Early outcomes of the PLATO ACT5 randomised trial: Personalizing anal cancer radiotherapy dose.

1 Background: The optimal dose of radiotherapy (RT) in advanced anal squamous cell carcinoma (ASCC) is uncertain. Cure rates need to improve, but higher dose RT may result in significant morbidity. Methods: PLATO ACT5 is a seamless pilot/phII/phIII prospective, multi-centre, 3-arm RCT investigating dose-escalated intensity modulated radiotherapy (de-IMRT) with chemotherapy in patients (pts) with T3/4N0 and TanyN+ ASCC. Primary outcome is 3-year locoregional failure (LRF). We report planned 6-month endpoints: acute toxicity (CTCAEv5), treatment compliance, radiological and clinical complete response rates (cCR) and patient reported outcomes (PROs; EORTC-QLQ C30 and ANL27). Pts were randomised 1:1:1 in 28 fractions to standard dose IMRT (sd-IMRT; 53.2Gy), de1-IMRT (58.8Gy) or de2-IMRT (61.6 Gy) with concurrent mitomycin 12mg/m2 day (D) 1 & capecitabine (CAP) 825mg/m2 BD on RT days or 5FU 1000mg/m2 D1-4 & D29-32. 459 pts including 10% drop out were required to compare each experimental arm against sd-IMRT for 3-year LRF-free survival. Results: 463 pts were recruited from 34 UK sites (sd-IMRT n=154; de1-IMRT n=155; de2-IMRT n=154) between Feb 2017 – Aug 2023. 82% received CAP RT and 18% received 5FU RT. Pts characteristics were balanced across 3 arms: Overall median age was 62 years (range 29-81); 73% ECOG 0; 73% female; 30% T4; 45%/18%/21% N1/2/3 respectively; 21% required pre-RT stoma; 1.5% HIV positive. ≥G3 acute toxicity was reported in 57% (sd-IMRT; n=90), 56% (de1-IMRT n=86) and 58, and at 6 mo 19 patients (5/5/9 respectively) reported ≥G3. 460 completed per protocol RT. RT interruptions: sd-IMRT n=40 (26.1%), de1-IMRT n=33 (21.4%), de2-IMRT n=39 (25.7%) of which 25% were due toxicity. 70 (36%) had CAP reduction/omission (sd-IMRT n=13/50; de1-IMRT n=12/47 de2-IMRT n=39/9 respectively); the majority were due to toxicity (46-58%). 6 mo cCR: (MRI TRG 1&2 with no visible T2 weighted pelvic lymph nodes) are: sd-IMRT =100 (65%); de1-IMRT =103 (67%); de2-IMRT= 101 (66%). For PROs, there was a similar large deterioration in pain, fatigue, bowel function, quality of life, physical, role and social function at the end of CRT across all arms which resolved to baseline by 6 months in all arms. Conclusions: Dose escalation has similar toxicity, but does not improve early outcomes. Further stage stratification and novel biology approaches for personalisation are needed. Clinical trial information: ISRCTN88455282.