Physician- and Patient-Reported Outcomes of the MC1635 Phase 3 Trial of Ultrahypofractionated Versus Moderately Hypofractionated Adjuvant Radiation Therapy After Breast-Conserving Surgery.

PURPOSE: 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). METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: UHF WBI showed similar treatment-related late toxicities and similar provider-scored cosmesis compared with MHF radiation in patients treated adjuvantly after BCS.

Initial Quality of Life and Toxicity Analysis of a Randomized Phase 3 Study of Moderately Hypofractionated Radiation Therapy With or Without Androgen Suppression for Intermediate-Risk Adenocarcinoma of the Prostate: PCG GU003.

Purpose: Our objective was to report the quality of life (QoL) analysis and toxicity in patients with intermediate-risk prostate cancer treated with or without androgen deprivation therapy (ADT) in Proton Collaborative Group (PCG) GU003. Methods and Materials: Between 2012 and 2019, patients with intermediate-risk prostate cancer were enrolled. Patients were randomized to receive moderately hypofractionated proton beam therapy (PBT) to 70 Gy relative biologic effectiveness in 28 fractions to the prostate with or without 6 months of ADT. Expanded Prostate Cancer Index Composite, Short-Form 12, and the American Urological Association Symptom Index instruments were given at baseline and 3, 6, 12, 18, and 24 months after PBT. Toxicities were assessed according to Common Terminology Criteria for Adverse Events (version 4). Results: One hundred ten patients were randomized to PBT either with 6 months of ADT (n = 55) or without ADT (n = 55). The median follow-up was 32.4 months (range, 5.5-84.6). On average, 101 out of 110 (92%) patients filled out baseline QoL and patient-reported outcome surveys. The compliance was 84%, 82%, 64%, and 42% at 3, 6, 12, and 24 months, respectively. Baseline median American Urological Association Symptom Index was comparable between arms (6 [11%] ADT vs 5 [9%] no ADT, P = .359). Acute and late grade 2+ genitourinary and gastrointestinal toxicity were similar between arms. The ADT arm experienced a QoL decline of mean scores in the sexual (-16.1, P < .001) and hormonal (-6.3, P < .001) domains, with the largest time-specific hormonal differences at 3 (-13.8, P < .001) and 6 (-11.2, P < .001) months. The hormonal QoL domain returned to baseline 6 months after therapy. There was a trend to baseline in sexual function 6 months after completion of ADT. Conclusions: After 6 months of ADT, sexual and hormonal domains returned to baseline 6 months after completion of treatment for men with intermediate-risk prostate cancer.

Pilot/Phase II Trial of Hypofractionated Radiation Therapy to the Whole Breast Alone Before Breast Conserving Surgery.

Purpose: Our purpose was to report the results of a phase II trial of patients with breast cancer treated with hypofractionated whole breast radiation therapy (RT) before breast-conserving surgery (BCS). Methods and materials: Between 2019 and 2020, patients with cT0-T2, N0, M0 breast cancer were enrolled. Patients were treated with hypofractionated whole breast RT, 25 Gy in 5 fractions, 4 to 8 weeks before BCS. Pathologic assessment was performed using the residual cancer burden (RCB). Toxicities were assessed according to Common Terminology Criteria for Adverse Events (version 4). Quality of life was assessed with Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, The Breast Cancer Treatment Outcome Scale, Linear Analogue Self-Assessment, and Patient-Reported Outcomes Measurement Information System. Results: Twenty-two patients were enrolled. Median follow-up was 7.6 months (range, 0.2-16.8). Seven (32%) and 2 (9%) patients experienced grade 2+ or 3 toxicities, respectively. Overall quality of life Linear Analogue Self-Assessment and Patient-Reported Outcomes Measurement Information System did not change significantly from baseline (P = .21 and P = .72, respectively). There was no clinically significant change (≥1 point) in any of The Breast Cancer Treatment Outcome Scale domains. Only 1 (5%) patient experienced a clinical deterioration that corresponded to a "fair" outcome on the Harvard Cosmesis Scale. At pathologic evaluation, 14 (64%) patients had RCB-0 or RCB-I, including 3 (14%) patients with a pathologic complete response (RCB-0). Eight patients (36%) had RCB-II. No local or distant recurrences have been observed. Conclusions: Extremely hypofractionated whole breast RT before BCS is a feasible approach. There were low rates of toxicities and good cosmesis. Further investigation into this approach with RT before BCS is warranted.

