The EORTC 22922/10925 trial investigating regional nodal irradiation in stage I-III breast cancer: Outcomes according to locoregional and systemic therapies.

The EORTC 22922/10925 trial aimed to investigate the impact on overall survival (OS) of elective internal mammary and medial supraclavicular (IM-MS) radiation therapy (RT) in breast cancer stage I-III. Surgery for the primary tumour and axillary lymph nodes, chest wall RT, boost RT after whole breast RT in breast conserving therapy (BCT), RT to operated axilla, and systemic therapy were per physician's preference. The aim of the current analysis is to assess breast cancer outcomes according to different locoregional and systemic therapy used in the trial. MATERIAL/METHODS: Data with a median follow-up of 15.7 years were extracted from the trial's case report forms. Kaplan-Meier curves of disease-free and OS and cumulative incidence curves of breast cancer events were produced. An exploratory analysis of the effect of the type of locoregional and systemic therapy on breast cancer outcomes was conducted using the Cox model or the Fine & Gray model accounting for competing risks, both models being adjusted for baseline patient and disease characteristics and treatment. The significance level was set at 5 %, 2-sided. RESULTS: Of the 4,004 patients included, 625 (16%) did not receive any postoperative systemic therapy, 1,185 (30%) received endocrine therapy only, 994 (25%) chemotherapy only, and 1,200 (30%) both chemotherapy and endocrine therapy, without differences between the randomisation arms. Administration and type of therapy was associated with age, menopausal status, clinical T- and N-stage and ER status (p < 0.0001). Local control was better with mastectomy (with/without postmastectomy RT) as compared to BCT, but mastectomy was associated with more distant metastasis (DM) as first event. Similarly, DM as first event occurred more in the BCT group that received a boost as compared to no boost and in those who received RT to the lower axillary level. IM-MS RT reduced significantly regional recurrences and improved disease-free survival in a sensitivity stratified analysis. OS was worse with mastectomy as compared to BCT and with irradiation of the axilla but better with sentinel node dissection and adjuvant combined chemo and hormonal therapy. CONCLUSION: Different components of therapy influenced the site of first event. IM-MS RT improved outcomes in different breast cancer outcomes were most probably related that the group were balanced due to the trial arms and stratification methods.

From guidelines to clinical practice in care for ischaemic stroke patients: A systematic review and expert opinion.

BACKGROUND AND PURPOSE: Guidelines help physicians to provide optimal care for stroke patients, but implementation is challenging due to the quantity of recommendations. Therefore a practical overview related to applicability of recommendations can be of assistance. METHODS: A systematic review was performed on ischaemic stroke guidelines published in scientific journals, covering the whole acute care process for patients with ischaemic stroke. After data extraction, experts rated the recommendations on dimensions of applicability, that is, actionability, feasibility and validity, on a 9-point Likert scale. Agreement was defined as a score of ≥8 by ≥80% of the experts. RESULTS: Eighteen articles were identified and 48 recommendations were ultimately extracted. Papers were included only if they described the whole acute care process for patients with ischaemic stroke. Data extraction and analysis revealed variation in terms of both content and comprehensiveness of this description. Experts reached agreement on 34 of 48 (70.8%) recommendations in the dimension actionability, for 16 (33.3%) in feasibility and for 15 (31.3%) in validity. Agreement on all three dimensions was reached for seven (14.6%) recommendations: use of a stroke unit, exclusion of intracerebral haemorrhage as differential diagnosis, administration of intravenous thrombolysis, performance of electrocardiography/cardiac evaluation, non-invasive vascular examination, deep venous thrombosis prophylaxis and administration of statins if needed. DISCUSSION AND CONCLUSION: Substantial variation in agreement was revealed on the three dimensions of the applicability of recommendations. This overview can guide stroke physicians in improving the care process and removing barriers where implementation may be hampered by validity and feasibility.

Coverage with evidence development program on stereotactic body radiotherapy in Belgium (2013-2019): a nationwide registry-based prospective study.

