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Background Magnetic resonance imaging localises cancer in the prostate, allowing for a targeted biopsy with or without transrectal ultrasound-guided systematic biopsy. Targeted biopsy methods include cognitive fusion, where prostate lesions suspicious on magnetic resonance imaging are targeted visually during live ultrasound, and software fusion, where computer software overlays the magnetic resonance imaging image onto the ultrasound in real time. The effectiveness and cost-effectiveness of software fusion technologies compared with cognitive fusion biopsy are uncertain. Objectives To assess the clinical and cost-effectiveness of software fusion biopsy technologies in people with suspected localised and locally advanced prostate cancer. A systematic review was conducted to evaluate the diagnostic accuracy, clinical efficacy and practical implementation of nine software fusion devices compared to cognitive fusion biopsies, and with each other, in people with suspected prostate cancer. Comprehensive searches including MEDLINE, and Embase were conducted up to August 2022 to identify studies which compared software fusion and cognitive fusion biopsies in people with suspected prostate cancer. Risk of bias was assessed with quality assessment of diagnostic accuracy studies-comparative tool. A network meta-analysis comparing software and cognitive fusion with or without concomitant systematic biopsy, and systematic biopsy alone was conducted. Additional outcomes, including safety and usability, were synthesised narratively. A de novo decision model was developed to estimate the cost-effectiveness of targeted software fusion biopsy relative to cognitive fusion biopsy with or without concomitant systematic biopsy for prostate cancer identification in biopsy-naive people. Scenario analyses were undertaken to explore the robustness of the results to variation in the model data sources and alternative assumptions. Results Twenty-three studies (3773 patients with software fusion, 2154 cognitive fusion) were included, of which 13 informed the main meta-analyses. Evidence was available for seven of the nine fusion devices specified in the protocol and at high risk of bias. The meta-analyses show that patients undergoing software fusion biopsy may have: (1) a lower probability of being classified as not having cancer, (2) similar probability of being classified as having non-clinically significant cancer (International Society of Urological Pathology grade 1) and (3) higher probability of being classified at higher International Society of Urological Pathology grades, particularly International Society of Urological Pathology 2. Similar results were obtained when comparing between same biopsy methods where both were combined with systematic biopsy. Evidence was insufficient to conclude whether any individual devices were superior to cognitive fusion, or whether some software fusion technologies were superior to others. Uncertainty in the relative diagnostic accuracy of software fusion versus cognitive fusion reduce the strength of any statements on its cost-effectiveness. The economic analysis suggests incremental cost-effectiveness ratios for software fusion biopsy versus cognitive fusion are within the bounds of cost-effectiveness (£1826 and £5623 per additional quality-adjusted life-year with or with concomitant systematic biopsy, respectively), but this finding needs cautious interpretation. Limitations There was insufficient evidence to explore the impact of effect modifiers. Conclusions Software fusion biopsies may be associated with increased cancer detection in relation to cognitive fusion biopsies, but the evidence is at high risk of bias. Sufficiently powered, high-quality studies are required. Cost-effectiveness results should be interpreted with caution given the limitations of the diagnostic accuracy evidence. Study registration This trial is registered as PROSPERO CRD42022329259. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135477) and is published in full in Health Technology Assessment; Vol. 28, No. 61. See the NIHR Funding and Awards website for further information. Plain language summary Men with an magnetic resonance imaging scan that shows possible prostate cancer (PCa) are offered prostate biopsies, where samples of the prostate tissue are collected with a needle, to confirm the presence and severity of cancer. Different biopsy methods exist. In a cognitive fusion biopsy, clinicians will target abnormal looking parts of the prostate by looking at the magnetic resonance imaging scan alongside ‘live’ ultrasound images. During a software fusion (SF) biopsy, a computer software is used to overlay the magnetic resonance imaging scan onto the ultrasound image. This study evaluated whether SF is better at detecting cancer compared with cognitive fusion biopsy, and whether it represents value for money for the National Health Service. We did a comprehensive review of the literature. We combined and re-analysed the evidence, and assessed its quality. We investigated whether SF biopsies are sufficient value for money. Compared with cognitive fusion, patients receiving