Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

Validation of a Quality Metric Score to Assess the Placement of Hydrogel Rectal Spacer in Patients Treated With Prostate Stereotactic Radiation Therapy.

Purpose: To evaluate the quality of the interspace between the prostate and rectum and assess the effect on the dose to the rectum by measuring the spacer quality score (SQS) before and after implanting a hydrogel rectal spacer. Methods and Materials: Thirty patients with prostate cancer were treated with stereotactic ablative body radiation therapy as part of the SPORT clinical trial. Each patient had a 10 mL polyethylene glycol hydrogel spacer inserted transperineally. Computed tomography scans were acquired before and after spacer insertion, 10MV flattening filter free (FFF) stereotactic ablative body radiation therapy (SABR) treatment plans were generated using each image set. To calculate the SQS, the prostate-rectal interspace (PRI) was measured in the anterior-posterior orientation, parallel to the anatomic midline at the prostate base, apex, and midgland on the prespacer and postspacer computed tomography. Measurements were taken in 3 transverse positions between the prostate and the rectum, and PRI scores of 0, 1, and 2 were assigned if the interspace between prostate and rectum was <0.3, 0.3 to 0.9, or ≥1 cm, respectively. The overall SQS was the lowest of the PRI scores. Differences between prespacer and postspacer PRIs and SQS were investigated by performing Fisher's exact test and differences between doses to the rectum were investigated by performing the paired samples Wilcoxon rank-sum test and Student t test. Results: Statistically significant differences between prespacer versus postspacer patients were found when grouping patients according to their overall SQS. The PRI summary score did not reach statistical significance between prespacer and postspacer at the base but was significantly higher for the prostate midline and apex. Statistically significant differences in some rectum dose-volume metrics were found when grouping patients according to their PRIs and SQS. Conclusions: SQS before and after the spacer insertion was evaluated and was found to be correlated with pre- and postspacer rectal dosimetry. Sources of improvement of the SQS scoring metric and limitations are discussed.

Pulmonary vein dose and risk of atrial fibrillation in patients with non-small cell lung cancer following definitive radiotherapy: An NI-HEART analysis.

BACKGROUND AND PURPOSE: Symptomatic arrhythmia is common following radiotherapy for non-small cell lung cancer (NSCLC), frequently resulting in morbidity and hospitalization. Modern treatment planning technology theoretically allows sparing of cardiac substructures. Atrial fibrillation (AF) comprises the majority of post-radiotherapy arrhythmias, but efforts to prevent this cardiotoxicity have been limited as the causative cardiac substructure is not known. In this study we investigated if incidental radiation dose to the pulmonary veins (PVs) is associated with AF. MATERIAL AND METHODS: A single-centre study of patients completing contemporary (chemo)radiation for NSCLC, with modern planning techniques. Oncology, cardiology and death records were examined, and AF events were verified by a cardiologist. Cardiac substructures were contoured on planning scans for retrospective dose analysis. RESULTS: In 420 eligible patients with NSCLC treated with intensity-modulated (70%) or 3D-conformal (30%) radiotherapy with a median OS of 21.8 months (IQR 10.8-35.1), there were 26 cases of new AF (6%). All cases were grade 3 except two cases of grade 4. Dose metrics for both the left (V55) and right (V10) PVs were associated with the incidence of new AF. Metrics remained statistically significant after accounting for the competing risk of death and cardiovascular covariables for both the left (HR 1.02, 95%CI 1.00-1.03, p = 0.005) and right (HR 1.01 (95%CI 1.00-1.02, p = 0.033) PVs. CONCLUSION: Radiation dose to the PVs during treatment of NSCLC was associated with the onset of AF. Actively sparing the PVs during treatment planning could reduce the incidence of AF during follow-up, and screening for AF may be warranted for select cases.

A multimodality assessment of the protective capacity of statin therapy in a mouse model of radiation cardiotoxicity.

