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

Multicentre, Prospective, Open-label Feasibility Study of Radiotherapy Dose Escalation for the Non-operative Management of Patients With Unresectable Locally Recurrent Rectal Cancer

The optimal curative-intent management of locally recurrent rectal cancer (LRRC) typically involves multimodality therapy, comprising neoadjuvant therapy and subsequent salvage surgery. However, in patients with unresectable LRRC, where surgical intervention is not feasible, management is limited to non-operative bimodality therapy with systemic therapy and radiotherapy. For this patient group, evidence guiding the optimisation of non-operative management remains limited, particularly regarding strategies to optimise radiotherapy and achieve durable control. In this context, the therapeutic goal is to achieve prolonged local control while minimising treatment-related toxicity. 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 symptomatic control and oncological outcomes.

Study Overview

• Status: Recruiting
• Conditions: Locally Recurrent Rectal Cancer
• Intervention / Treatment: Radiation: SBRT; Radiation: Hyperfractionated chemo-reirradiation; Radiation: Full-course chemoradiotherapy

Detailed Description

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:

1. (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)).
2. 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:

1. (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.
2. 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:

1. (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.
2. 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).

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: H.M.U. Peulen, MD, PhD; Phone Number: +31 040 - 239 64 00; Email: heike.peulen@catharinaziekenhuis.nl
• Study Contact Backup: Name: F.E.C. Vande Kerckhove, MD; Phone Number: +31 0402398858; Email: stepup@catharinaziekenhuis.nl

Study Locations

• Netherlands
  • Arnhem, Netherlands
    • Not yet recruiting
    • Rijnstate
    • Contact: I.M. Werter, MD, PhD; Phone Number: +31 088 - 005 8888; Email: iwerter@rijnstate.nl
  • Arnhem, Netherlands
    • Not yet recruiting
    • Radiotherapiegroep
    • Contact: M.D. den Hartogh, MD, PhD; Phone Number: +31 088-779 00 00; Email: m.denhartogh@radiotherapiegroep.nl
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina Hospital
    • Contact: H.M.U. Peulen, MD, PhD; Phone Number: +31 040 - 239 64 00; Email: heike.peulen@catharinaziekenhuis.nl
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Erasmus Medical Centre
    • Contact: C.S.E.W. Schuurhuizen, MD, PhD; Phone Number: +31 (010) 704 02 53; Email: c.schuurhuizen@erasmusmc.nl
  • Utrecht, Netherlands
    • Not yet recruiting
    • University Medical Centre Utrecht
    • Contact: M.P.W. Intven, MD, PhD; Phone Number: +31 088 - 75 588 00; Email: m.intven@umcutrecht.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Previously irradiated, unresectable LRRC; Eligible for SBRT or CRT hyperfractionation	Radiation: SBRT; 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.; Radiation: Hyperfractionated chemo-reirradiation; 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.
Experimental: Radiotherapy-naive, unresectable LRRC; Eligible for SIB	Radiation: Full-course chemoradiotherapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the feasibility of radiotherapy dose-escalation in the non-operative management of patients with unresectable locally recurrent rectal cancer.	Outcome measure: the number of subjects with acute grade 3-5 radiation-induced toxicity (<3 months), according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Feasibility-maximum: defined as ≤7 participants with acute grade 3-5 radiation-induced toxicity (<3 months), according to CTCAE, version 5.0.	During radiotherapy treatment and up to 3 months after completion of radiotherapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute and late grade 3-5 radiation-induced toxicity per fractionation schedule	To determine acute (<3 months) and late (presenting after 3 months up to 36 months) grade 3-5 radiation-induced toxicity , according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, stratified per fractionation schedule.	During radiotherapy treatment, up to 3 months after completion of radiotherapy (acute toxicity), and from >3 months through 36 months after completion of radiotherapy (late toxicity).
Patient-reported quality of life and duration of symptomatic control	To determine patient-reported quality of life and duration of symptomatic control following treatment with radiotherapy dose escalation. Generic and cancer-specific quality of life assessments are assessed with European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Questionnaires: QLQ-C30. The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	Baseline (at inclusion, before start of radiotherapy) and at 3, 6, 12, 24, and 36 months after completion of radiotherapy.
Patient-reported quality of life and duration of symptomatic control	To determine patient-reported quality of life and duration of symptomatic control following treatment with radiotherapy dose escalation. Generic and cancer-specific quality of life assessments are assessed with European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Questionnaires: QLQ-CR29. The QLQ-CR29 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	Baseline (at inclusion, before start of radiotherapy) and at 3, 6, 12, 24, and 36 months after completion of radiotherapy.
Patient-reported quality of life and duration of symptomatic control	To determine patient-reported quality of life and duration of symptomatic control following treatment with radiotherapy dose escalation. Generic and cancer-specific quality of life assessments are assessed with EuroQol Group 5-level EQ-5D (EQ-5D-5L), a 5 point scale. Higher scores corresponds with a higher level of symptoms on the symptom scale.	Baseline (at inclusion, before start of radiotherapy) and at 3, 6, 12, 24, and 36 months after completion of radiotherapy.
Infield progression-free survival	To determine 1-, 2- and 3-year infield progression-free survival. Defined as the time interval from start of radiotherapy dose escalation to radiological or clinical confirmed infield progression (defined as recurrence or disease progression within the PTV).	1, 2- and 3-years after the start of radiotherapy treatment.
Outfield progression-free survival	To determine 1-, 2- and 3-year outfield progression-free survival. Defined as the time interval from start of radiotherapy dose escalation to radiological or clinical confirmed outfield progression (defined as recurrence or disease progression outside the PTV).	1, 2- and 3-years after the start of radiotherapy treatment.
Progression-free survival	To determine 1-, 2- and 3-year progression-free survival. Defined as the time interval from start of radiotherapy dose escalation to radiological or clinical confirmed locoregional progression. Progression is registered by the treating physician in the patient file during follow-up.	1, 2- and 3-years after the start of radiotherapy treatment.
Disease-free survival	To determine 1, 2-, and 3-year disease-free survival. Defined as the time interval from start of radiotherapy dose escalation to first documented sign of disease progression (including locoregional progression or distant metastases) or death from any course.	1, 2- and 3-years after the start of radiotherapy treatment.
Overall survival	To determine 1-, 2- and 3-year overall survival. Defined as the time interval from date of inclusion to date of death. Mortality is registered in the patient file which is linked to municipal personal records database.	1-, 2- and 3-year after study inclusion.
Compliance of treatment with radiotherapy dose escalation	Information on the completion of radiotherapy dose escalation is registered by the treating radiation oncologist.	From the start of radiotherapy through completion of radiotherapy (approximately 2-5 weeks depending on treatment arm).

Collaborators and Investigators

• Sponsor: Heike M.U. Peulen
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: H.M.U. Peulen, MD, PhD, Catharina Hospital, Department of Radiation Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: June 30, 2026
• First Submitted That Met QC Criteria: July 20, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 20, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Radiotherapy Dose Escalation; Unresectable Locally Recurrent Rectal Cancer; Non-Operative Management
• Other Study ID Numbers: NL-011150

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No