a SF biopsy may have: (1) a lower probability of having a ‘no cancer’ result, (2) similar probability of having a benign, non-clinically significant (CS) cancer result and (3) higher probability of detecting CS cancer. However, it is uncertain to what extent SF is more accurate than cognitive fusion, because of concerns about the quality of the evidence. We found no evidence that any SF devices were superior to others. Using additional, random biopsies alongside software or cognitive fusion would increase the detection of PCa. We also looked for evidence on the value for money of the SF biopsies to detect PCa and found no relevant studies. We weighed the costs and the benefits of SF biopsy compared to cognitive fusion to determine whether it could be a good use of National Health Service money. The poor quality of information makes the value of the technologies largely unknown. Scientific summary Background Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the UK. In the NHS people with suspected PCa are offered multiparametric magnetic resonance imaging (mpMRI). People with suspected PCa, according to MRI, are offered a biopsy procedure to confirm the presence and severity of cancer. Traditionally patients were offered a systematic transrectal, ultrasound-guided prostate biopsy (or systematic biopsy). Since the introduction of mpMRI, specific areas of abnormal tissue can be targeted, by combining (or fusing) the results of mpMRI and ultrasound imaging. Several methods for fusing MRI and ultrasound images exist, including cognitive fusion (CF), in which a region of interest is identified prior to biopsy and the biopsy operator estimates where it might be on an ultrasound image, and software fusion (SF), where regions of interest on magnetic resonace images are identified and contoured before biopsy and overlayed with the prostate contours on ultrasound images during the biopsy. Systematic biopsy may be used in addition to targeted biopsy. A number of SF technologies are available. However, the effectiveness and cost-effectiveness of SF compared with CF is uncertain. Objectives This study aimed to assess the clinical and cost-effectiveness of SF biopsy systems in people with suspected localised and locally advanced PCa. Methods Systematic review A systematic review of the diagnostic accuracy, clinical effectiveness, safety and practical implementation of nine SF systems compared with CF and with each other, in people suspected PCa according to MRI was conducted. Comprehensive bibliographic searches, including MEDLINE and EMBASE and supplementary sources, were conducted up to 2 August 2022 for published and unpublished literature. Studies of people with suspected PCa who have had a MRI scan that indicates a significant lesion [Likert or prostate imaging – reporting and data system (PI-RADS) score of 3 or more], including biopsy-naive and repeat biopsy patients with a previous negative prostate biopsy, and comparing SF with CF or with another SF device, were included. The following SF technologies were included: ARTEMIS (InnoMedicus ARTEMIS), BioJet (Healthcare Supply Solutions Ltd), BiopSee (Medcom), bkFusion (BK Medical UK Ltd and MIM Software Inc.), Fusion Bx 2.0 (Focal Healthcare), FusionVu (Exact Imaging), iSR’obot Mona LisaTM (Biobot iSR’obot), KOELIS Trinity (KOELIS and Kebomed) and UroNav Fusion Biopsy System (Phillips). Previous versions were also eligible. In-bore (or in-gantry) biopsies were excluded. Prospective, randomised and non-randomised comparative studies were included, and retrospective evidence where no prospective evidence could be found for an eligible SF device. To provide sufficient evidence for a network meta-analysis (NMA), within-patient comparisons or randomised controlled trials (RCTs) between SF and systematic biopsy, and between CF and systematic biopsy, were also eligible to inform indirect comparisons of diagnostic accuracy. Two researchers independently screened the titles and abstracts of all reports identified by the bibliographic searches and of all full-text papers subsequently obtained. Data extraction and quality assessment were conducted by at least one researcher and checked by a second. Risk of bias of diagnostic accuracy studies was assessed using quality assessment of diagnostic accuracy studies-comparative (QUADAS-C). For diagnostic accuracy outcomes, studies reporting sufficient data were included in network meta-analyses comparing SF and CF with or without concomitant systematic biopsy, and systematic biopsy alone, where odds of being categorised in each of different cancer grades were allowed to vary by biopsy type. Results were reported as odds ratios with 95% credible intervals (CrIs). Additional diagnostic accuracy results that could not be pooled in a meta-analysis and clinical effectiveness, safety and implementation outcomes were synthesised narratively. Economic analysis Cost-effectiveness evidence comparing SF biopsy systems with CF for targeted prostate biopsy in men with suspected PCa was identified by the previously mentioned searches, with evidence narratively summarised and tabulated. Studies were appraised for their quality, generalisability and appropriateness