Comparison of prone and supine positioning for breast cancer radiotherapy using REQUITE data: dosimetry, acute and two years physician and patient-reported outcomes.

OBJECTIVE: Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk. To confirm these findings, we compared toxicity outcomes, photographic assessment, and dosimetry between both positions using REQUITE data. METHODS: REQUITE is an international multi-centre prospective observational study that recruited 2069 breast cancer patients receiving radiotherapy. Data on toxicity, health-related quality of life (HRQoL), and dosimetry were collected, as well as a photographic assessment. A matched case control analysis compared patients treated prone (n = 268) versus supine (n = 493). Exact matching was performed for the use of intensity-modulated radiotherapy, boost, lymph node irradiation, chemotherapy and fractionation, and the nearest neighbour for breast volume. Primary endpoints were dermatitis at the end of radiotherapy, and atrophy and cosmetic outcome by photographic assessment at two years. RESULTS: At the last treatment fraction, there was no significant difference in dermatitis (p = .28) or any HRQoL domain, but prone positioning increased the risk of breast oedema (p < .001). At 2 years, patients treated in prone position had less atrophy (p = .01), and higher body image (p < .001), and social functioning (p < .001) scores. The photographic assessment showed no difference in cosmesis at 2 years (p = .22). In prone position, mean heart dose (MHD) was significantly lower for left-sided patients (1.29 Gy vs 2.10 Gy, p < .001) and ipsilateral mean lung dose (MLD) was significantly lower for all patients (2.77 Gy vs 5.89 Gy, p < .001). CONCLUSIONS: Prone radiotherapy showed lower MLD and MHD compared to supine position, although the risk of developing breast oedema during radiotherapy was higher. At 2 years the photographic assessment showed no difference in the cosmetic outcome, but less atrophy was seen in prone-treated patients and this seems to have a positive influence on the HRQoL domain of body image.

Four irradiation and three positioning techniques for whole-breast radiotherapy: Is sophisticated always better?

PURPOSE: We report on a dosimetrical study of three patient positions (supine, prone dive, and prone crawl) and four irradiation techniques for whole-breast irradiation (WBI): wedged-tangential fields (W-TF), tangential-field intensity-modulated radiotherapy (TF-IMRT), multi-beam IMRT (MB-IMRT), and intensity-modulated arc therapy (IMAT). This is the first study to evaluate prone crawl positioning in WBI and the first study to quantify dosimetrical and anatomical differences with prone dive positioning. METHODS: We analyzed five datasets with left- and right-sided patients (n = 51). One dataset also included deep-inspiration breath hold (DIBH) data. A total of 252 new treatment plans were composed. Dose-volume parameters and indices of conformity were calculated for the planning target volume (PTV) and organs-at-risk (OARs). Furthermore, anatomical differences among patient positions were quantified to explain dosimetrical differences. RESULTS: Target coverage was inferior for W-TF and supine position. W-TF proved overall inferior, and IMAT proved foremost effective in supine position. TF-IMRT proved competitive to the more demanding MB-IMRT and IMAT in prone dive, but not in prone crawl position. The lung-sparing effect was overall confirmed for both prone dive and prone crawl positioning and was largest for prone crawl. For the heart, no differences were found between prone dive and supine positioning, whereas prone crawl showed cardiac advantages, although minor compared to the established heart-sparing effect of DIBH. Dose differences for contralateral breast were minor among the patient positions. In prone crawl position, the ipsilateral breast sags deeper and the PTV is further away from the OARs than in prone dive position. CONCLUSIONS: The prone dive and prone crawl position are valid alternatives to the supine position in WBI, with largest advantages for lung structures. For the heart, differences are small, which establishes the role of DIBH in different patient positions. These results may be of particular interest to radiotherapy centers with limited technical resources.

Accelerated radiotherapy in patients over sixty years old after mastectomy: Acute and one-year physician-assessed toxicity and health-related quality of life.