PURPOSE: Despite technological advances in radiotherapy (RT), cardiotoxicity remains a common complication in patients with lung, oesophageal and breast cancers. Statin therapy has been shown to have pleiotropic properties beyond its lipid-lowering effects. Previous murine models have shown statin therapy can reduce short-term functional effects of whole-heart irradiation. In this study, we assessed the efficacy of atorvastatin in protecting against the late effects of radiation exposure on systolic function, cardiac conduction, and atrial natriuretic peptide (ANP) following a clinically relevant partial-heart radiation exposure. MATERIALS AND METHODS: Female, 12-week old, C57BL/6j mice received an image-guided 16 Gy X-ray field to the base of the heart using a small animal radiotherapy research platform (SARRP), with or without atorvastatin from 1 week prior to irradiation until the end of the experiment. The animals were followed for 50 weeks with longitudinal transthoracic echocardiography (TTE) and electrocardiography (ECG) every 10 weeks, and plasma ANP every 20 weeks. RESULTS: At 30-50 weeks, mild left ventricular systolic function impairment observed in the RT control group was less apparent in animals receiving atorvastatin. ECG analysis demonstrated prolongation of components of cardiac conduction related to the heart base at 10 and 30 weeks in the RT control group but not in animals treated with atorvastatin. In contrast to systolic function, conduction disturbances resolved at later time-points with radiation alone. ANP reductions were lower in irradiated animals receiving atorvastatin at 30 and 50 weeks. CONCLUSIONS: Atorvastatin prevents left ventricular systolic dysfunction, and the perturbation of cardiac conduction following partial heart irradiation. If confirmed in clinical studies, these data would support the use of statin therapy for cardioprotection during thoracic radiotherapy.

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.

Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

Feasibility of home-based exercise training during adjuvant treatment for metastatic castrate-resistant prostate cancer patients treated with an androgen receptor pathway inhibitor (EXACT).

BACKGROUND: Exercise is an effective adjuvant therapy that can alleviate treatment-related toxicities for men with prostate cancer (PC). However, the feasibility of delivering exercise training to men with advanced disease and the wider impact on clinical outcomes remain unknown. The purpose of the EXACT trial was to determine the feasibility and effects of home-based exercise training in men with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: Patients with mCRPC receiving ADT + an androgen receptor pathway inhibitor (ARPI) were prescribed 12 weeks of home-based, remotely monitored, moderate intensity, aerobic and resistance exercise. Feasibility was assessed using recruitment, retention and adherence rates. Safety and adverse events were monitored throughout, with functional and patient-reported outcomes captured at baseline, post-intervention and at 3-month follow-up. RESULTS: From the 117 screened, 49 were deemed eligible and approached, with 30 patients providing informed consent (61% recruitment rate). Of those who consented, 28 patients completed baseline assessments, with 24 patients completing the intervention and 22 completing follow-up (retention rates: 86% and 79% respectively). Task completion was excellent throughout, with no intervention-related adverse events recorded. Self-reported adherence to the overall intervention was 82%. Exercise training decreased mean body mass (-1.5%), improved functional fitness (> 10%) and improved several patient-reported outcomes including clinically meaningful changes in fatigue (p = 0.042), FACT-G (p = 0.054) and FACT-P (p = 0.083), all with moderate effect sizes. CONCLUSION: Home-based exercise training, with weekly remote monitoring, was feasible and safe for men with mCRPC being treated with an ARPI. Given that treatment-related toxicities accumulate throughout the course of treatment, and as a result, negatively impact functional fitness and health-related quality of life (HRQoL), it was positive that exercise training improved or prevented a decline in these clinically important variables and could better equip patients for future treatment. Collectively, these preliminary feasibility findings support the need for a definitive, larger RCT, which downstream may lead to the inclusion of home-based exercise training as part of adjuvant care for mCRPC.

Association between statin therapy dose intensity and radiation cardiotoxicity in non-small cell lung cancer: Results from the NI-HEART study.