Background: Although stereotactic body radiotherapy (SBRT) was progressively adopted in clinical practice in Belgium, a reimbursement request in 2011 was not granted because of remaining clinical and economic uncertainty. A coverage with evidence development (CED) program on SBRT started in 2013, with the aim to assess clinical and technical patterns-of-care in Belgium and monitor survival per indication, in view of supporting inclusion in the reimbursement system. Methods: The Belgian National Institute for Health and Disability Insurance (NIHDI) initiated this prospective observational registry. Participating departments, using SBRT in clinical practice, signed the 'NIHDI convention'. Eligible patients had a primary tumour (PT) or oligometastatic disease (OMD). Patient, tumour, and treatment characteristics were collected through an online module of the Belgian Cancer Registry, prerequisite for financing. Five-year overall survival (5YOS) and 30- and 90-days mortality were primary outcomes, derived from vital status information. Findings: Between 10/2013 and 12/2019, 20 of the 24 accredited radiotherapy departments participated, 6 were academic. Registered cases per department ranged from 21 to 867. Of 5675 registrations analysed, the majority had good performance status and limited number of lesions. Enrolment of PTs remained stable over time, OMDs almost doubled. Peripheral lung lesions dominated in PTs as in OMDs. Other metastases were (para)spinal, 'non-standard' and hepatic. Thirty- and 90-days mortalities remained below 0.5% [95% CI 0.3%-0.8%] respectively 2.1% [95% CI 1.6%-2.7%]. 5YOS varied by indication, primary prostate patients performing best (85%, 95% CI [76%, 96%]), those with liver metastases worst (19%, 95% CI [15%, 24%]). Better OS was observed in academic departments, department size did not significantly impact survival. OMD survival was better in 2018-19. Interpretation: CED can be used to define patterns-of-care and real-life outcome of innovative radiotherapy. As the observed survival for different indications was in line with outcome in emerging literature, SBRT was included in the Belgian reimbursement system as of January 2020. Funding: NIHDI financed participating departments per registered case.

Development of a set of measurable outcome indicators for Flemish patients with inflammatory bowel disease.

OBJECTIVE: Uniform and standardised quality measurement allows care assessment and improvement. Following a pragmatic consensus method we aimed to agree on a selection of measurable quality indicators that can be used to assess, benchmark and gradually improve inflammatory bowel disease (IBD) care in Flanders. METHODS: Of 49 structures, 135 processes and 37 outcome indicators identified through literature, 58 were preselected and reformulated into measurable outcome indicators by four IBD physicians. A larger expert group scored the 58 indicators on a 10-point importance scale twice, endorsed by patient and expert perspectives in between rounds. Additional items could be suggested. A final selection and subset of indicators with room for improvement were agreed upon during a consensus meeting. RESULTS: Fifty indicators received an importance score of 7 or higher by ≥80% of the participants (seven IBD nurses, one abdominal surgeon, one chief medical officer and 31 IBD physicians including two paediatricians). Eight indicators scored highly important by 60-80%, two indicators reintroduced by patients and one newly suggested, were discussed during the consensus meeting. Among 26 participants, eight indicators were agreed to be added to the final selection. Of the 58 selected items, 19 were retained in the improvement subset, related to patient-reported outcomes, use of hospital services and survival, patient characteristics, monitoring of disease activity and remission, endoscopy guidelines, infection prevention, steroid and other medication use. CONCLUSION: Fifty-eight indicators were selected to assess IBD care in Flanders and a subset of 19 for use in clinical practice to steer quality improvement initiatives.

High-grade HER2-positive mucoepidermoid carcinoma of the breast: a case report and review of the literature.

BACKGROUND: Mucoepidermoid carcinoma of the breast is a rare special type of salivary gland-like tumor of the breast, usually displaying triple-negative phenotype. To date, only 64 cases have been reported in the English literature. Herein, we report the first case of mucoepidermoid carcinoma of the breast with human epidermal growth factor receptor 2 gene amplification. CASE PRESENTATION: A 58-year-old Caucasian woman treated with breast-conserving surgery, radiotherapy, and chemotherapy for an invasive breast carcinoma of no special type, relapsed 20 years later in the ipsilateral left breast. Histological examination of the core needle biopsy of the relapse deferred to the surgical specimen for the definitive diagnosis, because of the broad differential diagnosis. On the resected specimen we observed the presence of a poorly differentiated carcinoma with mucoepidermoid carcinoma of the breast typical features consisting of epidermoid, intermediate and mucinous cells lacking true keratinization, in keeping with the latest World Health Organization diagnostic criteria. The mucoepidermoid carcinoma of the breast was weakly estrogen receptor and androgen receptor positive and progesterone receptor negative, but exceptionally showed human epidermal growth factor receptor 2 gene amplification. Mastermind-like transcriptional coactivator 2 gene translocations were not detected by fluorescent in situ hybridization. The patient received adjuvant chemotherapy with anti-human epidermal growth factor receptor 2 therapy but no endocrine therapy. After 61 months of follow-up, no signs of local or distant recurrence were observed. CONCLUSIONS: Mucoepidermoid carcinoma of the breast is a very rare entity. Despite being most frequently triple negative, the standard evaluation of receptor status is mandatory, as well as strict application of World Health Organization diagnostic criteria for correct patient management.

