Radiotherapy dose escalation for the non-operative management of patients with unresectable locally recurrent rectal cancer (STEP-UP): Study protocol for a multicentre, prospective, open-label feasibility study

Background Curative-intent management of locally recurrent rectal cancer (LRRC) generally comprises neoadjuvant therapy and surgery. In patients with unresectable LRRC, where surgical intervention is not feasible, management is limited to non-operative bimodality therapy with systemic therapy and radiotherapy. Evidence guiding the optimisation of non-operative management remains limited. In this context, the therapeutic goal is to achieve prolonged local control while minimising treatment-related adverse events and preserving quality of life. Radiotherapy dose escalation has been proposed as a potential strategy to achieve this balance. However, its feasibility and safety in the non-operative management of unresectable LRRC have not yet been established. As such, this study aims to evaluate the feasibility and safety of this radiotherapeutic approach, and to determine its impact on both symptom control and oncological outcomes. Methods This prospective, multicentre, single-arm feasibility study will enrol 30 patients with unresectable or inoperable LRRC without distant metastases, or with (oligo)metastatic disease not requiring immediate systemic therapy. Previously irradiated patients will undergo reirradiation with stereotactic body radiotherapy (re-SBRT; 5 × 9 Gy) when feasible, or, alternatively hyperfractionated chemo-reirradiation (50.4 Gy in 1.2 Gy twice-daily fractions with concurrent capecitabine). Radiotherapy-naïve patients will receive chemoradiotherapy with a simultaneous integrated boost (25 × 2.6 Gy, EQD2Gy α/β=5Gy of 71 Gy with concurrent capecitabine).Suwinski et al. (2007) [1] The primary endpoint is treatment regimen feasibility, defined as grade ≥ 3 acute radiotherapy-related adverse events (CTCAE version 5.0) occurring in no more than seven patients (23%). Secondary endpoints include late adverse events, quality of life and symptom control, and 1- and 3-year progression-free survival, disease-free survival, and overall survival. Discussion This protocol describes the STEP-UP study, which will determine the feasibility of radiotherapy dose escalation in unresectable LRRC. If feasible and safe, this approach could provide an effective treatment intensification strategy to improve local control and symptom burden in patients with unresectable LRRC, addressing a major unmet clinical need. Trial registration ClinicalTrials.gov: NCT07721181 Overview of Medical-Scientific Research in the Netherlands (OMON) Registry: NL-011150. International Clinical Trial Registry Platform (ICTRP): NL-OMON61161.