Changes in breast cancer treatment during the COVID-19 pandemic: a Dutch population-based study.

PURPOSE: We aimed to compare (1) treatments and time intervals between treatments of breast cancer patients diagnosed during and before the COVID-19 pandemic, and (2) the number of treatments started during and before the pandemic. METHODS: Women were selected from the Netherlands Cancer Registry. For aim one, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the treatment of women diagnosed within four periods of 2020: pre-COVID (weeks 1-8), transition (weeks 9-12), lockdown (weeks 13-17), and care restart (weeks 18-26), with data from 2018/2019 as reference. Wilcoxon rank-sums test was used to compare treatment intervals, using a two-sided p-value < 0.05. For aim two, number of treatments started per week in 2020 was compared with 2018/2019. RESULTS: We selected 34,097 women for aim one. Compared to 2018/2019, neo-adjuvant chemotherapy was less likely for stage I (OR 0.24, 95%CI 0.11-0.53), stage II (OR 0.63, 95%CI 0.47-0.86), and hormone receptor+/HER2- tumors (OR 0.55, 95%CI 0.41-0.75) diagnosed during transition. Time between diagnosis and first treatment decreased for patients diagnosed during lockdown with a stage I (p < 0.01), II (p < 0.01) or III tumor (p = 0.01). We selected 30,002 women for aim two. The number of neo-adjuvant endocrine therapies and surgeries starting in week 14, 2020, increased by 339% and 18%, respectively. The number of adjuvant chemotherapies decreased by 42% in week 15 and increased by 44% in week 22. CONCLUSION: The pandemic and subsequently altered treatment recommendations affected multiple aspects of the breast cancer treatment strategy and the number of treatments started per week.

The impact of hyperbaric oxygen therapy on late radiation toxicity and quality of life in breast cancer patients.

PURPOSE: To evaluate symptoms of late radiation toxicity, side effects, and quality of life in breast cancer patients treated with hyperbaric oxygen therapy (HBOT). METHODS: For this cohort study breast cancer patients treated with HBOT in 5 Dutch facilities were eligible for inclusion. Breast cancer patients with late radiation toxicity treated with ≥ 20 HBOT sessions from 2015 to 2019 were included. Breast and arm symptoms, pain, and quality of life were assessed by means of the EORTC QLQ-C30 and -BR23 before, immediately after, and 3 months after HBOT on a scale of 0-100. Determinants associated with persistent breast pain after HBOT were assessed. RESULTS: 1005/1280 patients were included for analysis. Pain scores decreased significantly from 43.4 before HBOT to 29.7 after 3 months (p < 0.001). Breast symptoms decreased significantly from 44.6 at baseline to 28.9 at 3 months follow-up (p < 0.001) and arm symptoms decreased significantly from 38.2 at baseline to 27.4 at 3 months follow-up (p < 0.001). All quality of life domains improved at the end of HBOT and after 3 months follow-up in comparison to baseline scores. Most prevalent side effects of HBOT were myopia (any grade, n = 576, 57.3%) and mild barotrauma (n = 179, 17.8%). Moderate/severe side effects were reported in 3.2% (n = 32) of the patients. Active smoking during HBOT and shorter time (i.e., median 17.5 vs. 22.0 months) since radiotherapy were associated with persistent breast pain after HBOT. CONCLUSION: Breast cancer patients with late radiation toxicity reported reduced pain, breast and arm symptoms, and improved quality of life following treatment with HBOT.

Effects of exercise in breast cancer patients: implications of the trials within cohorts (TwiCs) design in the UMBRELLA Fit trial.

PURPOSE: The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL) and fatigue in inactive breast cancer survivors. METHODS: UMBRELLA Fit was conducted within the prospective UMBRELLA breast cancer cohort. Patients provided consent for future randomization at cohort entry. We randomized inactive patients 12-18 months after cohort enrollment. The intervention group (n = 130) was offered a 12-week supervised exercise intervention. The control group (n = 130) was not informed and received usual care. Six-month exercise effects on QoL and fatigue as measured in the cohort were analyzed with intention-to-treat (ITT), instrumental variable (IV), and propensity scores (PS) analyses. RESULTS: Fifty-two percent (n = 68) of inactive patients accepted the intervention. Physical activity increased in patients in the intervention group, but not in the control group. We found no benefit of exercise for dimensions of QoL (ITT difference global QoL: 0.8, 95% CI = - 2.2; 3.8) and fatigue, except for a small beneficial effect on physical fatigue (ITT difference: - 1.1, 95% CI = - 1.8; - 0.3; IV: - 1.9, 95% CI = - 3.3; - 0.5, PS: - 1.2, 95% CI = - 2.3; - 0.2). CONCLUSION: TwiCs gave insight into exercise intervention acceptance: about half of inactive breast cancer survivors accepted the offer and increased physical activity levels. The offer resulted in no improvement on QoL, and a small beneficial effect on physical fatigue. TRIAL REGISTRATION: Netherlands Trial Register (NTR5482/NL.52062.041.15), date of registration: December 07, 2015.