to inform the decision problem as defined by the National Institute for Health and Care Excellence Diagnostics Assessment Report (NICE DAR) scope. A targeted search was conducted to identify evidence to support the development of a de novo decision model. The searches aimed to identify cost-effectiveness evidence of diagnostic strategies at the point of biopsy to support the model conceptualisation. Evidence was reviewed to (1) identify value components of the biopsy approaches, (2) characterise alternative mechanisms of evidence linkage from disease prevalence, diagnostic accuracy, choice of treatment to final outcomes, and (3) identify any UK-relevant sources of evidence. A de novo decision analytic model was developed to estimate the cost-effectiveness of SF compared to CF. The model evaluated two strategies for two alternative comparisons: (1) targeted SF biopsy versus targeted cognitive biopsy and (2) combined (targeted and systematic) SF biopsy versus combined cognitive biopsy. The four strategies could not be incrementally compared due to the mechanism of evidence generation for the diagnostic accuracy, which relied on separate evidence networks. The de novo model consisted of two components: (1) a decision tree, which captured biopsy adverse events (AEs), repeated biopsies and classified individuals according to their biopsy results and underlying true disease status, and (2) long-term model to link classification to clinical management decisions and this to longer-term costs and consequences (e.g. disease progression and PCa mortality) so that differences in costs, life-year gains and quality-adjusted life-years (QALYs) were quantified over a lifetime horizon. The model required the development of (1) an extension to the evidence synthesis to allow quantifying the extension of test misclassification in the diagnostic model with SF biopsy and CF biopsy, and (2) an inference model to derive unobservable transition probabilities for the long-term model. Results The systematic review of clinical evidence included a total of 3733 patients who received SF and 2154 individuals with CF from 23 studies. Evidence was included for all devices specified in the protocol, except for Fusion Bx 2.0 and FusionVu. Overall, the evidence for all devices was at high risk of bias. Overall, biopsy-naive patients were under-represented. Fourteen studies were included in the meta-analyses. Diagnostic accuracy Across all analyses results must be interpreted with caution due to the high risk of bias in the evidence base and wide uncertainty over the results. The meta-analyses show that patients undergoing SF biopsy may have: (1) a lower probability of being classified as not having cancer, (2) similar probability of being classified as having non-clinically significant cancer [International Society of Urological Pathology (ISUP) grade 1], and (3) higher probability of being classified at higher ISUP grades, particularly ISUP 2. Similar results were obtained where both biopsy methods were combined with systematic biopsy. Additional meta-analyses of cancer detection rates suggest that, compared with CF biopsy, SF may identify more PCa (any grade) (OR 1.30; 95% CrI 1.06, 1.61). Adding systematic biopsy to cognitive or SF may increase the detection of all PCa and of clinically significant (CS) cancer, and from this evidence there is no suggestion that SF with concomitant systematic biopsy is superior to CF with systematic biopsy. Meta-analyses of cancer detection rates, by individual device, showed that compared with CF biopsy, BioJet and Urostation are associated with a higher detection of PCa overall. There was no evidence that any of the SF devices increased detection of CS cancer (except for BioJet, although this is based on one low-quality study), and overall, the evidence was insufficient to conclude whether any individual devices were superior to CF, or whether some SF technologies are more accurate than others. Clinical effectiveness There is no evidence that biopsy positivity rates and safety outcomes differ significantly between SF and CF, or between SF devices. There was some evidence that systems with rigid registration (BioJet or UroNav) are easier and faster to use than elastic registration (KOELIS Trinity), although this is informed by a single, small study and is not conclusive. Cost-effectiveness One full cost-effectiveness study of SF compared targeted SF to targeted CF. However, the findings of the study were not considered generalisable to the decision problem under assessment. Sixteen studies were identified of which nine were selected to inform the conceptualisation and parameterisation of the de novo decision model. The base-case cost-effectiveness analysis suggests for the targeted biopsy and the combined biopsy comparisons, that SF strategy is on average costlier and yields greater QALYs than the CF strategy, resulting in a probabilistic incremental cost-effectiveness ratio (ICER) of £6197 and £2199 per additional QALY for each comparison, respectively. These ICERs are below the lower bound of the cost-effectiveness threshold range recommended by NICE, suggesting that SF may be cost-effective compared to CFs in