Kruskal-Wallis tests were performed to compare worst reported toxicities with clinical variables., Results: The population included 27 patients with a history of prior radiation and treated with proton therapy for LRR between 2012 and 2019. The median interval between courses was 9.7 years. Proton reirradiation regimens included whole breast/chest wall (WB/CW) with regional nodal RT (22/27), nodal RT alone (2/27), or WB/CW alone (3/27). The median dose was 51 Gy, and the most common fractionation was 1.5 Gy twice daily. Median follow-up after reirradiation was 16.6 months. Acute grade 3 toxicities included dermatitis in 2 patients and breast pain in 2 patients. Grade 2 or higher late toxicities included 6 G2 rib fractures and 1 G2 brachial plexopathy, 1 G3 dermatitis, 1 G3 breast pain, and 1 G4 dermatitis. Twelve patients had new documented recurrences of which 1 was a second in-field LRR, and there were 7 deaths., Conclusions: Proton salvage reirradiation to median 51 Gy in 1.5 Gy twice daily appears to be safe with acceptable acute and late toxicity, and effective with >95% local-regional control., (© 2021 The Authors.)

Purpose: To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD)., Methods and Materials: In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function., Results: The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function., Conclusions: With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease., (Copyright © 2020. Published by Elsevier Inc.)

Context: Advanced gynecologic malignancies can cause significant vaginal bleeding. Radiotherapy (RT) is often used to palliate symptoms, but limited data exist concerning the optimal dose and expected time to bleeding hemostasis in this population., Objectives: 1) To investigate the overall hemostasis response and kinetics of hemostasis in women with gynecologic malignancies receiving palliative RT. 2) To compare the efficacy of short-course RT (SCRT, less than or equal to five fractions, >3.5 Gy per fraction) vs. conventionally fractionated long-course regimens (greater than five fractions)., Methods: We identified women receiving palliative RT for bleeding gynecologic malignancies. Initial and maximal hemostasis responses (IHR and MHR) were recorded and categorized as progressive bleeding (PD), stable disease (SD), partial response (PR), or complete response (CR). Clinical variables were correlated with response or toxicity using binary logistic regression statistical methods., Results: Thirty-three women (median age 63) were identified between 2010 and 2019. Median follow-up and survival after RT were 131 days. About 54.5% (18 of 33) received SCRT. Median time to IHR was five days (two-and-a-half days with SCRT) and 78.8% (26 of 33) responded during treatment. Median time to MHR was 13 days. About 100% achieved PR or CR at MHR. Rates of CR were similar between SCRT (83%) and conventionally fractionated schedules (87%). Average durability of hemostatic control was 5.4 months. Overall rate of rebleeding and Grade 3+ toxicity was 9.1% (3 of 33 each)., Conclusion: Women receiving SCRT for bleeding gynecologic malignancies achieved rapid symptom control (often during treatment) with minimal rebleeding. In a population whose median survival is four months, SCRT effectively addresses symptomatic disease while minimizing patient burden and toxicity., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies., Methods and Materials: A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing., Results: Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response ( P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions ( P = .049). Bony sites were associated with worse clinical ( P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%)., Conclusions: PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen., (© 2020 The Author(s).)