Health-related quality of life of early-stage breast cancer patients after different radiotherapy regimens.

PURPOSE: To evaluate and compare health-related quality of life (HRQL) of women with early-stage breast cancer (BC) treated with different radiotherapy (RT) regimens. METHODS: Data were collected from five prospective cohorts of BC patients treated with breast-conserving surgery and different RT regimens: intraoperative RT (IORT, 1 × 23.3 Gy; n = 267), external beam accelerated partial breast irradiation (EB-APBI, 10 × 3.85 Gy; n = 206), hypofractionated whole breast irradiation(hypo-WBI, 16 × 2.67 Gy; n = 375), hypo-WBI + boost(hypo-WBI-B, 21-26 × 2.67 Gy; n = 189), and simultaneous WBI + boost(WBI-B, 28 × 2.3 Gy; n = 475). Women ≥ 60 years with invasive/in situ carcinoma ≤ 30 mm, cN0 and pN0-1a were included. Validated EORTC QLQ-C30/BR23 questionnaires were used to asses HRQL. Multivariable linear regression models adjusted for confounding (age, comorbidity, pT, locoregional treatment, systemic therapy) were used to compare the impact of the RT regimens on HRQL at 12 and 24 months. Differences in HRQL over time (3-24 months) were evaluated using linear mixed models. RESULTS: There were no significant differences in HRQL at 12 months between groups except for breast symptoms which were better after IORT and EB-APBI compared to hypo-WBI at 12 months (p < 0.001). Over time, breast symptoms, fatigue, global health status and role functioning were significantly better after IORT and EB-APBI than hypo-WBI. At 24 months, HRQL was comparable in all groups. CONCLUSION: In women with early-stage breast cancer, the radiotherapy regimen did not substantially influence long-term HRQL with the exception of breast symptoms. Breast symptoms are more common after WBI than after IORT or EB-APBI and improve slowly until no significant difference remains at 2 years posttreatment.

Deep Learning for Automatic Calcium Scoring in CT: Validation Using Multiple Cardiac CT and Chest CT Protocols.

Background Although several deep learning (DL) calcium scoring methods have achieved excellent performance for specific CT protocols, their performance in a range of CT examination types is unknown. Purpose To evaluate the performance of a DL method for automatic calcium scoring across a wide range of CT examination types and to investigate whether the method can adapt to different types of CT examinations when representative images are added to the existing training data set. Materials and Methods The study included 7240 participants who underwent various types of nonenhanced CT examinations that included the heart: coronary artery calcium (CAC) scoring CT, diagnostic CT of the chest, PET attenuation correction CT, radiation therapy treatment planning CT, CAC screening CT, and low-dose CT of the chest. CAC and thoracic aorta calcification (TAC) were quantified using a convolutional neural network trained with (a) 1181 low-dose chest CT examinations (baseline), (b) a small set of examinations of the respective type supplemented to the baseline (data specific), and (c) a combination of examinations of all available types (combined). Supplemental training sets contained 199-568 CT images depending on the calcium burden of each population. The DL algorithm performance was evaluated with intraclass correlation coefficients (ICCs) between DL and manual (Agatston) CAC and (volume) TAC scoring and with linearly weighted κ values for cardiovascular risk categories (Agatston score; cardiovascular disease risk categories: 0, 1-10, 11-100, 101-400, >400). Results At baseline, the DL algorithm yielded ICCs of 0.79-0.97 for CAC and 0.66-0.98 for TAC across the range of different types of CT examinations. ICCs improved to 0.84-0.99 (CAC) and 0.92-0.99 (TAC) for CT protocol-specific training and to 0.85-0.99 (CAC) and 0.96-0.99 (TAC) for combined training. For assignment of cardiovascular disease risk category, the κ value for all test CT scans was 0.90 (95% confidence interval [CI]: 0.89, 0.91) for the baseline training. It increased to 0.92 (95% CI: 0.91, 0.93) for both data-specific and combined training. Conclusion A deep learning calcium scoring algorithm for quantification of coronary and thoracic calcium was robust, despite substantial differences in CT protocol and variations in subject population. Augmenting the algorithm training with CT protocol-specific images further improved algorithm performance. © RSNA, 2020 See also the editorial by Vannier in this issue.