both the targeted and the combined comparisons. However, these results should be interpreted cautiously given the uncertainties in the relative diagnostic accuracy evidence which informs the model. The probabilistic analysis suggests a higher probability of cost-effectiveness for SF versus CF at the range of cost-effectiveness thresholds recommended by NICE (0.64 and 0.68 at £20,000 and £30,000 per additional QALY for targeted SF biopsy). Discussion This assessment includes a broad, comprehensive literature search for software and CF technologies and has been conducted following recognised guidelines to ensure high quality. The review identified evidence on the diagnostic accuracy of nine SF technologies, and is the first systematic review to formally compare the relative accuracy of SF and CF, with and without systematic biopsy, as well as different SF devices, using both direct and indirect evidence in a NMA. Unlike recent systematic review evidence, our review found that SF increased detection of clinically insignificant cancer compared with CF. Our review has a number of limitations. The evidence included in the systematic review is at high risk of bias overall. There was variation in patient and study characteristics. Biopsy-naive patients, who form the large majority of patients eligible for targeted biopsy, were under-represented, although there was insufficient evidence to evaluate whether the relative accuracy of software and CF differed between biopsy-naive and repeat biopsy patients. There was insufficient evidence to explore the impact of a number of other potential effect modifiers, including lesion location, operator experience, biopsy routes and anaesthesia methods. There were few studies per comparison, not all studies reported outcomes by all cancer grades, and most estimates from the meta-analyses were imprecise, particularly at higher cancer grades where data were most sparse. The network meta-analyses relied on the assumption that CF was equivalent across different centres, which is uncertain. No evidence was found for most of this assessment’s prespecified outcomes: biopsy sample suitability/quality, number of repeat biopsies performed, procedure completion rates, software failure rate, time to diagnosis, length of hospital stay, time taken for MR image preparation, subsequent PCa management, re-biopsy rate, hospitalisation, overall survival, progression-free survival (PFS), patient- and carer- reported outcomes [including tolerability and health-related quality of life (HRQoL)], barriers and facilitators to implementations. The cost-effectiveness results are driven by the modelled differences in diagnostic accuracy between software and CF, particularly the increased correct detection of Cambridge Prognostic Group 1 (CPG 1) (resulting in net losses for SF) and CPG 2 (resulting in net gains for SF). The External Assessment Group (EAG)’s NMA and its extension underpinned the economic model, so its limitations apply to the cost-effectiveness estimates. The magnitude of value realised for SF, compared with CF, depends on the balance between different degrees of misclassification and correct classification with the two technologies and on the prevalence of disease at each cancer grade. The value of SF is thus driven by comparative diagnostic accuracy (compared to ‘gold standard’) derived where evidence is particularly sparse (cancer grades above 2), and by prevalence, which is also affected by evidence sparsity. Therefore, the estimates of cost-effectiveness are affected by unquantified uncertainty and should be interpreted with caution. Conclusions Compared to CF biopsy, patients undergoing SF biopsy may show a lower probability of being classified as not having cancer, similar probability of being classified as having non-CS cancer, and a higher probability of being classified at higher ISUPs, particularly ISUP 2. Both SF and CF biopsy can miss CS cancer lesions, and the addition of standard-systematic biopsy increases the detection of all PCa and CS cancer for both fusion methods. There is insufficient evidence to conclude on the relative accuracy and clinical effectiveness of different software devices. Cost-effectiveness estimates comparing software to CF were generally favourable to SF, except where the technologies were assumed to have the same diagnostic accuracy. The drivers of economic value of SF, comparative diagnostic accuracy and prevalence, are affected by unquantified uncertainty. Judgements on the economic value of SF require integration of the uncertainties over the clinical evidence with the overall cost-effectiveness. Recommendations for further research High-quality, sufficiently powered RCT evidence comparing SF biopsy with CF biopsy is required to address limitations from the existing evidence. Improved reporting of diagnostic accuracy outcomes would enable future syntheses to make use of a larger body of evidence. Study registration This trial is registered as PROSPERO CRD42022329259. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135477) and is published in full in Health Technology Assessment; Vol. 28, No. 61. See the NIHR Funding and Awards website for further information.

