Most patients reported positively or neutrally of having served as controls in the trials within cohorts design

Objectives: To evaluate patients’ experience of having served as controls without a notification at the time of randomization in the context of the trial within cohorts (TwiCs) design. Methods: Patients were asked for their opinion on having served as controls in TwiCs, before and after having been provided the trial results. Patients had provided broad consent to randomization at cohort entry and had served as controls in one of two TwiCs (an exercise program after breast cancer treatment or radiotherapy dose-escalation for rectal cancer). Results: Two to 6 years after cohort entry, 15% (n = 16) of all patients remembered having provided broad consent to randomization. Before disclosure of trial results, 47% (n = 52) of patients thought positively, 45% (n = 50) neutrally, and 2% (n = 2) negatively of having served as controls in one of the two trials. Seventeen percent (n = 18) of patients were positive, 65% (n = 71) neutral, and 11% (n = 12) negative about not having been notified when serving as controls. The survey results were comparable after disclosure of trial results. Conclusions: These results support the use of the TwiCs design with the staged-informed consent procedure. Keeping patients engaged and aware of the consents provided might further improve patients’ experience of serving as controls in TwiCs

Oncology patients were found to understand and accept the Trials within Cohorts design

Background and Objective: The Trials within Cohorts design aims to reduce recruitment difficulties and disappointment bias in pragmatic trials. On cohort enrollment, broad informed consent for randomization is asked, after which cohort participants can be randomized to interventions or serve as controls without further notification. We evaluated patients' recollection, understanding, and acceptance of broad consent in a clinical oncology setting. Methods: We surveyed 610 patients with cancer participating in ongoing TwiCs; 482 patients (79%) responded, of which 312 patients shortly after cohort enrollment, 108 patients after randomization to an intervention (12-18 months after cohort enrollment), and a random sample of 62 cohort participants who had not been selected for interventions (1-6 months after cohort enrollment). Results: Shortly after providing cohort consent, 76% of patients (238/312) adequately remembered whether they had given broad consent for randomization. Of patients randomly offered interventions, 76% (82/108) remembered giving broad consent for randomization; 41% (44/108) understood they were randomly selected, 44% (48/108) were not interested in selection procedures, and 10% (11/108) did not understand selection was random. Among patients not selected for interventions, 42% (26/62) understood selection was random; 89% felt neutral regarding the scenario of "not being selected for an intervention while your data were being used in comparison with patients receiving interventions,"10% felt reassured (6/62) and 2% scared/insecure (2/62). Conclusion: Patients adequately remember giving broad consent for randomization shortly after cohort enrollment and after being offered an intervention, but recollection is lower in those never selected for interventions. Patients are acceptant of serving as control without further notifications. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Accumulated bladder wall dose is correlated with patient-reported acute urinary toxicity in prostate cancer patients treated with stereotactic, daily adaptive MR-guided radiotherapy

Background and purpose: Magnetic resonance (MR)-guided linear accelerators (MR-Linac) enable accurate estimation of delivered doses through dose accumulation using daily MR images and treatment plans. We aimed to assess the association between the accumulated bladder (wall) dose and patient-reported acute urinary toxicity in prostate cancer (PCa) patients treated with stereotactic body radiation therapy (SBRT). Materials and methods: One-hundred-and-thirty PCa patients treated on a 1.5 T MR-Linac were included. Patients filled out International Prostate Symptom Scores (IPSS) questionnaires at baseline, 1 month, and 3 months post-treatment. Deformable image registration-based dose accumulation was performed to reconstruct the delivered dose. Dose parameters for both bladder and bladder wall were correlated with a clinically relevant increase in IPSS (≥ 10 points) and/or start of alpha-blockers within 3 months using logistic regression. Results: Thirty-nine patients (30%) experienced a clinically relevant IPSS increase and/or started with alpha-blockers. Bladder D5cm3, V10–35Gy (in %), and Dmean and Bladder wall V10–35Gy (cm3 and %) and Dmean were correlated with the outcome (odds ratios 1.04–1.33, p-values 0.001–0.044). Corrected for baseline characteristics, bladder V10–35Gy (in %) and Dmean and bladder wall V10–35Gy (cm3 and %) and Dmean were still correlated with the outcome (odds ratios 1.04–1.30, p-values 0.001–0.028). Bladder wall parameters generally showed larger AUC values. Conclusion: This is the first study to assess the correlation between accumulated bladder wall dose and patient-reported urinary toxicity in PCa patients treated with MR-guided SBRT. The dose to the bladder wall is a promising parameter for prediction of patient-reported urinary toxicity and therefore warrants prospective validation and consideration in treatment planning