Proton therapy for isolated local regional recurrence of breast cancer after mastectomy alone.

Purpose/Objectives: To assess adverse events (AEs) and disease-specific outcomes after proton therapy for isolated local-regional recurrence (LRR) of breast cancer after mastectomy without prior radiotherapy (RT). Materials/Methods: Patients were identified from a multi-institutional prospective registry and included if diagnosed with invasive breast cancer, initially underwent mastectomy without adjuvant RT, experienced an LRR, and subsequently underwent salvage treatment, including proton therapy. Follow-up and cancer outcomes were measured from the date of RT completion. Results: Nineteen patients were included. Seventeen patients were treated with proton therapy to the chest wall and comprehensive regional lymphatics (17/19, 90%). Maximum grade AE was grade 2 in 13 (69%) patients and grade 3 in 4 (21%) patients. All patients with grade 3 AE received > 60 GyE (p=0.04, Spearman correlation coefficient=0.5). At the last follow-up, 90% of patients were alive with no LRR or distant recurrence. Conclusions: For breast cancer patients with isolated LRR after initial mastectomy without adjuvant RT, proton therapy is well-tolerated in the salvage setting with excellent loco-regional control. All grade 3 AEs occurred in patients receiving > 60 GyE.

Patient-reported outcomes for patients with breast cancer undergoing radiotherapy: A single-center registry experience.

Background: We present Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for patients undergoing adjuvant radiotherapy for breast cancer with curative intent. We describe the frequency and severity of PRO-CTCAE and analyze them with respect to dose fractionation. Methods: Patients were included in this study if they were treated with curative intent for breast cancer and enrolled on a prospective registry. Patients must have completed at least one baseline and one post-radiation survey that addressed PRO-CTCAE. For univariate and multivariate analysis, categorical variables were analyzed by Fisher's exact test and continuous variables by Wilcoxon rank sum test. PRO-CTCAE items graded ≥2 and ≥3 were analyzed between patients who received hypofractionation (HF) versus standard conventional fractionation (CF) therapy by the Chi-square test. Results: Three hundred thirty-one patients met inclusion criteria. Pathologic tumor stage was T1-T2 in 309 (94%) patients. Eighty-seven (29%) patients were node positive. Two hundred forty-seven patients (75%) experienced any PRO-CTCAE grade ≥2, and 92 (28%) patients experienced any PRO-CTCAE grade ≥3. CF was found to be associated with an increased risk of grade ≥3 skin toxicity, swallowing, and nausea (all p < 0.01). HF (OR 0.48, p < 0.01) was significant in the multivariate model for decreased risk of any occurrence of PRO-CTCAE ≥3. Conclusions: Our study reports one of the first clinical experiences utilizing multiple PRO-CTCAE items for patients with breast cancer undergoing radiation therapy with curative intent. Compared with CF, HF was associated with a significant decrease in any PRO-CTCAE ≥3 after multivariate analysis.

An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides.

Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3'-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.

Biologically Effective Dose and Rectal Bleeding in Definitive Proton Therapy for Prostate Cancer.