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.

Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. RESULTS: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level. CONCLUSIONS: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.

Mapping the location of local and regional recurrences according to breast cancer surgery and radiation therapy: Results from EORTC 22922/10925.

The purpose of this study is to evaluate the influence of the extent of surgery and radiation therapy (RT) on the rates and sites of local (LR) and regional recurrences (RR) in the EORTC 22922/10925 trial. PATIENTS AND METHODS: All data were extracted from the trial's individual patients' case report forms (CRF) and analysed with a median follow-up of 15.7 years. Cumulative incidence curves were produced for LR and RR accounting for competing risks: an exploratory analysis of the effect of the extent of surgical and radiation treatments on LR rate was conducted using the Fine & Gray model accounting for competing risks and adjusted for baseline patient and disease characteristics. The significance level was set at 5%, 2-sided. Frequency tables were used to describe the spatial location of LR and RR. RESULTS: Out of 4004 patients included in the trial, 282 (7%) patients experienced LR and 165 (4.1%) RR, respectively. Cumulative incidence rate of LR at 15 years was lower after mastectomy (3.1%) compared to BCS + RT (7.3%) (F&G: HR (Hazard Ratio) = 0.421, 95%CI = 0.282-0.628, p-value < 0.0001). LR were similar up to 3 years for both mastectomy and BCS but continued to occur at a steady rate for BCS + RT, only. The spatial location of the recurrence was related to the locoregional therapy applied and the absolute gain of RT correlated to stage of disease and extent of surgery. CONCLUSIONS: The extent of locoregional therapies impacts significantly on LR and RR rates and spatial location.

Mortality and Major Adverse Cardiac Events in Patients With Breast Cancer Receiving Radiotherapy: The First Decade.

Background Treatment for breast cancer (BC) frequently involves radiotherapy. Guidelines recommend screening for cardiac adverse events starting 10 years after radiotherapy. The rationale for this interval is unclear. Methods and Results We aimed to study cardiovascular event rates in the first decade following curative radiotherapy for BC. We compared mortality and cardiovascular event rates with an age- and risk factor-matched control population. We included 1095 patients with BC (mean age 56±12 years). Two hundred and eighteen (19.9%) women died. Cancer and cardiovascular mortality caused 107 (49.1%) and 22 (10.1%) deaths, respectively. A total of 904 cases were matched to female FLEMENGHO (Flemish Study on Environment, Genes and Health Outcomes) participants. Coronary artery disease incidence was similar (risk ratio [RR], 0.75 [95% CI, 0.48-1.18]), yet heart failure (RR, 1.97 [95% CI, 1.19-3.25]) and atrial fibrillation/flutter (RR, 1.82 [95% CI, 1.07-3.08]) occurred more often in patients with BC. Age (hazard ratio [HR], 1.033 [95% CI, 1.006-1.061], P=0.016), tumor grade (HR, 1.739 [95% CI, 1.166-2.591], P=0.007), and neoadjuvant treatment setting (HR, 2.782 [95% CI, 1.304-5.936], P=0.008) were risk factors for mortality. Risk factors for major adverse cardiac events were age (HR, 1.053 [95% CI, 1.013-1.093]; P=0.008), mean heart dose (HR, 1.093 [95% CI, 1.025-1.167]; P=0.007), history of cardiovascular disease (HR, 2.386 [95% CI, 1.096-6.197]; P=0.029) and Mayo Clinic Cardiotoxicity Risk Score (HR, 2.664 [95% CI, 1.625-4.367]; P<0.001). Conclusions Ten-year mortality following curative treatment for unilateral BC was mainly cancer related, but heart failure and atrial fibrillation/flutter were already common in the first decade following irradiation. Mean heart dose, pre-existing cardiovascular diseases, and Mayo Clinic Cardiotoxicity Risk Score were risk factors for cardiac adverse events. These results suggest a need for early dedicated cardio-oncological follow-up after radiotherapy.

