Background: In locally advanced rectal cancer (LARC), local recurrence is uncommon with good quality total mesorectal excision (TME) allowing preoperative chemo-radiotherapy (PCRT) to be omitted. The risk of developing metastases can be partly predicted using magnetic resonance imaging (MRI). PCRT does not benefit all patients with LARC, and is associated with long-term morbidity. Chemotherapy (Cty) may reduce the chance of local recurrence, but compliance to postoperative adjuvant Cty is poor, and its efficacy following CRT has been questioned. Neoadjuvant Cty is being examined in primary colon and rectal cancer (FOXTROT). BACCHUS will examine the efficacy and safety of intensified systemic Cty for LARC prior to TME. Methods: This is a multi-centre, randomized phase II trial. Eligible pts must have histologically confirmed LARC, distal part of the tumour 4-12 cm from anal verge, no metastases, poor prognostic features on pelvic MRI, WHO performance status 0-1. Pts receive folinic acid + fluorouracil + oxaliplatin (FOLFOX) + bevacizumab or FOLFOX + irinotecan (FOLFOXIRI) + bevacizumab, given in two weekly cycles for up to six cycles prior to TME. MRI and positron emission tomography–computed tomography (PET/CT) are repeated prior to cycle four. Pts stop treatment if they fail to respond (defined as ≥30% decrease in Standardised Uptake Value compared to baseline PET/CT). The primary endpoint is pathological complete response (pCR) rate. Secondary endpoints are response rate (RECIST v1.1), circumferential resection margin-negative resection rate, T and N stage downstaging, progression-free, disease-free and overall survival, local control, one-year colostomy rate, acute toxicity, compliance to chemotherapy, tumour regression grade, and tumour cell density. Thirty pts in each arm are required to detect an improvement from 5-20% pCR rate for each regimen compared to RT alone (80% power, α=0.05, assuming 10% non-evaluable rate). A regimen will be considered successful if at least 4/27 pCRs are observed. Clinical trial information: NCT01650428.