Purpose and Objectives: With increasing use of hypofractionation and extreme hypofractionation for prostate cancer, rectal dose-volume histogram (DVH) parameters that apply across dose fractionations may be helpful for treatment planning in clinical practice. We present an exploratory analysis of biologically effective rectal dose (BED) and equivalent rectal dose in 2 Gy fractions (EQD2) for rectal bleeding in patients treated with proton therapy across dose fractionations. Materials and Methods: From 2016 to 2018, 243 patients with prostate cancer were treated with definitive proton therapy. Rectal DVH parameters were obtained from treatment plans, and rectal bleeding events were recorded. The BED and EQD2 transformations were applied to each rectal DVH parameter. Univariate analysis using logistic regression was used to determine DVH parameters that were significant predictors of grade ≥ 2 rectal bleeding. Youden index was used to determine optimum cutoffs for clinically meaningful DVH constraints. Stepwise model-selection criteria were then applied to fit a "best" multivariate logistic model for predicting Common Terminology Criteria for Adverse Events grade ≥ 2 rectal bleeding. Results: Conventional fractionation, hypofractionation, and extreme hypofractionation were prescribed to 117 (48%), 84 (34%), and 42 (17.3%) patients, respectively. With a median follow-up of 20 (2.5-40) months, 10 (4.1%) patients experienced rectal bleeding. On univariate analysis, multiple rectal DVH parameters were significantly associated with rectal bleeding across BED, EQD2, and nominal doses. The BED volume receiving 55 Gy > 13.91% was found to be statistically and clinically significant. The BED volume receiving 55 Gy remained statistically significant for an association with rectal bleeding in the multivariate model (odds ratio, 9.81; 95% confidence interval, 2.4-40.5; P = .002). Conclusion: In patients undergoing definitive proton therapy for prostate cancer, dose to the rectum and volume of the rectum receiving the dose were significantly associated with rectal bleeding across conventional fractionation, hypofractionation, and extreme hypofractionation when using BED and EQD2 transformations.

Using Novel Statistical Techniques to Accurately Determine the Predictive Dose Range in a Study of Overall Survival after Definitive Radiotherapy for Stage III Non-Small Cell Lung Cancer in Association with Heart Dose.

PURPOSE: Recent studies of radiotherapy (RT) for stage III non-small-cell lung cancer (NSCLC) have associated high dose to the heart with cardiac toxicity and decreased overall survival (OS). We used advanced statistical techniques to account for correlations between dosimetric variables and more accurately determine the range of heart doses which are associated with reduced OS in patients receiving RT for stage III NSCLC. METHODS: From 2006 to 2013, 119 patients with stage III NSCLC received definitive RT at our institution. OS data was obtained from institutional tumor registry. We used multivariate Cox model to determine patient specific covariates predictive for reduced overall survival. We examined age, prescription dose, mean lung dose, lung V20, RT technique, stage, chemotherapy, tumor laterality, tumor volume, and tumor site as candidate covariates. We subsequently used novel statistical techniques within multivariate Cox model to systematically search the whole heart dose-volume histogram (DVH) for dose parameters associated with OS. RESULTS: Patients were followed until death or 2.5 to 81.2 months (median 30.4 months) in those alive at last follow up. On multivariate analysis of whole heart DVH, the dose of 51 Gy was identified as a threshold dose above which the dose volume relationship becomes predictive for OS. We identified V55Gy (percentage of the whole heart volume receiving at least 55 Gy) as the best single DVH index which can be used to set treatment optimization constraints (Hazard Ratio = 1.044 per 1% increase in heart volume exposed to at least 55 Gy, P = 0.03). Additional characteristics correlated with OS on multivariate analysis were age, stage (IIIA/IIIB), and administration of chemotherapy. CONCLUSION: Doses above 51 Gy, applied to small volumes of the heart, are associated with worse OS in stage III NSCLC patients treated with definitive RT. Higher stage, older age and lack of chemotherapy were also associated with reduced OS.

Dose-volume histogram parameters and patient-reported EPIC-Bowel domain in prostate cancer proton therapy.

PURPOSE: To analyze rectal dose and changes in quality of life (QOL) measured with the Expanded Prostate and Cancer Index Composite (EPIC) bowel domain in patients being treated for prostate cancer with curative-intent proton beam therapy (PBT) within a large single-institution prospective registry. MATERIALS AND METHODS: Data was collected from 243 patients with localized prostate cancer treated with PBT from 2016 to 2018. The EPIC survey was administered at baseline, end-of-treatment, 3, 6, and 12 months, then annually. Dose-volume histogram (DVH) parameters for the rectum were computed, and rectal dose was analyzed using BED (α/ß = 3), EQD2Gy, and total dose. Repeated measures mixed models were implemented to determine the effect of patient, clinical, and treatment factors (including DVH) on patient-reported bowel symptom burden (EPIC-Bowel). RESULTS: Treatment overall resulted in changes in EPIC-Bowel scores (baseline score = 93.7), most notably at end-of-treatment (90.6) and 12 months (89.7). However, they returned to baseline at 36 months (92.9). On multivariate modeling, rectal BED D25 (Gy) ≥23% was significantly associated with decline in QOL scores measuring bother (p < 0.01; 4.06 points different). CONCLUSION: Rectal doses, specifically BED D25 (Gy) ≥23%, are significantly associated with decline in bowel bother-related QOL in patients undergoing definitive radiotherapy for localized prostate cancer. This study demonstrates BED as an independent predictor of bowel QOL across dose fractionations of PBT.

