Dose escalation of preoperative short-course radiotherapy followed by neoadjuvant chemotherapy in locally advanced rectal cancer: protocol for an open-label, single-centre, phase I clinical trial.

INTRODUCTION: Preoperative radiotherapy followed by total mesorectal excision with adjuvant chemotherapy has been recommended as the preferred treatment method for locally advanced rectal cancer (LARC). Similar rates of local control, survival and toxicity were observed in preoperative long-course chemoradiotherapy (LCRT) (45-50.4 Gy in 25-28 fractions) and in short-course radiotherapy (SCRT) with 25 Gy over five fractions. Both regimens lower the local recurrence rates compared with that of surgery followed by postoperative radiotherapy. With the simplicity and lower cost of SCRT, a growing number of patients have been receiving SCRT as preoperative radiotherapy. However, the currently established SCRT (25 Gy over five fractions) followed immediately by surgery resulted in poor downstaging and sphincter preservation rate. The pathological complete response (pCR) rate is also markedly lower with SCRT than with LCRT (0.7%vs16%). Several studies recommended SCRT with delayed surgery for more than 4 weeks with expectation of improved pathological outcomes and fewer postoperative complications. While a number of clinical trials demonstrated a persistently better overall local control with SCRT than with LCRT, overall survival advantage has not been observed. Since survival is mainly depended on distant metastases, efforts should be made towards more effective pathological response and systemic treatment. Given the apparent advantages of SCRT, we aimed to establish a dose escalation of SCRT and sequential modified FOLFOX6 (mFOLFOX6) as preoperative therapy for LARC with objectives of achieving an optimal balance of safety, cost effectiveness and clinical outcome, and to support further investigation of this regimen in a phase II/III setting.

METHODS: In this phase I study, three dose levels (6Gy×5F, 7Gy×5F, 8Gy×5F to gross tumour volume, while keeping the rest of irradiated volume at 5Gy×5) of SCRT followed by four cycles of mFOLFOX6 chemotherapy as neoadjuvant therapy will be tested by using the traditional 3+3 design. The pCR rate, R0 resection rate, sphincter preservation rate and treatment related toxicity will be assessed.

ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Fujian Medical University Union Hospital (No. 2017YF020-02) and all participants provided written informed consent. Results from our study will be disseminated in international peer-reviewed journals. All study procedures were developed in order to assure data protection and confidentiality.

TRIAL REGISTRATION NUMBER: NCT03466424; Pre-results.