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Background: Mammographic screening programmes reduce breast cancer mortality, but detect many small tumours with favourable biological features which may not progress during a woman’s lifetime. Screen-detected cancers are treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies have evaluated the omission of radiotherapy in this context. However, there is little evidence to support surgical de-escalation, although percutaneous minimally invasive treatment approaches have been described. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Methods: SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected good prognosis cancers. The main eligibility criteria are age ≥47 years, unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery; with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are: 1. Non-inferiority comparison of the requirement for a second procedure following excision 2. Single arm analysis of local recurrence (LR) at 5 years following VAE Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A novel feature of SMALL is the integration of a QuinteT Recruitment Intervention (QRI), which aims to optimise recruitment to the study. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of trial screening logs, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results: SMALL opened in December 2019, but recruitment halted in 2020 for 5 months due to COVID-19. At 7st July 2022, 142 patients had been randomised from 26 centres, with a randomisation rate of approximately 45%, and a per site recruitment rate of 0.4-0.5 patients/month, approaching the feasibility recruitment target of 144 patients. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on providing balanced information about treatments, encouraging recruiters to engage with patient preferences, and explaining randomisation). Individual recruiter feedback has commenced, with wider feedback delivered across sites via recruitment training workshops. Conclusion: Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme, award 17/42/32 Citation Format: Stuart A. McIntosh, Charlotte E. Coles, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Jenna Morgan, Sangeetha Paramasivan, Sarah E. Pinder, Sarah Pirrie, Shelley Potter, Tracy Roberts, Nisha Sharma, Hilary Stobart, Elizabeth Southgate, Sian Taylor-Phillips, Matthew Wallis, Daniel Rea. SMALL: Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screen-detected breast cancer – a UK phase III randomised multi-centre trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-20-02.

To assess feasibility and preliminary efficacy of adding cetuximab to standard chemoradiotherapy for muscle-invasive bladder cancer.TUXEDO was a prospective, single-arm, open-label, phase I/II trial conducted in six UK hospitals. Cetuximab was administered with an initial loading dose of 400mg/mBetween Sept-2012 and Oct-2016, 33 patients were recruited; 7 in phase I, 26 in phase II. Three patients in phase II were subsequently deemed ineligible and received no trial therapy. Eight patients discontinued cetuximab due to adverse effects. Median age of patients was 70.1 years (range 60.6-75.1), 20 were PS 0, 27 male and 26 had already received neoadjuvant chemotherapy. In phase I, all patients completed planned radiotherapy, with no delays or dose reductions. Of the 30 evaluable patients in phase II, 25 had confirmed local control 3-months post treatment (77%, 95% CI: 58-90). During the trial there were 18 serious adverse events. The study was halted due to slow accrual.Phase I data demonstrate it is feasible and safe to add cetuximab to chemoradiotherapy. Exploratory analysis of phase II data provides evidence to consider further clinical evaluation of cetuximab in this setting.

Background:. Mammographic screening programmes have been shown to reduce breast cancer mortality. However, they detect many small tumours with favourable biological features which may not progress during a woman’s lifetime. These are treated with standard surgery and adjuvant therapies, which have associated morbidities. Thus, there is a need to reduce overtreatment of good prognosis tumours found by screening. Minimally invasive treatment approaches have been described but there is no prospective randomised evidence to support their routine use. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Methods:. SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected good prognosis breast cancers. The main eligibility criteria are age ≥47 years, screen-detected unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery; with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are:1.Non-inferiority comparison of the requirement for a second procedure following excision2.Single arm analysis of local recurrence (LR) at 5 years following VAE. Recruitment of 800 patients over 4 years will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A QuinteT Recruitment Intervention (QRI) is integrated throughout SMALL to optimise recruitment and informed consent. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of screening, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results:. SMALL opened in December 2019, but recruitment halted in 2020 due to suspension of the NHS BSP for 5 months due to COVID-19. As of 1st July 2021, 55 patients had been approached in 10 centres, with 33 patients randomised (randomisation rate 60%). A further 23 centres are in set-up, with 8 suspended due to the pandemic. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on introducing and discussing SMALL, providing balanced information. on treatment options and explaining randomisation). individual recruiter feedback has commenced, with wider feedback planned shortly. Conclusion:. Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme, award 17/42/32 Citation Format: Stuart A McIntosh, Charlotte E Coles, Carmel Conefrey, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Jenna Morgan, Sangeetha Paramasivan, Sarah Pinder, Sarah Pirrie, Shelley Potter, Tracy Roberts, Nisha Sharma, Hilary Stobart, Elizabeth Southgate, Sian Taylor-Phillips, Matthew Wallis, Daniel Rea. SMALL - Open surgery versus minimally invasive vacuum-assisted excision for small screen detected breast cancer: A phase 3 randomised trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-06-02.

