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

Phase 3Active Not RecruitingNCT06246344

Shandong Cancer Hospital and Institute128 enrolled

Overview

This prospective, single-center, randomized controlled trial evaluates whether online adaptive radiotherapy (ART) with a sequential boost to both the primary rectal tumor and clinically involved lymph nodes improves pathologic complete response in patients with high-risk, node-positive locally advanced rectal cancer. Participants were randomly assigned 1:1 to online ART with a sequential boost or conventional non-adaptive intensity-modulated radiotherapy (IMRT). Both groups received concurrent capecitabine during long-course chemoradiotherapy, followed by 3-4 cycles of CAPEOX consolidation chemotherapy and planned total mesorectal excision. The planned sample size was 128 participants. Enrollment was discontinued after an interim review after 76 participants had been randomized; long-term follow-up of enrolled participants is ongoing.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

Online Adaptive Radiotherapy With Sequential BoostRADIATION

MR- or CBCT-guided online adaptive radiotherapy with daily imaging, target and organ-at-risk review, and plan reoptimization. A sequential boost of 9 Gy in 3 fractions or 10 Gy in 2 fractions is delivered to GTVp and GTVn, followed by 50 Gy in 25 fractions to the pelvic CTV.

Conventional Non-Adaptive IMRTRADIATION

Conventional non-adaptive intensity-modulated radiotherapy to the pelvic CTV at 50 Gy in 25 fractions without dose escalation.

CapecitabineDRUG

Capecitabine 825 mg/m² orally twice daily during long-course chemoradiotherapy.

CAPEOXDRUG

Consolidation chemotherapy consisting of capecitabine 1000 mg/m² orally twice daily on days 1-14 plus oxaliplatin 130 mg/m² intravenously on day 1 every 3 weeks for 3-4 cycles after chemoradiotherapy.

Total Mesorectal ExcisionPROCEDURE

Total mesorectal excision planned after completion of neoadjuvant treatment according to standard surgical principles.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. Age 18 years or older. 2. ECOG performance status of 0 or 1. 3. Histologically confirmed rectal adenocarcinoma. 4. Primary tumor located within 10 cm of the anal verge by pelvic MRI and/or rigid sigmoidoscopy. 5. Clinically involved regional lymph nodes (cN1-2) according to the AJCC 8th edition. 6. 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). 7. Baseline locoregional staging with contrast-enhanced pelvic MRI and chest/abdominal imaging excluding distant metastases. 8. Treatment-naïve with respect to systemic therapy and pelvic radiotherapy for the index rectal cancer and suitable for total mesorectal excision. 9. Adequate organ function and no medical contraindication to chemoradiotherapy. 10. Written informed consent before study-specific procedures. Exclusion Criteria 1. Prior pelvic radiotherapy. 2. Prior rectal surgery for the index cancer, including local excision or transanal procedures. 3. Radiologically or pathologically confirmed distant metastasis. 4. Locally recurrent rectal cancer. 5. Active inflammatory bowel disease. 6. History of another primary malignancy within the preceding 5 years, except adequately treated non-melanoma skin cancer or carcinoma in situ. 7. Pregnancy or lactation. 8. Severe or uncontrolled medical condition contraindicating chemoradiotherapy or surgery. 9. Clinically significant hypersensitivity to protocol systemic therapy that precludes treatment.

Outcomes

Primary Outcomes

pCR

Proportion of participants achieving ypT0N0, defined as absence of viable tumor cells in the resected primary tumor and regional lymph nodes after neoadjuvant treatment.

Time frame: At total mesorectal excision after completion of neoadjuvant therapy, up to approximately 6 months after randomization

Secondary Outcomes

Surgical Difficulty

urgical difficulty is assessed using a predefined 8-item composite score incorporating operative time, conversion to laparotomy, non-routine transanal assistance, visible pelvic fibrosis, bowel edema, intraoperative blood loss, postoperative hospital stay, and postoperative complications. The total score ranges from 0 to 12; a score ≥3 defines difficult surgery.

Time frame: Time Frame: Perioperative through 30 days after surgery

Clinical Complete Response (cCR) Rate

Proportion of participants meeting the protocol-defined criteria for clinical complete response at restaging, based on pelvic MRI, endoscopy, and digital rectal examination, with biopsy when performed. Criteria include no residual tumor or only residual fibrosis on MRI, no suspicious residual lymph nodes, no residual tumor on endoscopy or only a small scar/ulcer, and no palpable residual tumor.

Time frame: At preoperative restaging after completion of neoadjuvant therapy, before planned surgery

3-year overal survival rate

The proportion of patients from the commencement of self-diagnosis to the time of death for any reason within 3 years

Time frame: 3 years

5-year overal survival rate

The proportion of patients from the commencement of self-diagnosis to the time of death for any reason within 5 years

Time frame: 5 years

3-year disease free survival rate

The proportion of patients from the initiation of surgery to tumor recurrence or death within 3 years

Time frame: 3 years

5-year disease free suvival rate

The proportion of patients from the initiation of surgery to tumor recurrence or death within 5 years

Time frame: 5 years

Treatment-related adverse events

Number and proportion of participants experiencing treatment-related adverse events, graded according to CTCAE version 5.0 and protocol-specified radiation morbidity criteria.

Time frame: 1 year

Perioperative complications

Incidence of perioperative complications after TME, including wound/incision complications, bleeding, infection, and procedure-specific complications

Time frame: From surgery through 30 days after surgery

Perineal wound healing after APR

Perineal wound-healing outcomes and wound complications among participants undergoing abdominoperineal resection.

Time frame: Through 6 months after surgery