Radiotherapy Dose Escalation for Non-operative Management of Unresectable Locally Recurrent Rectal Cancer (STEP-UP)

Objective: The primary objective of this study is to assess the feasibility of radiotherapy dose escalation in the non-operative treatment of previously irradiated and radiotherapy naïve patients with unresectable LRRC. Feasibility is defined as ≤7 participants with acute grade 3-5 radiation-induced toxicities (CTCAE version 5.0). Radiotherapy dose escalation is offered in a feasibility trial at a predefined dose level in two settings:

• (Chemo-)reirradiation: previously irradiated patients with unresectable LRRC undergo stereotactic body radiation therapy (SBRT) (daily adaptive magnetic resonance (MR) or cone beam computed tomography (CBCT)-guided) reirradiation (5 x 9 Gy) when feasible or, alternatively, hyperfractionated chemoreirradiation (50.4 Gy in 1.2 Gy BID fractions with concurrent capecitabine 825mg/m2 bidaily (BD)). SBRT feasibility is dependent on specific tumour criteria (i.e., <6 cm in tumour diameter, and tumour not infiltrating the lumen of the bowel- or bladder wall, as in accordance with the UK SABR consortium guidance(1)).
• Full-course chemoradiotherapy: radiotherapy naïve patients undergo full-course chemoradiotherapy with a simultaneous integrated boost (SIB; 25 × 2.6 Gy; EQD2Gy = 71 Gy, α/β = 5 Gy)(2) with concurrent capecitabine 825mg/m2 BD.

The investigators anticipate a safe toxicity profile, and potentially improved oncological outcomes. The secondary objectives are to determine symptomatic control, quality of life, local control, progression-free survival and overall survival.

Study design: This is a prospective, single-arm feasibility study. Eligible patients receive radiotherapy dose escalation at one predefined dose level in either a (chemo-)reirradiation or full-course radiotherapy setting.

Study population: A total of 30 patients will be included in the study. Eligible patients are divided in two treatment groups:

• (Chemo-)reirradiation: Previously irradiated patients with unresectable LRRC (without distant metastases, or, with (oligo)metastatic disease that does not require imminent start of systematic therapy) treated with non-operative management.
• Full-course chemoradiotherapy: Radiotherapy-naïve patients with unresectable LRRC (without distant metastases, or, with (oligo)metastatic disease that does not require imminent start of systematic therapy) treated with non-operative management.

Intervention study: All cases are reviewed in a multidisciplinary tumour board before enrolment. Interventions are defined as follows:

• (Chemo-)reirradiation: SBRT (daily adaptive MR or CBCT-guided) will be delivered when feasible, depending on tumour characteristics (i.e., <6 cm in tumour diameter, and tumour not infiltrating the lumen of the bowel- or bladder wall, as in accordance with the UK SABR consortium guidance). The SBRT regimen consists of 5 fractions of 9 Gy. Alternatively, hyperfractionated chemo-reirradiation will be delivered, consisting of 50.4 Gy in 1.2 Gy twice-daily fractions (BID), in combination with concurrent capecitabine 825mg/m2 BD.
• Full-course chemoradiotherapy: delivered with a simultaneous integrated boost (SIB) technique (25x2.6 Gy), corresponding to an EQD2Gy (α/β = 5 Gy, rectum) of 71 Gy, with concurrent capecitabine 825mg/m2 BD.

Main study parameters/endpoints: The primary objective is to evaluate the feasibility of radiotherapy dose escalation, as defined by the incidence of acute (<3 months) grade 3-5 radiation-induced toxicities ≤7 participants (CTCAE version 5.0). Secondary objectives include acute and late radiation-induced toxicity stratified per fractionation schedule, quality of life and symptomatic control (using validated patient-reported outcome questionnaires), and 1- and 3- year (infield and outfield) progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS).

Inclusion criteria

• Age ≥ 18 years old.
• Diagnosis of locally recurrent rectal cancer, defined as recurrent disease within the pelvis after surgical excision for primary rectal or distal sigmoidal cancer, diagnosed either by histopathology or clinically proven (evidence on imaging in combination with clinical findings, with consensus in MDT). A second recurrence is eligible if (chemo-)reirradiation is considered feasible, with consensus in MDT.
• Recurrent disease is determined as unresectable where surgery has been ruled out by clinicians (or refused by patient), with consensus in MDT.

Unresectable is defined as: expected gross incomplete resection with overt tumour remaining in the patient after resection, encasement of the ischiadic nerve and invasion of the cortex and/or neuroforamina from S2 and upwards.

• Either radiological absence of distant metastatic disease (M0), or, with (oligo)metastatic disease that does not require imminent start of systematic therapy at time of inclusion.

If systematic chemotherapy was previously administered prior to inclusion, and there is a current indication for local treatment with radiotherapy, patients are still eligible.

• WHO/ECOG performance score 0-2.
• MR pelvis and thoracoabdominal CT with interpretation no longer than 6 weeks prior to inclusion.
• Written informed consent according to the ICH-GCP and national/local regulations.

Exclusion criteria

• Radiological evidence of extensive metastatic disease (e.g., extensive liver or lung metastases) at time of inclusion, that requires imminent start of systemic therapy, with consensus in MDT.
• Radiotherapy in the past 6 months.
• Any contraindication for planned radiotherapy dose escalation, as determined by the radiation oncologist (e.g., residual grade 3 toxicity from previous radiotherapy).
• Administration of bevacizumab/panitumumab/cetuximab <6 weeks prior to start radiotherapy dose escalation.
• Severe active morbidity, concomitant disease or active infections.
• dMMR/MSI status