Radiotherapy intensification for atypical and malignant meningiomas: A systematic review.

Background: The outcomes of nonbenign (WHO Grades 2 and 3 [G2, G3]) meningiomas are suboptimal and radiotherapy (RT) dose intensification strategies have been investigated. The purpose of this review is to report on clinical practice and outcomes with particular attention to RT doses and techniques. Methods: The PICO criteria (Population, Intervention, Comparison, and Outcomes) were used to frame the research question, directed at outlining the clinical outcomes in patients with G2-3 meningiomas treated with RT. The same search strategy was run in Embase and MEDLINE and, after deduplication, returned 1 807 records. These were manually screened for relevance and 25 were included. Results: Tumor outcomes and toxicities are not uniformly reported in the selected studies since different endpoints and time points have been used by different authors. Many risk factors for worse outcomes are described, the most common being suboptimal RT. This includes no or delayed RT, low doses, and older techniques. A positive association between RT dose and progression-free survival (PFS) has been highlighted by analyzing the studies in this review (10/25) that report the same endpoint (5y-PFS). Conclusions: This literature review has shown that standard practice RT leads to suboptimal tumor control rates in G2-3 meningiomas, with a significant proportion of disease recurring after a relatively short follow-up. Randomized controlled trials are needed in this setting to define the optimal RT approach. Given the increasing data to suggest a benefit of higher RT doses for high-risk meningiomas, novel RT technologies with highly conformal dose distributions are preferential to achieve optimal target coverage and organs at risk sparing.

The use of radiotherapy, surgery and chemotherapy in the curative treatment of cancer: results from the FORTY (Favourable Outcomes from RadioTherapY) project.

OBJECTIVES: Radiotherapy, surgery and chemotherapy play key roles in the curative treatment of cancer, alone and in combination. Quantifying their roles is essential for equipment provision and workforce planning. The estimate that 40% of cancer patients are cured by RT has been used extensively to inform and influence policy but is relatively old and warrants review. METHODS: Patient, tumour and treatment event data was obtained for the 5 year period from 2009 to 2013, allowing a further 5 years for survival outcomes to be known. We analysed patient-level data on utilisation of surgery, radiotherapy, and chemotherapy in cancer patients in England. Data were sourced from Public Health England, using National Cancer Registrations, the National Radiotherapy Dataset (RTDS) and the Systemic Anti-Cancer Therapy Dataset (SACT). All tumour sites (excluding C44) and ages were included. We analysed three cohorts: all patients [n = 1,029,569], patients who survived 5 years or more [n = 537,970] and patients who survived <5 years [n = 491,599]. RESULTS: Overall cancer-specific 5-year survival was 52%, and in those patients, surgery was the most common curative treatment, with 80% receiving surgery, alone or in combination; radiotherapy was delivered to 39% and chemotherapy to 29%; 45% received two and 13% all three modalities. CONCLUSIONS: The high proportion receiving multi-modality treatment emphasises the importance of integrated, resourced, multidisciplinary cancer care. Radiotherapy was delivered to almost 40% of patients who survived 5 years which underlines its importance in cancer management. ADVANCES IN KNOWLEDGE: The results are essential in planning cancer services. They also inform the public health narrative.

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

Proton Beam Therapy in the Oligometastatic/Oligorecurrent Setting: Is There a Role? A Literature Review.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS) with conventional photon radiotherapy (XRT) are well-established treatment options for selected patients with oligometastatic/oligorecurrent disease. The use of PBT for SABR-SRS is attractive given the property of a lack of exit dose. The aim of this review is to evaluate the role and current utilisation of PBT in the oligometastatic/oligorecurrent setting. METHODS: Using Medline and Embase, a comprehensive literature review was conducted following the PICO (Patients, Intervention, Comparison, and Outcomes) criteria, which returned 83 records. After screening, 16 records were deemed to be relevant and included in the review. RESULTS: Six of the sixteen records analysed originated in Japan, six in the USA, and four in Europe. The focus was oligometastatic disease in 12, oligorecurrence in 3, and both in 1. Most of the studies analysed (12/16) were retrospective cohorts or case reports, two were phase II clinical trials, one was a literature review, and one study discussed the pros and cons of PBT in these settings. The studies presented in this review included a total of 925 patients. The metastatic sites analysed in these articles were the liver (4/16), lungs (3/16), thoracic lymph nodes (2/16), bone (2/16), brain (1/16), pelvis (1/16), and various sites in 2/16. CONCLUSIONS: PBT could represent an option for the treatment of oligometastatic/oligorecurrent disease in patients with a low metastatic burden. Nevertheless, due to its limited availability, PBT has traditionally been funded for selected tumour indications that are defined as curable. The availability of new systemic therapies has widened this definition. This, together with the exponential growth of PBT capacity worldwide, will potentially redefine its commissioning to include selected patients with oligometastatic/oligorecurrent disease. To date, PBT has been used with encouraging results for the treatment of liver metastases. However, PBT could be an option in those cases in which the reduced radiation exposure to normal tissues leads to a clinically significant reduction in treatment-related toxicities.

