The hereby proposed ACO/ARO/AIO-18.1 randomized trial aims to directly compare the newly established TNT concepts applying either short-course RT according to RAPIDO, or CRT according to CAO/ARO/AIO-04/-12, both followed by consolidation chemotherapy, and surgery or a watch&wait (W&W) approach for patients with clinical complete response (cCR).

The ACO/ARO/AIO-18.1 study incorporates several novel and innovative aspects to further optimize multimodal rectal cancer treatment, partly established by our preceding CAO/ARO/AIO-04 and CAO/ARO/AIO-12 randomized trials: (1) patient selection is based on strict, quality controlled MRI features of intermediate and high-risk characteristics (and, thus, complementary to our ACO/ARO/AIO-18.2 trial in "low-risk" rectal cancer), (2) the CRT regimens incorporates 5-FU/oxaliplatin with doses and intensities shown to be effective and well-tolerated without compromising treatment compliance in CAO/ARO/AIO-04, (3) the sequence of CRT, CT, and surgery/W&W adopts the TNT approach as established by our CAO/ARO/AIO-12 and OPRA trial, (4) surgical stratification allows for W&W management for strictly selected patients with clinical complete response (cCR). Thus, we hypothesize that TNT with 5-FU/oxaliplatin-CRT followed by consolidation chemotherapy may increase organ preservation while maintaining DFS as compared to RAPIDO-like short-course RT followed by consolidation chemotherapy.

The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-cCR, or for any locoregional regrowth after initial cCR requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first. We hypothesized that the 3-year organ preservation rate will improve from 30% in the control arm to 40% in the investigational arm (hazard ratio of 0.76). With a power of 90% and a two-sided type I error of 5%, the sample size required to obtain a statistically significant difference is 702 patients (564 events) in total.

Inclusion Criteria:

• diagnosis of rectal adenocarcinoma localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum)
• Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
• MRI-defined inclusion criteria: presence of at least one of the following high-risk conditions:
• any cT3 if the distal extent of the tumor is < 6 cm from the anocutaneous line, or
• cT3c/d in the middle third of the rectum (≥ 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (>cT3b), or
• cT3 with clear cN+ based on strict MRI-criteria
• cT4 tumors, or
• Tany middle/low third of rectum with clear MRI criteria for N+
• mrCRM+ (< 1mm), or
• Extramural venous invasion (EMVI+)
• Trans-rectal endoscopic ultrasound (EUS) is additionally used when MRI is not definitive to exclude early cT1/T2 disease in the lower third of the rectum or early cT3a/b tumors in the middle third of the rectum.
• Spiral-CT of the abdomen and chest to exclude distant metastases.
• Aged at least 18 years. No upper age limit.
• WHO/ECOG Performance Status 0-1
• Adequate haematological, hepatic, renal and metabolic function parameters:
• Leukocytes ≥ 3.000/mm^3, ANC ≥ 1.500/mm^3, platelets ≥ 100.000/mm^3, 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 • Informed consent of the patient

Exclusion Criteria:

• Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy
• 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 after the end of treatment.
• 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
• 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 on study medication
• 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).

Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy

multicentre, open-labeled, Phase III study