INTRODUCTION: Postmastectomy radiotherapy reduces the risk of locoregional recurrence in breast cancer patients. The first results on accelerated radiotherapy in five fractions after breast conserving surgery are promising. The data on postmastectomy radiotherapy in five or six fractions is limited. We now present the data on acute and one-year toxicity and health related quality of life (HRQoL) after postmastectomy radiotherapy in patients of sixty years or older. METHODOLOGY: 119 patients received five fractions of 5.7 Gy to the chest wall and five fractions of 5.4 Gy to the lymph nodes over ten to twelve days. Physician-assessed toxicity were scored using the Common Terminology Criteria for Adverse Events version 4.03 toxicity scoring system and the LENT-SOMA scale. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI-206). HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire the breast cancer specific module and the BREAST-Q questionnaire. RESULTS: Fatigue and edema were the most frequently observed physician-assessed toxicities. One year after radiotherapy only 12.9% experienced a clinically important deterioration in chest wall symptoms and in 22.9% of the patients were improved. Future perspective at one year after radiotherapy was improved in 40.0% of the patients. Patient-reported fatigue showed the greatest improvement. CONCLUSION: Accelerated radiotherapy should be considered to minimize the burden of breast cancer treatment, especially in older patients.

Prone Breast and Lymph Node Irradiation in 5 or 15 Fractions: A Randomized 2 × 2 Design Comparing Dosimetry, Acute Toxicity, and Set-Up Errors.

PURPOSE: Prone whole breast irradiation results in lower dose to organs at risk compared with supine position, especially lung dose. However, the adoption of prone position for whole breast irradiation + lymph node irradiation remains limited and data on lymph node irradiation in 5 fractions are lacking. Although the study was ended prematurely for the primary endpoint (breast retraction at 2 years), we decided to report acute toxicity for prone and supine positions and 5 and 15 fractions. Additionally, dosimetry and set-up accuracy between prone and supine positions were evaluated. METHODS AND MATERIALS: A randomized open-label factorial 2 × 2 design was used for an acute toxicity comparison between prone and supine positions and 5 and 15 fractions. The primary endpoint of the trial was breast retraction 2 years after treatment. In total, 57 patients were evaluated. Dosimetry and set-up errors were compared between prone and supine positions. All patients were positioned on either our in -house developed prone crawl breast couch or a Posirest-2 (Civco). RESULTS: No difference in acute toxicity between prone and supine positions was found, but 5 fractions did result in a lower risk of desquamation (15% vs 41%; P = .04). Prone positioning resulted in lower mean ipsilateral lung dose (2.89 vs 4.89 Gy; P < .001), mean thyroid dose (3.42 vs 6.61 Gy; P = .004), and mean contralateral breast dose (0.41 vs 0.54 Gy; P = .007). No significant difference in mean heart dose (0.90 vs 1.07 Gy; P = .22) was found. Set-up accuracy was similar between both positions. CONCLUSIONS: Unfortunately, the primary endpoint of the trial was not met due to premature closure of the trial. Acceleration in 5 fractions resulted in a lower risk of desquamation. Prone positioning did not influence acute toxicity or set-up accuracy, but did result in lower ipsilateral mean lung dose, thyroid dose, and contralateral breast dose.

Reproducibility of repeated breathhold and impact of breathhold failure in whole breast and regional nodal irradiation in prone crawl position.