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. Plain language summary Patients diagnosed with early breast cancer are often recommended to have radiotherapy after surgery because research has shown that it lowers the risk of the cancer returning. However, it may cause some short- and long-term side effects. Previous clinical trials showed that the same, or even better, outcomes with a lower total dose of radiotherapy given in fewer, larger daily doses compared with older historical treatment schedules. The National Institute for Health and Care Research Health Technology Assessment Programme-funded FAST-Forward Trial aimed to see whether the number of doses could be reduced further without reducing the beneficial effects of radiotherapy. Between November 2011 and June 2014, 4096 patients agreed to take part in the FAST-Forward Main Trial testing three schedules of radiotherapy to the breast. Standard treatment given on 15 days over 3 weeks (Control Group) was compared with two different lower dose schedules where treatment was given on 5 days over 1 week (lower dose Test Groups). An additional 469 patients entered a sub-study where the gland area under the arm also received radiotherapy (Nodal Sub-Study). Main Trial 5-year results reported in April 2020 showed that the number of patients whose cancer had returned in the treated breast was low in all groups: around 2 in 100 (2.1%) for the Control Group, and 1.7% in the higher dose and 1.4% in the lower dose Test Groups. The majority of reported side effects assessed by patients and doctors up to 5 years after radiotherapy were mild for all treatment groups. Patients in the Control Group and in the lower dose Test Group experienced similar levels of side effects. More side effects were reported in the higher dose Test Group, although differences were small. Overall, the FAST-Forward findings suggest that the lower dose 1-week schedule gave similar results in terms of the cancer returning and side effects to the standard 3-week treatment and this schedule can now be used to help treat future patients. Scientific summary Background Breast cancer is the most common malignancy in women and the second leading cause of cancer death. After a diagnosis of early breast cancer, a combination of treatments is planned by a multidisciplinary team. This usually involves surgery to remove the cancer with additional radiotherapy (RT) and systemic therapies tailored to the stage and biology of the cancer, and to the individual patient’s characteristics and wishes. Meta-analyses confirm that RT after surgery for early breast cancer reduces local cancer relapse and breast cancer deaths. Randomised controlled trials involving over 8000 patients with long-term follow-up confirmed that hypofractionated RT [fewer larger fractions (Fr; daily doses)] can be at least as safe and effective as the historic standard of 50 Gray (Gy) in 25 fractions (5 weeks) if a lower total dose is used. The UK START trials contribute much of the global data for moderate hypofractionation. START-A maintained the 5-week treatment time across all randomised groups and included two doses of a 13-fraction regimen, enabling the investigators to make unconfounded estimates of the sensitivity to fraction size. START-B tested 40 Gy in 15 fractions over 3 weeks against 50 Gy in 25 fractions over 5 weeks. Five- and ten-year results for local tumour control and late-occurring normal tissue effects (NTE) assessed by patients, clinicians and from photographs were consistent with the hypothesis that breast cancer tissue and the dose-limiting normal tissues are similarly sensitive to fraction size. The START trials had a large effect on breast cancer RT practice in the UK and worldwide. A 15-fraction schedule has been the UK standard-of-care recommended by the National Institute for Health and Care Excellence since 2009, but was thought unlikely to represent the useful limits of hypofractionation for whole breast RT. The UK FAST trial compared 28.5 Gy in 5 fractions of 5.7 Gy or 30 Gy in 5 fractions of 6 Gy, both delivered once weekly over 5 weeks, to 50 Gy in 25 fractions. The first results of the FAST trial, subsequently confirmed with the 10-year results, identified a 5-fraction schedule estimated to be radiobiologically equivalent to the 25-fraction standard in terms of late NTE. This gave impetus to the investigation of 1-week 5-fraction schedules in the phase III FAST-Forward Trial. Objectives Main Trial: to identify a 5-fraction schedule of curative RT delivered in once-daily fractions (1 week) that is at least as effective and safe as the current UK standard 15-fraction (3-week) regimen after primary surgery for early breast cancer, in terms of local tumour control, adverse effects, patient-reported outcomes (PRO) and health economic (HE) consequences. Nodal Sub-Study: to show that a 5-fraction schedule of adjuvant RT to