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The optimal approach for partial breast irradiation (PBI) is unknown. We investigated a novel de-intensified 3-fraction PBI regimen for photons, protons, and brachytherapy. A multicenter nonrandomized controlled trial with the primary outcome of adverse cosmesis at 3 years versus before PBI. Eligibility criteria were age ≥50 years treated with breast-conserving surgery for node-negative estrogen receptor–positive (ER+) invasive breast cancer or any ductal carcinoma in situ (DCIS) measuring ≤2.5 cm. Photon and proton PBI were prescribed 21.9 Gy (relative biological effectiveness) and brachytherapy 21 Gy in 3 fractions. Radiation therapy technique and adjuvant endocrine therapy were selected at physician and patient discretion. Between June 17, 2015, and July 13, 2017, 161 eligible patients were treated with photons (56), protons (49), or brachytherapy (56). Median patient age was 66.8 years. One hundred twenty-six (78.3%) had invasive breast cancer (all ER+) and 35 (21.7%) had DCIS (88.6% ER+). Fifty-four percent of patients with invasive breast cancer and 25.8% of patients with ER+ DCIS initiated and adhered to the prescribed endocrine therapy. The proportion of patients with adverse cosmesis (by trained nurse assessment) was 14.5% at baseline and 2.3% at 3 years (difference, −12.2%; 95% CI, −100% to −6.4%). Adverse cosmesis at the last follow-up, with a median follow-up of 5 years, was 5.7% by nurse assessment, 5.6% by panel assessment of digital photographs, and 5.2% by patient self-report. There were no observed clinically meaningful changes in other patient-reported outcomes, and just 2 grade 2 or higher adverse events, both grade 2, in the brachytherapy cohort. Five-year local recurrence–free survival and progression-free survival were 98.0% and 95.5%, respectively. There were no local recurrences among 60 patients with invasive breast cancer and Ki67 ≤13.25%. Deintensified 3-day PBI provided favorable disease control, tolerability, and cosmetic outcomes, meeting the prespecified criteria for acceptability. This approach is an attractive option for patients with small node-negative ER+ breast cancer and DCIS. [ABSTRACT FROM AUTHOR]

Proton therapy is under investigation in breast cancer as a strategy to reduce radiation exposure to the heart and lungs. So far, studies investigating proton postmastectomy radiotherapy (PMRT) have used conventional fractionation over 25–28 days, but whether hypofractionated proton PMRT is feasible is unclear. We aimed to compare conventional fractionation and hypofractionation in patients with indications for PMRT, including those with immediate breast reconstruction. We did a randomised phase 2 trial (MC1631) at Mayo Clinic in Rochester (MN, USA) and Mayo Clinic in Arizona (Phoenix, AZ, USA) comparing conventional fractionated (50 Gy in 25 fractions of 2 Gy [relative biological effectiveness of 1·1]) and hypofractionated (40·05 Gy in 15 fractions of 2·67 Gy [relative biological effectiveness of 1·1]) proton PMRT. All patients were treated with pencil-beam scanning. Eligibility criteria included age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0–2, and breast cancer resected by mastectomy with or without immediate reconstruction with indications for PMRT. Patients were randomly assigned (1:1) to either conventional fractionation or hypofractionation, with presence of immediate reconstruction (yes vs no) as a stratification factor, using a biased-coin minimisation algorithm. Any patient who received at least one fraction of protocol treatment was evaluable for the primary endpoint and safety analyses. The primary endpoint was 24-month complication rate from the date of first radiotherapy, defined as grade 3 or worse adverse events occurring from 90 days after last radiotherapy or unplanned surgical interventions in patients with immediate reconstruction. The inferiority of hypofractionation would not be ruled out if the upper bound of the one-sided 95% CI for the difference in 24-month complication rate between the two groups was greater than 10%. This trial is registered with ClinicalTrials.gov , NCT02783690 , and is closed to accrual. Between June 2, 2016, and Aug 23, 2018, 88 patients were randomly assigned (44 to each group), of whom 82 received protocol treatment (41 in the conventional fractionation group and 41 in the hypofractionation group; median age of 52 years [IQR 44−64], 79 [96%] patients were White, two [2%] were Black or African American, one [1%] was Asian, and 79 [96%] were not of Hispanic ethnicity). As of data cutoff (Jan 30, 2023), the median follow-up was 39·3 months (IQR 37·5–61·2). The median mean heart dose was 0·54 Gy (IQR 0·30−0·72) for the conventional fractionation group and 0·49 Gy (0·25−0·64) for the hypofractionation group. Within 24 months of first radiotherapy, 14 protocol-defined complications occurred in six (15%) patients in the conventional fractionation group and in eight (20%) patients in the hypofractionation group (absolute difference 4·9% [one-sided 95% CI 18·5], p=0·27). The complications in the conventionally fractionated group were contracture (five [12%] of 41 patients]) and fat necrosis (one [2%] patient) requiring surgical intervention. All eight protocol-defined complications in the hypofractionation group were due to infections, three of which were acute infections that required surgical intervention, and five were late infections, four of which required surgical intervention. All 14 complications were in patients with immediate expander or implant-based reconstruction. After a median follow-up of 39·3 months, non-inferiority of the hypofractionation group could not be established. However, given similar tolerability, hypofractionated proton PMRT appears to be worthy of further study in patients with and without immediate reconstruction. The Department of Radiation Oncology, Mayo Clinic, Rochester, MN, the Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA, and the US National Cancer Institute. [ABSTRACT FROM AUTHOR]

