A joint physics and radiobiology DREAM team vision - Towards better response prediction models to advance radiotherapy.

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines.

Prehabilitation for Patients with Cancer Undergoing Radiation Therapy: a Scoping Review.

AIMS: Prehabilitation is a process of identifying and assessing factors that could compromise the physical and psychological health of patients undergoing cancer treatment and implementing an intervention to combat such concerns. The use of prehabilitation in cancer surgery has yielded positive outcomes in rectal, lung and abdominal cancers. Prehabilitation strategies have potential to improve the management of patients receiving radiation therapy or chemoradiation. The aim of the present study was to map the evidence of the assessment and evaluation of prehabilitation for radiation therapy patients. MATERIALS AND METHODS: A database search using EMBASE and PubMed was conducted. The PRISMA guidelines were adhered to. Keywords included prehabilitation, radiation therapy/radiotherapy, chemoradiotherapy/chemoradiation, intervention and exercise. Types of prehabilitation strategy, their purposes and impact, according to cancer site, were analysed. RESULTS: Prehabilitation is most commonly evaluated in head and neck cancer, whereby unimodal, physical interventions manage dysphagia. Prehabilitation for lung cancer demonstrated its ability to widen treatment options for patients. Physical prehabilitation is administered to combat adverse effects of neoadjuvant chemoradiation therapy in patients with rectal cancer. CONCLUSION: Prehabilitation is adaptive and tailored to specific patient and site needs; thus it is applied across a wide range of cancer sites. More interventions by which radiation therapy is the definitive treatment modality and larger sample sizes within these studies are warranted to increase prehabilitation utilisation for patients undergoing radiation therapy.

Investigating the Needs and Concerns of Lesbian, Gay, Bisexual, Transgender, Queer, or Questioning Cancer Patients.

The needs and concerns of lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ+) patients with cancer remain poorly understood. This is important as LGBTQ+ patients have an elevated risk of developing certain cancers and have poorer oncologic outcomes compared to non-LGBTQ+ patients. The lack of research may be linked to the complexity of studying the needs and concerns of this patient population. This review aimed to describe the evidence that sought to identify the needs and concerns of LGBTQ+ cancer patients. Studies were extracted using keywords such as "LGBTQ" and "Oncology." Patient participants were excluded if they did not identify as LGBTQ+ and if they did not have cancer or were not cancer survivors. Healthcare professionals were excluded if they were not oncology specific. A total of 22 studies met our inclusion criteria. LGBTQ+ cancer patients expressed concerns surrounding heteronormative assumptions made by healthcare professionals, a lack of LGBTQ±specific cancer support groups, and psychosexual concerns such as erectile dysfunction following cancer treatment. Oncology healthcare professionals lacked the knowledge and education that are required to manage this patient cohort. Further research is required to investigate the needs and concerns of LGBTQ+ cancer patients specifically in the radiation oncology setting.

Influence of inter-observer delineation variability on radiomic features of the parotid gland.

PURPOSE: This study aimed to quantify the variability in the values of radiomic features extracted from a right parotid gland (RPG) delineated by a series of independent observers. METHODS: This was a secondary analysis of anonymous data from a delineation workshop. Inter-observer variability of the RPG from 40 participants was quantified using DICE similarity coefficient (DSC) and Hausdorff distance (HD). An additional contour was generated using Varian SmartSegmentation. Radiomic features extracted include four shape features, six histogram features, and 32 texture features. The absolute mean paired percentage difference (PPD) in feature values from the expert and participants were ranked . Feature robustness was classified using pre- determined thresholds. RESULTS: 63% of participants achieved a DSC > 0.7, the auto- segmentation DSC was 0.76. The average HD for the participants was 16.16 mm ± 0.66 mm, and 15.16 mm for the auto-segmentation. 48% (n = 20) and 33% (n = 14) of features were deemed to be robust with a mean absolute PPD < 5%, for the auto-segmentation and manual delineations respectively; the majority of which were from the grey-run length matrix family. 7% (n = 3) of features from the auto- segmentation and 10% (n = 4) from the manual contours were deemed to be unstable with a mean absolute PPD > 50%. The value of the most robust feature was not related to DSC and HD. CONCLUSION: Inter-observer delineation variability affects the value of the radiomic features extracted from the RPG. This study identifies the radiomic features least sensitive to these uncertainties. Further investigation of the clinical relevance of these features in prediction of xerostomia is warranted.

Geometric and Dosimetric Evaluation of a Commercially Available Auto-segmentation Tool for Gross Tumour Volume Delineation in Locally Advanced Non-small Cell Lung Cancer: a Feasibility Study.