level I–III axilla and/or level IV axilla [supraclavicular fossa (SCF)] is non-inferior to a 15-fraction standard in terms of patient-reported arm swelling and function, and to contribute additional information to the endpoints of the Main Trial. Methods FAST-Forward is a UK-wide phase III randomised non-inferiority trial testing two 1-week schedules against the 3-week regimen. Patients with early breast cancer requiring adjuvant RT were randomly allocated (1 : 1 : 1) to 40 Gy in 15 fractions over 3 weeks, 27 Gy or 26 Gy in 5 fractions over 1 week to the whole breast or chest wall (Main Trial) plus the regional lymph nodes (Nodal Sub-Study). A sequential tumour bed RT boost to the conserved breast was allowed, with centres required to specify boost intention before randomisation. Primary endpoints were local relapse (Main Trial) and patient-reported arm/hand swelling (Nodal Sub-Study). Secondary endpoints were late NTE assessed by patients and clinicians, cancer and survival outcomes. The Main Trial target sample size was 4000 patients, providing 80% power (one-sided α = 0.025) to exclude an absolute increase of 1.6% in 5-year ipsilateral breast tumour relapse (IBTR) incidence for a 5-fraction schedule compared with control, assuming 2% 5-year incidence in the 40 Gy group. Eligibility for the Main Trial was patients with complete microscopic resection of early invasive breast cancer, following breast conservation surgery or mastectomy, prescribed local RT. Inclusion criteria was age ≥ 18 years, axillary staging and/or dissection, pT1-3 pN0-1 M0 disease, written informed consent, able to comply with follow-up; concurrent anti-human epidermal growth factor receptor-2 (HER-2) therapy and/or endocrine therapies were allowed. Age ≥ 65 years with pT1 G1/2 ER+ve/HER-2−ve pN0 M0 invasive disease was excluded from protocol v2.0 due to the very low risk of local cancer relapse. Exclusions included ipsilateral microinvasive disease and/or non-gradeable tumours, contralateral and/or previous ipsilateral breast cancer, concurrent cytotoxic chemotherapy (sequential neoadjuvant or adjuvant cytotoxic therapy allowed if ≥ 2 weeks between chemotherapy and RT) and RT to any regional lymph node area (excepting lower axilla included in standard tangential fields to breast/chest wall). The whole breast clinical target volume (CTV) was either determined retrospectively from field-based tangential fields or volumed prospectively. Post-mastectomy chest wall CTV encompassed post-surgical skin flaps and underlying soft tissues to the deep fascia; underlying muscle and rib cage excluded. The lymph node CTV included the axillary chain and/or the SCF (level IV axilla) either in entirety or levels specified by the clinician. The treatment plan was optimised with 3D dose compensation to achieve the dose constraints. A comprehensive quality assurance programme involved every RT centre before trial activation and continued throughout trial accrual. The RT planning packs for the Main Trial and Nodal Sub-Study are available from www.icr.ac.uk/fastforward. Patients were assessed by clinicians for IBTR and late NTE at annual follow-up visits. Late-onset NTE in ipsilateral breast or chest wall (breast distortion, shrinkage, induration and telangiectasia; and breast or chest wall oedema and discomfort) were graded by clinicians on a 4-point scale, interpreted as none, mild, moderate, or marked. Symptomatic rib fracture, symptomatic lung fibrosis, and ischaemic heart disease were recorded. In the PRO sub-study, questionnaires were administered at baseline (pre-randomisation), 3, 6, 12, 24 and 60 months. Patient assessments used a 4-point ordinal scale, as for the clinical assessments. In the photographic sub-study, photographs were taken at baseline (pre-RT), 2 and 5 years after RT and scored on a 3-point ordinal scale. In the acute toxicity sub-study, patients were assessed pre-treatment, then weekly for 6 weeks, or longer if there was higher than grade 1 toxicity still present. Two acute toxicity studies were performed; in the first study the scoring system included oedema, which is usually related to recent surgery, and also included patients with a boost. A second study was done without these confounding issues to more accurately assess the acute toxicity of the 1-week schedules compared with the 3-weekly standard. Acute reactions of the treated breast skin were graded using Radiation Therapy Oncology Group (RTOG) criteria for the first sub-study and standard common toxicity criteria for adverse effects (CTCAE) criteria for the second. The Nodal Sub-Study inclusion criteria required pT1-3 pN1-3a M0 disease and histological involvement of axillary lymph nodes with an indication for RT to level I-III axilla and/or level IV axilla. From 2018 the Nodal Sub-Study design was amended to a 2-group trial, with no further randomisation to Test Group 1 (27 Gy). All patients