Radiotherapy-specific quality indicators at national level: How to make it happen.

PURPOSE /OBJECTIVE: To promote best practice and quality of care, the Belgian College of Physicians for Radiotherapy Centers established a set of radiotherapy specific quality indicators for benchmarking on a national level. This paper describes the development, the collected QIs, the observed trends and the departments' evaluation of this initiative. MATERIAL AND METHODS: The Donabedian approach was used, focussing on structural, process and outcome QIs. The criteria for QI selection were availability, required for low-threshold regular collection, and applicability to guidelines and good practice. The QIs were collected yearly and individualized reports were sent out to all RT departments. In 2021, a national survey was held to evaluate the ease of data collection and submission, and the perceived importance and validity of the collected QIs. RESULTS: 18 structural QI and 37 process and outcome parameters (n = 25 patients/pathology/department) were collected. The participation rate amounted to 95 % overall. The analysis gave a national overview of RT activity, resources, clinical practice and reported acute toxicities. The individualized reports allowed departments to benchmark their performance. The 2021 survey indicated that the QIs were overall easy to collect, relevant and reliable. The collection of acute recorded toxicities was deemed a weak point due to inter-observer variabilities and lack of follow-up time. CONCLUSION: QI collection on a national level is a valuable process in steering quality improvement initiatives. The feasibility and relevance was demonstrated with a high level of participation. The national initiative will continue to evolve as a quality monitoring and improvement tool.

Variation in stroke care at the hospital level: A cross-sectional multicenter study.

Introduction: Stroke is one of the leading causes of mortality and disability. Improving patient outcomes can be achieved by improving stroke care and adherence to guidelines. Since wide variation in adherence rates for stroke guidelines still exists, we aimed to describe and compare stroke care variability within Belgian hospitals. Materials and methods: An observational, multicenter study was performed in 29 Belgian hospitals. We retrospectively collected patient characteristics, quality indicators, and time metrics from the last 30 consecutive patients per hospital, diagnosed with ischemic stroke in 2019 with structured questionnaires. Mean adherence ratios (%) ± SD (minimum - maximum) were calculated. Results: We analyzed 870 patient records from 29 hospitals. Results showed large inter- and intrahospitals variations in adherence for various indicators. Almost all the patients received brain imaging (99.7%) followed by admission at a stroke unit in 82.9% of patients. Of patients not receiving thrombolysis, 92.5% of patients were started on antithrombotic drugs. Indicators with moderate median adherence but large interhospital variability were glycemia monitoring [82.3 ± 16.7% (26.7-100.0%)], performing clinical neurological examination and documentation of stroke severity [63.1 ± 36.8% (0-100%)], and screening for activities of daily living [51.1 ± 40.3% (0.0-100.0%)]. Other indicators lacked adequate adherence: swallowing function screening [37.0 ± 30.4% (0.0-93.3%)], depression screening [20.2 ± 35.8% (0.0-100%)], and timely body temperature measurement [15.1 ± 17.0% (0.0-60%)]. Conclusion: We identified high adherence to guidelines for some indicators, but lower rates with large interhospital variability for other recommendations also based on robust evidence. Improvement strategies should be implemented to improve the latter.

Elevated CA 15.3 in Newly Diagnosed Breast Cancer: A Retrospective Study.

