Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer

Inclusion criteria

• Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 - 16 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below).
• Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
• Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and early T3 tumors.
• MRI-defined inclusion criteria:
• i. Lower third (0-6 cm):
• cT1/2 with clear cN+ based on defined MRI criteria or T3a-b (i.e. maximum infiltration into the perirectal fat of 5mm), provided CRM \> 2mm and EMVI-\*\* ii. Middle third (≥ 6-12 cm):
• cT1/2 with clear cN+ provided CRM- and EMVI-\*\*
• cT3 irrespective of the depth of invasion into the perirectal fat, provided no evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM \> 2 mm), N0 or N1, EMVI-\*\* iii. Upper third (≥ 12-16 cm):
• cT1/2 with clear cN+, irrespective of CRM and EMVI
• any cT3-4 irrespective of nodal status, CRM and EMVI.
• Spiral-CT of the abdomen and chest to exclude distant metastases.
• Aged at least 18 years. No upper age limit.
• WHO/ECOG Performance Status ≤1.
• Adequate haematological, hepatic, renal and metabolic function parameters:
• Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb \> 9 g/dl
• Serum creatinine ≤ 1.5 x upper limit of normal
• Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.
• QTc interval (Bazett\*\*) ≤ 440 ms
• Informed consent of the patient.
• "\*\*" Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR (sec))= ((QT) ̅" (ms)" )/√(60/(frequency (1/min)))

Exclusion criteria

• Distant metastases (to be excluded by CT scan of the thorax and abdomen).
• Prior antineoplastic therapy for rectal cancer.
• Prior radiotherapy of the pelvic region.
• Major surgery within the last 4 weeks prior to inclusion.
• Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
• Subject (male or female) is not willing to use highly effective\*\*\* methods of contraception during treatment and for 6 months (male or female) after the end of treatment Male patients treated with Oxaliplatin should take legal advice concerning sperm conservation before start of therapy and should additionally use a condom during treatment period. Their female partner of childbearing potential should also use an appropriate contraceptive measure.
• On-treatment participation in a clinical study in the period 30 days prior to inclusion.
• Previous or current drug abuse.
• Other concomitant antineoplastic therapy.
• Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
• Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
• Chronic diarrhea (\> grade 1 according NCI CTCAE).
• Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free.
• Known allergic reactions or hypersensitivity on study medication or to any of the other excipients.
• Evidence of peripheral sensory neuropathy \> grade 1 according to CTCAE version 5.0 (see appendix).
• Severe kidney dysfunction (creatinine clearance \< 30 ml/min).
• Recent or concurrent treatment with brivudine.
• Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
• Known dihydropyrimidine dehydrogenase deficiency.
• Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial).
• "\*\*\*"highly effective (i.e. failure rate of \<1% per year when used consistently and correctly) methods: intravaginal and transdermal combined (estrogen and progestogen containing) hormonal contraception; injectable and implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments).