From multisource data to clinical decision aids in radiation oncology:The need for a clinical data science community

Big data are no longer an obstacle; now, by using artificial intelligence (AI), previously undiscovered knowledge can be found in massive data collections. The radiation oncology clinic daily produces a large amount of multisource data and metadata during its routine clinical and research activities. These data involve multiple stakeholders and users. Because of a lack of interoperability, most of these data remain unused, and powerful insights that could improve patient care are lost. Changing the paradigm by introducing powerful AI analytics and a common vision for empowering big data in radiation oncology is imperative. However, this can only be achieved by creating a clinical data science community in radiation oncology. In this work, we present why such a community is needed to translate multisource data into clinical decision aids

Combined RBE and OER optimization in proton therapy with FLUKA based on EF5-PET

Introduction Tumor hypoxia is associated with poor treatment outcome. Hypoxic regions are more radioresistant than well-oxygenated regions, as quantified by the oxygen enhancement ratio (OER). In optimization of proton therapy, including OER in addition to the relative biological effectiveness (RBE) could therefore be used to adapt to patient-specific radioresistance governed by intrinsic radiosensitivity and hypoxia. Methods A combined RBE and OER weighted dose (ROWD) calculation method was implemented in a FLUKA Monte Carlo (MC) based treatment planning tool. The method is based on the linear quadratic model, with α and β parameters as a function of the OER, and therefore a function of the linear energy transfer (LET) and partial oxygen pressure (pO2). Proton therapy plans for two head and neck cancer (HNC) patients were optimized with pO2 estimated from [18F]-EF5 positron emission tomography (PET) images. For the ROWD calculations, an RBE of 1.1 (RBE1.1,OER) and two variable RBE models, Rørvik (ROR) and McNamara (MCN), were used, alongside a reference plan without incorporation of OER (RBE1.1). Results For the HNC patients, treatment plans in line with the prescription dose and with acceptable target ROWD could be generated with the established tool. The physical dose was the main factor modulated in the ROWD. The impact of incorporating OER during optimization of HNC patients was demonstrated by the substantial difference found between ROWD and physical dose in the hypoxic tumor region. The largest physical dose differences between the ROWD optimized plans and the reference plan was 12.2 Gy. Conclusion The FLUKA MC based tool was able to optimize proton treatment plans taking the tumor pO2 distribution from hypoxia PET images into account. Independent of RBE-model, both elevated LET and physical dose were found in the hypoxic regions, which shows the potential to increase the tumor control compared to a conventional optimization approach.publishedVersio

Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer

Background Systemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy. Methods In two high-risk patient cohorts, we assessed the circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L), a factor reflecting both therapy-induced myelosuppression and activation of tumour antigen-presenting dendritic cells, at baseline and following induction chemotherapy and sequential chemoradiotherapy, both modalities containing oxaliplatin. The primary end point was progression-free survival (PFS). Results In both cohorts, the median Flt3L level was significantly higher at completion of each sequential modality than at baseline. The 5-year PFS (most events being metastatic progression) was 68% and 71% in the two cohorts consisting of 33% and 52% T4 cases. In the principal cohort, a high Flt3L level following the induction chemotherapy was associated with low risk for a PFS event (HR: 0.15; P < 0.01). These patients also had available dose scheduling and toxicity data, revealing that oxaliplatin dose reduction during chemoradiotherapy, undertaken to maintain compliance to the radiotherapy protocol, was associated with advantageous PFS (HR: 0.47; P = 0.046). Conclusion In high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression

Professional development through mentoring: Final evaluation of the pilot mentoring programme of the European society of radiotherapy and oncology

: The European SocieTy for Radiotherapy and Oncology (ESTRO) organized a one-year pilot mentoring programme. At evaluation after one year, both mentors and mentees scored the programme with a median score of 9 on a scale of 10. All of the mentors indicated that they wanted to participate again as mentors

Professional practice changes in radiotherapy physics during the COVID-19 pandemic.

Background and purpose The COVID-19 pandemic has imposed changes in radiotherapy (RT) departments worldwide. Medical physicists (MPs) are key healthcare professionals in maintaining safe and effective RT. This study reports on MPs experience during the first pandemic peak and explores the consequences on their work. Methods A 39-question survey on changes in departmental and clinical practice and on the impact for the future was sent to the global MP community. A total of 433 responses were analysed by professional role and by country clustered on the daily infection numbers. Results The impact of COVID-19 was bigger in countries with high daily infection rate. The majority of MPs worked in alternation at home/on-site. Among practice changes, implementation and/or increased use of hypofractionation was the most common (47% of the respondents). Sixteen percent of respondents modified patient-specific quality assurance (QA), 21% reduced machine QA, and 25% moved machine QA to weekends/evenings. The perception of trust in leadership and team unity was reversed between management MPs (towards increased trust and unity) and clinical MPs (towards a decrease). Changes such as home-working and increased use of hypofractionation were welcomed. However, some MPs were concerned about pressure to keep negative changes (e.g. weekend work). Conclusion COVID-19 affected MPs through changes in practice and QA procedures but also in terms of trust in leadership and team unity. Some changes were welcomed but others caused worries for the future. This report forms the basis, from a medical physics perspective, to evaluate long-lasting changes within a multi-disciplinary setting