Unplanned implant removal in locally advanced breast cancer.

Study conducted to determine frequency and timing of unplanned breast implant removal after mastectomy, reconstruction, and postmastectomy radiation (PMRT). From 2010-2017, 52 patients underwent mastectomy, reconstruction, and PMRT. With median follow-up of 3.1 years, 23 patients (44%) experienced implant removal. Implant removal occurred in 9 (17%) patients before starting PMRT and 14 (27%) patients after starting PMRT. Implant removal rates were similar for hypofractionated PMRT compared with standard fractionation and for proton compared with photon PMRT. Implant removal is common for women undergoing mastectomy and reconstruction followed by PMRT. The risk is clinically significant even before starting radiation.

Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome.

IMPORTANCE: Hereditary factors play a key role in the risk of developing several cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and germline testing. OBJECTIVE: To examine the prevalence of pathogenic germline variants (PGVs) in patients with cancer using a universal testing approach compared with targeted testing based on clinical guidelines and the uptake of cascade family variant testing (FVT). DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter cohort study assessed germline genetic alterations among patients with solid tumor cancer receiving care at Mayo Clinic cancer centers and a community practice between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer type, disease stage, family history of cancer, ethnicity, or age. EXPOSURES: Germline sequencing using a greater than 80-gene next-generation sequencing platform. MAIN OUTCOMES AND MEASURES: Proportion of PGVs detected with a universal strategy compared with a guideline-directed approach and uptake of cascade FVT in families. RESULTS: A total of 2984 patients (mean [SD] age, 61.4 [12.2] years; 1582 [53.0%] male) were studied. Pathogenic germline variants were found in 397 patients (13.3%), including 282 moderate- and high-penetrance cancer susceptibility genes. Variants of uncertain significance were found in 1415 patients (47.4%). A total of 192 patients (6.4%) had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. Of those with a high-penetrance PGV, 42 patients (28.2%) had modifications in their treatment based on the finding. Only younger age of diagnosis was associated with presence of PGV. Only 70 patients (17.6%) with PGVs had family members undergoing no-cost cascade FVT. CONCLUSIONS AND RELEVANCE: This prospective, multicenter cohort study found that universal multigene panel testing among patients with solid tumor cancer was associated with an increased detection of heritable variants over the predicted yield of targeted testing based on guidelines. Nearly 30% of patients with high-penetrance variants had modifications in their treatment. Uptake of cascade FVT was low despite being offered at no cost.

Impact of adjuvant trastuzumab on locoregional failure rates in a randomized clinical trial: North Central Cancer Treatment Group N9831 (alliance) study.

BACKGROUND: The goal of this study was to assess the impact of trastuzumab on locoregional failure. METHODS: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis. RESULTS: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%-5.7%). LFR10 was 5.5% (95% CI 4.3%-7.2%), 4.9% (95% CI 3.7%-6.4%), and 2.8% (95% CI 1.9%-4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor-positive patients, LFR10 was 3.7% (95% CI 2.8%-4.8%) and for estrogen receptor-negative patients, it was 6.1% (95% CI 5.0%-7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%-7.8%), 3.0% (95% CI 2.1%-4.3%), and 5.5% (95% CI 4.0%-7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%-8.9%), 4.1% (95% CI 2.4%-7.0%), and 4.3% (95% CI 2.9%-6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6). CONCLUSION: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

Patient-reported quality-of-life outcomes in relation to provider-assessed adverse events during head and neck radiotherapy.