Stereotactic Radiotherapy Followed by Surgical Stabilization Within 24 h for Unstable Spinal Metastases; A Stage I/IIa Study According to the IDEAL Framework

Background: Routine treatment for unstable spinal metastases consists of surgical stabilization followed by external beam radiotherapy (EBRT) or stereotactic body radiotherapy (SBRT) after a minimum of 1–2 weeks to allow for initial wound healing. Although routine treatment, there are several downsides. First, radiotherapy induced pain relief is delayed by the time interval required for wound healing. Second, EBRT often requires multiple hospital visits and only 60% of the patients experience pain relief. Third, spinal implants cause imaging artifacts hindering SBRT treatment planning and delivery. Reversing the order of surgery and radiotherapy, with dose sparing of the surgical area by SBRT, could overcome these disadvantages and by eliminating the interval between the two treatments, recovery, and palliation may occur earlier.Design: The safety of SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases was investigated. Safety was evaluated using the Common-Toxicity-Criteria-Adverse-Events-4.0, with the occurrence of wound complications within 90-days being the primary concern.Results: Between June-2015 and January-2017, 13 patients underwent SBRT followed by surgical stabilization for unstable spinal metastases. The median time between SBRT and surgery was 17-h (IQR 5–19). None of the patients experienced wound complications. Improvements in pain and quality of life were observed over time for all patients.Conclusion: SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases is safe. Palliation may be experienced earlier and with both treatments being performed in one hospital admission the treatment burden decreases

Stereotactic Body and Conventional Radiotherapy for Painful Bone Metastases: A Systematic Review and Meta-Analysis

IMPORTANCE: Conventional external beam radiotherapy (cEBRT) and stereotactic body radiotherapy (SBRT) are commonly used treatment options for relieving metastatic bone pain. The effectiveness of SBRT compared with cEBRT in pain relief has been a subject of debate, and conflicting results have been reported. OBJECTIVE: To compare the effectiveness associated with SBRT vs cEBRT for relieving metastatic bone pain. DATA SOURCES: A structured search was performed in the PubMed, Embase, and Cochrane databases on June 5, 2023. Additionally, results were added from a new randomized clinical trial (RCT) and additional unpublished data from an already published RCT. STUDY SELECTION: Comparative studies reporting pain response after SBRT vs cEBRT in patients with painful bone metastases. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data from eligible studies. Data were extracted for the intention-to-treat (ITT) and per-protocol (PP) populations. The study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. MAIN OUTCOMES AND MEASURES: Overall and complete pain response at 1, 3, and 6 months after radiotherapy, according to the study's definition. Relative risk ratios (RRs) with 95% CIs were calculated for each study. A random-effects model using a restricted maximum likelihood estimator was applied for meta-analysis. RESULTS: There were 18 studies with 1685 patients included in the systematic review and 8 RCTs with 1090 patients were included in the meta-analysis. In 7 RCTs, overall pain response was defined according to the International Consensus on Palliative Radiotherapy Endpoints in clinical trials (ICPRE). The complete pain response was reported in 6 RCTs, all defined according to the ICPRE. The ITT meta-analyses showed that the overall pain response rates did not differ between cEBRT and SBRT at 1 (RR, 1.14; 95% CI, 0.99-1.30), 3 (RR, 1.19; 95% CI, 0.96-1.47), or 6 (RR, 1.22; 95% CI, 0.96-1.54) months. However, SBRT was associated with a higher complete pain response at 1 (RR, 1.43; 95% CI, 1.02-2.01), 3 (RR, 1.80; 95% CI, 1.16-2.78), and 6 (RR, 2.47; 95% CI, 1.24-4.91) months after radiotherapy. The PP meta-analyses showed comparable results. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, patients with painful bone metastases experienced similar overall pain response after SBRT compared with cEBRT. More patients had complete pain alleviation after SBRT, suggesting that selected subgroups will benefit from SBRT

Pain Response After Stereotactic Body Radiation Therapy Versus Conventional Radiation Therapy in Patients With Bone Metastases-A Phase 2 Randomized Controlled Trial Within a Prospective Cohort