Machine-learning with region-level radiomic and dosimetric features for predicting radiotherapy-induced rectal toxicities in prostate cancer patients.

BACKGROUND AND PURPOSE: This study aims to build machine learning models to predict radiation-induced rectal toxicities for three clinical endpoints and explore whether the inclusion of radiomic features calculated on radiotherapy planning computerised tomography (CT) scans combined with dosimetric features can enhance the prediction performance. MATERIALS AND METHODS: 183 patients recruited to the VoxTox study (UK-CRN-ID-13716) were included. Toxicity scores were prospectively collected after 2 years with grade ≥ 1 proctitis, haemorrhage (CTCAEv4.03); and gastrointestinal (GI) toxicity (RTOG) recorded as the endpoints of interest. The rectal wall on each slice was divided into 4 regions according to the centroid, and all slices were divided into 4 sections to calculate region-level radiomic and dosimetric features. The patients were split into a training set (75%, N = 137) and a test set (25%, N = 46). Highly correlated features were removed using four feature selection methods. Individual radiomic or dosimetric or combined (radiomic + dosimetric) features were subsequently classified using three machine learning classifiers to explore their association with these radiation-induced rectal toxicities. RESULTS: The test set area under the curve (AUC) values were 0.549, 0.741 and 0.669 for proctitis, haemorrhage and GI toxicity prediction using radiomic combined with dosimetric features. The AUC value reached 0.747 for the ensembled radiomic-dosimetric model for haemorrhage. CONCLUSIONS: Our preliminary results show that region-level pre-treatment planning CT radiomic features have the potential to predict radiation-induced rectal toxicities for prostate cancer. Moreover, when combined with region-level dosimetric features and using ensemble learning, the model prediction performance slightly improved.

Sub-regional analysis of the parotid glands: model development for predicting late xerostomia with radiomics features in head and neck cancer patients.

BACKGROUND: The irradiation of sub-regions of the parotid has been linked to xerostomia development in patients with head and neck cancer (HNC). In this study, we compared the xerostomia classification performance of radiomics features calculated on clinically relevant and de novo sub-regions of the parotid glands of HNC patients. MATERIAL AND METHODS: All patients (N = 117) were treated with TomoTherapy in 30-35 fractions of 2-2.167 Gy per fraction with daily mega-voltage-CT (MVCT) acquisition for image-guidance purposes. Radiomics features (N = 123) were extracted from daily MVCTs for the whole parotid gland and nine sub-regions. The changes in feature values after each complete week of treatment were considered as predictors of xerostomia (CTCAEv4.03, grade ≥ 2) at 6 and 12 months. Combinations of predictors were generated following the removal of statistically redundant information and stepwise selection. The classification performance of the logistic regression models was evaluated on train and test sets of patients using the Area Under the Curve (AUC) associated with the different sub-regions at each week of treatment and benchmarked with the performance of models solely using dose and toxicity at baseline. RESULTS: In this study, radiomics-based models predicted xerostomia better than standard clinical predictors. Models combining dose to the parotid and xerostomia scores at baseline yielded an AUCtest of 0.63 and 0.61 for xerostomia prediction at 6 and 12 months after radiotherapy while models based on radiomics features extracted from the whole parotid yielded a maximum AUCtest of 0.67 and 0.75, respectively. Overall, across sub-regions, maximum AUCtest was 0.76 and 0.80 for xerostomia prediction at 6 and 12 months. Within the first two weeks of treatment, the cranial part of the parotid systematically yielded the highest AUCtest. CONCLUSION: Our results indicate that variations of radiomics features calculated on sub-regions of the parotid glands can lead to earlier and improved prediction of xerostomia in HNC patients.

Assessing the generalisability of radiomics features previously identified as predictive of radiation-induced sticky saliva and xerostomia.

