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Background Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM. Methods The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa. Discussion Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer. Trial registration NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Cognitive complaints are common in breast cancer (BC). Previous studies have linked sleep-disordered breathing (SDB) to cognitive decline in the general population, highlighting hypoxia as a key factor in cognitive decline severity. This link is understudied in BC patients. We investigated the association between nocturnal hypoxia and cognitive performance in 35 BC patients compared to 21 healthy controls (HC; mean ages: 61.6 ± 5.3 and 62.6 ± 4.3, respectively) using in-home ambulatory polysomnography, including oximeter to record oxygen saturation. All participants completed questionnaires and cognitive tests. Non-parametric Wilcoxon tests were conducted to compare the two groups and multivariable models to measure the association between hypoxia and cognitive performance, adjusting for anxiety and depression. Our results showed more frequent nocturnal hypoxia and more cognitive complaints in BC patients compared to HCs ( p  < 0.05). However, cognitive tests did not show significant impairment in the BC group, and no significant association was found between nocturnal hypoxia and cognitive performance. Our patients were treated with radiotherapy and/or endocrine therapy, but without chemotherapy, which may explain their normal cognitive scores despite subjective cognitive complaints. Nocturnal hypoxia is more prevalent in BC patients than in HCs, but it may not be the primary factor influencing cognitive performance in this population. Trial registration: NCT03420105, registered: January 10, 2018.

Background Non-metastatic breast cancer treatment is mainly based on surgery, with or without chemotherapy, radiotherapy and/or hormone therapy. To reduce the risk of hormone receptor positive (HR+) disease recurrence, hormone therapy is prescribed for at least 5 years. It may induce adverse drug reactions (ADRs) as joint pain, sexual dysfunction, weight increase, fatigue, mood disorders and vasomotor symptoms. Around 30–40% of patients withhold hormone therapy within 5 years after initiation. Based on encouraging results of mobile health in patient follow-up, we developed a web-application addressed for breast cancer patients initiating adjuvant hormonal therapy and aimed to assess its impact on hormone therapy adherence, ADRs management, and health-related quality of life. Methods The WEBAPPAC trial is a randomized, open-label, prospective, single-center phase 3 study aiming to assess the interest of a web-application support as compared to standard management among breast cancer patients initiating hormone therapy. The main endpoint is the proportion of patients with hormone therapy adherence failure within 18 months after treatment start, in each arm. Eligible patients will be 1:1 randomized between the WEBAPPAC web-application support (experimental arm,) or standard support (control arm), with stratification on type of hormone therapy (Aromatase inhibitor or Tamoxifen). We plan to enroll 438 patients overall. Failure to hormone therapy will be assessed using the Morisky 8-item self-questionnaire (MMSA8), patient adherence logbook, and medical consultations. Secondary outcomes include hormone therapy adherence at 6 months, pain (Visual Analogue Scale and Brief Pain Inventory), quality of life (EORTC QLQ-C30 and BR23 self-questionnaires), anxiety and depression (Hospital and Depression Scale), and return to work and/or daily activities. The user experience with the WEBAPPAC web-application will be assessed using the System Usability Scale (SUS) questionnaire. Discussion Hormone therapy discontinuation or adherence failure in breast cancer patients may be indirectly related to an increased risk of recurrence. A better control of medication adherence, through the detection of side effects and some proposed actions trying to reduce them, appears therefore essential to limit the risk of disease recurrence. The WEBAPPAC web-application thus aims better monitoring and allowing higher level of responsiveness in case of ADRs, thus improving treatment adherence. Trial registration NCT04554927, registered September 18, 2020. Protocol version Version 2.1 dated from December 21, 2021.

Background Until 50% of patients with renal cancer or melanoma, develop brain metastases during the course of their disease. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. The purpose of this retrospective study was to elucidate if hypofractionated stereotactic radiotherapy (HFSRT) impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer, in comparison with radiosurgery (SRS). Methods Between 2012 and 2016, 193 metastases, smaller than 3 cm, from patients suffering from radioresistant primaries (melanoma and renal cancer) were treated with HFSRT or SRS. The primary outcome was local progression free survival (LPFS) at 6, 12 and 18 months. Overall survival (OS) and cerebral progression free survival (CPFS) were secondary outcomes, and were evaluated per patient. Objective response rate and radionecrosis incidence were also reported. The statistical analysis included a supplementary propensity score analysis to deal with bias induced by non-randomized data. Results After a median follow-up of 7.4 months, LPFS rates at 6, 12 and 18 months for the whole population were 83, 74 and 70%, respectively. With respect to fractionation, LPFS rates at 6, 12 and 18 months were 89, 79 and 73% for the SRS group and 80, 72 and 68% for the HFSRT group. The fractionation schedule was not statistically associated with LPFS (HR = 1.39, CI95% [0.65–2.96], p  = 0.38). Time from planning MRI to first irradiation session longer than 14 days was associated with a poorer local control rate. Over this time, LPFS at 12 months was reduced from 86 to 70% ( p  = 0.009). Radionecrosis occurred in 7.1% for HFSRT treated metastases to 9.6% to SRS treated metastases, without any difference according to fractionation ( p  = 0.55). The median OS was 9.6 months. Six, 12 and 18 months CPFS rates were 54, 24 and 17%, respectively. Conclusion Fractionation does not decrease LPFS. Even for small radioresistant brain metastases (< 3 cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1 year with a rate of 7.1% of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS.

