Optimising inter-patient image registration for image-based data mining in breast radiotherapy.

Background and purpose: Image-based data mining (IBDM) requires spatial normalisation to reference anatomy, which is challenging in breast radiotherapy due to variations in the treatment position, breast shape and volume. We aim to optimise spatial normalisation for breast IBDM. Materials and methods: Data from 996 patients treated with radiotherapy for early-stage breast cancer, recruited in the REQUITE study, were included. Patients were treated supine (n = 811), with either bilateral or ipsilateral arm(s) raised (551/260, respectively) or in prone position (n = 185). Four deformable image registration (DIR) configurations for extrathoracic spatial normalisation were tested. We selected the best-performing DIR configuration and further investigated two pathways: i) registering prone/supine cohorts independently and ii) registering all patients to a supine reference. The impact of arm positioning in the supine cohort was quantified. DIR accuracy was estimated using Normalised Cross Correlation (NCC), Dice Similarity Coefficient (DSC), mean Distance to Agreement (MDA), 95 % Hausdorff Distance (95 %HD), and inter-patient landmark registration uncertainty (ILRU). Results: DIR using B-spline and normalised mutual information (NMI) performed the best across all evaluation metrics. Supine-supine registrations yielded highest accuracy (0.98 ± 0.01, 0.91 ± 0.04, 0.23 ± 0.19 cm, 1.17 ± 1.18 cm, 0.51 ± 0.26 cm for NCC, DSC, MDA, 95 %HD, and ILRU), followed by prone-prone and supine-prone registrations. Arm positioning had no significant impact on registration performance. For the best DIR strategy, uncertainty of 0.44 and 0.81 cm in the breast and shoulder regions was found. Conclusions: B-spline algorithm using NMI and registered supine and prone cohorts independently provides the most optimal spatial normalisation strategy for breast IBDM.

Half body irradiation (HBI) for bone metastases in the modern radiotherapy technique era - A systematic review.

Bone metastases (BMs) are the most common cause of cancer-related pain and radiation therapy plays a key role in treating pain caused by it. The half-body irradiation (HBI) is a modality that can be used to treat patients with multiple painful BMs. In the modern era, concerns about toxicity and the availability of new agents requiring robust bone marrow function have limited the use of HBI in advanced cancer. Concerns about HBI toxicity stem from outdated techniques; modern methods like volumetric modulated arc therapy (VMAT) and helical tomotherapy now allow safer irradiation of complex target volumes. We conducted a systematic review to present updated information about HBI efficacy and potential toxicity. Pain relief usually occurs very quickly 2-3 weeks after HBI. The overall pain response rate was high in all the series, accounting for a median of 84 % (75.6-89 %), with a median of 36 % complete pain response. The toxicity is usually limited to G1/G2, with very rare G3 cases. More than 50 % of patients can reduce analgesic intake after HBI. Additionally, with modern radiotherapy techniques, quality of life is improved in most patients. HBI is a safe and effective method and should once again be reconsidered for more frequent use.

Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) using dose-volume constraints development: a study protocol.

INTRODUCTION: Radiotherapy improves local tumour control in patients with soft tissue sarcoma of the extremities (STSE) but it also increases the probability of long-term toxicities such as tissue fibrosis, joint stiffness and lymphoedema. The use of radiation dose and volume thresholds, called dose constraints, may potentially reduce the development of toxicities in STSE. The aim of this study is to determine predictors of radiotherapy-related side effects for STSE. METHODS AND ANALYSIS: Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) is a multicentre observational study comprising two cohorts (PredicT A and B). PredicT A, a retrospective analysis of the UK VorteX (NCT00423618) and IMRiS clinical trials (NCT02520128), is aimed at deriving a statistical model for development of dose-volume constraints. This model will use receiving operator characteristics and multivariate analysis to predict radiotherapy side effects and patient-reported outcomes. PredicT B, a prospective cohort study of 150 patients with STSE, is aimed at testing the validity of those dose-volume constraints. PredicT B is open and planned to complete recruitment by September 2024. ETHICS AND DISSEMINATION: PredicT B has received ethical approval from North West - Liverpool Central Research Ethics Committee (20/NW/0267). Participants gave informed consent to participate in the study before taking part. We will disseminate our findings via publications, presentations, national and international conference meetings and engage with local charities. TRIAL REGISTRATION NUMBER: NCT05978024.