INTRODUCTION: Radiation cardiotoxicity is a dose-limiting toxicity and major survivorship issue for patients with non-small cell lung cancer (NSCLC) completing curative-intent radiotherapy, however patients' cardiovascular baseline is not routinely optimised prior to treatment. In this study we examined the impact of statin therapy on overall survival and post-radiotherapy cardiac events. METHODS: Patients treated between 2015-2020 at a regional center were identified. Clinical notes were interrogated for baseline patient, tumor and cardiac details, and both follow-up cancer control and cardiac events. Three cardiologists verified cardiac events. Radiotherapy planning scans were retrieved for application of validated deep learning-based autosegmentation. Pre-specified Cox regression analyses were generated with varying degrees of adjustment for overall survival. Fine and Gray regression for the risk of cardiac events, accounting for the competing risk of death and cardiac covariables was undertaken. RESULTS: Statin therapy was prescribed to 59% of the 478 included patients. The majority (88%) of patients not prescribed a statin had at least one indication for statin therapy according to cardiovascular guidelines. In total, 340 patients (71%) died and 79 patients (17%) experienced a cardiac event. High-intensity (HR 0.68, 95%CI 0.50-0.91, p = 0.012) and medium-intensity (HR 0.70, 95%CI 0.51-0.97, p = 0.033) statin therapy were associated with improved overall survival after adjustment for patient, cancer, treatment, response and cardiovascular clinical factors. There were no consistent differences in the rate or grade of cardiac events according to statin intensity. CONCLUSIONS: Statin therapy is associated with improved overall survival in patients receiving curative-intent radiotherapy for NSCLC, and there is evidence of a dose-response relationship. This study highlights the importance of a pre-treatment cardiovascular risk assessment in this cohort. Further studies are needed to examine if statin therapy is cardioprotective in patients undergoing treatment for NSCLC with considerable incidental cardiac radiation dose and a low baseline cardiac risk.

Using the AR-V7 biomarker to determine treatment in metastatic castrate resistant prostate cancer, a feasibility randomised control trial, conclusions from the VARIANT trial [version 2; peer review: 2 approved].

Background: Prostate cancer is the most commonly diagnosed malignancy in the UK. Castrate resistant prostate cancer (CRPC) can be difficult to manage with response to next generation hormonal treatment variable. AR-V7 is a protein biomarker that can be used to predict response to treatment and potentially better inform management in these patients. Our aim was to establish the feasibility of conducting a definitive randomised controlled trial comparing the clinical utility of AR-V7 biomarker assay in personalising treatments for patients with metastatic CRPC within the United Kingdom (UK) National Health Service (NHS).  Due to a number of issues the trial was not completed successfully, we aim to discuss and share lessons learned herein. Methods: We conducted a randomised, open, feasibility trial, which aimed to recruit 70 adult men with metastatic CRPC within three secondary care NHS trusts in the UK to be run over an 18-month period. Participants were randomised to personalised treatment based on AR-V7 status (intervention) or standard care (control). The primary outcome was feasibility, which included: recruitment rate, retention and compliance. Additionally, a baseline prevalence of AR-V7 expression was to be estimated. Results: Fourteen participants were screened and 12 randomised with six into each arm over a nine-month period. Reliability issues with the AR-V7 assay meant prevalence was not estimated. Due to limited recruitment the study did not complete to target. Conclusions: Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials.

A pulmonary vein atlas for radiotherapy planning.

BACKGROUND AND PURPOSE: Cardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated. MATERIALS AND METHODS: The gross and radiological anatomy relevant to atrial fibrillation was derived from cardiology and radiology literature by a multidisciplinary team. A region of interest and contouring instructions for radiotherapy computed tomography scans were iteratively developed and subsequently evaluated. Radiation oncologists (n = 5) and radiation technologists (n = 2) contoured the PVs on the four-dimensional planning datasets of five patients with locally advanced lung cancer treated with 1.8-2.75 Gy fractions. Contours were compared to reference contours agreed by the researchers using geometric and dosimetric parameters. RESULTS: The mean dose to the PVs was 35% prescription dose. Geometric and dosimetric similarity of the observer contours with reference contours was fair, with an overall mean Dice of 0.80 ± 0.02. The right superior PV (mean DSC 0.83 ± 0.02) had better overlap than the left (mean DSC 0.80 ± 0.03), but the inferior PVs were equivalent (mean DSC of 0.78). The mean difference in mean dose was 0.79 Gy ± 0.71 (1.46% ± 1.25). CONCLUSION: A PV atlas with multidisciplinary approval led to reproducible delineation for radiotherapy planning, supporting the utility of the atlas in future clinical radiotherapy cardiotoxicity research encompassing arrhythmia endpoints.