AIMS: To quantify the reliability of a commercially available auto-segmentation tool in locally advanced non-small cell lung cancer using serial four-dimensional computed tomography (4DCT) scans during conventionally fractionated radiotherapy. MATERIALS AND METHODS: Eight patients with serial 4DCT scans (n = 44) acquired over the course of radiotherapy were assessed. Each 4DCT had a physician-defined primary tumour manual contour (MC). An auto-contour (AC) and a user-adjusted auto-contour (UA-AC) were created for each scan. Geometric agreement of the AC and the UA-AC to the MC was assessed using the dice similarity coefficient (DSC), the centre of mass (COM) shift from the MC and the structure volume difference from the MC. Bland Altman analysis was carried out to assess agreement between contouring methods. Dosimetric reliability was assessed by comparison of planning target volume dose coverage on the MC and UA-AC. The time trend analysis of the geometric accuracy measures from the initial planning scan through to the final scan for each patient was evaluated using a Wilcoxon signed ranks test to assess the reliability of the UA-AC over the duration of radiotherapy. RESULTS: User adjustment significantly improved all geometric comparison metrics over the AC alone. Improved agreement was observed in smaller tumours not abutting normal soft tissue and median values for geometric comparisons to the MC for DSC, tumour volume difference and COM offset were 0.80 (range 0.49-0.89), 0.8 cm3 (range 0.0-5.9 cm3) and 0.16 cm (range 0.09-0.69 cm), respectively. There were no significant differences in dose metrics measured from the MC and the UA-AC after Bonferroni correction. Variation in geometric agreement between the MC and the UA-AC were observed over the course of radiotherapy with both DSC (P = 0.035) and COM shift from the MC (ns) worsening. The median tumour volume difference from the MC improved at the later time point. CONCLUSIONS: These findings suggest that the UA-AC can produce geometrically and dosimetrically acceptable contours for appropriately selected patients with non-small cell lung cancer. Larger studies are required to confirm the findings.

Multiplex profiling identifies clinically relevant signalling proteins in an isogenic prostate cancer model of radioresistance.

The exact biological mechanism governing the radioresistant phenotype of prostate tumours at a high risk of recurrence despite the delivery of advanced radiotherapy protocols remains unclear. This study analysed the protein expression profiles of a previously generated isogenic 22Rv1 prostate cancer model of radioresistance using DigiWest multiplex protein profiling for a selection of 90 signalling proteins. Comparative analysis of the profiles identified a substantial change in the expression of 43 proteins. Differential PARP-1, AR, p53, Notch-3 and YB-1 protein levels were independently validated using Western Blotting. Pharmacological targeting of these proteins was associated with a mild but significant radiosensitisation effect at 4Gy. This study supports the clinical relevance of isogenic in vitro models of radioresistance and clarifies the molecular radiation response of prostate cancer cells.

Fractionated radiation exposure amplifies the radioresistant nature of prostate cancer cells.

The risk of recurrence following radiation therapy remains high for a significant number of prostate cancer patients. The development of in vitro isogenic models of radioresistance through exposure to fractionated radiation is an increasingly used approach to investigate the mechanisms of radioresistance in cancer cells and help guide improvements in radiotherapy standards. We treated 22Rv1 prostate cancer cells with fractionated 2 Gy radiation to a cumulative total dose of 60 Gy. This process selected for 22Rv1-cells with increased clonogenic survival following subsequent radiation exposure but increased sensitivity to Docetaxel. This RR-22Rv1 cell line was enriched in S-phase cells, less susceptible to DNA damage, radiation-induced apoptosis and acquired enhanced migration potential, when compared to wild type and aged matched control 22Rv1 cells. The selection of radioresistant cancer cells during fractionated radiation therapy may have implications in the development and administration of future targeted therapy in conjunction with radiation therapy.

MGMT testing allows for personalised therapy in the temozolomide era.

Adjuvant temozolomide (TMZ)-based chemoradiation is the standard of care for most glioblastoma patients (GBMs); however, a large proportion of these patients do not respond to TMZ. Silencing of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is thought to induce chemosensitivity, and testing for methylation may allow for patient stratification; however, this has yet to become routine clinical practice despite an abundance of literature on the subject. The databases PubMed, Embase, The Cochrane Library, Science Direct and Medline were searched for relevant articles published between 1999 and 2015. Articles utilising MGMT testing in glioblastomas, and treatment of glioblastomas with temozolomide were assessed. Immunohistochemistry, methylation-specific PCR (MSP), reverse transcriptase PCR, pyrosequencing and bisulphite sequencing were the main testing methods identified. Nested-MSP techniques produced poor correlation with survival, whilst bisulphite sequencing showed no evident benefit over MSP. Testing is limited by sample quality and contamination; however, efforts are made to minimise this. Strong evidence for MGMT-based personalised therapy was presented in the elderly but remains controversial in the entire GBM population. MGMT testing presents many obstacles yet to be overcome, and these warrant attention prior to the routine implementation of MGMT testing to aid decision making in GBMs. However, there is evidence to support its use, particularly in the elderly.

Identification of suitable endogenous controls for gene and miRNA expression studies in irradiated prostate cancer cells.