In whole breast and regional nodal irradiation (WB + RNI), breathhold increases organ at risk (OAR) sparing. WB + RNI is usually performed in supine position, because positioning materials obstruct beam paths in prone position. Recent advancements allow prone WB + RNI (pWB + RNI) with increased sparing of OARs compared to supine WB + RNI. We evaluate positional and dosimetrical impact of repeated breathhold (RBH) and failure to breathhold (FTBH) in pWB + RNI. Twenty left-sided breast cancer patients were scanned twice in breathhold (baseline and RBH) and once free breathing (i.e. FTBH). Positional impact was evaluated using overlap index (OI) and Dice similarity coefficient (DSC). Dosimetrical impact was assessed by beam transposition from the baseline plan. Mean OI and DSC ranges were 0.01-0.98 and 0.01-0.92 for FTBH, and 0.73-1 and 0.69-1 for RBH. Dosimetric impact of RBH was negligible. FTBH significantly decreased minimal dose to CTV WBI, level II and the internal mammary nodes, with adequate mean doses. FTBH significantly increased heart, LAD, left lung and esophagus dose. OI and DSC for RBH and FTBH show reproducible large ROI positions. Small ROIs show poor overlap. FTBH maintained adequate target coverage but increased heart, LAD, ipsilateral lung and esophagus dose. RBH is a robust technique in pWB + RNI. (Clinicaltrials.gov: NCT05179161, registered 05/01/2022).

Safety of pre- or postoperative accelerated radiotherapy in 5 fractions: A randomized pilot trial.

OBJECTIVE: Neo-adjuvant radiotherapy (NART) for breast cancer has shown promising survival results in retrospective trials. However, there are some obstacles such as a chemotherapy delay, an increased overall treatment time (OTT) and the risk of increasing surgical morbidity. Accelerated radiotherapy (RT) in 5 fractions allows to deliver NART in a very short time span and minimizes the delay of surgery and chemotherapy. This trial investigates this NART schedule for safety, feasibility and OTT. MATERIAL AND METHODS: Twenty patients eligible for neo-adjuvant chemotherapy (NACT) and breast conserving surgery, were randomized between NART before NACT or NACT and postoperative RT. In both arms, RT treatment was given in 5 fractions to the whole breast with a simultaneously integrated boost (SIB) on the tumor(bed). Lymph node irradiation was given concomitantly in case of lymph node involvement. OTT was defined as the time from diagnosis to last surgery in the intervention group, while in the control group the time between diagnosis and last RT-fraction was used. In the intervention group NACT-delay was defined as time between diagnosis and start of chemotherapy. RESULTS: 20 patients were included, and 19 patients completed treatment. OTT was significantly shorter in the intervention group (mean 218 days, range 196-253) compared to the control group (mean 237, range 211-268, p = 0.001). The difference in mean duration from diagnosis to the first treatment was a non-significant 4 days longer (31 vs 27 days, p = 0.28), but the start of NACT after diagnosis was delayed by 21 days (48 vs 27 days, p < 0.001). NART did not result in additional surgery complications. CONCLUSION: This pilot trial is the first to report on accelerated NART in 5 fractions with SIB. NART before NACT resulted in a shorter OTT with good safety results.

Development and Optimization of a Machine-Learning Prediction Model for Acute Desquamation After Breast Radiation Therapy in the Multicenter REQUITE Cohort.

Purpose: Some patients with breast cancer treated by surgery and radiation therapy experience clinically significant toxicity, which may adversely affect cosmesis and quality of life. There is a paucity of validated clinical prediction models for radiation toxicity. We used machine learning (ML) algorithms to develop and optimise a clinical prediction model for acute breast desquamation after whole breast external beam radiation therapy in the prospective multicenter REQUITE cohort study. Methods and Materials: Using demographic and treatment-related features (m = 122) from patients (n = 2058) at 26 centers, we trained 8 ML algorithms with 10-fold cross-validation in a 50:50 random-split data set with class stratification to predict acute breast desquamation. Based on performance in the validation data set, the logistic model tree, random forest, and naïve Bayes models were taken forward to cost-sensitive learning optimisation. Results: One hundred and ninety-two patients experienced acute desquamation. Resampling and cost-sensitive learning optimisation facilitated an improvement in classification performance. Based on maximising sensitivity (true positives), the "hero" model was the cost-sensitive random forest algorithm with a false-negative: false-positive misclassification penalty of 90:1 containing m = 114 predictive features. Model sensitivity and specificity were 0.77 and 0.66, respectively, with an area under the curve of 0.77 in the validation cohort. Conclusions: ML algorithms with resampling and cost-sensitive learning generated clinically valid prediction models for acute desquamation using patient demographic and treatment features. Further external validation and inclusion of genomic markers in ML prediction models are worthwhile, to identify patients at increased risk of toxicity who may benefit from supportive intervention or even a change in treatment plan.