Patient Preferences for Minimally Invasive and Open Locoregional Treatment for Early-Stage Breast Cancer.

BACKGROUND: Noninvasive or minimally invasive treatments are being developed as alternatives to surgery for patients with early-stage breast cancer. Patients' preferences with regard to these new treatments have not been investigated. OBJECTIVES: To assess preferences of patients with breast cancer and of healthy women regarding these new techniques, compared with conventional surgical treatments. METHODS: Six hypothetical breast cancer treatment-outcome scenarios were developed: three standard surgical scenarios (mastectomy, mastectomy with immediate implant-based reconstruction, and breast-conserving therapy [BCT]) and three minimally invasive or noninvasive scenarios (radiofrequency ablation, magnetic resonance-guided high-intensity focused ultrasound ablation, and single-dose ablative radiotherapy). Participants rated treatment-outcome scenarios by visual analogue scale (VAS) and time trade-off (TTO). The Friedman and post hoc Wilcoxon signed-rank tests were used to test whether scores were significantly different from BCT. RESULTS: Seventy-one patients with breast cancer and 50 healthy volunteers participated. Overall, BCT was rated the highest in terms of VAS (0.80) and TTO (0.90) scores. After stratification, BCT ranked the highest in most subgroups, with the exception of healthy individuals, who had given the highest score to ablative boost (VAS, 0.80; TTO, 0.88). Mastectomy with immediate reconstruction was the least preferred in most subgroups. CONCLUSIONS: This study showed no significant preference for minimally invasive treatment for breast cancer. Using hypothetical scenarios, breast cancer survivors attributed the highest scores to BCT, whereas healthy volunteers showed a slight preference for minimally invasive treatments.

Implementation of ultra-hypofractionated radiotherapy schedules for breast cancer during the COVID-19 pandemic in the Netherlands.

Background and purpose: The COVID-19 pandemic resulted in an accelerated recommendation to use five-fraction radiotherapy schedules, according to the FAST- and FAST-Forward trial. In this study, trends in the use of different radiotherapy schedules in the Netherlands were studied, as well as the likelihood of receiving five fractions. Materials and methods: Data from the NABON Breast Cancer Audit-Radiotherapy and Netherlands Cancer Registry was used. Women receiving radiotherapy for their primary invasive breast cancer or DCIS between 01-01-2020 and 31-12-2021 were included. Logistic regression was used to investigate the association between patient-, tumour-, treatment-, and radiotherapy institution-related characteristics and the likelihood of receiving five fractions in tumours meeting the FAST and FAST-Forward criteria. Results: Detailed information about radiotherapy treatment was available for 9,392 tumours. Shortly after the start of the COVID-19 pandemic, i.e. April 2020, 19% of the tumours being treated with radiotherapy received five fractions of 5.2 or 5.7 Gray (Gy). While only 3% of the tumours received five fractions in March 2020. The usage of five fractions increased to 26% in December 2021. Partial breast irradiation, compared to whole breast irradiation, was significantly associated with the administration of five fractions, as well as radiotherapy delivered in an academic radiotherapy institution compared to an independent institution. Conclusion: The start of the COVID-19 pandemic was associated with the early use of ultra-hypofractionated radiotherapy schedules. After publication of the trials, and mainly after the recommendation by the national radiotherapy society, the implementation further increased. These schedules were not yet used in all patients meeting the eligibility criteria for the FAST- or FAST-Forward trial.

Hyperbaric Oxygen Therapy and Late Local Toxic Effects in Patients With Irradiated Breast Cancer: A Randomized Clinical Trial.