Background and purpose: While core to the scientific approach, reproducibility of experimental results is challenging in radiomics studies. A recent publication identified radiomics features that are predictive of late irradiation-induced toxicity in head and neck cancer (HNC) patients. In this study, we assessed the generalisability of these findings. Materials and Methods: The procedure described in the publication in question was applied to a cohort of 109 HNC patients treated with 50-70 Gy in 20-35 fractions using helical radiotherapy although there were inherent differences between the two patient populations and methodologies. On each slice of the planning CT with delineated parotid and submandibular glands, the imaging features that were previously identified as predictive of moderate-to-severe xerostomia and sticky saliva 12 months post radiotherapy (Xer12m and SS12m) were calculated. Specifically, Short Run Emphasis (SRE) and maximum CT intensity (maxHU) were evaluated for improvement in prediction of Xer12m and SS12m respectively, compared to models solely using baseline toxicity and mean dose to the salivary glands. Results: None of the associations previously identified as statistically significant and involving radiomics features in univariate or multivariate models could be reproduced on our cohort. Conclusion: The discrepancies observed between the results of the two studies delineate limits to the generalisability of the previously reported findings. This may be explained by the differences in the approaches, in particular the imaging characteristics and subsequent methodological implementation. This highlights the importance of external validation, high quality reporting guidelines and standardisation protocols to ensure generalisability, replication and ultimately clinical implementation.

Predicting radiotherapy-induced xerostomia in head and neck cancer patients using day-to-day kinetics of radiomics features.

Background and purpose: The images acquired during radiotherapy for image-guidance purposes could be used to monitor patient-specific response to irradiation and improve treatment personalisation. We investigated whether the kinetics of radiomics features from daily mega-voltage CT image-guidance scans (MVCT) improve prediction of moderate-to-severe xerostomia compared to dose/volume parameters in radiotherapy of head-and-neck cancer (HNC). Materials and Methods: All included HNC patients (N = 117) received 30 or more fractions of radiotherapy with daily MVCTs. Radiomics features were calculated on the contra-lateral parotid glands of daily MVCTs. Their variations over time after each complete week of treatment were used to predict moderate-to-severe xerostomia (CTCAEv4.03 grade ≥ 2) at 6, 12 and 24 months post-radiotherapy. After dimensionality reduction, backward/forward selection was used to generate combinations of predictors.Three types of logistic regression model were generated for each follow-up time: 1) a pre-treatment reference model using dose/volume parameters, 2) a combination of dose/volume and radiomics-based predictors, and 3) radiomics-based predictors. The models were internally validated by cross-validation and bootstrapping and their performance evaluated using Area Under the Curve (AUC) on separate training and testing sets. Results: Moderate-to-severe xerostomia was reported by 46 %, 33 % and 26 % of the patients at 6, 12 and 24 months respectively. The selected models using radiomics-based features extracted at or before mid-treatment outperformed the dose-based models with an AUCtrain/AUCtest of 0.70/0.69, 0.76/0.74, 0.86/0.86 at 6, 12 and 24 months, respectively. Conclusion: Our results suggest that radiomics features calculated on MVCTs from the first half of the radiotherapy course improve prediction of moderate-to-severe xerostomia in HNC patients compared to a dose-based pre-treatment model.

Urinary symptoms and prostate cancer-the misconception that may be preventing earlier presentation and better survival outcomes.

BACKGROUND: Prostate cancer is an epidemic of the modern age, and despite efforts to improve awareness, it remains the case that mortality has hardly altered over the decades, driven largely by late presentation. There is a strong public perception that male urinary symptoms is one of the key indicators of prostate cancer, and this continues to be part of messaging from national guidelines and media health campaigns. This narrative, however, is not based on evidence and may be seriously hampering efforts to encourage early presentation. DISCUSSION: Anatomically, prostate cancer most often arises in the peripheral zone, while urinary symptoms result from compression of the urethra by prostatic enlargement more centrally. Biopsy studies show that mean prostate volume is actually lower in men found to have (early) prostate cancer compared to those with benign biopsies. This inverse relationship between prostate size and the probability of cancer is so strong that PSA density (PSA corrected for prostate volume) is known to be significantly more accurate in predicting a positive biopsy than PSA alone. Thus, this disconnect between scientific evidence and the current perception is very striking. There is also evidence that using symptoms for investigating possible cancer may lead to higher proportions of men presenting with locally advanced or metastatic disease compared to PSA testing or screening programmes. Concerns about overwhelming health care services if men are encouraged to get tested without symptoms may also be overstated, with recent newer approaches to reduce over-investigation and treatment. In this article, we explore the link between urinary symptoms and prostate cancer and propose that public and professional messaging needs to change. CONCLUSION: If rates of earlier diagnosis are to improve, we call for strong clear messaging that prostate cancer is a silent disease especially in the curable stages and men should come forward for testing regardless of whether or not they have symptoms. This should be done in parallel with other ongoing efforts to raise awareness including targeting men at highest risk due to racial ancestry or family history. While the current resurgence in interest and debate about prostate cancer screening is timely, change of this message by guideline bodies, charities and the media can be a first simple step to improving earlier presentation and hence cures rates.