Acute toxicity and health-related quality of life after accelerated whole breast irradiation in 5 fractions with simultaneous integrated boost.

INTRODUCTION: Acceleration of radiotherapy in 5 fractions for breast cancer can reduce the burden of treatment. We report on acute toxicity after whole-breast irradiation with a simultaneous integrated boost in 5 fractions over 10-12 days. MATERIAL AND METHODS: Acute toxicity and health-related quality of life (HRQoL) of 200 patients, randomized between a 15- or 5-fractions schedule, were collected, using the CTCAE toxicity scoring system, the Multidimensional Fatigue Inventory, EORTC QLQ-C30 and BR23 and the BREAST-Q questionnaire. The prescribed dose to the breast was either 15∗2.67 Gy (40.05 Gy) or 5∗5.7 Gy (28.5 Gy). 90% of patients received a SIB to a cumulative dose of 46.8 Gy (15∗3.12 Gy) or 31 Gy (5∗6.2 Gy). RESULTS: Physician-assessed toxicity was lower for the 5-fractions group. A significant difference was observed for breast pain (p = 0.002), fatigue (p < 0.0001), breast edema (p = 0.001) and dermatitis (p = 0.003). Patients treated in 5 fractions reported better mean HRQoL scores for breast symptoms (p = 0.001) and physical well-being (p = 0.001). A clinically important deterioration in HRQoL of 10 points or more was also less frequently observed in the latter group for physical functioning (p = 0.0005), social functioning (p = 0.0007), fatigue (p = 0.003), breast symptoms (p = 0.0002) and physical well-being (p = 0.002). CONCLUSION: In this single institute study, acute toxicity of accelerated breast radiotherapy in 5 fractions over 10-12 days seems to compare favourably to hypofractionated breast radiotherapy in 15 fractions. Less breast edema, dermatitis, desquamation, breast pain and fatigue are seen. Social and physical functioning are also less disturbed and patients have a better future perspective.

5-Year Outcomes of a Randomized Trial Comparing Prone and Supine Whole Breast Irradiation in Large-Breasted Women.

PURPOSE: Prone position for whole breast irradiation (WBI) results in lower rates of toxicity and reduced ipsilateral mean lung and heart doses. No randomized trials comparing toxicity and cosmesis at 5 years with prone and supine positioning are available. METHODS AND MATERIALS: In this phase 2 open-label trial, 100 patients with large breast size requiring WBI were randomized between prone and supine positioning. Physician-assessed toxicity (retraction, fibrosis, edema, telangiectasia, pigmentation changes) was scored yearly for a total of 5 years, and photographs were taken at 5 years to assess cosmesis. The data were analyzed longitudinally and cross-sectionally. RESULTS: Longitudinal analysis shows lower grade 2 late toxicity with prone positioning. The results for at least grade 1 physician-assessed toxicity at 5 years are similar between supine and prone position, respectively, for retraction (56% vs 54%), fibrosis outside the tumor bed (33% vs 24%), tumor bed fibrosis (49% vs 46%), edema (11% vs 8%), telangiectasia (8% vs 3%), and breast pain (6% vs 8%) using cross-sectional analysis. However, the risk of pigmentation changes in prone position (0% vs 19%) 5 years after radiation therapy was significantly lower. Cosmesis was good or excellent in 92% and 75% of patients who used prone and supine positioning, respectively. The 5-year overall survival is 96% in both groups. CONCLUSION: Prone positioning results in reduced rates of late toxicity.

