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

Estimating structural exchange rate models by artificial neural networks

No theory of structural exchange rate determination has yet been found that performs well in prediction experiments. Only very seldom has the simple random walk model been significantly outperformed. Referring to three, sometimes highly nonlinear, monetary and nonmonetary structural exchange rate models, a feedforward artificial neural network specification is investigated to determine whether it improves the prediction performance of structural and random walk exchange rate models. A new test for univariate nonlinear cointegration is also derived. Important nonlinearities are not detected for monthly data of US dollar rates in Deutsche marks, Dutch guilders, British pounds and Japanese yens.

Evaluation of intrafraction duodenum positional stability for pancreatic SABR on the MR-Linac

PurposeThe duodenum is a dose-limiting organ at risk (OAR) in pancreatic stereotactic ablative radiotherapy (SABR). MR-Linac SABR delivery can be associated with longer treatment times than conventional Linacs, increasing the possible impact of intrafraction motion on planned dosimetry. The purpose of this study is to evaluate the intrafraction stability of the duodenum, the impact of treatment duration on stability, and whether a 5 mm planning at risk volume (PRV) is adequate.MethodsPancreatic SABR patients with intact duodenum treated with abdominal compression on the MR-Linac under an international prospective registry study (NCT04075305) were included. 3D T2-weighted or motion compensated MRIs were acquired before treatment (MRIpre) and either before treatment delivery (verification) or post-treatment (MRIpost). Intrapatient sequences were consistent. The duodenum was contoured on all images by one observer and divided into 4 anatomical segments (Fig. 1a). We assessed intrafraction duodenum changes by 1) difference in volume, 2) displacement of centre of mass (COM) of duodenum and individual segments and 3) mean distance to agreement (mDTA) of whole duodenum on MRIpre (Dpre) and on MRIpost (Dpost). Time between images was calculated for each patient on all fractions.A 5 mm PRV was generated using Dpre, and then rigidly copied to MRIpost. The volume of underlap of Dpost with the Dpre PRV was calculated. The underlap between this volume and the planning target volume (PTV) expanded by 2cm was evaluated to determine whether the duodenum was displacing towards the high-dose region. The difference in pooled mean absolute 3D vector of segment COM of Dpre and Dpost was tested for significance with single factor ANOVA, and association with time between scans assessed using Pearson’s correlation. Results15 patients received 33-40 Gy in 5 fractions (#). MRIpost treatment/verification data were not available for 3 patients for 1 # each. These were excluded from analysis, leaving 72 evaluable fractions.There was evidence of some intra-fraction duodenal drift; the number of fractions where Dpost was outside of PRV, and number of # where this underlap was within 2cm of PTV are shown in Table 1. No strong association was found between time between scans and duodenum COM displacement in X, Y or Z planes (r=-0.17, 0.02, -0.04 respectively), nor for absolute 3D vector of displacement (r=0.15) (Fig. 1B). The difference in pooled mean absolute 3D displacement vector between segments was not significant (p=0.6).ConclusionWhole and sub-organ duodenum position and volume is stable for the majority of patients across a treatment fraction of approximately 40mins, with a 5mm PRV being adequate within 2 cm of PTV. Longer treatment durations may increase the risk of motion so position should be monitored throughout. Future work is required to evaluate individual patient factors associated with increased duodenum motion.<br/

First multicentre experience of SABR for lymph node and liver oligometastatic disease on the unity MR-Linac

15siThe treatment of oligometastatic disease using MR guidance is an evolving field. Since August 2018 patients are treated on a 1.5 Tesla MR-Linac (MRL). We present current workflows and practice standards from seven institutions for the initial patients treated for lymph node and liver metastases.noneJanssen, Tomas M; Aitken, Katharine; Alongi, Filippo; Barry, Aisling; Bernchou, Uffe; Boeke, Simon; Hall, William A; Hosni, Ali; Kroon, Petra S; Nachbar, Marcel; Saeed, Hina; Jürgenliemk-Schulz, Ina M; Schytte, Tine; Verkooijen, Helena M; Nowee, Marlies EJanssen, Tomas M; Aitken, Katharine; Alongi, Filippo; Barry, Aisling; Bernchou, Uffe; Boeke, Simon; Hall, William A; Hosni, Ali; Kroon, Petra S; Nachbar, Marcel; Saeed, Hina; Jürgenliemk-Schulz, Ina M; Schytte, Tine; Verkooijen, Helena M; Nowee, Marlies

Can we deliver randomized trials of focal therapy in prostate cancer?

Tissue-preserving focal therapies, such as brachytherapy, cryotherapy, high-intensity focused ultrasound and photodynamic therapy, aim to target individual cancer lesions rather than the whole prostate. These treatments have emerged as potential interventions for localized prostate cancer to reduce treatment-related adverse-effects associated with whole-gland treatments, such as radical prostatectomy and radiotherapy. In this article, the Prostate Cancer RCT Consensus Group propose that a novel cohort-embedded randomized controlled trial (RCT) would provide a means to study men with clinically significant localized disease, which we defined on the basis of PSA level (≤ 15 ng/ml or ≤ 20 ng/ml), Gleason grade (Gleason pattern ≤ 4 + 4 or ≤ 4 + 3) and stage (≤ cT2cN0M0). This RCT should recruit men who stand to benefit from treatment, with the control arm being whole-gland surgery or radiotherapy. Composite outcomes measuring rates of local and systemic salvage therapies at 3-5 years might best constitute the basis of the primary outcome on which to change practice