in the Nodal Sub-Study were asked to consent to the PRO sub-study and photographic assessments. The following additional PRO were included in the Nodal Sub-Study: shoulder stiffness, upper limb pain, sensorimotor symptoms and arm function. A HE evaluation was conducted to assess the cost-effectiveness of whole breast RT with 26 Gy/5 fractions over 1 week compared with the 3-week schedule of 40 Gy/15 fractions. We report the 5-year primary analysis of the Main Trial and a descriptive interim analysis of the Nodal Sub-Study up to 3 years’ follow-up; formal analysis of the Nodal Sub-Study will await 5 years’ follow-up. Results Between November 2011 and June 2014, 4110 patients were enrolled in the FAST-Forward Main Trial from 97 UK centres (47 RT and 50 referring centres); 14 patients subsequently withdrew consent. One hundred and ninety patients were recruited into acute toxicity study 1, 161 patients into acute toxicity study 2, 1798 patients into the PRO sub-study, 1737 patients into the photographic assessment sub-study, 3878 patients consented to donate a blood sample and 4077 patients consented to donate their primary tissue sample. Four hundred and sixty-nine patients were recruited to the Nodal Sub-Study. The demographic and clinical characteristics at baseline were well balanced between groups. In the Main Trial, after a median follow-up of 71.5 months IBTR was recorded in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group and 21 in the 26 Gy group); hazard ratios (HRs) versus 40 Gy in 15 fractions were 0.86 (95% confidence interval 0.51 to 1.44) for 27 Gy/5 fractions and 0.67 (0.38 to 1.16) for 26 Gy/5 fractions. Estimated 5-year cumulative incidence of IBTR was 2.1% for 40 Gy (expected incidence 2%), 1.7% for 27 Gy and 1.4% for 26 Gy. Estimated absolute differences in IBTR versus 40 Gy were –0.3% (–1.0 to 0.9) for 27 Gy and –0.7% (–1.3 to 0.3) for 26 Gy. As the upper confidence limits excluded an increase in IBTR of 1.6% or more so non-inferiority can be claimed for both 5-fraction schedules compared with 40 Gy/15 fractions. At least one annual clinical assessment of NTE was available in the Main Trial for 3975 (97.0%) of 4096 patients. At 5 years, any moderate or marked clinician-assessed NTE in the breast or chest wall was reported for 98 of 986 (9.9%) 40 Gy patients, 155 (15.4%) of 1005.27 Gy patients, and 121 of 1020 (11.9%) 26 Gy patients, with a significant difference between 40 Gy and 27 Gy (0.0003) but not between 40 Gy and 26 Gy (p = 0·17). Breast shrinkage was the most prevalent moderate or marked effect at 5 years, reported in 50 (5.5%) of 916.40 Gy patients, 78 (8.2%) of 948.27 Gy patients, and 65 (6.8%) of 954.26 Gy patients. Longitudinal analysis of all annual clinical assessments of NTE over follow-up showed a significantly increased risk of any moderate or marked effect in the breast or chest wall for the 27 Gy group compared with 40 Gy with no significant difference between 26 and 40 Gy. Comparing the two 5-fraction schedules, 26 Gy had significantly lower risk of any moderate or marked breast or chest wall NTE and breast shrinkage compared with 27 Gy. Estimates of 5-year cumulative incidence of any moderate or marked clinician-assessed NTE in the breast or chest wall were 26.8% for 40 Gy, 35.1% for 27 Gy and 28.5% for 26 Gy. Retrospective subgroup analyses in the Main Trial comparing IBTR in 26 Gy versus 40 Gy provide no evidence of a differential effect according to age, grade, pathological tumour size, nodal status, tumour bed boost, treatment with adjuvant chemotherapy, HER-2 status or in triple-negative patients. Confidence intervals for the HR overlap for the subgroups, although the number of events in these analyses was small, hence results should be interpreted with caution as the statistical power is low. Subgroup analysis in the Main Trial according to type of primary surgery was not possible as there was only one IBTR event post-mastectomy in a control group patient (out of 91) and none in the 173 patients treated with 5 fractions. The two acute toxicity sub-studies comprised a total of 350 patients. Incidence of grade 3+ acute skin toxicity according to RTOG criteria was 14% for 40 Gy/15 fractions, 10% for 27 Gy/5 fractions, and 6% for 26 Gy/5 fractions in sub-study 1. For sub-study 2, acute toxicity grade 3+ according to CTCAE was 0%, 2.4% and 0%, respectively. Grade 2 toxicity was more common in 40 Gy/15 fractions compared with the two 5-fraction schedules. Four hundred and sixty-nine patients from 28 RT and 22 referral centres (183 for 40 Gy/15 fractions, 104 for 27 Gy/5 fractions and 182 for 26 Gy/5 fractions) were entered into the Nodal Sub-Study. Compared with the Main Trial, as expected more patients had higher-grade disease and nearly half had a mastectomy. Axillary clearance was performed in around 50% of patients, with the remainder having some form of nodal sampling. At