Adoption and effectiveness of de-escalated radiation and endocrine therapy strategies for older women with low-risk breast cancer.

PURPOSE: Recent clinical trials support de-escalation of adjuvant radiation therapy following lumpectomy in some older women with low-risk HR+ breast cancers planning to take endocrine therapy. The adoption of these findings into clinical practice, and the effectiveness of de-escalated therapy in real-world populations, remain under investigation. MATERIALS AND METHODS: We evaluated use of adjuvant radiation therapy and/or endocrine therapy among older women with T1-2 node-negative, HR+ breast cancer in the United States between 2007 and 2011. The study included patients from the Surveillance, Epidemiology and End Results-Medicare linked database and the North Carolina Cancer Information and Population Health Resource database. RESULTS: Radiation therapy was received by 65.5% of patients, with no decrease over time. Older women and those with T2 (compared to T1) tumors were less likely to receive radiation therapy. In propensity-adjusted analyses, both radiation therapy alone (HR 0.75, 95% CI 0.67-0.84) and radiation + endocrine therapy (HR 0.62, 95% CI 0.54-0.69) were associated with significantly lower recurrence risk compared to endocrine therapy alone. Non-adherence to endocrine therapy was common (37%) and similar across groups. With a median follow-up of 48 months (range 13-84), we were not able to detect an association of non-adherence with recurrence risk in endocrine therapy-containing treatment arms. CONCLUSION: Most older women with stage I HR+ breast cancers continue to receive radiation, at higher rates than patients with node-negative stage II tumors. These findings suggest that while multiple evidence-based treatment options exist in these patients, improvements are needed to ensure that radiation therapy is applied equitably and rationally.

Cost-effectiveness of endocrine therapy versus radiotherapy versus combined endocrine and radiotherapy for older women with early-stage breast cancer.

PURPOSE: To evaluate the cost-effectiveness of endocrine therapy (ET), radiation therapy (XRT), and combination ET + XRT as post-surgical treatment for older women with early-stage breast cancer from the societal perspective. METHODS: We constructed a Markov state-transition model consisting of three mutually exclusive health-states: Disease-Free, Recurrence, or Death. Osteoporotic fracture, radiation-induced breast fibrosis, and radiation pneumonitis were modeled as treatment-related adverse events (AEs). Cancer registry-linked-Medicare data were used to assess probability of recurrence and total costs, after propensity adjustment to account for treatment selection, among women aged >65 years diagnosed with estrogen receptor positive or progesterone receptor positive (ER+/PR+) breast cancer receiving ET, XRT, or ET + XRT in 2007-2011. Following randomized controlled trials, overall survival was assumed equivalent, but locoregional recurrence varied. Indirect costs and health-state utilities were literature-driven and varied in sensitivity analyses. Costs and outcomes were discounted at 3% annually. RESULTS: In a cohort of 10,000 women over ten years, we estimated 1620 total recurrences in the ET-only group, 1296 in the XRT-only group, and 1076 with ET + XRT. Compared to ET-only, the base-case incremental cost-effectiveness ratio (ICER) was $10,826 per quality-adjusted life-year (QALY)-gained for XRT-only and $26,834/QALY-gained for ET + XRT. Similarities in cost and effectiveness between treatments led to highly sensitive results. We also present clinically-relevant patient preference scenarios for recurrence risk-averse patients and near-term AE risk-averse patients. CONCLUSIONS: The cost-effectiveness of regimens including ET and/or XRT in older women with early-stage breast cancer is sensitive to small differences in costs, as well as risk of, and utilities associated with, locoregional recurrence, suggesting that patient preferences concerning treatment benefits and risks should be considered by physicians.

Prospective Assessment of Patient-Reported Dry Eye Syndrome After Whole Brain Radiation.