Importance: Hyperbaric oxygen therapy (HBOT) is proposed as treatment for late local toxic effects after breast irradiation. Strong evidence of effectiveness is lacking. Objective: To assess effectiveness of HBOT for late local toxic effects in women who received adjuvant radiotherapy for breast cancer. Design, Setting, and Participants: This was a hospital-based, pragmatic, 2-arm, randomized clinical trial nested within the prospective UMBRELLA cohort following the trials within cohorts design in the Netherlands. Participants included 189 women with patient-reported moderate or severe breast, chest wall, and/or shoulder pain in combination with mild, moderate, or severe edema, fibrosis, or movement restriction 12 months or longer after breast irradiation. Data analysis was performed from May to September 2023. Intervention: Receipt of 30 to 40 HBOT sessions over a period of 6 to 8 consecutive weeks. Main Outcomes and Measures: Breast, chest wall, and/or shoulder pain 6 months postrandomization measured by the European Organization for Research and Treatment of Cancer QLQ-BR23 questionnaire. Secondary end points were patient-reported fibrosis, edema, movement restriction, and overall quality of life. Data were analyzed according to intention-to-treat (ITT) and complier average causal effect (CACE) principles. Results: Between November 2019 and August 2022, 125 women (median [range] age at randomization, 56 [37-85] years) with late local toxic effects were offered to undergo HBOT (intervention arm), and 61 women (median [range] age at randomization, 60 [36-80] years) were randomized to the control arm. Of those offered HBOT, 31 (25%) accepted and completed treatment. The most common reason for not accepting HBOT was high treatment intensity. In ITT, moderate or severe pain at follow-up was reported by 58 of 115 women (50%) in the intervention arm and 32 of 52 women (62%) in the control arm (odds ratio [OR], 0.63; 95% CI, 0.32-1.23; P = .18). In CACE, the proportion of women reporting moderate or severe pain at follow-up was 32% (10 of 31) among those completing HBOT and 75% (9.7 of 12.9) among control participants expected to complete HBOT if offered (adjusted OR, 0.34; 95% CI, 0.15-0.80; P = .01). In ITT, moderate or severe fibrosis was reported by 35 of 107 (33%) in the intervention arm and 25 of 49 (51%) in the control arm (OR, 0.36; 95% CI, 0.15-0.81; P = .02). There were no significant differences in breast edema, movement restriction, and quality of life between groups in ITT and CACE. Conclusions and Relevance: In this randomized clinical trial, offering HBOT to women with late local toxic effects was not effective for reducing pain, but was effective for reducing fibrosis. In the subgroup of women who completed HBOT, a significant reduction in pain and fibrosis was observed. A smaller than anticipated proportion of women with late local toxic effects was prepared to undergo HBOT. Trial Registration: ClinicalTrials.gov Identifier: NCT04193722.

The use of a wearable cardioverter defibrillator during postmastectomy radiotherapy as an alternative for relocation of the pulse generator.

Purpose: We describe a case in which a breast cancer patient with an implantable cardioverter-defibrillator (ICD) was treated with postmastectomy followed by axillary radiation therapy. The ICD was partly within the target volume and according to the treatment planning system would receive a maximum dose of about 36 Gy. Methods and Materials: Postoperatively, the patient had a wound infection needing surgical intervention and 3 months of antibiotics. Therefore, it was decided not to relocate the ICD but instead to switch off the shock function of the ICD for the entire radiation therapy course. Results: The ICD was successfully substituted with a wearable cardioverter defibrillator (WCD), which the patient wore during the 3-week radiation therapy period until 2 weeks after the end of treatment. The ICD function was monitored from the start of the treatment until 6 months after treatment. Conclusions: In situations in which an ICD needs to be switched off semipermanently, a WCD can be used as alternative. The patient in this report tolerated the WCD well. Despite the high dose received by the ICD, the device and its battery continued to function normally.

Breast cancer patients' most important quality of life themes for a radiotherapy decision aid.

BACKGROUND AND AIM: The BRASA patient decision aid (BRASA-PtDA) facilitates shared decision making for breast cancer patients (BCPs) facing a radiotherapy treatment decision. During evaluations, patients indicated the wish for quantitative information on side effects. Therefore, this study assessed BCPs opinion on which and how information on side effects should be incorporated in the BRASA-PtDA. METHODS: A workshop was organized with BCPs (n = 9), researchers (n = 5) and clinicians (n = 3). Subsequently, a survey was sent to BCPs (n = 744) investigating the generalisability of the workshop findings, and posing additional questions. The survey entailed multiple choice questions on quality of life themes, the use of a decision aid and risk communication. RESULTS: The workshop revealed BCPs wish for a layered, all encompassing information system. Information on the impact of side effects on daily life was preferred above the risk of these side effects. The survey revealed that important quality of life (QoL) themes were having energy (81%; n = 605), arm function (61%; n = 452), pain (55%; n = 410). Despite the focus on qualitative effects in the workshop, 89% of the survey respondents also wanted to be informed on individualized risks of side effects. 54% Of the survey respondents had never heard of a PtDA. CONCLUSIONS: BCPs preferred information on the impact of side effects, but also their individualized risks on side effects. Most important QoL themes were having enough energy, arm function and pain. Consequently, the BRASA-PtDA should be reshaped, starting with quality of life themes, rather than side effects.

AI-Based Radiation Dose Quantification for Estimation of Heart Disease Risk in Breast Cancer Survivors After Radiation Therapy.

