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

Shandong First Medical University

Status: Enrolling

Conditions: Rectal Cancer

Treatments: Procedure: Total mesorectal excision (TME) surgery; Drug: Consolidation Chemotherapy; Drug: Concurrent chemotherapy; Radiation: Adaptive Boost Radiotherapy; Radiation: Long course non-ART radiotherapy

Study type: Observational

Funder types: Other

Identifiers

NCT06246344

SDZLEC2023-390-01

Details and patient eligibility

About

This is a multicenter, randomized, controlled phase III trial to evaluate the efficacy and safety of adaptive boost radiotherapy to the primary lesions and positive lymph nodes based on MR or CBCT or FBCT-guided adaptive radiotherapy in the neoadjuvant treatment of locally advanced rectal cancer.

Full description

Locally advanced rectal cancer (LARC), typically stage II (cT3-4/N0) or stage III (cT1-4/N1-3), requires multimodal treatment. Surgical resection alone is associated with a high rate of local recurrence. Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME), on the other hand, can better control local recurrence in LARC patients. However, the overall pathological complete response (pCR) rate and clinical complete response (cCR) rate are still low, and there is an inconsistency between them, Therefore, the preservation of the anus is still a challenge. Optimizing neoadjuvant treatment strategies, including strategies such as increasing concurrent chemotherapy and increasing the dose of radiotherapy, is essential to improve tumor regression and anal preservation.

Radiotherapy is an important treatment for controlling local recurrence and downstaging LARC. A common cause of cancer recurrence in rectal cancer is that tumor cells metastasise nearby positive lymph nodes, such as the lateral pelvic lymph nodes These sites can serve as refuges where the cancer can regroup and either recur at the original site or spread to other areas. Various studies have also investigated the role of radiotherapy dose escalation in promoting tumor regression. Seldom have these studies examined dose escalation to both the primary lesions and positive lymph nodes. One of the major limiting factors is the tradeoff between destruction of the cancer itself and collateral damage to the neighboring healthy tissues. However, recent advances in the field have made great strides in overcoming this obstacle. Adaptive radiation therapy (ART), including magnetic resonance (MR)-guided, cone beam computed tomography (CBCT)-guided, and fan beam computed tomography (FBCT)-guided, allows direct imaging of the target and organs at risk (OAR), combined with optimization of the treatment plan for anatomical changes, to deliver high-quality dose escalation regimens to improve treatment response while protecting OAR such as the bladder, femoral heads, and small bowel.

We hypothesize that by implementing simultaneous integrated boost (SIB) or sequential boost (SB) radiotherapy to both the primary lesions and positive lymph nodes based on ART, we can improve the cCR and pCR rates without increasing surgical difficulty, while maintaining tolerable safety.

Against the above background, this study aims to conduct a multicenter, randomized, controlled phase III trial to evaluate the efficacy and safety of SIB or SB radiotherapy to the primary lesions and positive lymph nodes based on MR or CBCT or FBCT-guided ART in the neoadjuvant treatment of LARC. Eligible patients will be randomized 1:1 into experimental and control groups, both of which will undergo long course concurrent chemoradiotherapy (LCCRT), consolidation chemotherapy and TME surgery. During LCCRT, the experimental group will receive SIB or SB dose escalation based on MR or CBCT or FBCT-guided ART, while the control group will receive conventional dose without ART.

Enrollment: 128 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histopathologically confirmed rectal adenocarcinoma.
• Tumor located ≤10cm from the anal verge.
• Age ≥18 years.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1.
• Primary treatment-naive tumor confirmed by endorectal ultrasound (ERUS) or -
• Magnetic resonance imaging (MRI) as cT3-4/N+ according to the 8th edition of AJCC staging.
• Ability to provide tissue and blood samples for translational research.
• Anticipated survival of ≥6 months.
• Normal major organ function (within 14 days prior to enrollment) and suitability for receiving chemoradiotherapy.

Exclusion criteria

• History of prior chemotherapy, radiotherapy, or surgical treatment for rectal cancer, including transanal tumor resection.
• Locally recurrent rectal cancer.
• History of familial adenomatous polyposis.
• Active Crohn's disease or ulcerative colitis.
• Allergy or hypersensitivity history to 5-fluorouracil (fluorouracil) and/or oxaliplatin.
• History of difficulty or inability to take or absorb oral medications.
• Diagnosis of malignancy other than rectal cancer within the past 5 years (excluding completely cured basal cell carcinoma, squamous cell carcinoma of the skin, and/or in situ carcinoma treated with radical resection).
• Confirmed distant metastasis, i.e., cM1, through imaging or biopsy.
• History of pelvic radiotherapy.
• Pregnant or lactating women.
• Presence of any severe or uncontrollable systemic illness.

Trial design

128 participants in 2 patient groups

Non-ART + non-boost

Description:

Radiotherapy: The pelvic lymph node drainage area (CTV) is targeted with a dose of 45-50 Gy delivered in 25 fractions. Concurrent Chemotherapy: During radiotherapy, concurrent administration of capecitabine at a dose of 825 mg/m2, twice daily. Consolidation Chemotherapy Phase: On Day 1, two cycles of the CAPEOX regimen are administered (capecitabine 1.0 g/m2 po bid d1-14 + oxaliplatin 130 mg/m2, q3w). Initiated 7-10 days after completion of LCCRT. Surgical Phase: Commencing on Day 1, the patient undergoes Total Mesorectal Excision (TME) following consolidation chemotherapy.

Treatment:

Radiation: Long course non-ART radiotherapy

Drug: Concurrent chemotherapy

Procedure: Total mesorectal excision (TME) surgery

Drug: Consolidation Chemotherapy

ART + Boost

Description:

ART Option 1 (SIB): GTVp+GTVn: A total dose of 60-65 Gy delivered in 25 fractions using a simultaneous integrated boost approach. CTV: A total dose of 45-50 Gy delivered in 25 fractions. ART Option 2 (SB): GTVp+GTVn: An initial hypofractionated boost with a total dose of either 9-12 Gy delivered in 3 fractions or 10 Gy delivered in 2 fractions. Concurrent Chemotherapy: During radiotherapy, concurrent administration of capecitabine at a dose of 825 mg/m2, twice daily. Consolidation Chemotherapy Phase: On Day 1, two cycles of the CAPEOX regimen are administered (capecitabine 1.0 g/m2 po bid d1-14 + oxaliplatin 130 mg/m2, q3w). Initiated 7-10 days after completion of LCCRT. Surgical Phase: Commencing on Day 1, the patient undergoes Total Mesorectal Excision (TME) following consolidation chemotherapy.

Treatment:

Radiation: Adaptive Boost Radiotherapy

Drug: Concurrent chemotherapy

Procedure: Total mesorectal excision (TME) surgery

Drug: Consolidation Chemotherapy