FOLFOX before surgey compared to risk-adapted chemotherapy after surgery in patients with locally advanced rectal cancer and low risk for local failure

Prior treatment

• Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
• Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
• 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.
• Recent or concurrent treatment with brivudine.
• Known dihydropyrimidine dehydrogenase deficiency (activity score < 1,5 after genetic testing of DPYD variants).† † For adjustments of chemotherapy for patients with DPYD activity score = 1,5 see Protocol section 4.2.4.3
• Prior antineoplastic therapy for rectal cancer.
• Prior radiotherapy of the pelvic region.
• Major surgery within the last 4 weeks prior to inclusion.
• 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. ****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).
• On-treatment participation in a clinical study in the period 30 days prior to inclusion.
• Previous or current drug abuse.
• Other concomitant antineoplastic therapy.

Other illness

• Known allergic reactions or hypersensitivity on study medication or to any of the other excipients.
• 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).

Lab values

• Severe kidney dysfunction (creatinine clearance < 30 ml/min).

Other

• Distant metastases (to be excluded by CT scan of the thorax and abdomen).
• Chronic diarrhea (> grade 1 according NCI CTCAE).
• Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0 (see appendix).
• Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
• Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.

• Male and female patients* with histologically confirmed diagnosis of rectal adenocarcinoma localized 0 – 16 cm from the anal verge as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below). *Thera are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
• 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 Formula for QTc interval calculation (Bazett): 𝑄𝑇𝑐=𝑄𝑇̅̅̅̅(ms)√ (𝑠𝑒𝑐)=𝑄𝑇̅̅̅̅(ms)√60𝐹𝑒𝑞𝑢𝑒𝑧 (1𝑚𝑖)
• Informed consent of the patient.
• Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
• Transrectal endoscopic ultrasound (EUS) is mandatory and used to help discriminate between T1/2 and early T3 tumors.
• MRI-defined inclusion criteria: - Lower third (0-6 cm): cT1/2 with clear cN+ based on MRI-criteria and cT3a-b (i.e. infiltration up to 5mm into the perirectal fat) (see SOP in chapter 12.3 of the appendix), provided CRM >2mm and EMVI-** (defined as MRI-EMVI score 0-3; see SOP in chapter 12 of the appendix) - Middle third (≥ 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; cT3 irrespective of the depths of infiltration 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-** - 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 hematological, hepatic, renal and metabolic function parameters:
  • Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb > 9 g/dl