The goal of this prospective study is to evaluate if a higher radiation dose to the tumor can increase the organ preservation rate in non-locally advanced rectal cancer.

Rationale:

Organ preservation has emerged as a promising alternative to total mesorectal excision (TME) for non-locally advanced rectal cancer, aiming to reduce long-term functional impairments and improve quality of life. While magnetic resonance (MR)-guided radiotherapy boosts have shown potential in enhancing organ preservation rates, their high costs, prolonged treatment times and limited accessibility prevent widespread adoption. To address this gap in current treatment options, this study investigates a more accessible online adaptive boost strategy based on cone-beam computed tomography (CBCT) imaging, with the aim of expanding organ-preserving treatment options for rectal cancer patients.

Objective:

The primary objective of this study is to evaluate the organ preservation rate at two-year follow-up in patients with non-locally advanced rectal cancer. Secondary objectives include the assessment of clinical and pathological response rates, recurrence and survival outcomes, biological effects, treatment-related toxicities, bowel function, quality of life, tumor regression, CBCT-based workflow, and target and organ motion during treatment.

Study design:

This study is designed as a non-randomized, single arm, monocenter, phase II clinical trial.

Study population:

Patients (n=25) older than 18 years with non-locally advanced rectal cancer (defined as cT1-3N0-IM0) and a wish for organ preservation, who are referred for treatment.

Intervention (if applicable):

Addition of a simultaneous integrated boost (SIB) to the standard chemoradiotherapy (CRT) scheme of 2.0 Gy to the mesorectum. The radiotherapy scheme consists of 25 fractions, delivering 2.0 Gy per fraction to the mesorectum and 2.4 Gy per fraction to the tumor and positive mesorectal lymph nodes.

Main study parameters/endpoints:

This study aims to demonstrate that the investigated treatment approach results in an increased organ preservation rate of 70% at two year follow-up compared to historical data.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Preclinical data confirmed the feasibility of the investigated SIB-CRT approach, demonstrating limited and clinically acceptable increases in organ at risk doses compared to the standard CRT scheme, all remaining well within clinical constraints. Furthermore, current literature supports the safety of dose escalation CRT strategies for rectal cancer, reporting manageable acute toxicity profiles, with symptoms typically returning to baseline after treatment. Based on these data, the investigated SIB-CRT strategy is expected to result in only minimal additional toxicities compared to standard CRT therapy.

The additional burden for the participants includes five MRI scans (approximately five hours total), scheduled alongside routine visits to minimize inconvenience. Patients will also be asked to complete three questionnaires at five time points, requiring approximately two hours in total, and to provide one additional 20 mL blood sample during three routine blood withdrawals.

The principal investigators consider the additional potential risk and burden for patients in the study to be acceptable. This study aims to significantly improve organ preservation rates, offering a meaningful benefit to individual patients by potentially avoiding TME surgery.

Inclusion Criteria:

• Age ≥18 years
• Eastern cooperative oncology group (ECOG) performance status ≤2
• Histologically confirmed rectal adenocarcinoma
• Non-locally advanced rectal cancer, defined as (magnetic resonance imaging (MRI)-based) T1-3, N0/N1 (≤3 positive mesorectal lymph nodes), MX/M0
• Indication for curative treatment with organ preservation
• Discussed in the multidisciplinary tumor board (MTB)
• Written informed consent

Exclusion Criteria:

• Previous radiotherapy in the pelvic area
• Other malignancies, except for adequately treated basal cell carcinoma (BCC), at time of inclusion or within 3 years prior to inclusion
• Contra-indications for (chemo)radiotherapy or surgery
• Presence of lateral lymph nodes, cN2 status, extramural vascular invasion (EMVI) or mesorectal fascia involvement as seen on MRI
• Mucinous defined tumor on MRI
• Prior local excision of the primary tumor
• DPD (dihydropyrimidine dehydrogenase) deficiency
• Unable to understand the requirements of the study and to give written informed consent, as determined by the treating physician