A Randomized Feasibility Trial of Stereotactic Prostate Radiation Therapy With or Without Elective Nodal Irradiation in High-Risk Localized Prostate Cancer (SPORT Trial).

PURPOSE: The aim of this study was to establish the feasibility of a randomized clinical trial comparing SABR with prostate-only (P-SABR) or with prostate plus pelvic lymph nodes (PPN-SABR) in patients with unfavorable intermediate- or high-risk localized prostate cancer and to explore potential toxicity biomarkers. METHODS AND MATERIALS: Thirty adult men with at least 1 of the following features were randomized 1:1 to P-SABR or PPN-SABR: clinical magnetic resonance imaging stage T3a N0 M0, Gleason score ≥7 (4+3), and prostate-specific antigen >20 ng/mL. P-SABR patients received 36.25 Gy/5 fractions/29 days, and PPN-SABR patients received 25 Gy/5 fractions to pelvic nodes, with the final cohort receiving a boost to the dominant intraprostatic lesion of 45 to 50 Gy. Phosphorylated gamma-H2AX (γH2AX) foci numbers, citrulline levels, and circulating lymphocyte counts were quantified. Acute toxicity information (Common Terminology Criteria for Adverse Events, version 4.03) was collected weekly at each treatment and at 6 weeks and 3 months. Physician-reported late Radiation Therapy Oncology Group (RTOG) toxicity was recorded from 90 days to 36 months postcompletion of SABR. Patient-reported quality of life (Expanded Prostate Cancer Index Composite and International Prostate Symptom Score) scores were recorded with each toxicity time point. RESULTS: The target recruitment was achieved, and treatment was successfully delivered in all patients. A total of 0% and 6.7% (P-SABR) and 6.7% and 20.0% (PPN-SABR) experienced acute grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity, respectively. At 3 years, 6.7% and 6.7% (P-SABR) and 13.3% and 33.3% (PPN-SABR) had experienced late grade ≥2 GI and GU toxicity, respectively. One patient (PPN-SABR) had late grade 3 GU toxicity (cystitis and hematuria). No other grade ≥3 toxicity was observed. In addition, 33.3% and 60% (P-SABR) and 64.3% and 92.9% (PPN-SABR) experienced a minimally clinically important change in late Expanded Prostate Cancer Index Composite bowel and urinary summary scores, respectively. γH2AX foci numbers at 1 hour after the first fraction were significantly higher in the PPN-SABR arm compared with the P-SABR arm (P = .04). Patients with late grade ≥1 GI toxicity had significantly greater falls in circulating lymphocytes (12 weeks post-radiation therapy, P = .01) and a trend toward higher γH2AX foci numbers (P = .09) than patients with no late toxicity. Patients with late grade ≥1 bowel toxicity and late diarrhea experienced greater falls in citrulline levels (P = .05). CONCLUSIONS: A randomized trial comparing P-SABR with PPN-SABR is feasible with acceptable toxicity. Correlations of γH2AX foci, lymphocyte counts, and citrulline levels with irradiated volume and toxicity suggest potential as predictive biomarkers. This study has informed a multicenter, randomized, phase 3 clinical trial in the United Kingdom.

Spatial Gene Expression Changes in the Mouse Heart After Base-Targeted Irradiation.

PURPOSE: Radiation cardiotoxicity (RC) is a clinically significant adverse effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterize late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity. METHODS AND MATERIALS: An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. After echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions. RESULTS: Ejection fraction was reduced at 30 weeks after a 16 Gy irradiation to the heart base, compared with the sham-irradiated controls. There were markedly more significant gene expression changes within the irradiated regions compared with nonirradiated regions. Variation was observed in the transcriptomic effects of radiation on different cardiac base structures (eg, between the right atrium [n = 86 dysregulated genes], left atrium [n = 96 dysregulated genes], and the vasculature [n = 129 dysregulated genes]). Disrupted biological processes spanned extracellular matrix as well as circulatory, neuronal, and contractility activities. CONCLUSIONS: This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity and support the development of actionable targets for pharmacologic intervention and biologically relevant dose constraints.

