Rectal Cancer
Conditions
Keywords
neoadjuvant, rectal cancer, chemoradiotherapy
Brief summary
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.
Detailed description
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.
Interventions
RADIATIONOnline Adaptive Radiotherapy With Sequential Boost
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.
RADIATIONConventional Non-Adaptive IMRT
Conventional non-adaptive intensity-modulated radiotherapy to the pelvic CTV at 50 Gy in 25 fractions without dose escalation.
DRUGCapecitabine
Capecitabine 825 mg/m² orally twice daily during long-course chemoradiotherapy.
DRUGCAPEOX
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.
PROCEDURETotal Mesorectal Excision
Total mesorectal excision planned after completion of neoadjuvant treatment according to standard surgical principles.
Sponsors
Shandong Cancer Hospital and Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| pCR | At total mesorectal excision after completion of neoadjuvant therapy, up to approximately 6 months after randomization | Proportion of participants achieving ypT0N0, defined as absence of viable tumor cells in the resected primary tumor and regional lymph nodes after neoadjuvant treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Surgical Difficulty | Time Frame: Perioperative through 30 days after surgery | 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. |
| Clinical Complete Response (cCR) Rate | At preoperative restaging after completion of neoadjuvant therapy, before planned surgery | 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. |
| 3-year overal survival rate | 3 years | The proportion of patients from the commencement of self-diagnosis to the time of death for any reason within 3 years |
| 5-year overal survival rate | 5 years | The proportion of patients from the commencement of self-diagnosis to the time of death for any reason within 5 years |
| 3-year disease free survival rate | 3 years | The proportion of patients from the initiation of surgery to tumor recurrence or death within 3 years |
| 5-year disease free suvival rate | 5 years | The proportion of patients from the initiation of surgery to tumor recurrence or death within 5 years |
| Treatment-related adverse events | 1 year | Number and proportion of participants experiencing treatment-related adverse events, graded according to CTCAE version 5.0 and protocol-specified radiation morbidity criteria. |
| Perioperative complications | From surgery through 30 days after surgery | Incidence of perioperative complications after TME, including wound/incision complications, bleeding, infection, and procedure-specific complications |
| Perineal wound healing after APR | Through 6 months after surgery | Perineal wound-healing outcomes and wound complications among participants undergoing abdominoperineal resection. |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORJinbo Yue, Doctor
Shandong Cancer Hospital and Institute
Outcome results
None listed