PURPOSE: To assess the relationship between patient-reported quality-of-life (QOL) outcomes and provider-assessed adverse events (AEs) during head-and-neck (H&N) radiotherapy (RT). METHODS: Sixty-five patients undergoing H&N RT prospectively completed 12-domain linear analogue self-assessments (LASA) at baseline, before biweekly appointments, and at last week of RT. At the same time points, provider-assessed AEs were graded using Common Terminology Criteria for Adverse Events v4.0. LASA scores were stratified by maximum-grade AE and analyzed using Kruskal-Wallis methodology. Agreement between LASA scores and maximum-grade AE was assessed using Bland-Altman analysis. RESULTS: Patient-reported QOL outcomes showed clinically meaningful decreases in most domains, predominantly fatigue (77.8% of patients), social activity (75.4%), and overall QOL (74.2%). Provider-assessed AEs showed 100% grade 2 AE, 35.4% grade 3 AE, and 3.1% grade 4 AE. At baseline, patients with higher grade AEs reported worse physical well-being (WB) (P = .04). At week 1, the following QOL domains were worse for patients with higher grade AEs: overall QOL (P = .03), mental WB (P = .02), and physical WB (P = .03). Bland-Altman analysis showed that QOL scores were relatively worse than AE burden at baseline and relatively better at RT completion. CONCLUSIONS: Worse QOL was associated with higher-grade AEs at baseline and early in RT. The impact of AEs on QOL appears to lessen with time. Patient-reported QOL outcomes and provider-assessed AEs provide complementary information.

Consecutive 5'- and 3'-amide linkages stabilise antisense oligonucleotides and elicit an efficient RNase H response.

Antisense oligonucleotides are now entering the clinic for hard-to-treat diseases. New chemical modifications are urgently required to enhance their drug-like properties. We combine amide coupling with standard oligonucleotide synthesis to assemble backbone chimera gapmers that trigger an efficient RNase H response while improving serum life time and cellular uptake.

Acute toxicities after proton beam therapy following breast-conserving surgery for breast cancer: Multi-institutional prospective PCG registry analysis.

We investigated adverse events (AEs) and clinical outcomes for proton beam therapy (PBT) after breast-conserving surgery (BCS) for breast cancer. From 2012 to 2016, 82 patients received PBT in the prospective multi-institutional Proton Collaborative Group registry. AEs were recorded prospectively at each institution. Median follow-up was 8.1 months. Median dose was 50.4 Gy in 28 fractions. Most patients received a lumpectomy bed boost (90%) and regional nodal irradiation (RNI)(83%). Six patients (7.3%) experienced grade 3 AEs (5 with dermatitis, 5 with breast pain). Body mass index (BMI) was associated with grade 3 dermatitis (P = .015). Fifty-eight patients (70.7%) experienced grade ≥2 dermatitis. PBT including RNI after BCS is well-tolerated. Elevated BMI is associated with grade 3 dermatitis.

Proton beam therapy reirradiation for breast cancer: Multi-institutional prospective PCG registry analysis.

To investigate adverse events (AEs, CTCAE v4.0) and clinical outcomes for proton beam therapy (PBT) reirradiation (reRT) for breast cancer. From 2011 to 2016, 50 patients received PBT reRT for breast cancer in the prospective Proton Collaborative Group (PCG) registry. Acute AEs occurred within 180 days from start of reRT. Late AEs began or persisted beyond 180 days. Fisher's exact and Mann-Whitney rank-sum tests were utilized. Kaplan-Meier methods were used to estimate overall survival (OS) and local recurrence-free survival (LFRS). Median follow-up was 12.7 months (0-41.8). Median prior RT dose was 60 Gy (10-96.7). Median reRT dose was 55.1 Gy (45.1-76.3). Median cumulative dose was 110.6 Gy (70.6-156.8). Median interval between RT courses was 103.8 months (5.5-430.8). ReRT included regional nodes in 84% (66% internal mammary node [IMN]). Surgery included the following: 44% mastectomy, 22% wide local excision, 6% lumpectomy, 2% reduction mammoplasty, and 26% no surgery. Grade 3 AEs were experienced by 16% of patients (10% acute, 8% late) and were associated with body mass index (BMI) > 30 kg/m2 (P = 0.04), bilateral recurrence (P = 0.02), and bilateral reRT (P = 0.004). All grade 3 AEs occurred in patients receiving IMN reRT (P = 0.08). At 1 year, LRFS was 93%, and OS was 97%. Patients with gross disease at time of PBT trended toward worse 1-year LRFS (100% without vs. 84% with, P = 0.06). PBT reRT is well tolerated with favorable local control. BMI > 30, bilateral disease, and IMN reRT were associated with grade 3 AEs. Toxicity was acceptable despite median cumulative dose > 110 Gy.

