Joanne Haviland

Aim: Sacral neuromodulation (SNM) is considered the first‐line surgical treatment in adults with refractory faecal incontinence (FI). However, its clinical efficacy has not been rigorously tested in a trial setting. Method: Randomised, multicentre, double‐blind crossover trial (two 16‐week periods) of active stimulation versus sham, and open‐label follow‐up to 58 weeks. Participants: adults aged 18–80 with refractory FI. Interventions: Active : subsensory sacral nerve stimulation with an implanted pulse generator; Sham : identical implant but turned off. Primary outcome: FI episodes per week (paper bowel diary) during final 4 weeks of crossover periods (allowing 12 weeks' washout). Randomised allocation (1:1) to arm 1 (SNM/sham) or arm 2 (sham/SNM). Blinding: participants, surgeons, assessors; tamper‐proof tape‐masked stimulation settings. Sample size: 80 patients to detect a 30% reduction in episodes. Groups compared using a paired t ‐test, and treatment effects summarised by mean differences. Results: Trial delivery was severely affected by COVID‐19. Thirty‐nine patients of 220 screened (arm 1: N = 17; arm 2: N = 22) were recruited at 10 sites (February 2018–July 2022), of whom only 16 (arm 1: N = 9; arm 2: N = 7) had complete primary outcome data. Of the 39, 19 completed follow‐up to 58 weeks. SNM conferred a non‐significant reduction in mean FI episodes per week compared to sham (−0.795 [95% CI: −1.5 to 0.0], p = 0.06). Improvements were observed in FI symptoms at 58 weeks compared to baseline (FI episodes per week: 3.2 [SD 3.3] vs. 6.2 [SD 5.9]). Conclusions: The SUBSoNIC trial failed to find conclusive evidence of the experimental efficacy of SNM. Further demonstration of experimental efficacy remains important as SNM is a high‐cost and invasive therapy.

The traditional model for testing new treatments, before widespread usage in clinical practice, is the parallel group randomised trial. However, these are often inefficient, time-consuming and expensive, which can be barriers to the timely improvement of clinical care. This is a particular issue for anaesthesia and perioperative medicine where funding for large clinical trials is often scarce. Platform trials are an emerging methodology for testing new interventions, which offer benefits over the traditional parallel group paradigm. Platform trials have the ability to test multiple interventions at the same time, and to add or remove interventions during the course of the programme without undermining the validity or integrity of the trial findings. They are most often structured around a master protocol, which describes the core methods and research governance processes, with each intervention described in either a sub-section or appendix to the master protocol. The principal benefit to researchers and to research funders is that, unlike the sequential parallel group trial model, platform trials can use the same research infrastructure (e.g. database, standard operating procedures etc.) to answer multiple research questions, which is much more time and cost effective. The benefits of platform trials can be further enhanced with the use of adaptive designs or by sharing control patients, for example, by using a multi-arm multi-stage design. Perioperative medicine, anaesthesia and surgery are ideally placed to benefit from platform trials.

Introduction: The equity-focused Implementing Long-Acting Novel Antiretrovirals study evaluated feasibility, acceptability, appropriateness of delivering on-label 2-monthly cabotegravir and rilpivirine (CAB + RPV) injections for human immunodeficiency virus (HIV)-1 therapy in clinics and community settings. Methods: The study, which mandated inclusive recruitment, was conducted May–December 2022 at 6 UK sites. Injections were delivered in clinic (month [M] 1–6) and in clinic or community setting according to patient choice (M6–12). Surveys were completed at baseline, M4, and M12 using validated measures for feasibility (FIM), acceptability (AIM), and appropriateness (IAM). Primary endpoint: proportion of participants agreeing that the injection and community setting were feasible (FIM ≥4) at M12. Fourteen participants completed interviews at baseline and M12. Results: Community settings offered by sites included: home visits (n = 3), HIV support organizations (n = 2), and community clinic (n = 1). Of 114 participants, 54% were female, 70% racially minoritized, and 40% aged ≥50 years. A total of 27/114 chose to receive injections in community settings. FIM/AIM/IAM scores at M12 were high for the injection (79.0–87.4%) and lower for the community setting (44.2–47.4%) overall. Subgroup analyses indicated differences in scores by gender and ethnicity. Among those who attended the community, FIM/AIM/IAM scores for the community setting at M12 were high (73.1–80.8%). Concerns about stigma, inconvenience, and losing access to trusted clinicians negatively influenced perceptions of receiving injections at community settings, amongst other factors. Conclusions: CAB + RPV injections were considered highly feasible, acceptable, and appropriate; however, few chose community delivery. Those that chose community delivery found it highly acceptable and feasible. Further exploration of CAB + RPV delivery in alternative community sites not offered (eg, primary care, pharmacies) is warranted. ClinicalTrials.gov: NCT05294159