PURPOSE: Dry eye is not typically considered a toxicity of whole brain radiation therapy (WBRT). We analyzed dry eye syndrome as part of a prospective study of patient-reported outcomes after WBRT. METHODS AND MATERIALS: Patients receiving WBRT to 25 to 40 Gy were enrolled on a study with dry mouth as the primary endpoint and dry eye syndrome as a secondary endpoint. Patients received 3-dimensional WBRT using opposed lateral fields. Per standard practice, lacrimal glands were not prospectively delineated. Patients completed the Subjective Evaluation of Symptom of Dryness (SESoD, scored 0-4, with higher scores representing worse dry eye symptoms) at baseline, immediately after WBRT (EndRT), and at 1 month (1M), 3 months, and 6 months. Patients with baseline SESoD ≥3 (moderate dry eye) were excluded. The endpoints analyzed were ≥1-point and ≥2-point increase in SESoD score at 1M. Lacrimal glands were retrospectively delineated with fused magnetic resonance imaging scans. RESULTS: One hundred patients were enrolled, 70 were eligible for analysis, and 54 were evaluable at 1M. Median bilateral lacrimal V20Gy was 79%. At 1M, 17 patients (32%) had a ≥1-point increase in SESoD score, and 13 (24%) a ≥2-point increase. Lacrimal doses appeared to be associated with an increase in SESoD score of both ≥1 point (V10Gy: P = .042, odds ratio [OR] 1.09/%; V20Gy: P = .071, OR 1.03/%) and ≥2 points (V10Gy: P = .038, OR 1.15/%; V20Gy: P = .063, OR 1.04/%). The proportion with increase in dry eye symptoms at 1M for lacrimal V20Gy ≥79% versus <79% was 46% versus 15%, respectively, for ≥1 point SESoD increase (P = .02) and 36% versus 12%, respectively, for ≥2 point SESoD increase (P = .056). CONCLUSIONS: Dry eye appears to be a relatively common, dose/volume-dependent acute toxicity of WBRT. Minimization of lacrimal gland dose may reduce this toxicity, and patients should be counseled regarding the existence of this potential side effect and treatments for dry eye.

Phase II study of stereotactic radiosurgery for the treatment of patients with oligoprogression on erlotinib.

INTRODUCTION: Retrospective studies have evaluated the approach of stereotactic radiotherapy (SRT) to address oligoprogression in patients with EGFR mutant NSCLC on TKI therapy, it has never been prospectively studied. MATERIALS AND METHODS: We treated 25 patients with EGFR mutant NSCLC on erlotinib who had 3 or fewer sites of extra-cranial progression with SRT to progressing sites, followed by re-initiation of erlotinib. RESULTS: Median PFS from the initiation of SRT was 6 months (95% CI 2.5 to 11.6) and median OS was 29 months (95% CI 21.7 to 36.3). Neither baseline nor changes in the Veristrat proteomic predicted PFS. CONCLUSIONS: SRT and TKI continuation may be considered for select patients with EGFR mutant NSCLC and oligo-progression on EGFR TKI therapy.

Assessment of Risk of Xerostomia After Whole-Brain Radiation Therapy and Association With Parotid Dose.

Importance: Whole-brain radiation therapy (WBRT) delivers a substantial radiation dose to the parotid glands, but the parotid glands are not delineated for avoidance and xerostomia has never been reported as an adverse effect. Minimizing the toxic effects in patients receiving palliative treatments, such as WBRT, is crucial. Objective: To assess whether xerostomia is a toxic effect of WBRT. Design, Setting, and Participants: This observational cohort study enrolled patients from November 2, 2015, to March 20, 2018, at 1 academic center (University of North Carolina Hospitals) and 2 affiliated community hospitals (High Point Regional Hospital and University of North Carolina Rex Hospital). Adult patients (n = 100) receiving WBRT for the treatment or prophylaxis of brain metastases were enrolled. Patients who had substantial baseline xerostomia or did not complete WBRT or at least 1 postbaseline questionnaire were prospectively excluded from analysis and follow-up. Patients received 3-dimensional WBRT using opposed lateral fields covering the skull and the C1 or C2 vertebra. Per standard practice, the parotid glands were not prospectively delineated. Main Outcomes and Measures: Patients completed the University of Michigan Xerostomia Questionnaire and a 4-point bother score at baseline, immediately after WBRT, at 1 month, at 3 months, and at 6 months. The primary end point was the 1-month xerostomia score, with a hypothesized worsening score of 10 points from baseline. Results: Of the 100 patients enrolled, 73 (73%) were eligible for analysis and 55 (55%) were evaluable at 1 month. The 73 patients included 43 women (59%) and 30 men (41%) with a median (range) age of 61 (23-88) years. The median volume of parotid receiving at least 20 Gy (V20Gy) was 47%. The mean xerostomia score was 7 points at baseline and was statistically significantly higher at each assessment period, including 21 points immediately after WBRT (95% CI, 16-26; P < .001), 23 points (95% CI, 16-30; P < .001) at 1 month, 21 points (95% CI, 13-28; P < .001) at 3 months, and 14 points (95% CI, 7-21; P = .03) at 6 months. At 1 month, the xerostomia score increased by 20 points or more in 19 patients (35%). The xerostomia score at 1 month was associated with parotid dose as a continuous variable and was 35 points in patients with parotid V20Gy of 47% or greater, compared with only 9 points in patients with parotid V20Gy less than 47% (P < .001). The proportion of patients who self-reported to be bothered quite a bit or bothered very much by xerostomia at 1 month was 50% in those with parotid V20Gy of 47% or greater, compared with only 4% in those with parotid V20Gy less than 47% (P < .001). At 3 months, this difference was 50% vs 0% (P = .001). Xerostomia was not associated with medication use. Conclusions and Relevance: Clinically significant xerostomia occurred by the end of WBRT, appeared to be persistent, and appeared to be associated with parotid dose. The findings from this study suggest that the parotid glands should be delineated for avoidance to minimize these toxic effects in patients who undergo WBRT and often do not survive long enough for salivary recovery.

