Results of a randomised phase II study of hypofractionated bladder radiotherapy (RT) with or without image guided adaptive planning (HYBRID - CRUK/12/055).

Abstract

283 Background: Muscle invasive bladder cancer (MIBC) incidence increases with age, with many patients (pts) unfit for radical therapy. We aimed to demonstrate feasibility of delivery & acceptable rates of hypofractionated RT toxicity using image guided adaptive techniques for these pts in a multicentre trial. Methods: Pts with T2-T4aN0M0 MIBC had 36 Gray (Gy) in 6 fractions (fr) over 6 weeks & were randomised (1:1) to standard (SP) or adaptive planning (AP). For AP 3 RT plans (small, medium, large) were generated with preRT cone beam (CB) CT used to select best fitting ‘plan of the day’ at each fr. A QA programme aided standardised CBCT image interpretation. The SP group had RT with 1 plan. The aim was to exclude ≥30% grade ≥3 (≥G3) acute (to 3 months (m)) non-genitourinary (GU) toxicity for AP in pts with no MIBC death by 3m (p0=0.7 p1=0.9 α=0.05 β=0.2). Secondary endpoints included 36Gy/6fr acute toxicity in pts who had ≥1 RT fr & proportion of AP fr using small/large plan. Adverse events (AEs) were assessed (CTCAE v4) weekly on RT, 4 weeks & 3m post RT. Blind independent review assessed relatedness of non-GU AEs to RT. Results: Between Apr 2014 & Aug 2016 65 pts were randomised (SP (n=32) AP (n=33)) from 12 UK sites. Median age was 85yrs; 68% male; 92% transitional cell MIBC; 99% grade 3; 25% clinical stage T3 & 6% T4. 58 pts are evaluable to date, ≥G3 acute non-GU adverse reactions (AR) were reported in 2/30 (7%; 90% CI: 1%–20%) AP (G3 hyperkalemia & hyponatremia; G3 diarrhea & dehydration) & 3/28 (11%; 90% CI: 3% –25%) SP pts (G3 fatigue; G3 hyperkalemia, weight loss & anorexia; G3 diarrhoea). 24/65 (37%; 90% CI: 27%-48%) pts who had ≥1 RT fr had ≥G3 acute AEs including G4 hyponatremia (2 AP pts), G5 pneumonia (1 SP, 1 AP), G5 sepsis (1 AP) & G5 renal failure (1 SP) (all G4/5 unrelated to RT). 7/65 pts received <6 fr RT due to toxicity. In the 33 AP pts 40/182 fr (22%) used a small plan & 29/182 (16%) large (adaption rate=38%; 95% CI: 31%-45%). Conclusions: Though overall ≥G3 AE rate was significant, 36Gy/6fr with AP is feasible, met predefined toxicity criteria (<30% ≥G3 acute non-GU ARs) & with >25% fr adapted has potential for benefit. Comparative randomised studies are needed to quantify benefits of AP over SP. Clinical trial information: 18815596.