short rt versus rct,followed by chemo.and organ preservation for interm and high-risk rectal cancer patients

Conditions: Rectal Cancer Stage III

Summary: 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.

Eligibility criteria:
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).