Delineation guidelines for the lymphatic target volumes in 'prone crawl' radiotherapy treatment position for breast cancer patients.

Our recently developed prone crawl position (PCP) for radiotherapy of breast cancer patients with lymphatic involvement showed promising preliminary data and it is being optimized for clinical use. An important aspect in this process is making new, position specific delineation guidelines to ensure delineation (for treatment planning) is uniform across different centers. The existing ESTRO and PROCAB guidelines for supine position (SP) were adapted for PCP. Nine volunteers were MRI scanned in both SP and PCP. Lymph node regions were delineated in SP using the existing ESTRO and PROCAB guidelines and were then translated to PCP, based on the observed changes in reference structure position. Nine PCP patient CT scans were used to verify if the new reference structures were consistently identified and easily applicable on different patient CT scans. Based on these data, a team of specialists in anatomy, CT- and MRI radiology and radiation oncology postulated the final guidelines. By taking the ESTRO and PROCAB guidelines for SP into account and by using a relatively big number of datasets, these new PCP specific guidelines incorporate anatomical variability between patients. The guidelines are easily and consistently applicable, even for people with limited previous experience with delineations in PCP.

Safely achieving single prolonged breath-holds of > 5 minutes for radiotherapy in the prone, front crawl position.

OBJECTIVE: Breast cancer radiotherapy is increasingly delivered supine with multiple, short breath-holds. There may be heart and lung sparing advantages for locoregional breast cancer of both prone treatment and in a single breath-hold. We test here whether single prolonged breath-holds are possible in the prone, front crawl position. METHODS: 19 healthy volunteers were trained to deliver supine, single prolonged breath-holds with pre-oxygenation and hypocapnia. We tested whether all could achieve the same durations in the prone, front crawl position. RESULTS: 19 healthy volunteers achieved supine, single prolonged breath-holds for mean of 6.2 ± 0.3 min. All were able to hold safely for the same duration while prone (6.1 ± 0.2 min ns. by paired ANOVA). With prone, the increased weight on the chest did not impede chest inflation, nor the ability to hold air in the chest. Thus, the rate of chest deflation (mean anteroposterior deflation movement of three craniocaudally arranged surface markers on the spinal cord) was the same (1.2 ± 0.2, 2.0 ± 0.4 and 1.2 ± 0.4 mm/min) as found previously during supine prolonged breath-holds. No leakage of carbon dioxide or air was detectable into the facemask. CONCLUSION: Single prolonged (>5 min) breath-holds are equally possible in the prone, front crawl position. ADVANCES IN KNOWLEDGE: Prolonged breath-holds in the front crawl position are possible and have the same durations as in the supine position. Such training would therefore be feasible for some patients with breast cancer requiring loco-regional irradiation. It would have obvious advantages for hypofractionation.

Two-year toxicity of simultaneous integrated boost in hypofractionated prone breast cancer irradiation: Comparison with sequential boost in a randomized trial.

INTRODUCTION: A simultaneous integrated boost (SIB) leads to less acute toxicity. Less is known for late toxicity due to SIB. In this first and only randomized trial, two-years toxicity is analysed. MATERIALS AND METHODS: Physician-assessed toxicity, using the LENT SOMA scale, and photographs, analysed with the BCCT.core software, was examined for 150 patients, randomized between SIB and sequential boost (SEB). RESULTS: Differences in physician-assessed two-years toxicity and photographic analysis between SIB and SEB are very small and not significant. CONCLUSION: There is no indication that a SIB leads to an excess in toxicity or worse cosmetic outcome at 2 years.

Prolonging deep inspiration breath-hold time to 3 min during radiotherapy, a simple solution.

