Extracellular vesicles and the "six Rs" in radiotherapy.

Over half of patients with cancer receive radiation therapy during the course of their disease. Decades of radiobiological research have identified 6 parameters affecting the biological response to radiation referred to as the 6 "Rs": Repair, Radiosensitivity, Repopulation, Redistribution, Reoxygenation, and Reactivation of the anti-tumour immune response. Extracellular Vesicles (EVs) are small membrane-bound particles whose multiple biological functions are increasingly documented. Here we discuss the evidence for a role of EVs in the orchestration of the response of cancer cells to radiotherapy. We highlight that EVs are involved in DNA repair mechanisms, modulation of cellular sensitivity to radiation, and facilitation of tumour repopulation. Moreover, EVs influence tumour reoxygenation dynamics, and play a pivotal role in fostering radioresistance. Last, we examine how EV-related strategies could be translated into novel strategies aimed at enhancing the efficacy of radiation therapy against cancer.

In silico analysis of overall survival with YBX1 in male and female solid tumours.

The Y-box binding protein-1 (YBX1) gene codes for a multifunctional oncoprotein that is increasingly being linked to the regulations of many aspects of cancer cell biology. Disparities in treatment outcomes between male and female cancer patients are increasingly reported. This study aimed to examine the relationship between YBX1 expression and overall survival in male and female patients with solid tumours. Overall survival and YBX1 expression data for cohorts of male and female cancer patients obtained from freely available databases were analysed with a cox proportional hazard model with covariates of biological sex and YBX1 expression. Kaplan-Meier curves and Violin plots were constructed for segregated male and female cohorts. High YBX1 expression was significantly associated with poor survival in 2 female-only and 4 mixed-sex cancer sites. In female lung cancer patients, better survival and lower YBX1 expression were identified. The clinical importance of YBX1 expression in cancer ought to be evaluated in a sex-specific manner, especially in lung cancer.

In vitro and in vivo characterization of [64Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors.

PURPOSE: Hypoxic tumors are associated with therapy resistance and poor cancer prognosis, but methods to detect and counter tumor hypoxia remain insufficient. Our purpose was to investigate 64Cu(II)-elesclomol ([64Cu][Cu(ES)]) as a novel theranostic agent for hypoxic tumors, by implementing an improved production method and assessing its therapeutic and diagnostic potential compared to the established Cu-64 radiopharmaceuticals [64Cu]CuCl2 and [diacetyl-bis(N4-methylthiosemicarbazone) [64Cu][Cu(ATSM)]. METHODS: Cu-64 was produced using a biomedical cyclotron at 12 MeV with the reaction 64Ni(p,n)64Cu, followed by synthesis of [64Cu]CuCl2, [64Cu][Cu(ATSM)], and [64Cu][Cu(ES)]. In vitro therapeutic effects were assessed in both normoxic and hypoxic cells (22Rv1 and PC3 prostate cancer cells, and U-87MG glioblastoma cells) using the clonogenic assay and analyzing cellular uptake and internalization. In vivo therapeutic effects were assessed in 22Rv1 xenografts in BALB/cAnN-Foxn1nu/nu/Rj mice receiving a single or multiple doses of radiopharmaceutical, before their feasibility to detect tumor hypoxia was assessed by positron emission tomography (PET) in 22Rv1 and U-87MG xenografts. RESULTS: In vitro and in vivo studies demonstrated that [64Cu][Cu(ES)] reduced cell survival and inhibited tumor growth more effectively than [64Cu][Cu(ATSM)] and [64Cu]CuCl2. Hypoxia increased the cellular uptake and internalization of [64Cu][Cu(ES)] and [64Cu][Cu(ATSM)]. [64Cu][Cu(ES)]-PET tumor hypoxia detection was feasible and also revealed an unexpected finding of uptake in the brain. CONCLUSION: To the best of our knowledge, this is the first time that ES is radiolabeled with [64Cu]CuCl2 to [64Cu][Cu(ES)]. We demonstrated superior therapeutic effects of [64Cu][Cu(ES)] compared to [64Cu][Cu(ATSM)] and [64Cu]CuCl2 and that [64Cu][Cu(ES)]-PET is feasible. [64Cu][Cu(ES)] is a promising theranostic agent for hypoxic solid tumors.