PURPOSE: To investigate whether the dose planned for cardiac structures is associated with the risk of heart disease (HD) in patients with breast cancer treated with radiation therapy, and whether this association is modified by the presence of coronary artery calcification (CAC). METHODS AND MATERIALS: Radiation therapy planning computed tomographic (CT) scans and corresponding dose distribution maps of 5561 patients were collected, 5300 patients remained after the exclusion of ineligible patients and duplicates; 1899 patients received their CT scan before 2011, allowing long follow-up. CAC was detected automatically. Using an artificial intelligence-based method, the cardiac structures (heart, cardiac chambers, large arteries, 3 main coronary arteries) were segmented. The planned radiation dose to each structure separately and to the whole heart were determined. Patients were assigned to a low-, medium-, or high-dose group based on the dose to the respective heart structure. Information on HD hospitalization and mortality was obtained for each patient. The association of planned radiation dose to cardiac structures with risk of HD was investigated in patients with and without CAC using Cox proportional hazard analysis in the long follow-up population. Tests for interaction were performed. RESULTS: After a median follow-up of 96.0 months (interquartile range, 84.2-110.4 months) in the long follow-up group, 135 patients were hospitalized for HD or died of HD. If the dose to a structure increased 1 Gy, the relative HD risk increased by 3% to 11%. The absolute increase in HD risk was substantially higher in patients with CAC (event-ratelow-dose = 14-15 vs event-ratehigh-dose = 15-34 per 1000 person-years) than in patients without CAC (event-ratelow-dose = 6-8 vs event-ratehigh-dose = 5-17 per 1000 person-years). No interaction between CAC and radiation dose was found. CONCLUSIONS: Radiation exposure of cardiac structures is associated with increased risk of HD. Automatic segmentation of cardiac structures enables spatially localized dose estimation, which can aid in the prevention of radiation therapy-induced cardiac damage. This could be especially valuable in patients with breast cancer and CAC.

Oncology patients were found to understand and accept the Trials within Cohorts design.

BACKGROUND AND OBJECTIVE: The Trials within Cohorts design aims to reduce recruitment difficulties and disappointment bias in pragmatic trials. On cohort enrollment, broad informed consent for randomization is asked, after which cohort participants can be randomized to interventions or serve as controls without further notification. We evaluated patients' recollection, understanding, and acceptance of broad consent in a clinical oncology setting. METHODS: We surveyed 610 patients with cancer participating in ongoing TwiCs; 482 patients (79%) responded, of which 312 patients shortly after cohort enrollment, 108 patients after randomization to an intervention (12-18 months after cohort enrollment), and a random sample of 62 cohort participants who had not been selected for interventions (1-6 months after cohort enrollment). RESULTS: Shortly after providing cohort consent, 76% of patients (238/312) adequately remembered whether they had given broad consent for randomization. Of patients randomly offered interventions, 76% (82/108) remembered giving broad consent for randomization; 41% (44/108) understood they were randomly selected, 44% (48/108) were not interested in selection procedures, and 10% (11/108) did not understand selection was random. Among patients not selected for interventions, 42% (26/62) understood selection was random; 89% felt neutral regarding the scenario of "not being selected for an intervention while your data were being used in comparison with patients receiving interventions," 10% felt reassured (6/62) and 2% scared/insecure (2/62). CONCLUSION: Patients adequately remember giving broad consent for randomization shortly after cohort enrollment and after being offered an intervention, but recollection is lower in those never selected for interventions. Patients are acceptant of serving as control without further notifications.

Impact of the COVID-19 pandemic on diagnosis, stage, and initial treatment of breast cancer in the Netherlands: a population-based study.