this interim review at 2 years patients reported moderate or marked hand/arm swelling in 10% (40 Gy), 7% (26 Gy) and 13% (27 Gy). Prevalence of clinician-assessed lymphodema at 3 years was 8% (40 Gy), 12% (26 Gy) and 11% (27 Gy). In the cost-effectiveness work the base case analysis, mean costs and quality-adjusted life-years (QALYs) for 40 Gy/15 fractions were £31,640 and 11.08 QALYs; for 26 Gy/5 fractions these were £29,638 and 11.12 QALYs. Therefore the 26 Gy/5 fractions regimen was expected to dominate with expected cost savings of £2002 (95% interval £1245 to £2804) and higher expected QALYs: 0.04 (95% interval −0.01 to 0.09). Across simulations there was a 99.9% chance that 26 Gy/5 fractions either dominated 40 Gy/15 fractions or had an incremental cost-effectiveness ratio below £15,000/QALY. Conclusion The 26 Gy/5 fractions 1-week schedule is non-inferior to 40 Gy/15 fractions over 3 weeks for IBTR. The 26 Gy dose level is comparable to 40 Gy/15 fractions in terms of NTE assessed by patients, clinicians and from photographs, and is comparable to NTE expected after 46–48 Gy in 2 Gy fractions. The 27 Gy/5 fractions regimen was non-inferior for IBTR but had statistically significantly higher levels of many late NTE compared with the 40 and 26 Gy schedules, with late NTE rates of comparable magnitude to 50 Gy/25 fractions, the historic standard schedule. Acute skin reactions reported within the trial are low, whichever regimen is used. Prevalence rates suggest that erythema after the 1-week schedule came on slightly quicker, is less intense and settles about 2 weeks earlier than after the 3-week schedule although no formal statistical analysis of this was performed. The mildness of the acute skin toxicity associated with the 5-fraction regimens was expected. Interim results from the Nodal Sub-Study at 2–3 years’ follow-up indicate no cause for concern of an excess in NTE for 26 Gy/5 fractions compared with 40 Gy/15 fractions. Low rates of IBTR and of moderate/marked late NTE can be attributed to improvements in all diagnostic and treatment modalities and to the commitment of patients to early diagnosis and randomised trials. Beyond its safety and effectiveness, the 26 Gy/5 fractions schedule is convenient and less expensive for patients and for health services. The 26 Gy/5 fractions schedule reduces the estimated healthcare fiscal cost of breast RT by over 50%. The 5-fraction regimen reduces the machine time required for breast RT patients, thus improving patient access for other groups of cancer patients within the NHS. Study registrations FAST-Forward is registered at www.isrctn.com, ISRCTN19906132. The Main Trial is published in Lancet 2020;395:1613–26. See the NIHR Journals Library website for further project information. 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.

A 34-year-old female presented to the emergency department with neck pain, dysphonia and dysphagia ten days after a fall from an electric scooter. Subsequent computed tomography of the neck revealed bilateral vertebral artery and unilateral internal carotid artery non-occlusive dissections, which were managed with antiplatelet therapy. This case describes mechanisms of injury, clinical presentation, imaging appearances, and subsequent management of cervical artery dissection.

This paper demonstrates a case of multiple glomangiomas, or glomangiomatosis, including clinical presentation, imaging appearances, and subsequent management. Differentiating features from typical glomus tumors are described. To the best of our knowledge, this is the first reported case of a glomangioma involving the distal tibiofibular syndesmosis.

Denervation pseudohypertrophy is an uncommon cause of limb swelling, which may be overlooked. It is an important diagnosis to arrive at, as it instructs the search for an underlying cause which may itself require intervention. We present the case of a 32-year-old male rugby player with a 2-year history of left calf swelling and intermittent pain and tightness. He described a previous history of 2 left sided lumbar micro-discectomy surgeries. There was no tenderness or sensory deficit on examination. MRI of the left calf revealed muscular enlargement, with fat interspersed between the muscle fibers, in keeping with pseudohypertrophy. This has a number of causes, in this cause attributed to lumbar radiculopathy. This case highlights a rare but important cause of limb swelling which should be considered in the workup of a unilateral swollen limb.

Background: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. Methods: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. Results: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. Conclusions: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. Further research: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. Funding: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.