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

PURPOSE: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. PATIENTS AND METHODS: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. CONCLUSION: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. CLINICAL TRIAL: (NCT01305941).

Erratum: Multidisciplinary Management of Breast Cancer During Pregnancy.

[This corrects the article DOI: 10.1634/theoncologist.2016-0208.].

Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies.

BACKGROUND: Given the wide adoption of human epidermal growth factor receptor 2 (HER2)-targeted therapies for advanced HER2-positive breast cancer, we studied the natural history of patients with HER2-positive breast cancer brain metastases (BCBM) over time. PATIENTS AND METHODS: Patients with HER2-positive BCBM identified from a prospectively maintained database at the University of North Carolina were divided into 3 cohorts by year of BCBM diagnosis. Cohorts were selected by year of HER2-targeted therapy US Food and Drug Administration approval. Overall survival (OS), time to first metastasis, time to BCBM, and BCBM survival were estimated by the Kaplan-Meier method. Associations between OS after BCBM and clinical variables were assessed by Cox proportional hazards regression models. RESULTS: One hundred twenty-three patients were identified. Median age was 51 years, and 58% were white and 31% African American. OS from initial breast cancer diagnosis improved over time: 3.6 years (95% confidence interval [CI], 2.8-6.1) in the 1998-2007 cohort, 6.6 years (95% CI, 4.5-8.6) in the 2008-2012 cohort, and 7.6 years (95% CI, 4.4-9.6) in the 2013-2015 cohort (P = .05). While time from initial diagnosis to first metastasis did not differ (P = .12), time to BCBM increased over time (2.6 years [95% CI, 1.3-3.5] for 1998-2007; 2.6 years [95% CI, 2.1-4.3] for 2008-2012, and 3.3 years [95% CI, 2.2-6] for 2013-2015; P = .05). Although OS from BCBM did not significantly differ by cohort, patients who received HER2-targeted therapy after BCBM had a prolonged OS (2.1 years [95% CI, 1.6-2.6] vs. 0.65 years [95% CI, 0.4-1.3]; P = .001). CONCLUSION: OS from initial breast cancer diagnosis significantly improved over time for patients with HER2-positive breast cancer who develop BCBM, now exceeding 7 years; survival from BCBM diagnosis may now exceed 2 years.

Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for Stage III non-small-cell lung cancer.

BACKGROUND AND PURPOSE: To assess associations between radiation dose/volume parameters for cardiac subvolumes and different types of cardiac events in patients treated on radiation dose-escalation trials. MATERIAL AND METHODS: Patients with Stage III non-small-cell lung cancer received dose-escalated radiation (median 74 Gy) using 3D-conformal radiotherapy on six prospective trials from 1996 to 2009. Volumes analyzed included whole heart, left ventricle (LV), right atrium (RA), and left atrium (LA). Cardiac events were divided into three categories: pericardial (symptomatic effusion and pericarditis), ischemia (myocardial infarction and unstable angina), and arrhythmia. Univariable competing risks analysis was used. RESULTS: 112 patients were analyzed, with median follow-up 8.8 years for surviving patients. Nine patients had pericardial, seven patients had ischemic, and 12 patients had arrhythmic events. Pericardial events were correlated with whole heart, RA, and LA dose (eg, heart-V30 [p=0.024], RA-V30 [p=0.013], and LA-V30 [p=0.001]), but not LV dose. Ischemic events were correlated with LV and whole heart dose (eg, LV-V30 [p=0.012], heart-V30 [p=0.048]). Arrhythmic events showed borderline significant associations with RA, LA, and whole heart dose (eg, RA-V30 [p=0.082], LA-V30 [p=0.076], heart-V30 [p=0.051]). Cardiac events were associated with decreased survival on univariable analysis (p=0.008, HR 2.09), but only disease progression predicted for decreased survival on multivariable analysis. CONCLUSIONS: Cardiac events were heterogeneous and associated with distinct heart subvolume doses. These data support the hypothesis of distinct etiologies for different types of radiation-associated cardiotoxicity.