Background: This study investigates daily breast geometry and delivered dose to prone-positioned patients undergoing tangential whole breast radiation therapy (WBRT) on an O-ring linear accelerator with 6X flattening filter free mode (6X-FFF), planned with electronic compensation (ECOMP) method. Most practices rely on skin marks or daily planar image matching for prone breast WBRT. This system provides low dose daily CBCT, which was used to study daily robustness of delivered dose parameters for prone-positioned WBRT., Methods: Eight patients treated with 16-fraction prone-breast WBRT were retrospectively studied. Planning CTs were deformed to daily CBCT to generate daily synthetic CTs, on which delivered dose distributions were calculated. A total of 8 × 16 = 128 synthetic CTs were generated. Consensus ASTRO definition was used to contour Breast PTV Eval for each daily deformed CT. Breast PTV Eval coverage (V90%) and hotspot (V105% and Dmax) were monitored daily to compare prescription dose with daily delivered dose. Various predictors including patient weight, breast width diameter (BWD), and Dice similarity coefficient (DSC) were fit into an analysis of covariance model predicting V90% and V105% deviation from prescribed (ΔV90%, ΔV105%). Statistical significance is indicated with asterisks (* for p < 0.05; ** for p < 0.001)., Results: Daily delivered Breast PTV Eval V90% was moderately smaller than prescribed (median ΔV90% = - 0.1%*), while V105% was much larger (median ΔV105% = + 10.1%** or + 92.4 cc**). Patient's weight loss correlated with significantly increased ΔV105% (+ 4.6%/ - 1% weight, R 2  = 0.4**) and moderately decreased ΔV90% (- 0.071%/ - 1% wt., R 2  = 0.2**). Comprehensive ANCOVA models indicated three factors affect ΔV90% and ΔV105% the most: (1) BWD decrease (- 0.09%* and + 10%**/ - 1 cm respectively), (2) PTV Eval volume decrease (- 0.4%** and + 9%**/ - 100 cc), and for ΔV105% only, (3) the extent of breast deformation (+ 10%**/ - 0.01 DSC). Breast PTV Eval volume also decreased with time (- 2.21*cc/fx), possibly indicating seroma resolution and increase in V105% over time., Conclusions: Daily CBCT revealed key delivered dose parameters vary significantly for patients undergoing tangential prone breast WBRT planned with ECOMP using 6X-FFF. Patient weight, BWD, and breast shape deformation could be used to predict dosimetric variations from prescribed. Preliminary findings suggest an adaptive plan based on daily CBCT could reduce excessive dose to the breast.

Objective: To assess the efficacy and safety of stereotactic body radiation therapy (SBRT) for oligometastatic gynecologic malignancies., Method: A comprehensive search of the PubMed, Medline, and EMBASE databases was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. "Oligometastatic" was defined as a limited number of uncontrolled/untreated metastatic lesions (typically ≤ 5), including regional nodal metastases. Primary outcomes were response rate (complete response or partial response), local control of oligometastatic lesions, and toxicity., Results: Of 716 screened records, 17 studies (13 full length articles, 4 conference abstracts) were selected and analyzed as 16 unique studies. A total of 667 patients were treated with ~1071 metastatic lesions identified. Primary sites included ovarian (57.6%), cervical (27.1%), uterine (11.1%), vaginal (0.4%), vulvar (0.3%), and other/unspecified (3.4%). Most patients (65.4%) presented with a single metastatic lesion. Metastatic lesion sites included the abdomen (44.2%), pelvis (18.8%), thorax (15.5%), neck (4.6%), central nervous system (4.3%), bone (1.6%), and other/unspecified (11%). Of the lesions, 64% were nodal. Response rate (among 8 studies) ranged from 49% to 97%, with 7/8 studies reporting > 75% response rate. Local control ranged from 71% to 100%, with 14/16 studies reporting ≥ 80% local control. No grade ≥ 3 toxicities were observed in 9/16 (56%) studies. Median progression-free survival (PFS) (among 10 studies) ranged from 3.3 months to 21.7 months. Disease progression most commonly occurred outside of the SBRT radiation field (79% to 100% of failures)., Conclusions: SBRT for oligometastatic gynecologic malignancies is associated with favorable response and local control rates but a high rate of out-of-field progression and heterogeneous PFS. Additional study into rational combinations of SBRT and systemic therapy appears warranted to further improve patient outcomes., Competing Interests: Declaration of Competing Interest S.K. Jabbour has research funding from Merck and Nestle, outside of the submitted work. The remaining authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Cancer-related fatigue (CRF), a prevalent symptom among cancer patients, is a side effect of external beam radiation therapy (EBRT). Even when targeting organs unrelated to caloric intake or the central nervous system, radiation therapy can increase CRF, a poorly understood toxicity resulting from patient-specific, systemic therapy-related, and radiation-specific factors. We sought to determine factors associated with fatigue among patients receiving EBRT for breast cancer., Methods and Materials: To determine the variables associated with fatigue among patients with nonmetastatic breast cancer, we retrospectively analyzed prospectively collected toxicity data for a cohort of 1286 adult females with breast cancer who began curative-intent EBRT between April 4, 2010, and October 10, 2017. We hypothesized certain variables are associated with provider-reported Common Terminology Criteria for Adverse Events version 4 fatigue, graded 0 to 3, at baseline and over the course of radiation treatment., Results: All patients were women, with a median age of 57 (range, 24-90). Mean fatigue was low (0.35 [95% confidence interval, 0.32-0.38]) at the start of radiation, increasing weekly and peaking at week 6 (0.85 [0.81-0.90]). Baseline fatigue was associated with higher American Joint Committee on Cancer stage (P < .001), N-stage (P < .001), anxiolytics (P < .001), anticonvulsants (P = .002), antidepressants (P = .006), antihistamines (P < .001), and antipsychotics (P < .001). Chemotherapy was not associated with baseline fatigue. Over the course of treatment, on multivariable analysis, only lower dose per fraction (P < .001) was significantly associated with increasing fatigue. In a subgroup analysis, heart and lung mean, V5, and V20 doses were not found to be associated with increasing fatigue., Conclusions: This work informs clinicians which factors are associated with CRF at the start of radiation therapy (more advanced disease and prescription of anxiolytics, anticonvulsants, antidepressants, antihistamines, and antipsychotics) and increase CRF over the course of radiation (smaller fraction size). This extensive analysis of factors associated with fatigue provides further evidence that hypofractionated radiation therapy for breast cancer is associated with less acute toxicity than conventionally fractionated treatment., (Copyright © 2020 American Society for Radiation Oncology. All rights reserved.)

