Standard versus reduced-dose chemoradiotherapy in anal cancer (PLATO-ACT4): short-term results of a phase 2 randomised controlled trial.

BACKGROUND

Localised squamous cell carcinoma of the anus is treated with radical chemoradiotherapy. Cure rates are high, but treatment can result in substantial acute and long-term morbidity. We aimed to assess whether lower dose chemoradiotherapy maintains high local control rates in patients with early-stage disease, with the secondary aim of reducing toxicity.

METHODS

ACT4 is a phase 2, prospective, multicentre, open-label, two-arm non-comparative, randomised, controlled trial, investigating reduced-dose intensity-modulated radiotherapy (rd-IMRT: 41·4 Gy in 23 fractions) in patients with early-stage anal cancer; T1-2 (≤4 cm) N0-NxM0. Eligible patients were at least 16 years of age, with an Eastern Cooperative Oncology Group performance status of 0-1. The primary outcome is 3-year loco-regional failure rates. Patients were randomly assigned 1:2 (with stratification by T stage, N stage, gender, HIV status, and randomising site) to standard-dose IMRT (sd-IMRT: 50·4 Gy in 28 fractions) or rd-IMRT with concurrent mitomycin and capecitabine chemotherapy. Here, we report the pre-planned, modified intention-to-treat analysis of secondary endpoints 6 months after treatment end-complete clinical response, compliance, patient-reported outcomes (EORTC QLQ-C30 and ANL27), and safety data. The trial is registered at the ISRCTN registry (ISRCTN88455282) and is ongoing but no longer recruiting.

FINDINGS

163 patients were recruited from 28 UK tertiary centres between April 24, 2017, and Dec 1, 2020. 160 patients were included in the primary analysis (sd-IMRT n=55; dr-IMRT n=105). Data on ethnicity were not collected. The median patient age was 66 years (IQR 58-72 years); 117 (73%) were female and 43 (27%) male; and 129 (94%) of 138 evaluable samples were p16 positive. Complete clinical responses at 6 months were 87% (46 of 53) for sd-IMRT and 92% (89 of 97) for rd-IMRT. Radiotherapy interruptions of 3 days or more occurred in 14 (26%) of 55 patients in sd-IMRT and 16 (15%) of 105 patients in rd-IMRT. Chemotherapy modifications occurred in 27 (49%) of 55 patients in sd-IMRT and 39 (37%) of 105 patients in rd-IMRT. Grade 3 or worse acute toxicity was reported in 25 (46%) of 55 patients in sd-IMRT and 37 (35%) of 105 patients in rd-IMRT. The most common grade 3 or worse adverse events were radiation dermatitis (seven [13%] of 55 in sd-IMRT and ten [10%] of 105 in rd-IMRT), and diarrhoea (four [7%] of 55 in sd-IMRT and nine [9%] of 105 in rd-IMRT). Serious adverse events occurred in eight (15%) of 55 patients in sd-IMRT and ten (10%) of 105 patients in rd-IMRT. Patient-reported outcomes for most issues deteriorated at the end of treatment and resolved to baseline by 6 weeks in both groups. Poorer sexual function for men and women was observed at 6 months following sd-IMRT.

INTERPRETATION

Good 6-month complete clinical responses rates were seen in both groups. Early results suggest rd-IMRT is well tolerated with oncological outcomes maintained. 3-year locoregional failure rates are awaited.

FUNDING

Cancer Research UK and Stand Up to Cancer.