PURPOSE: To examine the relationship between baseline elevated CA 15.3 (>30 kU/L) and the prevalence of primary or secondary metastatic disease in breast cancer. METHODS: We performed a retrospective, single-center cohort study on patients with newly diagnosed breast cancer and baseline CA 15.3> 30 kU/L, diagnosed between 2000-2015. Information on tumor characteristics, pre-treatment CA 15.3, staging results, treatment approach, disease recurrence and death were collected from individual medical files. For every tumor subtype, the optimal cut-off value of CA 15.3 for determining primary metastatic disease is determined. RESULTS: Eight hundred ninety-four patients with baseline CA15.3 > 30 kU/L were included of which 38% were diagnosed with primary metastatic disease while 15% subsequently developed secondary metastatic disease, with a median follow-up of 74 months. LuminalHER2 tumors had the highest proportion of primary metastatic disease (48%), Triple Negative tumors had the highest proportion of secondary metastatic disease (24%) (p=0.008). A higher CA 15.3 value corresponds to higher risk of both primary and secondary metastatic disease (p<0.001). For the determination of primary metastatic disease, optimal cut-off values for CA 15.3 range between 44 kU/L (Triple Negative) and 59 kU/L (Luminal B). CONCLUSION: In patients with newly diagnosed breast cancer and baseline elevated CA 15.3>30 kU/L, 38% presents with primary metastatic disease and 15% develops secondary metastatic disease, with a median follow-up of 74 months. Our results can help clinicians to identify patients at risk of primary or secondary metastatic disease via information on tumor subtype and baseline CA 15.3.

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.

The association of internal mammary and medial supraclavicular lymph node radiation technique with clinical outcomes: Results from the EORTC 22922/10925 randomised trial.

BACKGROUND AND PURPOSE: The multicentre EORTC 22922/10925 trial (ClinicalTrials.gov, NCT00002851) was conducted between 1996 and 2004. The trial evaluated the effect of irradiation of the internal mammary and medial supraclavicular lymph node chains (IM-MS) vs no further radiation therapy (RT) on survival and cause of death in breast cancer stage I-III patients. At 15.7 years of median follow-up, a significant reduction of breast cancer specific mortality (BCSM) and any recurrence, not translating in improved overall survival (OS), and low absolute rates of side effects were found. The aim of the current analysis was to evaluate the association of RT techniques of IM-MS lymph node irradiation with long-term outcomes. PATIENTS AND METHODS: Three RT techniques were used for IM-MS: a standard technique using a fixed set-up combining photon/electron beams to the IM and tangential fields to the breast or chest wall vs a standard-modified technique with minor adaptation for beam settings vs a more individualised technique based on individual localisation of the IM. Techniques used were fixed per institution over the duration of the trial. We performed an exploratory and descriptive analysis of the outcomes after 15 years follow-up for the three RT techniques. RESULTS: Between July 1996 and January 2004, 46 radiation oncology departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. The number of patients treated by each technique was 2440 (61%) by standard vs 635 (16%) by standard-modified vs 929 (23%) patients by individualised technique. The absolute improvements of oncological outcomes in terms of disease-free survival (DFS), OS and BCSM with IM-MS RT compared to no IM-MS RT were 6.8%, 4.9% and -5.8% for the individualised technique, vs 1.6%, 2.9% and -4.3% for modified standard and -1.4%, 1.1% and -3% for standard technique, respectively. The increase in 15-year rates of side effects due to IM-MS RT, both scored longitudinally and cross-sectionally, were similar among the techniques. CONCLUSION: Even though a straightforward comparison by technique is not possible because of variations in baseline characteristics between institutions, our findings suggest that the use of more individualised RT techniques is associated with higher rates of oncological improvements without increased risks for late side effects.

Validation of a prognostic scoring system for postmastectomy locoregional recurrence in breast cancer.

BACKGROUND: To date, it remains unclear which patients with breast cancer (BC) benefit from post-mastectomy radiotherapy (PMRT). Cheng et al. developed and validated a scoring system based on 4 prognostic factors for locoregional recurrence (LRR) to identify patients in need for PMRT. These factors include age, estrogen receptor status, lymphovascular status and number of affected axillary lymph nodes. PURPOSE: To validate the scoring system for LRR in BC developed by Cheng et al. by using an independent BC database. METHODS AND MATERIALS: We retrospectively identified 1989 BC cases, treated with mastectomy (ME) with or without PMRT at the University Hospitals Leuven between 2000 and 2007. The primary endpoint was 5-year locoregional control rate with and without PMRT, according to the LRR score. RESULTS: Median follow-up time was 11.4 years. After excluding patients with missing variables 1103 patients were classified using the LRR scoring system: 688 (62.38%) patients were at low risk of recurrence (LRR score 0-1), 335 (30.37%) patients were at intermediate risk of recurrence (LRR score 2-3) and 80 (7.25%) patients were at high risk of recurrence (LRR score ≥4). 5-year locoregional control rates with and without PMRT were 99.20% versus 99.21% (p = 0.43) in the low-risk group; 98.24% versus 85.74% (p < 0.0001) in the intermediate-risk group and 96.87% versus 85.71% (p = 0.10) in the high-risk group respectively. CONCLUSION: Our validation of the LRR scoring system suggests it can be used to point out patients that would benefit from PMRT. We recommend further validation of this scoring system by other independent institutions before application in clinical practice.