Immune effects of α and ß radionuclides in metastatic prostate cancer.

External beam radiotherapy is used for radical treatment of organ-confined prostate cancer and to treat lesions in metastatic disease whereas molecular radiotherapy with labelled prostate-specific membrane antigen ligands and radium-223 (223Ra) is indicated for metastatic prostate cancer and has demonstrated substantial improvements in symptom control and overall survival compared with standard-of-care treatment. Prostate cancer is considered an immunologically cold tumour, so limited studies investigating the treatment-induced effects on the immune response have been completed. However, emerging data support the idea that radiotherapy induces an immune response in prostate cancer, but whether the response is an antitumour or pro-tumour response is dependent on the radiotherapy regime and is also cell-line dependent. In vitro data demonstrate that single-dose radiotherapy regimes induce a greater immune-suppressive profile than fractionated regimes; less is known about the immune response induced by molecular radiotherapy agents, but evidence suggests that these agents might induce an immune-suppressive systemic immune response, indicated by increased expression of inhibitory checkpoint molecules such as programmed cell death 1 ligand 1 and 2, and that these changes could be associated with clinical response. Different radiotherapy modalities can induce distinct immune profiles, which can either activate or suppress immune-mediated tumour killing and the current preclinical models used for prostate cancer research are not yet optimal for studying the complexity of the radiotherapy-induced immune response.

Single-dose high-dose-rate brachytherapy versus two and three fractions for locally advanced prostate cancer.

BACKGROUND: Single-dose high-dose-rate brachytherapy (SD-HDR-BT) was compared to two or three fraction HDR BT in intermediate and high-risk localized prostate cancer with median follow-up of 10 years. MATERIALS AND METHODS: 293 patients received 1 × 19Gy or 1 × 20Gy (Group A = 49), 2 × 13Gy (Group B = 138), or 3 × 10.5 Gy (Group C = 106) HDR BT. The primary endpoint was biochemical relapse-free interval (bRFI). Late genitourinary (GU) and gastrointestinal (GI) morbidity used RTOG scales and the International Prostate Symptom Score (IPSS). Freedom from biochemical relapse (bRFI), overall survival (OS) and GU, GI and IPSS morbidity were calculated using Kaplan-Meier (K-M) method and log-rank test. Univariate and multivariate hazard ratios (HR) were obtained using Cox's proportional hazard. RESULTS: At 10 years, K-M estimates of bRFI were 64 % (Group A), 72 % (Group B), and 76 % (Group C) (p = 0.2). No statistically significant difference was seen in OS. In multivariate analysis risk-category and ADT administration, but not dose, were significant predictors of relapse (p = 0.0003 and 0.03, respectively). At ten years, GU grade 3 events were 8 % (A), 2 % (B) and 13 % (C); (p = 0.01). IPSS ≥ 20 was 31 % (A), 20 % (B) and 23 % (C); (p = 0.6) and grade 3 GI was 0 % in groups A and B and 2 % in C; (p = 0.3). No GU or GI grade-4 events were observed. Pre-treatment IPSS was a highly significant predictor of failure in multivariate analysis. CONCLUSIONS: Long-term outcome data show reduced but not statistically significant difference in PSA control, and no difference in overall survival, between SD-HDR-BT and 2 or 3 fractions of HDR-BT.

CRISPR-Cas9 potential for identifying novel therapeutic targets in muscle-invasive bladder cancer.