PURPOSE: Pain response after conventional external beam radiation therapy (cRT) in patients with painful bone metastases is observed in 60% to 70% of patients. The aim of the VERTICAL trial was to investigate whether stereotactic body radiation therapy (SBRT) improves pain response. METHODS AND MATERIALS: This single-center, phase 2, randomized controlled trial was conducted within the PRESENT cohort, which consists of patients referred for radiation therapy of bone metastases to our tertiary center. Cohort participants with painful bone metastases who gave broad informed consent for randomization were randomly assigned to cRT or SBRT. Only patients in the intervention arm received information about the trial and were offered SBRT (1 × 18 Gy, 3 × 10 Gy, or 5 × 7 Gy), which they could accept or refuse. Patients who refused SBRT underwent standard cRT (1 × 8 Gy, 5 × 4 Gy, or 10 × 3 Gy). Patients in the control arm were not informed. Primary endpoint was pain response at 3 months after radiation therapy. Secondary outcomes were pain response at any point within 3 months, mean pain scores, and toxicity. Data were analyzed intention to treat (ITT) and per protocol (PP). This trial was registered with Clinicaltrials.gov, NCT02364115. RESULTS: Between January 29, 2015, and March 20, 2019, 110 patients were randomized. ITT analysis included 44 patients in the cRT arm and 45 patients in the SBRT arm. In the intervention arm, 12 patients (27%) declined SBRT, and 7 patients (16%) were unable to complete the SBRT treatment. In ITT, 14 of 44 patients (32%; 95% confidence interval [CI], 18%-45%) in the control arm and 18 of 45 patients (40%; 95% CI, 26%-54%) in the SBRT arm reported a pain response at 3 months (P = .42). In PP, these proportions were 14 of 44 (32%; 95% CI, 18%-45%) and 12 of 23 patients (46%; 95% CI, 27%-66%), respectively (P = .55). In ITT, a pain response within 3 months was reported by 30 of 44 control patients (82%; 95% CI, 68%-90%) and 38 of 45 patients (84%; 95% CI, 71%-92%) in the SBRT arm (P = .12). In PP, these proportions were 36 of 44 (82%; 95% CI, 68%-90%) and 26 of 27 patients (96%; 95% CI; 81%-100%), respectively (P = .12). No grade 3 or 4 toxicity was observed in either arm. CONCLUSIONS: SBRT did not significantly improve pain response in patients with painful bone metastases. One in 4 patients preferred to undergo cRT over SBRT, and 1 in 5 patients starting SBRT was unable to complete this treatment. Because of this selective dropout, which can be attributed to the character of the intervention, the trial was underpowered to detect the prespecified difference in pain response

Clinical utility of convolutional neural networks for treatment planning in radiotherapy for spinal metastases

Background and purpose: Spine delineation is essential for high quality radiotherapy treatment planning of spinal metastases. However, manual delineation is time-consuming and prone to interobserver variability. Automatic spine delineation, especially using deep learning, has shown promising results in healthy subjects. We aimed to evaluate the clinical utility of deep learning-based vertebral body delineations for radiotherapy planning purposes. Materials and methods: A multi-scale convolutional neural network (CNN) was used for automatic segmentation and labeling. Two approaches were tested: the combined approach using one CNN for both segmentation and labeling, and the sequential approach using separate CNN's for these tasks. Training and internal validation data included 580 vertebrae, external validation data included 202 vertebrae. For quantitative assessment, Dice similarity coefficient (DSC) and Hausdorff distance (HD) were used. Axial slices from external images were presented to radiation oncologists for subjective evaluation. Results: Both approaches performed comparably during the internal validation (DSC: 96.7%, HD: 3.6 mm), but the sequential approach proved more robust during the external validation (DSC: 94.5% vs 94.4%, p < 0.001, HD: 4.5 vs 7.1 mm, p < 0.001). Subsequently, subjective evaluation of this sequential approach showed that experienced radiation oncologists could distinguish automatic from human-made contours in 63% of cases. They rated automatic contours clinically acceptable in 77% of cases, compared to 88% of human-made contours. Conclusion: We present a feasible approach for automatic vertebral body delineation using two variants of a multi-scale CNN. This approach generates high quality automatic delineations, which can save time in a clinical radiotherapy workflow