BACKGROUND: The onset of the COVID-19 pandemic forced the Dutch national screening program to a halt and increased the burden on health care services, necessitating the introduction of specific breast cancer treatment recommendations from week 12 of 2020. We aimed to investigate the impact of COVID-19 on the diagnosis, stage and initial treatment of breast cancer. METHODS: Women included in the Netherlands Cancer Registry and diagnosed during four periods in weeks 2-17 of 2020 were compared with reference data from 2018/2019 (averaged). Weekly incidence was calculated by age group and tumor stage. The number of women receiving initial treatment within 3 months of diagnosis was calculated by period, initial treatment, age, and stage. Initial treatment, stratified by tumor behavior (ductal carcinoma in situ [DCIS] or invasive), was analyzed by logistic regression and adjusted for age, socioeconomic status, stage, subtype, and region. Factors influencing time to treatment were analyzed by Cox regression. RESULTS: Incidence declined across all age groups and tumor stages (except stage IV) from 2018/2019 to 2020, particularly for DCIS and stage I disease (p < 0.05). DCIS was less likely to be treated within 3 months (odds ratio [OR]wks2-8: 2.04, ORwks9-11: 2.18). Invasive tumors were less likely to be treated initially by mastectomy with immediate reconstruction (ORwks12-13: 0.52) or by breast conserving surgery (ORwks14-17: 0.75). Chemotherapy was less likely for tumors diagnosed in the beginning of the study period (ORwks9-11: 0.59, ORwks12-13: 0.66), but more likely for those diagnosed at the end (ORwks14-17: 1.31). Primary hormonal treatment was more common (ORwks2-8: 1.23, ORwks9-11: 1.92, ORwks12-13: 3.01). Only women diagnosed in weeks 2-8 of 2020 experienced treatment delays. CONCLUSION: The incidence of breast cancer fell in early 2020, and treatment approaches adapted rapidly. Clarification is needed on how this has affected stage migration and outcomes.

Identification of Risk of Cardiovascular Disease by Automatic Quantification of Coronary Artery Calcifications on Radiotherapy Planning CT Scans in Patients With Breast Cancer.

IMPORTANCE: Cardiovascular disease (CVD) is common in patients treated for breast cancer, especially in patients treated with systemic treatment and radiotherapy and in those with preexisting CVD risk factors. Coronary artery calcium (CAC), a strong independent CVD risk factor, can be automatically quantified on radiotherapy planning computed tomography (CT) scans and may help identify patients at increased CVD risk. OBJECTIVE: To evaluate the association of CAC with CVD and coronary artery disease (CAD) in patients with breast cancer. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter cohort study of 15 915 patients with breast cancer receiving radiotherapy between 2005 and 2016 who were followed until December 31, 2018, age, calendar year, and treatment-adjusted Cox proportional hazard models were used to evaluate the association of CAC with CVD and CAD. EXPOSURES: Overall CAC scores were automatically extracted from planning CT scans using a deep learning algorithm. Patients were classified into Agatston risk categories (0, 1-10, 11-100, 101-399, >400 units). MAIN OUTCOMES AND MEASURES: Occurrence of fatal and nonfatal CVD and CAD were obtained from national registries. RESULTS: Of the 15 915 participants included in this study, the mean (SD) age at CT scan was 59.0 (11.2; range, 22-95) years, and 15 879 (99.8%) were women. Seventy percent (n = 11 179) had no CAC. Coronary artery calcium scores of 1 to 10, 11 to 100, 101 to 400, and greater than 400 were present in 10.0% (n = 1584), 11.5% (n = 1825), 5.2% (n = 830), and 3.1% (n = 497) respectively. After a median follow-up of 51.2 months, CVD risks increased from 5.2% in patients with no CAC to 28.2% in patients with CAC scores higher than 400. After adjustment, CVD risk increased with higher CAC score (hazard ratio [HR]CAC = 1-10 = 1.1; 95% CI, 0.9-1.4; HRCAC = 11-100 = 1.8; 95% CI, 1.5-2.1; HRCAC = 101-400 = 2.1; 95% CI, 1.7-2.6; and HRCAC>400 = 3.4; 95% CI, 2.8-4.2). Coronary artery calcium was particularly strongly associated with CAD (HRCAC>400 = 7.8; 95% CI, 5.5-11.2). The association between CAC and CVD was strongest in patients treated with anthracyclines (HRCAC>400 = 5.8; 95% CI, 3.0-11.4) and patients who received a radiation boost (HRCAC>400 = 6.1; 95% CI, 3.8-9.7). CONCLUSIONS AND RELEVANCE: This cohort study found that coronary artery calcium on breast cancer radiotherapy planning CT scan results was associated with CVD, especially CAD. Automated CAC scoring on radiotherapy planning CT scans may be used as a fast and low-cost tool to identify patients with breast cancer at increased risk of CVD, allowing implementing CVD risk-mitigating strategies with the aim to reduce the risk of CVD burden after breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03206333.

Compression Vest Treatment for Symptomatic Breast Edema in Women Treated for Breast Cancer: A Pilot Study.

