Given the growing focus on preserving organ function and the utilization of neoadjuvant therapy, it is important to investigate and enhance the application of comprehensive neoadjuvant therapy in low rectal cancer. This approach aims to minimize or circumvent the organ dysfunction and subsequent decline in quality of life associated with radical surgery, with improving disease-free survival (DFS), while . Consequently, we propose to initiate a multicenter clinical trial to examine the medium- and long-term effectiveness of complete neoadjuvant therapy (comprising either short-course radiotherapy or long-course chemoradiation, followed by consolidation chemotherapy with mFOLFOXIRI) in increasing organ preservation rates in patients with low rectal cancer.
This randomised, open-label, multicentre,phase II trial began in December, 2022, as a neoadjuvant trial about short-course radiotherapy or long-course chemoradiation followed by mFOLFOXIRI consolidation chemotherapy,in patients aged 18 years to 70 with clinical stage II-III locally advanced low rectal cancer from six Chinese institutions. The primary endpoint of the study was the 1-year organ preservation rate, with a comparison to historical data. Additionally, the study compared the differences between two radiotherapy regimens within the TNT treatment and explored biomarkers to predict tumor response Patients with local advanced rectal cancer (cT2-4aN0-2,M0, 8cm from the anus verge) were recruited. Patients receive short-course radiotherapy (25Gy/5 times) followed by consolidation chemotherapy or long-course chemoradiation (50Gy/25 times;capecitabine 825 mg/m² twice daily) with mFOLFOXIRI (Irinotecan 150 mg/m2 iv gtt (2h) d1, Oxaliplatin 85 mg/m2 iv gtt (2h) d1, Calcium folinate 400 mg/m2 iv gtt (2h) d1, Total amount of fluorouracil 2400 mg/m2 iv gtt (48h)), treatment repeats every 14 days for 8 courses in the absence of disease progression or unacceptable toxicity. The efficacy evaluation occurs after the fourth and eighth chemotherapy cycle. Patients showing a complete response (CR), partial response (PR), or stable disease (SD) with reduction or stability in tumor size are advised to continue and complete all planned consolidation chemotherapy. However, if the evaluation indicates stable disease with an increase (SD increased) or progressive disease (PD), and if an R0 resection (complete removal of the tumor with no cancer cells at the margins) is feasible, radical total mesorectal excision (TME) should be pursued. In cases where R0 resection is not achievable, the treatment should align with the guidelines for managing unresectable rectal cancer. Upon the final efficacy assessment after the eighth chemotherapy cycle, several pathways are considered based on the outcomes: patients achieving a clinical complete response (cCR) may proceed to a Watch \& Wait approach. Those with a near clinical complete response (near cCR) undergo local transanal resection. If the patient's condition is evaluated as PR/SD with a reduction but does not qualify as near cCR, radical TME is recommended. For patients showing SD with an increase or PD, yet with a potential for R0 resection, radical TME is again the suggested course of action. If R0 resection is unattainable, treatment should adhere to the guidelines for unresectable rectal cancer.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
66
The total dosage was 25Gy consisted of 5 fractions of 5 Gy to clinical target volume without a boost dose
150 mg/m² iv drip over 2 hours on day 1, repeated every 14 days.
85 mg/m² iv drip over 2 hours on day 1, repeated every 14 days.
400 mg/m² iv drip over 2 hours on day 1, repeated every 14 days.
2400 mg/m² iv drip over 48 hours on day 1-2, repeated every 14 days.
The total dosage was 50Gy consisted of 25 fractions of 2 Gy to clinical target volume without a boost dose
825 mg/m² twice daily administered orally and concurrently with radiation therapy for 5 days per week.
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Guangzhou, Guangdong, China
Organ preservation rate
The 1-year organ preservation rate is the percentage of patients attaining a complete clinical response (cCR) or near-complete clinical response (near-cCR) following neoadjuvant therapy, who then proceeded with non-surgical management or local excision, was monitored under a Watch \& Wait strategy or for 1 year post-local resection without undergoing radical surgery.
Time frame: Up to 1 years
Clinical complete response
The definition of a cCR is (1) substantial downsizing with no residual tumor or residual fibrosis only (with low signal on high b-value DWI, if available), shown in Figure 1. Residual wall thickening due to edema only was also an indication for a possible cCR ; (2) no suspicious lymph nodesonMRI; (3) no residual tumor at endoscopyor onlya small residual erythematousulcer or scar; (4) negative biopsiesfromthe scar, ulcer, orformertumorlocation;and (5)nopalpabletumor,wheninitially palpable with digital rectal examination
Time frame: Up to 24 weeks
Pathological complete response
Pathological response will be made based on assessment of the surgical specimen at the primary treatment site. This assessment is made in addition to the AJCC 7th edition summary staging. A pCR must include no gross or microscopic tumor identified anywhere within the surgical specimen. This must include: No evidence of malignant cells in the primary tumor specimen No lymph nodes that contain tumor. The definition of a non-pCR will include any surgical specimen that has any evidence of residual tumor manifest in the primary or regional lymph nodes. For patients who do not meet criteria for a pCR, the extent of response to preoperative therapy will be graded using the Tumor Regression Grade (TRG) schema that is included in the AJCC 7th edition. This was also used by Rodel in the pre/postoperative rectal cancer study and was subsequently adopted by the AJCC \[Rodel (JCO 2005; 23:8688-8696)\].
Time frame: Up to 24 weeks
Near clinical complete response
Near-cCR suggests a significant reduction in tumor size and extent, but with slight evidence of disease that stops short of the criteria for a complete clinical response, which is the total disappearance of all signs of cancer in response to treatment.
Time frame: Up to 24 weeks
Disease free survival
The time interval between the date of randomization and the date of the first cancer-related event, second cancer, or death from any cause, whichever occurred first.
Time frame: Up to 3 years
Overall survival
The time interval between the date of randomization to the date of death. If the patient has been alive, the time until the last follow-up is taken as the overall survival period.
Time frame: Up to 3 years
Local surgery rate
The local surgery rate is defined as the proportion of patients who undergo surgical intervention limited to the area of the primary tumor site, without extensive removal of surrounding tissue or organs.
Time frame: Up to 24 weeks
Local recurrence rate
The local recurrence rate refers to the proportion of patients in whom cancer returns at the site of the original tumor after treatment.
Time frame: Up to 3 years
Distant metastasis rate
The distant metastasis rate is defined as the proportion of patients who develop metastases at sites remote from the primary tumor location after initial treatment.
Time frame: Up to 3 years
Relapse-free survival
The time interval between the date of randomization and the date of the first cancer-related event, second cancer, or death from any cause, whichever occurred first.
Time frame: Up to 3 years
Stoma-free survival
Stoma-free survival is defined as the duration of time during which a patient with cancer, particularly colorectal or rectal cancer, remains alive without the need for a stoma following treatment.
Time frame: Up to 3 years
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