Background: International medical graduates (IMGs) comprise more than half of GP registrars but are more likely to fail postgraduate assessments than UK graduates. Aim: To assess whether there is an association between the language of the primary medical qualification (PMQ) and Membership of the Royal College of General Practitioners (MRCGP) results, and whether performance in previous prequalification assessments is correlated. Design and setting: Retrospective observational study in the UK. Method: The World Directory of Medical Schools and the UK Medical Education databases were used to obtain data for all candidates who sat the MRCGP exams between October 2013 and July 2021 ( n = 28 020). Candidates were split into three cohorts: cohort 1 comprised UK graduates; cohort 2 comprised IMGs with English as the language of the PMQ, who trained in countries with English (cohort 2a) or non-English (cohort 2b) as a first language; and cohort 3 included IMGs with non-English as the language of the PMQ. Logistic and linear regression analyses were used to compare the odds of exam passing and the scores relative to pass. Associations with past Multi-Specialty Recruitment Assessment (MSRA) scores, International English Language Testing System (IELTS) scores, and Professional and Linguistic Assessments Board (PLAB) scores were examined. Results: IMGs who trained in countries with non-English as a first language had statistically significantly lower odds of passing the exams and lower exam scores across all exam components. There were statistically significant positive correlations between MRCGP exam scores and MSRA, IELTS, and PLAB scores. Conclusion: English being the language of the PMQ and undertaking medical training in a country with English as the native language seemed to result in statistically significantly better chances of passing the exams and better exam scores. Performance in prequalification assessments can help to identify those IMG registrars who may benefit from tailored support.

Background: FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. Design: Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. Sub-studies: Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. Limitations: A sequential hypofractionated or simultaneous integrated boost has not been studied. Participants: Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. Results: Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were −0.3% (−1.0–0.9) for 27 Gy (p = 0.0022) and −0.7% (−1.3–0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94–1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. Interpretation: Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. Future work: Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. Trial registration: FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information.

Background: In trials using normofractionated regimen, the radiation-induced lymphocyte apoptosis (RILA) and the chromosomal damage assays (CDA) have shown prognostic roles of radiation-induced adverse events. The main objectives here were to validate RILA and CDA in extreme and moderate hypofractionation regimens for breast (FAST) and prostate (CHHiP) cancers. Methods: Blood samples were collected from 400 volunteers included in FAST and CHHiP trials. The primary endpoints (PE) were first change in photographic breast appearance and first grade ≥2 RTOG bladder or bowel toxicity (BBT) in FAST and CHHiP, respectively. The secondary endpoints was first grade ≥2 breast clinical changes (BCC) in FAST and BBT using different scales in CHHiP. Results: 103 FAST and 297 CHHiP patients with lab and clinical data were included. In FAST trial, no significant association of RILA with the primary endpoint was observed. A significant association of higher RILA levels with lower risk of any RIAE was found. The risk of developing grade ≥2 RIAE decreased significantly for patients with RILA≥24% compared to those with RILA≤16% with a HR of 0.50 (95%CI 0.25-1.00, p=0.012). Concerning chromosomic aberrations, no significant associations were found with change in photographic breast appearance nor with the secondary endpoint of any RIAE. In CHHiP trial, a decreased risk of grade≥2 RTOG bladder or bowel RIAE was observed for increasing values of RILA (HR 0.97, 95%CI 0.94-1.01, p=0.11) but did not reach statistical significance. Concerning chromosomic aberrations, we found significant association of higher levels of micronuclei per cell with lower risk of gr2+ RTOGAE (p=0.021 for trend test across tertiles; p=0.023 for upper vs lower tertile). Conclusions: This study is the first to evaluate RILA and CDA as predictors of late effects after breast and prostate RT in the “hypofractionation” era. Development of toxicity biomarkers whatever the RT fractionation are urgently needed.

Purpose: We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. Methods: We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. Results: In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. Conclusions: Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system.