Synthesis and biophysical properties of carbamate-locked nucleic acid (LNA) oligonucleotides with potential antisense applications.

Antisense oligonucleotides (ASOs) are becoming important drugs for hard to treat diseases. Modifications to their DNA backbones are essential to inhibit degradation in vivo, but they can reduce binding affinity to RNA targets. To address this problem we have combined the enzymatic resistance of carbamate (CBM) DNA backbone analogues with the thermodynamic stability conferred by locked nucleic acid sugars (LNA). Using a dinucleotide phosphoramidite strategy and automated solid phase synthesis, we have synthesised a set of oligonucleotides modified with multiple LNA-CBM units. The LNA sugars restore binding affinity to RNA targets, and in this respect LNA position with respect to the CBM linkage is important. Oligonucleotides containing carbamate flanked on its 5'and 3'-sides by LNA form stable duplexes with RNA and unstable duplexes with DNA, which is desirable for antisense applications. Carbamate-LNA modified oligonucleotides also show increased stability in the presence of snake venom and foetal bovine serum compared to LNA or CBM backbones alone.

Radiation and the heart: systematic review of dosimetry and cardiac endpoints.

INTRODUCTION: Recent trials in radiotherapy have associated heart dose and survival, inadequately explained by the existing literature for radiation-related late cardiac effects.  Authors aimed to review the recent literature on cardiac dosimetry and survival/cardiac endpoints. Areas covered: Systematic review of the literature in the past 10 years (2008-2017) was performed to identify manuscripts reporting both cardiac dosimetry and survival/cardiac endpoints.  Authors identified 64 manuscripts for inclusion, covering pediatrics, breast cancer, lung cancer, gastrointestinal diseases (primarily esophageal cancer), and adult lymphoma. Expert commentary: In the first years after radiotherapy, high doses (>40 Gy) to small volumes of the heart are associated with decreased survival from an unknown cause.  In the long-term, mean heart dose is associated with a small increased absolute risk of cardiac death.  For coronary disease, relative risk increases roughly 10% per Gy mean heart dose, augmented by age and cardiac risk factors.  For valvular disease and heart failure, doses >15 Gy substantially increase risk, augmented by anthracyclines.  Arrhythmias after radiotherapy are poorly described but may account for the association between upper heart dose and survival.  Symptomatic pericardial effusion typically occurs with doses >40 Gy.  Close follow-up and mitigation of cardiovascular risk factors are necessary after thoracic radiotherapy.

Multi-institutional Analysis of Vaginal Brachytherapy Alone for Women With Stage II Endometrial Carcinoma.

PURPOSE: To investigate the survival endpoints in women with International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer who received adjuvant vaginal brachytherapy (VBT) alone using multi-institutional pooled data. METHODS AND MATERIALS: We performed a multi-institutional analysis of surgically staged patients with FIGO stage II endometrioid-type endometrial cancer treated with VBT alone. Patient, tumor, and treatment characteristics were collected and analyzed. Univariable and multivariable frailty survival models were performed to assess clinicopathologic risk factors for recurrence and death. RESULTS: One hundred six patients were included (92 VBT alone and 14 VBT with chemotherapy) with median follow-up of 39.0 months. Pelvic node dissection was performed in 89.6% of patients. One hundred four patients (98.1%) and 2 patients (1.9%) had microscopic and macroscopic cervical stromal invasion, respectively. Grade 1 or 2 disease occurred in 88.6% of patients. For patients treated with VBT without chemotherapy, the 5-year estimates of vaginal failure, pelvic nodal failure, and distant metastases were 2.6%, 4.2%, and 7.2%, respectively. Five-year progression-free survival and overall survival were 74.0% and 76.2%, respectively. On univariable and multivariable models for progression-free survival, increasing age and lack of pelvic node resection were hazardous (P < .05). CONCLUSIONS: Vaginal and pelvic failure rates were low in this selected population of stage II patients receiving adjuvant VBT without external beam radiation therapy. It is reasonable to consider adjuvant VBT alone in selected patients with grade 1 or 2 disease and microscopic cervical stromal invasion who underwent pelvic lymphadenectomy.