No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity.

PURPOSE: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. METHODS AND MATERIALS: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. RESULTS: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10-5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10-5). CONCLUSIONS: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

The suitability of micronuclei as markers of relative biological effect.

Micronucleus (MN) formation is routinely used as a biodosimeter for radiation exposures and has historically been used as a measure of DNA damage in cells. Strongly correlating with dose, MN are also suggested to indicate radiation quality, differentiating between particle and photon irradiation. The "gold standard" for measuring MN formation is Fenech's cytokinesis-block micronucleus (CBMN) cytome assay, which uses the cytokinesis blocking agent cytochalasin-B. Here, we present a comprehensive analysis of the literature investigating MN induction trends in vitro, collating 193 publications, with 2476 data points. Data were collected from original studies that used the CBMN assay to quantify MN in response to ionizing radiation in vitro. Overall, the meta-analysis showed that individual studies mostly have a linear increase of MN with dose [85% of MN per cell (MNPC) datasets and 89% of percentage containing MN (PCMN) datasets had an R2 greater than 0.90]. However, there is high variation between studies, resulting in a low R2 when data are combined (0.47 for MNPC datasets and 0.60 for PCMN datasets). Particle type, species, cell type, and cytochalasin-B concentration were suggested to influence MN frequency. However, variation in the data meant that the effects could not be strongly correlated with the experimental parameters investigated. There is less variation between studies when comparing the PCMN rather than the number of MNPC. Deviation from CBMN protocol specified timings did not have a large effect on MN induction. However, further analysis showed less variation between studies following Fenech's protocol closely, which provided more reliable results. By limiting the cell type and species as well as only selecting studies following the Fenech protocol, R2 was increased to 0.64 for both measures. We therefore determine that due to variation between studies, MN are currently a poor predictor of radiation-induced DNA damage and make recommendations for futures studies assessing MN to improve consistency between datasets.

Estimating the percentage of patients who might benefit from proton beam therapy instead of X-ray radiotherapy.

OBJECTIVES: High-energy Proton Beam Therapy (PBT) commenced in England in 2018 and NHS England commissions PBT for 1.5% of patients receiving radical radiotherapy. We sought expert opinion on the level of provision. METHODS: Invitations were sent to 41 colleagues working in PBT, most at one UK centre, to contribute by completing a spreadsheet. 39 responded: 23 (59%) completed the spreadsheet; 16 (41%) declined, arguing that clinical outcome data are lacking, but joined six additional site-specialist oncologists for two consensus meetings. The spreadsheet was pre-populated with incidence data from Cancer Research UK and radiotherapy use data from the National Cancer Registration and Analysis Service. 'Mechanisms of Benefit' of reduced growth impairment, reduced toxicity, dose escalation and reduced second cancer risk were examined. RESULTS: The most reliable figure for percentage of radical radiotherapy patients likely to benefit from PBT was that agreed by 95% of the 23 respondents at 4.3%, slightly larger than current provision. The median was 15% (range 4-92%) and consensus median 13%. The biggest estimated potential benefit was from reducing toxicity, median benefit to 15% (range 4-92%), followed by dose escalation median 3% (range 0 to 47%); consensus values were 12 and 3%. Reduced growth impairment and reduced second cancer risk were calculated to benefit 0.5% and 0.1%. CONCLUSIONS: The most secure estimate of percentage benefit was 4.3% but insufficient clinical outcome data exist for confident estimates. The study supports the NHS approach of using the evidence base and developing it through randomised trials, non-randomised studies and outcomes tracking. ADVANCES IN KNOWLEDGE: Less is known about the percentage of patients who may benefit from PBT than is generally acknowledged. Expert opinion varies widely. Insufficient clinical outcome data exist to provide robust estimates. Considerable further work is needed to address this, including international collaboration; much is already underway but will take time to provide mature data.

The European Particle Therapy Network (EPTN) consensus on the follow-up of adult patients with brain and skull base tumours treated with photon or proton irradiation.