Radiation therapy plays an important role in the multidisciplinary management of breast cancer. Recent years have seen improvements in breast cancer survival and a greater appreciation of potential long-term morbidity associated with the dose and volume of irradiated organs. Proton therapy reduces the dose to nontarget structures while optimizing target coverage. However, there remain additional financial costs associated with proton therapy, despite reductions over time, and studies have yet to demonstrate that protons improve upon the treatment outcomes achieved with photon radiation therapy. There remains considerable heterogeneity in proton patient selection and techniques, and the rapid technological advances in the field have the potential to affect evidence evaluation, given the long latency period for breast cancer radiation therapy recurrence and late effects. In this consensus statement, we assess the data available to the radiation oncology community of proton therapy for breast cancer, provide expert consensus recommendations on indications and technique, and highlight ongoing trials' cost-effectiveness analyses and key areas for future research. [ABSTRACT FROM AUTHOR]

The relative biologic effectiveness (RBE) rises with increasing linear energy transfer toward the end of proton tracks. Presently, there is no consensus on how RBE heterogeneity should be accounted for in breast cancer proton therapy treatment planning. Our purpose was to determine the dosimetric consequences of incorporating a brachial plexus (BP) biologic dose constraint and to describe other clinical implications of biologic planning. We instituted a biologic dose constraint for the BP in the context of MC1631, a randomized trial of conventional versus hypofractionated postmastectomy intensity modulated proton therapy (IMPT). IMPT plans of 13 patients treated before the implementation of the biologic dose constraint (cohort A) were compared with IMPT plans of 38 patients treated on MC1631 after its implementation (cohort B) using (1) a commercially available Eclipse treatment planning system (RBE = 1.1); (2) an in-house graphic processor unit-based Monte Carlo physical dose simulation (RBE = 1.1); and (3) an in-house Monte Carlo biologic dose (MCBD) simulation that assumes a linear relationship between RBE and dose-averaged linear energy transfer (product of RBE and physical dose = biologic dose). Before implementation of a BP biologic dose constraint, the Eclipse mean BP D0.01 cm3 was 107%, and the MCBD estimate was 128% (ie, 64 Gy [RBE = biologic dose] in 25 fractions for a 50-Gy [RBE = 1.1] prescription), compared with 100.0% and 116.0%, respectively, after the implementation of the constraint. Implementation of the BP biologic dose constraint did not significantly affect clinical target volume coverage. MCBD plans predicted greater internal mammary node coverage and higher heart dose than Eclipse plans. Institution of a BP biologic dose constraint may reduce brachial plexopathy risk without compromising target coverage. MCBD plan evaluation provides valuable information to physicians that may assist in making clinical judgments regarding relative priority of target coverage versus normal tissue sparing. [ABSTRACT FROM AUTHOR]

Abstract Purpose We investigated the feasibility and accuracy of using carbon fiducials to localize the lumpectomy cavity with 2-dimensional kV imaging for early stage breast cancer radiation therapy. Methods and Materials Carbon fiducials were placed intraoperatively in the periphery of the lumpectomy cavity. Nine patients received whole breast irradiation with a boost, and 2 patients received 3-dimensional conformal partial breast irradiation. A total of 89 fractions were assessed for setup errors relative to a predefined gold standard, cone beam computed tomography (CBCT) match to the lumpectomy cavity, using the following 4 setup methods: (1) Align skin tattoos with lasers; (2) match bone with 2-dimensional–2-dimensional (2D/2D) kV onboard imaging (OBI); (3) match the whole breast with CBCT; and (4) match carbon fiducials with 2D/2D kV OBI. The margin for the planning target volume (PTV) was calculated by 2 standard deviations of the setup errors, and compared among the 4 setup methods. Setup errors for patients treated with free breathing and patients with deep inspiration breath hold were also compared. Results The carbon fiducials were sufficiently visible on OBI for matching and introduced minimal artifacts. Of the 4 alignment methods, 2D/2D OBI match to fiducials resulted in the smallest setup errors. The PTV margin was 12 mm for aligning skin tattoos using lasers, 9.2 mm for matching bone on OBI, 6.5 mm for matching breast on CBCT, and 3.5 mm for matching fiducials on 2D/2D OBI. Compared with free breathing, deep inspiration breath hold generally reduced the standard deviations of the setup errors, but further investigation would be needed. Conclusions Matching to carbon fiducials increased the localization accuracy to the lumpectomy cavity. This reduces residual setup error and PTV margins, facilitating tissue sparing without diminishing treatment efficacy. [ABSTRACT FROM AUTHOR]