Gene editing technologies help identify the genetic perturbations driving tumour initiation, growth, metastasis and resistance to therapeutics. This wealth of information highlights tumour complexity and is driving cancer research towards precision medicine approaches based on an individual's tumour genetics. Bladder cancer is the 11th most common cancer in the UK, with high rates of relapse and low survival rates in patients with muscle-invasive bladder cancer (MIBC). MIBC is highly heterogeneous and encompasses multiple molecular subtypes, each with different responses to therapeutics. This evidence highlights the need to identify innovative therapeutic targets to address the challenges posed by this heterogeneity. CRISPR-Cas9 technologies have been used to advance our understanding of MIBC and determine novel drug targets through the identification of drug resistance mechanisms, targetable cell-cycle regulators, and novel tumour suppressor and oncogenes. However, the use of these technologies in the clinic remains a substantial challenge and will require careful consideration of dosage, safety and ethics. CRISPR-Cas9 offers considerable potential for revolutionizing bladder cancer therapies, but substantial research is required for validation before these technologies can be used in the clinical setting.

Are we making progress in curing advanced cervical cancer-again?

Major improvements in radiotherapy over the past two decades in the definitive treatment of locally advanced cervical cancer have significantly improved loco-regional control and survival, whereas little progress has been made with chemotherapy since the implementation of concomitant cisplatin 25 years ago. However, the randomized study INTERLACE (A phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer) of neoadjuvant chemotherapy presented recently, has shown significant improvement in survival with the use of six cycles of weekly carboplatin and paclitaxel. Although INTERLACE is yet to be published, neoadjuvant chemotherapy is already being advocated as the new standard, and studies are being designed with neoadjuvant chemotherapy followed by chemoradiation and brachytherapy as the standard arm. It is noteworthy that INTERLACE was initiated before the improvements in radiotherapy mentioned above were broadly implemented. The survival rate in the standard arm of INTERLACE was therefore inferior to the results obtained with the latest state-of-the-art external beam radiotherapy and image guided adaptive brachytherapy (EMBRACE, Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer). Moreover, patient selection impedes the comparison of INTERLACE with other studies as the patients included in INTERLACE were younger, had better performance status, and had less advanced disease than in other studies. Notably patients with involved para-aortic nodes were excluded. In this review, we discuss neoadjuvant chemotherapy in the frame of the EMBRACE studies and show how the impact of modern radiotherapy and patient selection affects the interpretation of the results of INTERLACE. This has led us to conclude that neoadjuvant chemotherapy is not needed for the majority of patients with cervical cancer treated with definitive modern radiotherapy, and may cause harm. However, it is possible that short course neoadjuvant chemotherapy may benefit a minor subgroup of patients who need to be identified. Comprehensive understanding, including cost utility analyses, are needed to draw conclusions regarding the potential benefit of neoadjuvant chemotherapy in low and middle income countries with limited access to modern radiotherapy.

Digital spatial profiling of the microenvironment of muscle invasive bladder cancer.

Muscle invasive bladder cancer (MIBC) is a molecularly diverse disease with varied clinical outcomes. Molecular studies typically employ bulk sequencing analysis, giving a transcriptomic snapshot of a section of the tumour. However, tumour tissues are not homogeneous, but are composed of distinct compartments such as the tumour and stroma. To investigate the molecular profiles of bladder cancer, whilst also maintaining the spatial complexity of the tumours, we employed whole transcriptome Digital Spatial Profiling (DSP). With this method we generated a dataset of transcriptomic profiles of tumour epithelium, stroma, and immune infiltrate. With these data we investigate the spatial relationship of molecular subtype signatures and ligand signalling events. We find that Basal/Squamous and Classical subtypes are mostly restricted to tumour regions, while the stroma-rich subtype signatures are abundant within the stroma itself. Additionally, we identify ligand signalling events occurring between tumour, stroma, and immune infiltrate regions, such as immune infiltrate derived GPNMB, which was highly correlated with VEGFA expression within the tumour. These findings give us new insights into the diversity of MIBC at a molecular level and provide a dataset with detailed spatial information that was not available before in bladder cancer research.

Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

Re-irradiation practice and ESTRO/EORTC consensus recommendations: 2023 ASTRO education panel.