BACKGROUND AND PURPOSE: Deep inspiration breath-hold is an established technique to reduce heart dose during breast cancer radiotherapy. However, modern breast cancer radiotherapy techniques with lymph node irradiation often require long beam-on times of up to 5 min. Therefore, the combination with deep inspiration breath-hold (DIBH) becomes challenging. A simple support technique for longer duration deep inspiration breath-hold (L-DIBH), feasible for daily use at the radiotherapy department, is required to maximize heart sparing. MATERIALS AND METHODS: At our department, a new protocol for multiple L-DIBH of at least 2 min and 30 s was developed on 32 healthy volunteers and validated on 8 breast cancer patients during radiotherapy treatment, using a pragmatic process of iterative development, including all major stakeholders. Each participant performed 12 L-DIBHs, on 4 different days. Different methods of pre-oxygenation and voluntary hyperventilation were tested, and scored on L-DIBH duration, ease of use, and comfort. RESULTS: Based on 384 L-DIBHs from 32 healthy volunteers, voluntary hyperventilation for 3 min whilst receiving high-flow nasal oxygen at 40 L/min was the most promising technique. During validation, the median L-DIBH duration in prone position of 8 breast cancer patients improved from 59 s without support to 3 min and 9 s using the technique (p < 0.001). CONCLUSION: A new and simple L-DIBH protocol was developed feasible for daily use at the radiotherapy center.

Effects of deep inspiration breath hold on prone photon or proton irradiation of breast and regional lymph nodes.

We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN_MI). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In patients with high risks for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~ 8% disease-specific survival benefit of WB + LN_MI radiotherapy in any of the assessed treatments.

Crawl positioning improves set-up precision and patient comfort in prone whole breast irradiation.

Prone positioning for whole-breast irradiation (WBI) reduces dose to organs at risk, but reduces set-up speed, precision, and comfort. We aimed to improve these problems by placing patients in prone crawl position on a newly developed crawl couch (CrC). A group of 10 right-sided breast cancer patients requiring WBI were randomized in this cross-over trial, comparing the CrC to a standard prone breastboard (BB). Laterolateral (LL), craniocaudal (CC) and anterioposterior (AP) set-up errors were evaluated with cone beam CT. Comfort, preference and set-up time (SUT) were assessed. Forty left and right-sided breast cancer patients served as a validation group. For BB versus CrC, AP, LL and CC mean patient shifts were - 0.8 ± 2.8, 0.2 ± 11.7 and - 0.6 ± 4.4 versus - 0.2 ± 3.3, - 0.8 ± 2.5 and - 1.9 ± 5.7 mm. LL shift spread was reduced significantly. Nine out of 10 patients preferred the CrC. SUT did not differ significantly. The validation group had mean patient shifts of 1.7 ± 2.9 (AP), 0.2 ± 3.6 (LL) and - 0.2 ± 3.3 (CC) mm. Mean SUT in the validation group was 1 min longer (P < 0.05) than the comparative group. Median SUT was 3 min in all groups. The CrC improved precision and comfort compared to BB. Set-up errors compare favourably to other prone-WBI trials and rival supine positioning.

Health-related quality of life after accelerated breast irradiation in five fractions: A comparison with fifteen fractions.

INTRODUCTION: In breast cancer patients, duration of illness and treatment have a negative impact on the quality of life. The duration of radiotherapy can be shortened by reducing the number of treatment fractions. In this study, the impact of an accelerated breast irradiation schedule in 5 fractions over 10 to 12 days on health-related quality of life (HRQoL) was investigated and compared to a standard hypofractionation schedule of 15 fractions. METHODOLOGY: The study population was composed of 530 patients treated in 15 fractions and 196 patients treated in 5 fractions. Patients were included in different trials evaluating HRQoL. Radiotherapy-related items of the EORTC QLQ-C30 and BR23 and Breast-Q questionnaires were evaluated by comparing baseline scores to scores at 2-4 weeks and 1 year after radiotherapy. Clinically important improvements and deteriorations of HRQoL were compared between the 2 radiation schedules. RESULTS: Patients treated in 5 fractions show less deterioration of physical well-being 2-4 weeks after radiotherapy. One year after radiotherapy, the 5 fractions schedule results in more patients reporting a clinically important improvement in pain, arm and breast symptoms and future perspective. CONCLUSION: Radiotherapy in 5 fractions over 10-12 days results in more improvement and less deterioration of HRQoL than a 15 fractions schedule over 3 weeks.