Purpose: Chest wall (CW) pain has recently been recognized as an important adverse effect of stereotactic body radiation therapy (SBRT) for non–small-cell lung cancer (NSCLC). We developed a dose–volume model to predict the development of this toxicity. Methods and Materials: A total of 126 patients with primary, clinically node-negative NSCLC received three to five fractions of SBRT to doses of 40–60 Gy and were prospectively followed. The dose–absolute volume histograms of two different definitions of the CW as an organ at risk (CW3cm and CW2cm) were examined for all 126 patients. Results: With a median follow-up of 16 months, the 2-year estimated actuarial incidence of Grade ≥ 2 CW pain was 39%. The median time to onset of Grade ≥ 2 CW pain (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0) was 9 months. There was no predictive advantage for biologically corrected dose over physical dose. Neither fraction number (p = 0.07) nor prescription dose (p = 0.07) were significantly correlated with the development of Grade ≥ 2 CW pain. Cox Proportional Hazards analysis identified significant correlation with a broad range of dose-volume combinations, with the CW volume receiving 30 Gy (V30) as one of the strongest predictors (p < 0.001). CW2cm consistently enabled better prediction of CW toxicity. When a physical dose of 30 Gy was received by more than 70 cm3 of CW2cm, there was a significant correlation with Grade ≥ 2 CW pain (p = 0.004). Conclusions: CW toxicity after SBRT is common and long-term follow-up is needed to identify affected patients. A volume of CW ≥ 70 cm3 receiving 30 Gy is significantly correlated with Grade ≥ 2 CW pain. We are currently applying this constraint at our institution for patients receiving thoracic SBRT. An actuarial atlas of our data is provided as an electronic supplement to facilitate data-sharing and meta-analysis relating to CW pain. [ABSTRACT FROM AUTHOR]

Purpose: Survivin, a member of the inhibitor of apoptosis gene family, has also been shown to regulate mitosis. It binds Aurora B kinase and the inner centromere protein to form the chromosome passenger complex. Both Aurora B and survivin are overexpressed in many tumors. In this study, we examined whether irradiation affected survivin and Aurora B expression in mesothelioma cells, and how inhibition of these molecules affected radiosensitivity. Methods and Materials: ZM447439 and survivin antisense oligonucleotides were used to inhibit survivin and Aurora B kinase respectively. Western blot was performed to determine the expression of survivin, Aurora B, phosphorylated-histone H3 (Ser 10), and caspase cleavage. Multinucleated cells were counted using flow cytometry, and cell survival after treatment was determined using clonogenic assay. Results: At 3-Gy irradiation an increase was observed in levels of survivin and Aurora B as well as the kinase activity of Aurora B, with an increase in G2/M phase. The radiation-induced upregulation of these molecules was effectively attenuated by antisense oligonucleotides against survivin and a small-molecule inhibitor of Aurora B, ZM447439. Dual inhibition of survivin and Aurora B synergistically radiosensitized mesothelioma cells with a dose enhancement ratio of 2.55. This treatment resulted in increased formation of multinucleated cells after irradiation but did not increase levels of cleaved caspase 3. Conclusion: Inhibition of survivin and Aurora B induces mitotic cell arrest in mesothelioma cells after irradiation. These two proteins may be potential therapeutic targets for the enhancement of radiotherapy in malignant pleural mesothelioma. [Copyright &y& Elsevier]