The use of psychological supportive care services and psychotropic drugs in patients with early-stage breast cancer: a comparison between two institutions on two continents.

The aim of this study was to evaluate the mental health consumption among patients with early-stage breast cancer in two radiation oncology departments in two countries (USA and Italy). Data were extracted from the medical records of consecutive patients treated between 2014 and 2015 in two centers. Extracted data included patient's demographics, treatment, referral to psychological supportive care programs, and prescribed psychotropic drugs. Data from the two centers were compared using Student's t, Wilcoxon, Fisher's exact, and Jonckheere-Terpstra tests. Adjusted relative risks (RR) were estimated using Poisson regression. A total of 231 (Italy = 110, USA = 121) patients were included, with a mean age of 60 years. The crude rate of psychological supportive care visits was similar in the US versus the Italian cohort (28.9 vs. 21.8%, p = 0.23). The crude rate of prescribed psychotropic drug was higher in the US cohort versus Italian cohort (43.8 vs. 18.2%, p < 0.0001). These differences remained significant after adjusting for breast cancer subtype, stage, and treatment (RR 1.8, 95 CI 1.17-2.76). Between 20 and 30% of patients receive psychological supportive care during treatment for breast cancer. The use of psychotropic medication was higher in the US cohort than the cohort from Italy. The reasons for these differences might be related to social and cultural differences and the method of prescribing medication.

Early cardiac perfusion defects after left-sided radiation therapy for breast cancer: is there a volume response?

PURPOSE: Cardiac single-photon emission computed tomography (SPECT) is often used to identify defects in myocardial perfusion due to atherosclerotic coronary artery disease. It was also used in studies to evaluate radiation therapy (RT)-associated cardiac abnormalities. In the current review, we aim to evaluate the rates of post-RT cardiac SPECT early perfusion abnormalities and relate this to the irradiated left ventricular volume. METHODS: The studies cited in this systematic review were identified using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS: Six studies between 1996 and 2016 fulfilled the inclusion criteria. The reported perfusion defects in these studies were seen in the apical and anterolateral aspects of the left ventricle. Three studies show correlation between the percent of the left ventricle within the RT-field and percent of patients with early perfusion defects on cardiac SPECT. In two studies that used cardiac sparing techniques (such as deep inspiration), that resulted in a low mean heart dose, no perfusion defects were noted. CONCLUSIONS: Data suggest that incidental irradiation of the heart in cases of left breast/chest wall RT can result in early post-RT perfusion defects on cardiac SPECT. There appears to be strong dose/volume dependence to the risk, and hence techniques to reduce cardiac exposure are recommended.

The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.

Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.

Utility of Deep Inspiration Breath Hold for Left-Sided Breast Radiation Therapy in Preventing Early Cardiac Perfusion Defects: A Prospective Study.

PURPOSE: To evaluate early cardiac single photon computed tomography (SPECT) findings after left breast/chest wall postoperative radiation therapy (RT) in the setting of deep inspiration breath hold (DIBH). METHODS AND MATERIALS: We performed a prospective single-institution single-arm study of patients who were planned for tangential RT with DIBH to the left breast/chest wall (± internal mammary nodes). The DIBH was done by use of a controlled surface monitoring technique (AlignRT, Vision RT Ltd, London, UK). The RT was given with tangential fields and a heart block. Radiation-induced cardiac perfusion and wall motion changes were assessed by pre-RT and 6-month post-RT SPECT scans. A cumulative SPECT summed-rest score was used to quantify perfusion in predefined left ventricle segments. The incidence of wall motion abnormalities was assessed in each of these same segments. RESULTS: A total of 20 patients with normal pre-RT scans were studied; their median age was 56 years (range, 39-72 years). Seven (35%) patients also received irradiation to the left internal mammary chain, and 5 (25%) received an additional RT field to supraclavicular nodes. The median heart dose was 94 cGy (range, 56-200 cGy), and the median V25Gy was zero (range, 0-0.1). None of the patients had post-RT perfusion or wall motion abnormalities. CONCLUSIONS: Our results suggest that DIBH and conformal cardiac blocking for patients receiving tangential RT for left-sided breast cancer is an effective means to avoid early RT-associated cardiac perfusion defects.