Background: Lymphedema of the breast/chest wall after breast cancer treatment is often associated with pain and reduced quality of life. We conducted a pilot study to evaluate whether the use of a compression vest reduced symptoms of breast/chest wall edema in breast cancer patients. Methods and Results: This single-center study included patients (n = 25) with symptomatic breast/chest wall edema with a pain score of ≥3 on the Numerical Rating Scales (range 1-10). The patients were instructed to wear a compression vest (Lymphatrex, Class II) for 6 months. Wilcoxon signed-rank tests were used to compare differences in patient-reported pain intensity/severity. Analyses included all patients with available data. In total, 17 (68%) continued to wear their vests for 6 months, whereas the other 8 withdrew prematurely. At baseline, median pain severity (4.9, interquartile range [IQR] 3.6-6.0) and pain interference (4.3, IQR 2.1-5.9) scores were significantly higher compared with pain scores after wearing the compression vest for 6 months (1.8 IQR 1.0-4.8 and 1.4 IQR 0.9-4.4, resp.). Patient-reported breast/chest wall swelling decreased from 92% (n = 22) at baseline to 71% (n = 12) at 6 months. The prevalence of moderate/severe patient-reported breast/chest wall pain declined from 63% (n = 15) at baseline to 18% (n = 3) at 6 months. Physical, emotional, and social functioning improved over time and was comparable to scores of the Dutch reference population. Conclusion: The results of this pilot study suggest that a compression vest could be an acceptable and effective treatment option for patients with painful breast/chest wall edema. In compliant patients, swelling and pain was significantly reduced.

Trends in the risk of cardiovascular disease in women with breast cancer in a Dutch nationwide cohort study.

OBJECTIVES: To investigate trends in cardiovascular disease (CVD) risk following breast cancer using national registry data. METHODS: A nationwide cohort study was conducted, comprising 163 881 women with in situ (7.6%) or invasive (92.4%) breast cancer and women of the general population, ranging from 3 661 141 in 1996 to 4 566 573 in 2010. CVD mortality rate in women with and without breast cancer and hospitalisation rate after breast cancer were calculated for the years 1996-2010. Age-adjusted CVD and breast cancer mortality within 5 years after breast cancer admission (1997-2010) were compared with 1996 calculated with a Cox proportional hazard analysis. RESULTS: The absolute 10-year CVD mortality risk following breast cancer decreased from 56 per 1000 women in 1996 to 41 in 2005 (relative reduction=27.8%). In the general population, this decreased from 73 per 1000 women in 1996 to 55 in 2005 (-23.9%). The absolute risk of CVD hospitalisation within 1 year following breast cancer increased from 54 per 1000 women in 1996 to 67 in 2009 (+23.6%), which was largely explained by an increase in hospitalisation for hypertension, pulmonary embolism, rheumatoid heart/valve disease and heart failure. The 5-year CVD mortality risk was 42% lower (HR 0.58, 95% CI=0.48 to 0.70) for women admitted for breast cancer in 2010 compared with 1996. CONCLUSIONS: CVD mortality risk decreased in women with breast cancer and in women of the general population, with women with breast cancer having a lower risk of CVD mortality. By contrast, there was an increase in hospitalisation for CVD in women with breast cancer.

The Trials within Cohorts design faced methodological advantages and disadvantages in the exercise oncology setting.

OBJECTIVES: The Trials within Cohorts (TwiCs) design is an alternative for pragmatic randomized controlled trials (RCTs) and might overcome disadvantages such as difficult recruitment, dropout after randomization to control, and contamination. We investigated the applicability of the TwiCs design in an exercise oncology study regarding the recruitment process, representativeness of the study sample, contamination, participation, and dropout. METHODS: The Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA) Fit TwiCs evaluates an exercise intervention in inactive breast cancer patients. Eligible patients participating in the prospective UMBRELLA were identified and randomized. Patients randomized to the intervention (n = 130) were offered the intervention, whereas controls (n = 130) were not informed. RESULTS: Fifty-two percent (n = 68) accepted the intervention. Because this rate was lower than expected, a larger sample size was required than initially estimated (n = 166). However, recruitment of 260 patients was still completed by one researcher within 30 months. Unselective eligibility screening and randomization before invitation improved representativeness. Disadvantage of the design might be inclusion of ineligible patients when cohort information is limited. Furthermore, the design faced higher noncompliance in the intervention group, but prevention of contamination. CONCLUSION: The TwiCs design improved logistics in recruitment and prevented contamination, but noncompliance due to refusal of the intervention was higher compared with conventional pragmatic exercise oncology RCTs, which may dilute the estimated intervention effect.

Impact of modern-day axillary treatment on patient reported arm morbidity and physical functioning in breast cancer patients.