Autophagy is an alternative cell death pathway that is induced by mammalian target of rapamycin (mTOR) inhibitors and up-regulated when apoptosis is defective. We investigated radiation-induced autophagy in the presence or absence of Bax/Bak with or without an mTOR inhibitor, Rad001. Two isogenic cell lines, wild type (WT) and Bak/Bak-/- mouse embryonic fibroblasts and tumor cell lines were used for this study. Irradiated Bak/Bak-/- cells had a decrease of Akt/mTOR signaling and a significant increase of pro-autophagic proteins ATG5-ATG12 COMPLEX and Beclin-1. These molecular events resulted in an up-regulation of autophagy. Bax/Bak-/- cells were defective in undergoing apoptosis but were more radiosensitive than the WT cells in autophagy. Both autophagy and sensitization of Bak/Bax-/- cells were further enhanced in the presence of Rad001. In contrast, inhibitors of autophagy rendered the Bak/Bax-/- cells radioresistant, whereas overexpression of ATG5 and Beclin-1 made the WT cells radiosensitive. When this novel concept of radiosensitization was tested in cancer models, small interfering RNAs against Bak/Bax also led to increased autophagy and sensitization of human breast and lung cancer cells to gamma radiation, which was further enhanced by Rad001. This is the first report to demonstrate that inhibition of pro-apoptotic proteins and induction of autophagy sensitizes cancer cells to therapy. Therapeutically targeting this novel pathway may yield significant benefits for cancer patients. [ABSTRACT FROM AUTHOR]

Minibeam radiation therapy (MBRT) is characterized by the delivery of submillimeter-wide regions of high "peak" and low "valley" doses throughout a tumor. Preclinical studies have long shown the promise of this technique, and we report here the first clinical implementation of MBRT. A clinical orthovoltage unit was commissioned for MBRT patient treatments using 3-, 4-, 5-, 8-, and 10-cm diameter cones. The 180 kVp output was spatially separated into minibeams using a tungsten collimator with 0.5 mm wide slits spaced 1.1 mm on center. Percentage depth dose (PDD) measurements were obtained using film dosimetry and plastic water for both peak and valley doses. PDDs were measured on the central axis for offsets of 0, 0.5, and 1 cm. The peak-to-valley ratio was calculated at each depth for all cones and offsets. To mitigate the effects of patient motion on delivered dose, patient-specific 3-dimensional-printed collimator holders were created. These conformed to the unique anatomy of each patient and affixed the tungsten collimator directly to the body. Two patients were treated with MBRT; both received 2 fractions. Peak PDDs decreased gradually with depth. Valley PDDs initially increased slightly with depth, then decreased gradually beyond 2 cm. The peak-to-valley ratios were highest at the surface for smaller cone sizes and offsets. In vivo film dosimetry confirmed a distinct delineation of peak and valley doses in both patients treated with MBRT with no dose blurring. Both patients experienced prompt improvement in symptoms and tumor response. We report commissioning results, treatment processes, and the first 2 patients treated with MBRT using a clinical orthovoltage unit. While demonstrating the feasibility of this approach is a crucial first step toward wider translation, clinical trials are needed to further establish safety and efficacy. [ABSTRACT FROM AUTHOR]

Our purpose was to evaluate the measurement properties of patient-reported outcome (PRO) measures used in the ongoing RadComp pragmatic randomized clinical trial (PRCT). The deidentified and blinded data set included 774 English-speaking female participants who completed their 6-month posttreatment assessment. Eleven PRO measures were evaluated, including the Trial Outcome Index from the Functional Assessment of Cancer Therapy-Breast (FACT-B), Satisfaction with Breast Cosmetic Outcomes, the BREAST-Q, and selected Patient-Reported Outcomes Measurement Information System (PROMIS) measures. PROs were measured at 3 timepoints: baseline, completion of radiation therapy (RT), and 6 months post-RT. Ten variables were used as validity anchors. Pearson or Spearman correlations were calculated between PROs and convergent validity indicators. Mean PRO differences between clinically distinct categories were compared with analysis of variance methods (known-groups validity). PRO change scores were mapped to change in other variables (sensitivity to change). Most correlations between PROs and validity indicators were large (≥0.5). Mean score for Satisfaction with Breast Cosmetic Outcomes was higher (better) for those with a lumpectomy compared with those with a mastectomy (P <.001). Mean scores for the FACT-B Trial Outcome Index and for PROMIS Fatigue and Ability to Participate in Social Roles and Activities were better for those with good baseline performance status compared with those with poorer baseline performance status (P <.05). At completion of RT and post-RT, mean scores for Satisfaction with Breast Cosmetic Outcomes and BREAST-Q Radiation were significantly different (P <.001) across categories for all Functional Assessment of Chronic Illness Therapy -Treatment Satisfaction – General items. There were medium-sized correlations between change scores for FACT-B Trial Outcome Index, Fatigue, Anxiety, and Ability to Participate in Social Roles and change scores in the Visual Analog Scale. For patients with nonmetastatic breast cancer receiving radiation in the RadComp PRCT, our findings demonstrate high reliability and validity for important PRO measures, supporting their psychometric strength and usefulness to reflect the effect of RT on health-related quality of life. [ABSTRACT FROM AUTHOR]