Background SMALL (ISRCTN 12240119) is a novel UK phase III multicentre randomised trial comparing vacuum-assisted excision (VAE) to surgery for small screen-detected breast cancers with biologically favourable characteristics. Acceptance by the clinical community and recruitment to SMALL was anticipated to be challenging as it involves randomisation, surgical de-escalation and minimally-invasive percutaneous treatment (VAE). A QuinteT Recruitment Intervention (QRI) has therefore been integrated throughout SMALL’s recruitment period, with the aim of optimising recruitment and informed consent. Methods The QRI in SMALL has involved the analysis of: a) screening log data b) written views from recruiters on the two treatments and their advantages/disadvantages c) in-depth semi-structured interviews with members of the Trial Management Group (TMG) and clinician-recruiters and d) audio-recordings of recruitment discussions with potentially eligible patients. Recruitment challenges were identified and addressed through the provision of written recruitment tips documents, and group and individual feedback sessions with recruiters. Results There was widespread support for the concept of the SMALL trial within the clinical community. Recruiters recognised the pioneering role of SMALL as the only current surgical de-escalation randomised trial in screen-detected breast cancer. Key recruitment challenges revolved around i) healthcare professionals (HCPs) who met patients early in the pathway providing information indicating that they were being referred for surgery (without mentioning SMALL or VAE), ii) concerns around the balance of de-escalation/escalation of different treatment modalities (e.g. some clinicians may prefer to de-escalate radiotherapy in preference to surgery in low-risk patients), iii) challenges in articulating equipoise in a surgical de-escalation trial, iv) patient preferences (primarily for surgery) and recruiter discomfort in exploring/addressing such preferences and v) fewer eligible patients than anticipated. QRI actions to overcome these issues included developing a tips document for HCPs meeting patients early in the pathway, highlighting the need to refrain from making treatment recommendations. A more generic tips document was also developed emphasising the importance of the early introduction of the study, provision of balanced information about both treatments, encouraging recruiters to engage with patients’ concerns and preferences, and adequate explanation of randomisation. Group and individual feedback sessions focussed on two key areas – articulating equipoise through balanced information provision, and considering optimal ways to explore patient preferences where they are expressed. Despite the many set-up and recruitment challenges that arose from opening at the start of the pandemic, SMALL has recruited 142 patients to date from 23 sites, with an approached to randomised patient ratio of ~50%. Conclusion SMALL is a novel surgical de-escalation study in breast cancer, which will provide critical evidence to support reductions in treatment of good prognosis disease. Using a range of qualitative methodology, the QRI has identified both broad support for the study within the clinical community, but has also identified barriers to recruitment at both clinician and patient level. These challenges have been addressed employing a range of methods, and the recruitment level and approach/randomised ratio shows the overall acceptability of this study to patients. Further work will involve interviews with patients, with a focus on their views on de-escalation, and further recruiter feedback sessions. Taken together, theis data will help inform the development and design of future de-escalation and treatment optimisation studies in breast cancer. SMALL is funded by the UK NIHR HTA programme, award 17/42/32 Citation Format: Stuart A. McIntosh, Charlotte E. Coles, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Jenna Morgan, Sarah E. Pinder, Sarah Pirrie, Shelley Potter, Tracy Roberts, Nisha Sharma, Hilary Stobart, Elizabeth Southgate, Sian Taylor-Phillips, Matthew Wallis, Daniel Rea, Sangeetha Paramasivan. Recruitment challenges in a UK surgical de-escalation study: preliminary qualitative research findings from the SMALL trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-17.

