This is a multicenter, prospective, randomized, stratified, controlled, open-label study comparing preoperative FOLFOX versus postoperative risk-adapted chemotherapy in patients with locally advanced rectal cancer and low risk for local failure

Patients with locally advanced rectal cancer are generally treated with preoperative 5-FU- or capecitabine-based chemo-radiotherapy (CRT) and total mesorectal excision (TME) surgery in order to decrease the rate of local failure. In patients with low risk for local failure in the middle third of the rectum (cT3a/b, N-) as determined with quality controlled MRI, the German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant radiotherapy may be omitted. However, distant failure rate is still substantial in the range of 20-25% in these patients highlighting the need for more effective systemic treatment.

The hereby proposed ACO/ARO/AIO-18.2 randomized trial incorporates three novel aspects: (1) patient selection relies on strict and quality controlled MRI features and therefore identifies a cohort without imminent need for radiotherapy, (2) the sequence of chemotherapy and surgery is changed in a way that chemotherapy is administered preoperatively to increase the rate of patients treated with chemotherapy, and (3) three months of neoadjuvant FOLFOX or XELOX (instead of up to 6 months adjuvant chemotherapy) are used as a sole perioperative treatment in order to administer effective doses of the presumably most effective perioperative treatment at an early time point during the course of disease.

Thus, patients with locally advanced rectal cancer but low risk for local failure (cT1/2N+ in all thirds of the rectum, cT3a/b N- in the middle third, and cT3-4 Nany in the upper third) will be included and randomized between three months of neoadjuvant FOLFOX/XELOX in Arm A and primary resection of the tumor followed by risk (i.e. stage) adapted chemotherapy in Arm B.

Inclusion Criteria:

1. 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).

2. Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.

3. Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and early T3 tumors.

4. 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.

5. Spiral-CT of the abdomen and chest to exclude distant metastases.

6. Aged at least 18 years. No upper age limit.

7. WHO/ECOG Performance Status ≤1.

8. Adequate haematological, hepatic, renal and metabolic function parameters:

9. Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb > 9 g/dl

10. Serum creatinine ≤ 1.5 x upper limit of normal

11. Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.

12. QTc interval (Bazett**) ≤ 440 ms

13. Informed consent of the patient.

"**" Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR (sec))= ((QT) ̅" (ms)" )/√(60/(frequency (1/min)))

Exclusion Criteria:

1. Distant metastases (to be excluded by CT scan of the thorax and abdomen).
2. Prior antineoplastic therapy for rectal cancer.
3. Prior radiotherapy of the pelvic region.
4. Major surgery within the last 4 weeks prior to inclusion.
5. Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
6. 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.
7. On-treatment participation in a clinical study in the period 30 days prior to inclusion.
8. Previous or current drug abuse.
9. Other concomitant antineoplastic therapy.
10. Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
11. Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
12. Chronic diarrhea (> grade 1 according NCI CTCAE).
13. 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.
14. Known allergic reactions or hypersensitivity on study medication or to any of the other excipients.
15. Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0 (see appendix).
16. Severe kidney dysfunction (creatinine clearance < 30 ml/min).
17. Recent or concurrent treatment with brivudine.
18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
19. Known dihydropyrimidine dehydrogenase deficiency.
20. 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).

open-label