Feasibility study on pre or postoperative accelerated radiotherapy (POP-ART) in breast cancer patients.

BACKGROUND: In early-stage breast cancer, the cornerstone of treatment is surgery. After breast-conserving surgery, adjuvant radiotherapy has shown to improve locoregional control and overall survival rates. The use of breast radiotherapy in the preoperative (preop) setting is far less common. Nevertheless, it might improve disease-free survival as compared to postoperative radiotherapy. There is also a possibility of downsizing the tumour which might lead to a lower need for mastectomy. There are some obstacles that complicate its introduction into daily practice. It may complicate surgery or lead to an increase in wound complications or delayed wound healing. Another fear of preop radiotherapy is delaying surgery for too long. At Ghent University Hospital, we have experience with a 5-fraction radiotherapy schedule allowing radiotherapy delivery in a very short time span. METHODS: Twenty female breast cancer patients with non-metastatic disease receiving preop chemotherapy will be randomized between preop or postoperative radiotherapy. The feasibility of preop radiotherapy will be evaluated based on overall treatment time. All patients will be treated in 5 fractions of 5.7 Gy to the whole breast with a simultaneous integrated boost to the tumour/tumour bed of 5 × 6.2 Gy. In case of lymph node irradiation, the lymph node regions will receive a dose of 27 Gy in 5 fractions of 5.4 Gy. The total duration of therapy will be 10 to 12 days. In the preop group, overall treatment time is defined as the time between diagnosis and the day of last surgery, in the postop group between diagnosis and last irradiation fraction. Toxicity related to surgery, radio-, and chemotherapy will be evaluated on dedicated case-report forms at predefined time points. Tumour response will be evaluated on the pathology report and on MRI at baseline and in the interval between chemotherapy and surgery. DISCUSSION: The primary objective of the trial is to investigate the feasibility of preop radiotherapy. Secondary objectives are to search for biomarkers of response and toxicity and identify the involved cell death mechanisms and the effect of preop breast radiotherapy on the in-situ immune micro-environment.

Chronic obstructive pulmonary disease and the development of atrial fibrillation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been associated with atrial fibrillation (AF). More insight into the epidemiology and underlying mechanisms is required to optimize management. METHODS: The Rotterdam Study is a large, population-based cohort study with long-term follow-up. Time dependent Cox proportional hazard models were constructed to study the effect of COPD on incident AF, adjusted for age, sex and pack years of cigarette smoking, and additionally stratified according to exacerbation frequency, left atrial size and baseline systemic inflammatory levels. RESULTS: 1369 of 10,943 subjects had COPD, of whom 804 developed AF. The AF incidence rate was 14 per 1000 person years in COPD and 8 per 1000 person years in subjects without COPD. The adjusted hazard ratio (HR) for COPD subjects to develop AF as compared to subjects without COPD was 1.28 (95%CI [1.04, 1.57]). COPD subjects with frequent exacerbations had a twofold increased AF risk (HR 1.99 [1.42, 2.79]) and COPD subjects with a left atrial size ≥40 mm also had an elevated AF risk (HR 1.77 [1.07, 2.94]). COPD subjects with baseline systemic inflammatory levels above the median had significantly increased AF risks (hsCRP≥1.83 mg/L: HR 1.51 [1.13, 2.03] and IL6 ≥ 1.91 ng/L: HR 2.49 [1.18, 5.28]), whereas COPD subjects below the median had in both analyses no significantly increased AF risk. CONCLUSIONS: COPD subjects had a 28% increased AF risk, which further increased with frequent exacerbations and an enlarged left atrium. The risk was driven by COPD subjects having elevated systemic inflammatory levels.