Indications for re-irradiation are increasing both for palliation and potentially curative attempts to achieve durable local control. This has been in part driven by the technological advances in the last decade including image-guided brachytherapy, volumetric-modulated arc therapy and stereotactic body radiotherapy. These enable high dose focal irradiation to be delivered to a limited target volume with minimal normal tissue re-irradiation. The European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) have collaboratively developed a comprehensive consensus on re-irradiation practices, aiming to standardise definitions, reporting, and clinical decision-making processes. The document introduces a universally applicable definition for re-irradiation, categorised into two primary types based on the presence of geometric overlap of irradiated volumes and concerns for cumulative dose toxicity. It also identifies "repeat organ irradiation" and "repeat irradiation" for cases without such overlap, emphasising the need to consider toxicity risks associated with cumulative doses. Additionally, the document presents detailed reporting guidelines for re-irradiation studies, specifying essential patient and tumour characteristics, treatment planning and delivery details, and follow-up protocols. These guidelines are designed to improve the quality and reproducibility of clinical research, thus fostering a more robust evidence base for future re-irradiation practices. The consensus underscores the necessity of interdisciplinary collaboration and shared decision-making, highlighting performance status, patient survival estimates, and response to initial radiotherapy as critical factors in determining eligibility for re-irradiation. It advocates for a patient-centric approach, with transparent communication about treatment intent and potential risks. Radiobiological considerations, including the application of the linear-quadratic model, are recommended for assessing cumulative doses and guiding re-irradiation strategies. By providing these comprehensive recommendations, the ESTRO-EORTC consensus aims to enhance the safety, efficacy, and quality of life for patients undergoing re-irradiation, while paving the way for future research and refinement of treatment protocols in the field of oncology.

AAPM Task Group Report 267: A joint AAPM GEC-ESTRO report on biophysical models and tools for the planning and evaluation of brachytherapy.

Brachytherapy utilizes a multitude of radioactive sources and treatment techniques that often exhibit widely different spatial and temporal dose delivery patterns. Biophysical models, capable of modeling the key interacting effects of dose delivery patterns with the underlying cellular processes of the irradiated tissues, can be a potentially useful tool for elucidating the radiobiological effects of complex brachytherapy dose delivery patterns and for comparing their relative clinical effectiveness. While the biophysical models have been used largely in research settings by experts, it has also been used increasingly by clinical medical physicists over the last two decades. A good understanding of the potentials and limitations of the biophysical models and their intended use is critically important in the widespread use of these models. To facilitate meaningful and consistent use of biophysical models in brachytherapy, Task Group 267 (TG-267) was formed jointly with the American Association of Physics in Medicine (AAPM) and The Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) to review the existing biophysical models, model parameters, and their use in selected brachytherapy modalities and to develop practice guidelines for clinical medical physicists regarding the selection, use, and interpretation of biophysical models. The report provides an overview of the clinical background and the rationale for the development of biophysical models in radiation oncology and, particularly, in brachytherapy; a summary of the results of literature review of the existing biophysical models that have been used in brachytherapy; a focused discussion of the applications of relevant biophysical models for five selected brachytherapy modalities; and the task group recommendations on the use, reporting, and implementation of biophysical models for brachytherapy treatment planning and evaluation. The report concludes with discussions on the challenges and opportunities in using biophysical models for brachytherapy and with an outlook for future developments.

Clinical Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy: A Systematic Review.