Generation of Radioresistant Prostate Cancer Cells.

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. Owing to the complex nature of the biological effect of ionizing radiation, the generation and validation of these models requires the careful consideration of radiation exposure protocols and cellular endpoints. This chapter presents a protocol we used to derive and characterize an isogenic model of radioresistant prostate cancer cells. This protocol may be applicable to other cancer cell lines.

Exploring Hypoxia in Prostate Cancer With T2-weighted Magnetic Resonance Imaging Radiomics and Pimonidazole Scoring.

BACKGROUND/AIM: Radiomics involves high throughput extraction of mineable precise quantitative imaging features that serve as non-invasive prognostic or predictive biomarkers. High levels of hypoxia are associated with a poorer prognosis in prostate cancer and limit radiation therapy efficacy. Most patients with prostate cancer undergo magnetic resonance imaging (MRI) as a part of their diagnostics, and T2 imaging is the most utilised imaging method. The aim of this study was to determine whether hypoxia in prostate tumors could be identified using a radiomics model extracted from T2-weighted MR images. MATERIALS AND METHODS: Eighty eight intermediate or high-risk prostate cancer patients were evaluated. Prior to radical prostatectomy, all patients received pimonidazole (PIMO). PIMO hypoxic scores were assigned in whole-mount sections from prostatectomy specimens by an experienced pathologist who was blinded to MRI. The region of interest used for radiomics analysis included the prostatic index tumor. Radiomics extraction yielded 165 features using a special evaluation version of RadiomiX [RadiomiX Research Toolbox version 20180831 (OncoRadiomics SA, Liège, Belgium)] for non-clinical use. Multivariable logistic regression with Elastic Net regularization was utilised using 10 times repeated 10-fold cross-validation to select the best model hyperparameters, optimizing for area under the receiver operating characteristic curve (AUC). RESULTS: The average (out of sample) performance based on the repeated cross validation using the ONESE model yielded an AUC of 0.60±0.2. Shape-based features were the most prominent in the model. CONCLUSION: The development of a radiomics hypoxia model using T2 weighted MR images, standard in the staging of prostate cancer, is possible.

Mini review: Personalization of the radiation therapy management of prostate cancer using MRI-based radiomics.

Decisions on how to treat prostate cancer with radiation therapy are guideline-based but as such guidelines have been developed for populations of patients, this invariably leads to overly aggressive treatment in some patients and insufficient treatment in others. Heterogeneity within prostate tumors and in metastatic sites, even within the same patient, is believed to be a major cause of treatment failure. Radiomics biomarkers, more commonly referred to as radiomics 'features", provide readily available, cost-effective, non-invasive tools for screening, detecting tumors and serial monitoring of patients, including assessments of response to therapy and identification of therapeutic complications. Radiomics offers the potential to analyse whole tumors in 3D, as well as sub-regions or 'habitats' within tumors. Combining quantitative information from imaging with pathology, demographic details and other biomarkers will pave the way for personalised treatment selection and monitoring in prostate cancer. The aim of this review is to consider if MRI-based radiomics can bridge the gap between population-based management and personalised management of prostate cancer.

Pro-con of proton: Dosimetric advantages of intensity-modulation over passive scatter for thoracic malignancies.

The use of passively scattered proton therapy (PSPT) or intensity modulated proton therapy (IMPT) opens the potential for dose escalation or critical structure sparing in thoracic malignancies. While the latter offers greater dose conformality, dose distributions are subjected to greater uncertainties, especially due to interplay effects. Exploration in this area is warranted to determine if there is any dosimetric advantages in using IMPT for thoracic malignancies. This review aims to both compare organs-at-risk sparing and plan robustness between PSPT and IMPT and examine the mitigation strategies for the reduction of interplay effects currently available. Early evidence suggests that IMPT is dosimetrically superior to PSPT in thoracic malignancies. Randomised control trials are required before any clinical benefit of IMPT can be confirmed.

YB-1: The key to personalised prostate cancer management?

Y-box-binding protein 1 (YB-1) is a DNA/RNA binding protein increasingly implicated in the regulation of cancer cell biology. Normally located in the cytoplasm, nuclear localisation in prostate cancer is associated with more aggressive, potentially treatment-resistant disease. This is attributed to the ability of YB-1 to act as a transcription factor for various target genes associated with androgen receptor signalling, survival, DNA repair, proliferation, invasion, differentiation, angiogenesis and hypoxia. This review aims to examine the clinical potential of YB-1 in the detection and therapeutic management of prostate cancer.