Intra-fraction motion monitoring during fast modulated radiotherapy delivery in a closed-bore gantry linac.

BACKGROUND AND PURPOSE: New closed-bore linacs allow for highly streamlined workflows and fast treatment delivery resulting in brief treatment sessions. Motion management technology has only recently been integrated inside the bore, yet is required in future online adaptive workflows. We measured patient motion during every step of the workflow: image acquisition, evaluation and treatment delivery using surface scanning. MATERIALS AND METHODS: Nineteen patients treated for breast, lung or esophageal cancer were prospectively monitored from the end of setup to the end of treatment delivery in the Halcyon linac (Varian Medical Systems). Motion of the chest was tracked by way of 6 degrees-of-freedom surface tracking. Baseline drift and rate of drift were determined. The influence of fraction number, patient and fraction duration were analyzed with multi-way ANOVA. RESULTS: Median fraction duration was 4 min 48 s including the IGRT procedure (kV-CBCT acquisition and evaluation) (N = 221). Baseline drift at the end of the fraction was -1.8 ± 1.5 mm in the anterior-posterior, -0.0 ± 1.7 mm in the cranio-caudal direction and 0.1 ± 1.8 mm in the medio-lateral direction of which 75% occurred during the IGRT procedure. The highest rate of baseline drift was observed between 1 and 2 min after the end of patient setup (-0.62 mm/min). Baseline drift was patient and fraction duration dependent (p < 0.001), but fraction number was not significant (p = 0.33). CONCLUSION: Even during short treatment sessions, patient baseline drift is not negligible. Drift is largest during the initial minutes after completion of patient setup, during verification imaging and evaluation. Patients will need to be monitored during extended contouring and re-planning procedures in online adaptive workflows.

Side Effects 15 Years After Lymph Node Irradiation in Breast Cancer: Randomized EORTC Trial 22922/10925.

BACKGROUND: Uncertainty about the benefit-risk ratio of regional lymph node irradiation led to varying clinical protocols. We investigated long-term late side effects after internal mammary and medial supraclavicular (IM-MS) lymph node irradiation to improve shared decision making. METHODS: The multicenter European Organization for Research and Treatment of Cancer trial (ClinicalTrials.gov, NCT00002851) randomly assigned stage I-III breast cancer patients with involved axillary nodes and/or a medially located primary tumor. We analyzed late side effects both longitudinally at every follow-up and cross-sectionally at 5-year intervals. All statistical tests were 2-sided. RESULTS: Between 1996 and 2004, 46 departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. Longitudinal follow-up data showed cumulative incidence rates at 15 years of 2.9% (95% confidence interval [CI] = 2.2% to 3.8%) vs 5.7% (95% CI = 4.7% to 6.9%) (P < .001) for lung fibrosis, 1.1% (95% CI = 0.7% to 1.7%) vs 1.9% (95% CI = 1.3% to 2.6%) (P = .07) for cardiac fibrosis, and 9.4% (95% CI = 8.0% to 10.8%) vs 11.1% (95% CI = 9.6% to 12.7%) (P = .04) for any cardiac disease when treated without or with IM-MS lymph node irradiation. There was no evidence for differences between left- and right-sided breast cancer (Wald χ2 test of treatment by breast side interaction, P = .33 and P = .35, for cardiac fibrosis and for any cardiac disease, respectively). The cumulative incidence probabilities of cross-sectionally reported side effects with a score of 2 or greater at 15 years were 0.1% (95% CI = 0.0% to 0.5%) vs 0.8% (95% CI = 0.4% to 1.4%) for pulmonary (P = .02), 1.8% (95% CI = 1.1% to 2.8%) vs 2.6% (95% CI = 1.8% to 3.7%) for cardiac (P = .15), and 0.0% (95% CI not evaluated) vs 0.1% (95% CI = 0.0% to 0.4%) for esophageal (P = .16), respectively. No difference was observed in the incidence of second malignancies, contralateral breast cancer, or cardiovascular deaths. CONCLUSIONS: The incidence of late pulmonary side effects was statistically significantly higher after IM-MS lymph node irradiation, as were some of the cardiac events, without a difference between left- and right-sided treatments. Absolute rates and differences were very low, without increased non-breast cancer-related mortality, even before introducing heart-sparing techniques.