PURPOSE: Treatment-related toxicity after irradiation of brain tumours has been underreported in the literature. Furthermore, there is considerable heterogeneity on how and when toxicity is evaluated. The aim of this European Particle Network (EPTN) collaborative project is to develop recommendations for uniform follow-up and toxicity scoring of adult brain tumour patients treated with radiotherapy. METHODS: A Delphi method-based consensus was reached among 24 international radiation-oncology experts in the field of neuro-oncology concerning the toxicity endpoints, evaluation methods and time points. RESULTS: In this paper, we present a basic framework for consistent toxicity scoring and follow-up, using multiple levels of recommendation. Level I includes all recommendations that are considered minimum of care, whereas level II and III are optional evaluations in the advanced clinical or research setting, respectively. Per outcome domain, the clinical endpoints and evaluation methods per level are listed. Where relevant, the organ at risk threshold doses for recommended referral to specific organ specialists are defined. CONCLUSION: These consensus-based recommendations for follow-up will enable the collection of uniform toxicity data of brain tumour patients treated with radiotherapy. With adoptation of this standard, collaboration will be facilitated and we can further propel the research field of radiation-induced toxicities relevant for these patients. An online tool to implement this guideline in clinical practice is provided at www.cancerdata.org.

Current practice in proton therapy delivery in adult cancer patients across Europe.

BACKGROUND AND PURPOSE: Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. MATERIALS AND METHODS: We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. RESULTS: Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). CONCLUSION: Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT.

50 years of radiotherapy research: Evolution, trends and lessons for the future.

Rapid and relentless technological advances in an ever-more globalized world have shaped the field of radiation oncology in which we practise today. These developments have drastically modified the habitus1 of health professionals and researchers at an individual and organisational level. In this article we present an analysis of trends in radiation oncology research over the last half a century. To do so, the data from >350,000 scientific publications pertaining to a yearly search of the PubMed database with the keywords cancer radiotherapy was analysed. This analysis revealed that, over the years, radiotherapy research output has declined relative to alternative cancer therapies, representing 64% in 1970 it decreased to 31% in 2019. Also, the pace of research has significantly accelerated with, in the last 15 years, a doubling in the number of articles published by the 10% most productive researchers. Researchers are also facing stronger competition today with a proportion of first authors that will never get to publish as a last author increasing steadily from 58% in 1970 to 84% in 2000. Additionally, radiotherapy research output is extremely unequally distributed in the world, with Africa and South America contributing to ∼3% of radiotherapy articles in 2019 while representing 23% of the world's population. This disparity, reflecting economic situations and radiotherapy capabilities, has a knock-on effect for the provision of routine clinical treatment. Since research activity is inherent to delivery of high quality clinical care, this contributes to the global inequity of radiotherapy services. Learning from these trends is crucial for the future not only of radiation oncology research but also for effective and equitable cancer care.

Does the uncertainty in relative biological effectiveness affect patient treatment in proton therapy?

Clinical treatment with protons uses the concept of relative biological effectiveness (RBE) to convert the absorbed dose into an RBE-weighted dose that equals the dose for radiotherapy with photons causing the same biological effect. Currently, in proton therapy a constant RBE of 1.1 is generically used. However, empirical data indicate that the RBE is not constant, but increases at the distal edge of the proton beam. This increase in RBE is of concern, as the clinical impact is still unresolved, and clinical studies demonstrating a clinical effect of an increased RBE are emerging. Within the European Particle Therapy Network (EPTN) work package 6 on radiobiology and RBE, a workshop was held in February 2020 in Manchester with one day of discussion dedicated to the impact of proton RBE in a clinical context. Current data on RBE effects, patient outcome and modelling from experimental as well as clinical studies were presented and discussed. Furthermore, representatives from European clinical proton therapy centres, who were involved in patient treatment, laid out their current clinical practice on how to consider the risk of a variable RBE in their centres. In line with the workshop, this work considers the actual impact of RBE issues on patient care in proton therapy by reviewing preclinical data on the relation between linear energy transfer (LET) and RBE, current clinical data sets on RBE effects in patients, and applied clinical strategies to manage RBE uncertainties. A better understanding of the variability in RBE would allow development of proton treatments which are safer and more effective.

Update of the EPTN atlas for CT- and MR-based contouring in Neuro-Oncology.

BACKGROUND AND PURPOSE: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs. MATERIALS AND METHODS: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature. RESULTS: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online. CONCLUSION: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org.