PURPOSE: To reduce arm morbidity, routine axillary lymph node dissection (ALND) is often omitted or replaced by axillary radiotherapy (AxRT) in patients with limited nodal involvement. We evaluated patient-reported arm morbidity and physical functioning in breast cancer patients undergoing modern-day axillary treatment. METHODS: All patients within the UMBRELLA cohort undergoing local radiotherapy with sentinel lymph node biopsy (SLNB), ALND and/or AxRT were selected. Patient-reported arm morbidity and physical functioning were assessed with EORTC QLQ C30/BR23 questionnaires up to eighteen months after initiation of radiotherapy. Patient-reported outcomes were compared between patients with SLNB only, ALND only, AxRT (level I-II), AxRT (level I-IV) or AxRT plus ALND by means of mixed model analysis. RESULTS: In total, 949 patients were identified; 641 (68%) SLNB only, 57 (6%) ALND only, 94 (10%) AxRT level I-II, 72 (8%) AxRT level I-IV and 85 (9%) ALND + AxRT. SLNB only resulted in the least arm morbidity scores. ALND + AxRT resulted in most arm morbidity, with clinically relevant differences at 18 months. AxRT (level I-II or level I-IV) resulted in significantly less arm symptoms in the first 3 months compared to ALND. Arm symptom scores between those receiving AxRT on levels I-II and I-IV were similar. CONCLUSION: Of all axillary management strategies, ALND plus AxRT is associated with worst patient-reported outcomes. AxRT resulted in less arm morbidity compared to ALND. Selective radiotherapy treatment of the axilla, i.e. radiotherapy of levels I-II only instead of levels I-IV, did not lead to clinically relevant reduced arm morbidity.

Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of Paclitaxel in patients with solid tumors.

BACKGROUND: The aim of this study was to quantitatively assess the effect of anthropometric and biochemical variables and third-space effusions on paclitaxel pharmacokinetics in solid tumor patients. MATERIALS AND METHODS: Plasma concentration-time data of paclitaxel were collected in patients with non-small cell lung cancer (n = 84), ovarian cancer (n = 40), and various solid tumors (n = 44), totaling 168 patients. Paclitaxel was given as a 3-hour infusion (n = 163) at doses ranging from 100 to 250 mg/m(2), or as a 24-hour infusion (n = 5) at a dose of 135 or 175 mg/m(2). Data were analyzed using nonlinear mixed-effect modeling. RESULTS: A three-compartment model with saturable elimination and distribution was used to describe concentration-time data. Male gender and body surface area were positively correlated with maximal elimination capacity of paclitaxel (VM(EL)); patient age and total bilirubin were negatively correlated with VM(EL) (P < 0.005 for all correlations). Typically, male patients had a 20% higher VM(EL); a 0.2 m(2) increase of body surface area led to a 9% increase of VM(EL); a 10-year increase of patient age led to a 5% decrease of VM(EL); and a 10-micromol increase of total bilirubin led to a 14% decrease of VM(EL). Third-space effusions were not correlated with paclitaxel pharmacokinetics. CONCLUSIONS: This extended retrospective population analysis showed patient gender to significantly and independently affect paclitaxel distribution and elimination. Body surface area, total bilirubin, and patient age were confirmed to affect paclitaxel elimination. This pharmacokinetic model allowed quantification of the covariate effects on the elimination of paclitaxel and may be used for covariate-adapted paclitaxel dosing.

Treatment constraints for single dose external beam preoperative partial breast irradiation in early-stage breast cancer.

BACKGROUND: Following breast-conserving surgery and post-operative 3D-conformal accelerated partial breast irradiation (APBI), suboptimal cosmetic results have been reported. Preoperative radiation delivery to the intact tumor enables better target visualization and treatment volume reduction. Single dose preoperative APBI has the potential to improve toxicity profiles, reduce treatment burden and enable in vivo exploration of breast cancer radiogenomics. PURPOSE: Develop practical guidelines for single dose external beam preoperative APBI. METHODS: Recommended dose constraints were derived from pooled dosimetry estimates from 2 clinical trials. In an American dose escalation trial, a uniform 15, 18 or 21 Gy dose has previously been evaluated for non-lobular cT1N0 or low/intermediate grade DCIS <2 cm in prone position (n = 32). In the Netherlands, the feasibility of ablative APBI (20 Gy to GTV, 15 Gy to CTV) to non-lobular cT1N0 in supine position, is currently being explored (n = 15). The dosimetric adherence to the developed constraints was evaluated in new APBI plans with a 21 Gy uniform dose but an extended CTV margin (n = 32). RESULTS: Dosimetric data pooling enabled the development of practical guidelines for single dose preoperative APBI. CONCLUSION: The developed guidelines will allow further explorations in the promising field of single dose preoperative external beam APBI for breast cancer treatment.