Short RT Versus RCT,Followed by Chemo and Organ Preservation for Interm and High-risk Rectal Cancer Patients

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.

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).