Purpose: Safe delivery of brachytherapy and establishing a safety culture are critical in high-quality brachytherapy. The American Brachytherapy Society (ABS) Quality and Safety Committee surveyed members regarding brachytherapy services offered, safety practices during treatment, quality assurance procedures, and needs to develop safety and training materials., Methods and Materials: A 22-item survey was sent to ABS membership in early 2019 to physicians, physicists, therapists, nurses, and administrators. Participation was voluntary. Responses were summarized with descriptive statistics and relative frequency distributions., Results: There were 103 unique responses. Approximately one in three was attending physicians and one in three attending physicists. Most were in practice >10 years. A total of 94% and 50% performed gynecologic and prostate brachytherapy, respectively. Ninety-one percent performed two-identification patient verification before treatment. Eighty-six percent performed a time-out. Ninety-five percent had an incident reporting or learning system, but only 71% regularly reviewed incidents. Half reviewed safety practices within the last year. Twenty percent reported they were somewhat or not satisfied with department safety culture, but 92% of respondents were interested in improving safety culture. Most reported time, communication, and staffing as barriers to improving safety. Most respondents desired safety-oriented webinars, self-assessment modules, learning modules, or checklists endorsed by the ABS to improve safety practice., Conclusions: Most but not all practices use standards and quality assurance procedures in line with society recommendations. There is a need to heighten safety culture at many departments and to shift resources (e.g., time or staffing) to improve safety practice. There is a desire for society guidance to improve brachytherapy safety practices. This is the first survey to assess safety practice patterns among a national sample of radiation oncologists with expertise in brachytherapy., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Eliminating patient computed tomography (CT) scans for tandem and ring (T&R) brachytherapy can reduce overall procedure time and eliminates imaging dose. However, reconstructing titanium applicators in magnetic resonance imaging (MRI) is challenging. We evaluated the uncertainty of different applicator reconstruction workflows in MR-guided brachytherapy, and assessed the clinical impact of reconstruction uncertainties., Methods and Materials: Titanium MRI-compatible T&Rs with aqueous gel in the buildup cap were reconstructed on CTs and MRIs to assess the uncertainties of four different workflows. Reconstruction was performed using (1) proton density-weighted MRIs with solid applicator from a library, (2) applicator-only reference CT fused with MRIs, (3) T2-weighted (T2W) MRIs following GEC-ESTRO guidelines, and (4) patient CTs fused with patient MRIs with in situ applicators. We evaluated dwell positions and plan quality differences using high-risk clinical target volume coverage, and EQD2 D 2cc of rectum, sigmoid, bladder, and small bowel., Results: The 2σ uncertainty for dwell positions for each workflow were (1) 2.7 mm for both ring and tandem, (2) 1.4 mm ring and 0.8 mm tandem, (3) 0.2 mm ring and 0.8 mm tandem, and (4) 1.9 mm ring and 0.4 mm tandem. Reconstruction uncertainties resulted in dose variations within acceptable levels (below 10%) except for (1) which resulted in larger dose to the rectum (20%). Dose uncertainties were similar between reference CT and patient CT., Conclusions: Reconstruction with a reference CT results in similar uncertainty to a patient CT. T2W MRI plans have acceptable uncertainty levels for the applicator reconstruction and resulting dose distributions., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)