Adjuvant radiotherapy in patients with high-risk primary cutaneous Squamous Cell Carcinoma AFTER surgery (SCC-AFTER): an open label, multicentre, two-arm phase III randomised trial

Research question Following complete excision of high-risk primary cutaneous squamous cell carcinoma (HR cSCC) is adjuvant radiotherapy (ART) plus active monitoring superior in reducing loco-regional recurrence compared with active monitoring alone? Background UK cSCC incidence exceeds 52,000, increasing by 6% p.a (1,2). Surgery cures 95% (3,4). 5%, usually T2b/T3 (Brigham and Women’s Hospital classification) develop loco-regional recurrence (LRR) which accounts for 75% of cSCC-specific deaths, substantial morbidity and reduced quality of life (5,6). Approximately 10% of cSCC are T2b or T3 (5000 p.a in the UK) (2), with LRR rates of 20-30% and 50% respectively (7-11), designated high-risk (HR). LRR treatment has limited efficacy. Anti-PD1 immunotherapy has CR of 20% (12, 13). ART is used to prevent LRR, despite lack of randomised data (14-18). In our extensive feasibility work we have confirmed clinical equipoise, clinician and patient support in the UK for SCC-After (19,20). Aim /objectives SCC-After is an open label, multicentre, two-arm, phase III, pragmatic group sequential RCT to evaluate superiority, cost-effectiveness and effects on QoL of ART in completely resected high-risk (BWH T2b/3) primary cSCC. Methods · Population: Patients (n=840) with completely excised high-risk primary cSCC (T2b/T3 by BWH staging criteria) recruited from 25 UK SSMDTs. · Intervention: ART followed by active monitoring · Comparator: Active monitoring only · Inclusion criteria: Adults aged >18 years, ECOG =3, fit for ART, life expectancy >6 months · Exclusion criteria: cSCC on anatomic sites which interfere with suitability for ART; clinical or histological evidence of loco-regional cSCC. · Primary outcome: LRR-free survival time - time from randomisation to date of clinical detection of what is subsequently confirmed to be local, regional or loco-regional recurrent disease (21). · Secondary outcomes: QoL; cost-effectiveness; distant metastasis-free survival; overall survival; safety/toxicity (21). An internal pilot targeting recruitment of 100 patients within the first 12 months will determine feasibility. Recruitment prediction is based on site interest and experience on speed of site opening. Two interim analyses after 77 and 115 events (600-760 randomised) trigger early stopping if the log-rank statistic is larger than +/- 3.36 and +/- 2.68 respectively. Stopping for efficacy means fewer participants and shorter follow-up. Otherwise, the trial will be analysed when at least 194 events have been reported. A Quintet Recruitment Intervention and SWAP are included to optimise recruitment and inclusion of people with multiple longterm conditions, safeguard informed consent, address clinician equipoise, identify organisational barriers. Timelines for delivery Set up 6 months; recruitment 4 years; follow-up 3 years; 6 months analysis, publication and closure. Patients will be assessed by UK guidance including baseline, mid-ART (Intervention arm only), 4 monthly for 2 years, then 6-monthly (22-24). QoL and Health Economics (HE) will be assessed 4-monthly for year 1, annually in years 2 and 3. Progression and survival data will be collected throughout the trial. Establishing if ART is clinically and cost-effective will be of immediate benefit to patients (22-24). If effective, ART will be incorporated into NHS treatment pathways. We will share updates and results with patients, support organisations and healthcare professionals.