This study aimed to to evaluate the stability of commonly used endogenous control genes for messenger RNA (mRNA) (N = 16) and miRNAs (N = 3) expression studies in prostate cell lines following irradiation. The stability of endogenous control genes expression in irradiated (6 Gy) versus unirradiated controls was quantified using NormFinder and coefficient of variation analyses. HPRT1 and 18S were identified as most and least stable endogenous controls, respectively, for mRNA expression studies in irradiated prostate cells. SNORD48 and miR16 miRNA endogenous controls tested were associated with low coefficient of variations following irradiation (6 Gy). This study highlights that commonly used endogenous controls can be responsive to radiation and validation is required prior to gene/miRNAs expression studies.

Active surveillance for low-risk prostate cancer: diversity of practice across Europe.

BACKGROUND: Active surveillance (AS) is a recognised treatment option for low-risk prostate cancer (PCa). AIMS: To review AS criteria in terms of patient selection, follow-up and indications for intervention. METHODS: A total of 2,959 potential participants were identified and invited via email to complete an online survey. Only urologists practising in an EU country were eligible to participate. Statistical analyses were carried out using SPSS version 18.0. The χ (2) test was used to compare responses between those who do and do not follow an AS protocol. RESULTS: Response rate was 8% (n = 226). Ninety-seven per cent urologists offer AS; 25% (n = 53/215) within a clinical trial and a further 28% (n = 60/215) using an official AS protocol. Gleason score ≤ 3 + 3 = 6 (87 %, n = 173/200) and prostate-specific antigen (PSA) ≤ 10 ng/ml (86%, n = 170/198) are the commonest selection criteria. There was a statistically significant association between having an AS protocol and using PSA as an eligibility criterion (p = 0.03). For urologists not following a protocol, 11% do not consider PSA as an eligibility criterion and 81% consider PSA ≤ 10 ng/ml to decide on AS, compared to 2 and 90%, respectively, who adhere to a protocol. Twenty-four per cent of urologists without a protocol do not re-biopsy in comparison to 11% with a protocol (p = 0.026). Gleason score progression trigger the most intervention (n = 168/192, 87%). CONCLUSIONS: Urologists not adhering to an AS protocol or participating in a clinical trial appear to apply less rigorous criteria for both eligibility and monitoring in AS.

The tissue plasminogen activator gene promoter: a novel tool for radiogenic gene therapy of the prostate?

BACKGROUND: Radiation therapy is a treatment modality routinely used in cancer management so it is not unexpected that radiation-inducible promoters have emerged as an attractive tool for controlled gene therapy. The human tissue plasminogen activator gene promoter (t-PA) has been proposed as a candidate for radiogenic gene therapy, but has not been exploited to date. The purpose of this study was to evaluate the potential of this promoter to drive the expression of a reporter gene, the green fluorescent protein (GFP), in response to radiation exposure. METHODS: To investigate whether the promoter could be used for prostate cancer gene therapy, we initially transfected normal and malignant prostate cells. We then transfected HMEC-1 endothelial cells and ex vivo rat tail artery and monitored GFP levels using Western blotting following the delivery of single doses of ionizing radiation (2, 4, 6 Gy) to test whether the promoter could be used for vascular targeted gene therapy. RESULTS: The t-PA promoter induced GFP expression up to 6-fold in all cell types tested in response to radiation doses within the clinical range. CONCLUSIONS: These results suggest that the t-PA promoter may be incorporated into gene therapy strategies driving therapeutic transgenes in conjunction with radiation therapy.

Hypoxia in prostate cancer: a powerful shield against tumour destruction?

Tumour hypoxia is progressively emerging as a common feature of prostate tumours associated with poor prognosis. While the molecular basis of disease progression is increasingly well documented, the potential role of hypoxia in these processes remains poorly evaluated. By dissecting the impact of hypoxia-inducible factor 1 alpha on molecular responses, this review provides evidence for a powerful protecting role of oxygen deprivation against oxidative stress injury, androgen deprivation, chemotherapeutic and radiation cytotoxicity. We propose hypoxia as a potent tumour-induced shield against destruction and suggest its targeting may need to be routinely addressed in the management of prostate cancer.

Achieving hypoxia-inducible gene expression in tumors.

Hypoxia is an inevitable feature of solid tumors and a common cause of treatment failure. Hypoxia acts as a trigger to genetic instability, apoptosis and possibly metastases. The adaptive response to cellular hypoxia involves the modulation of the synthesis of multiple proteins controlling processes such as glucose homeostasis, angiogenesis, vascular permeability and inflammation. The hypoxia responsive element (HRE) sequences isolated from oxygen-responsive genes have been shown to selectively induce gene expression in response to hypoxia when placed upstream of a promoter. The levels of induced gene expression were dependent on the number of HRE copies and the oxygen tension. Hypoxia-mediated cancer gene therapy strategies may represent a promising mean to significantly improve the efficacy of standard radiation therapy and chemotherapy approaches.