Our aim was to report physician- and patient-reported outcomes of patients with localized breast cancer treated with moderate versus ultrahypofractionated whole breast irradiation (WBI) after breast-conserving surgery (BCS). Between February 2018 and February 2020, patients with localized breast cancer (pT0-3 pN0-1 M0) were offered participation in a phase 3 randomized clinical trial assessing adjuvant moderate hypofractionation (MHF) to 40 Gy in 15 fractions versus ultrahypofractionation (UHF) to 25 Gy in 5 fractions after BCS, with an optional simultaneously integrated boost. Toxicities, cosmesis, and quality of life were assessed at baseline, end of treatment (EOT), and 3 months, 1 year, 2 years, and 3 years from irradiation using validated metric tools. One hundred seven patients were randomized to MHF (n = 54) or UHF (n = 53) adjuvant WBI. The median follow-up was 42.8 months. Grade 2 radiation dermatitis was experienced by 4 patients (7.4%) in the MHF arm and 2 patients (3.7%) in the UHF arm at EOT (P =.726). No grade 3 or higher toxicities were observed. Deterioration of cosmesis by physician assessment was observed in 2 (6.7%) patients treated in the UHF arm and 1 (1.9%) patient treated in the MHF arm at EOT (P =.534), whereas at 3 months, only 1 (1.8%) patient treated in the MHF arm demonstrated deterioration of cosmesis (P =.315). At EOT, 91% and 94% of patients reported excellent/good cosmesis among those treated with MHF and UHF regimens, respectively (P =.550). At 3 months, more patients within the MHF arm reported excellent/good cosmesis compared with those in the UHF arm (100% vs 91%; P =.030). However, the difference in patient-reported cosmesis disappeared at the 1-, 2-, and 3-year time points. UHF WBI showed similar treatment-related late toxicities and similar provider-scored cosmesis compared with MHF radiation in patients treated adjuvantly after BCS. [ABSTRACT FROM AUTHOR]

Purpose The feasibility of proton postmastectomy radiation therapy in patients reconstructed with expanders has not been previously reported, limiting treatment options. We analyzed the dosimetric impact of the metallic port contained within expanders on intensity modulated proton therapy (IMPT) and report our techniques and quality control for treating patients in this setting. Methods and materials Twelve patients with the same expander model underwent 2-field IMPT as part of a prospective registry. All planning dosimetry was checked with an in-house graphic processing unit--based Monte Carlo simulation. Proton ranges through the expander were validated using a sample implant. Dosimetric impact of setup metallic port position uncertainty was evaluated. Pre- and posttreatment photographs were obtained and acute toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0. Results Nine patients had bilateral skin-sparing mastectomy with bilateral tissue expander reconstruction, and 3 patients had unilateral skin-sparing mastectomy and reconstruction. The left side was treated in 10 patients and the right side in 2. Target coverage and normal tissue dose uncertainties resulting from the expander were small and clinically acceptable. The maximum physician-assessed acute radiation dermatitis was grade 3 in 1 patient, grade 2 in 5 patients, and grade 1 in 6 patients. Conclusions Postmastectomy IMPT in breast cancer patients with expanders is feasible and associated with favorable clinical target volume coverage and normal tissue sparing, even when taking into account treatment uncertainties; therefore, these patients should be eligible to participate in clinical trials studying the potential role of proton therapy in breast cancer. We caution, however, that institutions should carry out similar analyses of the physical properties and dosimetric impact of the particular expanders used in their practice before considering IMPT. [ABSTRACT FROM AUTHOR]