TPS614 Background: Mammographic screening programmes reduce breast cancer mortality but detect many small tumours with favourable biology which may not progress. These are treated with surgery and adjuvant therapies, but associated morbidities mean there is a need to reduce overtreatment. Minimally invasive treatments such as vacuum-assisted excision (VAE) have been described but there is no prospective randomised evidence to support their routine use. SMALL (ISRCTN 12240119) is designed to establish the feasibility of using VAE to treat small tumours detected within the UK NHS Breast Screening Programme (BSP). Methods: Phase III multicenter randomized trial comparing surgery with VAE for screen-detected good prognosis cancers. Eligibility criteria are age ≥47 years, unifocal grade 1 tumors (maximum diameter 15mm), strongly ER/PR+ve and HER2-ve, with negative axillary staging. Patients are randomized 2:1 to VAE or surgery, with no axillary surgery in the VAE arm. Excision is assessed radiologically, and if incomplete, patients undergo surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm. Coprimary end-points are: (1) Non-inferiority comparison of the requirement for a second procedure. (2) Single-arm analysis of local recurrence (LR) at 5 years after VAE. Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure, ensuring sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. The DMC will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A QuinteT Recruitment Intervention (QRI) is integrated throughout SMALL to optimize recruitment and informed consent. Recruitment challenges are identified by analyzing recruiter/patient interviews, audio-recordings of trial discussions, and by review of screening, eligibility and recruitment data and study documentation. Solutions are developed collaboratively, including recruiter feedback and recruitment tips documents. Results: SMALL opened in December 2019, but recruitment halted for 5 months due to COVID-19. At 11th February 2022, 91 patients had been recruited from 22 centers, with an approached/consented ration of 50%. Drawing from preliminary QRI findings, a recruitment tips document has been circulated (on discussing SMALL, providing balanced information on treatment options and explaining randomization). Individual recruiter feedback has commenced, with wider feedback planned shortly. Conclusion: Despite pandemic-related challenges, SMALL has excellent recruitment to date and is expected to have a global impact on treatment of screen-detected breast cancer. Clinical trial information: 12240119.

491 Background: Chemoradiotherapy (cRT) with 5FU and Mitomycin C (5FU/MMC) is an accepted standard of care for muscle invasive bladder cancer. Cetuximab is an approved radio-sensitiser in head and neck cancer and EGFR is over-expressed in bladder cancer. We report a phase 1/2 trial of the addition of cetuximab to standard cRT. Methods: Phase 1/2 single-arm, multicentre, open-label study conducted in 5 UK centres. Treatment: RT: 64 Gy/32 fractions, 5FU 2.5g/m2 over days 1-5 & 22-26, MMC 12g/m2 day 1, cetuximab 400mg/m2 day -8, 200mg/m2 day 1 and weekly x7. Main inclusion criteria: T2-4aN0M0 urothelial cancer, PS 0-1; prior neoadjuvant therapy permitted. Endpoints: Phase 1; feasibility and safety of cRT with cetuximab + 5FU/MMC in combination. Phase 2; local control (LC) at 3 months. Secondary outcomes: invasive loco-regional progression free survival (LPFS), noninvasive LPFS, metastasis free survival (MFS), overall survival (OS) & patient reported outcomes (PROMs). Sample size; phase 1 between 6 and 18, phase 2 up to 45 including those recruited in phase 1. Results: Between Sept 2012 and Oct 2016, 33 patients were recruited; 7 in phase 1 26 in phase 2. Median age 70.1 (IQR 65.4-80.2) yrs, 60.6% WHO Performance Status 0; 81.8% male, 26/33 neoAd chemotherapy. 3 patients ineligible post registration. 30 evaluable pts started RT, 1 patient didn’t complete RT due to serious adverse event (interstitial pneumonitis), 3 with delays. Phase 1, 6/7 pts completed Cetux therapy, 1 omitted 1 dose for grade 3 rash. LC was 77% (95% CI 58, 90). Overall median dose intensities Cetux 100%, MMC 99% 5FU 99.8%. 8 pts developed recurrence; 2 MIBC. The 6 & 12 month muscle-invasive LPFS was 93 &; non-invasive LPFS 97% & 85%, MFS 90% & 90%, OS 97% & 87%. PROMs showed a transient dip at 1 mo, back to baseline at 3 mo. Conclusions: Phase 1 data demonstrate it’s feasible and safe to add cetuximab to cRT with 5FU/MMC with high delivered dose intensities. Although recruitment failed to reach the pre-specified target for phase 2 exploratory analysis indicate the 3 month bladder control rates and recurrence rates are above those reported in BC2001 with good PROMs provides evidence to consider further evaluation of cetuximab. Clinical trial information: 80733590.

