Adaptive Boost Radiotherapy to Primary Lesions and Positive Nodes in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer

The trial was originally designed to evaluate adaptive dose escalation to the primary rectal tumor and clinically involved lymph nodes during neoadjuvant treatment for locally advanced rectal cancer. During trial conduct, the protocol was amended to reflect the treatment strategy implemented in the enrolled cohort. Enrollment was operationally consolidated at the lead center. Online ART was delivered using either MR-guided or CBCT-guided workflows. In the experimental arm, a sequential boost of 9 Gy in 3 fractions or 10 Gy in 2 fractions was delivered to the primary tumor and clinically involved lymph nodes, followed by online ART to 50 Gy in 25 fractions to the pelvic clinical target volume. The control arm received conventional non-adaptive IMRT to 50 Gy in 25 fractions without dose escalation. Both groups received concurrent capecitabine and 3-4 cycles of CAPEOX consolidation chemotherapy.

The planned enrollment was 128 participants. During trial conduct, an interim review was undertaken after 76 participants had been randomized. The interim analysis had not been specified in the original protocol and no formal group-sequential efficacy or futility boundary had been prespecified. Enrollment was subsequently discontinued, while protocol-defined follow-up of enrolled participants continues.

Inclusion criteria

• Age 18 years or older.
• ECOG performance status of 0 or 1.
• Histologically confirmed rectal adenocarcinoma.
• Primary tumor located within 10 cm of the anal verge by pelvic MRI and/or rigid sigmoidoscopy.
• Clinically involved regional lymph nodes (cN1-2) according to the AJCC 8th edition.
• At least one additional high-risk feature: cT4 disease, cN2 disease, extramural vascular invasion, mesorectal fascia involvement, lateral pelvic lymph-node involvement, tumor deposits, or low rectal cancer (≤5 cm from the anal verge).
• Baseline locoregional staging with contrast-enhanced pelvic MRI and chest/abdominal imaging excluding distant metastases.
• Treatment-naïve with respect to systemic therapy and pelvic radiotherapy for the index rectal cancer and suitable for total mesorectal excision.
• Adequate organ function and no medical contraindication to chemoradiotherapy.
• Written informed consent before study-specific procedures.

Exclusion criteria

• Prior pelvic radiotherapy.
• Prior rectal surgery for the index cancer, including local excision or transanal procedures.
• Radiologically or pathologically confirmed distant metastasis.
• Locally recurrent rectal cancer.
• Active inflammatory bowel disease.
• History of another primary malignancy within the preceding 5 years, except adequately treated non-melanoma skin cancer or carcinoma in situ.
• Pregnancy or lactation.
• Severe or uncontrolled medical condition contraindicating chemoradiotherapy or surgery.
• Clinically significant hypersensitivity to protocol systemic therapy that precludes treatment.