Concordance between results of inexpensive statistical models and multigene signatures in patients with ER+/HER2- early breast cancer.

Multigene signatures (MGS) are used to guide adjuvant chemotherapy (aCT) decisions in patients diagnosed with estrogen receptor (ER)-positive HER2-negative early breast cancer. We used results from three MGS (Oncotype DX® (ODX), MammaPrint® (MP) or Prosigna®) and assessed the concordance between high or low risk of recurrence and the predicted risk of recurrence based on statistical models. In addition, we looked at the impact of MGS results on final aCT administration during the multidisciplinary meeting (MDM). We retrospectively included 129 patients with ER-positive HER2-negative early breast cancer for which MGS testing was performed after MDM at University Hospitals Leuven between May 2013 and April 2019 in case there was doubt about aCT recommendation. Tumor tissue was analyzed either by ODX (N = 44), MP (N = 28), or Prosigna® (N = 57). Eight statistical models were computed: Magee equations (ME), Memorial Sloan Kettering simplified risk score (MSK-SRS), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL), Mymammaprint.com (MyMP), PREDICT, and SiNK. Concordance, negative percent agreement, and positive percent agreement were calculated. Of 129 cases, 53% were MGS low and 47% MGS high risk. Concordances of 100.0% were observed between risk results obtained by ODX and ME. For MP, BCRSE demonstrated the best concordance, and for Prosigna® the average of ME. Concordances of <50.0% were observed between risk results obtained by ODX and nAOL, ODX and MyMP, ODX and SiNK, MP and MSK-SRS, MP and nAOL, MP and MyMP, MP and SiNK, and Prosigna® and ODXC. Integration of MGS results during MDM resulted in change of aCT recommendation in 47% of patients and a 15% relative and 9% absolute reduction. In conclusion, statistical models, especially ME and BCRSE, can be useful in selecting ER-positive HER2-negative early breast cancer patients who may need MGS testing resulting in enhanced cost-effectiveness and reduced delay in therapeutic decision-making.

Spirometer-guided breath-hold breast VMAT verified with portal images and surface tracking.

BACKGROUND AND PURPOSE: Fast rotating closed-bore gantry linacs are ideally suited for breath-hold treatments due to reduced imaging and delivery times. We evaluated the reproducibility and stability of spirometer-guided breath-hold breast treatments, using intra-bore surface monitoring and portal imaging on Halcyon (Varian Medical Systems). MATERIALS AND METHODS: Seven left-sided breast cancer patients were treated in breath-hold using the SDX spirometer (Dyn'R) with an integrated boost volumetric arc protocol on Halcyon. A dual depth-camera surface scanning system monitored the left breast. The interfraction, intrafraction and intrabreath-hold motion was determined in the anterior-posterior (AP) and superior-inferior (SI) direction. Portal images (PI), acquired at a tangential gantry angle were manually registered to the planning-CT to determine inter- and intrafraction breath-hold errors for the SI and tangential-anterior-posterior ("AP") axis. Correlations between PI and surface imaging deviations were investigated. To evaluate workflow efficiency, the total time and the number of breath-holds were recorded. RESULTS: Systematic and random variability of breath-hold amplitude was below 0.7 mm for the AP and below 1.2 mm for the SI component as detected by surface monitoring (N = 130). Systematic and random errors retrieved from portal images (N = 140) were below 1.2 mm for the "AP" and 2.1 mm for SI axis. A limited correlation was found between PI and surface monitoring deviations for both the SI and "AP" axes (R2 = 0.27/0.38, p < 0.01). 75% of fractions were completed using four breath-holds and 82% within 10 min. CONCLUSION: Surface imaging indicated spirometer-guided breath-hold VMAT breast radiotherapy can be accurately and quickly performed on a closed-bore gantry linac. Intra-bore surface scanning proved a valuable technique for monitoring breathing motion in closed-bore systems.