Modern advanced radiotherapy techniques have improved the precision and accuracy of radiotherapy delivery, with resulting plans being highly personalised based on individual anatomy. Adaptation for individual tumour biology remains elusive. There is an unmet need for biomarkers of intrinsic radiosensitivity that can predict tumour response to radiation to facilitate individualised decision-making, dosing and treatment planning. Over the last few decades, the use of high throughput molecular biology technologies has led to an explosion of newly discovered cancer biomarkers. Gene expression signatures are now used routinely in clinic to aid decision-making regarding adjuvant systemic therapy. They have great potential as radiotherapy biomarkers. A previous systematic review published in 2015 reported only five studies of signatures evaluated for their ability to predict radiotherapy benefits in clinical cohorts. This updated systematic review encompasses the expanded number of studies reported in the last decade. An additional 27 studies were identified. In total, 22 distinct signatures were recognised (5 pre-2015, 17 post-2015). Seventeen signatures were 'radiosensitivity' signatures and five were breast cancer prognostic signatures aiming to identify patients at an increased risk of local recurrence and therefore were more likely to benefit from adjuvant radiation. Most signatures (15/22) had not progressed beyond the discovery phase of development, with no suitable validated clinical-grade assay for application. Very few signatures (4/17 'radiosensitivity' signatures) had undergone any laboratory-based biological validation of their ability to predict tumour radiosensitivity. No signatures have been assessed prospectively in a phase III biomarker-led trial to date and none are recommended for routine use in clinical guidelines. A phase III prospective evaluation is ongoing for two breast cancer prognostic signatures. The most promising radiosensitivity signature remains the radiosensitivity index (RSI), which is used to calculate a genomic adjusted radiation dose (GARD). There is an ongoing phase II prospective biomarker-led study of RSI/GARD in triple negative breast cancer. The results of these trials are eagerly anticipated over the coming years. Future work in this area should focus on (1) robust biological validation; (2) building biobanks alongside large radiotherapy randomised controlled trials with dose variance (to demonstrate an interaction between radiosensitivity signature and dose); (3) a validation of clinical-grade cost-effective assays that are deliverable within current healthcare infrastructure; and (4) an integration with biomarkers of other determinants of radiation response.

Quality-of-life outcomes in metastatic spinal cord compression: findings from the SCORAD trial.

PURPOSE: This article reports detailed quality-of-life data including preferred and actual place of care from SCORAD, the only large prospective randomized trial in metastatic spinal cord compression (MSCC). METHODS: SCORAD compared 2 doses of radiotherapy in patients with MSCC: 8 Gy single fraction and 20 Gy in 5 fractions. In total, 686 patients were randomized, of whom 590 had Health-Related Quality of Life (HRQoL) data collected at baseline and at least 1 later time point. HRQoL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 supplemented with the QLU-C10D and data on place of care at weeks 1, 4, 8, and 12 postrandomization. Quality-of-Life Adjusted Survival was computed by multiplying Kaplan-Meier survival probabilities with the UK utility weights obtained from the QLU-C10D. RESULTS: Patients with a baseline physical functioning score of above 50 demonstrated a 28% reduction in the risk of death (hazard ratio [HR] = 0.72, 99% confidence interval [CI] = 0.54 to 0.95; P = .003). An increased risk of death was associated with fatigue (HR = 1.35, 99% CI = 1.03 to 1.76; P = .0040), dyspnea (HR = 1.61, 99% CI = 1.24 to 2.08; P < .001), and appetite loss (HR = 1.25, 99% CI = 0.99 to 1.59; P = .014). The preferred place of care for the majority was at home or with relatives (61%-74% across the 12 weeks) but achieved by only 53% at 8 weeks. CONCLUSIONS: Prolonged survival in patients with MSCC was associated with better HRQoL. More than 60% of patients preferred to be cared for at home or with relatives, but only half were able to achieve this. There was no difference in HRQoL between the multifraction and single-fraction groups. TRIAL REGISTRATION: ISRCTN97555949 and ISRCTN97108008.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

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.

Brachytherapy for rhabdomyosarcoma: Survey of international clinical practice and development of guidelines.