The radiotherapy cancer patient: female inclusive, but male dominated.

Background: The sex-neutral language used in preclinical and clinical research intends to be inclusive of both the female and the male population, but the practice of data pooling prevents the detection of the impact of sex on cancer biology and response to medications and treatment. This study aimed to examine the consideration of sex as biological variable in the evaluation of radiation therapy in preclinical and clinical studies.Methods: Preclinical and clinical studies published over a 12-month period were reviewed for the reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both study design and data analysis.Results: A total of 321 articles met the inclusion criteria: 41 (13%) preclinical and 280 (87%) clinical studies. Two articles reported separate outcome data for males and females. Where the sex of participants was stated (230/280 (82%), 81% reported a larger number of male participants, compared to females. Less than half (45%) of studies used sex as a variable in data analysis. Sex disparity was not dependent on study location but may be more prominent in certain cancer sites. In preclinical studies, sex was at best stated in those reporting on animals (48% of studies).Conclusion: Referring to a radiotherapy cancer patient, the literature is female inclusive, but a gap does exist when it comes to consideration of sex in data analysis. The pooled analysis of female and male data could introduce statistical biases and prevent the identification of key sex-specific biological subtilities that do affect radiation responses.

Dosimetric impact of uncorrected systematic yaw rotation in VMAT for peripheral lung SABR.

AIM: This study aimed to evaluate the dosimetric impact of uncorrected yaw rotational error on both target coverage and OAR dose metrics in this patient population. BACKGROUND: Rotational set up errors can be difficult to correct in lung VMAT SABR treatments, and may lead to a change in planned dose distributions. MATERIALS AND METHODS: We retrospectively applied systematic yaw rotational errors in 1° degree increments up to -5° and +5° degrees in 16 VMAT SABR plans. The impact on PTV and OARs (oesophagus, spinal canal, heart, airway, chest wall, brachial plexus, lung) was evaluated using a variety of dose metrics. Changes were assessed in relation to percentage deviation from approved planned dose at 0 degrees. RESULTS: Target coverage was largely unaffected with the largest mean and maximum percentage difference being 1.4% and 6% respectively to PTV D98% at +5 degrees yaw.Impact on OARs was varied. Minimal impact was observed in oesophagus, spinal canal, chest wall or lung dose metrics. Larger variations were observed in the heart, airway and brachial plexus. The largest mean and maximum percentage differences being 20.77% and 311% respectively at -5 degrees yaw to airway D0.1cc, however, the clinical impact was negligible as these variations were observed in metrics with minimal initial doses. CONCLUSIONS: No clinically unacceptable changes to dose metrics were observed in this patient cohort but large percentage deviations from approved dose metrics in OARs were noted. OARs with associated PRV structures appear more robust to uncorrected rotational error.

An overview on personalisation of radiotherapy prescriptions in locally advanced non-small cell lung cancer: Are we there yet?

Standard of care radiotherapy in LA-NSCLC is 60-66 Gy in 30-33 fractions. However outcomes for these patients are poor with 5-year survival in the range of 10-20%. Randomised controlled trials have shown that dose escalation in a linear fashion does not improve outcomes for all patients, thus there is a need to tailor the prescription to the individual patient. This review assesses the strategies published to personalise the radiation therapy dose prescription in LA-NSCLC. A systematic and scoping search of the literature was performed to identify studies that met the inclusion criteria. 19 relevant studies were identified ranging from prospective clinical trials to mathematically modelled concept studies. Heterogeneity existed between all clinical studies. Nine heterogeneous publications proposed methodology to adapt the dose prescription to the individual patient. A number of encouraging strategies have been identified but fall short of the evidence level required to influence clinical practice.

Nomograms are key decision-making tools in prostate cancer radiation therapy.