Aim: The primary objective of the survey was to evaluate clinical skin care practice in radiotherapy departments across the United Kingdom. Methods and sample: A questionnaire containing sixty-one questions grouped into eight themed sections was developed and a link to an on-line survey, using the Survey Monkey™ tool, was e-mailed to all radiotherapy department managers in the United Kingdom (N=67). Each recipient was invited to provide one response per department. Key results: Fifty-four departments responded within the allocated timeframe giving a final response rate of 81%. Products and their use for skin conditions varied and some outdated and unfounded practices were still being used which did not always reflect the current evidence base. The amount of data routinely collected on skin toxicity was limited making it difficult to quantify the extent of skin morbidity following radiotherapy. Conclusion: The survey demonstrated variability in skin care practice in radiotherapy departments across the UK, with limited practice based on evidence or on skin toxicity measurement and monitoring. © 2011 The College of Radiographers.

4527 Background: This phase I/II trial assessed the safety, feasibility and efficacy of cetuximab (Cet) in combination with 5-fluorouracil (5FU) and mitomycin C (MMC) with concurrent radiotherapy (RT) for the treatment of muscle invasive bladder cancer (MIBC). BC2001 trial has previously reported significant improvement in locoregional control in patients (pts) with MIBC who were randomised to synchronous chemo-RT compared to RT alone (James, Hussain, Hall et al NEJM 2012). Results for phase I have been reported previously. This abstract reports the combined results of phases I/II. Methods: From September 2012 to October 2016, 33 pts were recruited (7 pts to phase I from 2 UK centres and 26 patients to phase II from 5 UK centres). Pts received loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2 for 7 weeks, continuous infusion 5FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC 12mg/m2on day 1 in combination with radical RT 64 Gy in 32 fractions. Neoadjuvant chemotherapy was mandatory in phase I but optional in phase II. Primary outcomes in phase I were feasibility and toxicity. Primary outcome in phase II was 3 month pathological complete response (CR) rate, secondary outcomes included toxicity, progression free survival (PFS) and overall survival (OS). Results: Median age of pts was 70 (range 46.9-85.6). Treatment completion rates in phase I were RT 100%, 5FU 100 %, MMC 100%, Cet 96%. Of the 28 analysable pts, phase II primary outcome data was available for 25 pts at the time of analysis with a 3 month pathological CR rate of 88%. 5 local progressions and 4 deaths were reported. 12 pts suffered at least one SAE. Grade 4 toxicities observed were dyspnoea, atrial fibrillation, interstitial pneumonitis, sepsis, thromboembolism, neutropenia and palpitations. The commonest grade 3 toxicities were skin rash, diarrhoea, low platelet count, low white blood cell count, fever and haematuria. The most common grade 1 and 2 toxicities were diarrhoea and skin rash. Data on PFS and OS will be presented. Conclusions: It was feasible and safe to add cetuximab to full dose chemo-RT with 5FU/MMC. The CR rate is encouraging and further randomised studies with this combination are warranted. Clinical trial information: ISRCTN80733590.

Chapter 8b discusses the considerable controversy as to the optimal management of localized, muscle invasive bladder cancer. Surgical removal of the bladder is considered the ‘gold standard’ in many countries but there is no randomized trial to underpin this statement, and many patients are unfit for surgery. Reported 5-year survival rates with radiotherapy are remarkably similar to surgical series. Thus even if surgery is genuinely better than radiotherapy for patients fit for both approaches, there are many patients for whom radical surgery is simply not suitable and hence bladder-preserving techniques are appropriate.