BACKGROUND AND PURPOSE: The purpose of this study was to address the lack of published data on the use of brachytherapy in pediatric rhabdomyosarcoma by describing current practice as starting point to develop consensus guidelines. MATERIALS AND METHODS: An international expert panel on the treatment of pediatric rhabdomyosarcoma comprising 24 (pediatric) radiation oncologists, brachytherapists and pediatric surgeons met for a Brachytherapy Workshop hosted by the European paediatric Soft tissue Sarcoma Study Group (EpSSG). The panel's clinical experience, the results of a previously distributed questionnaire, and a review of the literature were presented. RESULTS: The survey indicated the most common use of brachytherapy to be in combination with tumor resection, followed by brachytherapy as sole local therapy modality. HDR was increasingly deployed in pediatric practice, especially for genitourinary sites. Brachytherapy planning was mostly by 3D imaging based on CT. Recommendations for patient selection, treatment requirements, implant technique, delineation, dose prescription, dose reporting and clinical management were defined. CONCLUSIONS: Consensus guidelines for the use of brachytherapy in pediatric rhabdomyosarcoma have been developed through multicenter collaboration establishing the basis for future work. These have been adopted for the open EpSSG overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma (FaR-RMS).

Beyond surgery: bladder preservation and the role of systemic treatment in localised muscle-invasive bladder cancer.

Over the last two to three decades the non-surgical curative management of bladder cancer has significantly progressed. Increasing evidence supports the use of bladder preservation as an alternative to radical cystectomy (RC) for localised muscle-invasive bladder cancer (MIBC). Radiosensitisation with chemotherapy or hypoxia modification improves the efficacy of radiotherapy. Systemic treatments play an important role in the management of localised MIBC with the benefit of neoadjuvant chemotherapy prior to radical treatment well established. The use of immune checkpoint inhibitors (ICIs) in the radical treatment of bladder cancer, their safe combination with radical radiotherapy regimens and whether the addition of ICIs improve rates of cure are outstanding questions beginning to be answered by ongoing clinical trials. In this narrative review, we discuss the current evidence for bladder preservation and the role of systemic treatments for localised MIBC.

Exploratory study of using Magnetic resonance Prognostic Imaging markers for Radiotherapy In Cervix cancer (EMPIRIC): a prospective cohort study protocol.

INTRODUCTION: Radical chemoradiotherapy represents the gold standard for locally advanced cervical cancer. However, despite significant progress in improving local tumour control, distant relapse continues to impact overall survival. The development of predictive and prognostic biomarkers is consequently important to risk-stratify patients and identify populations at higher risk of poorer treatment response and survival outcomes. Exploratory study of using Magnetic resonance Prognostic Imaging markers for Radiotherapy In Cervix cancer (EMPIRIC) is a prospective exploratory cohort study, which aims to investigate the role of multiparametric functional MRI (fMRI) using diffusion-weighed imaging (DWI), dynamic contrast-enhanced (DCE) and blood oxygen level-dependent imaging (BOLD) MRI to assess treatment response and predict outcomes in patients undergoing radical chemoradiotherapy for cervical cancer. METHODS AND ANALYSIS: The study aims to recruit 40 patients across a single-centre over 2 years. Patients undergo multiparametric fMRI (DWI, DCE and BOLD-MRI) at three time points: before, during and at the completion of external beam radiotherapy. Tissue and liquid biopsies are collected at diagnosis and post-treatment to identify potential biomarker correlates against fMRI. The primary outcome is to evaluate sensitivity and specificity of quantitative parameters derived from fMRI as predictors of progression-free survival at 2 years following radical chemoradiotherapy for cervical cancer. The secondary outcome is to investigate the roles of fMRI as predictors of overall survival at 2 years and tumour volume reduction across treatment. Statistical analyses using regression models and survival analyses are employed to evaluate the relationships between the derived parameters, treatment response and clinical outcomes. ETHICS AND DISSEMINATION: The EMPIRIC study received ethical approval from the NHS Health Research Authority (HRA) on 14 February 2022 (protocol number RD2021-29). Confidentiality and data protection measures are strictly adhered to throughout the study. The findings of this study will be disseminated through peer-reviewed publications and scientific conferences, aiming to contribute to the growing body of evidence on the use of multiparametric MRI in cervical cancer management. TRIAL REGISTRATION NUMBER: NCT05532930.

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.