BACKGROUND: The use of nomograms for predicting clinical endpoints has been well documented. Nomograms provide an individualized prognosis and help clinicians determine the effectiveness of treatment for a given patient. Early identification of potential treatment failure or toxicity allows alternative approaches to be considered, reducing unnecessary treatment, morbidity, and cost. This review aims to evaluate clinical potential of nomogram use for the management of prostate cancer radiotherapy patients. METHODS: PubMed, Embase, and Scopus were searched for literature published between 2006 and 2016. The reported correlation between measured and nomogram-predicted probabilities of biochemical control, disease progression, survival and toxicity was reviewed, through an analysis of concordance indexes and areas under the curves. RESULTS: Sixteen studies were reviewed. Outcomes predicted by the nomogram were very close to outcomes measured (concordance index of 0.7 and above) in the majority. But a combination of under and overestimation of outcome was also reported. The predictive accuracy of nomograms was very variable, however, most nomograms had accuracy greater than chance, indicated by a concordance index higher than 0.5. CONCLUSION: Nomograms can be used as prognostic guides to aid clinical decision-making for prostate cancer patients until further research addresses the limitations presented in this review. Strict definitions of end points should be added to future models and perhaps models could be enhanced with the incorporation of genomic variables or tumor specific parameters.

Aspirin in the Management of Patients with Prostate Cancer Undergoing Radiotherapy: Friend or Foe?

Aspirin has cyclooxygenase-2 (COX2)-mediated anti-inflammatory and anti-coagulant properties that may confer a positive effect in preventing and limiting the progression of prostate cancer. Prostate cancer has been shown to have poor treatment outcomes due to therapeutic resistance; therefore, COX2 inhibition caused by aspirin could represent an opportunity to augment current therapies. This is particularly of interest to patients undergoing radiation therapy (RT) where inflammation is a common side-effect. This review discusses the evidence for the potential role of aspirin in the management of patients with prostate cancer undergoing RT.

Therapeutic potential of melatonin for breast cancer radiation therapy patients.

Melatonin is an endogenous hormone primarily known for its action on the circadian rhythms. But pre-clinical studies are reporting both its radioprotective and radiosensitizing properties, possibly mediated through an interaction between melatonin and the regulation of estrogens. Melatonin pre-treatment prior to ionizing radiation was associated with a decrease in cell proliferation and an increase in p53 mRNA expression, leading to an increase in the radiosensitivity of breast cancer cells. At the same time, a decrease in radiation-induced side effects was described in breast cancer patients and in rodent models. This review examines the potential for melatonin to improve the therapeutic outcomes of breast radiation therapy, specifically estrogen receptor positive patients. Evidence suggests that melatonin may offer a novel, non-toxic and cheap adjuvant therapy to improve the existing treatment modalities. But further research is required in the clinical setting before a clear understanding of its therapeutic benefits is determined.

Image-Guided Radiotherapy in Paediatrics: A Survey of International Patterns of Practice.

BACKGROUND AND PURPOSE: Image-guided radiation therapy (IGRT) is widely used in the treatment of various tumour types in both adult and paediatric patients. However, there are no international guidelines on its optimal use in paediatric radiotherapy. This study proposes to evaluate the current patterns of practice regarding IGRT policy in paediatric patients compared with adult patients through an international survey. MATERIALS AND METHODS: A five-item questionnaire was created to address IGRT protocols for paediatrics and adults. International Paediatric Radiation Oncology Society members were eligible to partake and were contacted via email (number = 119). RESULTS: Forty-three members have responded to the survey. Most (65%) centres did not have separate written IGRT protocols for paediatric and adult patients. The imaging frequency used was the same for adults and paediatrics in up to 74% of the centres responded, and scanning parameters used were different in adults and paediatrics in 47% of the centres for central nervous system treatment. Different measures to decrease exposure dose from IGRT in paediatrics have also been explored. CONCLUSION: Despite the extensive use of IGRT internationally, most centres use a series of site-specific protocols that fail to consider patient age or size. Given the desire to reduce radiation exposure in the paediatric patient cohort, further research is warranted to develop consensus guidelines on optimal IGRT use.

Topical Management of Acute Radiation Dermatitis in Breast Cancer Patients: A Systematic Review and Meta-Analysis.