Introduction Establishment of standards within a practice and across disease site groups for nomenclatures, prescription formatting, and measured dose-volume histogram (DVH) metrics is a key enabling step for creating software and database solutions to make routine aggregation of dosimetric data for all patients treated in a practice, practical. A process of physician-driven, iterative dialogs coupled with development of technical tools is required to implement the cultural and procedural changes. The cumulative reward for this effort is a database that can be used for defining practice norms, benchmarking against national standards, and tracking dosimetric effects of longitudinal practice pattern changes. Methods and materials A 4-year project was carried out to develop and introduce standardizations, modify processes, and develop computer-based tools for reporting, aggregation, and analysis of prescription and DVH metrics. Physician disease site groups developed 42 target and 81 normal tissue templates. From the database of 32,002 DVH metrics, benchmarking was illustrated for a subgroup of breast (281) and prostate (324) patients treated with conventional fractionation over a 16-month period. Breast patients were segregated according to prescription template used: simple (S, tangents only) vs complex (C, tangents + supraclavicular ± intramammary nodes) and left (S-L or C-L) versus right (S-R or C-R). Results Prostate patients’ median and 50% confidence intervals (CIs) for bladder, stated according to the nomenclature: the percentage of bladder volume receiving doses of ≥ 40 Gy (V40[%]), V65Gy[%], V70Gy[%], V75Gy[%], and V80Gy[%] were 45.5 (24.9-57.0), 15.6 (9.0-23.8), 7.6 (3.3-13.6), 2.0 (0.0-7.9), and 0.0 (0.0-1.4), respectively. Values for rectum: V50Gy[%], V60 Gy[%], V65Gy[%], V70Gy[%], and V75Gy[%] were 37.1 (27.8-43.5), 21.8 (15.6-25.5), 14.6 (9.6-18.0), 7.7 (1.9-12.3), and 1.0 (0–7.0), respectively. For breast patients, heart:mean Gray values were 1.5 (1.0-2.0), 3.1 (2.2-4.8), 0.4 (0.3-0.7), and 1.1 (0.8-2.2) for S-L, C-L, S-R, and C-R, respectively. Longitudinal, moving window plots of median, 50% CI, and 90% CI for 6-month periods demonstrated the effect of practice changes to reduce heart doses. Conclusions Standardization was challenging as a practice change, but has resulted in significant improvements for both our clinical and research efforts. [ABSTRACT FROM AUTHOR]

To report oncologic, physician-assessed, and patient-reported outcomes (PROs) for a group of women homogeneously treated with modern, skin-sparing multifield optimized pencil-beam scanning proton (intensity modulated proton therapy [IMPT]) postmastectomy radiation therapy (PMRT). We reviewed consecutive patients who received unilateral, curative-intent, conventionally fractionated IMPT PMRT between 2015 and 2019. Strict constraints were applied to limit the dose to the skin and other organs at risk. Five-year oncologic outcomes were analyzed. Patient-reported outcomes were evaluated as part of a prospective registry at baseline, completion of PMRT, and 3 and 12 months after PMRT. A total of 127 patients were included. One hundred nine (86%) received chemotherapy, among whom 82 (65%) received neoadjuvant chemotherapy. The median follow-up was 4.1 years. Five-year locoregional control was 98.4% (95% CI, 93.6-99.6), and overall survival was 87.9% (95% CI, 78.7-96.5). Acute grade 2 and 3 dermatitis was seen in 45% and 4% of patients, respectively. Three patients (2%) experienced acute grade 3 infection, all of whom had breast reconstruction. Three late grade 3 adverse events occurred: morphea (n = 1), infection (n = 1), and seroma (n = 1). There were no cardiac or pulmonary adverse events. Among the 73 patients at risk for PMRT-associated reconstruction complications, 7 (10%) experienced reconstruction failure. Ninety-five patients (75%) enrolled in the prospective PRO registry. The only metrics to increase by >1 point were skin color (mean change: 5) and itchiness (2) at treatment completion and tightness/pulling/stretching (2) and skin color (2) at 12 months. There was no significant change in the following PROs: bleeding/leaking fluid, blistering, telangiectasia, lifting, arm extension, or bending/straightening the arm. With strict dose constraints to skin and organs at risk, postmastectomy IMPT was associated with excellent oncologic outcomes and PROs. Rates of skin, chest wall, and reconstruction complications compared favorably to previous proton and photon series. Postmastectomy IMPT warrants further investigation in a multi-institutional setting with careful attention to planning techniques. [ABSTRACT FROM AUTHOR]

Secondary angiosarcoma of the breast is a rare complication of breast radiotherapy and is associated with a poor prognosis. There are many reported cases of secondary angiosarcoma following whole breast irradiation (WBI), however development of secondary angiosarcoma following brachytherapy-based accelerated partial breast irradiation (APBI) is not as well characterized. We reviewed and reported a case of a patient who developed secondary angiosarcoma of the breast following intracavitary multicatheter applicator brachytherapy APBI. A 69-year-old female was originally diagnosed with T1N0M0 invasive ductal carcinoma of the left breast and treated with lumpectomy followed by adjuvant intracavitary multicatheter applicator brachytherapy APBI. Seven years following her treatment, she developed secondary angiosarcoma. However, the diagnosis of secondary angiosarcoma was delayed due to nonspecific imaging findings and a negative biopsy. Our case highlights the need for secondary angiosarcoma to be considered in the differential diagnosis when patients present with symptoms such as breast ecchymosis and skin thickening following WBI or APBI. Prompt diagnosis and referral to a high-volume sarcoma treatment center for multidisciplinary evaluation is vital. [ABSTRACT FROM AUTHOR]

Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dependent protein kinase, which is a core component of the nonhomologous end-joining DNA repair pathway, and ataxia telangiectasia mutated, which coordinates cell cycle arrest, apoptosis, and DNA repair functionalities after radiation exposure. Unlike the more modest in vitro radiosensitizing effects seen with classic sensitizing agents such as cisplatin, 5-fluorouracil, or taxanes, DNA-dependent protein kinase or ataxia telangiectasia mutated inhibitors provide much more robust sensitizing effects in vitro, as might be anticipated from targeting these key DNA repair modulators. However, patients with homozygous inactivating mutations of ataxia telangiectasia mutated or mice with homozygous defects in DNA-dependent protein kinase (severe combined immunodeficiency) have profoundly enhanced acute normal tissue radiation reactions. Therefore, there is significant potential that the combination of small molecule inhibitors of these kinases with radiation could cause similar dose-limiting acute normal tissue toxicities. Similarly, although less understood, inhibition of these DNA repair response pathways could markedly increase the risk of late radiation toxicities. Because these potent radiosensitizers could be highly useful to improve local control of otherwise radiation-resistant tumors, understanding the potential for elevated risks of radiation injury is essential for optimizing therapeutic ratio and developing safe and informative clinical trials. In this review, we will discuss 2 straightforward models to assess the potential for enhanced mucosal toxicity in the oral cavity and small intestine established in our laboratories. We also will discuss similar strategies for evaluating potential drug-radiation interactions with regard to increased risks of debilitating late effects. [ABSTRACT FROM AUTHOR]

Immunotherapy using immune checkpoint blockade has revolutionized the treatment of many types of cancer. Radiation therapy (RT)-particularly when delivered at high doses using newer techniques-may be capable of generating systemic antitumor effects when combined with immunotherapy in breast cancer. These systemic effects might be due to the local immune-priming effects of RT resulting in the expansion and circulation of effector immune cells to distant sites. Although this concept merits further exploration, several challenges need to be overcome. One is an understanding of how the heterogeneity of breast cancers may relate to tumor immunogenicity. Another concerns the need to develop knowledge and expertise in delivery, sequencing, and timing of RT with immunotherapy. Clinical trials addressing these issues are under way. We here review and discuss the particular opportunities and issues regarding this topic, including the design of informative clinical and translational studies. [ABSTRACT FROM AUTHOR]

Purpose: To report early adverse events and patient-reported outcomes (PROs) of 3-fraction intracavitary catheter-based partial breast brachytherapy (ICBB).Materials and Methods: Eligible women ≥50 years of age with ≤2.5-cm, lymph node-negative invasive or in situ breast cancer underwent breast-conserving surgery and placement of a brachytherapy applicator. ICBB was initiated on the second weekday after surgery and prescribed to 21 Gy in 3 once-daily fractions. Common Terminology Criteria for Adverse Events, version 4.0; 10-point linear analog scale assessment; the PRO version of the Common Terminology Criteria for Adverse Events; and the Harvard Breast Cosmesis Scale were used for provider and patient-reported assessments.Results: Seventy-three women were treated for invasive (79%) or in situ (21%) breast cancer. The median time to completion of surgery and radiation therapy was 6 days. After 14-months median follow-up, 2 patients (3%) had developed breast infections that resolved with oral antibiotics. There was no other treatment-associated adverse event grade ≥2. The grade 1 seroma rate at 3 months was 20%, which dropped to 8% at 12 months; no events required intervention. At 12 months, 91% of patients reported an overall quality of life score as ≥8 of 10, and patient-reported cosmesis was good or excellent in 95%. All patients are alive without relapse at the last follow-up.Conclusions: Three-fraction ICBB is associated with low rates of early provider and patient- reported adverse events and compares favorably with early outcomes of more protracted ICBB regimens, including twice-daily (3.4 Gy × 10) fractionation studied in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39. Further investigation is warranted. [ABSTRACT FROM AUTHOR]