Background Brain metastases often occur in cancer evolution. They are not only responsible for death but also for disorders affecting the quality of life and the cognitive functions. Management of brain metastases usually consists in multi-modality treatments, including neurosurgery, whole brain radiotherapy (WBRT), and more recently radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT), systemic treatment (chemotherapy or targeted therapy), combined or not with corticosteroids. Almost 20% of brain metastases can present recent (within 15 days) bleeding signs on neuro-imagery. In these conditions, WBRT is the usual treatment. Yet, patients may benefit from a more aggressive strategy with SRT or FSRT. However, these options were suspected to possibly major the risk of brain haemorrhage, although no scientifically proven. Radiation oncologists therefore usually remain reluctant to deliver SRS/FSRT for bleeding brain metastases. It is therefore challenging to establish a standard of care for the treatment of bleeding brain metastases. We propose a phase II trial to simultaneously assess safety and efficacy of FSRT to manage brain metastases with hemorrhagic signal. Methods The STEREO-HBM study is a multicenter two-step non-randomised phase II trial addressing patients with at least one bleeding brain metastasis out of a maximum of 3 brain metastases. Each brain metastasis will be treated with 30 Gy in 3 fractions for 1 week. The main endpoint is based on both safety and efficacy endpoints as proposed by Bryant and Day’s design. Safety endpoint is defined as the rate of bleeding complications 4 months post-FSRT while efficacy endpoint is defined as the 6-month local control rate. Multi-modal MRI will be used to assess intra-tumoral hemorrhagic events before and after treatment. Patients’ quality of life will also be assessed. Discussion Management of bleeding brain metastases is still debated and poorly explored in clinical trials. There is sparse and weak data on the signification of pretreatment intra-tumour haemorrhagic signs or on the risk of brain bleeding complications after FSRT. We expect this first prospective phase 2 trial in this particular setting will allow to clarify the place of FSRT to optimally manage bleeding brain metastases. Trial registration NCT 03696680 , registered October, 4, 2018. Protocol version Version 2.1 dated from 2018/11/09.

Atrial fibrillation (AF) after radiotherapy (RT) in patients with breast cancer (BC) is a relatively new and understudied topic. AF can increase the risk of stroke and other serious cardiovascular complications, compromising patients' quality of life and survival. Screening of AF, both asymptomatic and symptomatic forms, is therefore essential for optimal management. The aim of the Watch Your Heart After Radiotherapy for Breast Cancer (WATCH) study is to assess the incidence of AF (symptomatic or asymptomatic) occurring throughout a 5-year follow-up after RT and to investigate whether cardiac radiation exposure is associated with the occurrence of such events. WATCH is a cohort study that will include 200 patients over 65 years old, treated with RT for BC 5 years before inclusion and without a history of AF. Cross-sectional screening for AF at the time of the scheduled 5-year post-RT visit will be conducted by recording data from a Withings ScanWatch smartwatch for 1 month, confirmed by an electrocardiogram (ECG), and validated by a physician. In addition, a transthoracic echocardiography (TTE) will be performed, providing a comprehensive assessment of cardiac structures, and allowing us to investigate the underlying etiology and assess the risk of complications. Patients' medical records will provide retrospective information about the timing and risk factors for the occurrence of AF and other arrhythmias and cardiac diseases during the 5 years following RT. The development of deep learning algorithms for autosegmentation analysis of potentially critical substructures for the occurrence of AF, including cardiac chambers, the sinoatrial node, the atrioventricular node, coronary arteries, and pulmonary veins (PVs), will produce dosimetry linked to previous RT treatment for all contoured structures. Enrollment started in October 2023 and will continue until mid-2026 to include 200 patients, which will ensure an 80% statistical power to detect a significant difference in AF incidence around 15% for the group of patients moderately exposed (<75th percentile of the mean heart radiation dose) and 25% for the group of patients highly exposed (>75th percentile of the mean heart radiation dose). The results are expected by the end of 2026. This study will contribute to generating new knowledge on AF after RT for BC and help considering the inclusion of AF screening into routine clinical practice for these patients. Identifying the dose-risk associations would improve RT delivery protocols to limit the occurrence of different forms of AF and, if necessary, initiate appropriate treatment. ClinicalTrials.gov NCT06073509; clinicaltrials.gov/study/NCT06073509?id=NCT06073509&rank=1. DERR1-10.2196/67875.

Introduction Improvement in overall survival (OS) by locoregional treatment (LRT) of the primary tumor in de novo metastatic breast cancer (MBC) patients remains controversial. Objective The aim of our study was to evaluate the impact of LRT on OS in a large retrospective cohort of de novo MBC patients, with regard to immunohistochemical characteristics and pattern of metastatic dissemination. Methods We conducted a multicentric retrospective study of patients diagnosed with de novo MBC selected from the French Epidemiological Strategy and Medical Economics MBC database (NCT03275311) between 2008 and 2014. Overall, 4276 women were included in the study. LRT comprised either radiotherapy, surgery, or both. Results LRT was used in 40% of patients. Compared with no LRT, patients who received LRT were younger ( p  < 0.0001) and were more likely to have only one metastatic site ( p  < 0.0001) or bone-only metastases ( p  < 0.0001). LRT was associated with a significantly better OS based on landmark multivariate analysis at 1-year (hazard ratio 0.65, 95% confidence interval 0.55–0.76, p  < 0.001). Similar results were observed in all sensitivity analyses, including propensity score matching. In subgroup analysis, LRT was associated with better OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (61.6 vs. 45.9 months, p  < 0.001) and HER2-positive tumors (77.2 vs. 52.6 months, p  = 0.008), but not in triple-negative tumors (19 vs. 18.6 months, p  = 0.54), and was also associated with a reduction in the risk of death in visceral metastatic patients ( p  < 0.001). Conclusions LRT was associated with a significantly better OS in de novo MBC patients, including patients with visceral involvement at diagnosis; however, LRT did not impact OS in triple-negative MBC.