AIM: To evaluate the efficacy of topical corticosteroids in managing acute radiation dermatitis (RD) in female breast cancer patients. MATERIALS AND METHODS: MEDLINE, EMBASE, CINAHL, CENTRAL, ScienceDirect, Google Scholar and Clinicaltrials.gov were searched up to and including March 2017 to identify Randomised Controlled Trials (RCTs) assessing topical corticosteroids for the management and prevention of acute RD. RESULTS: Ten RCTs (919 participants) were identified. Meta-analysis, including results for 845 participants, demonstrated significant benefits of topical corticosteroids in preventing the incidence of wet desquamation (OR: 0.29; 95%CI: 0.19-0.45; p<0.0001) and reducing the mean RD score (SMD: -0.47, 95%CI: -0.61 - -0.33, p<0.00001). CONCLUSION: Topical corticosteroids impacted on the incidence of wet desquamation and the average RD score observed in female breast cancer patients. The use of topical corticosteroids can reduce pruritus in participants and improve quality of life.

Clinical Potential of Statins in Prostate Cancer Radiation Therapy.

BACKGROUND/AIM: Statins are cholesterol- lowering drugs that have been shown to possess anti-tumour properties. Observational studies have shown that 3-hydroxy-3-methlyglutaryl coenzyme A reductase inhibitor (statin) use may be associated with reduced prostate cancer risk. Preclinical studies suggest that statins possess anticancer and radiosensitising properties. This review aims to determine the impact of statin use in the efficacy of radiation therapy and the therapeutic window in prostate cancer. MATERIALS AND METHODS: The scientific databases PubMed, Science Direct, EMBASE, Cochrane Collaboration, and Google Scholar were searched for articles identifying statin use in histologically confirmed prostate cancer treated with external beam radiation therapy. RESULTS: Improvement was observed in freedom from biochemical failure (91% vs. 79%), relapse free survival (72% vs. 69%), distant metastasis free survival (96% vs. 94%), and prostate-specific antigen (PSA) relapse free survival (89% vs. 83%) with statin use, however this did not translate into an overall survival benefit for patients. Conflicting data concerning clinical outcomes reduce the integrity of these findings. The literature supports the radiosensitising properties of statins and their potential antitumor effects in prostate cancer. CONCLUSION: Statin use in prostate cancer presents many obstacles yet to be overcome, which warrant attention prior to the routine implementation of statins in treatment regimes. However, there is evidence to support their beneficial use.

The Notch-3 receptor: A molecular switch to tumorigenesis?

The Notch pathway is a highly conserved pathway increasingly implicated with the progression of human cancers. Of the four existing receptors associated with the pathway, the deregulation in the expression of the Notch-3 receptor is associated with more aggressive disease and poor prognosis. Selective targeting of this receptor has the potential to enhance current anti-cancer treatments. Molecular profiling strategies are increasingly incorporated into clinical decision making. This review aims to evaluate the clinical potential of Notch-3 within this new era of personalised medicine.

68Ga-PSMA-PET/CT Has a Role in Detecting Prostate Cancer Lesions in Patients with Recurrent Disease.

BACKGROUND/AIM: Early detection of recurrent πrostate cancer (PCa) lesions is paramount to allow patients to avail of localised salvage therapy options. The most significant reason for failure of salvage therapy is undetected metastatic disease. This demonstrates the need for a more accurate monitoring tool. The prostate-specific membrane antigen (PSMA) is increasingly investigated as a novel tracer for gallium 68 PET/CT to detect PCa lesions in patients with recurrent disease. MATERIALS AND METHODS: The Embase, Pubmed and the Cochrane databases were searched to identify studies investigating the accuracy of 68Ga-PSMA-PET/CT in detecting PCa lesions. Studies were analysed with regards to image analysis, sensitivity, specificity and detection rates; compared to conventional methods and with the effects of contributing characteristics. RESULTS: 24 studies were analysed. 68Ga-PSMA-PET/CT was associated with sensitivity and specificity values of 33-93%, and >99% respectively. The tracer produced excellent contrast 1 h post injection. Probability of detection increases with increasing prostate-specific antigen (PSA), and at low PSA levels, is greater than that of current choline tracers. Early detection of lesions by the tracer allows alterations in follow up treatment. However, detectability may be affected by tracer trapping, androgen deprivation therapy and levels of PSMA expression. CONCLUSION: 68Ga-PSMA PET/CT shows promise as a tool for the detection of PCa lesions in patients with suspected recurrence. However further studies with more reports on sensitivity and specificity with longer follow-up times are needed.