Visualization of Rectal Cancer During Endoscopy, Using a Fluorescent Tracer

In this non-randomized, non-blinded, prospective, single center feasibility study, patients with locally advanced rectal cancer who are included in the RAPIDO study (NL36315.042.11) will undergo two times epi-illumination endoscopy (in other words flexible NIR fluorescence endoscopy).

The study consists of a total of five study procedure related visits:

• Visit 1: During a screening visit, eligibility will be evaluated and patient characteristics will be collected.
• Visit 2: During the second visit 4.5 mg of bevacizumab-IRDye800CW will be administered intravenously. The patient will then be observed for 1 hour post administration.
• Visit 3: First endoscopy will be performed at baseline (two days after tracer administration); before the start of chemoradiotherapy.
• Visit 4: After chemoradiotherapy patients will receive a second dose of 4.5 mg of bevacizumab-IRDye800CW (second tracer administration)
• Visit 5: A second flexible NIR fluorescence endoscopy procedure will be performed (two-three days after the second tracer injection), preferably right before surgery.

Optionally and when available, we will ask patients if they would like to undergo optoacoustic endoscopy. This is a form of endoscopic ultrasound which is able to detect bevacizumab-IRDye800CW up to 2 cm in depth. The procedure is comparable with NIR fluorescence endoscopy. If patients agree, after removal of the NIR fluorescence endoscope the optoacoustic endoscope will be introduced in the rectum of the patient for detection of bevacizumab-IRDye800CW in deeper areas of the tumor.

Inclusion criteria

• Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumor less than 16 cm from the anal verge using a rigid rectoscope or flexible endoscope.
• Locally advanced tumor fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:

• Clinical stage (c)T4a
• cT4b
• Extramural vascular invasion (EMVI+)
• N2 i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease
• positive mesorectal fascia (MRF), i.e. tumor or lymph node one mm or less from the mesorectal fascia
• metastatic lateral nodes, > 1 cm (lat Lymph Node+)
• Staging done within 5 weeks before randomization.
• No contraindications to chemotherapy, including adequate blood counts:

• White blood count ≥4.0 x 109/L;
• Platelet count ≥100 x 109/L;
• Clinically acceptable haemoglobin levels;
• Creatinine levels indicating renal clearance of ≥50 ml/min;
• Bilirubin <35 μmol/l
• Eastern Cooperative Oncology Group (ECOG) performance score < 1.
• Patient is considered to be mentally and physically fit for chemotherapy as judged by the medical oncologist.
• Age ≥ 18 years.
• Written informed consent.
• Adequate potential for follow-up.

Exclusion criteria

• Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
• Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis.
• Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Any contraindications to MRI (e.g. patients with pacemakers).
• Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
• Concurrent uncontrolled medical conditions.
• Any investigational treatment for rectal cancer within the past month.
• Pregnancy or breast feeding.
• Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
• Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
• Patients with symptoms or history of peripheral neuropathy.