Purpose Chemoradiation (CRT) is an integral treatment modality for patients with locally advanced lung cancer. It has been hypothesized that current use of an angiotensin-converting enzyme inhibitor during CRT may be protective for treatment-related lung damage and pneumonitis. Methods and Materials We conducted a pilot, double-blind, placebo-controlled, randomized trial. Study-eligible patients receiving curative thoracic radiation therapy (RT) were randomly assigned to 20 mg of lisinopril or placebo once daily during and up to 3 months after RT. All patients received concurrent chemotherapy. The primary endpoint was adverse event profiling. Multiple patient-reported outcome (PRO) surveys, including the Lung Cancer Symptom Scale, Function Assessment of Cancer Therapy–Lung, and the European Organisation for Research and Treatment of Cancer Lung Cancer Questionnaire, were applied with a symptom experience questionnaire. Exploratory comparative statistics were used to detect differences between arms with χ2 and Kruskal-Wallis testing. Results Five institutions enrolled 23 patients. However, accrual was less than expected. Eleven and 12 patients were in the placebo and lisinopril arms, respectively (mean age, 63.5 years; male, 62%). Baseline characteristics were balanced. Eighteen patients (86%) were former or current smokers. The primary endpoint was met; neither arm had grade 3 or higher hypotension, acute kidney injury, allergic reaction (medication-induced cough), or anaphylaxis (medication-related angioedema). Few PRO measures suggested that compared with the placebo arm, patients receiving lisinopril had less cough, less shortness of breath, fewer symptoms from lung cancer, less dyspnea with both walking and climbing stairs, and better overall quality of life (for all, P <.05). Conclusions Although underpowered because of low accrual, our results suggest that there was a clinical signal for safety—and possibly beneficial by limited PRO measures—in concurrently administering lisinopril during thoracic CRT to mitigate or prevent RT-induced pulmonary distress. Our results showed that a definitive, larger-scale, randomized phase 3 trial is needed in the future. [ABSTRACT FROM AUTHOR]

Purpose: The optimal clinical target volume for internal mammary (IM) node irradiation is uncertain in an era of increasingly conformal volume-based treatment planning for breast cancer. We mapped the location of gross internal mammary lymph node (IMN) metastases to identify areas at highest risk of harboring occult disease.Methods and Materials: Patients with axial imaging of IMN disease were identified from a breast cancer registry. The IMN location was transferred onto the corresponding anatomic position on representative axial computed tomography images of a patient in the treatment position and compared with consensus group guidelines of IMN target delineation.Results: The IMN location in 67 patients with 130 IMN metastases was mapped. The location was in the first 3 intercostal spaces in 102 of 130 nodal metastases (78%), whereas 18 of 130 IMNs (14%) were located caudal to the third intercostal space and 10 of 130 IMNs (8%) were located cranial to the first intercostal space. Of the 102 nodal metastases within the first 3 intercostal spaces, 54 (53%) were located within the Radiation Therapy Oncology Group consensus volume. Relative to the IM vessels, 19 nodal metastases (19%) were located medially with a mean distance of 2.2 mm (SD, 2.9 mm) whereas 29 (28%) were located laterally with a mean distance of 3.6 mm (SD, 2.5 mm). Ninety percent of lymph nodes within the first 3 intercostal spaces would have been encompassed within a 4-mm medial and lateral expansion on the IM vessels.Conclusions: In women with indications for elective IMN irradiation, a 4-mm medial and lateral expansion on the IM vessels may be appropriate. In women with known IMN involvement, cranial extension to the confluence of the IM vein with the brachiocephalic vein with or without caudal extension to the fourth or fifth interspace may be considered provided that normal tissue constraints are met. [ABSTRACT FROM AUTHOR]

Purpose Determine feasibility and resultant dosimetry of an intraoperatively placed multichannel intracavitary brachytherapy catheter for accelerated partial breast irradiation (APBI). Methods Patients with breast cancer underwent intraoperative brachytherapy catheter placement based on frozen section analysis with immediate postoperative APBI. The planning target volume evaluation (PTVEval) and organs at risk were contoured on daily pretreatment CT scans for each patient, and the original treatment plan was applied to assess full-course dosimetry. Results Of the first 21 patients consented for intraoperative catheter placement, 20 (95%) were able to proceed with treatment as planned. The mean volume of PTVEval receiving 90% of prescription dose ( V 90% ) and mean percentage of prescription dose to 90% of the PTVEval ( D 90% ) on initial planning were 96.7 (±1.1%) and 100.2 (±2.1%), respectively. Full-course dose coverage remained excellent with a mean PTVEval V 90% and D 90% of 95.0 (±4.4%) and 100.2 (±9.6%), respectively. Mean full-course maximum dose constraints for chest wall and skin were met by 70% and 95% of patients, respectively. Air accumulation >1 cc during treatment increased the risk of a daily fraction with PTVEval coverage below goal (odds ratio, 9.8; p = 0.05), whereas those with applicators <0.5 cm from the chest wall at planning were at risk of exceeding that organ's maximum dose constraint on a daily fraction (odds ratio, 45; p = 0.02). Conclusions Intraoperative catheter placement and early initiation of APBI based on frozen section pathology is feasible, yields acceptable dosimetry, and is an option for completing breast conserving therapy in less than 10 days. [ABSTRACT FROM AUTHOR]

Purpose To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. Methods and Materials Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Results Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. Conclusions For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted. [ABSTRACT FROM AUTHOR]