Particle swarm optimization artificial intelligence technique for gene signature discovery in transcriptomic cohorts.

The development of gene signatures is key for delivering personalized medicine, despite only a few signatures being available for use in the clinic for cancer patients. Gene signature discovery tends to revolve around identifying a single signature. However, it has been shown that various highly predictive signatures can be produced from the same dataset. This study assumes that the presentation of top ranked signatures will allow greater efforts in the selection of gene signatures for validation on external datasets and for their clinical translation. Particle swarm optimization (PSO) is an evolutionary algorithm often used as a search strategy and largely represented as binary PSO (BPSO) in this domain. BPSO, however, fails to produce succinct feature sets for complex optimization problems, thus affecting its overall runtime and optimization performance. Enhanced BPSO (EBPSO) was developed to overcome these shortcomings. Thus, this study will validate unique candidate gene signatures for different underlying biology from EBPSO on transcriptomics cohorts. EBPSO was consistently seen to be as accurate as BPSO with substantially smaller feature signatures and significantly faster runtimes. 100% accuracy was achieved in all but two of the selected data sets. Using clinical transcriptomics cohorts, EBPSO has demonstrated the ability to identify accurate, succinct, and significantly prognostic signatures that are unique from one another. This has been proposed as a promising alternative to overcome the issues regarding traditional single gene signature generation. Interpretation of key genes within the signatures provided biological insights into the associated functions that were well correlated to their cancer type.

Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT. METHODS: PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258. FINDINGS: We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe. INTERPRETATION: In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited. FUNDING: Accuray.

Validation of an established deep learning auto-segmentation tool for cardiac substructures in 4D radiotherapy planning scans.

Background: Emerging data suggest that dose-sparing several key cardiac regions is prognostically beneficial in lung cancer radiotherapy. The cardiac substructures are challenging to contour due to their complex geometry, poor soft tissue definition on computed tomography (CT) and cardiorespiratory motion artefact. A neural network was previously trained to generate the cardiac substructures using three-dimensional radiotherapy planning CT scans (3D-CT). In this study, the performance of that tool on the average intensity projection from four-dimensional (4D) CT scans (4D-AVE), now commonly used in lung radiotherapy, was evaluated. Materials and Methods: The 4D-AVE of n=20 patients completing radiotherapy for lung cancer 2015-2020 underwent manual and automated cardiac substructure segmentation. Manual and automated substructures were compared geometrically and dosimetrically. Two senior clinicians also qualitatively assessed the auto-segmentation tool's output. Results: Geometric comparison of the automated and manual segmentations exhibited high levels of similarity across parameters, including volume difference (11.8% overall) and Dice similarity coefficient (0.85 overall), and were consistent with 3D-CT performance. Differences in mean (median 0.2 Gy, range -1.6-0.3 Gy) and maximum (median 0.4 Gy, range -2.2-0.9 Gy) doses to substructures were generally small. Nearly all structures (99.5 %) were deemed to be appropriate for clinical use without further editing. Conclusions: Cardiac substructure auto-segmentation using a deep learning-based tool trained on a 3D-CT dataset was feasible on the 4D-AVE scan, meaning this tool is suitable for use on 4D-CT radiotherapy planning scans. Application of this tool would increase the practicality of routine clinical cardiac substructure delineation, and enable further cardiac radiation effects research.

Delphi study to identify consensus on patient selection for hydrogel rectal spacer use during radiation therapy for prostate cancer in the UK.