The prognostic value of pre-diagnosis health-related quality of life on survival: a prospective cohort study of older Americans with lung cancer.

PURPOSE: Health-related quality of life (HRQOL) after cancer diagnosis is prognostic for overall survival (OS). However, no studies have assessed if HRQOL before diagnosis is predictive for OS. The objective of this study was to determine the association between pre-lung cancer diagnosis HRQOL and OS. METHODS: Our prospective cohort study used surveillance, epidemiology, and end results linked to the Medicare Health Outcomes Survey. We included 6290 individuals 65 years or older diagnosed with incident lung cancer from 1998 to 2013. We assessed the prognostic value of (1) short-form 36 summary component and domain-specific scores, (2) activities of daily living (ADL), and (3) two global HRQOL questions. Cox-proportional hazards models were used to examine associations between HRQOL and OS, adjusting for demographics, comorbid conditions, and clinical characteristics. RESULTS: Worse pre-diagnosis HRQOL was significantly associated with greater risk of death across HRQOL measures. An above average physical or mental component summary score was associated with 16 and 24% decreases in the hazard of death, respectively (p < 0.0001). Being unable to perform ADLs, such as bathing oneself, was associated with an 89% increased hazard of death (p < 0.0001). Reporting "poor" versus "excellent" health was associated with a 74% increase in the hazard of death (p < 0.0001). CONCLUSION: This population-based study reinforces the importance of self-reported health status as a predictor for OS. Routine HRQOL screening may identify patients who could benefit from early interventions to improve HRQOL. Future studies should explore associations between changes in HRQOL before and after cancer diagnosis and OS.

Multidisciplinary Management of Breast Cancer During Pregnancy.

BACKGROUND: Although breast cancer during pregnancy (BCDP) is rare (occurring with only 0.4% of all BC diagnoses in female patients aged 16-49 years), management decisions are challenging to both the patient and the multidisciplinary team. MATERIALS AND METHODS: Experts in breast cancer at the University of North Carolina conducted a targeted literature search regarding the multidisciplinary treatment approaches to BCDP: medical, surgical, and radiation oncology. Supportive care, including antiemetic agents, and imaging approaches were also reviewed. RESULTS: Review of the literature revealed key points in the management of BCDP. Surgical management is similar to that in nonpregnant patients; pregnant patients may safely undergo breast-conserving surgery. Recommendations should be tailored to the individual according to the clinical stage, tumor biology, genetic status, gestational age, and personal preferences. Anthracycline-based chemotherapy can be safely initiated only in the second and third trimesters. The rate of congenital abnormalities in children exposed to chemotherapy is similar to the national average (approximately 3%). Dosing of chemotherapy should be similar to that in the nonpregnant patient (i.e., actual body surface area). Antihuman epidermal growth factor receptor 2 therapy, radiation, and endocrine treatment are contraindicated in pregnancy and lactation. Care should include partnership with obstetricians. The literature regarding prognosis of BCDP is mixed. CONCLUSION: To maximize benefit and minimize risk to the mother and fetus, an informed discussion with the patient and her medical team should result in an individualized treatment plan, taking into account the timing of the pregnancy and the stage and subtype of the breast cancer. Because BCDP is rare, it is essential to collect patient data in international registries. The Oncologist 2017;22:324-334 IMPLICATIONS FOR PRACTICE: Breast cancer during pregnancy is a major ethical and professional challenge for both the patient and the multidisciplinary treatment team. Although the oncologic care is based on that of the non-pregnant breast cancer patient, there are many challenges from regarding the medical, surgical and radiation oncology and obstetrical aspects of care that need to be considered to deliver the safest and best treatment plan to both the mother and developing fetus.

Cardiac Toxicity After Radiotherapy for Stage III Non-Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy.

Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.