Remineralization of lytic spinal metastases after radiotherapy

BACKGROUND CONTEXT: Palliative radiotherapy (RT) can lead to remineralization of osteolytic lesions thereby potentially restoring some of the weight-bearing capacity and preventing vertebral collapse. It is not clear, however, under which circumstances remineralization of osteolytic lesions occurs. PURPOSE: The aim of this study was to investigate the change in bone mineral density in spinal metastases after RT compared to a reference region, and find associated factors. STUDY DESIGN: Retrospective analysis within prospective observational cohort OUTCOME MEASURES: change in bone mineral density measured in Hounsfield Units (HU). PATIENT SAMPLE: patients treated with RT for (painful) bone metastases. METHODS: Patients with spinal metastases were included if computed tomography scans both pre- and post-RT were available. Bone density was measured in HU. A region of interest (ROI) was drawn manually in the metastatic lesion. As a reference, a measurement of bone density in adjacent, unaffected, and non-irradiated vertebrae was used. Factors tested for association were origin of the primary tumor, RT dose and fractionation scheme, and concomitant use of bisphosphonates. RESULTS: A total of 31 patients with 49 spinal metastases, originating from various primary tumors, were included. The median age on baseline was 58 years (IQR: 53–63) and median time between baseline and follow-up scan was 8.2 months (IQR: 3.0–18.4). Difference in HU in the lesion before and after treatment was 146.9 HU (95% CI 68.4–225.4; p<.01). Difference in HU in the reference vertebra between baseline and first follow-up was 19.1 HU (95% CI -47.9 to 86.0; p=.58). Difference between reference vertebrae and metastatic lesions on baseline was -194.1 HU (95% CI -276.2 to -112.0; p<.01). After RT, this difference was reduced to -50.3 HU (95% CI -199.6 to 99.0; p=.52). Patients using bisphosphonates showed a greater increase in HU, 194.1 HU versus 60.6 HU, p=.01. CONCLUSIONS: Palliative radiation of osteolytic lytic spinal metastases is positively associated with an increased bone mineral density at follow-up. The use of bisphosphonates was linked to an increased bone mineral density when used during or after RT

Appropriateness of the 30-day expected mortality metric in palliative radiation treatment: a narrative review

BACKGROUND AND OBJECTIVE The 30-day expected mortality rate is frequently used as a metric to determine which patients benefit from palliative radiation treatment (RT). We conducted a narrative review to examine whether its use as a metric might be appropriate for patient selection. METHODS A literature review was conducted to identify relevant studies that highlight the benefits of palliative RT in timely symptom management among patients with a poor performance status, the accuracy of predicting survival near the end of life and ways to speed up the process of RT administration through rapid response clinics. KEY CONTENT AND FINDINGS Several trials have demonstrated substantial response rates for pain and/or bleeding by four weeks and sometimes within the first two weeks after RT. Models of patient survival have limited accuracy, particularly for predicting whether patients will die within the next 30 days. Dedicated Rapid Access Palliative RT (RAPRT) clinics, in which patients are assessed, simulated and treated on the same day, reduce the number of patient visits to the radiation oncology department and hence the burden on the patient as well as costs. CONCLUSIONS Single-fraction palliative RT should be offered to eligible patients if they are able to attend treatment and could potentially benefit from symptom palliation, irrespective of predicted life expectancy. We discourage the routine use of the 30-day mortality as the only metric to decide whether to offer RT. More common implementation of RAPRT clinics could result in a significant benefit for patients of all life expectancies, but particularly those having short ones

The ethics of ‘Trials within Cohorts’ (TwiCs): 2nd international symposium - London, UK. 7-8 November 2016

On 7-8 th November 2016, 60 people with an interest in the ‘ Trials within Cohorts ’ (TwiCs) approach for randomised controlled trial design met in London. The purpose of this 2 nd TwiCs international symposium was to share perspectives and experiences on ethical aspects of the TwiCs design, discuss how TwiCs relate to the current ethical frame- work, provide a forum in which to discuss and debate ethical issues and identify future directions for conceptual and empirical research. The symposium was supported by the Wellcome Trust and the NIHR CLAHRC Yorkshire and Humber and organised by members of the TwiCs network led by Clare Relton and attended by people from the UK, the Netherlands, Norway, Canada and USA. The two-day sympo- sium enabled an international group to meet and share experiences of the TwiCs design (also known as the ‘ cohort multiple RCT design ’ ), and to discuss plans for future research. Over the two days, invited plenary talks were interspersed by discussions, posters and mini pre- sentations from bioethicists, triallists and health research regulators. Key findings of the symposium were: (1) It is possible to make a compelling case to ethics committees that TwiCs designs are ap- propriate and ethical; (2) The importance of wider considerations around the ethics of inefficient trial designs; and (3) some questions about the ethical requirements for content and timing of informed consent for a study using the TwiCs design need to be decided on a case-by-case basis