Hypoxia regulates Notch-3 mRNA and receptor activation in prostate cancer cells

The Notch-3 receptor is a recognized key regulator of vascular responses and is increasingly associated with tumorigenesis. Hypoxia-inducible factors activate specific signaling pathways such as Notch in a number of cellular models. This study aimed to evaluate the regulation of Notch-3 by hypoxia in prostate cancer cells. Notch-3 gene and protein expression was established in a panel of aerobic and hypoxic prostate cell lines in vitro, the CWR22 xenograft model and RNA extracted from low grade (Gleason score < = 6); high grade (Gleason score > = 7); non-hypoxic (low HIF, low VEGF); hypoxic (high HIF, high VEGF) patient FFPE specimens. NOTCH-3 was upregulated in PC3 (3-fold), 22Rv1 (4.1-fold) and DU145 (3.8-fold) but downregulated in LnCaP (12-fold) compared to the normal cell lines. NOTCH-3 expression was modified following hypoxic exposure in these cells. NOTCH-3 was upregulated (2.2-fold) in higher grade and hypoxic tumors, when compared to benign and aerobic pools. In the CWR22 xenograft model, Notch-3 expression was restored in castrate resistant tumors. Nuclear translocation of the Notch-3 intracellular domain was no longer detected following exposure of cells to hypoxia but not associated with a change in expression of HES-1. Our data further identifies Notch-3 as a potentially key hypoxic-responsive member of the Notch pathway in prostate tumorigenesis

Energy Metabolism Is Altered in Radioresistant Rectal Cancer

Resistance to neoadjuvant chemoradiation therapy is a significant clinical challenge in the management of rectal cancer. There is an unmet need to identify the underlying mechanisms of treatment resistance to enable the development of biomarkers predictive of response and novel treatment strategies to improve therapeutic response. In this study, an in vitro model of inherently radioresistant rectal cancer was identified and characterized to identify mechanisms underlying radioresistance in rectal cancer. Transcriptomic and functional analysis demonstrated significant alterations in multiple molecular pathways, including the cell cycle, DNA repair efficiency and upregulation of oxidative phosphorylation-related genes in radioresistant SW837 rectal cancer cells. Real-time metabolic profiling demonstrated decreased reliance on glycolysis and enhanced mitochondrial spare respiratory capacity in radioresistant SW837 cells when compared to radiosensitive HCT116 cells. Metabolomic profiling of pre-treatment serum samples from rectal cancer patients (n = 52) identified 16 metabolites significantly associated with subsequent pathological response to neoadjuvant chemoradiation therapy. Thirteen of these metabolites were also significantly associated with overall survival. This study demonstrates, for the first time, a role for metabolic reprograming in the radioresistance of rectal cancer in vitro and highlights a potential role for altered metabolites as novel circulating predictive markers of treatment response in rectal cancer patients

Dynamic multi-echo DCE- and DSC-MRI in rectal cancer: Low primary tumor Ktrans and ΔR2* peak are significantly associated with lymph node metastasis

Purpose: To implement a dynamic contrast-based multi-echo MRI sequence in assessment of rectal cancer and evaluate associations between histopathologic data and the acquired dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) -MRI parameters. Materials and Methods: This pilot study reports results from 17 patients with resectable rectal cancer. Dynamic contrast-based multi-echo MRI (1.5T) was acquired using a three-dimensional multi-shot EPI sequence, yielding both DCE- and DSC-data following a single injection of contrast agent. The Institutional Review Board approved the study and all patients provided written informed consent. Quantitative analysis was performed by pharmacokinetic modeling on DCE data and tracer kinetic modeling on DSC data. Mann-Whitney U-test and receiver operating characteristics curve statistics was used to evaluate associations between histopathologic data and the acquired DCE- and DSC-MRI parameters. Results: For patients with histologically confirmed nodal metastasis, the primary tumor demonstrated a significantly lower Ktrans and peak change in R 2, R 2-peakenh, than patients without nodal metastasis, showing a P-value of 0.010 and 0.005 for reader 1, and 0.043 and 0.019 for reader 2, respectively. Conclusion: This study shows the feasibility of acquiring DCE- and DSC-MRI in rectal cancer by dynamic multi-echo MRI. A significant association was found between both Ktrans and R 2-peakenh in the primary tumor and histological nodal status of the surgical specimen, which may improve stratification of patients to intensified multimodal treatment