OBJECTIVES: To identify consensus on patient prioritisation for rectal hydrogel spacer use during radiation therapy for the treatment of prostate cancer in the UK. DESIGN: Delphi study consisting of two rounds of online questionnaires, two virtual advisory board meetings and a final online questionnaire. SETTING: Radical radiation therapy for localised and locally advanced prostate cancer in the UK. PARTICIPANTS: Six leading clinical oncologists and one urologist from across the UK. INTERVENTIONS: Rectal hydrogel spacer. PRIMARY AND SECONDARY OUTCOME MEASURES: None reported. RESULTS: The panel reached consensus on the importance of minimising toxicity for treatments with curative intent and that even low-grade toxicity-related adverse events can significantly impact quality of life. There was agreement that despite meeting rectal dose constraints, too many patients experience rectal toxicity and that rectal hydrogel spacers in eligible patients significantly reduces toxicity-related adverse events. However, as a consequence of funding limitations, patients need to be prioritised for spacer use. A higher benefit of spacers can be expected in patients on anticoagulation and in patients with diabetes or inflammatory bowel disease, but consensus could not be reached regarding patient groups expected to benefit less. While radiation therapy regimen is not a main factor determining prioritisation, higher benefit is expected in ultrahypofractionated regimens. CONCLUSION: There is a strong and general agreement that all patients with prostate cancer undergoing radical radiation therapy have the potential to benefit from hydrogel spacers. Currently, not all patients who could potentially benefit can access hydrogel spacers, and access is unequal. Implementation of the consensus recommendations would likely help prioritise and equalise access to rectal spacers for patients in the UK.

In vivo dosimetry in pelvic brachytherapy.

ADVANCES IN KNOWLEDGE: This paper describes the potential role for in vivo dosimetry in the reduction of uncertainties in pelvic brachytherapy, the pertinent factors for consideration in clinical practice, and the future potential for in vivo dosimetry in the personalisation of brachytherapy.

Murine models of radiation cardiotoxicity: A systematic review and recommendations for future studies.

BACKGROUND AND PURPOSE: The effects of radiation on the heart are dependent on dose, fractionation, overall treatment time, and pre-existing cardiovascular pathology. Murine models have played a central role in improving our understanding of the radiation response of the heart yet a wide range of exposure parameters have been used. We evaluated the study design of published murine cardiac irradiation experiments to assess gaps in the literature and to suggest guidance for the harmonisation of future study reporting. METHODS AND MATERIALS: A systematic review of mouse/rat studies published 1981-2021 that examined the effect of radiation on the heart was performed. The protocol was published on PROSPERO (CRD42021238921) and the findings were reported in accordance with the PRISMA guidance. Risk of bias was assessed using the SYRCLE checklist. RESULTS: 159 relevant full-text original articles were reviewed. The heart only was the target volume in 67% of the studies and simulation details were unavailable for 44% studies. Dosimetry methods were reported in 31% studies. The pulmonary effects of whole and partial heart irradiation were reported in 13% studies. Seventy-eight unique dose-fractionation schedules were evaluated. Large heterogeneity was observed in the endpoints measured, and the reporting standards were highly variable. CONCLUSIONS: Current murine models of radiation cardiotoxicity cover a wide range of irradiation configurations and latency periods. There is a lack of evidence describing clinically relevant dose-fractionations, circulating biomarkers and radioprotectants. Recommendations for the consistent reporting of methods and results of in vivo cardiac irradiation studies are made to increase their suitability for informing the design of clinical studies.

Modulating Tumour Hypoxia in Prostate Cancer Through Exercise: The Impact of Redox Signalling on Radiosensitivity.

Prostate cancer is a complex disease affecting millions of men globally. Radiotherapy (RT) is a common treatment modality although treatment efficacy is dependent upon several features within the tumour microenvironment (TME), especially hypoxia. A hypoxic TME heightens radioresistance and thus disease recurrence and treatment failure continues to pose important challenges. However, the TME evolves under the influence of factors in systemic circulation and cellular crosstalk, underscoring its potential to be acutely and therapeutically modified. Early preclinical evidence suggests exercise may affect tumour growth and some of the benefits drawn, could act to radiosensitise tumours to treatment. Intracellular perturbations in skeletal muscle reactive oxygen species (ROS) stimulate the production of numerous factors that can exert autocrine, paracrine, and endocrine effects on the prostate. However, findings supporting this notion are limited and the associated mechanisms are poorly understood. In light of this preclinical evidence, we propose systemic changes in redox signalling with exercise activate redox-sensitive factors within the TME and improve tumour hypoxia and treatment outcomes, when combined with RT. To this end, we suggest a connection between exercise, ROS and tumour growth kinetics, highlighting the potential of exercise to sensitise tumour cells to RT, and improve treatment efficacy.