Optimization of Preoperative Treatment in Locally Advanced Rectal Cancer

Phase III Study of Short-term Radiotherapy Plus Neoadjuvant Chemotherapy Versus Preoperative Long-term Chemoradiotherapy in Locally Advanced Rectal Cancer

The purpose of this study is to compare effectiveness of short-term radiotherapy with neoadjuvant chemotherapy(TNT group) with preoperative long-term chemoradiotherapy(CRT group) in locally advanced rectal cancer. The hypothesis is 3-year disease-free survival in TNT group was non-inferior to that in CRT group.

The study is a prospective phase III randomized multicenter trial. The purpose of this study is to compare short-term radiotherapy with neoadjuvant chemotherapy(TNT group) with preoperative long-term chemoradiotherapy(CRT group) for middle-lower locally advanced rectal cancer. The primary endpoint is 3-year disease-free survival,defined as the interval from randomization to the first occurrence of local-regional failure, distant metastasis, second primary tumor or death from any cause. The primary hypothesis was that DFS in the TNT group would be non-inferior to that in the CRT group. After preoperative radiotherapy and surgery, the DFS rate of LARC fluctuated from 50% to 65%. Assuming a 3-year DFS rate in CRT group is 65%, we consider the 3-year DFS rate in the TNT group is not lower than 54% (e.g., a margin of 11% or equivalently, hazard ratio (HR) < 1.43). Guarding against a 5% ineligibility or drop-out rate, the accrual target was 600 patients, with the final analysis to occur after at least 194 DFS events to provide at least 80% power at 1-sided type 1 error of 0.05. The choices of type 1 error and power were made to provide an appropriate comprise between feasibility, timeliness and statistical rigor of evidence generation.

This study seeks to compare outcomes between two groups with respect to rates of overall survival(OS), distance metastasis free survival (DMFS), and locoregional recurrence free survival (LRRFS).In addition, acute and late toxicity profile, completion of preoperative treatment, the proportion of patients with radical resection (R0), surgical complication profile, the rate of pathological complete response (pCR), and quality of life (QoL) are also secondary endpoints.

The STELLAR-trial has been designed by National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, and the hypothesis is 3-year disease-free survival in TNT group was non-inferior to that in CRT group.

Inclusion Criteria:

• Biopsy proven rectal adenocarcinoma;
• Distance between tumour and anal verge≤ 10cm;
• Locally advanced tumour;(AJCC Cancer Staging:T3, T4 or N+)
• Cancer Staging must be based on pelvic MRI;
• Eastern Cooperative Oncology Group(ECOG) performance score ≤ 1;
• Written informed consent;
• Mentally and physically fit for chemotherapy;
• Adequate blood counts: White blood cell count ≥3.5 x 109/L Haemoglobin levels ≥100g/L Platelet count ≥100 x 109/L Creatinine levels ≤1.0× upper normal limit（UNL） Urea nitrogen levels ≤1.0× upper normal limit（UNL） Alanine aminotransferase(ALT) ≤1.5× upper normal limit（UNL） Aspartate aminotransferase(AST) ≤1.5× upper normal limit（UNL） Alkaline phosphatase(ALP) ≤1.5× upper normal limit（UNL） Total bilirubin(TBIL) ≤1.5× upper normal limit（UNL）
• No excision of tumor, chemotherapy or other anti-tumor treatment after the diagnosis.

Exclusion Criteria:

• Distant metastases;
• Recurrent rectal cancer;
• Active Crohn's disease or ulcerative colitis;
• Concomitant malignancies;(except basocellular carcinoma or in-situ cervical carcinoma)
• Allergic to Fluorouracil or Platinum drugs;
• Contraindications to MRI for any reason;
• Concurrent uncontrolled medical condition;
• Pregnancy or breast feeding;
• Known malabsorption syndromes or lack of physical integrity of upper gastrointestinal tract;
• Symptoms or history of peripheral neuropathy